Phytochemistry and Pharmacology of Medicinal Plants, 2-Volume Set 9781774911730, 9781774911747, 9781003334873, 9781774915622, 9781774915639, 9781774915646, 9781774915653

Table of contents :
Cover
Volume 01
Cover
Half Title
Title Page
Copyright Page
Series Page
Other Books from AAP
About the Editor
Table of Contents
Contributors
Abbreviations
Preface
1. Ilex paraguariensis—Green Gold from South America
2. The Pharmacological Properties of Brazilian Arnica (Solidago chilensis Meyen)
3. Therapeutic Properties of Strychnos nux-vomica L.
4. Phytochemistry and Bioactive Potential of Water Hyssop [Bacopa monnieri (L.) Wettst.]
5. An Overview on Phytochemistry and Pharmacology of Anastatica hierochuntica L.
6. Naphthalene—Isoquinoline Group of Alkaloid from Monotypic Family Ancistrocladaceae
7. Phytochemical and Pharmacological Profiles of Centella asiatica L.
8. Biomolecules and Therapeutics of Chlorophytum borivilianum Santapau & R.R. Fern. (Safed Musli)
9. Traditional Uses, Phytochemistry and Pharmacology of Bryonopsis laciniosa (L.) Naudin
10. Diplocyclos palmatus (L.) C. Jeffrey: An Important Medicinal Striped Cucumber
11. Bioactives and Pharmacology of Curcuma neilgherrensis Wight
12. Bioactives and Pharmacology of Aconitum heterophyllum Wall. ex Royle
13. New Insights on Bioactives and Pharmacology of Genipa americana L.
14. Phytochemical Constituents and Pharmacology of Cuminum cyminum L.
15. Ethnopharmacology and Phytochemistry of Lagenaria siceraria (Molina) Standl.
16. Phytochemistry and Pharmacological Studies of Plumbago indica L.: A Medicinal Plant
17. Biomolecules and Therapeutics of Terminalia bellirica Roxb.
18. Phytochemicals and Pharmacological Activities of Tinospora cordifolia (Willd.) Miers
19. A Pharmacological View on the Medicinal Properties of the Ziziphus joazeiro Mart.
20. Phytochemistry and Pharmacological Potentialities of Syzygium caryophyllatum (L.) Alston
21. Phytochemistry and Biological Activities of Crepidium acuminatum (D. Don) Szlach.: A Systematic Review
22. Phytochemistry and Bioactive Potential of Tiririca (Cyperus esculentus L.)
23. Phytochemistry and Pharmacological Properties of Justicia betonica L.
24. A Review on Phytochemistry and Pharmacology Profile of Pendant Amaranth (Amaranthus caudatus L.)
25. Bioactives and Therapeutic Potential of Blood Amaranth (Amaranthus cruentus L.)
26. Bioactive Compounds and Pharmacological Activity of Beta vulgaris L.
27. Phytoconstituents and Pharmacological Properties of Enicostemma axillare Raynal
28. Phytochemical and Pharmacological Potential of Ornamental Bougainvillea (Bougainvillea spectabilis)
29. Bioactives and Pharmacology of Couroupita guianensis Aubl.
30. Review on Pharmacological Activities of Gentiana scabra Bunge
31. Pharmacological Importance and Chemical Composition of Mallotus roxburghianus Müell.Arg.
32. Phytochemistry and Pharmacology of Phytolacca dodecandra L.
33. Phytochemical and Pharmacological Aspects of “Arogyapacha,” Trichopus zeylanicus Gaertn.
34. Pharmacological Activities of Manilkara hexandra (Roxb.)Dubard: A Comprehensive Review
35. Rhinacanthus nasutus (L.) Kurz: Prehistory to Current Uses to Humankind
36. Chemical Composition and Bioactivities of Great Mullein [Verbascum thapsus L. (Family: Scrophulariaceae)]
37. A Brief Review on Biological Properties and Pharmacological Activities of Litsea cubeba
38. Phytochemistry and Pharmacology of Calotropis procera L. and C. gigantea R.Br.
39. A Review on Bioactive and Pharmacological Activities of Adansonia digitata L.: A Majestic and Universal Remedy Plant
40. Phytochemistry and Bioactive Potential of Brassica oleracea L. var. botrytis L.
41. Medicinal Properties and Bioactive Compounds of Stemona tuberosa Lour
Index
Volume 02
Cover
Half Title
Title Page
Copyright Page
Series Page
Other Books from AAP
About the Editor
Table of Contents
Contributors
Abbreviations
Preface
42. Chemical Composition and Biological Properties of Musk Willow (Salix aegyptiaca L.)
43. Phytochemistry and Pharmacological Properties of Salvadora persica L.
44. Bioactive Components and Pharmacology of Memecylon
45. An Account of Traditional Uses, Bioactive Compounds, and Pharmacological Activities of the Genus Hydnocarpus (Family: Achariaceae)
46. Chemical Principles, Bioactivity, and Pharmacology of Hedychium spicatum Sm. (Family: Zingiberaceae)
47. Functional Components and Biological Activities of Kaempferia galanga L. (Chandramoolika)
48. Bioactive Compounds and Pharmacological Activities of Terminalia pallida Brandis
49. Phytochemistry and Pharmacology of an Aquatic Herb Nymphaea pubescens Willd
50. Phyla nodiflora (L.) Greene—Exquisite Plant with Therapeutic Effects
51. Phytochemical and Pharmacological Profile of Achyranthes aspera L. (Amaranthaceae)
52. Phytochemistry and Pharmacology of Garcinia mangostana (Mangosteen)—A Review
53. Bioactives and Pharmacology of Cycas beddomei Dyer
54. Phytochemical and Pharmacological Profile of Tridax procumbens L.: An Asteraceaeous Member
55. Bioactives and Their Biological Potentialities of Wild Cinnamon [Cinnamomum malabatrum (Burm.f.) J.Presl (Lauraceae)]
56. Therapeutic Potential and Bioactives of Amaranthus spinosus L.
57. Mussaenda macrophylla Wall.: Chemical Composition and Pharmacological Applications
58. Phytochemistry and Pharmacological Potentialities of Syzygium densiflorum Wall. ex Wight & Arn. and S. travancoricum Gamble (Myrtaceae)
59. Bioactives and Ethnopharmacology of Pittosporum napaulense (DC.) Rehder & E.H. Wilson
60. Tree of Heaven: Ailanthus excelsa Roxb.—Chemistry and Pharmacology
61. Pharmacology and Therapeutic Potential of Cynodon dactylon (L.) Pers.
62. A Review on Phytochemistry and Pharmacological Activities of Aristolochia indica L.
63. Pharmacological Activities of Diploclisia glaucescens (Blume) Diels
64. Phytochemical Composition and Pharmacological Properties of Red spinach (Amaranthus tricolor L.)
65. Bioactive Molecules and Pharmacology Studies of Ecbolium viride (Forssk.) Alston
66. Phytoconstituents and Pharmacological Activities of Star Fruit [Averrhoa carambola L. (Family: Oxalidaceae)]
67. Pharmacological and Phytochemical Review of a Vulnerable Medicinal Plant Embelia ribes Burm. f.
68. Bioactives and Pharmacology of Tamarix aphylla (L.) Karst.
69. Bioactives and Pharmacology Avicennia marina (Forssk.) Vierh.
70. Phytochemical and Pharmacological Properties of Himalayan Silver Birch (Betula utilis D. Don): A Dominant Treeline Forming Species
71. A Comprehensive Review on Phytochemistry and Pharmacological Potential of Musanga cecropioides R.Br. ex Tedlie
72. Angelica glauca Edgew.—An Ethnopharmacological, Phytochemical, and Pharmacological Review
73. Clusia nemorosa G. Mey: A Plant with Pharmacological Potential
74. Phytochemical Constituents and Pharmacology of Eclipta prostrata (L.) L.
75. Phytochemical Potential and Pharmacology of Ephedra alata Decne.
76. Ephedra sinica Stapf—An Exemplary Source of Ephedrine-Type Alkaloids
77. Pharmacological Review of Potential Underutilized Plant Rhus mysorensis G. Don
78. Devil’s Cherry (Atropa belladonna L.): A Systematic Review on Its Phytoactives and Pharmacological Properties
79. Traditional Use, Chemical Constituents, and Pharmacology of Cocos nucifera L.
Index

Citation preview

PHYTOCHEMISTRY AND

PHARMACOLOGY OF

MEDICINAL PLANTS

Volume 1

Phytochemistry and Pharmacology of Medicinal Plants, 2-volume set ISBN: 978-1-77491-173-0 (hbk) ISBN: 978-1-77491-174-7 (pbk) ISBN: 978-1-00333-487-3 (ebk) Phytochemistry and Pharmacology of Medicinal Plants, Volume 1 ISBN: 978-1-77491-562-2 (hbk) ISBN: 978-1-77491-563-9 (pbk) Phytochemistry and Pharmacology of Medicinal Plants, Volume 2 ISBN: 978-1-77491-564-6 (hbk) ISBN: 978-1-77491-565-3 (pbk)

AAP Focus on Medicinal Plants

PHYTOCHEMISTRY AND

PHARMACOLOGY OF

MEDICINAL PLANTS

Volume 1

Edited by T. Pullaiah, PhD

First edition published 2023 Apple Academic Press Inc. 1265 Goldenrod Circle, NE, Palm Bay, FL 32905 USA 760 Laurentian Drive, Unit 19, Burlington, ON L7N 0A4, CANADA

CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 USA 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN UK

© 2023 by Apple Academic Press, Inc. Apple Academic Press exclusively co-publishes with CRC Press, an imprint of Taylor & Francis Group, LLC Reasonable efforts have been made to publish reliable data and information, but the authors, editors, and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors, editors, and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library and Archives Canada Cataloguing in Publication Title: Phytochemistry and pharmacology of medicinal plants / edited by T. Pullaiah, PhD.

Names: Pullaiah, T., editor.

Series: AAP focus on medicinal plants.

Description: First edition. | Series statement: AAP focus on medicinal plants | Includes bibliographical references and indexes.

Identifiers: Canadiana (print) 20230149162 | Canadiana (ebook) 20230149219 | ISBN 9781774911730 (set ; hardcover) | ISBN 9781774911747 (set ; softcover) | ISBN 9781774915622 (v. 1 ; hardcover) | ISBN 9781774915639 (v. 1 ; softcover) | ISBN 9781003334873 (set ; ebook) Subjects: LCSH: Materia medica, Vegetable. | LCSH: Medicinal plants. | LCSH: Phytochemicals. | LCSH: Botanical chemistry. Classification: LCC RS164 .P49 2023 | DDC 615.3/21—dc23 Library of Congress Cataloging-in-Publication Data Names: Pullaiah, T., editor.

Title: Phytochemistry and pharmacology of medicinal plants / edited by T. Pullaiah.

Other titles: AAP focus on medicinal plants.

Description: First edition. | Palm Bay, FL, USA : Apple Academic Press, 2023. | Series: AAP focus on medicinal plants |

Includes bibliographical references and index. | Summary: “This 2-volume book set, Phytochemistry and Pharmacology of Medicinal Plants, introduces and provides extensive coverage of 79 important medicinal plant species. Each chapter, written by noted experts in the field, focuses on one important medicinal plant, giving a brief introduction about the species and then delving into the plant’s bioactive phytochemicals along with its chemical structures and pharmacological activities. A wide array of biological activities and potential health benefits of the medicinal plant-which includes antiviral, antimicrobial, antioxidant, anti-cancer, anti-inflammatory and antidiabetic properties as well as protective effects on liver, kidney, heart and nervous system-are given. An extensive collection of research literature on pharmacological activities on that species is reviewed. This volume, published under the AAP Focus on Medicinal Plants book series, edited by the accomplished editor, T. Pullaiah, who has taught, researched, written, and published on medicinal plants for over 35 years, will be an important reference resource for years to come for both new and experienced medicinal researchers”-- Provided by publisher. Identifiers: LCCN 2023001687 (print) | LCCN 2023001688 (ebook) | ISBN 9781774915622 (v. 1 ; hardback) | ISBN 9781774915639 (v. 1 ; paperback) | ISBN 9781774915646 (v. 2 ; hardback) | ISBN 9781774915653 (v. 2 ; paperback) | ISBN 9781774911730 (hardback) | ISBN 9781774911747 (paperback) | ISBN 9781003334873 (ebook) Subjects: LCSH: Materia medica, Vegetable. | Medicinal plants. | Phytochemicals. | Botanical chemistry. Classification: LCC RS164 .P5358 2023 (print) | LCC RS164 (ebook) | DDC 615.3/21--dc23/eng/20230320 LC record available at https://lccn.loc.gov/2023001687 LC ebook record available at https://lccn.loc.gov/2023001688 ISBN: 978-1-77491-562-2 (hbk) ISBN: 978-1-77491-563-9 (pbk)

AAP Focus on Medicinal Plants

ABOUT THE SERIES This new book series, edited by T. Pullaiah, focuses on bioactives and pharmacology of medicinal plants. For millennia, medicinal plants have been a valuable source of therapeutic agents, and still many of today’s drugs are based on plant-derived natural products or their derivatives. Bioactive compounds typically occur in small amounts, and they have more subtle effects than nutrients. Bioactive compounds influence cellular activities that modify the risk of disease and help to alleviate disease symptoms. The bioactive compounds have potentially important health benefits, and these compounds can act as antioxidants, enzyme inhibitors and inducers, inhibitors of receptor activities, and inducers and inhibitors of gene expression among other actions. A wide array of biological activities and potential health benefits of medicinal plants have been reported, which include antiviral, antibacterial, antifungal, antioxidant, anticancer, anti-inflammatory, antidiabetic, hepatoprotective, cardioprotective, nephroprotective properties as well as other protective effects on the liver, kidney, heart, and nervous system. The volumes aim to be comprehensive desk references on bioactives and pharmacology of all the medicinal plants. They will also be important sourcebooks for the development of new drugs. Book Series Editor Prof. T. Pullaiah Department of Botany Sri Krishnadevaraya University, Anantapur 515003, A.P., India Email: [email protected] Book in the Series • • • •

Bioactives and Pharmacology of Medicinal Plants, 2-volume set Biomolecules and Pharmacology of Medicinal Plants, 2-volume set Bioactives and Pharmacology of Legumes Phytochemistry and Pharmacology of Medicinal Plants, 2-volume set

vi

AAP Focus on Medicinal Plants

• Bioactives and Pharmacology of Lamiaceae • Frankincense – Gum Olibanum: Botany, Oleoresin, Chemistry, Extraction, Utilization, Propagation, Biotechnology, and Conservation • Phytochemical Composition and Pharmacy of Medicinal Plants, 2-volume set

Other Books from AAP by Dr. T. Pullaiah Ethnobotany of India, 5-volume set: Editors: T. Pullaiah, PhD, K. V. Krishnamurthy, PhD, and Bir Bahadur, PhD • • • • •

Volume 1: Eastern Ghats and Deccan Volume 2: Western Ghats and West Coast of Peninsular India Volume 3: North-East India and the Andaman and Nicobar Islands Volume 4: Western and Central Himalaya Volume 5: Indo-Gangetic Region and Central India

Global Biodiversity, 4-volume set: Editor: T. Pullaiah, PhD • • • •

Volume 1: Selected Countries in Asia Volume 2: Selected Countries in Europe Volume 3: Selected Countries in Africa Volume 4: Selected Countries in the Americas and Australia

Handbook of Research on Herbal Liver Protection: Hepatoprotective Plants T. Pullaiah, PhD, and Maddi Ramaiah, PhD Bio-Inspired Technologies for the Modern World R. Ramakrishna Reddy, PhD, and T. Pullaiah, PhD Biodiversity of Hotspots–36 volumes (forthcoming) Editor: T. Pullaiah, PhD

About the Editor

T. Pullaiah, PhD Former Professor, Department of Botany, Sri Krishnadevaraya University, Andhra Pradesh, India T. Pullaiah, PhD, is a former Professor at the Department of Botany at Sri Krishnadevaraya University in Andhra Pradesh, India, where he has taught for more than 35 years. He has held several positions at the university, including Dean of the Faculty of Biosciences, Head of the Department of Botany, Head of the Department of Biotechnology, and Member of Academic Senate. Under his guidance, 54 students earned their doctoral degrees. He was President of the Indian Botanical Society (2014), President of the Indian Association for Angiosperm Taxonomy (2013), and Fellow of the Andhra Pradesh Academy of Sciences. He was awarded the Panchanan Maheshwari Gold Medal, the Prof. P. C. Trivedi Medal, the Dr. G. Panigrahi Memorial Lecture Award of the Indian Botanical Society, and Prof. Y. D. Tyagi Gold Medal of the Indian Association for Angiosperm Taxonomy, and the Best Teacher Award from Government of Andhra Pradesh. A prolific author and editor, he has authored 52 books, edited 23 books, and published over 330 research papers. His books include Advances in Cell and Molecular Diagnostics (published by Elsevier), Camptothecin, and Camptothecin Producing Plants (Elsevier), Ethnobotany of India (5 volumes, published by Apple Academic Press), Global Biodiversity (4 volumes, Apple Academic Press), Red Sanders: Silviculture and Conservation (Springer), Genetically Modified Crops (2 volumes, Springer), Monograph on Brachystelma and Ceropegia in India (CRC Press), Flora of Andhra Pradesh (5 volumes), Flora of Eastern Ghats (4 volumes), Flora of Telangana (3 volumes), Encyclopedia of World Medicinal Plants (7 volumes, 2nd edition), and Encyclopedia of Herbal Antioxidants (3 volumes). He is currently working on 36 volumes of the new book series Biodiversity Hotspots of the World. Professor Pullaiah was a member of the Species Survival Commission of the International Union for Conservation of Nature (IUCN). He received his PhD from Andhra University, India, attended Moscow State University, Russia, and worked as postdoctoral fellow during 1976–1978.

Contents

Contributors........................................................................................................... xix

Abbreviations ...................................................................................................... xxvii

Preface ............................................................................................................... xxxiii

VOLUME 1 1.

Ilex paraguariensis—Green Gold from South America...............................1

Vania Zanella Pinto, Daniella Pilatti-Riccio, Bruna Trindade Paim,

Laura De Vasconcelos Costa, Sandra Gomes De Amorin, and

Adriana Dillenburg Meinhart

2.

The Pharmacological Properties of Brazilian Arnica (Solidago chilensis Meyen) ...........................................................................15 Felipe Lima Porto, Rafael Vrijdags Calado, Tayhana Priscila Medeiros Souza, Jamylle Nunes de Souza Ferro, Emiliano Barreto, and Maria Danielma dos Santos Reis

3.

Therapeutic Properties of Strychnos nux-vomica L. ..................................25

Jatin Aggarwal, Ria Singh, and Priyadarshini

4.

Phytochemistry and Bioactive Potential of Water Hyssop [Bacopa monnieri (L.) Wettst.] .....................................................................37 M. Indira, D. Sai Sushma, C. Divya, S. Siva Kumar, S. Krupanidhi, and D. John Babu

5.

An Overview on Phytochemistry and Pharmacology of Anastatica hierochuntica L. ..........................................................................55 Sebastian John Adams, and Thiruppathi Senthil Kumar

6.

Naphthalene—Isoquinoline Group of Alkaloid from Monotypic Family Ancistrocladaceae.............................................................................71 Vinayak Upadhya and Sandeep Ramchandra Pai

7. Phytochemical and Pharmacological Profiles of Centella asiatica L. .......83

Surabhi Tiwari and Brijesh Kumar

8. Biomolecules and Therapeutics of Chlorophytum borivilianum Santapau & R.R. Fern. (Safed Musli) .........................................................99 Vinod S. Undal

xii

Contents

9.

Traditional Uses, Phytochemistry and Pharmacology of Bryonopsis laciniosa (L.) Naudin ...............................................................121 Kumkum Agarwal Sinha

10. Diplocyclos palmatus (L.) C. Jeffrey: An Important Medicinal Striped Cucumber.......................................................................................131 Suraj B. Patel and Savaliram G. Ghane

11. Bioactives and Pharmacology of Curcuma neilgherrensis Wight ...........141

B. Kavitha and N. Yasodamma

12. Bioactives and Pharmacology of Aconitum heterophyllum Wall. ex Royle ..............................................................................................155 Tarun Pal, Harish Babukolla, and S. Asha

13. New Insights on Bioactives and Pharmacology of Genipa americana L. ...................................................................................171 Aline Oliveira Da Conceição

14. Phytochemical Constituents and Pharmacology of Cuminum cyminum L..................................................................................183 Thadiyan Parambil Ijinu, Ragesh Raveendran Nair, Maheswari Priya Rani,

Thomas Aswany, Mohammed S. Mustak, and Palpu Pushpangadan

15. Ethnopharmacology and Phytochemistry of Lagenaria siceraria (Molina) Standl. .........................................................201 Suraj B. Patel and Savaliram G. Ghane

16. Phytochemistry and Pharmacological Studies of Plumbago indica L.: A Medicinal Plant.....................................................213 Prachi Sharad Kakade and Saurabha Bhimrao Zimare

17. Biomolecules and Therapeutics of Terminalia bellirica Roxb. ................227

Vinod S. Undal

18. Phytochemicals and Pharmacological Activities of Tinospora cordifolia (Willd.) Miers............................................................259 A. Nagalakshmi, K. Abraham Peele, S. Siva Kumar, M. Indira, T.C. Venkateswarulu, and S. Krupanidhi

19. A Pharmacological View on the Medicinal Properties of the Ziziphus joazeiro Mart. ...............................................................................277 Rafael Vrijdags Calado, Felipe Lima Porto, Jamylle Nunes de Souza Ferro,

Tayhana Priscila Medeiros Souza, Emiliano Barreto, and

Maria Danielma dos Santos Reis

Contents

xiii

20. Phytochemistry and Pharmacological Potentialities of

Syzygium caryophyllatum (L.) Alston.........................................................285

Karuppa Samy Kasi, Anjana Surendran, and Raju Ramasubbu

21. Phytochemistry and Biological Activities of Crepidium acuminatum (D. Don) Szlach.: A Systematic Review .....................................................295

Sebastian John Adams, Thiruppathi Senthil Kumar, and Gnanamani Muthuraman

22. Phytochemistry and Bioactive Potential of Tiririca

(Cyperus esculentus L.) ...............................................................................303

José Francisco Dos Santos Silveira Junior

23. Phytochemistry and Pharmacological Properties of

Justicia betonica L. ......................................................................................315

Ch. Srinivasa Reddy, K. Ammani, and M. Santosh Kumari

24. A Review on Phytochemistry and Pharmacology Profile of Pendant Amaranth (Amaranthus caudatus L.).........................................323

Nayan Kumar Sishu, Parthasarathi Theivasigamani, and

Chinnadurai Immanuel Selvaraj

25. Bioactives and Therapeutic Potential of Blood Amaranth

(Amaranthus cruentus L.) ...........................................................................333

Nayan Kumar Sishu, Babu Subramanian, and Chinnadurai Immanuel Selvaraj

26. Bioactive Compounds and Pharmacological Activity of

Beta vulgaris L. ............................................................................................345

Raghvendra Dubey, Kushagra Dubey, Sibbala Subramanyam, and K. N. Jayaveera

27. Phytoconstituents and Pharmacological Properties of

Enicostemma axillare Raynal .....................................................................357

Jaishree Vaijanathappa

28. Phytochemical and Pharmacological Potential of Ornamental

Bougainvillea (Bougainvillea spectabilis) ..................................................367

Sinoy Sugunan, Rakesh Barik, G. Shiva Kumar, and K. N. Jayaveera

29. Bioactives and Pharmacology of Couroupita guianensis Aubl................379

S. Rajashekara and M. Muniraju

30. Review on Pharmacological Activities of Gentiana scabra Bunge ..........401

C. V. Jayalekshmi and V. Suresh

31. Pharmacological Importance and Chemical Composition of

Mallotus roxburghianus Müell.Arg............................................................413

Mary Zosangzuali, Marina Lalremruati, C. Lalmuansangi,

F. Nghakliana, and Zothansiama

xiv

Contents

32. Phytochemistry and Pharmacology of Phytolacca dodecandra L. ..........423

Hirpasa Teressa

33. Phytochemical and Pharmacological Aspects of

“Arogyapacha,” Trichopus zeylanicus Gaertn..........................................433

Thadiyan Parambil Ijinu, Thomas Aswany, Manikantan Ambika Chithra,

Maheswari Priya Rani, Varughese George, and Palpu Pushpangadan

34. Pharmacological Activities of Manilkara hexandra (Roxb.)

Dubard: A Comprehensive Review ...........................................................443

Neha Mishra, Yashaswani Chouhan, Ekta Menghani, and Arvind Pareek

35. Rhinacanthus nasutus (L.) Kurz: Prehistory to Current

Uses to Humankind.....................................................................................451

Jaya Preethi Peesa and B. Siva Sai Kiran

36. Chemical Composition and Bioactivities of Great Mullein

[Verbascum thapsus L. (Family: Scrophulariaceae)]................................467

Shreedhar S. Otari and Savaliram G. Ghane

37. A Brief Review on Biological Properties and Pharmacological

Activities of Litsea cubeba ..........................................................................477

Suparna Lodh

38. Phytochemistry and Pharmacology of Calotropis procera L. and C. gigantea R.Br. .........................................................................................485

Payal Soan

39. A Review on Bioactive and Pharmacological Activities of

Adansonia digitata L.: A Majestic and Universal Remedy Plant ............495

Pulicherla Yugandhar, Chennareddy Maruthi Kesava Kumar, Sade Ankanna, and

Nataru Savithramma

40. Phytochemistry and Bioactive Potential of Brassica oleracea L.

var. botrytis L. .............................................................................................517

Mitta Raghavendra, M. Mahesh, Sibbala Subramanyam, and K. N. Jayaveera

41. Medicinal Properties and Bioactive Compounds of

Stemona tuberosa Lour................................................................................527

C. Lalmuansangi, Marina Lalremruati, Mary Zosangzuali, F. Nghakliana, and Zothansiama

Index .....................................................................................................................539

Contents

xv

VOLUME 2

42. Chemical Composition and Biological Properties of Musk Willow (Salix aegyptiaca L.) ................................................................1 Gadwal Shaik Nishat Anjum, Sharmila Arunagiri, and Chinnadurai Immanuel Selvaraj

43. Phytochemistry and Pharmacological Properties of Salvadora persica L. ...................................................................................... 11 M. Santosh Kumari, K. Ammani, and CH. Srinivasa Reddy

44. Bioactive Components and Pharmacology of Memecylon.........................23

S. Asha, C. Umamaheswari, Tarun Pal, and U. Jaya Lakshmi

45. An Account of Traditional Uses, Bioactive Compounds, and Pharmacological Activities of the Genus Hydnocarpus (Family: Achariaceae)...................................................................................41 Harsha V. Hegde, Santoshkumar Jayagoudar, Pradeep Bhat, and Savaliram G. Ghane

46. Chemical Principles, Bioactivity, and Pharmacology of Hedychium spicatum Sm. (Family: Zingiberaceae)....................................53 Sinjumol Thomas, K. J. Binimol, and Bince Mani

47. Functional Components and Biological Activities of Kaempferia galanga L. (Chandramoolika) .................................................77 Chachad Devangi and Mondal Manoshree

48. Bioactive Compounds and Pharmacological Activities of Terminalia pallida Brandis............................................................................87 Pasupuleti Sivaramakrishna, Pulicherla Yugandhar, and Nataru Savithramma

49. Phytochemistry and Pharmacology of an Aquatic Herb Nymphaea pubescens Willd ..........................................................................99 Kiran Kumar Angadi, Ammani Kandru, and Ch. Srinivasa Reddy

50. Phyla nodiflora (L.) Greene—Exquisite Plant with Therapeutic Effects.....................................................................................109 Somasundaram Ramachandran and Veeramaneni Alekhya

51. Phytochemical and Pharmacological Profile of Achyranthes aspera L. (Amaranthaceae) ..................................................125

Raja Kullayiswamy and Sarojini Devi N

xvi

Contents

52. Phytochemistry and Pharmacology of Garcinia mangostana (Mangosteen)—A Review ...........................................................................139 Estefani Yaquelin Hernández-Cruz, Omar N. Medina-Campos, and José Pedraza-Chaverri

53. Bioactives and Pharmacology of Cycas beddomei Dyer...........................155

B. Kavitha and N. Yasodamma

54. Phytochemical and Pharmacological Profile of Tridax procumbens L.: An Asteraceaeous Member..................................165

Raja Kullayiswamy K and Sarojini Devi N

55. Bioactives and Their Biological Potentialities of Wild Cinnamon [Cinnamomum malabatrum (Burm.f.) J.Presl (Lauraceae)]....................181 Saranya Surendran, Chandra Prabha Ayyathurai, and Raju Ramasubbu

56. Therapeutic Potential and Bioactives of Amaranthus spinosus L...........193

Vrushali Manoj Hadkar, Kallipudi Charishma Reddy, and

Chinnadurai Immanuel Selvaraj

57. Mussaenda macrophylla Wall.: Chemical Composition and Pharmacological Applications....................................................................205 Marina Lalremruati, Mary Zosangzuali, C. Lalmuansangi, F. Nghakliana, and Zothansiama

58. Phytochemistry and Pharmacological Potentialities of Syzygium densiflorum Wall. ex Wight & Arn. and S. travancoricum Gamble (Myrtaceae).....................................................213

Athira Reghunath, Anjana Surendran, and Raju Ramasubbu

59. Bioactives and Ethnopharmacology of Pittosporum napaulense (DC.) Rehder & E.H. Wilson ............................229 B. Kavitha and N. Yasodamma

60. Tree of Heaven: Ailanthus excelsa Roxb.—Chemistry and Pharmacology..............................................................................................239 Digambar N. Mokat and Tai D. Kharat

61. Pharmacology and Therapeutic Potential of Cynodon dactylon (L.) Pers.........................................................................253 Jaishree Vaijanathappa

62. A Review on Phytochemistry and Pharmacological Activities of Aristolochia indica L. .............................................................267 Vishal P. Deshmukh

Contents

xvii

63. Pharmacological Activities of Diploclisia glaucescens (Blume) Diels .....289

Rutuja J. Tirbhane, Pradip V. Deshmukh, and Utkarsha M. Lekhak

64. Phytochemical Composition and Pharmacological

Properties of Red spinach (Amaranthus tricolor L.) ................................297

Vrushali Manoj Hadkar, Lankapothu Venkata Charishma, and

Chinnadurai Immanuel Selvaraj

65. Bioactive Molecules and Pharmacology Studies of

Ecbolium viride (Forssk.) Alston ................................................................315

Sibbala Subramanyam, V. L. Ashok Babu, V. Saleem Basha, and K. N. Jayaveera

66. Phytoconstituents and Pharmacological Activities of

Star Fruit [Averrhoa carambola L. (Family: Oxalidaceae)] ....................329

Savaliram G. Ghane, Samadhan R. Waghmode, and Rahul L. Zanan

67. Pharmacological and Phytochemical Review of a Vulnerable

Medicinal Plant Embelia ribes Burm. f. ....................................................347

Vidya V. Kamble, Vishwas A. Bapat, and Nikhil B. Gaikwad

69. Bioactives and Pharmacology of Tamarix aphylla (L.) Karst..................365

Chaudhary Hiral, Nainesh R. Modi, and Desai Krishna

69. Bioactives and Pharmacology Avicennia marina (Forssk.) Vierh. ..........375

Jitendra R. Patil, Savaliram G. Ghane, and Ganesh C. Nikalje

70. Phytochemical and Pharmacological Properties of

Himalayan Silver Birch (Betula utilis D. Don):

A Dominant Treeline Forming Species......................................................387

Khashti Dasila and Mithilesh Singh

71. A Comprehensive Review on Phytochemistry and Pharmacological

Potential of Musanga cecropioides R.Br. ex Tedlie...................................401

Vishal P. Deshmukh

72. Angelica glauca Edgew.—An Ethnopharmacological,

Phytochemical, and Pharmacological Review..........................................419

Swati and H. K. Pandey

73. Clusia nemorosa G. Mey: A Plant with Pharmacological Potential........431

Jamylle Nunes de Souza Ferro, Maria Danielma dos Santos Reis,

Felipe Lima Porto, Rafael Vrijdags Calado, Tayhana Priscila Medeiros Souza,

and Emiliano Barreto

xviii

Contents

74. Phytochemical Constituents and Pharmacology of

Eclipta prostrata (L.) L................................................................................439

Thadiyan Parambil Ijinu, Sreejith Pongillyathundiyil Sasidharan,

Vasantha Kavunkal Hridya, Sulochana Priji, Sharad Srivastava, and

Palpu Pushpangadan

75. Phytochemical Potential and Pharmacology of Ephedra alata Decne....457

Savaliram G. Ghane, Santoshkumar Jayagoudar, Pradeep Bhat, and Rahul L. Zanan

76. Ephedra sinica Stapf—An Exemplary Source of

Ephedrine-Type Alkaloids..........................................................................477

Suraj B. Patel, Pradeep Bhat, Santoshkumar Jayagoudar, Rahul L. Zanan, and

Savaliram G. Ghane

77. Pharmacological Review of Potential Underutilized Plant

Rhus mysorensis G. Don .............................................................................489

Nilesh Vitthalrao Pawar and Ashok Dattatray Chougale

78. Devil’s Cherry (Atropa belladonna L.): A Systematic Review on

Its Phytoactives and Pharmacological Properties....................................497

Pradeep Bhat, Harsha V. Hegde, Savaliram G. Ghane, and

Santoshkumar Jayagoudar

79. Traditional Use, Chemical Constituents, and Pharmacology of

Cocos nucifera L..........................................................................................507

Thadiyan Parambil Ijinu, Manikantan Ambika Chithra, Maheswari Priya Rani,

Thomas Aswany, Varughese George, and Palpu Pushpangadan

Index .....................................................................................................................523

Contributors

Sebastian John Adams

Department of Phyto-Pharmacognosy, Research, and Development, Sami Labs Ltd., 19/1 & 19/2,

1st main, 2nd Phase, Peenya Industrial Area, Bangalore 560058, India

National Center for Natural Products Research, School of Pharmacy, University of Mississippi,

Oxford, MS 38677, USA; E-mail: [email protected]

Jatin Aggarwal

Department of Biotechnology, Jaypee Institute of Information Technology, A-10 Sector 62, Noida 201309, Uttar Pradesh, India

Sandra Gomes De Amorin

Graduate Program of Food Science and Technology (PPGCTAL), Federal University of Federal da Fronteira Sul (UFFS), BR 158-km 405, 85301-970, Laranjeiras do Sul, PR, Brazil

K. Ammani

Department of Botany and Microbiology, Acharya Nagarjuna University, Guntur, India; E-mail: [email protected]

Sade Ankanna

Department of Botany, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India

S. Asha

Department of Biotechnology, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India

Thomas Aswany

Department of Biotechnology, Malankara Catholic College, Kanyakumari 629153, Tamil Nadu, India; E-mail: [email protected]

D. John Babu

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India; E-mail: [email protected]

Harish Babukolla

Department of Biotechnology, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India

Emiliano Barreto

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil

Rakesh Barik

Gitam School of Pharmacy, GITAM Deemed To Be University, Hyderabad Campus, Rudraram 502329, Telangana, India

Rafael Vrijdags Calado

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil

Manikantan Ambika Chithra

Amity Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India; E-mail: [email protected]

xx

Contributors

Yashaswani Chouhan

Department of Biotechnology, JECRC University, Jaipur 303905, India

Aline Oliveira Da Conceição

Biological Science Department, Santa Cruz State University, Km 16, Jorge Amado Road, Salobrinho, 45.662-900 Ilhéus, Bahia, Brazil; E-mail: [email protected]

Laura De Vasconcelos Costa

Department of Agroindustrial Science and Technology, Federal University of Pelotas (UFPel), Av. Eliseu Maciel, s/n, 96010-900, Capão do Leão, RS, Brazil

C. Divya

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India

Kushagra Dubey

Department of Pharmaceutical Chemistry, Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India

Raghvendra Dubey

Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, SAGE University, Indore, M.P., India; E-mail: [email protected]

Jamylle Nunes de Souza Ferro

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil

Varughese George

Amity Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India; E-mail: [email protected]

Savaliram G. Ghane

Plant Physiology Laboratory, Department of Botany, Shivaji University, Kolhapur 416004, Maharashtra, India; E-mail: [email protected]; [email protected]

Thadiyan Parambil Ijinu

Amity Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India; E-mail: [email protected] Naturæ Scientific, Kerala University Business Innovation and Incubation Centre, Karyavattom Campus, Thiruvananthapuram 695581, Kerala, India

M. Indira

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India

C. V. Jayalekshmi

Department of Botany, Government Victoria College, Palakkad, Kerala, India

K. N. Jayaveera

Department of Chemistry, Jawaharlal Nehru Technological University, Anantapur 515002, India

José Francisco Dos Santos Silveira Junior

Department of Food Science and Technology, Federal University of Santa Catarina, Florianópolis 88034-001, Santa Catarina, Brazil; E-mail: [email protected]

Prachi Sharad Kakade

Department of Botany, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, Maharashtra, India; E-mail: [email protected]

Contributors

xxi

Karuppa Samy Kasi

Department of Biology, The Gandhigram Rural Institute (Deemed to be University) Gandhigram, Dindigul, Tamil Nadu, India

B. Kavitha

Department of Botany, Rayalaseema University, Kurnool 518007, Andhra Pradesh, India; E-mail: [email protected]

B. Siva Sai Kiran

Department of Pharmaceutical Sciences, Krishna University, Machillipatnam, Andhra Pradesh, India

S. Krupanidhi

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India; Email: [email protected]

Brijesh Kumar

Sophisticated Analytical Instrument Facility Division (SAIF), CSIR-Central Drug Research Institute, Lucknow, India; E-mail: [email protected]

Chennareddy Maruthi Kesava Kumar

Department of Botany, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India

Thiruppathi Senthil Kumar

Department of Botany, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India

G. Shiva Kumar

Gitam School of Pharmacy, GITAM Deemed To Be University, Hyderabad Campus, Rudraram 502329, Telangana, India

S. Siva Kumar

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India

M. Santosh Kumari

Department of Botany and Microbiology, Acharya Nagarjuna University, Guntur, India

C. Lalmuansangi

Department of Zoology, Mizoram University (A Central University), Aizawl 796004, Mizoram, India

Marina Lalremruati

Department of Zoology, Mizoram University (A Central University), Aizawl 796004, Mizoram, India

Suparna Lodh

Asian Institute of Nursing Education, Guwahati, Assam, India; E-mail: [email protected]

M. Mahesh

Department of Pharmacy, JNTUA-Oil Technological and Pharmaceutical Research Institute, Ananthapuramu 515001, Andhra Pradesh, India

Adriana Dillenburg Meinhart

Department of Agroindustrial Science and Technology, Federal University of Pelotas (UFPel), Av. Eliseu Maciel, s/n, 96010-900, Capão do Leão, RS, Brazil

Ekta Menghani

Department of Biotechnology, JECRC University, Jaipur 303905, India

Neha Mishra

Vardhman Mahaveer Open University, Kota 324010, India

xxii

Contributors

M. Muniraju

Department of Studies in Botany, Bangalore University, Jnana Bharathi Campus, Off Mysuru Road, Bengaluru 560056, India

Mohammed S. Mustak

Department of Applied Zoology, Mangalore University, Dakshina Kannada 574199, Karnataka, India; E-mail: [email protected]

Gnanamani Muthuraman

Department of Phyto-Pharmacognosy, Research, and Development, Sami Labs Ltd., 19/1 & 19/2, 1st main, 2nd Phase, Peenya Industrial Area, Bangalore 560058, India

A. Nagalakshmi

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi 522213, Andhra Pradesh, India

F. Nghakliana

Department of Zoology, Mizoram University (A Central University), Aizawl 796004, Mizoram, India

Ragesh Raveendran Nair

Department of Botany, NSS College Nilamel, Kollam 691535, Kerala, India; E-mail: [email protected]

Shreedhar S. Otari

Plant Physiology Laboratory, Department of Botany, Shivaji University, Kolhapur 416004, Maharashtra, India

Sandeep Ramchandra Pai

Department of Botany, Rayat Shikshan Sanstha’s Dada Patil Mahavidyalaya, Karjat, District Ahmednagar 414402, Maharashtra, India; E-mail: [email protected]

Bruna Trindade Paim

Department of Agroindustrial Science and Technology, Federal University of Pelotas (UFPel), Av. Eliseu Maciel, s/n, 96010-900, Capão do Leão, RS, Brazil

Tarun Pal

Department of Biotechnology, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur 522213, Andhra Pradesh, India; E-mail: [email protected]

Arvind Pareek

Maharshi Dayanand Saraswati University, Ajmer 305009, India; E-mail: [email protected]

Suraj B. Patel

Plant Physiology Laboratory, Department of Botany, Shivaji University, Kolhapur 416004, Maharashtra, India

K. Abraham Peele

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Andhra Pradesh 522213, India

Jaya Preethi Peesa

Department of Pharmaceutical Sciences, Krishna University, Machillipatnam, Andhra Pradesh, India; E-mail: [email protected]

Vania Zanella Pinto

Graduate Program of Food Science and Technology (PPGCTAL), Federal University of Federal da Fronteira Sul (UFFS), BR 158-Km 405, 85301-970, Laranjeiras do Sul, PR, Brazil; E-mail: [email protected]

Contributors

xxiii

Felipe Lima Porto

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil

Maheswari Priya Rani

Phytochemistry and Pharmacology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram 695562, Kerala, India; E-mail: [email protected]

Priyadarshini

Department of Biotechnology, Jaypee Institute of Information Technology, A-10 Sector 62, Noida, Uttar Pradesh 201309, India; E-mail: [email protected]

Palpu Pushpangadan

Amity Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India; E-mail: [email protected]

Mitta Raghavendra

Department of Pharmacology, CMR College of Pharmacy, Hyderabad, Telangana State 501401, India; E-mail: [email protected]

S. Rajashekara

Centre for Applied Genetics, Department of Studies in Zoology, Bangalore University, Jnana Bharathi Campus, Off Mysuru Road, Bengaluru 560056, India; E-mail: [email protected]

Raju Ramasubbu

Department of Biology, The Gandhigram Rural Institute (Deemed to be University) Gandhigram, Dindigul, Tamil Nadu, India

Ch. Srinivasa Reddy

Department of Botany, SRR & CVR Government Degree College, Vijayawada, India

Maria Danielma dos Santos Reis

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil; E-mail: [email protected]

Daniella Pilatti-Riccio

Graduate Program of Food Sicence and Technology (PPGCTAL), Federal University of Federal da Fronteira Sul (UFFS), BR 158-km 405, 85301-970, Laranjeiras do Sul, PR, Brazil

Nataru Savithramma

Department of Botany, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India

Chinnadurai Immanuel Selvaraj

VIT School for Agricultural Innovations and Advanced Learning (VAIAL), Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India; E-mail: [email protected] School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India

Ria Singh

Department of Biotechnology, Jaypee Institute of Information Technology, A-10 Sector 62, Noida, Uttar Pradesh 201309, India

Kumkum Agarwal Sinha

Department of Botany, Shaheed Bhagat Singh Government Degree College, Ashta, District Sehore, Madhya Pradesh, India; E-mail: [email protected]

Nayan Kumar Sishu

Department of Biotechnology, School of Biosciences and Technology, VIT, Vellore 632014, Tamil Nadu, India

xxiv

Contributors

Payal Soan

Department of Botany, St. Wilfred College for Girls, Mansarover, Jaipur 302020, Rajasthan, India; E-mail: [email protected]

Tayhana Priscila Medeiros Souza

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil

Babu Subramanian

School of Agricultural Innovations and Advanced Learning, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India

Sibbala Subramanyam

Department of Pharmaceutical Sciences, Vignan’s Foundation for Science, Technology & Research (VFSTR) (Deemed to be University), Vadlamudi, Guntur 522 213, Andhra Pradesh, India

Sinoy Sugunan

Gitam School of Pharmacy, GITAM Deemed To Be University, Hyderabad Campus, Rudraram 502329, Telangana, India; E-mail: [email protected]

D. Sai Sushma

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh 522213, India

Anjana Surendran

Department of Biotechnology, Mother Teresa Women’s University, Kodaikanal, Tamil Nadu, India; E-mail: [email protected]

V. Suresh

Department of Botany, Government Victoria College, Palakkad, Kerala, India; E-mail: [email protected]

Hirpasa Teressa

Department of Biology, Wolkite University, Wolkite, Ethiopia; E-mail: [email protected]

Parthasarathi Theivasigamani

VIT School for Agricultural Innovations and Advanced Learning (VAIAL), Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India

Surabhi Tiwari

Sophisticated Analytical Instrument Facility Division (SAIF), CSIR-Central Drug Research Institute, Lucknow, India; E-mail: [email protected]

Vinod S. Undal

Department of Botany, Ghulam Nabi Azad College, Barshitakali, Dist - Akola, Maharashtra, India; E-mail: [email protected]

Vinayak Upadhya

Department of Forest Products and Utilization, College of Forestry (University of Agricultural Sciences, Dharwad), Sirsi, Uttara Kannada, Karnataka 581401, India

Jaishree Vaijanathappa

School of Life Sciences, JSS Academy of Higher Education and Research, Avenue Droopnath Ramphul, Bonne Terre 73103, Vacaos, Mauritius; E-mail: [email protected]

T. C. Venkateswarulu

Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Andhra Pradesh 522213, India

Contributors

xxv

N. Yasodamma

Department of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh, India; E-mail: [email protected]

Pulicherla Yugandhar

Survey of Medicinal Plants Unit, Regional Ayurveda Research Institute, Itanagar 791111, Arunachal Pradesh, India; E-mail:[email protected]

Saurabha Bhimrao Zimare

Naoroji Godrej Centre for Plant Research (NGCPR), Shindewadi, Shirwal, Satara 412801, Maharashtra, India

Mary Zosangzuali

Department of Zoology, Mizoram University (A Central University), Aizawl 796004, Mizoram, India

Zothansiama

Department of Zoology, Mizoram University (A Central University), Aizawl 796004, Mizoram, India; E-mail: [email protected]

Abbreviations

ABTS AC ACP ACA ACA ADA AE AETB AF64A AGEs AgNPs AI Akt ALP ALT APC APH APTT ARP AST AST AUUP BAs BHA BHT BM HE-ext BMOCs BIC BuOH bw CAT CCl4 CEBL CEO

2,2-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid asiaticoside acid phosphatase 1′-acetoxychavicol acetate A. caudatus agglutinin adenosine deaminase activity aqueous extract aqueous fruit pulp extract of T. bellirica ethyl choline aziridinium ion advanced glycation end products silver nanoparticles atherogenic index protein kinase B alkaline phosphatase alanine amino transferase amaranth protein concentrate amaranth protein hydrolysates activated partial thromboplastin time antiradical power amino transferase aspartate transaminase Amity University Uttar Pradesh bile acids butylated hydroxyanisole butylated hydroxytoluene hydroethanolic extract of Bacopa monnieri bone marrow derived dendritic cells biofilm inhibitory fixation butanolic fraction body weight catalase carbon tetrachloride chloroform extract of leaves Cyperus esculentus oil

xxviii

CFA CIA CK-MB CNS COR-L23 COX-2 CS Cyp2e1 Cyp2f2 DAF DCM D-GaIN DKA DLA DMBA DMEM DPPH DTCE EAC EAFWE EETB EHV-1 EO EPR ESBL EtOAc FBG FRAP FRSA FST GC GPx GSH GST HCA-7 HDL HEP2 HIV HIF-1

Abbreviations

Complete Freund’s Adjuvant collagen II-induced arthritis creatine kinase-muscle/brain central nervous system lung carcinoma cell line cyclo-oxygenase-2 cigarette smoke Cytochrome P450 2e1 Cytochrome P450 2f2 defatted amaranth flour dichloromethane D-galactosamine ketoacidosis Dalton’s Lymphoma Ascitic 7,12-dimethylbenz (a) anthracene Dulbecco’s modified eagle’s medium 1,1-diphenyl-2-picrylhydrazyl defatted tubers of Cyperus esculentus Ehrlich’s ascites carcinoma ethyl acetate fraction of water extract of C. guaianensis flowers ethanolic residues of T. bellirica leaf equine herpesvirus type-1 essential oil electron paramagnetic resonance spectroscopy extensive spectrum β-lactamase ethylacetate fasting blood glucose ferric reducing antioxidant power free radical scavenging action forced swim test gas chromatography glutathione peroxidase glutathione glutathione-s-transferase human colon adenocarcinoma cell line high-density lipoprotein human liver carcinoma cell lines human immunodeficiency virus hypoxia-inducible factor 1

Abbreviations

HLPC-DAD HMGR HPDE-6 HPLC HPTLC HRBC Hela HeLa cells HepG2 HSF HSV HSV-1 H1N1 IC50 IL IL-1β IL-6 iNOS iNOS IR IR K1 LCAT LC–MS LDH LDL LPO LPS MABA MCF-7 MDA MDA-MB-231 MDR MES MeTB MIC MMP MNCC MPO MRC-5

xxix

high-performance liquid chromatography hydroxymethylglutarate-coenzyme A reductase human pancreatic ductal epithelial high-pressure liquid chromatography high-performance thin layer chromatography human red blood cell cervical cancer cell line human cervical cancer cell line liver cancer cell line human skin fibroblast herpes simplex virus herpes simplex virus type 1 Influenza A inhibitory concentration interleukins interleukin-β interleukin-6 inhibition of enzymes inducible nitric oxide synthase insulin struggle inhibition rate chloroquine-resistant lecithin-cholesterol acyltransferase liquid chromatography–mass spectrometry lactate dehydrogenase low-density lipoprotein lipid peroxide lipopolysaccharide microplate alamar blue assay Michigan Cancer Foundation-7 malondialdehyde breast cancer cell lines multidrug-resistant maximal electroshock stimulation methanolic residues minimum inhibitory concentration matrix metalloproteinase maximum noncytotoxic concentration myeloperoxidase lung fibroblast cell

xxx

Abbreviations

methicillin-resistant Staphylococcus aureus methicillin-sensitive Staphylococcus aureus Bacillus subtilis Escherichia coli Staphylococcus aureus Pseudomonas aeruginosa 3-(4, 5-dimethyl thiazol-2yl)-2, 5-diphenyl tetrazolium bromide MTX methotrexate NDEA N-nitrosodiethylamine NFkB nuclear factor kappa B NIQ dimeric naphthylisoquinolines NK natural killer NO nitric oxide NPD nitrophenylenediamine NRU neutral red uptake OGTT oral glucose tolerance test ORAC oxygen radical absorbance capacity PBMCs peripheral blood mononuclear cells PC-3 prostate cancer PGE2 prostaglandin E2 PPARα and PPARγ peroxisome proliferator-activated receptors PPOs polyphenol oxidases PT prothrombin time PTZ pentylenetetrazole RBC red blood cells RBEF Ritnand Balved Education Foundation SAE Soxhlet-assisted extraction SCE sister chromatid exchange SEM scanning electron microscopy SGPT serum glutamate pyruvate transaminase SGOT serum glutamate oxaloacetate transferase SOD superoxide dismutase SPF sun protection factor SuHV-1 suid herpesvirus type 1 STZ streptozotocin TB T. bellirica TBE T. bellirica extract TC total cholesterol MRSA MSSA MTCC-441 MTCC-443 MTCC-737 MTCC-741 MTT

Abbreviations

TGs TLC TNF TST TT Tb-01 UA VLDL WBC XO 5-HIAA

xxxi

triglycerides thin layer chromatography tumor necrosis factor tail suspension test thrombin time isolated compound uric acid very low-density lipoprotein white blood cells xanthine oxidase 5-hydroxytryindole-3-acetic acid

Preface

Many young researchers used to approach me with the question, “Can you suggest to me a medicinal plant on which I can work?” For answering this question, I had to dig into the literature on the bioactives and pharmacology. During this search, I found that comprehensive reviews on biomolecules and pharmacology for many medicinal plants are not available. With a view to fill this gap, we started this series of 10 volume books in the series AAP Focus on Medicinal Plants. This is the fourth book in this series. A comprehensive review on more than 80 plant species is given in this two-volume book. In each chapter, a brief introduction on the species is given. Bioactive phytochemicals from the plant are then listed, and their chemical structures are given. These are followed by pharmacological activities. All the published literature on pharmacological activities on that species is reviewed. A wide array of biological activities and potential health benefits of the medicinal plant, which include antiviral, antimicrobial, antioxidant, anticancer, antiinflammatory, and antidiabetic properties as well as protective effects on liver, kidney, heart, and nervous system, are also given. Many contributors of this book are young researchers, mostly research scholars. In many cases, the manuscripts have been revised three to four times. The publisher insisted on bringing down the plagiarism to under 5%, which was a tough task because chemical names, disease names, and the methods cannot be modified. In spite of this, plagiarism was brought down to nearly 5%. I thank both the publisher and the contributors for the same. I wish to express my gratitude to all the authors who contributed to the review chapters. I thank them for their cooperation and erudition. I hope that this will be a source book for the development of new drugs. I request that readers give their suggestions to improve forthcoming volumes and future editions.

CHAPTER 1

Ilex paraguariensis—Green Gold from South America VANIA ZANELLA PINTO1,*, DANIELLA PILATTI-RICCIO1,

BRUNA TRINDADE PAIM2, LAURA DE VASCONCELOS COSTA2,

SANDRA GOMES DE AMORIN1, and

ADRIANA DILLENBURG MEINHART2

Graduate Program of Food Science and Technology (PPGCTAL),

Federal University of Federal da Fronteira Sul (UFFS),

BR 158—Km 405, 85301-970, Laranjeiras do Sul, PR, Brazil

1

Department of Agroindustrial Science and Technology,

Federal University of Pelotas (UFPel), Av. Eliseu Maciel, s/n,

96010-900, Capão do Leão, RS, Brazil

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Ilex paraguariensis A.St.-Hil. is a tree from South America known as yerba mate or maté with a natural occurrence in northwest Argentina, eastern Paraguay, and southern Brazil. It is the main non-timber forest product of these regions and has cultural and economic importance. Beyond these, its leaves and thin stalks have many bioactive compounds, especially chlorogenic acid isomers, caffeine, theobromine, rutin, and saponins. This bioactiverich composition is related to some antiviral, antibacterial, antifungal, and antioxidant effects, as well as positive effects on blood glucose and dyslipidemia, neurological, and against a few tumor cells. Other emerging uses include natural food antioxidants, cosmetics, and active packaging. The I.

Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

2

Phytochemistry and Pharmacology of Medicinal Plants, Volume 1

paraguariensis extracts are very sensitive to heat, light, and oxygen, among other oxidizing conditions, and partial degradation during the gastrointestinal tract. The preservation strategies for the mate extract are challenging and promising. 1.1

INTRODUCTION

The botanical genus Ilex belongs to the Aquifoliaceae family, which is cosmopolitan and comprises about 500 species (Alikaridis, 1987). Ilex paraguariensis A.St.-Hil. is a native tree from South America known as yerba mate or maté and it has a natural distribution area of 540,000 km² between northwest Argentina, eastern Paraguay, and southern Brazil (Berté et al., 2011). In these regions, it has a great environmental and socioeconomic impact, as it is the main nontimber forest product, which increases local employment and income (Signor and Marcolini, 2017). Its leaves are traditionally consumed as a hot infusion (chimarrão), cold tea (tereré), or even as hot or cold roasted tea (mate tea). These products are usually made with the leaves and thin stalks ( 300 µg/mL). It also inhibited in vitro colon cancer cell proliferation possibly mediated via pro-oxidant activities, being a potential source of chemopreventive agent (de Mejía et al., 2010). In vitro digested I. paraguariensis extracts inhibit the proliferation of HepG2 human liver cancer cells (Boaventura et al., 2015a). Also, dicaffeoylquinic acids from yerba mate inhibit NF-κB nucleus translocation in macrophages and induce apoptosis by activating caspases-8 and -3 in human colon cancer cells (Lückemeyer et al., 2012). 1.4

OTHER EMERGING APPLICATIONS

Besides the vast pharmacological interest, a plant matrix in such evidence also stands out in the development of new hygiene and cleaning products, agricultural, food, packaging, cosmetics, dermatological, and others. The aqueous and ethanolic extracts of I. paraguariensis have been used as antiseptic or disinfectant inputs, applicable in primary health care and production in small farming systems, with an emphasis on the prevention and control of S. enteritidis and Enterococus faecalis (Girolometto et al., 2009), serovars of Salmonella spp. of poultry origin (Salmonella derby, Salmonella orion, Salmonella enteritidis, Salmonella enterica, Salmonella infantis, Salmonella mbandaka, Salmonella lexigton, Salmonella kentucky) (De Bona et al., 2010). The use of I. paraguariensis extracts promotes the inhibition of lipid oxidation in different foods. Thus, the inclusion of hydrogels formed by chia extract and oil resulted in a reduction in saturated fatty acids and an increase in omega-6 and omega-3 in buffalo meat hamburgers, and the extract inhibited the lipid oxidation of the products (Heck et al., 2021). Precooked chicken meatballs may accordingly be protected against lipid oxidation by

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I. paraguariensis added before cooking (0.05% of dried leaves) either using the leaves or using an aqueous extract without affecting the flavor (Racanicci et al., 2008, 2009). The dried leaves or extracts are efficient on the growth and zootechnical performance of different slaughter animals, underfeed supplementation. The dry extract of I. paraguariensis in the diet of growing lambs increase wool production, feed intake, levels of leukocyte cells, and globulins in the serum, while there was a reduction in LDL cholesterol and triglycerides (Lobo et al., 2020; Po et al., 2012). In addition, production and carcass yield has been improved, by the great production of lean tissue (Lobo et al., 2020). These behaviors are considered positive, as they lead to improvements in the health of consumers, generating healthier meat for the human diet and thus, more desired in the meat industry. Packaging and cosmetic productions are the most promising emerging applications for I. paraguariensis. Starch biodegradable films are efficient in keeping the antioxidant properties (Knapp et al., 2019; Medina-Jaramillo et al., 2017) for food and nonfood application. Chitosan hydrochloride nanoparticles and microspheres incorporated by I. paraguariensis extract maintain antioxidant activity, have protective and hydrating characteristics, and have been identified as a potential way to incorporate natural antioxidants into cosmetics (Harris et al., 2011). 1.5 REMARKABLE TRENDS One of the great challenges of science and technology is the fact that the bioactive compounds present in I. paraguariensis have low stability to heat, light, oxygen, among other oxidizing conditions. In addition, when the compounds are ingested, they undergo partial degradation during passage in the gastrointestinal tract (Gómez-Juaristi et al., 2018). Therefore, preservation strategies for these compounds for late or controlled release have involved nanotechnological aspects, which include the formation of nanomaterials, including particles, capsules, fibers, gels, aerogels, hydrogels, liposomes, and others. In this context, the compounds of interest are involved and protected by wall materials or carriers, so that protection and release occur at a later time, in controlled or uncontrolled behavior. The results are still scarce, but it has been observed that the encapsulation of extracts of I. paraguariensis results in the protection of compounds against oxidation, with increased antioxidant activity and increased bioavailability

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in vivo (Córdoba et al., 2014; Dabulici et al., 2020; Fenoglio et al., 2021; Vargas et al., 2021), which shows the high potential of the use of nanotechnology and places it as a high scientific target. However, nanomaterials still deserving attention from regulatory affairs of the countries, and more and more research about their toxicological aspects. KEYWORDS • • • • •

maté phenolic compounds flavonoids antioxidative activity dyslipidemia control

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Antioxidant Activity of Aqueous Extract of Mate (Ilex paraguariensis A.St.Hil.) Through Freeze Concentration Technology. Food Res. Int. 2013, 53 (2), 686–692. Boaventura, B. C. B.; da Silva, E. L.; Liu, R. H.; Prudêncio, E. S.; Di Pietro, P. F.; Becker, A. M.; Amboni, R. D. M. C. Effect of Yerba Mate (Ilex paraguariensis A.St.Hil.) Infusion Obtained by Freeze Concentration Technology on Antioxidant Status of Healthy Individuals. LWT Food Sci. Technol. 2015b, 62 (2), 948–954. Bracesco, N. Ilex paraguariensis as a Healthy Food Supplement for the Future World. Biomed. J. Sci. Tech. Res. 2019, 16 (1), 11821–11823. Bracesco, N.; Sanchez, A. G.; Contreras, V.; Menini, T.; Gugliucci, A. Recent Advances on Ilex paraguariensis Research: Mini Review. J. Ethnopharmacol. 2011, 136 (3), 378–384. Branco, C. S.; Scola, G.; Rodrigues, A. D.; Cesio, V.; Laprovitera, M.; Heinzen, H.; dos Santos, M. T.; Fank, B.; de Freitas, S. C. V.; Coitinho, A. S.; Salvador, M. Anticonvulsant, Neuroprotective and Behavioral Effects of Organic and Conventional Yerba Mate (Ilex paraguariensis St.Hil.) on Pentylenetetrazol-Induced Seizures in Wistar Rats. Brain Res. Bull. 2013, 92, 60–68. Burris, K. P.; Davidson, P. M.; Stewart, C. N.; Zivanovic, S.; Harte, F. M. Aqueous Extracts of Yerba Mate (Ilex paraguariensis) as a Natural Antimicrobial Against Escherichia coli O157:H7 in a Microbiological Medium and pH 6.0 Apple Juice. J. Food Prot. 2012a, 75 (4), 753–757. Burris, K. P.; Harte, F. M.; Davidson, P. M.; Stewart Jr, C. N.; Zivanovic, S. 2012. Composition and Bioactive Properties of Yerba Mate (Ilex paraguariensis A.St.-Hil.): A Review. Chil. J. Agric. Res. 2012b, 72 (2), 268–275. Cahuê, F.; Souza, S.; dos Santos, C. F. M.; Machado, V.; Nascimento, J. H. M.; Barcellos, L.; Salermo, V. P. Short-Term Consumption of Ilex paraguariensis Extracts Protects Isolated Hearts from Ischemia/Reperfusion Injury and Contradicts Exercise-Mediated Cardioprotection. Appl. Physiol. Nutr. Metab. 2017, 42 (11), 1–41. Cardozo Jr., E. L.; Morand, C. Interest of Mate (Ilex paraguariensis A.St.-Hil.) as a New Natural Functional Food to Preserve Human Cardiovascular Health—A Review. J. Funct. Foods 2016, 21, 440–454. Cho, A. S.; Jeon, S. M.; Kim, M. J.; Yeo, J.; Seo, K. I.; Choi, M. S.; Lee, M. K. Chlorogenic Acid Exhibits Anti-Obesity Property and Improves Lipid Metabolism in High-Fat DietInduced-Obese Mice. Food Chem. Toxicol. 2010, 48 (3), 937–943. Colpo, A. C.; Rosa, H.; Eduarda, M.; Eliza, C.; Pazzini, F.; De Camargo, V. B.; Bassante, F. E. M.; Puntel, R.; Silva, D.; Mendez, A.; Folmer, V. Yerba Mate (Ilex paraguariensis St. Hill.)Based Beverages: How Successive Extraction Influences the Extract Composition and Its Capacity to Chelate Iron and Scavenge Free Radicals. Food Chem. 2016, 209, 185–95. Córdoba, A. L.; Deladino, L.; Martino, M. Release of Yerba Mate Antioxidants from Corn Starch-Alginate Capsules as Affected by Structure. Carbohydr. Polym. 2014, 99, 150–157. Croge, C. P.; Cuquel, F. L.; Pintro, P. T. M. Yerba Mate: Cultivation Systems, Processing and Chemical Composition: A Review. Sci. Agricola 2020, 78 (5), 1–11. Dabulici, C. M.; Sârbu, I.; Vamanu, E. The Bioactive Potential of Functional Products and Bioavailability of Phenolic Compounds. Foods 2020, 9 (7), 953. Dartora, N.; De Souza, L. M.; Santana-filho, A. P.; Iacomini, M.; Valduga, A. T.; Gorin, P. A. J.; Sassaki, G. L. UPLC-PDA—MS Evaluation of Bioactive Compounds from Leaves of Ilex paraguariensis with Different Growth Conditions, Treatments and Ageing. Food Chem. 2011, 129 (4), 1453–1461.

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da Silveira, T. F. F.; Meinhart, A. D.; Coutinho, J. P.; de Souza, T. C. L.; Cunha, E. C. E.; de Moraes, M. R.; Godoy, H. T. Content of Lutein in Aqueous Extracts of Yerba Mate (Ilex paraguariensis St. Hil). Food Res. Int. 2016, 82, 165–171. De Bona, E. A. M.; Pinto, F. G. S.; Borges, A. C. M.; Weber, L. D.; Fruet, T. K.; Alves, L. F. A.; Moura, A. C. Avaliação Da Atividade Antimicrobiana de Erva-Mate (Ilex paraguariensis ) Sobre Sorovares de Salmonella spp. de Origem Avícola. Rev. Unopar Cient. 2010, 12 (3), 45–48. de Lima, M. E.; Colpo, A. Z. C.; Rosa, H.; Salgueiro, A. C. F.; da Silva, M. P.; Noronha, D. S.; Santamaría, A.; Folmer, V. Ilex paraguariensis Extracts Reduce Blood Glucose, Peripheral Neuropathy and Oxidative Damage in Male Mice Exposed to Streptozotocin. J. Funct. Foods 2018, 44, 9–16. de Mejía, E. G.; Song, Y. S.; Heck, C. I.; Ramírez-Mares, M. V. Yerba Mate Tea (Ilex paraguariensis): Phenolics, Antioxidant Capacity and In Vitro Inhibition of Colon Cancer Cell Proliferation. J. Funct. Foods 2010, 2 (1), 23–34. De Morais, E. C.; Stefanuto, A.; Klein, G. A.; Boaventura, B. C. B.; De Andrade, F.; Wazlawik, E.; Di Pietro, P. F.; Maraschino, M.; Da Silva, E. L. Consumption of Yerba Mate (Ilex paraguariensis) Improves Serum Lipid Parameters in Healthy Dyslipidemic Subjects and Provides an Additional LDL-Cholesterol Reduction in Individuals on Statin Therapy. J. Agric. Food Chem. 2009, 57 (18), 8316–8324. de Resende, P. E.; Kaiser, S.; Pittol, V.; Hoefel, A. L.; Silva, R. D.; Marques, C. V.; Kucharski, L. C.; Ortega G. G. Influence of Crude Extract and Bioactive Fractions of Ilex praguariensis A.St.Hil. (Yerba Mate) on the Wistar Rat Lipid Metabolism. J. Funct. Foods 2015, 15, 440–451. Donaduzzi, C. M.; Cardozo Jr., E. L.; Donaduzzi, E. M.; da Silva, M. M.; Sturion, J. A.; Correa, G. Variação nos teores de polifenís totais e taninos em dezesseis progênies de ErvaMate (Ilex paraguariensis St. Hill.) cultivadas em três municípios do Paraná. Arquivos de Ciências Da Saúde Da Unipar 2003, 2 (7), 129–133. Fayad, E.; El-Sawalhi, S.; Azizi, L.; Beyrouthy, M.; Abdel-Massih, R. M. Yerba Mate (Ilex paraguariensis) a Potential Food Antibacterial Agent and Combination Assays with Different Classes of Antibiotics. LWT Food Sci. Technol. 2020, 125, 109267. Fenoglio, D.; Madrid, D. S.; Moyano, J. A.; Ferrario, M.; Guerrero, S.; Matiacevich, S. Active Food Additive Based on Encapsulated Yerba Mate (Ilex paraguariensis) Extract: Effect of Drying Methods on the Oxidative Stability of a Real Food Matrix (Mayonnaise). J. Food Sci. Technol. 2021, 58 (4), 1574–1584. Filip, R.; Davicino, R.; Anesini, C. Antifungal Activity of the Aqueous Extract of Ilex paraguariensis Against Malassezia Furfur. Phytother. Res. 2010, 24, 715–719. Filip, R.; Lotito, S. B.; Ferraro, G.; Fraga, C. G. Antioxidant Activity of Ilex paraguariensis and Related Species. Nutr. Res. 2000, 20 (10), 1437–1446. Gerke, I. B. B.; Hamerski, F.; Scheer, A. P.; Silva, V. R. Clarification of Crude Extract of Yerba Mate (Ilex paraguariensis) by Membrane Processes: Analysis of Fouling and Loss of Bioactive Compounds. Food Bioprod. Process. 2017, 102, 204–212. Girolometto, G.; Avancini, C. A. M.; Carvalho, H. H. C.; Wiest, J. M. Antibacterial Activity of Yerba Mate (Ilex paraguariensis A.St.-Hil.) Extracts. Rev. Bras. Plantas Med. 2009, 11 (1), 49–55. Gómez-Juaristi, M.; Martínez-López, S.; Sarria, B.; Bravo, L.; Mateos, R. Absorption and Metabolism of Yerba Mate Phenolic Compounds in Humans. Food Chem. 2018, 240, 1028–1038.

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Harris, R.; Lecumberri, E.; Mateos-Aparicio, I.; Mengíbar, M.; Heras, A. Chitosan Nanoparticles and Microspheres for the Encapsulation of Natural Antioxidants Extracted from Ilex paraguariensis. Carbohydr. Polym. 2011, 84 (2), 803–836. Hartwig, V. G.; Brumovsky, L. A.; Fretes, R. M.; Boado, L. S. 2012. Procedimento padronizado para avaliar a capacidade antioxidante dos extratos de Erva-Mate. Ciencia e Tecnologia de Alimentos 2012, 32 (1), 126–133. Heck, C. I.; Schmalko, M.; De Mejia, E. G. Effect of Growing and Drying Conditions on the Phenolic Composition of Mate Teas (Ilex paraguariensis). J. Agric. Food Chem. 2008, 56 (18), 8394–8403. Heck, R. T.; da Rosa, J. L.; Vendrusculo, R. G.; Cichoski, A. J.; Meinhart, A. D.; Lorini, A.; Paim, B. T.; Galli, V.; Robalo, S. S.; dos Santos, B. A.; de Pellegrin, L. F. V.; de Menezes, C. R.; Wagner, R.; Campagnol, P. C. B. Lipid Oxidation and Sensory Characterization of Omega-3 Rich Buffalo Burgers Enriched with Chlorogenic Acids from the Mate (Ilex paraguariensis ) Tree harvesting Residues. Meat Sci. 2021, 179, 108534. Isolabella, S.; Cogoi, L.; López, P.; Anesini, C.; Ferraro, G.; Filip, R. Study of the Bioactive Compounds Variation During Yerba Mate (Ilex paraguariensis ) Processing. Food Chem. 2010, 122 (3), 695–699. Jang, M. H.; Piao, X. L.; Kim, J. M.; Kwon, S. W.; Park, J. H. Inhibition of Cholinesterase and Amyloid-&bgr; Aggregation by Resveratrol Oligomers from Vitis amurensis. Phytother. Res. 2008, 22 (4), 544–549. Kang, Y.-R.; Lee, H.-Y.; Kim, J.-H.; Moon, D.-I.; Seo, M.-Y; Park, S.-H.; Choi, K.-H.; Kim, C. R.; Kim, S.-H.; Oh, J.-H.; Cho, S.-W.; Kim, S.-Y.; Kim, M. G.; Chae, S. W.; Kim, O.; Oh, H.-G. Anti-Obesity and Anti-Diabetic Effects of Yerba Mate (Ilex paraguariensis ) in C57BL/6J Mice Fed a High-Fat Diet. Lab. Anim. Res. 2012, 28 (1), 23. Knapp, M. A.; dos Santos, D. F.; Pilatti-Riccio, D.; Deon, V. G.; dos Santos, G. H. F.; Pinto, V. Z. Yerba Mate Extract in Active Starch Films: Mechanical and Antioxidant Properties. J. Food Process. Preserv. 2019, 43 (3), 1–12. Kungel, P. T. A. N.; Correa, V. G.; Corrêa, R. C. G.; Peralta, R. M. R. A.; Calhelha, M. S. R. C.; Bracht, A.; Ferreira, I. C. F. R.; Peralta, R. M. R. A. Antioxidant and Antimicrobial Activities of a Purified Polysaccharide from Yerba Mate (Ilex paraguariensis). Int. J. Biol. Macromol. 2018, 114, 1161–1167. Lobo, R. R. R.; Vincenzi, R.; Rojas-Moreno, D. A. A.; Lobo, A. A. G. A. G.; da Silva, C. M. M.; Benetel-Junior, V.; Ghussn, L. R. R.; Mufalo, V. C. C.; Berndt, A.; Gallo, S. B. B..; Pinheiro, R. S. B. S. B.; Bueno, I. C. d. S. C. d. S.; Faciola A. P. P. Inclusion of Yerba Mate (Ilex paraguariensis) Extract in the Diet of Growing Lambs: Effects on Blood Parameters, Animal Performance, and Carcass Traits. Animals 2020, 10 (6), 1–14. Lorini, A.; Damin, F. M.; de Oliveira, D. N.; Crizel, R. L.; Godoy, H. T.; Galli, V.; Meinhart, A. D. Characterization and Quantification of Bioactive Compounds from Ilex paraguariensis Residue by HPLC-ESI-QTOF-MS from Plants Cultivated Under Different Cultivation Systems. J. Food Sci. 2021, 86 (5), 1599–1619. Lückemeyer, D. D.; Müller, V. D. M.; Moritz, M. I. G.; Stoco, P. H.; Schenkel, E. P.; Barardi, C. R. M.; Reginatto, F. H.; Simões, C. M. O. Effects of Ilex paraguariensis A.St.Hil. (Yerba Mate) on Herpes Simplex Virus Types 1 and 2 Replication. Phytother. Res. 2012, 26 (4), 535–540. Luís, A. F. S.; Domingues, F. d. C.; Amaral, L. M. J. P. The Anti-Obesity Potential of Ilex paraguariensis: Results from a Meta-Analysis. Braz. J. Pharm. Sci. 2019, 55 (e17615), 1–15.

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Lunceford, N.; Gugliucci, A. Ilex paraguariensis Extracts Inhibit AGE Formation More Efficiently than Green Tea. Fitoterapia 2005, 76 (5), 419–427. Martin, J. G. P.; Porto, E.; De Alencar, S. M.; Glória, E. M.; Corrêa, C. B.; Cabral, I. S. R. Antimicrobial Activity of Yerba Mate (Ilex paraguariensis St.Hil.) Against Food Pathogens. Rev. Argent. Microl. 2013, 45 (2), 93–98. Medina-Jaramillo, C.; Ochoa-Yepes, O.; Bernal, C.; Famá L. Active and Smart Biodegradable Packaging Based on Starch and Natural Extracts. Carbohydr. Polym. 2017, 176, 187–194. Meinhart, A. D.; Lucas, C.; Damin, F. M.; Filho, J. T.; Godoy, H. T. Analysis of Chlorogenic Acids Isomers and Caffeic Acid in 89 Herbal Infusions (Tea). J. Food Compos. Anal. 2018, 73, 76–82. Meinhart, A. D.; Damin, F. M.; Caldeirão, L.; da Silveira, T. F. F.; Filho, J. T.; Godoy, H. T. Chlorogenic Acid Isomer Contents in 100 Plants Commercialized in Brazil. Food Res. Int. 2017, 99, 522–530. Murakami, A. N. N.; Amboni, R. D. d. M. C.; Prudêncio, E. S.; Amante, E. R.; Fritzen-Freire, C. B.; Boaventura, B. C. B.; Muñoz, I. D. B.; Branco, C. D. S.; Salvador, M.; Maraschin M. Concentration of Biologically Active Compounds Extracted from Ilex paraguariensis St.Hil. by Nanofiltration. Food Chem. 2013, 141 (1), 60–65. Nabechima, G. H.; Provesi, J. G.; Frescura, J. D. O.; Mantelli, M. B. H.; Vieira, M. A.; Prudêncio, E. S.; Amante, E. R. Thermal Inactivation of Peroxidase and Polyphenoloxidase Enzymes in Mate Leaves (Ilex paraguariensis) in a Conveyor Belt Oven. CYTA J. Food 2014, 12 (4), 399–406. Nunes, G. L.; Boaventura, B. C. B.; Pinto, S. S.; Verruck, S.; Murakami, F. S.; Prudêncio, E. S.; Amboni, R. D. D. M. C. Microencapsulation of Freeze Concentrated Ilex paraguariensis Extract by Spray Drying. J. Food Eng. 2015, 151, 60–68. Obanda, M. P.; Okinda, O.; Mang’oka, R. Changes in the Chemical and Sensory Quality Parameters of Black Tea Due to Variations of Fermentation Time and Temperature. Food Chem. 2001, 75 (4), 395–404. Pagliosa, C. M.; Vieira, M. A.; Podestá, R.; Maraschin, M.; Zeni, A. L. B.; Amante, E. R.; Castanho Amboni R. D. d. M. C. Methylxanthines, Phenolic Composition, and Antioxidant Activity of Bark from Residues from Mate Tree Harvesting (Ilex paraguariensis A.St.Hil.). Food Chem. 2010, 122 (1), 173–178. Pilatti-Riccio, D.; dos Santos, D. F.; Meinhart, A. D.; Knapp, M. A.; Hackbart, H. C. D. S.; Pinto, V. Z. Impact of the Use of Saccharides in the Encapsulation of Ilex paraguariensis Extract. Food Res. Int. 2019, 125, 108600. Pinto, V. Z.; Pilatti-Riccio, D.; da Costa, E. S.; Micheetto, Y. M. S.; Quast, E.; dos Santos, G. H. F. Phytochemical Composition of Extracts from Yerba Mate Chimarrão. SN Appl. Sci. 2021, 3, 1–5. Po, E.; Horsburgh, K.; Raadsma, H. W.; Celi, P. Yerba Mate (Ilex paraguarensis) as a Novel Feed Supplement for Growing Lambs. Small Rumin. Res. 2012, 106 (2–3), 131–36. Puangpraphant, S.; De Mejia, E. G. Saponins in Yerba Mate Tea (Ilex paraguariensis A. St.-Hil) and Quercetin Synergistically Inhibit INOS and COX-2 in LipopolysaccharideInduced Macrophages Through NFκB Pathways. J. Agric. Food Chem. 2009, 57 (19), 8873–8883. Queffélec, C.; Bailly, F.; Mbemba, G.; Mouscadet, J. F.; Hayes, S.; Debyser, Z.; Witvrouw, M.; Cotelle, P. Synthesis and Antiviral Properties of Some Polyphenols Related to Salvia Genus. Bioorg. Med. Chem. Lett. 2008, 18 (16), 4736–4740.

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Racanicci, A. M. C.; Danielsen, B.; Skibsted, L. H. Mate (Ilex paraguariensis) as a Source of Water Extractable Antioxidant for Use in Chicken Meat. Eur. Food Res. Technol. 2008, 227 (1), 255–260. Racanicci, A. M. C.; Helene, B.; Skibsted, L. H. Sensory Evaluation of Precooked Chicken Meat with Mate (Ilex paraguariensis ) Added as Antioxidant. Eur. Food Res. Technol. 2009, 229, 277–280. Rocha, D. S.; Model, J. F. A.; Von Dentz, M.; Maschio, J.; Ohlweiler, R.; Lima, M. V.; de Souza, S. K.; Sarapio, E.; Vogt, É. L.; Waszczuk, M.; Martiny, S.; Bassani, V. L.; Kucharski, L. C. Adipose Tissue of Female Wistar Rats Respond to Ilex paraguariensis Treatment After Ovariectomy Surgery. J. Trad. Complement. Med. 2021, 11 (3), 238–248. Rocha, D. S.; Casagrande, L.; Model, J. F. A.; dos Santos, J. T.; Hoefel, A. L.; Kucharski, L. C. Effect of Yerba Mate (Ilex paraguariensis) Extract on the Metabolism of Diabetic Rats. Biomed. Pharmacother. 2018, 105, 370–376. Schinella, G. R.; Troiani, G.; Daávila, V.; De Buschiazzo, P. M.; Tournier, H. A. Antioxidant Effects of an Aqueous Extract of Ilex paraguariensis. Biochem. Biophys. Res. Commun. 2000, 269 (2), 357–360. Signor, P.; Marcolini, M. Diagnóstico Do Consumo Industrial de Erva-Mate No Paraná; Instituto de Florestas Do Paraná, 2017. Valduga, A. T.; Dartora, N.; Mielniczki-pereira, A. A.; De Souza, L. M. Phytochemical Profile of Morphologically Selected Yerba-Mate Progenies. 2016, 40 (1), 114–120. Vargas, B. K.; Frota, E. G.; dos Santos, L. F.; Gutkoski, J. P.; Lopes, S. T.; Bertol, C. D.; Bertolin, T. E. Yerba Mate (Ilex paraguariensis) Microparticles Modulate Antioxidant Markers in the Plasma and Brains of Rats. Food Biosci. 2021, 41, 100999. Zielinski, A. A. F.; Alberti, A.; Bona, E.; Bortolini, D. G.; Benvenutti, L.; Bach, F.; Demiate, I. M.; Nogueira, A. A Multivariate Approach to Differentiate Yerba Mate (Ilex paraguariensis) Commercialized in the Southern Brazil on the Basis of Phenolics, Methylxanthines and In Vitro Antioxidant Activity. Food Sci. Technol. 2020, 40 (3), 645–652.

CHAPTER 2

The Pharmacological Properties of Brazilian Arnica (Solidago chilensis Meyen) FELIPE LIMA PORTO, RAFAEL VRIJDAGS CALADO,

TAYHANA PRISCILA MEDEIROS SOUZA,

JAMYLLE NUNES DE SOUZA FERRO, EMILIANO BARRETO, and

MARIA DANIELMA DOS SANTOS REIS*

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil Corresponding author. E-mail: [email protected]

*

ABSTRACT Solidago chilensis Meyen is a medicinal plant native from South America, popularly known in Brazil as “arnica”. This species is used in folk medicine to treat several diseases such as wound healing, muscle pain and inflammatory diseases. These properties can be associated with the presence of bioactive compounds such as caffeoylquinic acids, flavonoids, and terpenes. Indeed, extracts of different parts of this plant showed anti-inflammatory effects in both in vitro and vivo approaches. Moreover, preclinical studies demonstrated the action of S. chilensis extracts and isolated compounds in nociception, production of reactive oxygen species, gastroprotection, lipid and glucose metabolism, and proliferation of cancer cells, thus, corroborating the popular use of the plant.

Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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2.1 INTRODUCTION Solidago chilensis Meyen, popularly known in Brazil as “arnica,” “arnicabrasileira,” “arnica-silvestre,” “lancet,” “erva-lanceta,” “espiga-ouro,” and “rabo-de-foguete” figures in the National List of Medicinal Plants of Interest to SUS (Brazilian National Public Health System; RENISUS). This plant of the Asteraceae family is native to South America and is present in Northeast, Midwest, Southeast, and South Brazilian regions (Borges and Teles, 2015). It is a subshrub measuring 80–120 cm in height, composed of abundant rhizomes and erect stem, with inflorescences of yellow/golden color, pyramidal or spearhead-shaped at its apical end (Brito et al., 2020; Valverde et al., 2020). Its main synonyms are Solidago linearifolia DC. and Solidago microglossa DC. This species is widely used in folk medicine in the form of maceration, teas, and infusions of leaves, stems, rhizomes, and inflorescences for diverse diseases such as wound healing, muscle pain, inflammatory diseases, respiratory diseases, bruises, bone fractures, gastrointestinal diseases, and rheumatic diseases (Bieski et al., 2015; Tuler and da Silva, 2014; Goleniowski et al., 2006; Magalhães et al., 2019; Ribeiro et al., 2017; Tribess et al., 2015). 2.2 BIOACTIVES The main components found in the hydroalcoholic extract of aerial parts of S. chilensis were caffeoylquinic acids and flavonoids such as rutin, quercetin, and quercitrin (Tamura et al., 2009; Vechia et al., 2016). In the ethanolic extract obtained from the inflorescences were identified the compounds quinic acid, quercetin, chlorogenic acid, hyperoside, and rutin (Vogas et al., 2020). Also, flavonoids derived from quercetin and kaempferol were identified in the ether–ethanol extract obtained from inflorescences (Brito et al., 2020). Terpenes were also identified in this species. The solidagenone is a diterpene abundant in the rhizomes (Schmeda-Hirschmann, 1988). The pumiloxide, a labdane diterpene, was found as the major component of the volatile substances of essential oil (EO) from leaves and inflorescences (Vila et al., 2002). Germacrene D and limolene are the major components in the volatile compounds of the stem, fresh and dry inflorescences (Valverde et al., 2020).

Solidago chilensis Meyen

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PHARMACOLOGY

2.3.1 ANTI-INFLAMMATORY One of the main uses of S. chilensis aqueous extract (AE) is to treat inflammatory disorders. This effect was investigated using in vivo and in vitro preclinical studies. Treatment with the ether–ethanol extract obtained from the inflorescences was able to inhibit the production of nitric oxide (NO) induced by lipopolysaccharide (LPS) in a murine macrophage cell line J774A.1 (Brito et al., 2020). Another in vitro study with the HeLa cell line showed that treatment with this extract exerts an effect on the transcriptional activity of peroxisome proliferator-activated receptor-gamma, a nuclear receptor linked to the anti-inflammatory response (Vogas et al., 2020). The AE of aerial parts, inflorescences, and rhizomes inhibited leukocyte migration and exudation in a carrageenan-induced pleurisy model (Goulart et al., 2007). Neutrophils were the main leukocytes with inhibited migration and this effect was related to decreased levels of myeloperoxidase (MPO), NO, and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-β (IL-1β) (Goulart et al., 2007; Liz et al., 2008). The anti-inflammatory effects of this plant were also demonstrated for the hydroalcoholic extract in an ear inflammation model, in which the topical treatment had a stronger effect than the intraperitoneal route. Moreover, the oral treatment was not able to reduce edema in the ear region, suggesting a poor bioavailability of anti-inflammatory components due to first-pass metabolism or degradation due to the pH of the stomach or intestine (Tamura et al., 2009). This study also observed that the intraperitoneal treatment reduced the migration of polymorphonuclear leukocytes to the site of inflammation, which may explain the reduction in ear edema. Solidagenone diterpene isolated from the rhizomes of S. chilensis inhibited the inflammatory process in several models of ear edema in mice, by decreasing vasodilation, local edema, and leukocyte migration (Valverde et al., 2021). This study also showed that this diterpene interfered with the signaling pathways of inflammatory factors such as cyclooxygenase-1 and prostaglandin E2 9-reductase inhibitors. 2.3.2 ANTINOCICEPTIVE EFFECT The hydroalcoholic extract of aerial parts of the S. chilensis showed antinociceptive activity in animal models such as sensitivity to heat and mechanical

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stimuli, probably by a specific noninflammatory antinociceptive mechanism (Malpezzi-Marinho et al., 2019). The effect on nociception was also verified in the acetic acid-induced writhing test and formalin test in mice. The AE administered orally to mice was able to reduce the licking time in both phases of the formalin test, suggesting an antinociceptive and anti-inflammatory effect (Assini et al., 2013). The volatile fraction of EO extracted from fresh and dry inflorescences were able to reduce around 50% of the writhing in animals; this effect was attributed to limonene and germacrene D compounds present in the fraction (Valverde et al., 2020). In a preliminary clinical study, a decrease in the perception of pain in the hand and wrists was observed in individuals who received an application of the gel containing an alcoholic extract of S. chilensis compared with the placebo group, probably due to an anti-inflammatory action (da Silva et al., 2015). Also, the glycolic extract had a similar effect in the treatment of lumbago, with decreased pain perception in the lumbar region and increased flexibility when compared to the placebo group (da Silva et al., 2010). 2.3.3 ANTIOXIDANT EFFECT The ethanol extract and fractions of S. chilensis had a greater antioxidant activity compared with the antioxidant BHT, that may be due to the presence of flavonoids, which are capable of interrupting radical reactions (Güntner et al., 1999). A tincture with this plant also presented an antioxidant activity through the quantitative 2,2-diphenyl-1-picryl-hydrazyl-hydrate assay (Gastaldi et al., 2016). The AE of the aerial parts of this plant is rich in flavonoids such as quercetin, which would justify the antioxidant effect of this extract (Gastaldi et al., 2018). 2.3.4 ANTIMICROBIAL ACTIVITY The S. chilensis AE was active only against Gram-positive bacteria (Avancini et al., 2008), while, the AE and the butanolic fraction of the rhizome inhibited the growth of Gram-negative bacteria such as Pseudomonas aeruginosa with the minimum inhibitory concentration (MIC) value of 3.1 mg/mL (AE) and 12.5 mg/mL (butanolic fraction, BuOH) and Escherichia coli with a MIC of 6.2 mg/mL for both AE and BuOH (Liz et al., 2009). Also, the alcoholic extract was able to reduce the growth of Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, Acinetobacter baumannii, P.

Solidago chilensis Meyen

19

aeruginosa, and Stenotrophomonas maltophilia (Zampini et al., 2007). The hydroalcoholic extract had strong antimicrobial activity against Staphylococcus aureus with a MIC of 0.1 mg/mL (Duarte et al., 2004). The antifungal effect of EOs from leaves and inflorescences of S. chilensis was demonstrated against the dermatophyte fungi Microsporum gypseum and Trichophyton mentagrophytes, but it was not capable to inhibit the growth of other filamentous fungi. Pumiloxide is likely the phytochemical responsible for this antifungal activity (Vila et al., 2002). 2.3.5 GASTROPROTECTIVE EFFECT S. chilensis AE is used in folk medicine to treat gastrointestinal diseases (Bucciarelli and Skliar, 2007; Goleniowski et al., 2006). In a model of ethanol-induced ulcers in mice of the CF-1 strain, the AE of inflorescences had a gastroprotective effect at doses of 125, 250, and 400 mg/kg compared with the control (omeprazole), although it did not completely inhibit ulcer formation. In two animals, the formation of ulcers was not observed in the animals treated with the doses of 800, 1200, and 2000 mg/kg (Bucciarelli et al., 2010). The methanol extract of this plant also reduced the area of ulcers induced by the administration of ethanol/chloride acid in mice. In addition, there was observed an increase in the levels of the glutathione, decreased activity of MPO and TNF-α levels compared with the control group. These protective effects were attributed to the flavonoids quercetin and afzelin, conferring antisecretory, antioxidant and anti-inflammatory properties (de Barros et al., 2016). Solidagenone may also be responsible for the gastroprotective activity (Schmeda-Hirschmann et al., 2002). This diterpene was able to increase the defensive factors of the gastric mucosa of mice in three different models of gastric ulcer, probably independent of endogenous prostaglandins (Rodríguez et al., 2002). 2.3.6 ANTIDEPRESSIVE EFFECT In a model of LPS-induced depression, solidagenone isolated from S. chilensis leaves was able to reduce depression in mice. This effect was related to the reduction of inflammatory processes, such as the decrease of IL-6 and TNF-α levels and the regulation of antioxidant mechanisms (Locateli et al., 2020).

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2.3.7 HYPOLIPIDEMIC AND HYPOGLYCEMIC EFFECT The hydroalcoholic extract of S. chilensis was tested in rats conditioned to a hyperlipidemic diet. The oral treatment with the compound and also with the isolated flavonoid quercetin diminished the lipid levels in the blood of the animals, possibly by reducing the activity of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase and the antioxidant action (Roman et al., 2015). In addition to the hypolipidemic effect, the rodents submitted to the oral treatment with the extract had increased insulin production and secretion as well as augmented the insulinotropic activity, resulting in a reduction in the glucose levels in the bloodstream (Schneider et al., 2015). 2.3.8 PROLIFERATION, CELL VIABILITY, AND TOXIC EFFECTS No signs of cytotoxicity were found after 24 h of incubation of L929 with the methanolic extract of S. chilensis (de Barros et al., 2016). In another study, Brito and colleagues (2020) observed the cytotoxicity of ether–ethanol extract from the inflorescence in J774A.1 cells. The concentrations of 100 and 200 µg/mL decreased macrophage viability by 71% and 100%, respectively, while other lower concentrations tested (1 and 10 ug/mL) were not toxic, keeping the viability of these cells above 90%. The lyophilized AE of this plant had a great antiproliferative effect in T84 colon adenocarcinoma and HTR/SVneo trophoblast cell lines, with an inhibitory concentration (IC50) of 0.16 ± 0.07 and 0.24 ± 0.03, respectively, with gallic acid being the main responsible for this antiproliferative effect (Gastaldi et al., 2018). Solidagenone, one of the main components of the dichloromethane extract from aerial parts of S. chilensis, also had in vitro antiproliferative effect on tumors cell lines of the breast (MCF-7), kidney (786-0), and prostate cancer (PC-3). These effects are possibly due to the interaction of this compound with nuclear receptors and as an enzyme inhibitor (Gomes et al., 2018). Oral administration of the AE of S. chilensis did not produce histopathological, neuromotor, sensory, or autonomic system changes, thus demonstrating the absence of acute toxicity of this extract (Bucciarelli et al., 2010).

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KEYWORDS

• • • • •

Asteraceae pharmacology inflammation folk medicine arnica-brasileira

REFERENCES Assini, F. L.; Fabrício, E. J.; Lang, K. L. Efeitos farmacológicos do extrato aquoso de Solidago chilensis Meyen em camundongos. Revista Brasileira de Plantas Medicinais 2013, 15 (1), 130–134. Avancini, C.; Wiest, J. M.; Dall’Agnol, R.; Haas, J. S.; von Poser, G. L. Antimicrobial Activity of Plants Used in the Prevention and Control of Bovine Mastitis in Southern Brazil. Lat. Am. J. Pharm. 2008, 27 (6), 894–899. de Barros, M.; Da Silva, L. M.; Boeing, T.; Somensi, L. B.; Cury, B. J.; de Moura Burci, L.; et al. Pharmacological Reports About Gastroprotective Effects of Methanolic Extract from Leaves of Solidago chilensis (Brazilian Arnica) and Its Components Quercitrin and Afzelin in Rodents. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2016, 389 (4), 403–417. Bieski, I. G. C.; Leonti, M.; Arnason, J. T.; Ferrier, J.; Rapinski, M.; Violante, I. M. P.; et al. Ethnobotanical Study of Medicinal Plants by Population of Valley of Juruena Region, Legal Amazon, Mato Grosso, Brazil. J. Ethnopharmacol. 2015, 173, 383–423. Borges, R. A. X.; Teles, A. M. Solidago chilensis Meyen. Lista de Espécies Da Flora Do Brasil. Jardim Botânico Do Rio de Janeiro. 2015. http://floradobrasil.jbrj.gov.br/jabot/ FichaPublicaTaxonUC/FichaPublicaTaxonUC.do?id=FB5503 (accessed on April 21, 2021). Brito, T. M. D.; Amendoeira, F. C.; Oliveira, T. B. D.; Frutuoso, V. D. S.; Ferraris, F. K.; Valverde, S. S. Extract of Solidago chilensis Meyen Inflorescences: Cytotoxicity and Inhibitory Activity on Nitric Oxide Synthesis in Activated Macrophage Cell Line J774A. 1. Braz. J. Pharm. Sci. 2020, 56, e17707. Bucciarelli, A.; Minetti, A.; Milczakowskyg, C.; Skliar, M. Evaluation of Gastroprotective Activity and Acute Toxicity of Solidago chilensis Meyen (Asteraceae). Pharm. Biol. 2010, 48 (9), 1025–1030. Bucciarelli, A. Y.; Skliar, M. I. Plantas medicinales de Argentina con actividad gastroprotectora. Ars. Pharm. 2007, 48 (4), 361–369. Duarte, M. C. T.; Figueira, G. M.; Pereira, B.; Magalhães, P. M.; Delarmelina, C. Atividade antimicrobiana de extratos hidroalcólicos de espécies da coleção de plantas medicinais CPQBA/UNICAMP. Revista Brasileira de Farmacognosia 2004, 14, 6–8. Gastaldi, B.; Assef, Y.; van Baren, C.; Lira, P. D. L.; Retta, D.; Bandoni, A. L.; González, S. B. Antioxidant Activity in Teas, Tinctures and Essential Oils of Native Species from Patagonia Argentina. Rev. Cubana Plantas Med. 2016, 21 (1), 51–62.

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Gastaldi, B.; Marino, G.; Assef, Y.; Sofrás, F. S.; Catalán, C. A. N.; González, S. B. Nutraceutical Properties of Herbal Infusions from Six Native Plants of Argentine Patagonia. Plant Foods Hum. Nutr. 2018, 73 (3), 180–188. Goleniowski, M. E.; Bongiovanni, G. A.; Palacio, L.; Nuñez, C. O.; Cantero, J. J. Medicinal Plants from the “Sierra de Comechingones”, Argentina. J. Ethnopharmacol. 2006, 107 (3), 324–341. Gomes, D. B.; Zanchet, B.; Locateli, G.; Benvenutti, R. C.; Dalla Vechia, C. A.; Schönell, A. P.; et al. Antiproliferative Potential of Solidagenone Isolated of Solidago chilensis. Rev. Bras. Farmacogn. 2018, 28 (6), 703–709. Goulart, S.; Moritz, M. I. G.; Lang, K. L.; Liz, R.; Schenkel, E. P.; Fröde, T. S. AntiInflammatory Evaluation of Solidago chilensis Meyen in a Murine Model of Pleurisy. J. Ethnopharmacol. 2007, 113 (2), 346–353. Güntner, C.; Barra, C.; Cesio, M. V.; Dellacassa, E.; Ferrando, L.; Ferreira, F.; García, C.; González, G.; Heinzen, H.; Lloret, A.; Lorenzo, D.; Menéndez, P.; Paz, D.; Soule, S.; Vázquez, A.; Moyna, P. Antioxidant Properties of Solidago chilensis l. Flavonoids. Acta Hortic. 1999, 501, 159–164. Liz, R.; Neiva, T.; Moritz, M. I. G.; Dalmarco, E. M.; Fröde, T. S. Evaluation of Antimicrobial and Antiplatelet Aggregation Effects of Solidago chilensis Meyen. Int. J. Green Pharm. 2009, 3 (1), 35–39. Liz, R.; Vigil, S. V. G.; Goulart, S.; Moritz, M. I. G.; Schenkel, E. P.; Fröde, T. S. The AntiInflammatory Modulatory Role of Solidago chilensis Meyen in the Murine Model of the Air Pouch. J. Pharm. Pharmacol. 2008, 60 (4), 515–521. Locateli, G.; de Oliveira Alves, B.; Miorando, D.; Ernetti, J.; Alievi, K.; Zilli, G. A. L.; et al. Antidepressant-Like Effects of Solidagenone on Mice with Bacterial Lipopolysaccharide (LPS)-Induced Depression. Behav. Brain Res. 2020, 395, 112863. Magalhães, K. do N.; Guarniz, W. A. S.; Sá, K. M.; Freire, A. B.; Monteiro, M. P.; Nojosa, R. T.; et al. Medicinal Plants of the Caatinga, Northeastern Brazil: Ethnopharmacopeia (1980–1990) of the Late Professor Francisco José de Abreu Matos. J. Ethnopharmacol. 2019, 237, 314–353. Malpezzi-Marinho, E. L.; Molska, G. R.; Freire, L. I.; Silva, C. I.; Tamura, E. K.; Berro, L. F.; et al. Effects of Hydroalcoholic Extract of Solidago chilensis Meyen on Nociception and Hypernociception in Rodents. BMC Complem. Atern. Med. 2019, 19 (1), 1–9. Ribeiro, R. V.; Bieski, I. G. C.; Balogun, S. O.; de Oliveira Martins, D. T. Ethnobotanical Study of Medicinal Plants Used by Ribeirinhos in the North Araguaia Microregion, Mato Grosso, Brazil. J. Ethnopharmacol. 2017, 205, 69–102. Rodríguez, J. A.; Bustamante, C.; Astudillo, L.; Schmeda-Hirschmann, G. Gastroprotective Activity of Solidagenone on Experimentally-Induced Gastric Lesions in Rats. J. Pharm. Pharmacol. 2002, 54 (3), 399–404. Roman Jr., W. A.; Piato, A. L.; Conterato, G. M.; Wildner, S. M.; Marcon, M.; Mocelin, R.; et al. Hypolipidemic Effects of Solidago chilensis Hydroalcoholic Extract and Its Major Isolated Constituent Quercetrin in Cholesterol-Fed Rats. Pharm. Biol. 2015, 53 (10), 1488–1495. Schmeda-Hirschmann, G. S. A Labdan Diterpene from Solidago chilensis Roots. Planta Med. 1988, 54 (2), 179–180. Schmeda-Hirschmann, G.; Rodriguez, J.; Astudillo, L. Gastroprotective Activity of the Diterpene Solidagenone and Its Derivatives on Experimentally Induced Gastric Lesions in Mice. J. Ethnopharmacol. 2002, 81 (1), 111–115.

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Schneider, M.; Sachett, A.; Schönell, A. P.; Ibagy, E.; Fantin, E.; Bevilaqua, F.; et al. Hypoglycemic and Hypolipidemic Effects of Solidago chilensis in Rats. Rev. Bras. Farmacogn. 2015, 25 (3), 258–263. da Silva, A. G.; de Sousa, C. P.; Koehler, J.; Fontana, J.; Christo, A. G.; Guedes-Bruni, R. R. Evaluation of an Extract of Brazilian Arnica (Solidago chilensis Meyen, Asteraceae) in Treating Lumbago. Phytother. Res. 2010, 24 (2), 283–287. da Silva, A. G.; Machado, E. R.; de Almeida, L. M.; Menezes Nunes, R. M.; Giesbrecht, P. C. P.; Costa, R. M.; et al. A Clinical Trial with Brazilian Arnica (Solidago chilensis Meyen) Glycolic Extract in the Treatment of Tendonitis of Flexor and Extensor Tendons of Wrist and Hand. Phytother. Res. 2015, 29 (6), 864–869. Tamura, E. K.; Jimenez, R. S.; Waismam, K.; Gobbo-Neto, L.; Lopes, N. P.; MalpezziMarinho, E. A.; et al. Inhibitory Effects of Solidago chilensis Meyen Hydroalcoholic Extract on Acute Inflammation. J. Ethnopharmacol. 2009, 122 (3), 478–485. Tribess, B.; Pintarelli, G. M.; Bini, L. A.; Camargo, A.; Funez, L. A.; de Gasper, A. L.; Zeni, A. L. B. Ethnobotanical Study of Plants Used for Therapeutic Purposes in the Atlantic Forest Region, Southern Brazil. J. Ethnopharmacol. 2015, 164, 136–146. Tuler, A. C.; da Silva, N. C. Women’s Ethnomedicinal Knowledge in the Rural Community of São José da Figueira, Durandé, Minas Gerais, Brazil. Rev. Bras. Farmacogn. 2014, 24 (2), 159–170. Valverde, S. S.; Santos, B. C. S.; de Oliveira, T. B.; Gonçalves, G. C.; de Sousa, O. V. Solidagenone from Solidago chilensis Meyen Inhibits Skin Inflammation in Experimental Models. Basic Clin. Pharmacol. Toxicol. 2021, 128 (1), 91–102. Valverde, S. S.; Souza, S. P. D.; Oliveira, T. B. D.; Kelly, A. M.; Costa, N. F.; Calheiros, A. S.; et al. Chemical Composition and Antinociceptive Activity of Volatile Fractions of the Aerial Parts of Solidago chilensis (Compositae). Rodriguésia, 2020, 71. Vechia, C. A. D.; Morais, B.; Schonell, A. P.; Diel, K. A. P.; Faust, C.; Menin, C.; et al. Isolamento químico e validação analítica por cromatografia líquida de alta eficiência de quercitrina em Solidago chilensis Meyen (Asteraceae). Rev. Bras. Plantas Med. 2016, 18 (1), 288–296. Vila, R.; Mundina, M.; Tomi, F.; Furlán, R.; Zacchino, S.; Casanova, J.; Cañigueral, S. Composition and Antifungal Activity of the Essential Oil of Solidago chilensis. Planta Med. 2002, 68 (02), 164–167. Vogas, R. S.; Pereira, M.; Duarte, L. S.; Carneiro, M. J.; Farsura, A. F.; Machado, J. A. M.; et al. Evaluation of the Anti-Inflammatory Potential of Solidago microglossa (Arnica-brasileira) In Vivo and Its Effects on PPARγ Activity. An. Acad. Bras. Ciênc. 2020, 92 (2), e20191201. Zampini, I. C.; Cudmani, N.; Islas, M. I. Actividad antimicrobiana de plantas medicinales argentinas sobre bacterias antibiótico-resistentes. Acta Bioquímica Clínica Latinoamericana 2007, 41 (3), 385–393.

CHAPTER 3

Therapeutic Properties of Strychnos nux-vomica L. JATIN AGGARWAL, RIA SINGH, and PRIYADARSHINI* Department of Biotechnology, Jaypee Institute of Information Technology, A-10 Sector 62, Noida, Uttar Pradesh 201309, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Strychnos nux-vomica L. is native to Asian countries. The vast therapeutic properties of the S. nux-vomica had always attracted scientific interest. The seed of the plant that is rich in various phytocompounds of therapeutic importance. HPTLC technique had shown the existence of tannin, alkaloid, carbohydrate, triterpenoid, steroid, and glycoside in the hydroalcoholic extract of the plant seeds. The plant extract has various therapeutic properties like anti-inflammatory, analgesic, and antiallergic and antimicrobial activity. 3.1 INTRODUCTION Strychnos nux-vomica L. is a shrub of family Loganiaceae, and is native to Asian countries including Sri Lanka, India, China, and Oceania continent Australia. It usually attains the height of 5–25 m. The leaves are opposite to each other with decussate arrangement and are papery, with suborbicular blade (Guo et al., 2018). The ripe fruit pod with maximum of five seeds is hard when dried with around 1.5–3 cm diameter and 3–6 mm thickness. The embryo is housed in horny endosperm, usually grey in color and have bitter taste but no odor (Guo et al., 2018). In India, the plant is known as kuchla (Bhati et al., 2012). Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Being a commonly used plant in Chinese herbal medicine, the plant is well documented in the pharmacopeia of China for its therapeutic properties including treatment of diabetes, asthma, aphrodisiac, and to improve appetite, along with alleviating pain and swelling (Bhati et al., 2012; Guo et al., 2018). Owing to the diversities of phytoconstituents present in the plant, it had been validated for treatment of various disorders including cancer, cardiovascular diseases, inflammatory responses, and infection from microbial pathogens (Patel et al., 2017). It is the seed of the plant that is rich in various phytocompounds of therapeutic importance, and is called Nux vomica. The plant regulates the peristaltic movement of bowel associated with nutrient absorption. Such important action helps in preventing diarrhea. However, such studies are limited to animals and not human. The plant is having extensive and diverse use in South Asian subcontinent, especially India. According to reports from Kumar and Sinha (2009), nux vomica is utilized in more than 60 formulations of Indian systems of medicine of which 30 formulations are used in the disorders of vata dosha (Kumar and Sinha, 2009). 3.2 PHYTOCOMPOUNDS OF S. NUX-VOMICA The phytocompounds in the seeds are also of high therapeutic potential. The seeds extracts are observed to be rich in alkaloids. Some of the major constituents are phytocompounds, strychnine, and brucine (Kumar and Sinha, 2009). Some of the alkaloids present in minor amount in the seeds are protostrychnine, vomicine, n-oxystrychnine, pseudostrychnine, isostrychnine, chlorogenic acid, and a glycoside (Bhati et al., 2012). Maji et al. (2017) had compiled an excellent review on the phytocompounds of the plant their therapeutic potential. Some of the active phytocompounds, isolated from various plant parts and documented are tabulated in Table 3.1. According to Chinese pharmacopeia, the content of strychnine must be between 1.20% and 2.20%, and brucine equal to or more than 0.80%, in Nux vomica (Guo et al., 2018). Brucine and strychnine are two of the important active phytoconstituents of this plant, which stimulate central nervous system, but are toxic (Kushwaha et al., 2014; Patel et al., 2017). The poisonous compounds are not only limited to the seeds of the plants but are also found in leaves and barks of the tree. Zhao et al. (2016) study on the toxicity of the plant extract on zebrafish showed ill effect on several organs including heart, liver, brain, and kidney. Though S. nux-vomica induced cardiotoxicity was

Phytoconstituents of Strychnos nux-vomica L, and the Plant Parts from Which They Are Extracted. Chemical Nature Indole alkaloid

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Indole alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid

Brucine Pseudostrychnine Pseudobrucine β-colubrine α-colubrin Strychnine N-oxide Brucine N-oxide 2-hydroxy-3-methoxystrychnine 15-hydroxystrychnine 15-acetoxystrychnine 3-hydroxy-α-colubrine 3-hydroxy-β-colubrine Isostrychnine Isobrucine Isobrucine N-oxide Isostrychnine N-oxide Icajine Vomicine Novacine 15-hydroxyicajine 3-methoxyicajine Sungucine Isosungucine Protostrychnine Diaboline

Site of localization in plant Seeds (contain 1.25–1.5%), bark, fruit pericarp Seeds (contain 1.7%), bark Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Major/Minor phytoconstituents Major

References

Major Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor Minor

Daniel (2006) Kumar and Sinha (2009) Schmelzer and Gurib-Fakim (2008) Kushwaha et al. (2014) Iwu (2014) Bhati et al. (2012) Galeffi et al. (1979) Cai et al. (1998) Frederich et al. (2004) Xu et al. (2009) Zhang et al. (2012) Shi et al. (2014) Yang et al. (2010) Zhao et al. (2012) Fu et al. (2012) Zhang et al. (2003) Bisset and Choudhury (1974) Bisset et al. (1989) Thambi and Cherian (2015) Biala et al. (1998) Monache et al. (1968) Jonville et al. (2013) Baser et al. (1979) Baser and Bisset (1982) Quirin et al. (1965)

Patel et al. (2012), Sukul et al. (2001)

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S. Phytoconstituents No 1 Strychnine

Strychnos nux-vomica L.

TABLE 3.1

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reversible to some extent. Study from Ponraj et al. (2017) had reported the mild strychnine poisoning in patient with bradycardia. Studies by Cai et al. (1998) had reported that the IC50 of processed seeds were relatively higher than the unprocessed seeds in cell growth-inhibition assay against Vero cells. The vast therapeutic properties of the S. nux-vomica had always attracted scientific interest. Studies by Patel et al. (2012), using HPTLC technique, had shown the existence of tannin, alkaloid, carbohydrate, triterpenoid, steroid, and glycoside in the hydroalcoholic extract of the plant seeds. As per US Pharmacopeia, the alkaloid content should not be 1000 µg/mL) (Al Sobeai, 2016). The mean CC50 value of methanol, ethanol, and aqueous extract was lower than 1000 µg/mL. An acute toxicity screening made by Shah et al. (2014) showed that the mices treated for 24 h were alive with no mortality. But the mice showed less locomotor activity with a 3 g/kg body weight. Their study also showed that chronic toxicity on 40 Swiss albino mice which exposed to 100 mg/kg/day of A. hierochuntica ethanol extract in drinking water. The result showed that all the treated mice were healthy and active. The animal parts were not infected or affected by any toxicity during this period of study. The blood analysis indicated that white cells, red blood cells, hemoglobin, and platelets showed no significant deviations. And other parameters in biochemical assay also show no fetal toxicity effects. Rasheed et al. (1997) demonstrated an increased incidence of fetal resorption rate of 11 out of 105 resorptions of the total fetuses examined in the high dose group (4 g/kg). A higher incidence of anencephaly was also reported in the fetuses of mice treated with 0.25, 1, and 4 g/kg. KEYWORDS • • • • •

Brassicaceae Kaff Maryam monotypic taxon pharmacology review 

Anastatica hierochuntica L.

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REFERENCES

Abdulfattah, S. Y. Study of the Immunological Effect of Anastatica hierochuntica (Kaff Maryam) Plant Methanolic Extract on Albino Male Mice. J. Biotechnol. Res. Center. 2013, 7 (2), 3–10. Abou-Elella, F.; Hanafy, E. A.; Gavamukulya, Y. Determination of Antioxidant and AntiInflammatory Activities, as well as In Vitro Cytotoxic Activities of Extracts of Anastatica hierochuntica (Kaff Maryam) Against HeLa Cell Lines. J. Med. Plants Res. 2016, 10 (7), 77–87. Abou-Mandour, A. A.; Hartung, W. Tissue Culture of the Desert Plant Anastatica hierochuntica. Plant Cell Rep. 1995, 14, 657. AlGamdi, N.; Mullen, W.; Crozier, A. Tea Prepared from Anastatica hierochuntica Seeds Contains a Diversity of Antioxidant Flavonoids, Chlorogenic Acids and Phenolic Compounds. Phytochemistry 2011, 72 (2–3), 248–254. Al-Ghanayem, A. A.; Al Sobeai, S. M.; Alhussaini, A. S.; Joseph, B.; Saadabi, A. M. Antifungal Activity of Anastatica hierochuntica L. Extracts Against Different Groups of Fungal Pathogens: An In-Vitro Test. Rom. Biotechnol. Lett. 2018, 23 (6), 14135–14139. Al Sobeai, S. M. In Vitro Cytotoxxicity and Antibacterial Evaluation of Aqueous, Methanolic and Ethanolic Extracts of Anastatica hierochuntica Against Pathogenic Bacteria. Int. J. Curr. Res. Biosc. Plant Biol. 2016, 3 (6), 14–22. Batanouny, K. H. Wild Medicinal Plants in Egypt; The Palm Press: Cairo, 1999; p 207. Daoowd, W. S. In Vitro Antifungal Activity of Extracts of Anastatica hierochuntica. Kufa J. Vet. Med. Sci. 2013, 4 (1), 142–148. Daur, I. Chemical Properties of the Medicinal Herb Kaff Maryam (Anastatica hierochuntica L.) and Its Relation to Folk Medicine Use. Afr. J. Microbiol. Res. 2012, 6 (23), 5048–5051. El Ghazali, G. E.; Al-Khalifa, K. S.; Saleem, G. A.; Abdallah, E. M. Traditional Medicinal Plants Indigenous to Al-Rass Province. Saudi Arabia. J. Med. Plants Res. 2010, 4 (24), 2680–2683. El-Sayed, M.; El-Sherif, F.; Elhassaneen, Y.; El-Rahman, A. A. Potential Therapeutic Effects of Some Egyptian Plant Parts on Hepatic Toxicity Induced by Carbon Tetrachloride in Rats. Life Sci. J. 2012, 9 (4), 3747–3755. Eman, A. S.; Tailang, M.; Benyounes, S.; Gauthaman, K. Antimalarial and Hepatoprotective Effects of Entire Plants of Anastatica hierochuntica. Int. J. Res. Phytochem. Pharmacol. 2011, 1, 24–27. Farid, C. G.; Law. K. S. The True Rose of Jericho (Anastatica heirochuntica L.): UltraStructural Finding and Suggestion of Its Medicinal Properties. Malays. J. Microscope. 2009, 5 (1), 19–26. Friedman, J.; Stein, Z. The Influence of Seed-Dispersal Mechanisms on the Dispersion of Anastatica hierochuntica (Cruciferae) in the Negev Desert. Israel J. Ecology. 1980, 43–50. Hajjar, D.; Kremb, S; SIoud, S.; Emwas, A. H.; Voolstra, C. R.; Ravasi, T. Anti-Cancer Agents in Saudi Arabian Herbals Revealed by Automated High-Content Imaging. PLoS ONE. 2017, 12, e0177316. Hansen, M. Pathophysiology: Foundations of Diseases and Clinical Intervention; W. B. Saunders Company: Philadelphia, U.S.A., 1998; pp 851–852. Hashim, N. E.; Mohamed, Z. Biological Activities of Anastatica hierochuntica L.: A Systematic Review. Biomed. Pharmacother. 2017, 91, 611–620.

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Havsteen, B. H. The Biochemistry and Medical Significance of the Flavonoids. Pharmacol. Ther. 2002, 96 (2), 67–202. Jacob, F.; Zipporah, S. The Influence of Seed Dispersal Mechanisms on the Dispersion of Anastatica hierochuntica (Cruciferae) in the Negev Desert, Israel. J. Ecology 1980, 68 (1), 43–50. Jaradat, N. Ethnopharmacological Survey of Natural Products in Palestine. An-Najah Univ. J. Res. 2005, 19, 13–67. Karadaş, C.; Kara, D. Chemometric Approach to Evaluate Trace Metal Concentrations in Some Spices and Herbs. Food Chem. 2012, 130, 196–202. Khalifa, T. I. M. A. A Pharmacognostical Study of Certain Species of Anastatica; Ph.D Thesis, University of Cairo, Egypt, 1980. Knight, S., Devotion, Popular Belief and Sympathetic Magic Among Renaissance Italian Women: the Rose of Jericho as Birthing Aid. Stud. Church Hist. 2010, 46, 134–143. Law, K. S.; Soon, L. K.; Mohsin, S. S. S.; Farid, C. G. Ultrastructural Findings of Anastatica hierochuntica L., (Sanggul Fatimah) Towards Explaining Its Medicinal Properties. Ann. Microsc. 2009, 9, 50–56. Marzouk, M. M.; Abdel-Salam, M.; Al-Nowaihi.; Kawashty, S. A.; Saleh, N. A. M. Chemosystematic Studies on Certain Species of the Family Brassicaceae (Cruciferae) in Egypt. Biochem. Systemat. Ecol. 2010, 38, 680–685. Mohamed, A. A.; Khalil, A. A.; El-Beltagi, H. E. S. Antioxidant and Antimicrobial Properties of Kaff Maryam (Anastatica hierochuntica) and Doum Palm (Hyphaene thebaica). Grasas Y Aceites. 2010, 61 (1), 67–75. DOI: 10.3989/gya.064509. Mossa, J. S.; Al-Yahya, M. A.; Al-Meshal, I. Medicinal Plant of Saudi Arabia; King Saud University: Riyadh, 1987. Nakashima, S. H.; Matsuda, Y.; Oda, S.; Nakamura, F. M.; Xu, M.; Yoshikawa, Melanogenesis inhibitors from the desert plant Anastatica hierochuntica in B16 melanoma cells. Bioorgan Med. Chem. 2010, 18 (6), 2337–2345. Nani, D. Pengaruh air rendaman Rumput Fatimah (Anastatica hierochuntica L.) terhadap frekuensi kontraksi uterus tikus galur sprague dawley pada fase estrus. J. Keperawatan Soedirman. 2009, 4 (1), 1–8. Nani, D. Perubahan amplitudo kontraksi otot uterus tikus akibat pemberian Rumput Fatimah (Anastatica hierochuntica L.). Mandala Health 2010, 4 (1), 47–52. Nasir, E.; Ali, S. I. Flora of Pakistan; University of Karachi: Islamabad, Pakistan, 1980; pp 1010–4100. Qnais, E.; Modallal, N.; Bseiso, Y.; Wedyan, M.; Alkhateeb, H. Evalution of the Antinociceptive Effects of the Essential Oil from Aerial Parts of Anastatica hierochuntica in Experimental Models. Pharmacol. Online. 2017, 3, 112–122. Rahmy, T. R.; El-Ridi, M. R. Action of Anastatica hierochuntica Plant Extract on Islets of Langerhans in Normal and Diabetic Rats. Egypt. J. Biol. 2002, 4, 87–94. Rameshbabu, S.; Messaoudi, A.; Alehaideb, Z. I., ALi, M. S.; Venktraman, A.; Alajmi, H.; Al-Eidi, H.; Matou-Nasri, S. Anastatica hierochuntica (L.) Methanolic and Aqueous Extracts Exert Antiproliferative Effects Through the Induction of Apoptosis in MCF-7 Breast Cancer Cells. Saudi Pharm. J. 2020, S1319-0164(20)30146-8 Rasheed, R. A.; Bashir, A. K.; Ali, B. H. Fetal Toxicity of Anastatica hierochuntica L. in Mice. FASEB J. 1997, 11 (3), 2413–2413.

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Rizk, A. M.; Hammouda, F. M.; Ismail, S. I.; Hassan, N. M.; Ahmed, F. A. Constituents of Plants Growing in Qatar XX. Phytochemical Investigation of Anastatica hierochuntica: Note. Int. J. Pharmacogn. 2008, 31, 327–329. Rizk, A. M., Williamson, E. M.; Evans, F. J. Constituents of Plants Growing in Qatar VII an Examination of Certain Plants for Anti-Inflammatory Activity. Pharm. Biol. 1985, 23 (1), 1–4. Salah, S.; Abdou, H. S.; El-Azeem, A. S. A. B. D.; Abdel-Rahim, E. A. The Antioxidative Effects of Some Medicinal Plants as Hypoglycemic Agents on Chromosomal Aberration and Abnormal Nucleic Acids Metabolism Produced by Diabetes Stress in Male Adult Albino Rats. J. Diabetes Mellit. 2011, 1 (1), 6–14. DOI: 10.4236/jdm.2011.11002. Sennoune, S.; Gerbi, A.; Duran, M. J.; Benkoel, L.; Pierre, S.; Lambert, R.; et al. A Quantitative Immunocytochemical Study of Na+, K+ATPase in Rat Hepatocytes After STZ-Induced Diabetes and Determination of Blood Glucose Using an Oxidase-Peroxidase System: A Non Carcinogenic Chromagen. Am. Clin. Biochem. 1999, 6, 24–30. Shaban, F.; Al-Azzawie, H. F.; Mohammed, A. S. Effect of Alcoholic Anastatica hierochuntica Extract on some Biochemical and Histological Parameters in Alloxan Induced Diabetic Rats. Iraqi J. Sci. 2011, 52 (4), 445–455. Shah, A. H.; Bhandari, M. P.; N. O.; Al-Harbi, R. M.; Al-Ashban. Kaff-E-Maryam (Anastatica hierochuntica L.): Evaluation of Gastro-Protective Activity and Toxicity in Different Experimental Models. Biol. Med. 2014, 6 (197), 1–10. Sobhy, E. A.; Tailang, M.; Benyounes, S.; Gauthaman, K. Antimalarial and Hepatoprotective Effects of Entire Plants of Anastatic hierochuntica. Int. J. Res. Phytochem. Pharmacol. 2011, 1 (1), 24–27. Sooi, L. K.; Keng, S. L. Herbal Medicines: Malaysian Women’s Knowledge and Practice. Evid. Based Compl. Alt. Med. 2013, 1–10. Soong, Y. Y.; Barlow, P. J. Antioxidant Activity and Phenolic Content of Selected Fruit Seeds. Food Chem. 2004, 88 (3), 411–417. Tayel, A. A.; El-Tras, W. F. Possibility of Fighting Food Borne Bacterial by Egyptian Folk Medicinal Herbs and Spices Extracts. Egypt Public Health Assoc. 2009, 84 (1–2), 21–32. Van Oudtshoom, R. K.; Van Rooyen, M. W. Dispersal Biology of Desert Plants; SpringerVerlag: Berlin, Germany; 1999. Yoshikawa, M.; Morikawa, T.; Xu, F.; Ando, S.; Matsuda, H. (7R 8S) and (7S, 8R) 8-50 Linked Neolignans from Egyptian Herbal Medicine Anastatica hierochuntica and Inhibitory Activities of Lignans on Nitric Oxide Production. Heterocycles 2003b, 60, 1787–1792. Yoshikawa, M.; Xu, F.; Morikawa, T.; Ninomiya, K.; Matsuda, H. Anastatins A and b New Skeletal Flavonoids with Hepatoprotective Activities from the Desert Plant Anastatica hierochuntica. Bioorg. Med. Chem. Lett. 2003a, 13 (6), 1045–1049. Zin, S. R.; Kassim, N. M.; Alshawsh, M. A.; Hashim, N. E.; Mohamed, Z. Biological Activities of Anastatica hierochuntica L: A Systematic Review. Biomed. Pharmacother. 2017, 91, 611–620.

CHAPTER 6

Naphthalene—Isoquinoline Group of Alkaloid from Monotypic Family Ancistrocladaceae VINAYAK UPADHYA1 and SANDEEP RAMCHANDRA PAI2* Department of Forest Products and Utilization, College of Forestry (University of Agricultural Sciences, Dharwad), Sirsi, Uttara Kannada, Karnataka 581401, India

1

Department of Botany, Rayat Shikshan Sanstha’s Dada Patil Mahavidyalaya, Karjat, District Ahmednagar, Maharashtra 414402, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Ancistrocladus, a genus of monotypic family Ancistrocladaceae, comprises of ~25 species distributed in tropical Asia, Malaysia and West Africa. The genus is considered important due to its spending antimalarial, anti-HIV, antileishmanial, and a wide array of bioactivities. Most of the activities are attributed to a novel class of alkaloids categorised as naphthalene- isoquinoline. The current chapter is a comprehensive compilation of the family Ancistrocladaceae with respect to its distribution, bioactives and pharmacology. It can be inferred that more studies on bioactives from the family will help understand its extended use in pharmaceutical industries.

Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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6.1 INTRODUCTION Ancistrocladus, a genus of monotypic family Ancistrocladaceae, comprises ~25 species distributed in Tropical Asia, Malaysia, and West Africa. The family consists of a single genus, Ancistrocladus, and about 25 species of lianas, found in the tropics of the old world (Table 6.1). TABLE 6.1 Sr. no. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

Distribution of Ancistrocladus Species.

Species

Distribution

Ancistrocladus abbreviatus Ancistrocladus attenuatus Ancistrocladus barteri Ancistrocladus benomensis Ancistrocladus carallioides Ancistrocladus cochinchinensis Ancistrocladus congolensis Ancistrocladus ealaensis Ancistrocladus extensus Ancistrocladus griffithii Ancistrocladus guineensis Ancistrocladus hainanensis Ancistrocladus hamatus Ancistrocladus harmandii Ancistrocladus heyneanus Ancistrocladus korupensis Ancistrocladu sletestui Ancistrocladus likoko Ancistrocladus pachyrrhachis Ancistrocladus robertsoniorum Ancistrocladus stelligerus Ancistrocladus tanzaniensis Ancistrocladus tectorius Ancistrocladus uncinatus Ancistrocladus wallichii

Ivory Coast (Africa) Burma (Asia) Ivory Coast (Africa) Malaysia (Asia) Thailand (Asia) Vietnam (Asia) Congo (Africa) Congo (Africa) Burma (Asia) Thailand (Asia) Nigeria (Africa) China (Asia) Sri Lanka (Asia) Laos (Asia) India (Asia) Cameroon (Africa) Congo (Africa) Congo (Africa) Liberia (Africa) Kenya (Asia) Burma (Asia) Tanzania (Africa) China, Laos, Malaysia, Thailand (Asia) Nigeria (Africa) Sri Lanka (Asia)

A. heyneanus Wall. ex Grah. is a scandent shrub, with hooked branches, leaves are deep green, oblanceolate-oblong, subacute, glabrous, shining, and narrowed at base. Flowers are small, caducous, calyx lobes enlarged

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into fruits, obovate, cuneate, with prominently reticulate veins. The genus is endangered and endemic to the Western Ghats of India distributed in Konkan: Matheran, Pen, Thana, Khandala, Parghat, Ramghat, and Kanara, and in evergreen forests of North Kanara. Ramamoorthy (1976) suggested that A. heynenaus may be the taxonomic synonym of A. hamatus and the same with reference to Ramamoorthy’s publication has been mentioned by Gereau (1997). This may be probably because of the similarities in the habit of both the plants and its distribution. Ancistrocladus heyenanus is endemic to the Western Ghats of India, whereas A. hamatus is found in Sri Lanka. The Western Ghats of India and Sri Lanka is time and again considered as a single component for the reason that they share biogeographical history (Gunawardene et al., 2007). Thus, the suggestion made by Ramamoorthy should not be sidelined and should be restudied for the possible merging of the two. Previous reports indicated the curative potential of crude extract of roots, leaves, and stems of Ancistrocladus spp. in various ailments, such as dysentery, fever, diarrhea, malaria, etc. (Ruangrungsi et al., 1985; Bringmann et al., 1990). In Thailand, young leaves are used as food juice flavor (Burkill, 1966; Usher, 1974). Few of the other related studies present the optimization of extraction techniques for the quantification of betulinic acid in A. heyneanus (Pai et al., 2011). 6.2 BIOACTIVES The genus is a source of a novel group of alkaloids known as naphthaleneisoquinolines (Govindachari and Parthasarathy, 1977; Cordell, 1981). Michellamines A, B (Manfredi, 1991), and D–F (Hallock et al., 1997), a group of dimeric napthylisoquinoline alkaloid has shown to have promising anti-human immunodeficiency virus (HIV) activity. These michellamines have been reported from other species of Ancistrocladus; however, there were no reports of michellamines confirming from A. heynenaus. Hallock et al. (1994, 1997) reported new “monomeric” alkaloids, korupensamines A–E, and the related N–methyltetrahydroisoquinoine. Napthylisoquinoline alkaloids can be divided into subtypes according to the linkage between their napthyl and isoquioline moieties. Some of these alkaloids have antifungal, antimalarial, or antiviral activity (Bringmann et al., 1992; Francois et al., 1994, 1996; Boyd et al., 1994). Bringmann et al. (2003) described the isolation and structural elucidation of a bioactive alkaloid ancistrolikokine D,

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ancistroealanine A, and napthoic acid derivatives. Bringmann and co-workers (1998) reported polyketide folding mode in isoshinanolone and plumbagin biosynthesis from A. heynenaus. The napthylisoquinoline alkaloids constitute structurally, biosynthetically, and pharmacologically useful biaryls. About 120 alkaloids belonging to this category have been isolated so far and all of them from the family Ancistrocladaceae and Dionocophyllaceae, serving them as phytochemical markers. A. heyneanus is indigenous to India (Bringmann et al., 2004; Govindachari, 2002). It is a tropical liana distributed in the Western Ghats of India. Following are the different metabolites studied in A. heyneanus (Table 6.2). TABLE 6.2 Metabolites Produced in Different Parts of A. heyneanus and Methods Used in Their Detection and Structural Elucidation. Metabolite Ancistrocladine Ancistrocladisine Ancistrocladidine Ancistroheynine A Betulinic acid

Couplinga Plant parts 5,1′ Root C-7 and C-1′ 7,3′ C-7 and C-8′ –

Ancisheynine

C-8′ and N-2 Ancistrocladidine 7,3′ Ancistrotanzanine C 7,3′ Ancistroheynine B 7,3′

References

Method usedb

Govindachari and NMR, IR, MS, Parthasarathy (1970) FT-Raman Root Govindachari et al. (1972) NMR, IR, MS, FT-Raman Root Govindachari et al. (1973) NMR, GC-MSD, IR, CD, FT-Raman Shoot Bringmann et al. (1996) HPLC, IR, GC, NMR, FT-Raman Aerial Bringmann et al. (1997) NMR, IR, MS parts Shoot Yang et al. (2003) NMR, ROESY Leaves Bringmann et al. (2004) NMR, GC-MSD, IR, CD Leaves Bringamann et al. (2004) NMR, GC-MSD, IR, CD Leaves Bringamann et al. (2004) NMR, GC-MSD, IR, CD

Coupling of naphthalene with isoquinoline.

Methods used by different workers for detection and structural elucidation of metabolites.

a

b

6.3 PHARMACOLOGY 6.3.1 ANTIVIRAL ACTIVITY A. heyneanus plant extracts were active on Herpes simplex Virus Type 1 at 50 µg/mL (Silva et al., 1997). Betulinic acid from the plant is reported

CH3

H

H3C

H

H2C

H

H

O

CH3

Ancisheynine

Ancistrocladisine

Compounds from Ancistrocladus heyneanus.

Betulinic Acid

H

FIGURE 6.1

H

O

H3C

H3C

H3C

O

Ancistrocladine O

H O

H O

CH3

O

CH3

CH3

N

CH3

CH3

Ancistrotanzanine C

H3C

Ancistrocladidine

Ancistroheynine B

Ancistroheynine A

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to inhibit HIV (Bringmann et al., 1997; Singh et al., 2005). In the 1990s, a new dimension toward pharmacological activity of this small family arose by the identification of michellamines from A. korupensis (Boyd et al., 1994). These were the first dimericnaphthylisoquinolines (NIQ) with strong anticytopathic activities against the HIV. However, author has not found any direct reference of the presence of michellamine in A. heyneanus. 6.3.2 ANTIBACTERIAL ACTIVITY Aswathanarayan and Rai (2013) reported marked antibacterial activity against food-related bacteria Escherichia coli and Salmonella typhi of A. heyneanus and Rotula aquatica. Crude extracts as well as isolated alkaloid fractions of A. heyneanus showed considerable activity against Gram-positive bacteria but not against Gram-negative bacteria (More et al., 2012). 6.3.3 ANTIOXIDANT EFFICACY Antioxidant efficacy of A. heyneanus along with R. aquatica was reported by Aswathanarayan and Rai (2013). They reported significant antioxidant activity determined by total antioxidant capacity, ABTS, DPPH free radical scavenging activities, inhibitory activity toward β-carotene bleaching, lipid peroxidation, and DNA protection activity. 6.3.4 ANTIMALARIAL ACTIVITY Antiplasmodial activity of extracts of A. abbreviatus, A. barteri, Triphyophyllum peltatum (Francois et al., 1994, 1995), A. barteri, A. heyneanus, A. robertsoniorum, A. tectorius, and T. peltatum (Francois et al., 1997) has displayed considerable activity against Plasmodium falciparum and P. berghei, accentuating its potential antimalarial value. Betulinic acid has been reported to exhibit a wide array of biological properties. Bringmann et al. (1997) reported moderate antiplasmodial in vitro activity with IC50 value 10.46 pg/ml of betulinic acid against malaria. Also, in a separate study by François et al. (1997) similar in vitro activity against P. falciparum has been demonstrated. Similar activity has also been demonstrated in various new compounds identified under NIQ, namley, Ancisheynine A, ancistroheynine A, B, ancistrocladidine, ancistrotanzanine from A. heyneanus (Bringmann

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et al., 1996; Yang et al., 2003; Bringmann et al., 2004) suggesting the plant to be a source of antimalarial and antiviral compounds. Ancistrocladus robertsoniorum, an East African liana, was reported with four new naphthylisoquinoline alkaloids ancistrobertsonines B, C ancistrobertsonine D, and its 1,2-didehydro analog possessing moderate antimalarial activity (Bringmann et al., 1999). 6.3.5 ANTITRYPANOSOMAL AND ANTILEISHMANIAL ACTIVITIES The plant has also been studied for antitrypanosomal and antileishmanial activities (Bringmann et al., 2004). Apart from the above, a Chinese species A. tectorius is also reported to have such activity due to their phytocompounds, namely, ancistectorine A1, N-methylancistectorine A1, ancistectorine A2, 5-epi-ancistectorine A2, ancistectorine A3, ancistectorine B1, and ancistectorine C1 (Bringmann et al., 2012). Similar reports of chemical compounds from the same group have been reported in Ancistrocladus congolensis, against protozoan parasites causing severe tropical diseases (Bringmann et al., 2008). Scotti et al. (2016) reviewed natural products for antileishmanial and antitrypanosomal activity, it includes plants from the family Menispermaceae, Celastraceae, Malvaceae, Euphorbiaceae, Rubiaceae, Papaveraceae, Apocynaceae, Ancistrocladaceae, Rutaceae, Annonaceae, and Amaryllidaceae. In a separate review, Veigaco workers (2020) enlisted several species along with Ancistrocladus species as antileishmanial potential alkaloids. 6.3.6 ANTICANCER ACTIVITY Betulinic acid, a naturally occurring pentacyclictriterpene, has also been reported to show potential antitumor effects. Kuo et al. (2009) also reported a group of terrestrial plants possessing such activity, and A. heyneanus was among them. Antitumoral activity of A. tectorius is reported by Bringmann and co-workers (2013). 6.4 CONCLUSION A. heyneanus is the only member of the family Ancistrocladaceae available in the Indian subcontinent. Identification issues with Sri Lankan species A. hamatus needs more studies and clarification. The plant is a source of

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novel napthylisoquinolinealkaloids. Pharmacologically, the plant has been widely explored for its anti-HIV, antimalarial, antitrypanozomal, and antileishmanial properties. Antioxidant and antimicrobial activities are few others to be named that are explored very recently. Due to its wide array of phytocompounds, it will be interesting to study more biological activities. Antifungal, hepatoprotective, antidiabetic, and cardioprotective are some of the other activities that need to be studied and reported. ACKNOWLEDGMENT Authors are indebted to their respective Head of the Institutions. KEYWORDS • • • • •

napthalene-isoquinoline alkaloids Ancistrocladaceae bioactives pharmacology

REFERENCES Aswathanarayan, J. B.; Rai, R. V. In Vitro Evaluation of Antioxidant and Antibacterial Activities of Rotula aquatica and Ancistrocladus heyneanus: Antioxidant and Antimicrobial Activity of Medicinal Plants. J. Pharm. Res. 2013, 6 (2), 313–317. Boyd, M. R.; Hallock, Y. F.; Cardellina, J. H. II; Manfredi, K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit, R. W.Jr.; Bringmann, G.; Schaffer, M.; Gragg, G. M.; Thomas, D. W.; Jato, J. G. Anti-HIV Michellamines from Ancistrocladus korupensis. J. Med. Chem.1994, 37, 1740–1745. Bringmann, G.; AkeAssi, L.; Rubenacker, M.; Ammermann, E.; Lorenz G. D. O. S. DE Appl. 4117080 A1, 1991; European Patent Application EP 0515 856 A1, 1992. Bringmann, G.; Dreyer, M.; Michel, M.; Tayman, F. S. K.; Brun, R. Ancistroheynine B and Two Further 7,30-Coupled Naphthylisoquinoline Alkaloids from Ancistrocladus heyneanus Wall. Phytochem 2004, 65, 2903–2907. Bringmann, G.; Koppler, T. D.; Wiesen, B.; Francois, G.; Sankara Narayanan, A. S.; Almeida, M. R.; Schneider, H.; Zimmermann, U. Ancistroheynine A, the first 7,8′-Coupled

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Naphthylisoquinoline Alkaloids from Ancistrocladus heyneanus. Phytochemistry 1996, 43, 1405–1410. Bringmann, G.; Pokorny, F.;Reuscher, H.; Lisch, D.; Assi, L. Novel Ancistrocladaceae and Dioncophyllaceae Type Naphthyliosquinoline Alkaloids from Ancistrocladus abbreviatus: A Phylogenetic Link Between the Two Families? Planta Med. 1990, 56, 496–497. Bringmann, G.; Saeb, W.; Rückert, M.; Mies, J.; Michel M.; Mudogo V.; Brun R. Ancistrolikokine D, a 5,8′-Coupled Naphthylisoquinoline Alkaloid, and Related Natural Products from Ancistrocladus likoko. Phytochemistry 2003, 62, 631–636. Bringmann, G.; Teltschik, F.; Michel, M.; Busemann, S.; Ruckert, M.; Haller, R.; Bars Robertson, S. A.; Kaminsky, R. Ancistrobertsonines B, C, and D as well as 1, 2— Didehydroancistrobertsonine D from Ancistrocladus robertsoniorum. Phytochemistry 1999, 52, 321–332. Bringmann, G.; Zhang, G.; Ölschläger, T.; Stich, A.; Wud, J.;Chatterjee, M.; Brun, R. Highly Selective Antiplasmodial Naphthylisoquinoline Alkaloids from Ancistrocladus tectorius. Phytochemistry 2013, 91, 220−228. Bringmann G.; Spuziak J.; Faber, J. S.; Gulder, T.; Kajahn, I.; Dreyer, M.; Heubl, G.; Brun, R.; Mudogo V. Six Naphthylisoquinoline Alkaloids and a Related Benzopyranone from a Congolese Ancistrocladus Species Related to Ancistrocladus congolensis. Phytochemistry 2008, 69 (4), 1065–1075. Bringmann, G.; Saeb, W.; Assi, L.; Francois, G.; Sankara Narayanan, A. S.; Peters, K.; Peters, E. M. Betulinic Acid: Isolation from Triphyophyllum peltatum and Ancistrocladus heyneanus, Antimalarial Activity, and Crystal Structure of the Benzyl Ester. Planta Med. 1997, 63, 255–257. Bringmann, G.; Wohlfarth, M.; Rischer, H.; Rückert, M.; Schlauer, J. The Polyketide Folding Mode in the Biogenesis of Isoshinanolone and Plumbagin in Ancistrocladus heyneanus (Ancistrocladaceae).Tetrahedron Lett.1998, 39, 8445–8448. Burkill I. H. A Dictionary of the Economic Products of the Malay Peninsula; Crown Agents: London; 1966. Cordell G. A. Introduction to Alkaloids—A Biogenetic Approach. Wiley-Interscience:New York, 1981; p 219. Francois, G.; Bringmann, G.; Dochez, C.; Schneider, C.; Timperman, G.; AkéAssi, L. Activities of Extracts and Naphthylisoquinoline Alkaloids from Triphyophyllum peltatum, Ancistrocladus abbreviatus and Ancistrocladus barteri Against Plasmodium berghei (Anka strain) In Vitro. J. Ethnopharmacol. 1995, 46, 115–120. Francois, G.; Bringmann, G.; Phillipson, J. D.; AkéAssi, L.; Dochez, C.; Rübenacker, M.; Schneider, C.; Wéry, M.; Warhurst, D. C.; Kirby, G. C. Activity of Extracts and Naphthylisoquinoline Alkaloids from Triphyophyllum peltatum, Ancistrocladus abbreviatus and A. barteri Against Plasmodium falciparum In Vitro. Phytochemistry 1994, 35, 1461–1464. Francois, G.; Timperman, G.; Haller, R. D.; Bär, S.; Isahakia, M. A.; Robertson, S. A.; Zhao, C.; De Souza,N. J.; AkéAssi, L.; Holenz, J.; Bringmann, G. Growth Inhibition of Asexual Erythrocytic Forms of Plasmodium falciparum and P. berghei In Vitro by Naphthylisoquinoline Alkaloid—Containing Extracts of Ancistrocladus and Triphyophyllum Species. Int. J. Pharmacogn. 1997, 35 (1), 55–59. Francois, G.;Timperman, G.; Holenz, J.; Ake´ Assi, L.; Geuder, T.; Maes, L.; Dubois, J.; Hanocq, M.; Bringmann, G. Naphthylisoquinoline Alkaloids Exhibit Strong Growth-Inhibiting

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Activities Against Plasmodium falciparum and P. berghei In Vitro—Structure-Activity Relationships of Dioncophylline C. Ann. Trop. Med. Parasito. 1996, 90, 115–123. Gereau, R. E. Typification of Names in AncistrocladusWallich (Ancistrocladaceae). Novon 1997, 7 (3), 242–245. Govindachari, T. R. Five Decades in the Study of Natural Products. J. Chem. Sci. 2002, 114, 175–195. Govindachari, T. R.; Parthasarathy, P. C. Ancistrocladine, a Novel Isoquinoline Alkaloid from Ancistrocladus heyneanus Wall. Indian J. Chem. 1970, 8, 567–568. Govindachari, T. R.; Parthasarathy, P. C. Alkaloids of Ancistrocladaceae. Heterocycles 1977, 7, 661. Govindachari, T. R.; Parthasarathy P. C.; Desai H. K. Chemical Investigation of Ancistrocladus heyneanus Wall.: Part VI—Isolation & Structure of Ancistrocladisine, a Novel Alkaloid. Indian J. Chem. 1972, 10, 1117–1119. Govindachari, T. R.; Parthasarathy P. C.; Desai H. K. Chemical Investigation of Ancistrocladus heyneanus Wall. Ancistrocladidine, a New Isoquinoline Alkaloid. Indian J. Chem. 1973, 11, 1190–1191. Gunawardene, N. R.; Daniels, D. A. E.; Gunatilleke, I. A. U.N; Gunatilleke, C. V. S.; Karunakaran, P. V.; Nayak, G. K.; Prasad, S.; Puyravaud, P.; Ramesh, B. R.; Subramanian, K. A.; Vasanthy G. A Brief Overview of the Western Ghats—Sri Lanka Biodiversity Hotspot. Curr. Sci. 2007, 93 (11), 1567–1572. Hallock, Y. F.; Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H.; Schaffer, M.; Gulden, K.; Bringmann, G.; Lee, J. A. Y.; Clardy, J.; François, G.; Boyd, M. R. Korupensamines A–D, Novel Antimalarial Alkaloids from Ancistrocladus korupensis. J. Org. Chem. 1994, 59, 6349–6355. Hallock, Y. F.; Manfredi, K. P.; Dai, J.; Cardellina, J. H.; Gluakowski, R. J.; McMahon, J. B.; Schaffer, M.; Stahl, M.; Gulden, K.; Bringmann, G.; François, G.; Boyd, M. R. Alkaloid, and Korupensamine E, a New Antimalarial Monomer from Ancistrocladus korupensis. J. Nat. Prod. 1997, 60, 677–683. Kuo, R. Y.; Qian, K.; Morris-Natschke, S. L.; Lee, K. H. Plant-Derived Triterpenoids and Analogues as Antitumor and Anti-HIV Agents. Nat. Prod. Rep. 2009, 26 (10), 1321–1344. Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H. I.; McMahon, J. B.; Pannell, L. K.; Cragg, G. M.; Boyd, M. R. Novel Alkaloids from the Tropical Plant Ancistrocladus abbreviatus Inhibit Cell Killing by HIV-1 and HIV-2. J. Med. Chem. 1991, 34, 3402–3405. More, S.; Maldar, N. N.; Bhamra, P.; Sharon, M.; Sharon, M. Antimicrobial Activity of NaphthylIso-Quinoline Alkaloids of Ancistrocladus heyneanus: I Extracted from Leaves. Adv. App. Sci. Res. 2012, 3 (5), 2760–2765. Pai, S. R.; Nimbalkar, M. S.; Pawar, N. V.; Dixit, G. B. Optimization of Extraction Techniques and Quantification of Betulinic Acid (BA) by RP-HPLC Method from Ancistrocladus heyneanus Wall. ex Grah. Indus. Crops Prod. 2011, 34, 1458–1464. Ramamoorthy, T. P. Ancistrocladaceae. In Flora of Hassan District, Karnataka, India; Saldanha, C. J., Nicolson, D. H., Eds.; Amerind Publishing: New Delhi, 1976; pp 171–182. Ruangrungsi, N.; Wongpanich, V.; Tantivatana, P. Traditional Medicinal Plants of Thailand, V. Ancistrotectorine, a New Naphthalene—Isoquinoline Alkaloid from Acistrocladus tectorius. J. Nat. Prod. 1985, 48, 529–535. Scotti, M. T; Scotti, L.; Ishiki, H.; Ribeiro, F. F.; da Cruz, R. M. D.; de Oliveira, M. P.; Mendonça Jr., F. J. B. Natural Products as a Source for Antileishmanial and Antitrypanosomal Agents. Comb. Chem. High Throughput Screen. 2016, 19, 1–17.

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Silva, O.; Barbosa, S.; Diniz, A.; Valdeira, M. L.; Gomes, E. Plant Extracts Antiviral Activity Against Herpes Simplex Virus Type 1 and African Swine Fever Virus. Int. J. Pharmacogn. 1997, 35 (1), 12–16. Singh, I. P.; Bharate, S. B.; Bhutani, K. K. Anti-HIV Natural Products. Curr. Sci. 2005, 89 (2), 269–290. Usher, G. A. Dictionary of Plants Used by Man; Constable & Company Ltd.: London, 1974; pp 44. Veiga, A. do S. S. da; Brígido, H. P. C.; Percário, S.; Marinho, A. M. do R.; Dolabela, M. F. Antileishmanial Potential of Alkaloids Isolated from Plants: An Integrative Review. Res. Soc. Dev. 2020, 9, e9119109334. Yang, L.; Glover R. P.; Yoganathan, K.; Sarnaik, J. P.; Godbole, A. J.; Soejarto, D. D.; Bussa, A. D.; Butlera M. S. Ancisheynine, a Novel Naphthylisoquinolinium Alkaloid from Ancistrocladus heyneanus. Tetrahedron Lett.2003, 44, 5827–5829.

CHAPTER 7

Phytochemical and Pharmacological Profiles of Centella asiatica L. SURABHI TIWARI and BRIJESH KUMAR* Sophisticated Analytical Instrument Facility Division (SAIF), CSIR-Central Drug Research Institute, Lucknow, India Corresponding author. E-mail: [email protected]

*

ABSTRACT The plant-based drug discovery has drawn the attention of researchers, especially the one used as traditional medicines. Centella asiatica L. is a traditional medicine widely used in India and across countries for treating a variety of diseases. The aerial parts and roots of the plant are known for their folklore use and its chemical constituents have been reported to show various pharmacological activities. Many of its uses have been proven scientifically, and bioactive ingredients have been validated. In this review, we have done a critical evaluation of available literature looking for the phytochemical and pharmacological importance of C. asiatica. Further studies will be helpful to discover many more bioactive compounds with their exact mode of actions. 7.1

INTRODUCTION

Traditional plants are most important and they play an active role in the medical field to treat human disease since thousands of years. They contain active constituents with therapeutic value and show less or no side effects. Centella asiatica (L.) Urban (Syn.: Hydrocotyle asiatica L.) associated with the family Apiaceae (Umbelliferae), widely known as Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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gotu kola, mandukparni, brahma-manduki, brahmi-buti (Hindi), Indian pennywort (English), tsubokusa (Japanese), and tungchian and luei gong gen (Chinese) is known for its immense medicinal properties being practiced in the Indian system of medicine (Srivastava et al., 1997). Centella asiatica is a perennial herb distributed in Central and Southern Africa, Australia, China, India, Indonesia, Madagascar, Nepal, and Sri Lanka (Press et al., 2000). In India, it is widely distributed and found up to an altitude of 2200 m, mostly in moist places. Centella asiatica is an industrial herb commonly labeled as dirty herb in the sight of microbial loads and heavy metal contents (Prasad et al., 2019). Centella asiatica is used for skin-related problems, healing wounds, and enhancing memory. It has shown biological activities such as antibacterial, antioxidant, anticancer, antidepressant, sedative, antiinflamatory, antigastric, and antiulcer (Gohil et al., 2010; Sun et al., 2020). Centella asiatica is of very high commercial importance and several products of C. asiatica are available in the market for human consumption as dietary supplements or medicines. Centella asiatica is reported to contain several classes of chemical compounds, namely, terpenes, triterpene saponins and their sapogenin derivatives, phenols, flavonoids vitamins, minerals, polyacetylene, and fatty acids (Prasad et al., 2019). The triterpenes and saponins are vital for its medicinal uses and known biomarkers of C. asiatica. Centellosides are also reported bioactive constituents of C. asiatica plants which recognized as a quality marker (Prasad et al., 2019). Centella asiatica is recorded as an important drug plant in different pharmacopoeias of Indian, European, Chinese, and in the German homeopathy. 7.2 BIOACTIVES A comprehensive detail of secondary metabolites of C. asiatica which are found in the aerial parts of the plants, in the roots and rhizomes (Brinkhaus et al., 2000). The recently published C. asiatica leaf transcriptome gives information about the genes which are responsible for synthesis of bioactive phytoconstituents (Sangwan et al., 2013). Triterpenes, the major components of C. asiatica are known as the most bioactive phytoconstituents. Asiaticoside (AC), asiatic acid, madecassoside, and madecassic acid are the most important triterpenes present in C. asiatica. The isoprenoid pathway products are divided into four groups, namely, plant sterols, pentacyclic triterpenoids, sesquiterpene, and saponins. Phenylpropanoid

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scaffold pathway divides into three groups, namely, eugenol derivatives, caffeoylquinic acids, and flavonoids. The variational study for the preparation of essential oil of C. asiatica has been reported. The aerial part of C. asiatica contains rich source of sesquiterpenes and monoterpenoids which includes α-humulene, β-caryophyllene, germacrene-D, bi-cyclogermacrene and myrcene. Oxygenated sesquiterpenes has been characterized, namely, humulene epoxide, caryophyllene oxide, oxygenated monoterpenes (e.g., menthone), α-terpineol and a sulfide sesquiterpenoid (mintsulfide), arjunolic acid, centellasapogenol-A, centellasaponin-A, centellasaponin-B, centellasaponin-C, centellasaponin-D, centelloside-E, centelloside-D, asiaticoside-E, asiaticoside-F, asiaticoside-G, chebuloside-II, quadranoside-IV, scheffuroside-B, scheffuroside-F, asiatic acid and its isomers, chavicol, asiaticoside-B, eugenol acetate, madecassic acid, brahmic acid, madecassoside, methyleugenol, myrcene (Brinkhaus et al., 2000), asiaticoside-C, β-Caryophyllene, bicyclogermacrene, brahminoside-B (James and Dubery, 2009), campesterol, castillicetin, castilliferol (Chandrika and Kumara, 2015), catechin, chlorogenic acid (3-O-caffeoylquinic acid), cryptochlorogenic acid (4-O-caffeoylquinic acid), 1,3-dicaffeoylquinic acid, 1,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid (isochlorogenic acid B), 3,5-dicaffeoylquinic acid (isochlorogenic acid A), 4,5-dicaffeoylquinic acid (isochlorogenic acid C), neochlorogenic acid (5-O-dicaffeoylquinic acid) (Long et al., 2012), corosolic acid, ursolic acid, pomolic acid (Yoshida et al., 2005), epicatechin, 3-epimaslinic acid, germacrene-B, kaempferol, myricetin, patuletin, stigmasterol (Chandrika and Kumara, 2015), naringin, quercetin, rutin (Sangwan et al., 2013), and sitosterol (Yoshida et al., 2005). Chemotypic variational study provides the information about the most elite metabolite in the plant and its quantitative variation. Several analytical studies such as high-performance thin layer chromatography (HPTLC), highpressure liquid chromatography (HPLC), liquid chromatography–mass spectrometry (LC–MS) have been successfully completed the qualitative and quantitative analyses of the bioactive phytocompounds of C. asiatica (Gupta et al., 2014; Srivastava et al., 2014, 2015, 2019; Jain et al., 2008; Wang et al., 2020; Laugel et al., 1998; Monton et al., 2018; Tiwari et al., 2010; Rafamantanana et al., 2009; Hebbar et al., 2019; Sharifuldin et al., 2013; Nair et al., 2012; Zakaria et al., 2019). These studies are helpful in the quality checks of C. asiatica raw materials and products in various pharma industries.

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Bioactive compounds reported from C. asiatica.

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PHARMACOLOGY

7.3.1 ANTI-INFLAMMATORY ACTIVITY In C. asatica, the aqueous extract has anti-inflammatory effect (Somchit et al., 2004) and was shown by the asiatic acid and madecassic acid through the inhibition of enzymes (iNOS), cyclo-oxygenase-2 (COX-2), interleukins (IL; IL-6 and IL-1β), cytokine tumor necrosis factor (TNF-α) expression through the downregulation of NF-κB activation in lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophage cells whereas asiaticoside-G showed the anti-inflammatory property in LPS-stimulated RAW 264.7 cells. The madecassoside compound protects collagen II-induced arthritis (CIA) which occur in mice (Liu et al., 2008). In a previous study, the inhibitory effect of edema using extracts of C. asiatica has higher percentage as compared with the standard ibuprofen (George and Joseph, 2009). The extract of C. asiatica also helps in dental hygiene treatment in which it protects the teeth as well as the surrounding bone (Sastravaha et al., 2005) 7.3.2 ANTICANCER ACTIVITY Methanolic extract induced the apoptosis in MCF-7 cells of human breast. The anticancer activity in SK-MEL-2 cells and SW480 human colon cancer cells is much higher when AC and vincristine are given together than they are given separately (Huang et al., 2004). The aqueous extract of C. asiatica showed inhibitory concentration against human breast cancer, mouse melanoma, and rat glioma (Pittella et al., 2009). The crude extract of C. asiatica helps in antitumor effect as it slows down the formation of tumors in the body and also helps in DNA synthesis (Babu et al., 1995). 7.3.3 ANTICONVULSANT ACTIVITY The anticonvulsant activity has been shown on the cholinergic system reported by different extracts of C. asiatica (Visweswari et al., 2010). The leaves extracts showed protective activity against the increase in current electroshock, chemoconvulsions, and reduction in the spontaneous motor activity when administered orally (Ganachari et al., 2004).

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7.3.4 ANTIDEPRESSANT ACTIVITY The triterpenes from C. asiatica decreased the immobility time and improved the imbalance of amino acid levels in mice which showed the antidepressant activity (Chen et al., 2003; Gupta et al., 2003). 7.3.5 ANTIOXIDANT ACTIVITY Centella asiatica is a rich source of antioxidants. The water extracts possess flavanoids and phenolic contents which are good source of antioxidant and show the maximum amount of antioxidant activity (Pittella et al., 2009). The aqueous extract of C. asiatica also reduces the oxidative stress in male rats (Sainath et al., 2011) that helps in aging effect, and helps in preventing oxidative damage in rats’ brain (Subathra et al., 2005). The reports suggested that the alcoholic extracts of C. asiatica increases the level of enzymes such as superoxide dismutase and glutathione peroxidase in lymphoma-bearing mice (Jayashree et al., 2003). 7.3.6 ANTIULCER ACTIVITY Asiaticoside of C. asiatica mainly reduces the gastric ulcer in rats (Guo et al., 2004; Chatterjee et al., 1992; Cho, 1981; Rhee et al., 1981; Shin et al., 1982) and protects against ethanol, aspirin, and cold resistant stress when the fresh extracts were orally given (Sairam et al., 2001). Similarly, studies have also shown the healing effects in rats through aqueous extract of C. asiatica where AC acts as an active constituent (Cheng et al., 2004); also, the extract helps in boosting the mucosal barrier from ethanol-induced gastric wound (Cheng et al., 2000). 7.3.7 CARDIOPROTECTIVE ACTIVITY Centella asiatica extracts has cardioprotective effect in adult male albino rats of Wistar strain during adriamycin induced cardiac damage specially the madecassoside which mainly protect the myocardial injury in rabbits and rats (Li et al., 2007). Similarly, triterpenic fraction of C. asiatica decreases the level of endothelial cells in post phlebitis syndrome (Montecchio et al., 1991).

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7.3.8 HEPATOPROTECTIVE ACTIVITY In C. asiatica, compounds such as AC had showed the hepatoprotective effect on liver induced by LPS against mice (Zhang et al., 2010). 7.3.9

EFFECT ON SKIN

The alcoholic extract of C. asiatica has proved its useful effects in skinrelated disease and are used in cosmetic creams with the combination of other medicinal plants. Water extracts of C. asiatica encapsulated with gelatine reduces the matrix metalloproteinase (MMP)-1 in mouse skin. Asiaticoside reported for wound healing properties is also involved in stimulation of synthesis of type 1 collagen in fibroblast cells which helps in hypertrophic scars and keloids (Lee et al., 2006; Hausen et al., 1993; Parameshwaraiah et al., 1998). 7.3.10 IMMUNOMODULATING ACTIVITY The immunomodulatory effect has been shown by the triterpenoid saponins of C. asiatica. Alcoholic extracts of C. asiatica showed the phagocytic index in Swiss Albino mice, whereas the aqueous extract has shown the IL-2 and TNF-α in human peripheral blood mononuclear cells (PBMCs) (Jayathirtha and Mishra, 2004) 7.3.11 MEMORY ENHANCING ACTIVITY Centella asiatica is also known as the memory enhancer since long, boosting the cognitive function (Tiwari et al., 2008), and its extracts are used in memory enhancing and in various neurological disorders (Xu et al., 2008). The compounds, such as asiatic acid, have been isolated from the plant and a major bioactive compound from C. asiatica, which helps in the learning and shows memory enhancing property in male Sprague–Dawley rats (Nasir et al., 2011). 7.3.12 ANTIPSORIATIC ACTIVITY Centella asiatica showed the antipsoriatic effect on SVK-14 keratinocyte due to the presence of triterpenoid glycosides (Sampson et al., 2001).

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7.3.13 ANTIMICROBIAL ACTIVITY Centella asiatica is reported to have antibacterial activity on both gram-positive and gram-negative bacteria. Bacillus subtilis, Pseudomonas aeruginosa, Pseudomonas cichorii and Escherichia coli have shown the growth inhibition on different solvent extracts C. asiatica (Escop, 2003). The antiviral activity was reported by type 2 herpes simplex virus from the aqueous extract of C. asiatica. It showed antimicrobial activity in both in vitro and in vivo studies. It is being used in various cosmetic as well as food industries due to this property (Idris et al., 2021). 7.3.14 ANTIHYPERGLYCEMIC EFFECT Asiatic acid is the important active compound which controls the carbohydrate metabolism by balancing the regulatory enzymes in streptozotocin (STZ)-induced diabetic rats (Ramachandran and Saravanan, 2013). 7.3.15 VENOUS INSUFFICIENCY ACTIVITY Centella asiatica fraction extract regulated mucopolysachharide metabolism in connective tissue in a patient with varicose veins (Arpaia et al., 1990). The triterpenic fraction of C. asiatica is helpful in various arterial problems and in chronic venous hypertension (Incandela et al., 2001). The extract of C. asiatica helps the connective tissue by boosting the veins (Allegra, 1981) in various venous disorders (Cesarone et al., 1992). 7.3.16 WOUND HEALING ACTIVITY Several reports suggested the wound healing activity of C. asiatica. These extracts were very effective against any type of burns such as gas exploitation and electric current. The compounds such as AC in C. asiatica acts as an antibiotic for healing burns and burned wounds (Suguna et al., 1996). Mainly the aqueous extracts are used in the formulation of ointment, cream, and gels. The effects of AC showed protein synthesis, osteogenic differentiation, and proliferation in human periodontal ligament cells (Rosen et al., 1967). Asiaticoside also increases the antioxidant level at the primary stage which plays an important role in wound healing process (Shukla et al.,

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1999a, 1999b). Madecassoside increases the wound healing and diminish keloid formation in the primary keloid-derived fibroblasts, originating from human earlobe keloids (Nowwarote et al., 2012). The extract of C. asiatica containing a combination of its three major bioactive compounds, namely, AC, asiatic acid and madecassic acid, has been checked on human foreskin fibroblast monolayer cultures showed an increased level of intracellular-free proline pool (Tenni et al., 1988) whereas asiatic acid showed the collagen synthesis stimulation (Maquart et al., 1990). 7.3.17

OXIDATIVE STRESS

Centella asiatica is considered as a potential natural resource to increase the stamina especially in elderly persons (Mato et al., 2009). It also showed the protective effect on colchicine-induced cognitive impairment and its oxidative damage (Kumar and Gupta, 2003; Kumar et al., 2009). 7.3.18

NEUROPROTECTIVE EFFECT

Asiaticoside derivatives have the ability to protect neurons from Aβ-induced cell death as it blocks Aβ-neurotoxicity due to which it is used in Alzheimer’s disease as a healing drug (Mook-Jung et al., 1999). Centella asiatica showed the neuroprotective effect as it has the action of enzyme inhibition, dopamine neurotoxicity in Parkinson’s disease (Orhan et al., 2012). The aqueous extract of C. asiatica provides the increase level of cognitive effect on rats (Kumar and Gupta, 2002). Asiatic acid also helps in protecting neurons from oxidative damage through glutamate (Lee et al., 2000). 7.3.19 ANTIDEPRESSANT EFFECT The combination of triterpenes in C. asiatica enhances the level of monoamine neurotransmitters which directly effects antidepressant activity (Chen et al., 2005). 7.3.20 RADIOPROTECTION EFFECT The extract of C. asiatica helps in preventing from clinical radiotherapy when the radiation-induced behavior occurs (Shobi and Goel, 2001; Sharma and Sharma, 2002).

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7.3.21

HEPATIC EFFECT

Centella asiatica also helps in preventing from chronic hepatic disorders (Darnis et al., 1979). 7.3.22

SEDATIVE EFFECT

In C. asiatica, mainly the compound brahmoside has the ability to possess sedative effect and it is also known as sleeping pill (Ramaswamy et al., 1970). 7.3.23 ANTIFERTILITY EFFECT In various clinical studies, it has suggested that in chronic treatment, pregnancy become dangerous as it causes unconstrained abortion in females (Dutta et al., 1968). KEYWORDS • • • • •

Centella asiatica HPLC HPTLC LCMS pharmacological activity

REFERENCES Allegra, C. Comparative Capillaroscopic Study of Certain Bioflavonoids and Total Triterpenic Fractions of Centella asiatica in Venous Insufficiency. Clin. Ther. 1981, 99, 507–513. Arpaia, M. R.; Ferrone, R.; Amitrano, M.; Nappo, C.; Leonardo, G.; Del Guercio, R. Effects of Centella asiatica Extract on Mucopolysaccharide Metabolism in Subjects with Varicose Veins. Int. J. Pharm. Clin. 1990, 10 (4), 229–233. Babu, T. D.; Kuttan, G.; Padikkala, J. Cytotoxic and Anti-Tumour Properties of Certain Taxa of Umbelliferae with Special Reference to Centella asiatica (L.) Urban. J. Ethnopharmacol. 1995, 48 (1), 53–57.

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Brinkhaus, B.; Lindner, M.; Schuppan, D.; Hahn, E. G. Chemical, Pharmacological and Clinical Profile of the East Asian Medical Plant Centella asiatica. Phytomedicine 2000, 7 (5), 427–448. Cesarone, M. R.; Laurora, G.; De Sanctis, M. T.; Belcaro, G. Activity of Centella asiatica in Venous Insufficiency. Minerva Cardioangiol. 1992, 40 (4), 137–143. Chandrika, U. G.; Kumara, P. A. Gotu Kola (Centella asiatica): Nutritional Properties and Plausible Health Benefits. Adv. Food Nutr. Res. 2015, 76, 125–157. Chatterjee, T. K.; Chakraborty, A.; Pathak, M.; Sengupta, G. C. Effects of Plant Extract Centella asiatica (Linn.) on Cold Restraint Stress Ulcer in Rats. Indian J. Exp. Biol. 1992, 30 (10), 889–891. Chen, Y.; Han, T.; Qin, L.; Rui, Y.; Zheng, H. Effect of Total Triterpenes from Centella asiatica on the Depression Behavior and Concentration of Amino Acid in Forced Swimming Mice. J. Chin. Med. Mater. 2003, 26, 870–873. Chen, Y.; Han, T.; Rui, Y.; Yin, M.; Qin, L.; Zheng, H. Effects of Total Triterpenes of Centella asiatica on the Corticosterone Levels in Serum and Contents of Monoamine in Depression Rat Brain. Zhong Yao Cai. 2005, 28, 492–496. Cheng, C. L.; Guo, J. S.; Luk, J.; Koo, M. W. The Healing Effects of Centella Extract and Asiaticoside on Acetic Acid Induced Gastric Ulcers in Rats. Life Sci. 2004, 74, 2237–2249. Cheng, C. L.; Koo, M. W. L. Effects of Centella asiatica on Ethanol Induced Gastric Mucosal Lesions in Rats. Life Sci. 2000, 67 (21), 2647–2653. Cho, K. H. Clinical Experiences of Madecassol (Centella asiatica) in the Treatment of Peptic Ulcer. Korean J. Gastroenterol. 1981, 13, 49–56. Darnis, F.; Orcel, L.; de Saint-Maur, P. P.; Mamou, P. Use of a Titrated Extract of Centella asiatica in Chronic Hepatic Disorders (author’s Transl). La semaine des hopitaux: organe fonde par l’Association d’enseignement medical des hopitaux de Paris. 1979, 55 (37–38), 1749–1750. Dutta, T.; Basu, U. P. Crude Extract of Centella asiatica and Products Derived from Its Glycosides as Oral Antifertility Agents. Indian J. Exp. Biol. 1968, 6 (3), 181–182. Escop. Phytotherapy, E. S. C. Escop Monographs: The Scientific Foundation for Herbal Medicinal Products; Thieme, 2003. Ganachari, M. S.; Babu, V.; Katare, S. Neuropharmacology of an Extract Derived from Centella asiatica. Pharm. Biol. 2004, 42, 246–252. George, M.; Joseph, L. Anti-Allergic, Anti-Pruritic, and Anti-Inflammatory Activities of Centella asiatica Extracts. Afr. J. Trad. Complement. Altern. Med. 2009, 6 (4), 554–559. Gohil, K. J.; Patel, J. A.; Gajjar, A. K. Pharmacological Review on Centella asiatica: A Potential Herbal Cure-All. Indian J. Pharm. Sci. 2010, 72 (5), 546–556. Guo, J. S.; Cheng, C. L.; Koo, M. W. L. Inhibitory Effects of Centella asiatica Water Extract and Asiaticoside on Inducible Nitric Oxide Synthase During Gastric Ulcer Healing in Rats. Planta Med. 2004, 70, 1150–1154. Gupta, A.; Verma, S.; Kushwaha, P.; Srivastava, S.; Aks, R. Quantitative Estimation of Asiatic Acid, Asiaticoside & Madecassoside in Two Accessions of Centella asiatica (L) Urban for Morpho-Chemotypic Variation. Indian J. Pharm. Educ. Res. 2014, 48 (3), 75–79. Gupta, Y. K.; Kumar, M. V.; Srivastava, A. K. Effect of Centella asiatica on PentylenetetrazoleInduced Kindling, Cognition and Oxidative Stress in Rats. Pharmacol. Biochem. Behav. 2003, 74 (3), 579–585. Hausen, B. M. Centella asiatica (Indian pennywort), an Effective Therapeutic but a Weak Sensitizer. Contact Dermat. 1993, 29, 175–179.

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Hebbar, S.; Dubey, A.; Ravi, G. S.; Kumar, H.; Saha, S. RP-HPLC Method Development and Validation of Asiatic Acid Isolated from the Plant Centella asiatica. Int. J. App. Pharm. 2019, 11 (3), 72–78. Huang, Y. H.; Zhang, S. H.; Zhen, R. X.; Xu, X. D.; Zhen, Y. S. Asiaticoside Inducing Apoptosis of Tumor Cells and Enhancing Anti-Tumor Activity of Vincristine. Chin. J. Cancer 2004, 23, 1599–1604. Idris, F. N.; Mohd Nadzir, M. Comparative Studies on Different Extraction Methods of Centella asiatica and Extracts Bioactive Compounds Effects on Antimicrobial Activities. Antibiotics 2021, 10 (4), 457. Incandela, L.; Cesarone, M. R.; Cacchio, M.; De Sanctis, M. T.; Santavenere, C.; D’Auro, M. G.; et al. Total Triterpenic Fraction of Centella asiatica in Chronic Venous Insufficiency and in High-Perfusion Microangiopathy. Angiology 2001, 52, S9–13. Jain, P. K.; Agrawal, R. K. High Performance Liquid Chromatographic Analysis of Asiaticoside in Centella asiatica (L.) Urban. Chiang Mai J. Sci, 2008, 35 (3), 521–525. James, J. T.; Dubery, I. A. Pentacyclic Triterpenoids from the Medicinal Herb, Centella asiatica (L.) Urban. Molecules 2009, 14 (10), 3922–3941. Jayashree, G.; Kurup Muraleedhara, G.; Sudarslal, S.; Jacob, V. B. Anti-Oxidant Activity of Centella asiatica on Lymphoma-Bearing Mice. Fitoterapia 2003, 74, 431–434. Jayathirtha, M. G.; Mishra, S. H. Preliminary Immunomodulatory Activities of Methanol Extracts of Eclipta alba and Centella asiatica. Phytomedicine 2004, 11 (4), 361–365. Kumar, A.; Dogra, S.; Prakash, A. Neuroprotective Effects of Centella asiatica Against Intracerebroventricular Colchicine Induced Cognitive Impairment and Oxidative Stress. Int. J. Alzheimers Dis. 2009, 1–8. DOI: 10.4061/2009/972178. Kumar, M. H. V.; Gupta, Y. K. Effect of Different Extracts of Centella asiatica on Cognition and Markers of Oxidative Stress in Rats. J. Ethnopharmacol. 2002, 79, 253–260. Kumar, M. H. V.; Gupta, Y. K. Effect of Centella asiatica on Cognition and Oxidative Stress in an Intracerebroventricular Streptozotocin Model of Alzheimer’s Disease in Rats. Clin. Exp. Pharmacol. Physiol. 2003, 30, 336–342. Laugel, C.; Baillet, A.; Ferrier, D. Improved HPLC Determination of the Centella asiatica Terpenes: Analysis in a Multiple Emulsion, Influence of the Surfactants on the Retention. J. Liq. Chrom. Relat. Tech. 1998, 21 (9), 1333–1345. Lee, J.; Jung, E.; Kim, Y.; Park, J.; Park, J.; Hong, S.; Kim, J.; Hyun, C.; Kim, Y. S.; Park, D. Asiaticoside Induces Human Collagen I Synthesis Through TGFbeta Receptor I Kinase (TbetaRI Kinase)-Independent Smad Signaling. Planta Med. 2006, 72, 324–328. Lee, M. K.; Kim, S. R.; Sung, S. H.; Lim, D.; Kim, H.; Choi, H.; et al. Asiatic Acid Derivatives Protect Cultured Cortical Neurons from Glutamate-Induced Excitotoxicity. Res. Commun. Mol. Pathol. Pharmacol. 2000, 108, 75–86. Li, G. G.; Bian, G. X.; Ren, J. P.; Wen, L. Q.; Zhang, M.; Lü, Q. J. Protective Effect of Madecassoside Against Reperfusion Injury After Regional Ischemia in Rabbit Heart In Vivo. Acta Pharm. Sin. B. 2007, 42, 475–480. Liu, M.; Dai, Y.; Yao, X.; Li, Y.; Luo, Y.; Xia, Y.; Gong, Z. Anti-Rheumatoid Arthritic Effect of Madecassoside on Type II Collagen-Induced Arthritis in Mice. Int. Immunopharmacol. 2008, 8, 1561–1566. Long, H. S.; Stander, M. A.; Van Wyk, B. E. Notes on the Occurrence and Significance of Triterpenoids (Asiaticoside and Related Compounds) and Caffeoylquinic Acids in Centella Species. S. Afr. J. Bot. 2012, 82, 53–59.

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Maquart, F. X.; Bellon, G.; Gillery, P.; Wegrowski, Y.; Borel, J. P. Stimulation of Collagen Synthesis in Fibroblast Cultures by a Triterpene Extracted from Centella asiatica. Connect Tissue Res. 1990, 24,107–120. Mato, L.; Wattanathorn, J.; Muchimapura, S.; Terdthai Tongun, T.; Piyawatkul, N.; Yimtae, K.; et al. Centella asiatica Improves Physical Performance and Health Related Quality of Life in Healthy Elderly Volunteers. Evid. Based Complement. Altern. Med. 2009, 2, 465–473. Montecchio, G. P.; Samaden, A.; Carbone, S.; Vigotti, M.; Siragusa, S.; Piovella, F. Centella asiatica Triterpenic Fraction (CATTF) Reduces the Number of Circulating Endothelial Cells in Subjects with Post Phlebitic Syndrome. Haematologica 1991, 76 (3), 256–259. Monton, C.; Luprasong, C.; Suksaeree, J.; Songsak, T. Validated High Performance Liquid Chromatography for Simultaneous Determination of Stability of Madecassoside and Asiaticoside in Film Forming Polymeric Dispersions. Rev. Bras. Farmacogn. 2018, 28 (3), 289–293. Mook-Jung, I.; Shin, J. E.; Yun, S. H.; Huh, K.; Koh, J. Y.; Park, H. K.; et al. Protective Effects of Asiaticoside Derivatives Against Beta-Amyloid Neurotoxicity. J. Neurosci. Res. 1999, 58, 417–425. Nair, S. N.; Menon, S.; Shailajan, S. A Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometric Method for Quantification of Asiatic Acid from Plasma: Application to Pharmacokinetic Study in Rats. Rapid Commun. Mass Spectrom. 2012, 26 (17), 1899–1908. Nasir, M. N.; Habsah, M.; Zamzuri, I.; Rammes, G.; Hasnan, J.; Abdullah, J. Effects of Asiatic Acid on Passive and Active Avoidance Task in Male Spraque-Dawley Rats. J. Ethnopharmacol. 2011, 134, 203–209. Nowwarote, N.; Osathanon, T.; Jitjaturunt, P.; Manopattanasoontorn, S.; Pavasant, P. Asiaticoside Induces Type I Collagen Synthesis and Osteogenic Differentiation in Human Periodontal Ligament Cells. Phytother. Res. 2013, 27 (3), 457–462. Orhan, I. E. Centella asiatica (L.) Urban: from Traditional Medicine to Modern Medicine with Neuroprotective Potential. Evid. Based Complem. Altern. Med. 2012, 946259. Parameshwaraiah, S.; Shivakumar, H. G. Evaluation of topical formulations of Aqueous Extract of Centella asiatica on Open Wounds in Rats. Indian J. Exp. Biol. 1998, 36 (6), 569–572. Pittella, F.; Dutra, R. C.; Junior, D. D.; Lopes, M. T. P.; Barbosa, N. R. Antioxidant and Cytotoxic Activities of Centella asiatica (L) Urb. Int. J. Mol. Sci. 2009, 10, 3713–3721. Prasad, A.; Mathur, A. K.; Mathur, A. Advances and Emerging Research Trends for Modulation of Centelloside Biosynthesis in Centella asiatica (L.) Urban—A Review. Ind. Crop Prod. 2019, 141, 111768. Press, J. R.; Shrestha, K. K.; Sutton, D. A. Annotated Checklist of the Flowering Plants of Nepal; The Natural History Museum: London, Central Department of Botany, Tribhuvan University: Kathmandu, Nepal, 2000. Rafamantanana, M. H.; Rozet, E.; Raoelison, G. E.; Cheuk, K.; Ratsimamanga, S. U.; Hubert, P.; Quetin-Leclercq, J. An Improved HPLC-UV Method for the Simultaneous Quantification of Triterpenic Glycosides and Aglycones in Leaves of Centella asiatica (L.) Urb (Apiaceae). J. Chromatogr. B. 2009, 877 (23), 2396–2402. Ramachandran, V.; Saravanan, R. Efficacy of Asiatic Acid, a Pentacyclic Triterpene on Attenuating the Key Enzymes Activities of Carbohydrate Metabolism in StreptozotocinInduced Diabetic Rats. Phytomedicine 2013, 20 (3–4), 230–236.

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Ramaswamy, A. S.; Pariyaswami, S. M.; Basu, N. Pharmacological Studies on Centella asiatica Linn. Indian J. Med. Res. 1970, 4, 160–175. Rhee, J. C.; Choi, K. W. Clinical Effect of the Titrated Extract of Centella asiatica (madecassol) on Peptic Ulcer. Korean J. Gastroenterol. 1981, 13 (1), 35–40. Rosen, H.; Blumenthal, A.; McCallum, J. Effect of Asiaticoside on Wound Healing in the Rat. Proc. Soc. Exp. Biol. Med. 1967, 125, 279–280. Sainath, S. B.; Meena, R.; Supriya, C.; Reddy, K. P.; Reddy, P. S. Protective Role of Centella asiatica on Lead-Induced Oxidative Stress and Suppressed Reproductive Health in Male Rats. Environ. Toxicol. Pharmacol. 2011, 32, 146–154. Sairam, K.; Rao, C. V.; Goel, R. K. Effect of Centella asiatica Linn on Physical and Chemical Factors Induced Gastric Ulceration and Secretion in Rats. Indian J. Exp. Biol. 2001, 39, 137–142. Sampson, J. H.; Raman, A.; Karlsen, G.; Navsaria, H.; Leigh, I. M. In Vitro Keratinocyte Antiproliferant Effect of Centella asiatica Extract and Triterpenoid Saponins. Phytomedicine 2001, 8, 230–235. Sangwan, R. S.; Tripathi, S.; Singh, J.; Narnoliya, L. K.; Sangwan, N. S. De Novo Sequencing and Assembly of Centella asiatica Leaf Transcriptome for Mapping of Structural, Functional and Regulatory Genes with Special Reference to Secondary Metabolism. Gene 2013, 525 (1), 58–76. Sastravaha, G.; Gassmann, G.; Sangtherapitikul, P.; Grimm, W. D. Adjunctive Periodontal Treatment with Centella asiatica and Punica granatum Extracts in Supportive Periodontal Therapy. J. Int. Acad. Periodontol. 2005, 7 (3), 70–79. Sharifuldin, M. M. A.; Abdalrahim, F. A.; Ismail, Z. Quantification of Madecassoside, Asiaticoside, Madecassic Acid and Asiatic Acid in Centella asiatica by Reverse Phase HPLC. Open Conf. Proc. J. 2013, 4, 172. Sharma, J.; Sharma, R. Radioprotection of Swiss Albino Mouse by Centella asiatica Extract. Phytother. Res. 2002, 16 (8), 785–786. Shin, H. S.; Choi, I. G.; Lee, M. H.; Park, K. N. Clinical Trials of Madecassol (Centella asiatica) on Gastrointestinal Ulcer Patients. Korean J. Gastroenterol. 1982, 14, 49–56. Shobi, V.; Goel, H. C. Protection Against Radiation-Induced Conditioned Taste Aversion by Centella asiatica. Physiol. Behav. 2001, 73 (1–2), 19–23. Shukla, A.; Rasik, A. M.; Dhawan, B. N. Asiaticoside-Induced Elevation of Antioxidant Levels in Healing Wounds. Phytother. Res. 1999a, 13, 50–54. Shukla, A.; Rasik, A. M.; Jain, G. K.; Shankar, R.; Kulshrestha, D. K.; Dhawan, B. N. In Vitro and In Vivo Wound Healing Activity of Asiaticoside Isolated from Centella asiatica. J. Ethnopharmacol. 1999b, 65, 1–11. Somchit, M. N.; Sulaiman, M. R.; Zuraini, A.; Samsuddin, L.; Somchit, N.; Israf, D. A.; Moin, S. Antinociceptive and Antiinflammatory Effects of Centella asiatica. Indian J. Pharmacol. 2004, 36 (6), 377–380. Srivastava, R.; Shukla, Y. N.; Kumar, S. Chemistry and Pharmacology of Centella asiatica: A Review. J. Med. Arom. Plant. Sci. 1997, 19, 1049–1056. Srivastava, S.; Verma, S.; Gupta, A.; Rawat, A. K. S. Chemotypic Variation Among Different Accessions of Centella asiatica (L.) Urban from Central Zone of India and Strategies for Their Conservation. In Natural Products Recent Advances; Chauhan, A. K., Pushpangadan, P., George, V., Eds.; 2015; pp 276–285. Srivastava, S.; Verma, S.; Gupta, A.; Rajan, S.; Rawat, A. Studies on Chemotypic Variation in Centella asiatica (L.) Urban from Nilgiri Range of India. J. Planar Chromatogr. 2014, 27 (6), 454–459.

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Srivastava, S.; Tiwari, S.; Srivastava, N.; Verma, S.; Rawat, A. K. S. Chemotaxonomic Studies on Centella asiatica (L.) Urb. from Varied Phytogeographical Conditions of India for Its Industrial Prospection. Proc. Natl. Acad. Sci. India Sect. B Biol. Sci. 2019, 89 (3), 1057–1066. Subathra, M.; Shila, S.; Devi, M. A.; Panneerselvam, C. Emerging role of Centella asiatica in Improving Age-Related Neurological Antioxidant Status. Exp. Gerontol. 2005, 40, 707–715. Suguna, L.; Sivakumar, P.; Chandrakasan, G. Effects of Centella asiatica Extract on Dermal Wound Healing in Rats. Indian J. Exp. Biol. 1996, 34 (12), 1208–1211. Sun, B.; Wu, L.; Wu, Y.; Zhang, C.; Qin, L.; Hayashi, M.; Kudo, M.; Gao, M.; Liu, T. Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review. Front Pharmacol. 2020, 11. DOI: 10.3389/fphar.2020.568032. Tenni, R.; Zanaboni, G.; De Agostini, M. P.; Rossi, A.; Bendotti, C.; Cetta, G. Effect of the Triterpenoid Fraction of Centella asiatica on Macromolecules of the Connective Matrix in Human Skin Fibroblast Cultures. Ital. J. Biochem. 1988, 37, 69–77. Tiwari, R. K.; Chanda, S.; Deepak, M.; Agarwal, A. HPLC Method Validation for Simultaneous Estimation of Madecassoside, Asiaticoside and Asiatic Acid in Centella asiatica. J. Chem. Pharm. Res. 2010, 2 (3), 223–229. Tiwari, S.; Singh, S.; Patwardhan, K.; Gehlot, S.; Gambhir, I. S. Effect of Centella asiatica on Mild Cognitive Impairment (MCI) and Other Common Age-Related Clinical Problems. Digest J. Nanomat. Biostruct. 2008, 3, 215–220. Visweswari, G.; Prasad, K. S.; Chetan, P. S.; Lokanatha, V.; Rajendra, W. Evaluation of the Anticonvulsant Effect of Centella asiatica (Gotu Kola) in Pentylene Tetrazolinduced Seizures with Respect to Cholinergic Neurotransmission. Epilepsy Behav. 2010, 17, 332–335. Wang, C.; Zhao, Y.; Yang, R.; Liu, H. Simultaneous Analysis of Five Triterpenes in Centella asiatica by High Performance Liquid Chromatography with Cyclodextrins as the Mobile Phase Additives. Sci. Rep. 2020, 10 (1), 1–8. Xu, Y.; Cao, Z.; Khan, I.; Luo, Y. Gotu Kola (Centella asiatica) Extract Enhances Phosphorylation of Cyclic AMP Response Element Binding Protein in Neuroblastoma Cells Expressing Amyloid Beta Peptide. J. Alzheimers Dis. 2008, 13 (3), 341–349. Yoshida, M.; Fuchigami, M.; Nagao, T.; Okabe, H.; Matsunaga, K.; Takata, J.; Karube, Y.; Tsuchihashi, R.; Kinjo, J.; Mihashi, K. Antiproliferative Constituents from Umbelliferae Plants VII. Active Triterpenes and Rosmarinic Acid from Centella asiatica. Biol. Pharm. Bull. 2005, 28, 173–175. Zakaria, F.; Ibrahim, W. N. W.; Ismail, I. S.; Ahmad, H.; Manshoor, N.; Ismail, N.; Zainal, Z.; Shaari, K. LCMS/MS Metabolite Profling and Analysis of Acute Toxicity Effect of the Ethanolic Extract of Centella asiatica on Zebrafsh Model. Pertanika J. Sci. Technol. 2019, 27 (2), 985–1003. Zhang, L.; Li, H. Z.; Gong, X.; Luo, F. L.; Wang, B.; Hu, N.; Wang, C. D.; Zhang, Z.; Wan, J. Y. Protective Effects of Asiaticoside on Acute Liver Injury Induced by Lipopolysaccharide/DGalactosamine in Mice. Phytomedicine 2010, 17, 811–819.

CHAPTER 8

Biomolecules and Therapeutics of Chlorophytum borivilianum Santapau & R.R. Fern. (Safed Musli) VINOD S. UNDAL* Department of Botany, Ghulam Nabi Azad College, Barshitakali, Dist - Akola, Maharashtra, India E-mail: [email protected]

*

ABSTRACT Chlorophytum borivilianum Santapau & R.R.Fern., referred as Safed musli, belonging to the family Liliaceae, is a promising medicinal plant with great economic potential. The plant is a tiny annual herb that develops competently in tropical and sub-tropical environment with altitudes up to 1500 m and occurred in nearly all parts of the central region of India. Largely the tuberous roots are employed in the synthesis of medicines. The plant shows adaptogenic, aphrodisiac, immunomodulatory and antidiabetic activities. The dry safed musli largely is composed of carbohydrates, proteins, fibers, saponin, and alkaloids. The root contains steroidal saponins, phytosterols, polyphenols, flavonoids, and vitamin C composites. A comprehensive study was carried out by assessing national and international scientific databases like Pub Med, SciFinder, Scopus and Web of Science, thesis, and recognized books. The number of bioactive constituents with total 19 pharmacological activities have been assembled with published literature. Comparatively more reports were found on antimicrobial, antidiabetic, antitumor, immunomodulatory and antioxidant activity.

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Chlorophytum borivilianum Santapau & R.R. Fern., referred to as safed musli, belongs to the family Liliaceae. Safed musli occurs in almost all parts of the central region of India. C. borivilianum is a tiny annual herb that develops competently in tropical and sub-tropical environment with altitudes up to 1500 m (Kaushik, 2005). Chlorophytum borivilianim is an annual herb with tubers, crown leaves, and flowers. Subsequent to its innovation at Borivali, Mumbai, the plant has been reported from numerous locations in India such as Dang Forest in Gujarat, Aravali hills in Rajasthan, along plains and lower mount slopes of Akola, Amaravati, Mumbai, Kolhapur, Pune, and Raigad in Maharashtra (Vartak, 1959; Yadav and Sardesai, 2002). The native community of Dhule and Nandurbar districts of Maharashtra consumed the root tubers of C. borivilianum for therapeutic purposes and have initiated its agriculture, investigative of a fact that they are conscious of its socioeconomic significance (Patil, 2001). Largely, the tuberous roots are employed in the synthesis of medicines (Kothari, 2004). There has been a huge requirement of this plant in Indian and worldwide medicine markets, and this plant is an imperative entity of supplementary than hundreds of herbal medicine formulations (Oudhia, 2000, 2001a). The impact of C. borivilianum as drug on the central nervous system is parallel to Chinese herb Ginseng (Patel et al., 2011). The plant is gaining attractiveness as an alternative to “Viagra” due to its spermatogenic property for remedial impotency (Pratap and Rajender, 2012; Kaushik, 2005; Khanam et al., 2013). The C. borivilianum has remedial relevance in ayurvedic procedures. It is considered as an incredibly superior plant in providing common body resistance, aphrodisiac characteristics, helpful for those who are suffering from erectile dysfunction, and helpful to boost male strength. The roots have been extensively utilized for different remedial significances in the ayurvedic and Yunani procedures of remedy. Its roots (tubers) are especially prominent for different remedial significances such as adaptogenic, aphrodisiac, immunomodulatory, and antidiabetic. It is employed to treat substantial diseases and weakness, as an aphrodisiac mediator and regenerate, as a common sex stimulant, in preparation of medicines for diabetes, arthritis, and escalating body protection, in remedial for natural and postnatal troubles, for rheumatism and joint trouble, to increase lactation in feeding mothers; also employed in diarrhea, dysentery, gonorrhea, leucorrhea, and associated ailments. It is identified to treat numerous physical disease and weaknesses. It is furthermore considered as a remedial of natal and postnatal troubles and a treatment for diabetes and arthritis (Sharma and Chandrul,

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2017). Conventionally, safed musli is considered as a common healthinesspromotive stimulant and has been widely utilized to care for different male sexual abnormalities (Thakur et al., 2009). 8.2

BIOACTIVES

The dry safed musli largely composed of carbohydrates, proteins, fibers, saponin, and alkaloids. The saponin and alkaloids formed in the plant are the base for its considerable therapeutic characteristics (Haque et al., 2011). The GC-MS examination of medicine led to the detection of nine composites such as 4H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, diethyl phthalate, 1,3-propanediol, 2-(hydroxymethyl)-2-nitro-isobutylglycerol, diethyl phthalate, phthalic acid, butyl isopropyl ester, butyl nonyl ester, 2-fluorenecarboxaldehyde, 9,10-anthracenedione, and 5-methylhex-2-yl pentadecyl ester (Vyas et al., 2020). Safed musli contains carbohydrates (35–45%), fiber (25–35%), alkaloids (15–25%), saponins (2–20%), and proteins (5–10%) (Desale, 2013). It forms as a prosperous base for the supply of 25 alkaloids, vitamins, proteins, carbohydrates, steroids, saponins, potassium, phenol, resins, mucilage, and polysaccharides; furthermore, it includes an elevated amount of trouble-free sugars, chiefly sucrose, glucose, fructose, galactose, mannose, and xylose. Recently, stigmasterol and saponin identified as furostanol and chlorophytoside-I (3b, 5a, 22R, 25R)-26-(β-dglucopyranosyloxy)-22-hydroxyfurostan-12-one-3yl O-β-d-galactopyranosyl (1–4) glucopyranoside has been extracted (Chakraborthy and Aeri, 2010; Sagun and Srivastava, 2016). It is a base for the prosperous supply of more than 25 alkaloids, vitamins, proteins, carbohydrates, steroids, saponins, potassium, calcium, magnesium, phenol, resins, mucilage, and polysaccharides; furthermore, it is a basis for an elevated extent of trouble-free sugars, mainly sucrose, glucose, fructose, galactose, mannose, and xylose (Thakur et al., 2009). The investigation on extraction compounds bis(2-ethylhexyl) benzene-1,2-dicarboxylate (Fig. 8.1) was for the earliest instance from the roots of C. borivilianum. Highperformance liquid chromatography (HPLC) technique, with photodiode displayed identification, was recognized to discover and measure bis(2-ethylhexyl) benzene-1,2-dicarboxylate (Chua et al., 2015). The bis(2-ethylhexyl) benzene-1,2-dicarboxylate was claimed to acquire antileukemic, antimutagenic (Lee et al., 2000), antimicrobial, cytotoxic, antitumor and antiviral actions (Habib and Karim, 2009). Additionally, fructo–oligosaccharides were accessible from the plant and recognized as O-β-d-fructofuranosyl(2→1)-(β-d-fructofuranosyl)n-(2→1)-α-d-glucopyranoside (n = 5–30) (Fig.

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8.2), by means of high-force anion exchange chromatography, MALDI–MS, NMR, GC, HPTLC, and chemical examinations (Sreevidya et al., 2006). Additionally, the 1′-acetoxychavicol acetate (ACA) was extracted from the roots of C. borivilianum, the configuration of ACA was elucidated. This was the earliest account concerning the occurrence of ACA in C. borivilianum as well as its genus (Fig. 8.3). For the initial instance, a HPLC technique with photodiode selection recognition was invented for the quantitative purpose and detection of ACA (Chua et al., 2017). However, the root is an effective supply of steroidal saponins (i.e., neotigogenin, neohecogenin, stigmasterol, and tokorogenin), phytosterols, polyphenols, flavonoids, and vitamin C composites (Bhagat and Jadeja, 2003; Kaushik, 2005; Visavadiya and Narasimhacharya, 2007).

FIGURE 8.1

Structure of bis(2-ethylhexyl) benzene-1,2-dicarboxylate.

FIGURE 8.2

Structure of Fructans from C. borivilianum.

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FIGURE 8.3

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Structure of ACA.

8.3 PHARMACOLOGY 8.3.1 ANTIMICROBIAL ACTIVITY The antimicrobial potential of C. borivilianum was examined against eight bacteria and four pathogenic fungi, employing microbroth dilution evaluation. The water residues of the plant displayed antimicrobial action in an array of 75–1200 μg/mL (Dabur et al., 2007). The antibacterial action of leaves, stems, fruits, and the root fractions of the plant were predictable by means of cold extraction techniques. The water and organic solvents such as petroleum ether, acetone, and methanol were exploited as solution to obtain the plant residues. The extracted colonies of pathogenic bacteria of gram positive (Staphylococcus citreus) were recognized by typical biochemical experiments. The consequences exposed that water fraction from C. borivilianum possessed an exceptional antibacterial action against gram-positive UTI pathogens (Patel and Patel, 2015). The antibacterial characteristics of diverse residues such as ethanol, ethyl acetate, acetic acid, and aqueous against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis were reported by agar cup diffusion. The acetic acid residues of the plant displayed antibacterial action against the entire bacteria in order of sensitivity as S. aureus˃ P. aeruginosa ˃E. coli ˃B. subtilis (Sundaram et al., 2011). The zone of restriction was calculated in range of 2–24 mm at 10 mg mL−1 for entire residues, and suggested that the residues have ample variety of antibacterial characteristics than the supplementary residues. On the other hand, in another research work, the antimicrobial action of leaves and stems extract of C. borivilianum was considered against four bacteria by agar disc cup diffusion technique. Only the aerial parts of plant restricted the expansion of bacteria at the composition of 1000 and 500 mg/mL correspondingly. The extract displayed a greatest antibacterial action against the entire organisms tested in the following array of sensitivity: Staphylococcus > B. subtilis > Klebsiella > E. coli (Ahmad et al., 2014a).

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Also, the methanolic extracts of leaves and stems part of C. borivilianum were reported by Chakraborthy et al. (2014), with in vitro antimicrobial action employing agar disc diffusion procedure. The leaf extract of the plant showed a devastating composition-dependent antimicrobial characteristics, restricted the enlargement of S. aureus and Bacillus cereus, far beyond that of ampicillin utilized in the investigation at a composition of 1.0 g/mL. Moreover, the methanol residue of the stem indicated a composition-correlated antibacterial action, restricted the augmentation of S. aureus analogous to ampicillin at 1.0 g/mL. Additionally, the methanolic leaves, stems, and the root residues have restriction prospective against the enlargement of K. pneumoniae, B. subtilis, M. tuberculosis, E coli, and S aureus. The MIC of leaves, stem and the root fractions were established in the array of 1–0.125 mg/mL. Furthermore, the crude saponins designated MIC in between 0.5 and 0.0625 mg/mL, against the chosen microbial pathogens (Sharma et al., 2020). Additionally, the residues of leaves and stems of C. borivilianum were subjected to preliminary phytochemical examinations and in vitro antimicrobial investigation, employing agar disc diffusion technique. The leaves residues of plant exhibited awesome composition-dependent antimicrobial characteristics, restricting the development of S. aureus and B. cereus, compared to that of ampicillin, utilized in a composition of 1.0 g/mL. The methanol residue of stem also showed a composition-associated antibacterial action, restricting the development of S. aureus similar to ampicillin at 1.0 g/mL concentration (Chakraborthy and Aeri, 2009). Moreover, the foremost antibacterial actions investigated with Kirby–Bauer disc diffusion technique from the roots of the plant includes principally antibacterial actions of Enterococcus fecalis cold, E fecalis ethanolic, and E. coli methanolic extracts (Choudhary et al., 2015). 8.3.2 ANTIDIABETIC ACTIVITY A fructo–oligosaccharide, isolated from C. borivilianum residues was found to have considerable antidiabetic action with the blood sugar range being 118.32 ± 3.56 and 110.21 ± 4.22, correspondingly, as correlated to the normal assessment of 231.25 ± 3.03 through modest antioxidant action in streptozotocin (STZ)-activated diabetic animals (Sreevidya et al., 2006). Likewise, C. borivilianum root residue activity to diabetic rats maintained close to regular mass, blood glucose, hemoglobin A1c (HbA1c), lipid profile, and insulin range with superior HOMA-β cell performance index, number of islets/pancreas, number of β-cells/Islets; however, with lesser HOMA-insulin

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struggle (IR) index as correlated to non-treated diabetic rats. The negative correlations connecting serum insulin and blood glucose, HbA1c, triglyceride, and whole cholesterol ranges were examined. However, the plant root fraction administration prohibited the enlarged in lipid peroxidation and the reduction in action range of superoxide dismutase, catalase, and glutathione peroxidase through a mild histopathological substitute in the pancreas of diabetic animals (Giribabu et al., 2014a). Similarly, diabetes was activated by particular intraperitoneal injection of alloxan (150 mg/kg of body weight). There was a considerable decrease in blood glucose, urine sugar, and serum lipids through oral administration of alcoholic residues (doses of 25, 50, and 100 mg/kg) in alloxan diabetic rats. The alcoholic C. borivilianum root fraction at a dose of 100 mg/kg was extremely beneficial as it restored entire specifications to the ordinary ranges. The residues moreover increased the whole hemoglobin intensity, and the consequence was analogous to that of insulin (Chakraborthy and Aeri, 2008). Furthermore, the examination on water residue of roots of plant at an amount of 250 and 500 mg/kg body mass correspondingly was examined for antidiabetic action in STZ-activated hyperglycemic rats. The water residue decreased the blood glucose in STZactivated diabetic rats from a range of 285.56–206.82 mg/dL, 6 h subsequent to the oral administration of the residues. The antidiabetic action of water residue was correlated through glibenclamide, an oral hypoglycaemic representative (Mujeeb et al., 2009). In another report, the methanol residue was established to generate considerable decline of blood glucose composition in the array of 2–4 h of administration in alloxan-activated hyperglycemic animals at an examined quantity of range. However, in the normoglycemic animals, the residues at 200 mg/kg created a considerable decline of blood glucose in the time period between 2 and 4 h of administration (Panda et al., 2007). 8.3.3 ANTITUMOUR ANTIMUTAGENIC ACTIVITY The roots of C. borivilianum holding cytotoxic steroidal glycoside saponinchloromaloside-A and spirostanolpentaglycosides embracing β-dapiofuranose were accountable chemicals for anticancer characteristics (Kumar et al., 2010). The anticancer and antimutagenic characteristics of water residue of roots of C. borivilianum were furthermore recognized from the information in skin papillomagenesis investigation. It was confirmed a beneficial reduction in cumulative records of papilloma,

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tumor prevalence, tumor volume, and tumor mass with considerable enlarged in typical latent interval, while the animals received C. borivilianum root residues at 800 mg/kg body mass/day orally in dual distilled water at pre-, peri-, and post-opening phases of carcinogenesis (Mimaki et al., 1996). Additionally, the outcomes of C. borivilianum on cell kinetics and apoptosis in human breast tumor cell lines were investigated by Jamal (2005). In other experimental work, the antiproliferative action utilizing methanolic residue through crude saponin fraction of C. borivilianum has been examined. The study was carried out by MTT and SRB assay followed by DNA fragmentation observations. The conclusion of the examinations was suggestive that the crude saponin residue of plant have potential antitumor activity by means of extremely elevated percentage restrictions (Deore and Khadabadi, 2010b). Moreover, the Kumar et al. (2010) observed anticancer, antimutagenic, and chemomodulatory action of water root residues of C. borivilianum plant. The oral supervision of root residue at three commencing phases of papillomagenesis per day up to 7 days were employed. The papilloma in animals were activated by application of a carcinogen, 7,12-dimethylbenz (a) anthracene (DMBA) followed by a promoter (croton oil). With the residues displayed a considerable decline in the cancer prevalence and cumulative amount of papillomas as correlated to the control assemblage. However, in the antimutagenic investigation, the animals treated through the plant root residues at three phases of papillomagenesis displayed beneficial decline in the whole chromosomal aberrations in the form of chromatid and chromosome breaks, centric rings, dicentrics, interactions, acentric fragments, pulverized cells, and polyploids as compared to the normal. It furthermore evaluated the antitumor characteristics of methanolic, ethanolic, and water residues of C. borivilianum (safedmusli) in BHK-21 cell lines. The cell enlargement was restricted within day; ethanolic and water residues displayed better comeback. The composition of 10 mg/ mL of ethanolic residues displayed superior antitumor action (Joshi and Chauhan, 2013). Nevertheless, in other investigation four innovative spirostane-category saponins named borivilianosides E-H (1–4) were extracted from an ethanol residue of the roots of C. borivilianum collectively with two identified steroid saponins (5 and 6). The cytotoxicity of borivilianosides F (2), G (3), and H (4) and three identified compounds was examined employing two human colon tumor cell lines. Paclitaxel was used as positive control and displayed IC50 standards of 1.1 nM (HCT 116) and 3.6 nM (HT-29) (Acharya et al., 2009).

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8.3.4 LARVICIDAL ACTIVITY

The larvicidal characteristics of C. borivilianum saponin residues was examined for the mosquito species Anopheles stephensi, Culex quinquefasciatus, and Aedes aegypti on the basis of LC50 and EC50 standards. The entire extracts established to be larvicidal action, and among them, the purified saponin fraction was found to be supplementary valuable (Deore and Khadabadi, 2009a). 8.3.5 IMMUNOMODULATORY ACTIVITY The ethanolic root residue of C. borivilianum and its sapogenin were examined for their immunomodulatory action. Administration of residues significantly enhanced survival against Candida albicans contamination. An enhance in the delayed-kind hypersensitivity comeback, percentage neutrophil linkage and in vivo phagocytosis by carbon clearance technique was examined subsequent to the management with the residues. The immunostimulant action of ethanolic residue was additional evident as correlated to sapogenins (Thakur et al., 2007). Furthermore, the purified ethanolic residue of roots of C. borivilianum displayed restriction consequence on intensification of promastigotes with IC50 of 28.25 mg/mL and insignificant cytotoxicity. The residue was toxicologically protected in BALB/c mice, while administered orally with 5 g/kg body weight. The considerable decline in parasite load was examined along with dynamic immunomodulation during superior Th1 category of immune responses, and suppressed Th2 category of immune responses (Kaur and Kaur, 2020). Moreover, polysaccharide fraction (CBP) was resulting from hot aqueous isolation of C. borivilianum (Cb), consisting of ~31% inulin-kind fructans and ~25% acetylated mannans, were reported for its consequence on natural killer (NK) cell action. Human peripheral blood mononuclear cells, extracted from entire blood were examined in the presence or absence of unstable compositions of every plant fraction for modulation of NK cell cytotoxic action with the direction of K562 cells. The examination displayed the observations with considerable inducement of NK cell action to be due to the CBP. Furthermore, the in vivo assessment carried out on Wistar strain albino rats for humoral comeback to sheep RBC and immunoglobulin intensity determination, employing ELISA technique, displayed an efficiency of plant water residues in improving resistant function (Thakur et al., 2011).

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8.3.6 ANTHELMINTIC ACTIVITY The saponin isolation of C. borivilianum has anthelmintic characteristics against Pheretima posthuma, and Ascardia galli. In a research work report, the methanolic residue, crude saponin residue and purified saponin residue, piperazine as reference medicine and distilled water as control were employed. The specification utilized were instance of paralysis and instance of death of the worm. All residues displayed considerable anthelmintic action on preferred worms. The purified saponin residues was established additional dynamic than the other extracts (Deore and Khadabadi, 2010a). 8.3.7 ANTI STRESS ACTIVITY The antistress action of water and alcoholic tuber residues of C. borivilianum were reported by means of swim endurance stress, anorexic examination in rats and despair swim test. The cold tension-activated gastric ulceration representation was also preferred to assess antiulcer action. The consequence of particular oral quantity of the residues was reported at 30, 100, and 300 mg/kg. It was established that alcoholic residue considerably enlarged swimming instance and minimized the ulcer indicator, correlated to that of normal category. A considerable consequence from 200 mg/kg dose for two residues was examined in the entire four representative models (Deore and Khadabadi, 2009b). 8.3.8 ANTIOXIDANT EFFICACY Antioxidant action of the ethanolic residue was reported by 1,1-diphenyl2-picrylhydrazyl (DPPH) radical and hydroxyl radical scavenging action. The capability to decline lipid peroxidation in rat liver tissue along with chelating influence toward ferrous ion was additionally assessed. The ethanolic residue displayed effective antioxidant action as authenticated by scavenging of 85.51% of DPPH radical, 48.95% of hydroxyl radical, and ferryl bipyridyl complex (84.53%). The percentage restriction of lipid peroxidation was found to be 67.17% at 100 µg/mL composition. The considerable restriction of superoxide radical was also displayed in photochemiluminiscense action (Oudhia, 2001b). Another evaluation established the effective antioxidant prospective of this conventional Rasayana medicine. The efforts displayed antioxidant action of water residues of C. borivilianum

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by DPPH free radical scavenging attempt and lipid peroxidation assay. The water residue of plant (250 mg/kg for 7 days) restricts extensively the range of DPPH free radicals and thiobarbituric acid reactive composites, correspondingly in a dose-dependent method. The outcomes recommended that it may perhaps be employed for the management of oxidative stress-activated disorders (Kenjale et al., 2007). Additionally, the action of C. borivilianum root residue was authenticated by means of chemicals/metals-mediated oxidation. The water residue, when applied in graded-quantity, displayed an extremely superior antioxidant influences as authenticated by potent nitric oxide, superoxide, hydroxyl, DPPH, and ABTS radicals scavenging action through dropping competence (ferricyanide couple assays), metal chelating capacity, as well as noticeably restrained the lipid peroxidation in mitochondrial fractions. Further, the water residue extensively reduced copper-mediated human serum and kinetics of LDL oxidation (Visavadiya et al., 2010). Furthermore, an effective antioxidant action of ethanolic residue was established by their capability to scavenge DPPH, hydroxyl radical, and ferryl bi-pyridyl compounds along with the prohibition of lipid per oxidation at 100-µg/mL composition. The ethanolic residue also displayed considerable restriction of superoxide anion radical production by photochemiluminescence (Govindarajan et al., 2005). Moreover, the two dissimilar antioxidant actions [2,2-diphenyl-1-picrylhydrazyl radical scavenging (DPPH)] and hydrogen peroxide-scavenging representation of ethanol and water residues of C. borivilianum were conducted. It was established that ethanol residues of aerial parts of plant exhibited elevated scavenging action compared to the water residue (Ahmad et al., 2014b). A free radical scavenging action (FRSA) measured by α,α-diphenyl-β-picrylhydrazyl (DPPH) exhibited IC50 (restriction composition) 4.96 mg/mL; EC50 (proficient composition) 215.6 mg/mg DPPH and antiradical power (ARP) 0.46 in roots. The AOA in diverse techniques expressed as IC50 in a foresaid plant ingredient in the range 0.93–4.03 mg/mL. The residues displayed considerable shielding consequence against Fenton’s response on supercoiled pUC 18 DNA technique, by agarose gel electrophoresis (Niranjan et al., 2009). In the other investigation, three diverse antioxidant actions DPPH, FIC, and BCB of crude residues and whole saponin fraction of C. borivilianum tubers were conducted by Ashraf et al. (2013). The crude residues were established to possess elevated FRSA and bleaching action (IC50 = 0.7 mg mL−1), while whole saponin fraction exhibited superior ferrous ion chelation (EC50 = 1 mg mL−1). The cytotoxicity assessment of crude residue and whole saponin fraction in opposition to MCF-7, PC3, and HCT-116 tumor cell lines, employing

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3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cell capability experiments represented an elevated cytotoxicity action of the crude residues than the whole saponin fraction on the entire cell lines, being mainly successful and selective on MCF-7 human breast tumor cell line. Besides the discussed research work, aqueous, hydroalcoholic, and methanolic residues were also investigated for antioxidant action. The examination method utilized were DPPH and nitric oxide. In both free radicalsactivated assay techniques, methanolic residue exhibited the highest action as correlated to water, hydroalcoholic residues (Deore and Khadabadi, 2008). However, the water root residue prevents the reduction in sperm measures, percentages of onward motility, viability, HOS, and the enlargement in unusual sperm proportion and caspase-3 range in diabetic rats. The sperm LPO, H2O2, and NO ranges; FBG and HbA1c were poorer, whereas TAC, SOD, CAT, GPx, and epididymal sperm intensity were elevated in diabetic rats receiving C. borivilianum root residue management. The root showed a powerful in vitro FRSA which could be due to the phenolic complex. It was additionally recommended that the residue arrested impairment in sperm characteristics and morphology by means of preventing an increase of oxidative anxiety, apoptosis, and free radicals ranges of the sperm in diabetes. The consequences could be achieved throughout by maintaining sperm antioxidant level, which may perhaps be related to FRSA of the residue by phenolic ingredients (Giribabu et al., 2014b). One additional exploration was on outcome of sodium arsenite by means of dual distilled water lacking or with C. borivilianum in Swiss albino mice for 30 days. The arsenic management displayed a considerable enlarged in LPO, acid and alkaline phosphatase, cholesterol and decline in sperm amount, sperm motility, GSH, and serum testosterone. The collective management exhibited a considerable decline in LPO, acid and alkaline phosphatase, cholesterol and increase in sperm quantity, sperm motility, GSH, and serum testosterone. A testicular histopathology displayed that plant had condensed disintegration of germ cell in the seminiferous tubules and loss of sperms activated by arsenic intoxication (Sharma and Kumar, 2012). In another research work, an attempt has been made to verify the antioxidative prospective of water residue of peels of safed musli tubers employing different in vitro assays, such as DPPH free radical scavenging, deoxyribose degradation, reducing strength, ferrous ions chelation, and lipid peroxidation. The residues displayed a powerful restriction action toward lipid peroxidation of rat liver homogenate activated by the FeCl2–H2O2 system, in both sites and non-site, particularly, deoxyribose degradation as well as in DPPH free radical scavenging assays management.

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It recommended that the peels may perhaps be successfully utilized as ingredients in the fitness supplements, to improve oxidative anxiety (Kaur et al., 2010). Additionally, the research experiments were designed to report the antioxidant and antimutagenic prospective of methanol residue of seeds of C. borivilianum throughout different typical in vitro assays. The action of the seed methanol residues was determined during DPPH free radical scavenging assay, lipid peroxidation, deoxyribose degradation, reducing strength, and chelating influence assays. The residue exhibited beneficial FRSA in DPPH assay, while small to modest restriction prospective in entire the other antioxidant assays (Gill et al., 2015). 8.3.9 ANTI-INFLAMMATORY ACTIVITY Through the utilization of digital plethysmometer, the research work was carried out through dose of 200 mg/kg orally. Both methanolic residues (leaves and roots) of C. borivilianum formed statistically considerable and amount dependent restriction of edema activated by carrageenan at the entire doses, while correlated to the ordinary category. Both residues did not display toxicity in mice when injected intraperitoneally up to the composition of 2 g/ kg (Chakraborthy et al., 2008). 8.3.10 ANTIVIRAL ACTIVITY The antiviral characteristics of water residue and it is probable mechanism for C. borivilianum tubers employing BHV-1 and FMDV viruses as representation viral mediator were evaluated. No antiviral action was established in opposition to IBR virus, but antiviral action was noticed against FMD virus. The action was furthermore predicted by O.D. employing the ELISA test. The ex vivo investigation of HAE of plant demonstrated, that IFN-c activated in rats fed through either of 250 mg or 500 mg/kg body mass, exhibited upregulation at the time of amusement utilizing supernatant harvested from splenocytes developed with or without occurrence of ConA. It was furthermore established by the polymerase chain reaction accessing earlier available primers for IFN-c cDNA enlargement. The plant residues can be used as fitness involvement in fighting with little viral diseases by cytokine modulation; the comprehensive research work on the cytokine stimulation throughout residues of plant can lead to the enlargement of novel conception in designing of antiviral medicine (Singh and Yadav, 2013).

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8.3.11 ANTIHYPERLIPIDEMIC ACTIVITY The administration of C. borivilianum hypercholesteremic rats drastically enlarged high-density lipoprotein–cholesterol range and reduced plasma and hepatic lipid profiles. In addition, there were significant amplification in fecal cholesterol, neutral sterol and bile acid emission with superior hepatic 3-hydroxy-3-methylglutaryl coenzyme. A reductase activity and bile acid production were also designed. The administration of plant root concentrate moreover improved the actions. The antioxidant enzymes and vitamin C range may perhaps have improved the antioxidant competence of the liver (Visavadiya and Narasimhacharya, 2007). 8.3.12 ANTIARTHRITIC ACTIVITY The research investigation was carried out on antiarthritic consequence of water and alcoholic residues of C. borivilianum tubers on complete Freund’s adjuvant (CFA) activated arthritis with Wistar albino rats. It was considerably condensed the paw volume, restricted the body mass loss correlated to medium treated normal rats and thereby residues of plant showed antiarthritic action (Deore and Khadabadi, 2010c). Additionally, the saponin extracted from C. borivilianum (ISCB) were examined utilizing the carrageenan-activated paw edema, histamine-activated paw edema, cotton pellet-activated granuloma, and Freund’s adjuvant-activated arthritis in rats. It was displayed that the ISCB extensively condensed carrageenan-activated inflammation, histamine-activated inflammation, cotton pellet-activated granuloma, and Freund’s adjuvant-activated arthritis in animals. The ISCB at an amount of 30 mg/kg significantly restricted HDAC range in rat paw tissue. It was additionally recommended that ISCB could act by restriction histamine, prostaglandin and HDAC, consequently prospective for remedial exploit in the management of inflammation and arthritis (Lande et al., 2015). 8.3.13 ANTIULCER ACTIVITY The antiulcer action of the methanolic residue of C. borivilianum root tubers were reported by utilizing Pyloric ligation and aspirin activation ulceration models. The entire examination of samples revealed considerable antiulcer action and dose reliant. The consequences designated that the root tubers of plant were endowed with efficient antiulcer action. The antiulcer action

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of the medicine can be attributed to free radical scavenging characteristics, restriction of acid secretory specifications, and escalation of gastric mucosa obstruction (Panda et al., 2011). 8.3.14 ANALGESIC ACTIVITY With the analgesic research work of C. borivilianum, the root residue displayed considerable action. In the tail flick technique, residue at 100 mg/ kg exhibited action subsequent to 45 min, whereas in tail immersion examination, it indicated significant action subsequent to 30 min intermission (Panda et al., 2011). Furthermore, the determination of synergistic analgesic actions of chloroform residues of leaves and roots tubers of Lawsonia inermis Linn. and C. borivilianum in mice were investigated. It revealed that the chloroform residues of both preparations at the dose range of 200 mg/kg body mass appreciably generated analgesic action, but the mixture of both residues exhibited supplementary analgesic action as correlate to L. inermis Linn and C. borivilianum (Kumari et al., 2015). 8.3.15

HORMONAL ACTIVITY

Among the 15 men ingested the nutritional supplement, blood was collected from the subjects previous and subsequent to the ingestion. The GH was analyzed in serum samples by means of an ELISA test. The serum GH enlarged over instance, with superior standards at 60, 80, and 100 min correlated to pre ingestion. The immense deal of subject changeability existed in the part beneath the area under curve (AUC) for GH, with pooled standards ranging in between 0.49 and 61.2 ng mL−1 2 h−1. It was recommended to conclude if chronic application of such supplementation leads to positive modifications in health-associated specifications related with the enhanced circulation of GH (Alleman et al., 2011). 8.3.16

HEPATOPROTECTIVE ACTIVITY

The research wok was carried out on finding the hepatoprotective consequence of C. borivilianum root extract against arsenic activated toxicity. The results exhibited considerable decline in body and liver mass along with disturbed hepatoarchitecture and decline in ATPase action in arsenic

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intoxicated category as compared to the normal. In the combination group, enlarged body and liver mass along with augmented ATPase range and almost usual hepatoarchitecture were examined as compared to arsenictreated group of animals (Sharma and Kumar, 2011). 8.3.17 TOXICITY ACTION The intraperitoneal injection of nicotine (3 mg/kg body mass) for 21 days, displayed considerable decline in testicular mass, sperm amount, motility, serum range of LH, FSH, testosterone and testicular endogenous antioxidant in mature Wister male animals. However, these specifications were restored by C. borivilianum (Chlb) co-administration. The findings designated that Chlb could prospectively be protective against nicotine-activated testicular toxicity (Ray and Majumder, 2018). 8.3.18 APHRODISIAC AND SPERMATOGENIC POTENTIAL The experiments were conducted on aphrodisiac and spermatogenic prospective of the water residue of dried roots of C. borivilianum in rats. Their sexual performances were examined up to 28 days of management, by coupling with a pro-estrous female rat. At 125 mg/kg, residue had a noticeable aphrodisiac activity, enlarged libido, sexual vitality, and sexual arousal. Likewise, at the elevated quantity, the entire specifications of sexual performance were improved, but displayed a saturation consequence subsequent to day 14. On day 60, the sperm measure enlarged appreciably in both plant categories, 125 and 250 mg/kg, in a dose-reliant mode (Kenjale et al., 2008). 8.3.19 ANTIFUNGAL ACTIVITY The methanolic leaves, stem, and root residues have restricting prospective against the development of C. albicans, Aspergillus fumigatus, and Trichoderma in case of fungus. The MIC of leaves, stem and root residues were found in the array of 1–0.125 mg/mL. Additionally, the crude saponins designated MIC in the array of 0.5–0.0625 mg/mL against the preferred microbial pathogens. Saponins performed as one of the most important phytocomponent occurred in C. borivilianum (Sharma et al., 2020). Additionally in another antifungal evaluation, the development of Aspergillus

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niger and C. albicans, used were restricted in the similar style analogous to voriconazole the reference medicine incorporated in the investigation. The residues displayed a weak action against C. albicans as well as A. niger. Both plant sections appear to be validated for their ethnomedical significance (Chakraborthy et al., 2014). KEYWORDS • • • •

Chlorophytum borivilianum Safed musli phytochemistry pharmacology

REFERENCES Acharya, D.; Mitaine-Offer, A-C.; Kaushik, N.; Miyamoto, T.; Paululat, T.; Mirjolet, J-F.; Duchamp, O.; Lacaille-Dubois, M-A. Cytotoxic spirostane-type saponins from the roots of Chlorophytum borivilianum. J. Nat. Prod. 2009, 72, 177–181. https://doi.org/10.1021/ np800559z Ahmad, R. S.; Abul, K.; Pal, K. Phytochemical Analysis and Antimicrobial Activity of Chlorophytum borivilianum Against Bacterial Pathogen Causing Disease in Humans. Int. J. Appl. Sci. Eng. 2014a, 2 (2), 83–89. Ahmad, S. R.; Pal, K.; Kalam, A. In Vitro Antioxidant Properties of Chlorophytum borivilianum (Santapau & Fernandez). World J. Pharm. Pharmaceut. Sci. 2014b, 3 (12), 937–947. Alleman, R. J.; Robert, E. C.; Cameron, G. M. C.; Richard, J. B. A Blend of Chlorophytum borivilianum and Velvet Bean Increases Serum Growth Hormone in Exercise-Trained Men. Nutr. Metabol. Insight. 2011, 4, 55–63. http://dx.doi.org/10.4137/NMI.S8127 Ashraf, M. F.; Aziz, M. A.; Stanslas, J.; Ismail, I.; Kadir, M. A. Assessment of antioxidant and cytotoxicity activities of saponin and crude extracts of Chlorophytum borivilianum. The Scientific World J. 2013, 1–7. http://dx.doi.org/10.1155/2013/216894 Bhagat, C.; Jadeja, G. C. Variation and Correlation in Root Yield and Biochemical Traits of Safed Musali (Chlorophytum borivilianum). J. Med. Arom. Plant Sci. 2003, 25, 33–36. Chakraborthy, G. S.; Aeri, V. Antidiabetic and Anti Hyperlipidaemic Effect of Alcoholic Extract of Chlorophytum borivilianum Roots in Alloxan Induced Diabetic Albino Rats. J. Pharm. Res. 2008, 1 (1), 29–33. Chakraborthy, G. S.; Aeri, V. Phytochemical and Antimicrobial Studies of Chlorophytum borivilianum. Int. J. Pharm. Sci. Drug Res. 2009, 1 (2), 110–112. Chakraborthy, G. S.; Aeri, V. Pharmacognostical Studies of Potential Herb Chlorophytum borivilianum. Int. J. Pharm. Sci. Res. 2010, 1 (4), 89–95.

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Chakraborthy, G. S.; Aeri, V.; Verma, P.; Singh, S. Phytochemical and Antimicrobial Studies of Chlorophytum borivilianum. Pharmacophore 2014, 5 (2), 258–261. Chakraborthy, G. S.; Zafar, R.; Aeri, V. Antiinflammatory Activity of Methanolic Extract of Chlorophytum borivilianum. J. Pharm. Res. 2008, 1 (1), 58–60. Choudhary, N.; Bhati, R.; Bisht, T. Studies on the Anti-Bacterial and Antifungal Activities of Plant Safed Musli (Chlorophytum borivilianum). Int. J. Curr. Res. 2015, 7 (5), 16371–16378. Chua, B. L.; Abdullah, Z.; Pin, K. Y.; Abdullah, L. C.; Choong, T. S. Y.; Yusof, U. K. Isolation, Structure Elucidation, Identification and Quantitative Analysis of Di(2-Ethylhexyl) Phthalate (DEHP) from the Roots of Chlorophytum boriviliuanum (Safed Musli). Res. J. Pharm. Biol. Chem. Sci. 2015, 6 (5), 1090–1095. Chua, B. L.; Abdullah, Z.; Pin, K. Y.; Abdullah, L. C.; Choong, T. S. Y.; Yusof, U. K. Isolation, Structure Elucidation, Identification and Quantitative Analysis of 1′-Acetoxychavicol (aca) from the Roots of Chlorophytum borivilianum (Safed Musli). J. Eng. Sci. Tech. 2017, 12 (1), 198–213. Dabur, R.; Gupta, A.; Mandal, T. K.; Singh, D. D.; Bajpai, V.; Gurav, A. M.; Lavekar, G. S. Antimicrobial Activity of some Indian Medicinal Plants. Afr. J. Tradit. Complement. Altern. Med. 2007, 4 (3), 313–318. Deore, S. L.; Khadabadi, S. S. Antiinflammatory and Antioxidant Activity of Root Extracts. Asian J. Chem. 2008, 20 (2), 983–986. Deore, S. L.; Khadabadi, S. S. Larvicidal Activity of the Saponin Fractions of Chlorophytum borivilianum. J. Entomol. Nematol. 2009a, 1 (5), 64–66. Deore, S. L.; Khadabadi, S. S. Screening of Antistress Properties of Chlorophytum borivilianum tuber. Pharmacologyonline 2009b, 1, 320–328. Deore, S. L.; Khadabadi, S. S. In-Vitro Anthelmintic Studies of Chlorophytum borivilianum. Indian J. Nat. Prod. Resour. 2010a, 1 (1), 53–56. Deore, S. L.; Khadabadi, S. S. Antiproliferative Activity of Saponin Fractions of Chlorophytum borivilianum. Pharmacogn. J. 2010b, 2, 29–33. Deore, S. L.; Khadabadi, S. S. Effect of Chlorophytum borivilianum on Adjuvant Induced Arthritis in Rats. Ann. Biol. Res. 2010c, 1 (1), 36–40. Desale, P. Safed Musli: Herbal Viagra for Male Impotence. J. Med. Plants Stud. 2013, 3, 91–97. Deshwal, R. K.; Trivedi, P. C. Effect of Kinetin on Enhancement of Tuberous Root Production of Chlorophytum borivilianum. Int. J. Innov. Biol. Chem. Sci. 2011, 1, 28–31. Gill, R. K.; Arora, S.; Thukral, A. K. Evaluation of Protective Effects (Antioxidant and Antimutagenic) of Methanol Extract of Seeds of Chlorophytum borivilianum Sant. et Fernand. J. Pharmacogn. Phytochem. 2015, 3 (5), 167–172. Giribabu, N.; Kumar, K. E.; Somesula, S. R.; Muniandy, S.; Salleh, N. Chlorophytum borivilianum Root Extract Maintains Near Normal Blood Glucose, Insulin and Lipid Profile Levels and Prevents Oxidative Stress in the Pancreas of Streptozotocin-Induced Adult Male Diabetic Rats. Int. J. Med. Sci. 2014a, 11 (11), 1172–1184. https://doi.org/10.7150/ ijms.9056 Giribabu, N.; Kumar, K. E.; Somesula, S. R.; Muniandy, S.; Salleh, N. Chlorophytum borivilianum (Safed Musli) Root Extract Prevents Impairment in Characteristics and Elevation of Oxidative Stress in Sperm of Streptozotocin-Induced Adult Male Diabetic Wistar Rats. BMC Complement. Altern. Med. 2014b, 14 (1), 1–16.

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Govindarajan, G.; Sreevidya, N.; Vijayakumar, M.; Thakur, M.; Dixit, V. K.; Mehrotra, S.; Pushpangadan, P. In Vitro Antioxidant Activity of Ethanolic Extract of Chlorophytum borivilianum. Nat. Prod. Sci. 2005, 11 (3), 165–169. Habib, M. R.; Karim, M. R. Antimicrobial and Cytotoxic Activity of Di-(2-Ethylhexyl) Phthalate and Anhydrosophoradiol-3-Acetate Isolated from Calotropis gigantea (Linn.) Flower. Mycobiology 2009, 37 (1), 31–36. https://doi.org/6.10.4489/MYCO.2009.37.1.031 Haque, R.; Saha, S.; Bera, T. A Peer Reviewed of General Literature on Chlorophytum borivilianum Commercial Medicinal Plant. Int. J. Drug Dev. Res. 2011, 3 (1), 165–177. Jamal, M. A. Effects of Safed Musli on Cell Kinetics and Apoptosis in Human Breast Cancer Cell Lines. In International Conference on Promotion and Development of Botanicals with International Co-Ordination Exploring Quality, Safety, Efficacy and Regulation, School of Natural Product Study; Jadavpur University: Kolkata, India, 2005. Joshi, A.; Chauhan, R. S. Cytotoxicity Studies of Chlorophytum borivilianum Against BHK-21 Cells. J. Biol. Chem. Res. 2013, 30 (1), 302–309. Kaur, R.; Thukral, A. K.; Arora, S. Attenuation of Free Radicals by an Aqueous Extract of Peels of Safed Musli Tubers (Chlorophytum borivilianum Sant et Fernand). J. Chin. Clin. Med. 2010, 1 (5), 7–11. Kaur, R.; Kaur, S. Protective Efficacy of Chlorophytum borivilianum Root Extract Against Murine Visceral Leishmaniasis by Immunomodulating the Host Responses. J. Ayurveda Integr. Med. 2020, 11, 53–56. https://doi.org/10.1016/j.jaim.2017.10.009 Kaushik, N. Saponins of Chlorophytum Species. Phytochem. Rev. 2005, 4, 191–196. http:// dx.doi.org/10.1007/s11101-005-2607-5 Kenjale, R. D.; Shah, R. K.; Sathaye, S. S. Anti-Stress and Anti-Oxidant Effects of Roots of Chlorophytum borivilianum (Santapau & Fernandes). Indian J. Exp. Biol. 2007, 45, 974–979. Kenjale, R.; Shah, R.; Sathaye, S. Effects of Chlorophytum borivilianum on Sexual Behavior and Sperm Count in Male Rats. Phytother. Res. 2008, 22,796–801. https://doi.org/10.1002/ ptr.2369 Khanam, Z.; Singh, O.; Singh, R.; Bhat, I. U. H. Safed musli (Chlorophytum borivilianum): A Review of Its Botany, Ethnopharmacology and Phytochemistry. J. Ethnopharmacol. 2013, 150 (2), 421–441. http://dx.doi.org/10.1016/j.jep.2013.08.064 Kothari, S. K. Safed Musli (Chlorophytum borivilianum) Revisited. J. Med. Arom. Plant. Sci. 2004, 26, 60–69. Kumar, M.; Meena, P.; Verma, S.; Kumar, M.; Kumar, A. Anti-tumour, antimutagenic and chemomodulatory potential of Chlorophytum borivilianum. Asian Pac. J. Cancer Prev. 2010, 11 (2), 327–334. Kumari, P.; Singh, N.; Kumar, D. Synergistic Analgesic Activity of Chloroform Extract of Lawsonia inermis Linn. and Chlorophytum borivilianum Sant. J. Pharmacogn. Phytochem. 2015, 3 (6), 35–38. Lande, A. A.; Ambavade, S. D.; Swami, U. S.; Adkar, P. P.; Ambavade, P. D.; Waghamare, A. B. Saponins Isolated from Roots of Chlorophytum borivilianum Reduce Acute and Chronic Inflammation and Histone Deacetylase. J. Integr. Med. 2015, 13 (1), 25–33. http://dx.doi. org/10.1016/S2095-4964(15)60157-1 Lee, K. H.; Kim, J. H.; Lim, D. S.; Kim, C. H. Anti-Leukaemic and Anti-Mutagenic Effects of Di(2-Ethylhexyl) Phthalate Isolated from Aloe vera Linne. J. Pharm. Pharmacol. 2000, 52 (5), 593–598. http://dx.doi.org/doi:10.1211/0022357001774246

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Mimaki, Y.; Kammoto, T.; Sashida, Y. Steroidal Saponins from the Underground Parts of Chlorophytum and Their Inhibitory Activity on Tumor Promoter-Induced Phospholipids Metabolism of Hela Cells. Phytochemistry 1996, 41, 1405–1410. Mujeeb, M.; Khan, S. A.; Ali, M.; Mall, A.; Ahmad, A. Antidiabetic Activity of the Aqueous Extract of Chlorophytum borivilianum L. in Streptozotocin Induced-Hyperglycemic Rats—A Preliminary Study. J. Pharm. Res. 2009, 2, 51–53. Niranjan, A.; Tewari, S. K.; Das, B. Phytochemical and Antioxidant Potential of Chlorophytum borivilianum (Safed Musli) Under Different Agronomical Management Practices. Int. J. Appl. Agric. Res. 2009, 4 (1), 47–55. Oudhia, P. Problems Perceived by Safed Moosli (Chlorophytum borivilianum) Growers of Chhattisgarh (India) Region: A Study; Department of Agronomy, India Gandhi Agriculture University: Raipur, 2000. Oudhia, P. My Experiences with Wonder Crop Safed Moosli. In: Souvenir. International Seminar on Medicinal Plants and Quality Standardization; VHERDS: Chennai, India, 2001a. Oudhia, P. Problems Perceived by Safed Moosli (Chlorophytum borivilianum) Growers of Chhattisgarh (India) Region: A Study. J. Med. Arom. Plants Sci. 2001b, 22/4A & 23/1A, 396–399. Panda, S. K.; Si, S. C.; Bhatnagar, S. P. Studies on Hypoglycaemic and Analgesic Activities of Chlorophytum borivilianum Sant & Ferz. J. Nat. Remedies 2007, 7 (1), 31–36. Panda, S. K.; Das, D.; Tripathy, N. K. Studies on Anti-Ulcer Activity of Root Tubers of Chlorophytum borivilianum Santapau & Fernandes. Int. J. Pharm. Sci. Rev. Res. 2011, 9 (2), 65–68. Patel, D. K.; Kumar, R.; Prasad, S. K.; Hemalatha, S. Pharmacologically Screened Aphrodisiac Plant—A Review of Current Scientific Literature. Asian Pac. J. Trop. Biomed. 2011, 1 (1),131–138. http://dx.doi.org/10.1016/S2221-1691(11)60140-8 Patel, N. B.; Patel, K. C. Antibacterial Activity of Chlorophytum borivilianum Sant. & Fernand. Ethnomedicinal Plant Against Staphylococcus citreus. World J. Eng. Appl. Sci. 2015, 2 (1),1–10. Patil, D. A. Ethnography of the Drug Safed Musali in India: A Review. Anc. Sci. Life 2001, 21, 51–56. Pratap, S. A.; Rajender, S. Potent Natural Aphrodisiacs for the Management of Erectile Dysfunction and Male Sexual Debilities. Front. Biosci. 2012, 4, 67–180. http://dx.doi. org/10.2741/s259 Ray, D.; Majumder, S. The Protective Effects of Chlorophytum borivilianum on NicotineInduced Reproductive Toxicity, Oxidative Damage, Histological Changes and Haematotoxicity in Male Rats. J. Innov. Pharm. Biol. Sci. 2018, 5 (2), 76–81. Sagun, V.; Srivastava, P. Preparing Medicine from Chlorophytum borivilianum. Int. J. Biotechnol. Biomed. Sci. 2016, 2 (2), 178–180. Sharma, S. K.; Kumar, M. Hepatoprotective Effect of Chlorophytum borivilianum Root Extract Against Arsenic Intoxication. Pharmacologyonline 2011, 3, 1021–1032. Sharma, G.; Kumar, M. Antioxidant and Modulatory Role of Chlorophytum borivilianum Against Arsenic Induced Testicular Impairment. J. Environ. Sci. 2012, 24 (12), 2159–2165. Sharma, P.; Chandrul, K. K. Chlorophytum borivilianum (Safed Musli): A Vital Herbal Drug. Int. J. Pharm. Med. Res. 2017, 5 (1), 401–411. Sharma, P.; Singh, V.; Maurya, S. K.; Kamal, M. A.; Poddar, N. K. Antimicrobial and Antifungal Properties of Leaves to Root Extracts and Saponin Fractions of Chlorophytum

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borivilianum. Curr. Bioact. Compd.2020, 16, 1–11. http://dx.doi.org/10.2174/1573407216 999201006124428 Singh, B.; Yadav, S. K. Antiviral and Cytokine Modulating Potential of Chlorophytum borivilianum Hot Aqueous Extract. Abstract/Cytokine 2013, 63, 243–314. http://dx.doi. org/10.1016/j.cyto.2013.06.248 Sreevidya, N.; Govindarajan, R.; Madhavan, V.; Thakur, M.; Dixit, V. K.; Mehrotra, S.; Madhusudanan, K. P. Action of (2→1) Fructo-Oligo Polysaccharide Fraction of Chlorophytum borivilianum Against Streptozotocin-Induced Oxidative Stress. Planta Med. 2006, 72 (15), 1421–1424. http://dx.doi.org/10.1055/s-2006-951705 Sundaram, S.; Dwivedi, P.; Purwar, S. Antibacterial Activities of Crude Extracts of Chlorophytum borivilianum to Bacterial Pathogens. Res. J. Med. Plant. 2011, 5 (3), 343–347. http://dx.doi.org/10.3923/rjmp.2011.343.347 Thakur, M.; Bhargava, S.; Dixit, V. K. Immunomodulatory Activity of Chlorophytum borivilianum Sant. F. eCAM. 2007, 4 (4), 419–423. http://dx.doi.org/10.1093/ecam/nel094 Thakur, G. S.; Bag, M.; Sanodiya, B.; Debnath, S. M.; Zacharia, A.; Bhadauriya, P.; Prasad, G. B. K. S.; Bisen, P. S. Chlorophytum borivilianum: A White Gold for Biopharmaceuticals and Neutraceuticals. Curr. Pharm. Biotechnol. 2009, 10, 650–666. Thakur, M.; Paul, C.; Myrna, A. D.; Carol, M.; Dixit, V. K. Immunomodulatory Polysaccharide from Chlorophytum borivilianum Roots. Evid. Based Complement. Altern. Med. 2011, 1–8. http://dx.doi.org/10.1093/ecam/neq012 Vartak, V. D. Some Edible Wild Plants from the Hilly Regions of the Poona District, Bombay State. J. Bombay Nat. Hist. Soc.1959, 56 (1), 8–25. Visavadiya, N. P.; Narasimhacharya, A. V. R. L. Ameliorative Effect of Chlorophytum borivilianum Root on Lipid Metabolism in Hyperlipidemic Rats. Clin. Exp. Pharmacol. Physiolog. 2007, 34, 244–249. http://dx.doi.org/10.1111/j.1440-1681.2007.04579.x Visavadiya, N. P.; Soni, B.; Dalwadi, N.; Madamwar, D. Chlorophytum borivilianum as Potential Terminator of Free Radicals in Various In Vitro Oxidation Systems. Drug Chem. Toxicol. 2010, 33 (2), 173–182. Vyas, R.; Sharma, G.; Chaturvedi, A.; Devki, S.; Sisodia, R. GC-MS and HPLC Analysis of Chlorophytum borivilianum (Safed Musli) a Plant from Ayurveda-Herbal Viagra. Glob. J. Reprod. Med. 2020, 7 (5), 96–101. http://dx.doi.org/10.19080/ GJORM.2020.07.55567230097 Yadav, S. R.; Sardesai, M. M. Flora of Kolhapur District; Shivaji Univ: Kolhapur, 2002; pp 496–497.

CHAPTER 9

Traditional Uses, Phytochemistry and Pharmacology of Bryonopsis laciniosa (L.) Naudin KUMKUM AGARWAL SINHA* Department of Botany, Shaheed Bhagat Singh Government Degree College, Ashta, District Sehore, Madhya Pradesh, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Bryonopsis laciniosa is an ethnobotanical plant with immense medicinal importance. Its main active constituents are punicic acid, bryonin, non-ionic glucomannan, goniothalamin and triterpene glycosides. Quercetin, betasitosterol, syringic acid, ferulic acid, kaempferol have also been reported in the plant. These chemicals were found to confer a number of pharmacological activities as androgenic, anticancer, antidiabetic, antioxidant, and antimicrobial activities. 9.1

INTRODUCTION

Bryonopsis laciniosa (L.) Naudin is a creeper, belonging to the family Cucurbitaceae. It is globally distributed in the tropical regions. In India, it is distributed in plain lands. It is commonly known as shivlingi, because the structure of its seeds is similar to that of a shivling in Hindu religion. Seeds are used for various vaginal dysfunctions, promote fertility (Khare, 2007). It is an annual plant which grows in rainy season and dries at the end of rainy season, when winter starts. Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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This plant holds an important place in ethnobotany as well as in traditional system of medicine. The seed powder with a spoon of honey is taken twice daily to ensure conception and prevent miscarriage (Patel and Parekh, 2013; Tiwari, 2017). Seed powder mixed with root powder of Withania somnifera and Asparagus racemosus and bark powder of Drypetes roxburghii Linn. given with warm water once a day for 3 months promotes fertility in women (Kachare et al., 2010). Seed powder given with “bark decoction” of Ficus benghalensis promotes fertility in women (Kachare et al., 2010). Seed powder given with fruit powder of Thespesia populnea, taken with “jaggery” after menstrual cycle starting from fourth day of M.C. up to 3 days continuously in cases to promote fertility in women (Kachare et al., 2010). Seeds are useful in leucorrhea, menstrual troubles, and bleeding during pregnancy (Jeyalakshmi et al., 2014). The seeds are taken to increase fertility in women (Mohanty et al., 2015). Dried seeds fried in ghee ground into powder with water and milk is given to increase fertility in women (Nidagundi et al., 2018). Seeds rubbed and the paste is applied locally in the case of scorpion bite (Kachare et al., 2010). Powder of its seeds in water is given in the treatment of snake bite (Soman, 2014). Fresh ripened fruits taken with mixture of Kalmegh, Giloy, Neem, and Tulsi in the case of malaria and typhoid fever (Sharma et al., 2010). Fruits are considered to have antimalarial property (Pateriya et al., 2013). Fruits are used for the treatment of excessive bleeding during menstruation and lower abdominal pain during menstrual period. Its fruit juice is mixed with the juice of the leaves of Eclipta alba to which ash of any metal (dhatu bhasya) is added. This preparation is taken in the morning with banana in an empty stomach for 7 days (Mohammed et al., 2012). To cure infertility in woman, a fruit is inserted into a banana fruit and taken in an empty stomach in the morning once only. Alternately, a fruit of Bryonopsis is inserted into a banana and kept overnight. This fruit is eaten in the morning in an empty stomach once daily for 2 weeks (Mohammed et al., 2012). Tender root paste is taken with water in empty stomach for stomach disorder and crushed fruit mixed with gram seed is used to cure syphilis (Mohanty et al., 2015). The plants are used in bilious attacks and also in fever with flatulence (Chauhan, 2017; Sharma et al., 2014). Fresh leaves are crushed in cold water, this syrup is given with curd in the treatment of piles. The extract of its leaves is used in the case of round worm infection (Matte et al., 2014).

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BIOACTIVES

Chemical screening revealed the presence of different bioactives in various parts of B. laciniosa. The plant extracts in phytochemical screening showed the presence of steroids, saponins, alkaloids, flavonoids, phenolic compounds, tannins, and terpenoids (Sanjeevkumar et al., 2016b). The main active constituents of the plant are punicic acid, non-ionic glucomannan, goniothalamin and triterpene glycosides were also found to be present (Tiwari, 2017). Leaves contain p-coumaric acid, ferulic, syringic, caffeic, and p-hydroxybenzoic acids, flavonoids (quercetin, kaempferol), n-hentriacontane, n-triacontane, α and β amyrin, and sitosterol (Tiwari, 2017). Phytochemical screening of fruit by various investigators as Ramya et al. (2015a) and Bashyam et al. (2015) showed the presence of terpenoids, reducing sugar, amino acids, anthraquinone, polyphenols, glycosides, tannins, anthocyanins, saponins, coumarins, emodins, alkaloids, flavonoids, lignin, and serpentine. Along with these vitamins, such as C, D and E, iron, calcium, magnesium, potassium, chloride were also found in high amount. Sulfate and sodium were in a moderate level. Carbon, phosphorous, sodium, sulfur, zinc, and manganese were found in substantial amount, while copper, boron, selenium, and molybdenum were present in trace amounts (Velavan, 2015). Ramya et al., (2015a) did GC-MS analysis of methanolic extract of fruits which showed the presence of hexanoic acid, sulfurous acid, n-nonaldehyde, 2-hepten-3-ol, decadienal, 3-octenoic acid, 1,4-Cyclohexanedimethanol adipate, acetic acid 3-acetoxy-5-oxo-decyl ester, 9-octadecenoic acid, 2H-pyran-2-one, Z,Z-4,15-octadecadien-1-ol acetate. Similarly, Tiwari (2017) analyzed the fruit extract by the same technique and showed the presence of 2-ethylcyclohexane, oleic acid, 2-undecenal, 1,2-benzene dicarboxylic acid, 2-methyltetracosane, ascorbic acid, octadeconoic acid, 2,6-dihexadeconoate; (2E)-2-decenal, sulfurous acid, 2-hepten-3-ol, n-nonaldehyde, decadienal, oxooctyl acid, 3-octenoic acid, and goniothalamin. The methanolic extract of whole plant was fractionated, goniothalamin was also extracted from its ethyl acetate fraction (Mosaddik et al., 2000) while saponins were extracted from its whole plant (Verma et al., 2008). The aerial parts of Bryonopsis were examined for phenolic and flavonoid content which was found to be 126.1 mg GAE/g and 262.6 mg of CE/g in gallic acid and catechin equivalents, respectively (Valluri et al., 2017). Similarly, Yadavalli et al. (2012) showed the presence of punicic acid, lipids, bryonin, goniothalamin, glucomannan, and arabinoglucomannan in different extracts of Bryonopsis. Seeds were found to contain steroids in the form of

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beta-sitosterol (Swapna et al., 2014). The structures of important chemical constituents present in B. laciniosa were constructed using chemdraw online tool (https://chemdrawdirect.perkinelmer.cloud/ js/sample/index.html).

FIGURE 9.1 Structures of Quercetin (1), Beta-sitosterol (2), Syringic acid (3), Ferulic acid (4), Punic acid (5), Caffeic acid (6), Kaempferol (7), p-Coumaric acid (8), parahydroxybenzoic acid (9), Goniothalamin (10), Glucomannan (11) (https://chemdrawdirect.perkinelmer.cloud/ js/sample/index.html).

9.3 PHARMACOLOGY 9.3.1 ANDROGENIC ACTIVITY Ethanolic extract of seeds showed androgenic activity and its effect on hyphothalamic pituitary gonadal axis (Tiwari, 2017). In a study by Chauhan and Dixit (2010), ethanolic extract of seeds was administered to groups of male albino rats, orally at 50, 100, and 150 mg/kg dosage level for 28 days, which showed potent androgenic activity.

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9.3.2 ANTICANCER OR CYTOTOXICITY ACTIVITY

Potent anticancer activity against human breast adenocarcinoma, human squamous cell carcinoma, and cervix cancer was found in the water extract of its leaves (Moghe et al., 2011). Fruit extract showed anticancer activity on lung cancer cell line (A549) (Ramya, 2016) and on nitrosodiethyl amineinduced liver cancer in male albino rats (Mahalakshmi, 2017). Cytotoxicity activity of hexane extract of the fruit was noticeable against MCF-7 cell line (Sanjeevkumar et al., 2018). In a study by Mosaddik and Haque (2003) and Tiwari (2017), potent cytotoxicity with LC50 values (5.03 µg/mL) was shown by goniothalamin which was comparable with the reference standard agent, gallic acid. 9.3.3 ANTIDIABETIC ACTIVITY B. laciniosa seeds and saponin fraction showed potent anti-diabetic activity by decreasing urea and creatinine levels when compared with diabetic control group (Patel et al., 2015). Ethanolic extract of seed showed antihyperglycemic and antihyperlipidemic effects in streptozotocin-induced diabetes in rats (Bhide et al., 2017). 9.3.4 ANTI-INFLAMMATORY ACTIVITY Potent anti-inflammatory activity was found in the aqueous, methanolic, and chloroform extracts of B. laciniosa leaves (Suruse et al., 2009). In another study, various inflammation-inducing agents, such as carrageenan, histamine, dextran, and serotonin were used to induce paw edema, and granuloma (chronic) was induced using cotton pellet in rats. The chloroform extract of leaves (CEBL) exhibited prominent anti-inflammatory activity at 200 mg/kg dosage (Gupta et al., 2003). Similarly, anti-inflammatory activity of hexane extract of fruits was comparable to the anti-inflammator activity of diclofenac drug.Hexane extract showed promising activity for the inhibition of protein denaturation assay (Sanjeevkumar et al., 2018). 9.3.5 ANTI-MICROBIAL ACTIVITY Antimicrobial activity of ethanolic extract of different parts of B. laciniosa was evaluated. Leaf and stem extracts showed inhibition comparable to

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standard antibiotics. They inhibited the activity of Staphylococcus aureus, Micrococcus luteus, and Bacillus cerues at all concentrations except Pseudomonas aeruginosa for 10 mg/mL (Yadavalli et al., 2012; Bonyadi et al., 2009). Goniothalamin showed potent antifungal activity (Mosaddik and Haque, 2003; Tiwari, 2017). 9.3.6 ANALGESIC ACTIVITY Different extracts of leaves (aqueous, methanol, and chloroform extracts) showed potent analgesic activities (Suruse et al., 2009). 9.3.7 ANTIOXIDANT ACTIVITY Methanolic extract of fruits due to the presence of flavonoids and polyphenols was found to show potent antioxidant activity when tested by different assays as DPPH assay, superoxide anion scavenging assay, Fe2+ chelating assay, and nitric oxide scavenging assay (Ramya et al., 2015b). Chloroform extract of fruits showed antioxidant activity comparable to standards as ascorbic acid and BHT. Presence of phenol and other compounds were considered responsible for this (Sanjeevkumar et al., 2016a). 9.3.8 ANTICONVULSANT ACTIVITY Alcoholic extract (70%) of whole plant of B. laciniosa showed anticonvulsant activity by delaying the onset of MES-induced seizures and protecting treated mice from mortality induced by seizures as compared with the group treated with standard anticonvulsant drug Carbemazepine (95.58) which reveals that there was significant increase in anticonvulsant activity in the case of B. laciniosa-treated group (Reddy et al., 2010). 9.3.9 MOSQUITO LARVICIDAL ACTIVITY Goniothalamin isolated from B. laciniosa was found to be highly effective against the larvae of Culex quinquefasciatus mosquito (Kabir et al., 2003).

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KEYWORDS

• • • • • • • •

ethnobotanical shivlingi Bryonopsis laciniosa punicic acid bryonin anticancer androgenic seeds

REFERENCES Bashyam, R.; Thekkumalai, M.; Velavan, S. Evaluation of Phytoconstituents of Bryonopsis laciniosa Fruit by UV-Visible Spectroscopy and FTIR Analysis. Pharmacogn. J. 2015, 7 (3), 165–170. Bhide, S. S.; Maurya, M. R.; Gajbhiye, S. V.; Tadavi, F. M. Evaluation of Nephroprotective Effect of Bryonia laciniosa on Streptozotocin Induced Diabetic Nephropathy in Rats. Int. J. Basic Clin. Pharmacol. 2017, 6 (5), 1193–1200. Bonyadi, R. E.; Awad, V.; Kunchiraman, N. B. Antimicrobial Activity of the Ethanolic Extract of Bryonopsis laciniosa Leaf, Stem, Fruit and Seed. Afr. J. Biotechnol. 2009, 8 (15), 3565–3567. Chauhan, N. S.; Dixit, V. K. Effects of Bryonia laciniosa Seeds on Sexual Behaviour of Male Rats. Int. J. Impot. Res. 2010, 22, 190–195. Chauhan, R. S. Studies on Medicinal Plants Used by Tribal Communities in District Singrauli of Madhya Pradesh. Int. J. Sci. Res. Publ. 2017, 7 (1), 2250–3153. Gupta, M.; Mazumdar, U. K.; Thangavel, S;, Vamsi, M. L. M.; Karki, S. S.; Sambathkumar, R.; Manikandan, L. Evaluation of Anti-Inflammatory Activity of Chloroform Extract of Bryonia laciniosa in Experimental Animal Models. Biol. Pharm. Bull. 2003, 26 (9), 1342–1344. Jeyalakshmi, G.; Nithyananthi, M.; Jayashree, R.; Yuvaraj, D.; Hariram, S. B. A Review on the Herbs in Practice Among the Tribal Communities of Nilagiri District for Gynecological Problem. Int. J. Pharmacogn. Phytochem. Res. 2014, 6 (3), 580–583. Kabir, K. E.; Khan, A. R.; Mosaddik. M. A. Goniothalamin—A Potent Mosquito Larvicide from Bryonopsis laciniosa L. J. Appl. Entomol. 2003, 127 (2), 112–115. Kachare, S. V.; Raut, K. S.; Surywanshi, S. R. Medicinal Plants Used by Local Inhabitants in Marathwada. Int. J. Curr. Res. 2010, 4, 49–51. Khare, C. P. Bryonopsis laciniosa. In Indian Medicinal Plants: An Illustrated Dictionary; Khare, C. P., Ed.; Springer: New York, 2007; p 103.

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Mahalakshmi, S. Anticancer Activity of Bryonopsis laciniosa on Nitrosodiethyl Amine Induced Liver Cancer in Male Albino Rats. Ph.D. Thesis, Bharathidasan University, 2017, pp 1–182. Matte, R. S.; Kale, M. C.; Warhate, S. R. Ethnobotanical Studies on the Flora of Yavatmal District—Some Interesting Reports of Herbal Medicines. Int. J. Res. Biosci. Agric. Technol. 2014, 2 (2), 317–324. Moghe, A. S.; Gangal, S. G.; Shilkar, P. R. In Vitro Cytotoxicity of Bryonia laciniosa (Linn.) Naud. on Human Cancer Cell Lines. Indian J. Nat. Prod. Resour. 2011, 2 (3), 322–329. Mohammed, R.; Biswas, A.; Haq, W. M.; Seraj, S.; Jahan, R. An Ethnomedicinal Survey of Cucurbitaceae Family Plants Used in the Folk Medicinal Practices of Bangladesh. Chron. Young Sci. 2012, 3 (3), 212–222. Mohanty, N.; Panda, T.; Sahoo, S.; Rath, S. P. Herbal Folk Remedies of Dhenkanal District, Odisha, India. Int. J. Herb. Med. 2015, 3 (2), 24–33. Mosaddik, M. A.; Haque, M. E. Cytotoxicity and Antimicrobial Activity of Goniothalamin Isolated from Bryonopsis laciniosa. Phytother. Res. 2003, 17 (10), 1155–1157. Mosaddik, M. A.; Haque, M. E.; Rashid, M. A. Goniothalamin from Bryonopsis laciniosa Linn (Cucurbitaceae). Biochem. Syst. Ecol. 2000, 28, 1039–1040. Nidagundi, R.; Shoba, H.; Hosamani, V.; Krisnappa; Gangadharappa, P. M. Ethnomedicinal Plants and Their Utilization by Villagers in Koppal District of Karnataka. J. Pharmacogn. Phytochem. 2018, 3, 450–452. Patel, P. K.; Parekh, P. P. Therapeutic Uses of Some Seeds Among the Tribals of Banaskantha District, Gujarat, India. Rom. J. Biol. Plant Biol. 2013, 58 (1), 79–82. Patel, S. B.; Santani, D.; Patel, V.; Shah, M. Anti-Diabetic Effects of Ethanol Extract of Bryonia laciniosa Seeds and Its Saponins Rich Fraction in Neonatally Streptozotocin-Induced Diabetic Rats. Phcog. Res. 2015, 7 (1), 92–99. Pateriya, V.; Agrawal, P.; Tiwari, B. Ethnomedicinal Plants as Natural Remedies in Chhatarpur District of Madhya Pradesh. Int. J. Agric. Sci. 2013, 9 (1), 376–378. Ramya, B.; Malarvili, T.; Velavan, S. GC-MS Analysis of Bioactive Compounds in Bryonopsis laciniosa Fruit Extract. Int. J. Pharm. Sci. Res. 2015a, 6 (8), 3375–3379. Ramya, B.; Malarvili, T.; Velavan, S. In Vitro Antioxidant Activity of Bryonopsis laciniosa Fruit Extract. Indian J. Appl. Res. 2015b, 5 (9), 262–266. Ramya, M. B. Anticancer Activity of Bryonopsis laciniosa Fruit Extract on Lung Cancer Cell Line A549. Ph.D. Thesis, Bharathidasan University, 2016, pp 1–172. Reddy, J.; Vijay, D.; Gnanasekaran, D.; Ranganathan, T. V. In Vitro Studies on Anti Asthmatic, Analgesic and Anti Convulsant Activities of the Medicinal Plant Bryonia laciniosa Linn. Int. J. Drug Discov. 2010, 2 (2), 1–10. Sanjeevkumar, C. B.; Londonkar, R. L.; Kattegouda, U. M.; Tukappa, N. K. A. Screening of In Vitro Antioxidant Activity of Chloroform Extracts of Bryonopsis laciniosa Fruits. Int. J. Curr. Microbiol. App. Sci. 2016a, 5 (3), 590–597. Sanjeevkumar, C. B.; Londonkar, R. L.; Kattegouda, U. M.; Tukappa, N. K. A. In Vitro Antioxidant Anti-Inflammatory and Cytotoxicity Activities from Hexane Extract of Bryonopsis laciniosa Fruits. Res. Rev. J. Botany. 2018, 7 (1), 1–8. Sanjeevkumar, C. B.; Londonkar, R. L.; Umesh, M. K.; Aruna, L. H.; Amarvani, P. K. Preliminary Phytochemical Screening from Different Extracts of Bryonopsis laciniosa Fruits. Res. Rev. J. Herb. Sci. 2016b, 6 (2), 25–29.

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Sharma, A.; Santvan, V. K.; Sharma, P.; Chandel, S. Studies on Traditional Knowledge of Ethnomedicinal Plants in Jawalamukhi, Himachal Pradesh, India. Int. Res. J. Biol. Sci. 2014, 3 (10), 6–12. Sharma, V. K.; Diwan, R. K.; Saxena, R. C.; Shrivastava, P. N.; Saxena, R. Survey Report of Medicinal Plant Used in Folk Medicine in Tribal Areas of Pandhurna, District Chhindwara (Madhya Pradesh). Biomed. Pharmacol. 2010, 3 (2), 403–408. Soman, G. Some Medicinal Plants of Panhala Taluka Used as Antidotes. Int. J. Life Sci. 2014, 2 (3), 276–278. Suruse, P. B.; Duragkar, N. J.; Bodele, S. B. Anti-Inflammatory and Analgesic Activities of Leaf Extracts of Bryonopsis laciniosa Linn. Int. J. Plant Sci. 2009, 4 (1), 179–181. Swapna, N.; Alekhya, M.; Asfia, N.; Rahmath, S.; Darshini, D.; Likhitha, S.; Jyothirmayee, A.; Sohail, Md.; Rao, M. R.; Prathiba, G. Phytochemical Screening of Plant Bryonopsis laciniosa Linn. Seed. Acta Biomed. Sci. 2014, 1 (4), 173–178. Tiwari, V. J. Assessment of Validity of Ethnopharmacological Uses of Medicinal Plants Used by Tribal People of Gadchiroli District of Maharashtra State. India Res. J. Pharmacogn. Phytochem. 2017, 9 (1), 08–16. Valluri, L. B.; Krishna, K. S. M.; Madhu, C. Phytochemical Screening and In Vitro Antioxidant Potential of Hydroalcoholic Extract from the Aerial Parts of Bryonopsis laciniosa. Int. J. Pharm. Bio. Sci. 2017, 8 (4), 109–118. Velavan, S. Micronutrients and Vitamin Analysis of Bryonopsis laciniosa Fruits. Int. J. Pharm. Bio. Sci. 2015, 6 (4), 265–273. Verma, K. S.; Saxena, N.; Baliyani, N.; Kosta, D. K. Isolation, Purification and Pharmacological Studies of Saponins from a Medicinal Plant Bryonopsis laciniosa. J. Phytol. Res. 2008, 21 (1), 111–114. Yadavalli, R.; Gopal, Y. V.; Sreenivas, S. A. Phytochemisty and Pharmacology of Bryonia laciniosa: A Review. Int. J. Pharm. 2012, 2 (3), 542–547. theplantlist.Org https://chemdrawdirect.perkinelmer.cloud/js/sample/index.html#

CHAPTER 10

Diplocyclos palmatus (L.) C. Jeffrey: An Important Medicinal Striped Cucumber SURAJ B. PATEL and SAVALIRAM G. GHANE* Plant Physiology Laboratory, Department of Botany, Shivaji University,

Kolhapur, Maharashtra 416004, India

Corresponding author.

E-mail: [email protected]; [email protected]

*

ABSTRACT Diplocyclos palmatus (L.) C. Jeffrey (Family: Cucurbitaceae) commonly called as Lollipop climber. It is native to Australia, Malaysia, Papua New Guinea and Tropical Africa. Seed morphology is similar to “Shivling”, an icon of Lord Shiva; hence, locally known as ‘Shivlingi’. Traditionally, it is used in the treatment of many life-threatening diseases. Seeds are used for improving sexual behavior and as a general tonic. Root and seed powder used to induce fertility in women. Alcoholic seed extract promote spermatogenesis and also found helpful in increasing sperm count. Leaves, stem, fruits, seeds, and roots of D. palmatus showed presence of bioactive compounds like triterpenoids, phenolic acids, flavonoids, steroids, glycosides and fatty acids. Pharmacological activities such as antidiabetic, androgenic, antioxidant, cytotoxic, anti-inflammatory, analgesic, antimicrobial, antifertility, anticonvulsant, antivenom, antipyretic, antihyperglycemic, antihyperlipidemic etc. have been reported from this plant. The potential benefits, bioactivities and potent compounds from different plant parts of Diplocyclos have been thoroughly discussed in the current chapter.

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10.1 INTRODUCTION Diplocyclos palmatus (L.) C. Jeffrey (Family Cucurbitaceae) is commonly called as Lollipop Climber, Marble Vine, native bryon, and striped cucumber. Its basionym is Bryonia palmata L. The plant is native to Australia, Malaysia, Papua New Guinea, and Tropical Africa, and slightly warmer region. In India, it is found in wild and along the roadside. It is an annual climbing herb. Its tendrils are slender and bifid. Leavers are five-lobed, male and female flowers are separate. Male flowers are found in small fascicles of 3–6 peduncles, and female flower single, axillary. At maturity, fruit color becomes red with white lines on the upper surface. The outer surface of seed contains marking and morphology similar to “Shivling” which is an icon of Lord Shiva; Hence, commonly called as “Shivlingi” (Chauhan and Dixit, 2010). In addition, it is also identified by several vernacular names. Shivalingi (Gujarati, Hindi), Lingatonde balli (Kannada), Karta (Konkani), Aiviralikkova (Malayalam), Mahadevi and Shivalingi (Marathi), Sava (Nepali), Apashtambhini, Chitraphala, Lingaja, Lingini, Shivavalli (Sanskrit), Aivirali (Tamil), Lingadonda (Telugu), and Lingatonde (Tulu). Traditionally, it is used in the treatment of different life-threatening diseases. The historical ayurvedic books, such as Rajanighantu and Nighantu ratnakara reported the applicability of this plant (Vadnere et al., 2013). Seeds are constituent of “Striratival-labhpugpak” mentioned in ancient text, used to improve sexual behavior and general tonic (Vaidya, 1970). Due to the presence of versatile phytoconstituents, it shows several important bioactivities denoted. Various tribes from all over India and globe use this plant for curing different diseases (Misra et al., 2017; Patel et al., 2020). Due to different hidden compounds in plants, it has foetid smell, acrid, depurative and used as tonic. Gupta et al. (2010) performed ethnobotanical survey in Gond tribes from Maharashtra (Bhandara) and noted that root and seed powder are used twice a day in empty stomach for inducing fertility in women. Pushpangadan and Atal (1984) carried out ethnomedicobotanical investigations in seven primitive tribes viz., Cholanaikken, Pathinaikken, Paniyan, Kuruman, Irular, Adiyan, and Kurichan from dense forest of Western Ghats of Kerala and reported that daily consumption of two fresh fruits for 7 days before ovulation period found effective for conceiving male child. 10.2 BIOACTIVES Chemical screening of Diplocyclos revealed the presence of bioactive compounds, such as triterpenoids, phenolic acids, flavonoids, steroids,

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glycosides, and fatty acids (Patel et al., 2020; Misra et al., 2017; Attar and Ghane, 2017; Gowrikumar et al., 1981; Mahanthesh et al., 2017; Metri et al., 2019). Recently, tetracyclic triterpenoids, such as cucurbitacin I and cucurbitacin B have been reported from the fruit extract of D. palmatus with 514.28 and 558.712 molecular mass, respectively (Patel et al., 2020). Similarly, isoquercetin (flavonoid) isolated from methanol extract of whole plant and characterized by several separation techniques, such as TLC, UV, FTIR, H-NMR, and HR-LCMS (Metri et al., 2019). Rodge and Biradar (2016) separated rutin and quercetin from the methanolic extract of the leaves and fruits, respectively. In addition, Patel et al. (2020) reported isovaleric acid, luteolin 7-(2″-pcoumaroylglucoside), deserpidine (alkaloid), beta-hederin (saponin), cardiac glycosides (digitalose and bufadienolide), and cardioprotective steroids (digoxigenin monodigitoxoside and minabeolide-8) from the fruits. Gowrikumar et al. (1981) isolated punicic acid from the seeds of Diplocyclos. Patil et al. (2011) also separated β-carotene from the

fruits using HPTLC.

Several phenolic compounds (catechin, hydroxybenzoic acid, chlorogenic acid, gallic acid, protocatechuic acid, caffeic acid, caffeic acid 3-glucoside, and vanillic acid) have been also reported (Misra et al., 2017; Patel et al., 2020). GC-MS screening of chloroform extract showed several compounds, such as phosphonic acid (p-hydroxyphenyl), benzoic acid, 4-piperidinepropanoic acid, pyrrolidine-5-one, 2-pyrolidine, 3-oxo-4-phenylbutyronitrile, propanedioic acid, benzeneacetic acid, 3,5-bis(1,1-dimethyl) phenol, dodecanoic acid, 2(4H)-benzofuranone, 1-pentadecanol, 1-nonadecne, phenol, and di-n-octyl phthalate (Mahanthesh et al., 2017). Important bioactives are denoted in Figure 10.1. 10.3 PHARMACOLOGY 10.3.1 ANTIDIABETIC ACTIVITY Oral administration of methanolic seed extract was subjected to investigate antidiabetic potential in Swiss albino mice. After 15 days of treatment, reduction in blood glucose was observed. Similarly, significant increase in liver glycogen and decrease in urine sugar was reported (Tripathi et al., 2012). Recently, fruit extract revealed highest inhibition of α-amylase (68.68 ± 0.66%) and α-glucosidase (56.27 ± 0.60%) enzymes (Patel et al., 2020).

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FIGURE 10.1 Bioactive compounds from Diplocyclos palmatus.

10.3.2 ANDROGENIC ACTIVITY Ethanolic seed extract at 50–150 mg/kg body weight per day for 28 days was used to investigate the androgenic activity in albino male rat and changes in sexual behavior, reproductive organ weight, testis histology, and sperm density were studied. Results revealed that body weight, testis weight, and testosterone level were significantly increased in the treated animals (Chauhan and Dixit, 2010).

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GYNECOLOGICAL ACTIVITY

Abraham (1981) suggested that it has significant role in reproductive medicines and used in the treatment of female infertility, leucorrhea, and aphrodisiac. 10.3.4 ANTIOXIDANT ACTIVITY Antioxidant potential has been reported by several researchers (Attar and Ghane, 2017; Patel et al., 2020). Methanol fruit extract represented reliable DPPH (25.1 ± 0.1 µg AAE/g DW), ABTS (81.9 ± 0.45 µg TE/g DW), and phosphomolybdate activity (577.4 ± 9.6 µg AAE/g DW) (Patel et al., 2020). Attar and Ghane (2017) analyzed the leaf and fruit extracts and reported that methanol extract of fruits revealed highest DPPH, metal chelating, and phosphomolybdenum activity (26.73 ± 0.14, 0.80 ± 0.01 and 291.24 ± 2.19 mg AAE/g extract, respectively). Aqueous leaf extract also represented highest ABTS (12.11 ± 0.07 mg TE/g extract) and FRAP activity (141.54 ± 10.12 mg Fe (II)/g extract) (Attar and Ghane, 2017). 10.3.5

CYTOTOXIC ACTIVITY

Extract of fruits has been tested against breast (MCF-7) and colon (HT-29) cancer cell lines (Patel et al., 2020). Inhibition of growth in both the cancer cell lines was dependent on the concentration of extract. LC50 values were 44.27 and 63.20 µg/mL for MCF-7 and HT-29 cancer cell lines, respectively. It could be due to the presence of tetracyclic triterpenes called cucurbitacins and other major metabolites present in the fruit (Patel et al., 2020). 10.3.6 ANTIARTHRITIC ACTIVITY Ethanolic extract of seed at different doses (100, 200, and 400 mg/kg body weight) used to study antiarthritic activity. Several parameters (paw volume, joint diameter, thermal and mechanical hyperalgesia, biochemical and hematological parameters, and histopathology of synovial joint) have been studied. Increased concentration of the extract showed significant reduction in increased paw volume and joint diameter. Higher concentrations (200 and 400 mg/kg) revealed reduction in cell infiltration and erosion of joint

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cartilage in treated rat. Authors recommended that D. palmatus could be used in the treatment of arthritis, pain, and inflammation (Kadam and Bodhankar, 2013). 10.3.7 ANTI-INFLAMMATORY ACTIVITY Chloroform extract of leaves was tested for anti-inflammatory activity using carrageenan, dextran, histamine, serotonin-induced paw edema and cotton pellet-induced granuloma (chronic) rat models. Gradual increase in the extract concentration from 50, 100, and 200 mg/kg represents significant anti-inflammatory activity. Highest inhibition (52.4%) was found at 200 mg/kg dose in carrageenan-induced paw edema rat. Similarly, in dextraninduced paw oedema model, activity increases in dose-dependent manner. In the case of chronic model, chloroform extract (200 mg/kg) reduced the formation of granuloma tissue by 50.1%. Histamine and serotonin caused hind paw edema in rats and significant inhibition was observed when treated with extract (Gupta et al., 2003). 10.3.8 ANALGESIC ACTIVITY Ram Kishan et al. (2019) performed the study to assess the analgesic activity of ethanolic extract of fruit (100, 200, and 400 mg/kg) using tail tip, tail immersion, and radiant heat method. In tail tip method, 400 mg/kg at 10 min (11 ± 1.67) and 15 min (10 ± 0.707) attained significant output. In tail immersion method, best output was found for 200 mg/kg dose at 10 min (11.4 ± 1.93) and 15 min (13.4 ± 1.63). Similarly, in radiant heat method, 200 mg/kg extract dose represented outstanding output, that is, at 10 min (11.3 ± 1.67) and 15 min (14 ± 1.82). Reddy et al. (2010) evaluated analgesic activity of 70% alcoholic extract by using Eddy’s hot plate and analgesiometer tests. Results denoted that treated extract showed increase in analgesic activity as compared with control. 10.3.9 ANTIMICROBIAL ACTIVITY Ethanolic extract of D. palmatus was investigated against two bacteria Escherichia coli (Gram-negative bacteria) and Bacillus (Gram-positive bacteria) using agar diffusion method. The highest zone of inhibition (14 mm) was

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found in E. coli at 1:1 concentration of ethanol and extract (Ram Kishan et al., 2019). Supe (2013) studied the callus extracted with methanol and water against Bacillus cereus, Staphylococcus aureus, Enterobacter aerogenes, Escherichia coli, and Klebsiella pneumoniae. Author reported that K. pneumoniae strain was found more susceptible while others did not show any inhibitory effect. 10.3.10 ANTIFERTILITY ACTIVITY Traditionally, this plant is used in the treatment of infertility-related disorders. Ethanol extract has been shown to increase the body weight, testis, prostate, epididymis and seminal vesicle, spermatogenesis, sperm count, fructose content of seminal vesicle, serum testosterone, and LH that exhibited antifertility activity (Chaudhari and Avlaskar, 2013; Casson et al., 2000). 10.3.11 ANTICONVULSANT ACTIVITY Chloroform, alcohol, and aqueous extracts of dried leaves have been evaluated for anticonvulsant activity using pentylenetetrazole (PTZ) and maximal electroshock stimulation (MES) induced in Wistar albino rats. Among all, chloroform extract was found to be highly potent in both PTZ and MES models (Mahanthesh and Jalalpure, 2015). Alcoholic extract (70%) with electric shock (2 s) given to albino rat showed percent reduction of extensor phase. Results showed 39.27% reduction in extensor phase after treatment (Reddy et al., 2010). 10.3.12 ANTIVENOM AND ANTIDOTE ACTIVITY Mixture of 50 g of leaf paste and 2–3 spoonful of betal paste given to the patient immediately after snakebite for 3 days reduced body pain (Shah et al., 2015). 10.3.13 ANTIASTHMATIC ACTIVITY Alcoholic extract (70%) was tested for antiasthmatic activity in albino rats using Atopic allergy method (Reddy et al., 2010). Oral administration of the

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extract (300 mg/kg body weight, 7 days) showed 56.27% increase in percent granulation and 43.88% protection of cells in the treated rat when compared with predisolone. 10.3.14 ANTIPYRETIC ACTIVITY Methanol extract (125, 250, and 500 mg/kg body weight) was used to study the antipyretic activity in Swiss albino rat (Sivakumar and Perumal, 2004). Study revealed that 125 mg/kg dose showed significant decrease in body temperature up to 4 h. Subcutaneous injections of yeast suspension markedly increase the rectal temperature up to 19 h. Methanol extract significantly reduced the yeast-provoked elevation of body temperature and exhibited antipyretic effect as compared with paracetamol. 10.3.15 ANTIHYPERGLYCEMIC AND ANTIHYPERLIPIDEMIC ACTIVITY Oral administration of ethanolic seed extract (250 and 500 mg/kg; p.o. for 28 days) was used to test antihyperglycemic activity using streptozotocininduced diabetic rats. Results showed significant decrease in blood glucose, triglycerides, cholesterol, high and density lipoprotein, aspartate amino transferase, alanine amino transferase, urea and creatinine in streptozotocininduced diabetic rats. Animals treated with extract restored all these biochemical parameters near to control range (Patel et al., 2012). KEYWORDS • • • • •

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REFERENCES Abraham, Z. Glimpses of Indian Ethnobotany; Oxford and Publishing Co.: New Delhi, 1981; pp 308–320. Attar, U. A.; Ghane, S. G. Phytochemicals, Antioxidant Activity and Phenolic Profiling of Diplocyclos palmatus (L.) C. Jeffery. Int. J. Pharm. Pharm. Sci. 2017, 9, 101–106. Casson, P. R.; Lindsay, M. S.; Pisarska, M. D.; Carson, S.A.; Buster, J. E. Dehydroepiandrosterone Supplementation Augments Ovarian Stimulation in Poor Responders: A Case Series. Hum. Reprod. 2000, 15 (10), 2129–2132. Chaudhari, V. M.; Avlaskar, A. D. Role of Shivlingi in Infertility, J. Homeop. Ayurveda Med. 2013, 2–5. Chauhan, N. S.; Dixit, V. K. Effects of Bryonia laciniosa Seeds on Sexual Behavior of Male Rats. Int. J. Impot. Res. 2010, 22, 190–195. Gowrikumar, G.; Mani, V. V. S.; Rao, T. C.; Kaimal, T. N. B.; Lakshminarayana, G. Diplocyclos palmatus L.: A New Seed Source of Punicic Acid. Lipids 1981, 16, 558–559. Gupta, M.; Mazumdar, U. K.; Sivakumar, T.; Vamsi, M. L. M.; Karki, S. S.; Sambathkumar, R.; Manikandan, L. Evaluation of Anti-Inflammatory Activity of Chloroform Extract of Bryonia laciniosa in Experimental Animal Models. Biol. Pharma. Bull. 2003, 26 (9), 1342–1344. Gupta, R.; Vairale, M. G.; Deshmukh, R. R.; Chaudhary, P. R.; Wate, S. R. Ethnomedicinal Uses of Some Plants Used by Gond Tribe of Bhandara District, Maharashtra. Indian J. Tradit. Know. 2010, 9 (4), 713–717. Kadam, P.; Bodhankar, S. L. Antiarthritic Activity of Ethanolic Seed Extracts of Diplocyclos palmatus (L) C. Jeffrey in Experimental Animals. Der. Pharm. Lett. 2013, 5 (3), 233–242. Mahanthesh, M. C.; Gautam, G.; Jalalpure, S. S. Development and Screening of Anticonvulsant Polyherbal Formulation. Res. J. Pharm. Tech. 2017, 10 (5), 1402–1416. Mahanthesh, M. C.; Jalalpure, S. S. Pharmacognostical Evaluation and Anticonvulsant Activity of Leaves of Diplocyclos palmatus Linn. Int. J. Pharm. Bio. Sci. 2015, 6 (4), 734–751. Metri, S.; Singh, R. P.; Shah, M. Isolation and Identification of Isoquercetin—A Flavonoid from Bryonia laciniosa Linn. Int. J. Adv. Res. 2019, 7 (10), 780–786. Misra, A.; Shukla, P. K.; Kumar, B.; Niranjan, A.; Rawat, A. K. S.; Sharad, S. SimultaneousHPLC Quantification of Phenolic Acids in Traditionally Used Ayurvedic Herb Diplocyclos palmatus (L.) Jeffry. Pharmacogn. J. 2017, 9 (4), 483–487. Patel, S. B.; Attar, U. A.; Sakate, D. M.; Ghane, S. G. Efficient Extraction of Cucurbitacins from Diplocyclos palmatus (L.) C. Jeffrey: Optimization Using Response Surface Methodology, Extraction Methods and Study of Some Important Bioactivities. Sci. Rep. 2020, 10, 2109. https://doi.org/10.1038/s41598-020-58924-5 Patel, S. B.; Santani, D.; Shah, M. B.; Patel, V. S. Anti-Hyperglycemic and Anti-Hyperlipidemic Effects of Bryonia laciniosa Seed Extract and Its Saponin Fraction in StreptozotocinInduced Diabetes in Rats. J. Young Pharm. 2012, 4, 171–176. Patil, A.; Patil, D. A.; Sharma, A.; Chandra, N. Quantification of β-Carotene from Diplocyclos palmatus Jeff. Fruits Rind by Using High Performance Thin Layer Chromatography. Asian J. Chem. 2011, 23 (2), 788–790. Pushpangadan, P.; Atal, C. K. Ethno-Medico-Botanical Investigations in Kerala I. Some Primitive Tribals of Western Ghats and Their Herbal Medicine. J. Ethnopharmacol. 1984, 11, 72.

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Ram Kishan, J.; Khaja, Z.; Venkanna, P.; Sateesh, K. V. Evaluation of Antimicrobial and Analgesic Activity of Diplocyclos palmatus Fruits on Albino Mice. Asian J. Pharm. Clin. Res. 2019, 12 (2), 81–85. Reddy, J.; Gnanasekaran, D.; Vijay, D.; Ranganathan, T. V. In Vitro Studies on Anti-Asthmatic, Analgesic and Anti-Convulsant Activities of the Medicinal Plant Bryonia laciniosa Linn. Int. J. Drug Discov. 2010, 2 (2), 1–10. Rodge, S. V.; Biradar, S. D. Quantification of Rutin and Quercetin in Diplocyclos palmatus (Roxb.) Jeffrey. World J. Pharm. Res. 2016, 5 (9), 1485–1491. Shah, A.; Bharati, K. A.; Ahmad, J.; Sharma, M. P. New Ethnomedicinal Claims from Gujjar and Bakerwals Tribes of Rajouri and Poonch Districts of Jammu and Kashmir, India. J. Ethnopharmacol. 2015, 166, 119–128. Sivakumar, T.; Perumal, P. Evaluation of Analgesic, Antipyretic Activity and Toxicity Study of Bryonia laciniosa in Mice and Rats. Am. J. Chin. Med. 2004, 32 (4), 531–539. Supe, U. In Vitro Antibacterial Activity and Callogenesis of Bryonia laciniosa. Int. J. Pharm. Sci. Res. 2013, 4 (4), 1556–1560. Tripathi, J.; Kumari, R.; Ashwlayan, V. D.; Bansal, P.; Singh, R. Anti-Diabetic Activity of Diplocyclos palmatus Linn. in Streptozotocin-Induced Diabetic Mice. Indian J. Pharma. Educ. Res. 2012, 46 (4), 352–359. Vadnere, G. P.; Pathan, A. R.; Kulkarni, B. U.; Singhai, A. K. Diplocyclos palmatus: A Phytopharmacological Review. Int. J. Res. Pharm. Chem. 2013, 3 (1), 157–159. Vaidya, L. Bhavprakash; Motilal Banarsidas: Varanasi, 1970.

CHAPTER 11

Bioactives and Pharmacology of Curcuma neilgherrensis Wight B. KAVITHA1* and N. YASODAMMA2 Department of Botany, Rayalaseema University, Kurnool 518007,

A.P., India

1

Department of Botany, Sri Venkateswara University, Tirupati,

Andhra Pradesh, India

2

Corresponding author.

E-mail: [email protected]; [email protected]

*

ABSTRACT Curcuma neilgherrensis (family Zingiberaceae) is a rare and endemic medicinal plant. It is used for multiple therapeutic activities like antioxidant, hepatoprotective, antiasthmatic, cholagogue, antitumour, blood purifier, stomachic, antiinflammatory, chronic hepatitis, antiarthritis, antiseptic, menstrual disorders and skin diseases. The present review explores on chemical constituents and pharmacological activities of C. neilgherrensis. A range of phytochemicals including alkaloids, phenols, flavonoids, terpenoids, steroids, saponins, tannins, lignins, glycosides, anthocyanidins and indoles were reported from various parts of the C. neilgherrensis. The qualitative analysis revealed with 27 phenolic, 7 flavonoid and 8 anthocyanidin compounds in all parts of C. neilgherrensis.

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INTRODUCTION

An endemic medicinal plant Curcuma neilgherrensis Wight belongs to the family Zingiberaceae. This species is an herb, root fibers numerous, slender, root tuber small and white inside. Leafy shoot 25–35 cm tall, leaves 4–6, shortly petiolate, lanceolate or oblong- lanceolate, acuminate, narrowed at base, 15–25 × 8.5–9.5 cm. Inflorescence lateral, appears before the leaves 10–15 × 4–5 cm; coma bracts 5–7 oblong, lanceolate, pink or purple; fertile bracts oblong-lanceolate, pale yellowish green; flower 4–4.5 cm; bright yellow; calyx three-lobed, violet dotted, 0.8–1.2 cm long; corolla tube 1.5 cm long, lobes oblong, whitish yellow; anther thecae parallel, spurred, 3.5–4 mm long; style long, filiform, bilipped; ovary trilocular, ovules many. Capsule 1–1.3 cm in diameter; seeds ovoid or globose, arillate, brown 3–4 mm long (Jadhao and Bhuktar, 2018). It is commonly called as “Manjakoova” (Yesodaram and Sujana, 2007); “Katter-kalvazhai” (Arinathan et al., 2007), Narrow-leaved turmeric, East Indian Arrow root (English), Keturi haludhi (Bengali), Tikhur (Hindi), Tavakeera (Marathi), Kattumanjal, Koova, Vellakkua (Malayalam), and Yaipan (Manipuri) (Jadhao and Bhuktar, 2018). The plant has a lot of medicinal properties as anti-inflammatory, cholagogue, hepatoprotective, blood purifier, antioxidant, taoxifier, antiasthmatic, antitumor, stomachic, carminative, and regenerator of liver tissue (Gantait et al., 2011). It is also used for chronic hepatitis, antiarthritis, antiseptic. and menstrual disorders (Samydurai et al., 2012). According to the traditional data from the local herbalists, and from Yanadi tribes of Seshachalam hill ranges, the rhizomes of C. neilgherrensis are used to treat cuts, boils, wounds, skin diseases, jaundice, pimples, bone fractures, common cold, ulcers, swellings, small pox, chicken pox, snake bites, worm infestation, and wound infections. It is also used in their common diet to control the cholesterol levels (Chaithra et al., 2013a, 2013b). 11.2

BIOACTIVES

Preliminary phytochemical screening of various phytochemical constituents of leaf, scape, flower, root, and rhizome reveals the presence of alkaloids, flavonoids, phenols, terpenoids, steroids, anthocyanidins, saponins, tannins, lignins, glycosides, carbohydrates, proteins, indoles, and amino acids. The

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qualitative analysis of phenolic compounds reveals the presence of 27 components in all parts as 15 in leaf, 20 in scape, 15 in rhizome and 13 in root. Phloroglucinol, homo-protocatechuic acid, cis-p-coumaric acids are present only in scape, neo-chlorogenic acid is present only in leaf, p-hydroxy benzoic acid is specific in rhizome, coumarins in root are very significant compounds. Most common compounds are caffeic acid, gentisic acid, o-coumaric acid, trans-sinapic acid, vanillic acid, trans-ferulic acid, cis-sinapic acid, syringic acid, and salicylic acid are present in most of the parts (Yasodamma et al., 2014).

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The flavonoid compounds present in all parts of C. neilgherrensis were found to be six compounds. Leaf with 5, scape 3, rhizome 2, and root 2 compounds. Myricetin and kaempferol are present only in leaf. Common flavonoids are quercetin and apigenin in most of the parts (Yasodamma et al., 2014).

The anthocyanidin components that exist in all parts of the plant include eight different compounds in total. Leaf with 1, scape 5, rhizome 6 and root 6 compounds. Petunidin present only in scape, luteolinidin is present in root is a very significant compound. Peonidin, rosinidin and hirsutidin are most common anthocyanidins in majority of the parts (Yasodamma et al., 2014).

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The GC-MS results showed the presence of total 17 major compounds, namely, 2-heptanone, 3-thujene, β-pipene, camphor, 3-carene, eucalyptol, n-heptane, α-thujene, 3,5-dimethoxy (toluene), 2,7-napthalene-diol, pinocarvone, humulen-6,7-epoxide, terpineol, α-amorphene, caryophyllene, α-caryophyllene, and curcumol, respectively (Chaithra, 2017).

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PHARMACOLOGICAL STUDIES

11.3.1 ACUTE TOXICITY In acute toxicity studies of C. neilgherrensis leaf, rhizome, and root, aqueous and methanol extracts of a single oral dose did not show any significant toxicity signs and mortality on Wistar albino rats when observed for first 4 hours and followed by daily doses for 14 days and does not show toxicity and also there are no signs and symptoms, such as changes in body weight and food intake, psychomotor activities, restlessness, respiratory distress, diarrhea, convulsions, and coma. The drug was found to be safe at the tested dose levels of 1000, 2000, 3000, 4000, and 5000 mg/kg b.wt. according to 425 OECD guidelines (Chaithra et al., 2015).

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11.3.2 ANALGESIC ACTIVITY Analgesic activities of C. neilgherrensis rhizome extracts were tested on experimental rats. The aqueous and methanol extracts at 100–1000 gm/Kg b.wt. along with the standard drug Diazepam as positive control 10 gm/Kg b.wt. The acetic acid induced experimental animals were treated with test samples of plant extracts along with standard Diazepam. The analgesic activity was compared between test samples and positive control by measuring the mean writhing (specific body contraction) effects. In the study, it was found that the extracts of C. neilgherrensis were found effective in reducing the mean writhing effects and inhibition percentage at 500 mg by 9.1 number of writhings with 76.24% which is almost equal to the Diazepam-treated rats showing 8 number of writhings with 79.11% inhibition of analgesic effect. This clearly shows that the extracts have analgesic activity almost equal to that of standard drug Diazepam. The analgesic activity of C. neilgherrensis may be due to the phytoconstituents, such as curcuminoids and essential oils (Yasodamma and Chaithra, 2016). 11.3.3 ANTIARTHRITIC ACTIVITY The antiarthritic activity of the aqueous and methanol rhizome extracts of C. neilgherrensis with 250–1000 mg/Kg b.wt. using the Complete Freund’s Adjuvant (CFA)-induced arthritic rats was investigated. Antiarthritic effect of the extracts as well as standard drug Diclofenac sodium was evaluated by measuring injected paw volume on 0th, 7th, 14th, and 21st day by using sliding Vernier calipers. The mean change of injected paw volume with respect to initial paw volume was calculated and also compared with control and standard drug-treated rats and calculated the antiarthritic effect. The rhizome aqueous and methanol extracts of C. neilgherrensis were found effective at 500 mg/kg b.wt. The experimental results showed that there is a great reduction in the volume of rat hind paw with rhizome extractstreated rats compared with that of normal rats and diclofenac-treated rats. Also, the side effect such as loss or gain in body weight was not observed in rhizome extracts-treated rats. The hematological and biochemical parameters which get affected generally in the arthritis rats were not affected in the rhizome extracts-treated rats. Similar types of results were observed in studies conducted with the rhizome extracts of Alpinia galanga, C. longa, C. zedoaria and with Zingiber officinale. Therefore C. neilgherrensis rhizome extracts may be recommended as antiarthritic drug to that of the

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other Zingiberaceae species which possessed curcuminoids and essential oils (Yasodamma and Chaithra, 2016). 11.3.4 ANTHELMINTIC ACTIVITY The antihelmintic activity of rhizome aqueous and methanol extracts of C. neilgherrensis and Zingiber officinale, individually and in combination was investigated. The anthelmintic activity was measured by calculating the time taken for paralysis of worms and death of worms. The combination of both plant extracts in 1:1 ratio has been shown to be effective compared with individual plant extracts. The methanol and alcohol extracts of C. neilgherrensis and Z. officinale have shown the time taken for paralysis between 10.2 and 3.4 min whereas the time taken for the death of worms is in the range of 18–10 min. Combined plant extracts in 1:1 ratio for paralysis takes 6.9–1.9 min and the time taken for death is 15.6–7.2 min. Overall results of the plant extracts are more effective than the control drug Albendazole, as the time for paralysis is 91–34 min and the time taken for death is 110–41 min. These results clearly suggest that the rhizome extracts of C. neilgherrensis possess celic phytoconstituents mainly phenols (Yasodamma et al., 2013a). 11.3.5 ANTIBACTERIAL ACTIVITY The antibacterial activity of leaf and rhizome of C. neilgherrensis in cold water, hot water, alcohol, methanol, and hydro alcoholic extracts at different concentrations has been found as 10, 50, 100, and 150 mg/well. The mean inhibition concentration was observed as 10 mg/well. The antibacterial activity of leaf and rhizome extracts on four bacterial strains such as Bacillus subtilis (MTCC-441), Staphylococcus aureus (MTCC-737), Escherichia coli (MTCC-443), and Pseudomonas aeruginosa (MTCC-741) has shown excellent activity on all four strains when compared with the zone of inhibition with standard drug ampicillin. The antibacterial activity of leaf and rhizome extracts are in the order of alcohol> methanol > hot water > cold water > hydro alcoholic extracts, respectively. All extracts of leaf and rhizomes are showing minimum inhibitory concentrations at a very low level against all pathogens ranging between 0.078 to 2.5 mg (Yasodamma et al., 2013b). Zinc oxide nanoparticles (ZnO NPs) of C. neilgherrensis leaf extract also showed antibacterial activity. Pseudomonas aeruginosa was found to be more susceptible to ZnO NPs (Parthasarathy et al., 2017).

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11.3.6 ANTIDIABETIC ACTIVITY The antidiabetic activity of C. neilgherrensis aqueous and rhizome extracts was evaluated on Alloxan-induced diabetic albino rats 250 mg/kg b.wt. After 21 days of treatment of diabetic albino rats with the extracts and positive control, the blood glucose levels in diabetic albino rats treated with rhizome extracts were more or less equal to that of control rats and standard drug glibenclamide-treated rats. Along with antidiabetic activity several hematological and biochemical parameters were also measured. The results clearly show that the extracts have no side effects on these parameters. Acute toxicity studies as per OECD 425 guidelines showed that the extracts can be used up to 5000 mg (Chaithra and Yasodamma, 2016). 11.3.7 ANTIDIARRHEAL ACTIVITY Antidiarrheal activity of C. neilgherrensis aqueous and methanol leaf and rhizome extracts at 250, 500, and 1000 mg/kg b.wt. on castor oil-induced diarrhea and enteropooling in male Wistar albino rats. Atropine 3 mg/kg b.wt. as a standard positive control for antidiarrheal activity. Leaf methanol extracts at 1000 mg/kg b.wt. showed 6.1 dry and 2.1 wet defecations after 4 h with 65% of diarrheal inhibition, whereas rhizome methanol extracts showed 6.3 dry and 1.8 wet defecation with 70% of inhibition to that of the standard drug as 6.4 dry and 2.4 wet defecations with 60% of inhibition. Enteropooling activity was also very effectively reduced with rhizome methanol extracts as 1.4 mL and 60% of inhibition and 1.7 mL with 51.4% leaf methanol extracts to that of the control drug atropine with 1.6 mL and 54.2% of intestinal fluid inhibition. The antidiarrheal activity shown by aqueous extracts was comparatively less than methanol extracts. Methanol extracts of rhizome at 1000 mg/ kg b.wt. have proved to be more effective to that of Atropine 70% antidiarrheal activity and 60% of fluid inhibition than the aqueous extracts, which may be due to the presence of tannins, terpenoids, glycosides, flavonoids, and saponins. Acute toxicity studies proved that the drug is safe at a dose of 5000 mg/kg b.wt. without any behavioral changes (Chaithra et al., 2015). 11.3.8 ANTI-INFLAMMATORY ACTIVITY Rhizome aqueous and methanol extracts of C. neilgherrensis were tested for anti-inflammatory activity at various concentrations 250, 500, and

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1000 mg/kg b.wt. Diclofenac was standard drug for positive control at concentration 100 mg/kg b.wt. Acute inflammation in male Wistar rats was induced by injecting carrageenan with gum acacia in right hind paw. Carrageenan-induced rat paw edema was reduced by the C. neilgherrensis rhizome methanol extracts at 250 mg/kg b.wt. more effectively than aqueous extracts which showed equal activity compared with that of Diclofenac with 63.15% of inhibition of inflammation. Acute toxicity studies have shown that the drug was safe up to 5000 mg/kg b.wt. (Chaithra et al., 2016). 11.3.9 ANTIOXIDANT AND HEPATOPROTECTIVE ACTIVITY The antioxidant and hepatoprotective activity of aqueous and methanolic extracts of leaf and rhizomes of C. neilgherrensis on male albino Wistar rats were studied. Wistar rats were injected with 10% alcohol in drinking water on daily basis throughout the experiment and on the final day, CCl4 (2 mL/kg b.wt.) was injected. The alcohol induces Cytochrome P450 2E1 which metabolizes CCl4 to its oxidant form. The extracts were administered at a dose of 200 mg/kg b.wt. while Silymarin was given at 100 mg/ kg b.wt. as positive control for antioxidant activity. Activities of several enzymes, such as CAT, GSH, and GST and TBARS that are involved in antioxidation were restored by C. neilgherrensis pretreatment (Rubalakshmi et al., 2019). 11.3.10 ANTIFUNGAL ACTIVITY The antifungal activity of leaves and rhizome alcohol and methanol extracts of C. neilgherrensis on two fungal strains Candida albicans than Aspergillus niger was evaluated. Nystatin was used as positive control. Both leaf and rhizome extracts showed most effective nearly double the activity than the reference drug Nystatin with 10.2–12.1 mm on both the tested fungal strains respectively. A. niger 19.2–29.5 mm and C. albicans 20.3–31.3 mm of zone of inhibition. And it is also observed that C. albicans is most susceptible than A. niger with methanol and alcohol extracts followed by hot water and cold water extracts. Further, the minimum inhibitory concentration values also proved that the antifungal activity of extracts was effective than the standard drug Nystatin (Chaithra et al., 2013a, 2013b).

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KEYWORDS

• • • • •

endemic medicinal plant Zingiberaceae Curcuma neilgherrensis bioactives pharmacological studies

REFERENCES Arinathan, V.; Mohan, V. R.; De Britto, J.; Murugan, C. Wild Edibles Used by Palliyars of the Western Ghats, Tamil Nadu, Indian J. Trad. Knowl. 2007, 6 (1), 163–168. Chaithra, D. Pharmacognostic Studies and In Vivo Propagation of Curcuma neilgherrensis Wt. A Medicinal Plant of Seshachalam Hills. Ph.D. Thesis, Sri Venkateshwara University, 2017. Chaithra, D.; Yasodamma, N. Anti-Diabetic Activity of Curcuma neilgherrensis Wt. Rhizome Extracts on Alloxan Induced Diabetic Albino Rats. World J. Pharm. Res. 2016, 5 (4), 657–679. Chaithra, D.; Yasodamma, N.; Alekhya, C. Antidiarrhoeal Activity of Curcuma neilgherrensis Wt. World J. Pharm. Pharm. Sci. 2015, 4 (9), 545–555. Chaithra, D.; Yasodamma, N.; Alekhya, C. Antifungal Activity of Curcuma neilgherrensis Wt. A Wild Medicinal Plant. Indo Am. J. Pharm. Res. 2013a, 3 (5), 3903–3909. Chaithra, D.; Yasodamma, N.; Alekhya, C. Phytochemical Screening of Curcuma neilgherrensis Wt. An Endemic Medicinal Plant from Seshachalam Hills (AP) India. Int. J. Pharm. Bio. Sci. 2013b, 4 (2), 409–412. Chaithra, D.; Yasodamma, N.; Alekhya, C. Anti-Inflammatory Activity of Curcuma neilgherrensis wt. Rhizome Extracts. World J. Pharm. Pharm. Sci., 2016, 4, 1040–1053. Gantait, A.; Barman, T.; Mukherjee, P. Validated Method for Determination of Curcumin in Turmeric Powder. Indian J. Trad. Knowl. 2011, 10 (2), 247–250. Jadhao, A. S.; Bhuktar, A. S. Genus Curcuma L. (Zingiberaceae) from Maharashtra State— India. Int. J. Curr. Res. Biosci. Plant Biol. 2018, 5 (10), 39–48. Parthasarathy, G.; Saroja, M.; Venkatachalam, M. Biosynthesis and GCMS Analysis of Zinc Oxide Nanoparticles from Leaf Extract of Curcuma neilgherrensis Wight. Int. J. Adv. Eng. Res. Dev. 2017, 4 (10), 329–343. Rubalakshmi, G.; Karmegam, N.; Vijayakumar, N.; Vidya, M.; Nirubama, K. Evaluation of Bioactive Compounds, In Vivo Antioxidant and Hepatoprotective Analysis of an Endemic Indigenous Medicinal Plant, Curcuma neilgherrensis Wight—A Green Approach. Int. J. Anal. Exp. Model Anal. 2019, 11 (11), 109–136. Samydurai, P.; Jagatheshkumar, S.; Aravinthan, V.; Thangapandian, V. Survey of Wild Aromatic Ethnomedicinal Plants of Velliangiri Hills in the Southern Western Ghats of Tamil Nadu, India. Int. J. Med. Aromat. Plants 2012, 2 (2), 229–234.

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Yasodamma, N.; Chaithra, D. Effect of Curcuma neilgherrensis Wt. Rhizome Crude Extracts on Analgesic and Arthritis Induced Rats. World J. Pharm. Pharm. Sci. 2016, 5 (4), 1054–1077. Yasodamma, N.; Chaithra, D.; Alekhya, C. Anthelmintic Activity of Curcuma neilgherrensis Wt. from Seshachalam Hills. Int. J. Pharm. Pharm. Sci. 2013a, 5 (2), 143–145. Yasodamma, N.; Chaithra, D.; Alekhya, C. Antibacterial Activity of Curcuma neilgherrensis Wt. A Wild Curcuma Species. Int. J. Pharm. Pharm. Sci. 2013b, 5 (3), 571–576. Yasodamma, N.; Chaithra, D.; Alekhya, C. Qualitative Analysis of Phenols, Flavonoids and Anthocyanidins of Curcuma neilgherrensis Wt. A Medicinal Plant from Seshachalam Hills. Indo Am. J. Pharm. Res. 2014, 4 (9), 3618–3629. Yesodaram, K.; Sujana, K. A. Wild Edible Plants Traditionally Used by the Tribes in the Parambikulam Wildlife Sanctuary, Kerala, India. Nat. Prod. Radiance 2007, 6 (1), 74–80.

CHAPTER 12

Bioactives and Pharmacology of Aconitum heterophyllum Wall. ex Royle TARUN PAL*, HARISH BABUKOLLA, and S. ASHA Department of Biotechnology, Vignan’s Foundation for Science, Technology and Research (Deemed to be University), Vadlamudi, Guntur, Andhra Pradesh 522213, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Herbal revolution is around the globe and has enormous pharmacological potential. This book chapter deals with a critically endangered medicinal herb of the North-Western Himalayas, Aconitum heterophyllum. This plant is widely used in the treatment of diarrhea, vomiting, cough, cold, etc. This plant is harvested from its roots and its key medicinal properties is due to secondary metabolites named as aconites. The scientific studies on the plant were restricted due to various reasons, such as plant availability and poor literature available. The current chapter provides key insights about the geography, availability, phytochemistry and pharmacology of this novel plant species. The repertoire summarizes the basis knowledge about the plant. 12.1 INTRODUCTION Aconitum heterophyllum Wall. ex Royle, commonly called as Atish or Aruna is an indigenous plant of India with extensive medicinal properties. Medicinal properties of A. heterophyllum were well documented in Upaveda Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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of Atharvaveda in 1000 BC. In ancient Indian medicine, this particular plant was used in healing of wounds, immune modulation, treating urinary tract infections, and digestive diseases such as diarrhea (Shyaula, 2012; Verma et al., 2010; Ukani et al., 1996). It is also used as hepatoprotective solution and as an expectorant to promote sputum secretion in treating severe cough conditions. Aconitum is being used in Ayurvedic, Bhutanese, and Chinese medicines (Paramanick et al., 2017a). Extensive biological activity of A. heterophyllum is because of the presence of metabolites, such as glycosides, saponins, alkaloids, terpenoids, quinines, and flavonoids. However, the complete metabolome profile of these biochemical constituents varies among tissue systems in the plant. For instance, composition of metabolites in the root is entirely different from that of stem and bark metabolome. Metabolites or bioactive compounds are low molecular weight compounds that are very dynamic in nature. The chemical composition of the bioactive compounds or secondary metabolites varies among flower, roots, stem, and leaves. These bioactive compounds accounts for wide range of biological activities, such as antimicrobial, anticancerous, antifungal, antioxidative, anti-inflammatory, expectorative, and antiphlegmatic properties. A. heterophyllum is a member of Ranunculaceae family in plant kingdom (Anonymous, 2008). This plant is usually found in dense forests, humus-rich soils, alpines, and sub-alpine zones in Eastern Asia and Western Himalayas (Beigh et al., 2008; Singh et al., 2015). The stems of A. heterophyllum are simply branched, chlorophyllous, and their height ranges from 10 to 20 cm. The root of this plant appears to be whitish gray with 1.5–8 cm in length and 0.5–1.5 cm in thickness. The roots are thick at their upper extremities and tapered at the end. The roots of A. heterophyllum are the regions for the accumulation of secondary metabolites (Pal et al., 2015; Kumar et al., 2016). The flowers of A. heterophyllum are blue in color with panicle or raceme inflorescence. The leaves are dark green in color with special arrangement or alternative phyllotaxy (Rajakrishnan et al., 2016). With its medicinal values, derivatives of A. heterophyllum are yet to be used in drug formulations and therapeutics at industrial scale. With advancements in metabolomics and pharmaceutical sciences, researchers could investigate deeply into the insights of biological actions of A. heterophyllum secondary metabolites as drug candidates against various diseases. The biological activities, nature of secondary metabolites and their applications in biopharmaceutical industries were explored and discussed briefly in further sections to enable researchers in understanding the potential role of A. heterophyllum in the development of therapeutic molecules and nutraceuticals. A. heterophyllum was included in the list of critically endangered species by International union for conservation of

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nature and natural resources (IUCN). Hence, it is very essential to conserve the plant to meet the current medicinal requirement (Srivastava et al., 2011). 12.2 BIOACTIVE COMPOUNDS A. heterophyllum is a medicinal plant with great importance to human health and metabolism. These metabolites exert certain important biological activity ranging among antimicrobial, antitumor, antioxidant, and anti-inflammatory, etc. There exist important classes of bioactive compounds in A. heterophyllum alkaloids and non-alkaloids, such as flavonoids, phenylpropanoids, terpenoids, steroids, and other phenolics (Paramanick et al., 2017b). In ancient texts and medicine practices roots of A. heterophyllum were well documented for their therapeutic potentiality toward diarrhea and certain respiratory disorders (Shyaula, 2012; Verma et al., 2010; Ukani et al., 1996). Tuberous roots of Aconitum constitute alkaloids, such as 13-hydroxylappaconitine, 6-dehydroacetylsepaconitine, aconitine, atidine, atisine, benzoylheteratisine, delphatine, F-dihydroatisine, heteratisine, heterophyllidine, heterophylline, heterophyllisine, hetidine, hetisine, hetisone, lappaconitine and lycoctonine (Ukani et al., 1996; Paramanick et al., 2017b). The alkaloid aconitine, which is the major bioactive compound of other Aconitum species is present in lower concentrations in A. heterophyllum. The Aconitine found in the roots of A. heterophyllum inhibits the growth of Pseudomonas putida and Xanthomonas campestris (Yoirentomba et al., 2014). Unlike other Aconitum members, A. heterophyllum contains atisine as a major alkaloid. It is relatively a nontoxic alkaloid ensuring safety of A. heterophyllum. Atisine was the first compound to be isolated and later the presence of aconitic acid along with atisine was discovered. The roots and leaves are important reservoirs for diverse metabolites in Aconitum species. Phytochemicals, such as atisine, atidine, 20 α-atisine, 20 β-atisine, hetratisine, heterophylline, heterophyllidine, heterophyllisine, hetisine, hetidine, hetisinone, and isoatisine are found exclusively in this plant (Ukani et al., 1996). Few studies reported the presence of molecules o-methylaconitine, methyl-n-succinoylanthranilate, and N-diethyl-N-formyllaconitine A. heterophyllum (Paramanick et al., 2017a). The GC-MS profiling of A. heterophyllum leaves revealed 2-butenedioic acid (2e), cholestanol, 2-fromyl-3-benzyl and phytol isomer as major and 2,5-dihydroxy2,5-dimethyl-3-hexyne, hexanoic acid, 2-methyl, razoxane as minor compounds present in them (Tomar and Shalini, 2018). The phytochemical constituents, such as tannins, total phenolic fraction,

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saponins, alkaloids, and flavonoids are present in the ethanolic fraction of A. heterophyllum (Prasad et al., 2012). A larger number of fatty acids have been identified from Aconitum species. The esterification and GC-MS analysis of alcoholic extracts has shown the presence of three types of fatty acids, such as linoleic acid, oleic acid, and palmitic acid (Zhao et al., 2006; Yue et al., 2010). The list of metabolites present in A. heterophyllum are enlisted in Table 12.1. Currently, very less information is available with regard to the metabolic constituents in A. heterophyllum. The complete metabolome analysis was needed to establish various pharmacological benefits of the plant. The metabolome profiling, identification, and isolation is very essential in directing the current drug discovery toward natural therapeutics. 12.2.1 ALKALOIDS Alkaloids are the molecules that occur naturally in plants. They are cyclic organic compounds negative oxidation states (Pelletier, 1983; Zhaohong et al., 2006). The aconitine was the first alkaloid molecule to be identified in Aconitum species (Glasby, 1975; Jowett, 1896). Alkaloid molecules, such as atidine, aconitine, benzoylheteratisine, benzoylmesaconine, heteratisine, mesaconitine, hypaconitine, heterophylline, hetidine, and hetsinone, etc. were found in the roots of Aconitum plants (Pelletier et al., 1968). The most active alkaloids consist of coryphine and isoatisine molecules and this is due to the presence of oxazolidine rings (Shim et al., 2003). Two new non-diterpenoid alkaloids 13-hydroxylappoconitine and 6-dehydroacetylsepaconitine were isolated by Ahmad et al. (2008). Nisar et al. (2009) isolated two diterpenoid alkaloids like heterophylline A and B from the roots of A. heterophyllum. 12.2.2 FLAVONOIDS The flavonoids are the low molecular weight phenolic molecules and distributed widely in the plant kingdom. They play an important role in preventing lipid peroxidation and scavenging reactive oxygen species produced as a result to UV exposure (Treutter, 2005). The common flavonoids found in Aconitum species are kaempferol 7-O-(6-trans-caffeoyl)β-glucopyranosyl-(1→3)-α-rhamnopyranoside-3-O-β-glucopyranoside and kaempferol 7-O-(6-trans-p-coumaroyl)-β-glucopyranosyl-(1→3)-αrhamnopyranoside-3-O-β-glucopyranoside, quercetin 7-O-(6transcaffeoyl)-β-glucopyranosyl-(1→3)-α-rhamnopyranoside-3-O-β-

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glucopyranoside, and β-3,4-dihydroxyphenethyl β-glucopyranoside (Fico et al., 2001). 12.2.3

ISOPRENOID METABOLISM

Generally, plants utilize two different pathways for the biosynthesis of isoprenoids. These two pathways are mevalonte and non-mevalonate pathways. Mevalonate pathway takes place in cytosol whereas non-mevalonate pathway occurs in plastids of the plant. Totally, 15 genes were involved in the biosynthesis of isoprenoids. Six genes are involved in mevalonate pathway and 8 genes involved in non-mevalonate pathway. The gene that encodes for IPII enzyme interconverts DMAPP and IPP during isoprenoid biosynthesis. DMAPP and IPP are the building elements of isoprenoids and condense to GPP. GPP is a precursor for aconitine synthesis (Rodriguez-Concepcion and Boronat, 2002). TABLE 12.1 Phytochemical Constituents of Root and Leaf Parts of Aconitum heterophyllum. Phytochemical Atisine Atidine 20 α-Atisine 20 β-Atisine Hetratisine Heterophylline Heterophylline A Heterophylline B Heterophyllidine Heterophyllisine Hetidine Hetisinone Isoatisine Thymol Copaene 3H-3a,7-Methanoazulene Benzene Benzene Naphthalene Cyclohexene Naphthalene 1,6,10-Dodecatrien-3-ol

Plant part

References

Rajakrishnan et al. (2016) Root tubers and Ukani et al. (1996)

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TABLE 12.1 (Continued) Phytochemical Plant part β.-Asarone Caryophyllene oxide 3-Cyclohexen-1-carboxaldehyde 2,4a-Methanonaphthalen7(4aH)-one 1H-Cycloprop[e]azulene 2(3H)-Naphthalenone 7-Isopropenyl-1,4 adimethyl-4,4a,5,6,7,8-hexahydro-3H-naphthalen2-one n-Hexadecanoic acid Oleic acid Octadecanoic acid Octacosane Nonacosane 6-Benzoylheteratisine 11,13:11,16-Diepoxy-16,17-dihydro-11,12-seohetisan-2-ol 2,3-Dihydrobenzofuran 2-Methoxy-4-Vinylphenol Formic acid, Hex-2-Yl Ester Hexadecanoic acid 3-Hexadecene (Z)Razoxane 3,5-Di-Tert-Butylphenol Hexanoic acid, 2-Methyl2,5-Dihydroxy-2,5-Dimethyl-3-Hexyne Ethanone,1-(3,4-Dimethoxyphenyl)Decanoic acid 1-Tetradecanol Sabinyl acetate 3,6-Dimethyl-4-Octyn-3,6-diol Hexadecanoic acid, Methyl ester 5-Isopropyl-6-Methyl-3,5-Heptadien-2-ol 1-Hexadecene 2,6,10-Trimethyl,14-Ethylene-14-Pentadecene 2-Pentadecanone, 6,10,14-Trimethyl3,7,11,15-Tetramethyl-2-Hexadecen-1-ol Phytolacetate Oxirane, HexadecylPentadecanoic acid, 14-Methyl-, Methyl ester Leaf Benzenepropionic acid, 3,5-Bis(1,1-Dimethylethyl)-4-Hydrox

References

Tomar and Shalini (2018)

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TABLE 12.1 (Continued) Phytochemical 9-Octadecenoic acid (Z)Phosphonic acid, Dioctadecyl ester 1-Hexadecanol 9,12-Octdecadienoic acid, Methyl ester Hexadecadienoic acid, Methyl ester Cyclohexanol, 3,5-Dimethoxy-, Stereoisomer Phytol isomer Octadecanoic acid, Methyl ester Bis(2-Ethylhexyl) Maleate N-Tricosane Phytol, Acetate 2-Butenedioic acid (2E)9,10-Diazatricyclo[4.4.0.0(2,8)]Decane9,10-Dicarboximide, N Phenyl-7 Octadecane C16 Fatty acid Methyl N-Eicosanoate 1,1′-Biphenyl, 5,2′,3′,4′-Tetramethoxy2,6,10,15-Tetramethylheptadecane 17-Hydroxy-17-.Alpha.-PregN-4-EN-2 9-Octadecenoic acid Tetratetraconatne 3-Azidoandrost-16-ene 2-Methyloctacosane 2,6,10,15-Tetramethylheptadecane N-Heptacosane Eicosane 3-Adamantan-1-yl-6-Amino-4-Thiophen-2-yl-1,4Dihydro-Pyr Squalene -)-Sinularene Eicosane Des-N-26-Methylene-Dihydrotomatidine Eicocylbis(Trifluoromethyl)Phosphine sulfide Glutaric acid, Di (Dodec-9-ynyl) Ester Ergost-5-en-3-ol Cholestanol, 2-Formyl-3-BenzylBeta,-Caryophyllene

Plant part

References

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12.3

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PHARMACOLOGICAL PROPERTIES

Application of A. heterophyllum was well described in ancient texts of Ayurveda and Chinese medicine. It is a medicinal plant with great relevance on human metabolism and health. Medicinal activity of this plant lies in certain chemical constituents called metabolites. These metabolites exert certain important biological activities ranging among antimicrobial, anticancer, antioxidant, and anti-inflammatory, etc. 12.3.1 ANTIMICROBIAL ACTIVITY The majority of phytochemicals in the plant account for antibacterial activity. The extracts from this plant were found to exert their effect against various pathogens. Two aconitine compounds 13-hydroxylappaconitine and 6-dehydroacetylsepaconitine present in the extracts from the tuber tend to exert their antimicrobial affect on microbes, such as E. coli, Shigella species, S. typhi, and P. aeruginosa (Ahmad et al., 2008). The alkaloids in the root of A. heterophyllum are found to be potential in killing the microorganisms Bacillus subtilis, Staphylococcus aureus, and Bordetella bronchiseptica (Yoirentomba et al., 2014). On the other hand, the extract is static toward the pathogens P. putida and X. campestris (Yoirentomba et al., 2014). Besides this, A. heterophyllum extracts also have strong inhibitory actions on fungal and viral agents. Methanolic extract of A. heterophyllum could act as better antifungal agent against A. niger and A. solani (Munir et al., 2014). The diterpenoid alkaloids heterophylline A and B present in the roots of A. heterophyllum are found as efficient antifungals against T. longifusus and M. canis (Obaidullah et al., 2018). 12.3.2 ANTICANCER ACTIVITY Cancer is one of the fatal diseases being suffered by millions of patients across the globe. Death is associated with blockage of host survival mechanisms and tumor accumulation in the host. Although there are various therapeutic options to treat the cancer, none of these have met success due to the complex behavior of cancer cells, such as angiogenesis, metastasis, blockage of apoptosis and lack of contact inhibition. The anticancer drugs are designed to modulate the pathways involved in cancer development. There exist certain drugs which were targeted in controlling the tumor development by modulating and dictating immune system of the host. These drugs activate and boost the immune potentiality of the host immune cells to control the pathogenesis of cancer and potentially eradicate it. Currently,

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phytochemicals were being investigated widely for their anticancer and immune regulatory activities in various cancer models. An in vitro study published in 2016 documented the anticancer activity of A. heterophyllum on various cell lines, such as Lung A-549, Pancreatic MIAPaCa and Colon HCT-116 (Mushtaq et al., 2017). Aconitine, significantly shows its antiproliferative effect at the concentration of 150–400 μg/mL in hepal-6 hepatoma cells under in vitro conditions (Qian, 2015). Only few studies have reported the anticancerous activity of A. heterophyllum and studies need to be focused on the regulation of cancerous markers with A. heterophyllum compounds. 12.3.3

GASTROINTESTINAL FUNCTIONS

Root extracts of A. heterophyllum protects Albino wistar rats from ethanolinduced ulcers. The protective efficacy of A. heterophyllum was compared with the standard drug omeprazole (Vishal et al., 2017). The antiulcer property of A. heterophyllum root extracts was because of the presence of metabolic constituents, such as phenols, tannins, saponins, alkaloids, and terpenoids. The roots of A. heterophyllum also confer antidiarrheal activity. They reactivate the Na+ and K+ ATPase pumps and lead to decrease in mucosal secretion thereby increasing the mucosal absorption (Prasad et al., 2014). 12.3.4

METABOLIC EFFECTS

A. heterophyllum plant was mainly studied for its metabolic health benefits, such as anti-inflammatory, antioxidant, and immunomodulatory activities. In Ayurveda and Chinese medicine, Ativisha was documented for treating sore throat, fever, diarrhea, body aches, and gastritis, etc. Traditional medicines, such as mahavisagarbhataila, balachaurbhadrikacurna, sudarsancurna, rasnairandadikvatha, rodhrasavasivaguika, pancatiktaguggulughrta, and lakasminarayana rasa were formulated from A. heterophyllum and used to treat various metabolic and physiological imbalances in the body (Pan et al., 2014). Recent pharmacological observations have focused on the metabolic effects and health benefits of A. heterophyllum extracts. The A. heterophyllum being reservoir for biologically active ingredients, such as flavonoids, saponins, and tannins, extracts of A. heterophyllum are found to exhibit its nature on reducing the inflammation in the body. The ethanolic extracts of A. heterophyllum roots at various concentrations, such as 225, 450, and 900 mg/ kg p.o. reduced the inflammation in granuloma rats and reduced the weight of cotton pellet in rats. The ethanolic extract of A. heterophyllum comprises phytochemical constituents, such as alkaloids, glycosides, sterols, flavonoids,

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and phenols (Verma et al., 2010). The ethanolic extracts of A. heterophyllum roots reduce the sub-acute inflammation by interrupting arachidonic acid metabolism (Verma et al., 2010). The compounds of A. heterophyllum interrupt the prostagland in pathways and exert the antiproliferative functions (Kumar et al., 2013). The metabolites of this plant shows strong antioxidant activity and confer protection from the oxidative stress and reactive oxygen species. The antioxidant nature of the plant A. heterophyllum was studied by Munir et al. in 2014 through in vitro 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The ascorbic acid was used as a standard antioxidant in this study to determine the antioxidant potential of both methanol and ethanol extracts of A. heterophyllum roots. Both ethanol and methanol extracts of A. heterophyllum roots are found to exert greater antioxidant activity relative to ascorbic acid (Munir et al., 2014). From the research work by Prasad et al. (2012), ethanolic extracts from A. heterophyllum has shown less antioxidant activity than standard ascorbic acid (Prasad et al., 2012). The powder like churna and decoction form kashaya of A. heterophyllum were documented in Ayurveda for treating fever (Anonymous, 2001). On the other hand, extracts through hexane, water, chloroform significantly has no antipyretic nature (Nagarajan et al., 2015). A. heterophyllum also has immunomodulatory activity (Atal et al., 1986). Extracts of root tubers from this plant tend to enhance the phagocytic functions and lead to immune modulatory actions in the body (Atal et al., 1986). These observations made by Atal et al. in 1980s made the researchers to investigate on the plant for its route in the discovery of immune modulatory drugs. Methanolic extracts of A. heterophyllum reduce the total cholesterol and low-density lipoprotein (LDL) levels in the serum by regulating two enzymes hydroxymethylglutarate-Coenzyme A reductase (HMGR) and lecithin-cholesterol acyltransferase (LCAT). The inhibition and activation of these two enzymes could lead to the antihyperlipidemic activity (Subash and Augustine, 2012). The hypolipidemic activity of A. heterophyllum was achieved when methanolic extract was orally administered to diet-induced obese rats (Subash and Augustine, 2012). There exist very few studies focusing on the metabolic effects of A. heterophyllum till now. The research activities focusing on the therapeutic efficacy and health benefits of A. heterophyllum need to be carried out on various experimental models such as mammal models to understand the mechanistic and pharmacological actions of the metabolites constituted by the plant. Few outlines of various studies on pharmacological activities of A. heterophyllum are enlisted in Table 12.2, which will provide an overview of metabolic properties of this plant to the researchers.

Part Tuber Tuber Root

Biological activity Antibacterial Antibacterial Antibacterial

Methanolic extract Diterpenoid alkaloids Heterophylline A and B

–

– Root

Antifungal Antifungal

–

Anticancer

Aconitine Root extracts Ethanolic extract Ethanolic extract Methanolic extract Ethanolic extract Root extracts Methanolic Methanolic Diterpene alkaloids 13-oxocardiopetamine Heterophyllinines A and B

– Root Root – – – Tuber roots – –

Roots

Antiproliferative Antiulcer Antidiarrheal Anti-inflammatory Antioxidative Antioxidative Immunomodulatory Antihyperlipidemic Hypolipidemic Cytotoxicity Cytotoxicity Neuronal activity

Aqueous and alcoholic

Tubers

Antihelminthic

Model E. coli, Shigella, S. typhi, P. aeruginosa E. coli, Shigella, S. typhi, P. aeruginosa B. subtilis, B. bronchiseptica, S. aureus, P. putida, X. campestris niger, sofani T. longifuscus, M. canis

References Ahmad et al. (2008) Ahmad et al. (2008) Yoirentomba et al. (2014)

LungA-549, Pancreatic MIAPaCa, Colon HCT-116 Hepal-6-hepatoma Ethanol-induced ulcer in Albino wistar rats Castor induced Foster diarrhea albino rats Granuloma rats In vitro DPPH assay

Mushtaq et al. (2017)

– Pathway modulatory Diet-induced obese rats insect-derived Sf9 cells Mammalian CHO cells Inhibits enzyme butyrylcholinesterase than acetylcholinesterase Pheritemapostuma

Munir et al. (2014) Obaidullah et al. (2018)

Qian (2015) Vishal et al. (2017) Prasad et al. (2014) Verma et al. (2010) Munir et al. (2014) Atal et al. (1986) Subash and Augustine (2012) Subash and Augustine (2012) Gonzalez-Coloma et al. (2004) Nisar et al. (2009) Pattewar et al. (2012)

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Extract/Compound 13, hydroxylappaconitine 6-denydroacetylsepaconitine Alkaloids

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TABLE 12.2 Biological Activities of Different Plant Parts of A. heterophyllum.

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12.4

CONCLUSION AND FUTURE PROSPECTS

A. heterophyllum harbors diverse metabolic compounds in it (majorly in roots). In ancient texts and Ayurveda, the medicinal value and therapeutic practice of the plant were well described. Being medicinal plant, A. heterophyllum confers several metabolic properties. The scientific studies on the plant were restricted to several objectives due to various reasons, such as plant availability and poor literature available. The plant A. heterophyllum was included in critically endangered species by International union for conservation of nature and natural resources. Hence, it is very essential to conserve the plant for medicinal purposes. The plant biotechnological techniques, such as ex situ conservation, micropropagation, and genetic engineering could map medicinal importance of the plant aiding conservation of the plant. KEYWORDS • • • • • • •

Aconitum heterophyllum aconites atisine antimicrobial anticancer antioxidant anti-inflammatory

REFERENCES Ahmad, M.; Ahmad, W.; Ahmad, M.; Zeeshan, M.; Obaidullah; Shaheen, F. Norditerpenoid Alkaloids from the Roots of Aconitum heterophyllum Wall with Antibacterial Activity. J. Enzyme Inhib. Med. Chem. 2008, 23, 1018-1022. Anonymous. The Ayurvedic Pharmacopoeia of India. Part-I; 1st ed., Vol. 3; Government of India, Ministry of Health and Family Welfare, Department of Indian Systems of Medicine and Homoeopathy: New Delhi, 2001; pp 129-130. Anonymous. The Ayurvedic Pharmacopoeia 2008, 2, 156–167. Atal, C. K.; Sharma, M. L.; Kaul, A.; Khajuria, A. Immunomodulating Agents of Plant Origin. I: Preliminary Screening. J. Ethnopharmacol. 1986, 18, 133-141.

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Beigh, S. Y.; Nowchoo, I. A.; Iqbal, M. Cultivation and Conservation of Aconitum heterophyllum: A Critically Endangered Medicinal Herb of the Northwest Himalayas. J. Herbs. Spices. Med. Plants 2008, 11, 47–56. Fico, G.; Braca, A.; De Tommasi, N.; TomèF.; Morelli, I. Flavonoids from Aconitum napellus subsp. Neomontanum. Phytochemistry.2001, 57, 543–546. Glasby, J. Encyclopedia of the Alkaloids; Vol. 1; Plenum Press: New York, London, 1975; pp 15–16. Gonzalez-Coloma, A.; Reina, M.; Medinaveitia, A.; Guadano, A.; Santana, A.; MartinezDiaz, A.; Ruiz Mesía, L.; Alva, A.; Grandez, M.; Díaz, R.; Gavín, J. A.; la Fuente, G. D. Structural Diversity and Defensive Properties of Norditerpenoid Alkaloids. J. Chem. Ecol. 2004, 30, 1393–1408. Jowett, H. A. Contributions to Our Knowledge of the Aconite Alkaloids. Part XIII. On Atisine, the Alkaloid of Aconitum heterophyllum. XCIX. J. Chem. Soc. Trans. 1896, 69, 1518–1526. Kumar, S.; Bajwa, B. S.; Singh, K.; Kalia, A. N. Anti-Inflammatory Activity of Herbal Plants: A Review. Int. J. Adv. Pharm. Biol. Chem. 2013, 2, 272–281. Kumar, V.; Malhotra, N.; Pal, T.; Chauhan, R. S. Molecular Dissection of Pathway Components Unravel Atisine Biosynthesis in a Non-Toxic Aconitum Species, A. heterophylum Wall. 3 Biotech. 2016, 6, 106. Munir, N.; Ijaz, W.; Altaf, I.; Naz, S. Evaluation of Antifungal and Antioxidant Potential of Two Medicinal Plants: Aconitum heterophyllum and Polygonumbistorta. Asian Pac. J. Trop. Biomed. 2014, 4, S639–S643. Mushtaq, S.; Hassan, Q. P.; Sharma, R.; Majeed, R.; Dar, A. H.; Sultan, P.; Ali, M. N. Evaluation of Anticancer and Antimicrobial Activities of Selected Medicinal Plants of Kashmir Himalayas, India, Indian J. Trad. Knowl 2017, 16, 141–145. Nagarajan, M.; Gina, R.; Kuruvilla, K.; Subrahmany, K.; Venkatasubramanian, P. Pharmacology of Ativisha, Musta and Their Substitutes. J. Ayurveda Int. Med. 2015, 6, 121. Nisar, M.; Ahmad, M.; Wadood, N.; Lodhi, M. A.; Shaheen, F.; Choudhary, M. I. New Diterpenoid Alkaloids from Aconitum heterophyllum Wall: Selective Butyrylcholinestrase Inhibitors. J. Enzyme Inhib. Med. Chem. 2009, 24, 47–51. Obaidullah, M. N. A.; Ahmad, W.; Tariq, S. A. Najeebur Rahman. Isolation and Characterization of C19-Diterpenoid Alkaloids from the Roots of Aconitum heterophyllum Wall. J. Med. Chem. Drug. Des. 2018, 1, 101. Pal, T.; Malhotra, N.; Chanomolu, S. K.; Chauhan, R. S. Next-Generation Sequencing (NGS) Transcriptomes Reveal Association of Multiple Genes and Pathways Contributing to Secondary Metabolites Accumulation in Tuberous Roots of Aconitum heterophyllum Wall. Planta 2015, 242, 239–258. Pan, S. Y.; Litscher, G.; Gao, S. H.; Zhou, S. F.; Yu, Z. L.; Chen, H. Q.; Zhang, S. F.; Tang, M. K.; Sun, J. N.; Ko, K. M. Historical Perspective of Traditional Indigenous Medical Practices: The Current Renaissance and Conservation of Herbal Resources. Evid. Based. Complement. Altern. Med. 2014, 525340. Paramanick, D.; Sharma, N.; Parveen, N.; Patel, N.; Keshri, M. A Review Article on Ayurvedic/Herbal Plant. Int. J. Adv. Res. 2017a, 5, 319–325. Paramanick, D.; Panday, R.; Shukla, S. S.; Sharma, V. Primary Pharmacological and Other Important Findings on the Medicinal Plant “Aconitum heterophyllum” (Aruna). J. Pharmacopunct. 2017b, 20 (2), 89–92. Pattewar, M.; Pandharkar, T. M.; Yerawar P. P.; Patawar, V. A. Evaluation of In Vitro Antihelminthic Activity of Aconitum heterophyllum. J. Chem. Biol. 2012, 2, 2401–2407.

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Pelletier, S. W. Alkaloids: Chemical and Biological Perspectives; Wiley: New York, 1983. Pelletier, S. W.; Aneja, R.; Gopinath, K. W. The Alkaloids of Aconitum heterophyllum Wall: Isolation and Characterization. Phytochemistry 1968, 7, 625–635. Prasad, S. K.; Jain, D.; Patel, D. K.; Sahu, A. N.; Hemalatha, S. Antisecretory and Antimotility Activity of Aconitum heterophyllum and Its Significance in Treatment of diarrhea. Indian J. Pharmacol. 2014, 46, 82–87. Prasad, S. K.; Kumar, R.; Patel, D. K.; Sahu, A. N.; Hemalatha, S. Physicochemical Standardization and Evaluation of In-Vitro Antioxidant Activity of Aconitum heterophyllum Wall. Asian Pac. J. Trop. Biomed. 2012, 2, S526–S531. Qian Z. The Effect and Preliminary Mechanism Study on Monkshood Polysaccharide Combined with Aconitine to the Hepatocellualar Carcinoma Cell. Master’s Thesis, Nanjing University of Chinese Medicine, Nanjing, China, Jun, 2015. Rajakrishnan, R.; Lekshmi, R.; Samuel, D. Analytical Standards for the Root Tubers of Ativisha—Aconitum heterophyllum Wall. Ex Royle. Int. J. Sci. Res. 2016, 6, 531–534. Rodriguez-Concepcion, M.; Boronat, A. Elucidation of the Methylerythritol Phosphate Pathway for Isoprenoid Biosynthesis in Bacteria and Plastids. A Metabolic Milestone Achieved Through Genomics. Plant. Physiol. 2002, 130, 1079–1089. Shim, S. H.; Kim, J. S.; Kang, S. S.; Son, K. H.; Bae, K. Alkaloidal Constituents from Aconitum Jaulense. Arch. Pharmacal. Res. 2003, 9, 725–729. Shyaula, S. L. Phytochemicals, Traditional Uses and Processing of Aconitum Species in Nepal. Nepal J. Sci. Technol. 2012, 12, 171–178. Singh, K.; Saloni, S.; Shalini. Phytochemical Screening and TLC Profiling of Different Extracts of Leaves, Roots and Stem of Aconitum heterophyllum a Rare Medicinal Plant of Himalayan Region. Int. J. Pharm. Bio. Sci. 2015, 6, 194–200. Srivastava, N.; Sharma, V.; Dobriyal, A. K.; Kamal, B.; Gupta, S.; Jadon, V. S.; Influence of Pre-Sowing Treatments on In Vitro Seed Germination of Ativisha (Aconitum heterophyllum Wall) of Uttarakhand. Biotechnology 2011, 10, 215–219. Subash, A. K.; Augustine, A. Hypolipidemic Effect of Methanol Fraction of Aconitum heterophyllum Wall Ex Royle and the Mechanism of Action in Diet-Induced Obese Rats. J. Adv. Pharm. Technol. Res. 2012, 3, 224–228. Tomar S. K.; Shalini. Analysis of Phytochemical Constituents of the Methanolic Extracts of Leaves of Aconitum heterophyllum Using Gas Chromatography-Mass Spectroscopy (GC-MS) Techniques. Int. J. Res. Ayurveda Pharm. 2018, 9, 319–325. Treutter, D. Significance of Flavonoids in Plant Resistance and Enhancement of Their Biosynthesis. Plant Biol. 2005, 7, 581–591. Ukani, M. D.; Mehta, N. K.; Nanavati, D. D. Aconitum heterophyllum (Ativisha) in Ayurveda Anc. Sci. Life. 1996, 2, 166–171. Verma, S.; Ojha, S.; Raish, M. Anti-Inflammatory Activity of Aconitum heterophyllum on Cotton Pellet-Induced Granuloma in Rats. J. Med. Plants. Res. 2010, 4, 1566–1569. Vishal, R. R.; Vivek, V. P.; Mrunal, K. S.; Avinash, V. D. Evaluation of Antiulcer Activity of Aconitum heterophyllum on Experimental Animal. World J. Pharm. Pharm. Sci. 2017, 2, 819–839. Yoirentomba, M. S.; Sanjeev, K.; Sachin, H.; Satyendra, G.; Shantibala Devi, G. A.; Arun, S. Antibacterial Property of Aconitum heterophyllum Root Alkaloid. Int. J. Adv. Res. 2014, 2, 839–844.

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Yue, X. F.; Zhang, Y. N.; Zhangab, J.; Zhang, Z. Q. Free Fatty Acids Profile Analysis of Alcohol Extract of Aconitum taipeicum Hand.-Mazz. with Gas Chromatography-Mass Spectrometry. Anal. Methods 2010, 2, 668–672. Zhao, C.; Li, M.; Luo, Y.; Wu, W. Isolation and Structural Characterization of an Immunostimulating Polysaccharide from Fuzi, Aconitum carmichaeli. Carbohydr. Res. 2006, 341, 485–491. Zhaohong, W.; Wang, J.; Xing, J.; He, Y. Quantitative Determination of Alkaloids in Four Species of Aconitum by HPLC. J. Pharm. Biomed. Anal. 2006, 40, 1031–1034.

CHAPTER 13

New Insights on Bioactives and Pharmacology of Genipa americana L. ALINE OLIVEIRA DA CONCEIÇÃO* Biological Science Department, Santa Cruz State University, Km 16, Jorge Amado Road, Salobrinho, 45.662-900 Ilhéus, Bahia, Brazil Corresponding author. E-mail: [email protected]

*

ABSTRACT In this chapter, considering the multiple potentials of Genipa amerciana L., we address phytochemical, biological, clinical, and technological aspects of G. americana. From this plant the most known bioactive compounds are the iridoids; however, flavonoids, carboxylic acid, terpenes, and steroids from this plant have also showed biological activities. Action on bacteria and viruses, more specifically, herpesvirus is revised; also, the beneficial interactions of G. americana compounds with mammalian cells and no toxicity for experimental animals or humans is verified for this species. Finally, the review points out the ecological and pharmaceutical potential of G. americana fruit extract. 13.1 INTRODUCTION Genipa americana L. (Rubiaceae), popularly known as genip tree, jenipapeiro, caruto, huito, jaguar, genip, tapaculo, xagua, among others, is a neotropical fruit tree native of wet or flooded floodplains throughout Brazil (de Carvalho et al., 2020; SiBBr, 2021), and other countries in America, between Mexico and Peru (Francis, 2000; Bernal et al., 2015) and India (IBP, 2021). It is a tree with a narrow crown, measuring 8–14 Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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m high with a smooth trunk of 40–60 diam. The leaves are shiny and dark green, opposite, lanceolate to oblong, measuring 20–35 cm long and 10–19 cm wide. The flowers are large, initially white, turning yellow after fertilization. The fruits, named jenipapo in Brazil, are round, 8–10 cm in diameter with a sweetish pulp and flat, cream-colored seeds (Galvão, 2021). The jenipapo—from Tupi Guarani iá-nipaba—”rubbing fruit” has been known for the blue to black color juice obtained from unripe fruit used by certain indigenous people to tattoo their skin (Chiaradia, 2021). Also, when ripe, the fruit is suitable for eating and popular as a source of beverages of all kinds and jams (de Carvalho et al., 2020). It is worth to noting that this fruit has considerable nutritional values (Pacheco et al. 2014; de Assis et al., 2020), contributing to classify it in the category of functional food. All parts of genip tree are used in traditional medicine in Brazil. The bark is used as cathartic and antidiarrheal, against ulcers, against pains of various origins, and in cases of pharyngitis. The leaves, in the form of decoction, are indicated against diarrhea and syphilis. Ripe fruits are diuretic and indicated against anemia, jaundice, asthma, and liver and spleen problems. Pulp and heated seeds are applied over the affected area for dermatitis (Lorenzi and Mattos, 2002; Agra et al., 2008; de Carvalho et al. 2020). Moreover, this plant has environmental and commercial values that favor cultivation in reforestation areas (Crestana, 1996; Ramos-de-la-Peña et al., 2014; de Carvalho et al., 2020; Teixeira et al., 2021). 13.2 13.2.1

BIOACTIVES IRIDOIDS

Iridoids are most important bioactive compounds reported for G. americana due to its broad applicability (Fig. 13.1). They have been identified specially in ripe and unripe fruits but they can also be isolated from the leaves of genip tree. First iridoids reported were genipin, genipinic, and geniposidic acid (Djerassi et al., 1960; Guarnaccia et al., 1972). Later, other substances, such as geniposide, tareside and gardenoside (Ueda et al., 1991), genamesides A-D (Ono et al., 2005) and gardeniol, methilic ester of desacetilasperulosidic, and shanzhiside acids (Ono et al., 2007) were also identified on this part of the plant.

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FIGURE 13.1 Iridoids from Genipa americana L. of importance in industry and as potential biomarkers.

Leaves of G. americana have also been studied and also showed the presence of iridoids, such as geniposidic acid (Ueda et al., 1991) and genamesides A-D (Ono et al., 2005). More recently, new iridoids were added to the list: the iridoid 1-hydroxy-7-(hydroxymethyl)-1,4aH,5H,7aH-cyclopenta[c] pyran-4-carbaldehyde, and the iridoid 7-(hydroxymethyl)-1-methoxy1H,4aH,5H,7aH-cyclopenta[c]pyran-4-carbaldehyde (Alves et al., 2017). 13.2.2

FLAVONOIDS

Besides the iridoids, flavonoids were also identified in different parts of G. americana (Porto et al., 2014; Alves et al., 2017). Omena et al. (2012) described the presence of quercetin in fruit and seeds, and more recently, Silva et al. (2018) reported for the first time the presence of quercetin3-O-robinoside, kaempferol-3-O-robinoside, isorhamnetin-3-O-robinoside, kaempferol-3-O-robinoside-7-O-rhamnoside (robinin), and isorhamnetin3-O-robinoside-7-rhamnoside in leaves. 13.2.3 OTHER CLASSES OF BIOACTIVES Other classes of substances found in G. americana are carboxylic acid, terpenes, and steroids. Between them, carboxylic acids were found in the ripe fruit (Pinto et al., 2006). Monoterpenoids called genipacetal, genipamide, and genipaol were identified in the leaf extract (Ono et al., 2007), and campesterol, stigmasterol, β-sitosterol, and ergosta-4,6,22-triene, 4,4-dimethyl-cholesta-6,22,24-triene, and tremulone (Barbosa, 2008; Costa et al., 2010) were obtained from fruits.

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Myristic, palmitic, palmitoleic, stearic, oleic, linolenic, arachidonic acids, and the major compound linoleic acid (61.5%) were found in seed’s oil (Ávila et al., 2018) of G. americana. 13.2.4 ESSENTIAL OILS The G. americana essential oils composition has also been studied and the presence of carboxylic acids (majority), esters, and alcohols was assigned (Borges and Rezende, 2000; Pino et al., 2005; Pinto et al., 2006; Barbosa, 2008). Common substances found in fruits essential oils were decanoic acid, heptanol, heptadienal, 2,3-dimethyl-2-cyclopentene1-one, hexanoic acid, hexadecanoic acid, linoleic acid, 2-methylbutanoic acid, 2,4-octadiene, methylbenzaldehyde, methyl cinnamate, methyl decenoate, methyl octanoate, 2-methylbutanoic acid, nonanol, nonanoic acid, octanoic acid, 2,4-octadiene, oleic acid, and pentadecenol. From the leaves essential oil, major compounds described were (2E,4E)-decadienal, (E,E)-α-farnesene, hexyl benzoate, pentadecanal, and linoleic acid (de Jesus et al., 2020). 13.3 PHARMACOLOGY 13.3.1 ANTIMICROBIAL ACTIVITY Since the first researches, antimicrobial activity has been described as a biological action of G. americana (Ojeda, 1966). Subsequent studies conducted with the extracts from different organs of this plant have confirmed this potential. Santos et al. (2017) reported the activity of pulp hydroalcoholic extracts obtained from ripe fruits against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans. From the same organ, Codignoto et al. (2017) demonstrated bacteriostatic activity against E. coli and bactericidal effect on S. aureus. However, the effect against C. albicans was not confirmed by these authors nor by Ávila et al. (2018). Bioassays carried on with vegetal oil from seeds for the antimicrobial activity revealed a percentage of inhibition for Salmonella typhimurium of 42.12%, followed by Bacillus cereus (35.87%) and S. aureus (34.58%).

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However, any activity was seen for E. coli and C. albicans (Ávila et al., 2018). Less studied, the antiviral activity was also described for G. americana. Codignoto et al. (2017) reported the particular spectrum of ethanolic extract from fruits, leaves, and branches. Ethanolic extract from fruits was more active against equine herpesvirus type-1 (EHV-1), while ethanolic extracts from leaves and branches were more active against suid herpesvirus type 1 (SuHV-1) in vitro. 13.3.2 IN VITRO PHARMACOLOGICAL EFFECTS The interaction with mammal cells and enzymes has been an important subject regarding medicinal plants. In the case of G. americana, due to medicinal and industrial potential, the effect of extracts or isolated substances on cells has been investigated (Fig. 13.2). Cytotoxic effect at >250 µg/mL in kidney cell lines (Codignoto et al., 2017), mild in vitro interference on placental cell regulation signaling pathway (da Conceição et al., 2011), and eco-friendly characteristics (Kumar et al., 2016) reported in the literature show evidences of safe use of G. americana fruit extracts. In addition, the antitumoral effect of genipin (Ueda et al., 1991; Shanmugam et al., 2018; Li et al., 2018) and phenolic extracts (Finco et al., 2013) reinforces the idea of beneficial interactions of G. americana compounds with mammalian cells. Other evidences of this plant biological activities are the effect on parasites from different plant organs (Souza et al., 2018; Barbosa et al., 2014; Bispo et al., 2020), antiacetylcolinesterase activity of seed oil (Ávila et al., 2018), antiplatelet, anticoagulant, and antithrombotic effects of an arabinogalactanrich glycoconjugate of the leaves (Madeira et al., 2018). 13.3.3 PRECLINICAL AND CLINICAL PHARMACOLOGICAL EVIDENCES In addition to minor in vitro cytotoxicity described for G. americana and the exception of individual allergic reactions to the unripe fruit tincture for long-term tattoo usage (Bircher et al., 2017), preclinical and clinical studies indicated that G. americana derivatives can be safe and biological benefits.

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The polysaccharides-rich extract of G. americana leaves was tested in animal models and did not show signs of toxicity. The extract given per oral in Wistar rats, for example, did not show hematological and plasma biochemical parameters alteration or mortality, indicating the possible usage for thromboembolic diseases of long-term effect (Madeira et al., 2018). In the same manner, in a study concerning the anticonvulsant mediated by GABA receptor using a mouse model, any evidence of toxicity for this animal (Nonato et al., 2018). Searching for genipap biomarkers in humans, Dickson et al. (2018) showed that consumption of genipap juice allows large exposure of the body to iridoids that can be metabolized by microflora or passed by phase II biotransformation reactions. The fact suggests that these iridoids may have the same health effects, such as antioxidant, anti-inflammatory, and healing as in vitro and in preclinical tests. In addition, in the group and conditions established for the study, no toxicity for subjects were evident. 13.3.4 TECHNOLOGICAL PURPOSES OF G. AMERICANA BIOACTIVES For some time, industry has had a great interest in G. americana for the production of dye from the extract or juice of the fruit. This interest has been directed toward human needs and personal care, with the production of dyes for the cosmetic and food industry as the main focus of patents (Teixeira et al., 2021). Even more up-to-date, new scopes have been added to the technological benefits of the jackfruit. Kumar et al. (2016) developed a simple, rapid, stable, and eco-friendly method to synthesize gold nanoparticles using G. americana fruit extract with biological applications. Thereafter, reliable, low cost and useful alternative in the determination of phenolic compounds has been also explored. First, polyphenol oxidases (PPOs) obtained from crude extract of fruits have presented recovery levels of pollutants poplyphenols of 70–120% being these results comparable to the standard spectrophotometric techniques (Antunes et al., 2018). Second, these PPOs have shown effectiveness in determining methyldopa and paracetamol in pharmaceutical samples (Antunes et al., 2019). In this context, PPOrich extract of G. americana fruit gained ecological and pharmaceutical importance.

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FIGURE 13.2 Medicinal and industrial potentials of Genipa americana L. extracts and compounds. PPO—polyphenols oxidases; PRE—polysaccharides-rich extract.

KEYWORDS • • • • • •

iridoids antimicrobial agent polyphenols Rubiaceae edible plant toxicity

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CHAPTER 14

Phytochemical Constituents and Pharmacology of Cuminum cyminum L. THADIYAN PARAMBIL IJINU1,2*, RAGESH RAVEENDRAN NAIR3,

MAHESWARI PRIYA RANI4, THOMAS ASWANY5,

MOHAMMED S. MUSTAK6, and PALPU PUSHPANGADAN1

Amity Institute for Herbal and Biotech Products Development,

Thiruvananthapuram 695005, Kerala, India

1

Naturæ Scientific, Kerala University Business Innovation and

Incubation Centre, Karyavattom Campus, Thiruvananthapuram 695581,

Kerala, India

2

Department of Botany, NSS College Nilamel, Kollam 691535, Kerala,

India

3

Phytochemistry and Pharmacology Division,

Jawaharlal Nehru Tropical Botanic Garden and Research Institute,

Thiruvananthapuram 695562, Kerala, India

4

Department of Biotechnology, Malankara Catholic College,

Kanyakumari 629153, Tamil Nadu, India

5

Department of Applied Zoology, Mangalore University,

Dakshina Kannada 574199, Karnataka, India

6

Corresponding author. E-mail: [email protected]

ABSTRACT Cuminum cyminum or cumin, is an annual herbaceous spice plant and has a wide range of applications as a food and therapeutic agent. Cumin belongs to the family Apiaceae and has long been traditionally used to treat gastrointestinal discomforts. It is considered to have emmenagogue, stomachic, Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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carminative, antispasmodic and anthelmintic properties. Several reports show that essential oil from cumin is rich in cuminaldehyde, γ-terpinene, β-pinene and o-cymene. Cuminoids, apigenin, apigenin 7-O-β-D-glucoside, luteolin and luteolin 7-O-β-D-glucoside are other major compounds reported. Extracts, isolated compounds, and essential oils of various parts of cumin showed anti-inflammatory, immunomodulatory, antioxidant, hepatoprotective, antiallergic, antidiabetic, neuroprotective, anticancer, contraceptive and antimicrobial properties. 14.1 INTRODUCTION Cuminum cyminum L. (Syn.: Cuminia cyminum J.F. Gmel., Cuminum aegyptiacum Mérat ex DC., Cuminum hispanicum Mérat ex DC., Cuminum odorum Salisb., Cuminum officinale Garsault) belongs to the family Apiaceae. Vernacular names of this plant include ajaji, ajajika, ajmoda, dipaka, dipya, dirghajiraka, dirghaka, gaurajaji, gaurajiraka, hrasvanga, jaji, jarana, jaranam, jeeraka, jira, jiraka, jirakam, jirana, jirna, kanavha, kunchika, magadha, mitadipya, mitajaji, shuklajaji, suklajaji, svetajiraka, vahmisakha (Sanskrit), gajar, jeera, jira, safed jeera, safed-zira, shiajira, zeera, zira (Hindi), cheerakam, jeerakam, jirakam (Malayalam), acai, acai ciri, acaiyu, acanaveti, attimai, attinam, cankuvankanam, cheerakam, cicari, cikariccaram, ciraciram, cirakacutti, cirakam, cirnam, citakkakoli, cittirapattiri, cukkumapaciyam, cutapattirikam, jeerakam, jirakam, kaci, kanalvakiyam, kanati, ketakaciram, kokanaccirakam, kuncikkay, maisakukkilam, maravuri, mettiyam, mokal arjak, muttiratosanacani, naccirakam, nallacirakam, narcirakam, narumakaciram, nattuccirakam, pacumpi, pacuntiram, palika, pancakkini, pattirikam, pikam, pirattivika, pittanacini, pittapattiram, pocanakutari, seeragam, shimai-shombu, tilaka, tippiyam, tirkkakanam, tirunacati, tutta campalam, tuttacampalam, upakumpam, upakumpapicam, varivaricu (Tamil), jeera, jeeraka, jeerigay, jeerige, jirage, jiringe (Kannada), jeelakara, jilakara, jilakhrah, jiraka, jirana, jiranan, zeela-karra (Telugu), jeera, jeeram, jiregire (Marathi), Jira (Assamese), dzi-ra, go-snod, go-snod, zira (Tibetan), safaid zira, zeerasafed, zira safaid, zira safaid bariyan, zira safaid muddabir, zira safed, zira siyah muddabir, zira sufaid (Urdu), kamonabaize, kamoon, kamoon asfar, kamun, zirah safaid (Arabic), zira, zira or zirah, zira sefed, zira sufaid (Persian), cumin (English). It is an erect, much-branched, annual herb growing up to 50 cm tall. Stems are slender, glabrous. Leaves bi-or tripinnate, with ciliate ultimate segments, ca. 2–5 cm long. Basal petioles ca. 1–2 cm, sheaths lanceolate, lamina ca. 3–8 × 2–7 cm, margins white and membranous. Flowers white, 3–5 in each

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partial umbel, pedicels stout, umbels compound, rays 1–5, stout, bracts 2–4, filiform or trifid, longer than rays, bracteoles usually 3, unequal. Calyx subulate, unequal. Petals obovate-oblong, emarginate. Fruits ca. 0.4–0.5 cm, ovoid-oblong, setulose; primary ridges filiform, conspicuous, secondary ridges hispidulate; vittae large (Sasidharan, 2004). C. cyminum is native to the upper Nile region in Egypt and is widely distributed in North Africa, Mediterranean region, Middle East, Central Asia, and Indian subcontinent. Cumin seed powder or decoction has long been traditionally used to treat gastrointestinal discomforts. It is considered to have emmenagogue, stomachic, carminative, antispasmodic, and anthelmintic properties. Cumin is used as a poultice for treating acute infectious inflammations on the skin (Bellakhdar, 1997). Cumin seed paste along with onion juice has been applied over scorpion and bee stings (Vican, 2001). Cumin seeds have long been used in traditional Iranian medicine to cure toothaches and epilepsy (Janahmadi et al., 2006). In Ayurveda, it is used for the treatment of dyspepsia, diarrhea, and jaundice (Dhandapani et al., 2002). As a tonic and stimulant, cumin helps in digestion and alleviate colic, gas, and diarrhea (Bremness, 1996). It has been found to improve lactation and lessen nausea during pregnancy, and it can be used as a poultice to alleviate breast or testicular edema (Jalali-Heravi et al., 2007). 14.2 PHYTOCHEMICAL CONSTITUENTS Essential oil of cumin seeds obtained from Aleppo and Idleb regions of Syria contains cuminaldehyde (32.8–38.5%), γ-terpinene (16.3–12.62%), β-pinene (11.50–10.30%), o-cymene (9.74–10.98), 2-caren-10-al (6.24–7.35%), and trans-carveol (3.20–5.71%) as major compounds (Rihawy et al., 2014). Wongkattiya et al. (2019) found that cuminaldehyde (27.10%), β-pinene (25.04%), and γ-terpinene (15.68%) are the major components in the seeds of C. cyminum collected from Chiang Mai, Thailand. Essential oil of C. cyminum seeds obtained from Kashan, Iran contains cuminaldehyde (38.9%), γ-terpinene (18.3%), p-cymene (15.4%), and β-pinene (11.7%) as major components (Taghizadeh et al., 2017). Essential oil components of the seeds of C. cyminum obtained from Ilkhchi, Iran contains 3-caren-10-al (47.95%), cuminaldehyde (25.49%), 2-caren-10-al (8.16%), γ-terpinene (7.19%), (-)-β-pinene (5.10%), and p-cymene (2.05%) (Ghasemi et al., 2019). Essential oil of C. cyminum from Alborz Mountain, Iran revealed the presence of α-pinene (29.2%), limonene (21.7%), 1,8-cineole (18.1%), linalool (10.5%), and α-terpineole (3.17%) as major components (Mohammadpour et al., 2012). Essential oil of C. cyminum seeds obtained from Swassi, Mahdia District,

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Tunisia contains cuminaldehyde (39.48%), γ-terpinene (15.21%), O-cymene (11.82%), β-pinene (11.13%), 2-caren-10-al (7.93%), trans-carveol (4.49%), and myrtenal (3.5%) as major components (Hajlaoui et al., 2010). Derakhshan et al. (2008) found that the main components of C. cyminum essential oil are cuminaldehyde (25.2%), p-mentha-1,3-dien-7-al (13%), p-mentha-1,4-dien-7-al (16.6%), γ-terpinene (19%), p-cymene (7.2%), and β-pinene (10.4%). Jirovetz et al. (2005) found that the essential oil from the seeds of C. cyminum stored up to 36 years contains cuminaldehyde (36%), β-pinene (19.3%), p-cymene (18.4%), and γ-terpinene (15.3%) as the major constituents. The steam and water distilled oils of Turkish cumin seed contains cuminaldehyde (19.25–27.02%), p-mentha-l,3-dien-7-al (4.29–12.26%), p-mentha-l,4-dien-7-al (24.48–44.91%), α-terpinene (7.06–14.10%), p-cymene (4.61–12.01%), and β-pinene (2.98–8.90%) as the major components (Baser et al., 1992). The essential oil from the seeds of C. cyminum from China contains cuminal (36.31%), cuminic alcohol (16.92%), γ-terpinene (11.14%), safranal (10.87%), p-cymene (9.85%), and β-pinene (7.75%) as the major components (Li and Jiang, 2004). Wanner et al. (2010) found that cumin essential oil samples from four different geographical origins (Iran, Egypt, India, and Europe) contains cuminic aldehyde (41.5%, 29.3%, 23.2%, and 22.4%), p-cymene (17.4%, 10.1%, 18.4%, and 20.2%, β-pinene (10.7%, 15.7%, 12.6%, and 14.1%), γ-terpinene (6.5%, 18.5%, 31.1%, and 26.5%) and p-mentha-1,3-dien-7-al (5.5%, 10.6%, 7.2%, and 6.6%, respectively) as major compounds. C. cyminum essential oil contains α-pinene (29.1%), 1,8-cineole (17.9%), and linalool (10.4%) as the major compounds (Gachkar et al., 2007). Zhang et al. (2015) isolated 21 compounds from C. cyminum seeds including five new compounds (cuminoids A-E—two sesquiterpenoids, two pairs of monoterpenoid epimers, and a chalcone). The other 16 compounds include (1R,5R,6S,7S,9S,10S,11R)-1,9-dihydroxyeudesm-3-ene-12,6-olide 9-O-β-Dglucopyranoside (Takayanagi et al., 2003), glycerol 1-O-α-D-glucuronide 3-O-benzoyl ester (Cai et al., 2011), 3-hydroxy-1-(4-methylethyl)-benzaldehyde; 1-(4-methylethyl)-benzoic acid (Hu et al., 2007), 1-(4-methylethyl)-phenol (Han et al., 2009), 1-(4-methylethyl)-benzoic acid methyl ester, 1-hydroxymethylβ-methyl-benzeneethanol (van Meurs et al., 1977), (8R)-9-hydroxycuminyl β-D-glucopyranoside (Ishikawa et al., 2002), 1-(8-hydroxy-4-methylethyl)benzoic acid, 1-(9-hydroxy-4-methylethyl)-benzoic acid (Schievano et al., 2013), benzyl β-D-glucopyranoside (De Rosa et al., 1996), (E)-isoferulic acid-3-O-β-D-glucopyranoside (Perveen et al., 2008), apigenin (Van Loo et al., 1986), apigenin 7-O-β-D-glucoside (Lu and Foo, 2000), luteolin (Luo et al., 2003), and luteolin 7-O-β-D-glucoside (Malikov and Yuldashev, 2002). The

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methanolic extract of the fruits of C. cyminum contains n-tricosanyl n-octadec9-enoate, 1,4,5,8-tetrahydroxynaphthyl geranilan-10′-al 1′-oate, lanost-5,20 (22)-dien-3α-olyl ndocosanoate, labdan-6α,16,20-triol-16-(10′,11′-dihydroxy anthraquinone-2′-oate, stigmast-5-en3β-O-D-arabinopyranosyl-2′-benzoate, and lanost-5,24-dien-3β-ol 3β-O-D-arabinopyronosyl-2′-noctadec-9″, 12″-dienoate (Chaudhary et al., 2014a, 2014b). Reversed phase high performance liquid chromatography study found that C. cyminum root contains quercetin (26%) as the major phenolic compound, and the stem and leaves contain p-coumaric, rosmarinic, trans-2-dihydrocinnamic acid, and resorcinol as major compounds, and the flower contains vanillic acid (51%) as the major compound (Bettaieb et al., 2010).

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PHARMACOLOGICAL STUDIES

Extracts, isolated compounds, and essential oil of various parts of the C. cyminum showed wide range of pharmacological properties and are discussed below: 14.3.1 ANTI-INFLAMMATORY ACTIVITY Kang et al. (2019) found that 8-(amino(4-isopropylphenyl)methyl)-5hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4-oxo-4H-chromene-6-carboxylic acid isolated form C. cyminum seeds exhibited nitric oxide inhibitory with IC50 of 5.25 μM in the lipopolysaccharide-stimulated RAW264.7 together with decline in inducible nitric oxide synthase and cyclooxygenase-2. Cumin essential oil inhibited the lipopolysaccharide-induced transcriptional activation of nuclear factor-kappa B and inhibited the phosphorylation of extracellular signal regulated kinase and c-Jun N-terminal kinase in RAW264.7 cells (Wei et al., 2015). Cuminaldehyde isolated from C. cyminum showed inhibition of 15-LOX with an IC50 value of 1370 μM (Tomy et al., 2014). A clinical study conducted by Morovati et al. (2019) showed that Cuminum oil supplementation in 56 patients improved antioxidant indices superoxide

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dismutase and total antioxidant capacity, and decreased the malondialdehyde level. Cuminaldehyde isolated from C. cyminum significantly inhibited (12.5–50 mg/kg) formalin and acetic acid-induced nociception. In CCl4induced neuropathy, cuminaldehyde at a dose range of 25–100 mg/kg considerably improved allodynia and hyperalgesia, and reduced the levels of tumor necrosis factor-α and interleukin-1β indicating its effect on opioid receptors, L-arginine/ nitric oxide/cyclic guanosine monophosphate pathways and anti-inflammatory function (Koohsari et al., 2020). C. cyminum volatile oil at dose of 0.1 mL/kg body weight (intraperitoneal) showed dose-dependent inhibition of paw edema in carrageenan-induced rat model (Shivakumar et al., 2010). 14.3.2

IMMUNOMODULATORY ACTIVITY

Chauhan et al. (2010) found that the aqueous alcoholic extract of cumin and isolated compound 7-(1-O-β-D-galacturonide)-4-(1-O-β-glucopyranosyl)3′4′,5,7-tetrahydroxyflavone (1, 2 and 4 mg/kg) enhanced the production of the T cells and Th1 cytokines in normal animals. C. cyminum extract dose dependently (25, 50, 100, and 200 mg/kg) augmented CD4 and CD8 and Th1-mediated immune response in cyclosporine-A injected immunesuppressed mice. The isolated compound significantly countered the harmful effects of restraint stress and increased the reduced CD4 and CD8 count and interleukin-2 expression as compared with control. Cumin decreased the blood glucose level, total immunoglobulin E level, and inflammatory cytokine levels in streptozotocin-induced diabetic rats with Staphylococcus aureus infection, thereby improved the immune functions. Water-soluble polysaccharides (100 µL of 10, 25, and 50 µg/mL) from C. cyminum stimulated nuclear factor-kappa B and mitogen-activated protein kinase signal transduction pathways in RAW264.7 and NK-92 cells (Tabarsa et al., 2020). 14.3.3 ANTIOXIDANT ACTIVITY In β-carotene bleaching assay, thymol-rich (40.05%) C. cyminum essential oil showed good radical scavenging activity (IC50 26.05 mg/mL) which is comparable to that of Trolox standard (IC50 29.12 mg/mL). In ferric reducing antioxidant power assay, C. cyminum oil showed good reducing power (IC50 341.65 µmol Fe2+/g oil) and the IC50 of Trolox is 321.05 µmol Fe2+/g oil (Ali, 2016). In mice, cumin seed elevated glutathione level and stimulated other

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antioxidant systems (Gagandeep et al., 2003). Krishnakantha and Lokesh (1993) found the superoxide anion scavenging activity of cuminaldehyde. The aqueous extract of cumin exhibits strong antioxidant activity superior to that of ascorbic acid (Satyanarayana et al., 2004). Acetone extract of flowers showed strong 2,2-diphenyl-1-picrylhydrazyl radical scavenging, lipid peroxidation inhibiting, and ferric reducing activities with IC50 values of 4, 32, and 8 μg/mL, respectively (Bettaieb et al., 2010). Rebey et al. (2014) found that the total phenolic content of ripe fruit of C. cyminum (17.74 and 25.15 mg gallic acid equivalent/g dry weight) is greater than that of unripe (6.91 and 12.18 mg gallic acid equivalent/g dry weight), extracted by maceration and Soxhlet methods. In relation to the total phenolic content, the antioxidant capacity was also greater in ripe fruit extract (IC50 6.24 and 42.16 μg/mL) when compared with unripe (IC50 280.77 and 325.15 μg/mL), extracted by maceration and Soxhlet methods. 14.3.4

HEPATOPROTECTIVE ACTIVITY

Protective effect of C. cyminum essential oil against cyclophosphamideinduced liver toxicity in mice was demonstrated by Sheweita et al. (2016). Administration of essential oil at a dose of 0.106 mL/kg significantly increased the activity of endogenous antioxidant enzymes, such as superoxide dismutase, catalase, glutathione s-transferase, glutathione peroxidase, and glutathione reductase. Aqueous ethanolic extract of dried seeds C. cyminum (100, 200, and 300 mg/kg) showed good hepatoprotective potential against nimesulide-induced liver toxicity in rats mainly because of the reduction in the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatise, and total bilirubin. The highest dose 200 mg/kg showed maximum protection, which was further confirmed by histopathology (Aamir et al., 2014). 14.3.5 ANTIALLERGIC ACTIVITY Water-soluble fraction of C. cyminum seed on antigen-induced degranulation of RBL-2H3 cells was tested by Hada et al. (2019). The extract inhibited the elevation of intracellular calcium ion concentration and suppressed phosphorylation of phosphatidylinositol 3-kinase, Bruton’s tyrosine kinase, phospholipase C-γ1/2, and Akt (protein kinase B).

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14.3.6 ANTIDIABETIC ACTIVITY

Antidiabetic effect of cumin seeds in combination with glyburide in streptozotocin-induced diabetic rat model was evaluated by Kaur et al. (2019). The result showed that C. cyminum seed extract (600 mg/kg) significantly improved the glycemic index and showed pharmacodynamic interaction with glyburide to alleviate symptoms of diabetes. Oral administration of 0.25 g/kg of cumin seed powder for 6 weeks to alloxan-induced diabetic rats resulted in significant reduction in blood glucose to 82 mg/dL, and an increase in total hemoglobin (14.73 g/dL) and glycosylated hemoglobin (2.24 g/dL). It is also found that cumin seed powder showed more activity than glibenclamide with 103.33 mg/dL blood glucose (Dhandapani et al., 2002). Patil et al. (2013) found that cuminaldehyde and cuminol at a dose of 25 mg/mL showed potent insulinotrophic activity by closure of the ATP-sensitive K channel and improved the intracellular Ca²+ concentration, and thereby increased the insulin secretion from 3·34 to 3·85-fold. Administration of methanolic seed extract of cumin (100, 200, and 400 mg/kg) significantly prevented the increase in glucose level in diabetic rats. The highest dose 400 mg/kg showed best results with increased gastric mucus content, antioxidant status, and cellular ATPase enzyme level as compared with diabetic control group (Vador et al., 2012). Inhibitory activity of cuminaldehyde tested against lens aldose reductase and α-glucosidase isolated from Sprague-Dawley male rats showed good activity with IC50 values 0.00085 and 0.5 mg/mL, respectively (Lee, 2005). 14.3.7 NEUROPROTECTIVE ACTIVITY Administration of essential oil from the fruit of C. cyminum (0.001–2%, 5 mL/kg, intraperitoneal), 60 min before test on day 5 (expression) decreased the conditioning scores at the doses of 1% and 2%, while injection of oil 60 min before morphine injection (5 mg/kg, subcutaneous) during 3 days of conditioning session (acquisition) significantly resulted in decrement of rewarding properties at the doses of 0.1%, 0.5%, 1%, and 2% in mice (Khatibi et al., 2008). C. cyminum fruit essential oil significantly attenuated the development of morphine tolerance at a dose of 1% and 2%, and dependence at a dose of 0.5%, 1%, and 2% in morphine (50, 50, 75 mg/ kg, subcutaneous) induced mice (Haghparast et al., 2008). C. cyminum fruit essential oil showed protection against maximal electroshock and pentylenetetrazole in tonic seizure induced mice (Sayyah et al., 2002).

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14.3.8 ANTICANCER ACTIVITY Luteolin-7-O-glucoside isolated from C. cyminum showed potent anticancer activities against MCF-7 cell line (IC50 of 3.98 µg/mL) (Goodarzi et al., 2020). Silver nanoparticles (12.5 μg/mL) biosynthesized using cumin seed extract showed potent cell growth inhibition in human breast adeno carcinoma cell line (MCF-7, 87.5%), and human breast adeno carcinoma metastatic cell line (AU565, 96%) (Dinparvar et al., 2020). 14.3.9

CONTRACEPTIVE ACTIVITY

Fraction of C. cyminum extract was tested for contraceptive efficacy in male albino rats (Saxena et al., 2015). C. cyminum fraction at a dose of 50 mg/ rat/day for 60 days showed significant abnormalities in spermatogenesis including sperm motility, density, and morphology. There is no significant change in body weight. Testosterone level was also significantly declined. Gupta et al. (2011) evaluated the contraceptive activity of methanol extract of C. cyminum in male albino rats for 60 days showed marked reduction in sperm density and motility, showing 69% and 76% reduction in fertility with 100 and 200 mg/rat/day doses without producing any apparent toxic effects. 14.3.10 ANTIMICROBIAL ACTIVITY Alizadeh et al. (2019) found that cumin essential oil showed good antimicrobial activity against Escherichia coli and Listeria innocua by disrupting membrane integrity. C. cyminum essential oil showed strong antimicrobial activity against Bacillus cereus. Wongkattiya et al. (2019) found that cuminaldehyde showed potent antimicrobial activity in TLC-bioautography. Essential oil obtained from the C. cyminum seed at a dose of 10 mg/mL showed potent activity against S. aureus (Mostafa et al., 2018). C. cyminum essential oil inhibited the biofilm formation of bacterial strains, S. aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes, E. coli, Pseudomonas aeruginosa, Proteus mirabilis and Klebsiella pneumoniae (Condò et al., 2020). Sun et al. (2017) found that C. cyminum seed containing cuminic acid showed good activity against Fusarium oxysporum f. sp. niveum with IC50 of 22.53 μg/mL. Wang et al. (2016) studied the antifungal activity of cuminic acid against Phytophthora capsica, the IC50 value for inhibiting mycelial growth is 14.54 μg/mL and for zoospore germination is 6.97 μg/mL. Naeini et al. (2014) evaluated the antifungal potential of essential oil of C. cyminum against different pathogenic Candida species and

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found that the best minimal inhibitory concentration was against C. albicans and C. dubliniensis (289 mg/L). Antimicrobial effect of cumin oil tested against E. coli, S. aureus, and S. faecalis showed complete death time on exposure of 30, 90, and 120 min, respectively. The E. coli is most vulnerable and S. faecalis is the least vulnerable (Allahghadri et al., 2010). Chaudhary et al. (2014a, 2014b) compared the antimicrobial property of volatile oils, methanolic, hydroalcoholic, and aqueous extracts of the fruits of cumin and revealed that the volatile oil showed maximum activity against various strains of Staphylococcus sp., Propionibacterium acnes, and Corynebacterium diphtheriae. Derakhshan et al. (2008) showed that sub-minimum inhibitory concentration of C. cyminum extracts resulted in cell elongation, repression of capsule expression, and decreased urease activity in K. pneumoniae. Fakoor and Rasooli (2008) found that C. cyminum oil exhibited significant antimicrobial activity, a complete death time on exposure of 20, 180, and 90 min for E. coli, S. aureus, and L. monocytogenes, respectively. Iacobellis et al. (2005) evaluated the antimicrobial activity of C. cyminum essential oil against various bacterial species and high inhibition in growth was observed against the genera Clavibacter, Curtobacterium, Rhodococcus, Erwinia, Xanthomonas, Ralstonia, and Agrobacterium. Jirovetz et al. (2005) showed significant antimicrobial effect of essential oil from the seeds of C. cyminum stored up to 36 years against fungi Aspergillus niger, Saccharomyces cerevisiae, and C. albicans, and bacteria Bacillus subtilis and S. epidermidis. Sheikh et al. (2010) found that the methanol extract of C. cyminum seeds showed highest inhibition zone of 16.67 mm at a concentration of 10 μL of 250 mg/mL for E. coli. The inhibition zones for B. subtilis, Sarcina lutea, and K. pneumoniae are found to be 15.00 mm for ethanol (250 mg/mL), 15.33 for methanol (250 mg/mL), and 15.67 for acetone (250 mg/mL) extracts, respectively. Tavakoli et al. (2015) found significant reduction in growth of Salmonella typhimurium with the treatment of C. cyminum essential oil at a concentration of ≥30 µL/100 mL in combination with nisin ≥0.5 µg/mL at 10°C. In the case of S. aureus, essential oil ≥15 µL/100 mL with nisin ≥0.5 µg/mL at ≤ 25°C showed better activity. 14.3.11 TOXICITY STUDIES Essential oil obtained from C. cyminum (250, 500, and 1000 mg/kg/day) showed no adverse effects on clinical signs, mortality, body weight, blood parameters, biochemistry, and histopathology after 23 and 45 days, in female Wistar rats (Taghizadeh et al., 2017). Allahghadri et al. (2010) found that

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cumin oil showed 79% of cytotoxicity in Hela cells at a concentration of 0.1 μL/mL. Sub-chronic toxicity (30 days) study in Wistar rats showed the essential oil caused 17.38% decrease in white blood cells count, and 25.77%, 14.24%, and 108.81% increase in hemoglobin concentration, hematocrit and platelet count, respectively with lowered low-density lipoprotein/highdensity lipoprotein ratio. ACKNOWLEDGMENTS The authors express their sincere thanks to Dr. Ashok K. Chauhan, Founder President, Ritnand Balved Education Foundation (RBEF) and Amity Group of Institutions, and Dr. Atul Chauhan, Chancellor, Amity University Uttar Pradesh (AUUP) for facilitating this work. Thadiyan Parambil Ijinu is receiving Young Scientist Fellowship from the Department of Science and Technology, Government of India (SP/YO/413/2018). KEYWORDS • • • • • •

cumin cuminaldehyde apigenin luteolin anti-inflammatory antidiabetic

REFERENCES Aamir, M.; Mahmood, A.; Qaiser, J.; Anum, S.; Muhammad, W.; Muhammad, A. A. Hepatoprotective Investigations of Cuminum cyminum Dried Seeds in Nimesulide Intoxicated Albino Rats by Phytochemical and Biochemical Methods. Int. J. Pharm. Pharm. Sci. 2014, 6, 506–510. Ali, R. L. M. Chemical Composition and Antioxidant Activity Cuminum cyminum L. Essential Oils. Int. J. Food Prop. 2016, 19, 438–442. Alizadeh, B. B.; Noshad, M.; Falah, F. Cumin Essential Oil: Phytochemical Analysis, Antimicrobial Activity and Investigation of Its Mechanism of Action Through Scanning Electron Microscopy. Microb. Pathog. 2019, 136, 103716.

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Goodarzi, S.; Tabatabaei, M. J.; Mohammad, J. R.; Shemirani, F.; Tavakoli, S.; Mofasseri, M.; Tofighi, Z. Cuminum cyminum Fruits as Source of Luteolin-7-O-Glucoside, Potent Cytotoxic Flavonoid Against Breast Cancer Cell Lines. Nat. Prod. Res. 2020, 34, 1602–1606. Gupta, R. S.; Saxena, P.; Gupta, R.; Kachhawa, J. B. Evaluation of Reversible Contraceptive Activities of Cuminum cyminum in Male Albino Rats. Contraception 2011, 84, 98–107. Hada, M.; Nishi, K.; Ishida, M.; Onda, H.; Nishimoto, S.; Sugahara, T. Inhibitory Effect of Aqueous Extract of Cuminum cyminum L. Seed on Degranulation of RBL-2H3 Cells and Passive Cutaneous Anaphylaxis Reaction in Mice. Cytotechnology 2019, 71, 99–609. Haghparast, A.; Shams, J.; Khatibi, A.; Alizadeh, A. M.; Kamalinejad, M. Effects of the Fruit Essential Oil of Cuminum cyminum Linn. (Apiaceae) on Acquisition and Expression of Morphine Tolerance and Dependence in Mice. Neurosci. Lett. 2008, 440, 134–139. Hajlaoui, H.; Mighri, H.; Noumi, E.; Snoussi, M.; Trabelsi, N.; Ksouri, R.; Bakhrouf, A. Chemical Composition and Biological Activities of Tunisian Cuminum cyminum L. Essential Oil: A High Effectiveness Against Vibrio spp. Strains. Food Chem. Toxicol. 2010, 48, 2186–2192. Han, W. J.; Yang, R.; Dai, X. C. Synthesis and Anti-Depression Activities of Phenolic 2-Acetamido-2-Deoxy-β-D-Glucopyranoses. Zhongguo Yaowu Huaxue Zazhi 2009, 19, 99–105. Hu, L. F.; Feng, J. T.; Zhang, X.; Zhang, Y. L. Isolation and Structure Detection of Fungicidal Components from Cuminum cyminum Seed. Nongyaoxue Xuebao 2007, 9, 330–334. Iacobellis, N. S.; Lo Cantore, P.; Capasso, F.; Senatore, F. Antibacterial Activity of Cuminum cyminum L. and Carum carvi L. Essential Oils. J. Agric. Food Chem. 2005, 53, 57–61. Ishikawa, T.; Takayanagi, T.; Kitajima, J. Water-Soluble Constituents of Cumin: Monoterpenoid Glucosides. Chem. Pharm. Bull. 2002, 50, 1471–1478. Jalali-Heravi, M.; Zekavat, B.; Sereshti, H. Use of Gas Chromatography–Mass Spectrometry Combined with Resolution Methods to Characterize the Essential Oil Components of Iranian Cumin and Caraway. J Chromatogr A. 2007, 1143, 215–226. Janahmadi, M.; Niazi, F.; Danyali, S.; Kamalinejad, M. Effects of the Fruit Essential Oil of Cuminum cyminum Linn. (Apiaceae) on Pentylenetetrazol-Induced Epileptiform Activity in F1 Neurones of Helix aspersa. J. Ethnopharmacol 2006, 104, 278–282. Jirovetz, L.; Buchbauer, G.; Stoyanova, A. S.; Georgiev, E. V.; Stanka, T.; Damianova, S. T. Composition, Quality Control and Antimicrobial Activity of the Essential Oil of Cumin (Cuminum cyminum L.) Seeds from Bulgaria that had been Stored for up to 36 Years. Int. J. Food Sci. Technol. 2005, 40, 305–310. Kang, N.; Yuan, R.; Huang, L.; Liu, Z.; Huang, D.; Huang, L.; Gao, H.; Liu, Y.; Xu, Q. M.; Yang, S. Atypical Nitrogen-Containing Flavonoid in the Fruits of Cumin (Cuminum cyminum L.) with Anti-Inflammatory Activity. J. Agric. Food Chem. 2019, 67, 8339–8347. Kaur, G.; Upadhyay, N.; Tharappel, L. J. P.; Invally, M. Pharmacodynamic Interaction of Cumin Seeds (Cuminum cyminum L.) with Glyburide in Diabetes. J. Complement. Integr. Med. 2019, 20180080. Khatibi, A.; Haghparast, A.; Shams, J.; Dianati, E.; Komaki, A.; Kamalinejad, M. Effects of the Fruit Essential Oil of Cuminum cyminum L. on the Acquisition and Expression of Morphine-Induced Conditioned Place Preference in Mice. Neurosci. Lett. 2008, 448, 94–98. Koohsari, S.; Sheikholeslami, M. A.; Parvardeh, S.; Ghafghazi, S.; Samadi, S.; Poul, Y. K.; Pouriran, R.; Amiri, S. Antinociceptive and Antineuropathic Effects of Cuminaldehyde, the Major Constituent of Cuminum cyminum Seeds: Possible Mechanisms of Action. J. Ethnopharmacol. 2020, 255, 112786.

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Sayyah, M.; Mahboubi, A.; Kamalinejad, M. Anticonvulsant Effect of the Fruit Essential Oil of Cuminum cyminum in Mice. Pharm. Biol. 2002, 40, 478–480. Schievano, E.; Morelato, E.; Facchin, C.; Mammi, S. Characterization of Markers of Botanical Origin and Other Compounds Extracted from Unifloral Honeys. J. Agric. Food Chem. 2013, 61, 1747–1755. Sheikh, M. I.; Islam, S.; Rahman, A.; Rahman, M.; Rahim, A.; Alam, F. Control of Some Human Pathogenic Bacteria by Seed Extracts of Cumin (Cuminum cyminum L). Agric. Conspec. Sci. 2010, 75, 39–44. Sheweita, S. A.; El-Hosseiny, L. S.; Nashashibi, M. A. Protective Effects of Essential Oils as Natural Antioxidants Against Hepatotoxicity Induced by Cyclophosphamide in Mice. PLoS One 2016, 11, e0165667. Shivakumar, S. I.; Shahapurkar, A. A.; Kalmath, K. V.; Shivakumar, B. Antiinflammatory Activity of Fruits of Cuminum cyminum Linn. Der. Pharm. Lett. 2010, 2, 22–24. Sun, Y.; Wang, Y.; Han, L. R.; Zhang, X.; Feng, J. T. Antifungal Activity and Action Mode of Cuminic Acid from the Seeds of Cuminum cyminum L. Against Fusarium oxysporum f. sp. niveum (FON) Causing Fusarium Wilt on Watermelon. Molecules 2017, 22, 2053. Tabarsa, M.; You, S.; Yelithao, K.; Palanisamy, S.; Prabhu, N. M.; Nan, M. Isolation, Structural Elucidation and Immuno-Stimulatory Properties of Polysaccharides from Cuminum cyminum. Carbohydr. Polym. 2020, 230, 115636. Taghizadeh, M.; Ostad, S. N.; Asemi, Z.; Mahboubi, M.; Hejazi, S.; Sharafati-Chaleshtori, R.; Rashidi, A.; Akbari, H.; Sharifi, N. Sub-Chronic Oral Toxicity of Cuminum cyminum L. Essential oil in Female Wistar Rats. Regul. Toxicol. Pharmacol. 2017, 88, 138–143. Takayanagi, T.; Ishikawa, T.; Kitajima, J. Sesquiterpene Lactone Glucosides and Alkyl Glycosides from the Fruit of Cumin. Phytochemistry 2003, 63, 479–484. Tavakoli, H. R.; Mashak, Z.; Moradi, B.; Sodagari, H. R. Antimicrobial Activities of the Combined Use of Cuminum cyminum L. Essential Oil, Nisin and Storage Temperature Against Salmonella typhimurium and Staphylococcus aureus In Vitro. Jundishapur J. Microbiol. 2015, 8, e24838. Tomy, M. J.; Dileep, K. V.; Prasanth, S.; Preethidan, D. S.; Sabu, A.; Sadasivan, C.; Haridas, M. Cuminaldehyde as a Lipoxygenase Inhibitor: In Vitro and In Silico Validation. Appl. Biochem. Biotechnol. 2014, 174, 388–397. Vador, N.; Jagtap, A. G.; Damle, A. Vulnerability of Gastric Mucosa in Diabetic Rats, Its Pathogenesis and Amelioration by Cuminum cyminum. Indian J. Pharm. Sci. 2012, 74, 387–396. Van Loo, P.; De Bruyn, A.; Buděšínský, M. Re-Investigation of the Structural Assignment of Signals in the 1H and 13C NMR Spectra of the Flavone Apigenin. Magn. Reson. Chem. 1986, 24, 879–882. van Meurs, F.; Van Bekkum, H. Substituent Effects in π-(Tricarbonylchromium) Arenes: IV. 1H NMR Spectroscopy of Substituted Methyl π-(Tricarbonylchromium) Benzoates. J. Organomet. Chem. 1977, 133, 321–326. Vican, P. Encyclopédie des plantes medicinales; Larousse, Paris, 2001; p 355. Wang, Y.; Sun, Y.; Zhang, Y.; Zhang, X.; Feng, J. Antifungal Activity and Biochemical Response of Cuminic Acid Against Phytophthora capsici Leonian. Molecules 2016, 21, 756. Wanner, J.; Bail, S.; Jirovetz, L.; Buchbauer, G.; Schmidt, E.; Gochev, V.; Girova, T.; Atanasova, T.; Stoyanova, A. Chemical Composition and Antimicrobial Activity of Cumin Oil (Cuminum cyminum, Apiaceae). Nat. Prod. Commun. 2010, 5, 1355–1358.

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CHAPTER 15

Ethnopharmacology and Phytochemistry of Lagenaria siceraria (Molina) Standl. SURAJ B. PATEL AND SAVALIRAM G. GHANE* Plant Physiology Laboratory, Department of Botany, Shivaji University,

Kolhapur, Maharashtra 416004, India

Corresponding author.

E-mail: [email protected]; [email protected]

*

ABSTRACT Lagenaria siceraria (Molina) Standl. is man’s first domesticated and widely popular vegetable plant. It is commonly called as Bottle gourd, whiteflowered gourd, and long melon. After maturity, fruit changes its shape to round, bottle, dumble shaped. In countries like, India, China, and Brazil, it is traditionally used to treat several health-related issues. Fruits are used as general tonic, cardioprotectant, hypolipidemic, aphrodisiac, and purgative. Parts of this plant are used in treatment of ulcers, fever, pectoral cough, asthma, diabetes, hypertension, and kidney stone. Chemical characterization of L. siceraria showed presence of triterpenoids, phenolic compounds, glycosides, fatty acids, steroids, lipids, glycerols that known for various biological activities. Pharmacological activities like anticancer, anti-acetylcholine esterase, antioxidant, antidiabetic, antihyperglycemic, antiasthmatic, antihyperlipidemic, antistress, adaptogenic, antimicrobial, anticompulsive, anxiolytic and memory enhancing etc. The present chapter highlights the traditional uses, chemical compounds and several potential benefits of Bottle gourd.

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INTRODUCTION

Cucurbitaceae is considered as the family of vegetables. The family comprises about 122 genera and 940 species. Lagenaria siceraria (Molina) Standl. (Syn. Cucurbita siceraria Molina, Cucurbita lagenaria L.) is considered as man’s first domesticated and the most popular fruit vegetable throughout the world. It is commonly called as Bottle gourd, white-flowered gourd, and long melon (Warra et al., 2016). In India, most of the wild species are found in the area of Dehradoon and Malabar coastal area (Ahmad et al., 2011). It is large, climbing annual herb. Tendrils are bifid, leaves are trilobed. Petals are white in color. Mature fruits are in different shapes, such as rounded, dumble-shaped, bottle-shaped, or crookneck-shaped. Seeds are white, truncate, or bidentate at apex. Traditionally, this plant is used in India, China, Brazil, European countries in the treatment of several health-related issues. Medicinal importance of this plant is reported in Ayurvedic Pharmacopeia of India which revealed that fruit is used as general tonic, cardioprotectant, hypolipidemic, aphrodisiac, purgative, diuretic, as well as to treat rheumatism, ulcers, fever, pectoral cough, asthma, diabetes, hypertension, and kidney stone (Ahmad et al., 2011; Attar and Ghane, 2018, 2019). Some tribal communities (Koyas, Gutti Koyas, and Lambadas) from Northern Telangana, India use dry hard shell of bottle gourd for the preparation of bottles, bowls, milk pots, spoons, and several types of containers. Fruits are used for making stringed and wind musical instruments and pipes (Shah et al., 2010). Crushed leaf with water is used to treat baldness and applied to cure headache. Mixture of seed oil and castor oil applied externally by Gutti Koya tribal against headache (Shah et al., 2010). Lagenaria is an important source of different dietary components, such as ascorbic acid, β-carotene, vitamin B, fibers, amino acids (Ahmad et al., 2011). 15.2

BIOACTIVS

Lagenaria siceraria is an important source of several compounds, such as ascorbic acid, β-carotene, vitamin B, fibers, amino acids (Ahmad et al., 2011). Chemical investigations revealed the presence of triterpenoids, phenolic compounds, glycosides, fatty acids, steroids, lipids, glycerols

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etc. (Attar and Ghane, 2018, 2019; Jaiswal and Kuhnert, 2014; Liaqat et al., 2017; Ahmed et al., 2017; Warra et al., 2016; Tyagi et al., 2012). Tetracyclic triterpenes, such as cucurbitacin B, E, I, G, H, and 22-deoxycucurbitacin reported from the fruit pulp, stem, leaf and roots by earlier researchers (Rehm et al., 1957). Swietenine, a tetranortriterpenoid detected by LC-MS from the fruits (Attar and Ghane, 2018). Ahmed et al. (2017) reported several terpenoids viz. eucalyptol, cuminaldehyde, 4α-Methyl-1-methylidene-1,2,3,4,4a,9,10,10a-octahydrophenanthrene, (E)-2,3-epoxycarane, 4,8a-dimethyl-6-(prop-1-en-2-yl)-3,5,6,7,8,8ahexahydronaphthalen-2(1H)-one from the mesocarp tissue. Attar and Ghane (2018) detected two potent alkaloids (1,4-dideoxy-1,4-imino-D arabinitol and cuscohygrine), and a cardiac glycoside (oleandrin) from the mature fruits. Mirlosawa and Cisowski (1995) found several flavonoids (7-O-glucosyl-6-C-glucoside apigenin, 6-C-glucoside luteolin, 7,4′-O-diglucosyl-6-C-glucoside apigenin, 4-C-glycosylflavone, isovitexin, isoorientin, saponarin, and saponarin 4′-O-glucoside) from the fruits. In addition, ethanol extract of fruit peel showed the presence of quercetin and rutin glycosides (Liaqat et al., 2017). Attar and Ghane (2018) reported avocadene (a fatty alcohol) that have active role in suppression of inflammatory responses. 1-Monopalmitin (monoacylglycerol) and two spingolipids viz., C16 sphinganine and phytosphingosine were also observed in the fruits (Attar and Ghane, 2018). Attar and Ghane (2019) RP-HPLC analysis of fruits revealed the presence of total six phenolic compounds viz., gallic acid, hydroxybenzoic acid, vanillic acid, chlorogenic acid, catechin, and coumaric acid. Ahmed et al. (2017) reported phenol methyl 3-(4-hydroxy-3,5-dimethylphenyl) propanoate from the fruits. Bhat et al. (2017) analyzed the juice using LC-MS and GC-MS and observed several compounds, such as rhodopin, salicylic acid, 2-pentanone, ethyl iso-allocholate, phytoalexin, quercetin, O-coumaric acid, theaflavin-3-gallate, N,N-dimethylmethyl amine, glyoxal, 1,3-chloro pentadiene, hydroxytyrosol, ethyl iso-allocholate and nonanal. Attar and Ghane (2018) reported fatty acids, such as isovaleric acid, isopalmitic acid, 13-methyl-pentadecanoic acid from the fruits. Potent bioactives are presented in Figure 15.1.

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FIGURE 15.1

15.3

Bioactive compounds from Lagenaria siceraria.

PHARMACOLOGY

15.3.1 ANTICANCER ACTIVITY Attar and Ghane (2019) reported anticancer activity against MCF-7 and HT-29 cancer cell lines. Highest activity was noted against MCF-7 (LC50 301.21 μg/mL) and HT-29 (LC50 664.02 μg/mL) cell lines compared with adriamycin (LC50 63.20 μg/mL). Methanolic extract (200 and 400 mg/kg) of aerial part revealed potent cytotoxic activity when tested using Ehrlich’s Ascites Carcinoma (EAC) model in mice (Saha et al., 2011b).

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15.3.2 ANTI-ACETYLCHOLINE ESTERASE ACTIVITY

Seeds extracts (acetone, ethanol, methanol, and water) were used to evaluate acetylcholine inhibitory activity. Ethanol extract represent highest (56.49% at 300 μg extract) inhibitory action followed by methanol (15.09% at 300 μg extract) and water (6.97% at 300 μg extract) (Attar and Ghane, 2019). 15.3.3 ANTIOXIDANT ACTIVITY Patel et al. (2018) explored the antioxidant potential of the leaves and fruit using several solvents. Highest FRAP reported in ethanol and methanol extract of leaves and fruits (395.79 ± 2.00 and 196.00 ± 3.18 mg FeE/g extract, respectively). Similarly, leaf ethanol and fruit methanol extracts denoted significant DPPH activity (IC50 251 and 711 µg/mL, respectively). ABTS radical scavenging activity was found superior in ethanol extract of leaf (379.81 ± 9.21 mg TE/g extract) and methanol extract of fruit (274.64 ± 2.81 mg TE/g extract). Similarly, highest metal chelating and phosphomolybdate content reported from aqueous extracts of leaves and fruits. Attar and Ghane (2019) reported promising antioxidant activities from epicarp, mesocarp, and seeds of Bottle gourd. 15.3.4 ANTIDIABETIC ACTIVITY Antidiabetic potential of seed extracts (acetone, ethanol, methanol, and water) was tested and found that the highest α-amylase inhibition (28.96% at 1 mg extract) in ethanol extract followed by acetone, methanol, and water (Attar and Ghane, 2019). Similarly, highest α-glucosidase inhibitory activity was reported from methanol seed extract (71.85% at 300 μg extract) that provide scientific evidence for its use in diabetic medicine. 15.3.5 ANTIHYPERGLYCEMIC ACTIVITY Antihyperglycemic activity of methanol extract was evaluated by Saha et al. (2011a). Different doses (200 and 400 mg/kg p.o.) of extract were given to streptozotocin-induced hyperglycemic rats continuously for 14 days and fasting blood glucose (FBG), several biochemical (SGPT, SGOT, ALP, total cholesterol, triglycerides) and antioxidant assays were performed at an

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interval of 0, 4, 8, and 15 days. Authors found that FBG level reduced during the course of time. Histological studies of organs, such as liver, kidney, and pancreas tissue showed promising responses by decreasing blood glucose (Saha et al., 2011a). 15.3.6 ANTIASTHMATIC ACTIVITY Jasani et al. (2012) studied antiasthmatic activity of aqueous leaf extract using various animal models, such as histamine and acetylcholine induced bronchoconstriction in Guinea pigs, paw edema in mice and compound 48/80 induced mast cell degranulation in rats. At 150 and 300 mg/kg dose of extract significant bronchodilatory activity was noted. Similarly, at 10, 20, and 30 μg/mL concentration of aqueous leaf extract exhibited inhibition in compound 48/80 induced mast cell degranulation. 15.3.7 ANTIHYPERLIPIDEMIC ACTIVITY Different concentrations of methanolic extract (100, 200, and 300 mg/kg) of the fruit was investigated for antihyperlipidemic activity using high fat-dietinduced hyperlipidemic rats (Ghule et al., 2009). After experimental period (30 days), significant decrease in lipid, total cholesterol, low-density lipoprotein cholesterol, triglyceride, and very low-density lipoprotein cholesterol, and increase in bile acid high-density lipoprotein cholesterol were observed in treated rats. Different extracts (petroleum ether, chloroform, alcohol, and aqueous) were also investigated against triton-induced hyperlipidemic rats, and it has been observed that animals treated with extract (200 and 400 mg/ kg body weight) revealed significant antihyperlipidemic activity except petroleum ether extract (Ghule et al., 2009). 15.3.8

IMMUNOMODULATORY ACTIVITY

Immunomodulatory activity was studied from the fraction of methanol extract soluble in n-butanol and ethyl acetate. Rats were orally administered with different doses (100, 200, and 500 mg/kg) and found that hypersensitivity reaction was significantly inhibited. Doherty method was used to induce delayed type hypersensitivity reaction in rats. The primary and secondary antibodies in rat were increased with concentration. In addition, white blood

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cell count and lymphocytes count also showed gradual increase (Gangwal et al., 2008). 15.3.9 ANTISTRESS AND ADAPTOGENIC PROPERTY Ethanol extract of fruit was used to evaluate antistress potential in albino Wistar rats and effect of forced swimming endurance stress on swimming endurance time, organ weight, and biochemical parameters were studied (Lakshmi and Sudhakar, 2009). Authors studied effect of acute heat stress on biochemical parameters, weight of adrenal gland, stress-induced changes in blood cell count of albino Wistar rats. Rats were administered orally (100– 400 mg/kg) and significant variation reported in terms of serum glucose, cholesterol, triglyceride, cortisol level, blood cell count, and organ weight. Treated rats showed significant increase in swimming endurance time and ameliorated stress-induced changes in both stress models. All these findings revealed strong evidence for antistress and adaptogenic properties (Lakshmi and Sudhakar, 2009). 15.3.10 ANTIMICROBIAL ACTIVITY Hydromethanolic (80%) extracts of leaves, seeds, and fruits were used to investigate in vitro antimicrobial potential against selective species of bacteria using agar well diffusion method. Extract showed significant activity against Pseudomonas aeruginosa and Streptococcus pyogenes but negligible activity was found against Staphylococcus aureus and Escherichia coli (Goji et al., 2006). Chaudhery et al. (2014) reported antimicrobial activity of methanolic seed pulp extract against Achromobacter xylosoxidans, Pseudomonas aeruginosa, Bacillus megaterium, and Escherichia coli with highest zone of inhibition (21.5, 20.0, 17.5, and 15.0 mm, respectively) at 100 mg/ mL concentration. 15.3.11 ANTICOMPULSIVE ACTIVITY Prajapati et al. (2011) evaluated anticompulsive activity in Swiss albino mice and its marble-burying behavior was evaluated. Fluoxetine was used as standard in this experiment. Administration of fruit extract showed significant decrease in the total number of buried marbles (9.4 ± 0.748–6.4

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± 0.812) with gradual increase in extract concentration. Standard (10 mg/ kg) and plant extract (25 and 50 mg/kg) does not produce any overt motor dysfunction in animal. 15.3.12 DIURETIC ACTIVITY Methanol fruit extract and vacuum-dried extract were used to evaluate diuretic activity in albino rat and different parameters, such as urine volume, concentration of electrolytes (sodium, potassium, and chloride) in urine was measured. Extract administrated orally (100–200 mg/kg; p.o.) revealed higher urine volume as compared with standard furosemide (20 mg/kg; i.p.). Both the extracts revealed dose-dependent increase in electrolyte concentration as compared with control set and proved diuretic potential (Ghule et al., 2013). 15.3.13 ANTHELMINTIC ACTIVITY Different concentrations (10–100 mg/mL) of seed extracts, such as petroleum ether, benzene, and methanol were tested against an adult Indian earthworm, Pheretima posthuma and time for paralysis and time of death was measured (Thube et al., 2009). It was observed that methanol and benzene extract significantly paralyzed the worms and caused worm death at higher concentration (100 mg/mL) as compared with standard (Piperazine citrate 10 mg/mL). 15.3.14 ANXIOLYTIC AND MEMORY ENHANCING ACTIVITY Aqueous fruit extract of Lagenaria (200 mg/kg twice in a day) revealed promising anxiolytic and memory enhancing activity in tested mice (Aslam and Najam, 2013). 15.3.15 CYTOTOXIC ACTIVITY n-Hexane extract of flowers revealed antitumor property in brine shrimp lethality bioassay (LC50 99.167 µg/mL) (Sen et al., 2013).

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15.3.16 ANTIULCER ACTIVITY Manchala (2019) used chloroform extract (250 and 400 mg/kg) in Wistar rats to investigate the antiulcer activity. Animal treated with higher doses found harmless and changes in healing ulcer, mucosa, and no inflammation of cells was observed. 15.3.17 HEPATOPROTECTIVE ACTIVITY Ethanol extract of fruit epicarp was used against CCl4-induced hepatotoxicity. Different doses (100 and 200 mg/kg) of extract were given orally and noted significant decrease in elevated level of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transferase (SGOT), alkaline phosphatase (ALP), acid phosphatase (ACP), and bilirubin (Deshpande et al., 2008). 15.3.18 CARDIOPROTECTIVE ACTIVITY Fard et al. (2008) assessed doxorubicin-induced cardiotoxicity in rats. Extract treated orally (200 mg/kg for 18 days) prevented cardiotoxicity and decrease myocardial injury by preventing change in antioxidants, such as superoxide dismutase, reduced glutathione, and lipid peroxidation in rats. Cardiotoxicity markers, such as creatine kinase-MB and lactate dehydrogenase (LDH) were reduced significantly. KEYWORDS • • • • •

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REFERENCES Ahmad, I.; Irshad, Md.; Moshahid, M.; Rizvi, A. Nutritional and Medicinal Potential of Lagenaria siceraria. Int. J. Veg. Sci. 2011, 17, 157–170. Ahmed, D.; Dar, P.; Chaudhery, R.; Masih, R. Chemical Constituents of Lagenaria siceraria Mesocarp and Its Xanthine Oxidase and Alpha-Amylase Inhibitory Activities. Int. J. Fruit Sci. 2017, 17 (3), 310–322. Aslam, M.; Najam, R. Anxiolytic and Memory Enhancing Activity of Lagenaria siceraria in Rodents. Int. J. Biomed. Adv. Res. 2013, 4 (1), 40–46. Attar, U. A.; Ghane, S. G. In Vitro Antioxidant, Antidiabetic, Anti-Acetylcholine Esterase, Anticancer Activities and RP-HPLC Analysis of Phenolics from the Wild Bottle Gourd (Lagenaria siceraria (Molina) Standl.). S. Afr. J. Bot. 2019, 125, 360–370. DOI: https://doi. org/10.1016/j.sajb.2019.08.004. Attar, U. A.; Ghane, S. G. Optimized Extraction of Anti-Cancer Compound—Cucurbitacin I and LC–MS Identification of Major Metabolites from Wild Bottle Gourd (Lagenaria siceraria (Molina) Standl.). S. Afr. J. Bot. 2018, 119, 181–187. DOI: https://doi. org/10.1016/j.sajb.2018.09.006. Bhat, S.; Saini, C. S.; Kumar, S. H. Changes in Total Phenolic Content and Color of Bottle Gourd (Lagenaria siceraria) Juice upon Conventional and Ohmic Blanching. Food Sci. Biotechnol. 2017, 26 (1), 29–36. Chaudhery, R.; Ahmed, D.; Liaqat, I.; Dar, P.; Shaban, M. Study of Bioactivities of Lipid Content of Fresh Lagenaria siceraria Seeds Pulp and Identification of Its Chemical Constituents. J. Med. Plant Res. 2014, 8 (31), 1014–1020. Deshpande, J. R.; Choudhari, A. A.; Mishra, M. R. Beneficial Effect of Lagenaria siceraria (Mol.) Standley Fruit Epicarp in Animal Models. Indian J. Exp. Biol. 2008, 46, 234–242. Fard, M. H.; Bodhankar, S. L.; Dikshit, M. Cardioprotective Activity of Fruit of Lagenaria siceraria (Molina) Standley on Doxorubicin Induced Cardiotoxicity in Rats. Int. J. Pharmacol. 2008, 4, 466–471. Gangwal, A.; Parmar, S. K.; Gupta, G. L.; Rana, A. C.; Sheth, N. R. Immunomodulatory Effects of Lagenaria siceraria Fruits in Rats. Pharmacog. Mag. 2008, 4 (16), 234–238. Ghule, B. V.; Ghante, M. H.; Saoji, A. N.; Yeole, P. G. Antihyperlipidemic Effect of the Methanolic Extract from Lagenaria siceraria Stand. Fruit in Hyperlipidemic Rats. J. Ethnopharmacol. 2009, 124, 333–337. Ghule, B. V.; Ghante, M. H.; Yeole, P. G.; Saoji, A. N. Diuretic Activity of Lagenaria siceraria Fruit Extracts in Rats. Indian J. Pharm. Sci. 2013, 69, 817–819. Goji, M.; Asres, K.; Gemeda, N.; Yirsaw, K. Screening of the Antimicrobial Activities of some Plants Used Traditionally in Ethiopia for the Treatment of Skin Disorders. Ethio. Pharma. J. 2006, 24, 130–135. Jaiswal, R.; Kuhnert, N. Identification and Characterization of the Phenolic Glycosides of Lagenaria siceraria Stand. (Bottle Gourd) Fruit by Liquid Chromatography-Tandem Mass Spectrometry. J. Agric. Food. Chem. 2014, 62, 1261–1271. Jasani, N.; Kapoor, M.; Tripathi, N.; Acharya, N.; Acharya, S.; Kumar, V. Anti-Asthmatic and Anti-Allergic Activity of Lagenaria siceraria Mol. Standley. J. Nat. Rem. 2012, 12 (1), 72–76. Lakshmi, B. V.; Sudhakar, M. Adaptogenic Activity of Lagenaria siceraria: An Experimental Study Using Acute Stress Models on Rats. J. Pharmacol. Toxicol. 2009, 4, 300–306.

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Liaqat, I.; Ahmed, D.; Saleem, A.; Masih, R.; Chaudhery, R. Characterization of Natural Products from the Peel of Lagenaria siceraria Fruit Using Chromatographic Techniques. Acta Chromatogr. 2017, 30 (3), 191–194. Manchala, P. Evaluation of Anti-Ulcer Activity of Lagenaria siceraria Chloroform Extracts in Pylorus Ligated Rats. Electron. J. Biol. 2019, 15 (1), 27–37. Mirlosawa, K. B.; Cisowski, W. Isolation and Identification of C-glycosides Flavone from Lagenaria siceraria L. D Res. 1995, 52, 137–139. Patel, S. B.; Attar, U. A.; Ghane, S. G. Antioxidant Potential of Wild Lagenaria siceraria (Molina) Standl. Thai. J. Pharm. Sci. 2018, 42, 90–96. Prajapati, R. P.; Kalaria, M. V.; Karkare, V. P.; Parmar, S. K.; Sheth, N. R. Effect of Methanolic Extract of Lagenaria siceraria (Molina) Standley Fruits on Marble-Burying Behavior in Mice: Implications for Obsessive–Compulsive Disorder. Pharmacogn. Res. 2011, 3 (1), 62–66. Rehm, S.; Enslin, P. R.; Meeuse, A. D.J.; Wessels, J. H.; Bitter Principles of the Cucurbitaceae. VIII—The Distribution of Bitter Principles in This Plant Family. J. Sci. Food Agric. 1957, 8, 679–686. Saha, P.; Mazumdar, U. K.; Haldar, P. K.; Sen, S. K.; Naskar, S. Antihyperglycemic Activity of Lagenaria siceraria Aerial Parts on Streptozotocin Induced Diabetes in Rats. Diabetol. Croat. 2011a, 40 (2), 49–60. Saha, P.; Sen, S. K.; Bala, A.; Mazumder, U. K.; Haldar, P. K. Evaluation of Anticancer Activity of Lagenaria siceraria Aerial Parts. Int. J. Cancer Res. 2011b, 7 (3), 244–253. Sen, C. K.; Paul, B.; Biswas, B. K.; Shahid-Ud-Daula, A. F.M. Cytotoxic Effect of Lagenaria siceraria Crude Extracts Obtained from Its Flowers. Int. J. Phytother. Res. 2013, 3 (1), 15–21. Shah, B. N.; Seth, A. K.; Desai, R. V. Phytopharmacological Profile of Lagenaria siceraria: A Review. Asian J. Plant Sci. 2010, 9, 152–157. Thube, S.; Tambe, R.; Patel, M. F.; Patel, S. D. In-Vitro Anthelmintic Activity of Seed Extract of Lagenaria siceraria (Molina.) Standley Fruit. J. Pharm. Res. 2009, 2 (7), 1194–1195. Tyagi, N.; Sharma, G. N.; Hooda, V. Phytochemical and Pharmacological Profile of Lagenaria siceraria: An Overview. Int. Res. J. Pharm. 2012, 3 (3), 1–4. Warra, A. A.; Ukpanukpong, R. U.; Wawata, I. G. Physico-Chemical and GC-MS Analysis of Calabash (Lagenaria siceraria) Seed Oil. Int. J. Biochem. Res. Rev. 2016, 14 (1), 1–7.

CHAPTER 16

Phytochemistry and Pharmacological Studies of Plumbago indica L.: A Medicinal Plant PRACHI SHARAD KAKADE1* and SAURABHA BHIMRAO ZIMARE2 Department of Botany, Savitribai Phule Pune University, Ganeshkhind, Pune, Maharashtra 411007, India

1

Naoroji Godrej Centre for Plant Research (NGCPR), Shindewadi, Shirwal, Satara, Maharashtra 412801, India

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Corresponding author. E-mail: [email protected]

*

ABSTRACT Plumbago indica L. (Family: Plumbaginaceae) is commonly known as ‘Chitrak’. It is a rich source of therapeutically important phytoconstituents. The phytochemical profiling and pharmacological potency of the different plant parts of P. indica have been carried out for its antimicrobial, antiviral, antipyretic, anticancer, antioxidant, hepatoprotective, anti-inflammatory, macrofilaricidal, antimalarial, anthelmintic, CNS depressant, antiatherogenic, thrombolytic and wound healing activities. The objective of the present chapter is to present a concise overview on its phytochemical profile and its pharmacological activities.

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INTRODUCTION

Plumbago indica L. (Syn: Plumbago rosea L.) (Family: Plumbaginaceae; common name in India: ‘Chitrak’) is an important traditional medicinal plant. Roots are widely used in the Ayurved, folk, and Siddha medicine systems (NMPB, 2008). It is well known for a naphthoquinone “plumbagin” that is mostly isolated from the roots. P. indica is native to India, Eastern Himalaya, Vietnam, Bangladesh, Sumatera, Java, Sulawesi, Cambodia, Hainan, South-Central China, Thailand, Philippines, Laos, Sunda Island, and Maluku, and it was introduced in Leeward Island, Peru, Puerto Rico, Sri Lanka, and Trinidad-Tobago (http://www.plantsoftheworldonline.org). Considering the traditional and ethnobotanical medicinal uses, numerous studies have been carried out to evaluate its pharmacological potential. The present review intends to deliver a brief account on its phytochemical profile and potential pharmacological activities. 16.2 PHYTOCHEMICAL PROFILING OF PLUMBAGO INDICA L. P. indica is extensively used in the traditional medicine systems owing to its range of pharmacological activities due to its active constituents. Several investigations unveil the phytochemicals present the plant parts. Saha and Paul (2012) studied the aerial part of P. indica which showed the presence of reducing sugars, alkaloids, steroids, flavonoids, and gums. Eldhose et al. (2013) assessed the presence of steroids, tannins, glycosides, phenols, flavonoids, and saponins in the methanolic extract of P. indica root. Reducing sugars, alkaloids, flavonoids, gum, and steroids were detected in the P. indica methanolic leaf extract (Rafa et al., 2016). Qualitative phytochemical screening of root extracts of P. indica revealed the presence of alkaloids, flavonoids, carbohydrates, proteins, tannins, and phenols in methanol:chloroform (70:30 v/v) using cold maceration and Soxhlet extraction (Chavan et al., 2016). Ibrahim et al. (2018) confirmed the presence of alkaloids, steroids, flavonoids, and reducing sugars in the methanolic extract of P. indica L. Dissanayake and Peiris (2018) performed phytochemical analysis of the root bark of P. indica using four different solvents, namely, chloroform, n-hexane, methanol, and water. Chloroform extract showed the presence of anthraquinones, unsaturated sterols, and triterpenes; methanolic extract—tannins, phenols, anthraquinones, unsaturated sterols, and triterpenes; hexane extract—anthraquinones, unsaturated sterols, and triterpenes; and aqueous extract—saponins, tannins, phenols, and anthraquinones.

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Harborne (1967) reported the presence of plumbagin in root, leucodelphinidin in leaf and delphinidin, cyanidin and pelargonidin 3-rhamnosides, kaempferol-3-rhamnoside, galloylglucose and digalloylglucose in petal. Dinda and Chel (1992) investigated the aerial parts of P. indica and reported the isolation of plumbagin, campesterol, stigmasterol, and sitosterol and the structure elucidation of the new compound 5,6-dihydroxy-2-methyl1,4-naphthoquinone or 6-hydroxyplumbagin. Further, a dihydroflavonol named plumbaginol was isolated from the aerial parts of P. indica and its structure was elucidated as 3,5,3′-trihydroxy-6,7-methylenedioxy-8,5′dimethoxy-2R:3R-flavanone by the spectroscopic studies (Dinda et al., 1994). Naphthoquinone 3-0-3′-bidroserone, naphthoquinone derivatives 2,3-epoxyplumbagin, droserone, and plumbagic acid were isolated from the roots of P. indica. The structures were interpreted based on the chemical and spectral evidence and configuration of plumbagic acid was also assigned (Dinda et al., 1998). Palmitic acid, myricyl palmitate, azaleatin, ayanin, and plumbagin acid lactone were reported for the first time from the roots of P. indica (Dinda et al., 1999). Hazra et al. (2002) synthesized plumbagin derivatives (synthetic modification of plumbagin), namely, 1,4-dihydroxy-5-methoxy 2-methylnaphthalene (hydroquinone derivative of plumbagin methyl ether), 6-nitroplumbagin, and 2-cyanoplumbagin. Ariyanathan et al. (2010) isolated two novel carboxylic acids and flavonoids from the ethyl acetate extract of roots to P. indica (Syn. P.rosea). Based on the UV, IR, 1H, and 13C NMR and mass spectrum studies, structures of these compounds were established as myricetin-3ʹ,3ʹ,5ʹ,7-tetra methyl ether, ampelopsin-3ʹ,4ʹ,5ʹ,7-tetra methyl ether, plumbagic acid, and roseanoic acid. Plumbagin, α-amyrin, α-amyrin acetate, β-sitosterol, n-octacosanol, and β-sitosterol-3β-D-glucoside were also characterized. Dissanayake and Peiris (2018) verified the presence of fatty acids (hexadecanoic acid methyl ester and 9-octadecenoic acid methyl ester) as major constituents of the aqueous extract of root bark of P. indica by GC/MS analysis. 16.3

PHARMACOLOGICAL ACTIVITIES

16.3.1 ANTIMICROBIAL ACTIVITY Kumar et al. (2013) synthesized silver nanoparticles (AgNPs) by aqueous P. indica root extract to study its antimicrobial activity against different grampositive (Bacillus subtilis, Streptococcus spp., Staphylococcus aureus), gram-negative pathogenic bacteria (Escherichia coli, Proteus vulgaris,

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Proteus aeruginosa, Klebsiella pneumoniae), and fungi (Candida albicans, C. tropicalis, Cryptococcus neoformans). The study revealed that the green synthesized AgNPs were effective against all studied bacteria and were highly effective against clinically virulent bacteria. A significant inhibition activity was also observed in the fungi that were resistant to Fluconazole, a common antifungal agent. A standardized plumbagin derivative-rich P. indica root extract that contained total plumbagin derivatives not less than 13% (w/w) was subjected to study antibacterial activity against Propionibacterium acnes, Staphylococcus aureus, and S. epidermidis using the micro-dilution assay. The study endorsed the potential use of plumbagin derivative-rich P. indica root extract for antibacterial purposes in herbal medicines (Kaewbumrung and Panichayupakaranant, 2014). Kaur and Prasad (2016) reported antiacne activity of acetone extract of root of P. indica against two acnecausing bacteria, that is, Propionibacterium acnes and Staphylococcus epidermidis and yeast Malassezia furfur using well diffusion method. They recommended the use of P. indica in the topical antiacne preparations. Dissanayake et al. (2020) revealed the antimicrobial activity of the methanol extract of P. indica root bark against methicillin-resistant Staphylococcus aureus (MRSA) mainly due to the presence of plumbagin. 16.3.2 ANTIVIRAL ACTIVITY Forty-nine Thai medicinal plants widely used in folk medicines were selected for examining their in vitro activity against Herpes simplex virus type 1 (HSV-1), polio virus type 1, and measles virus. Ethanolic extract of P. indica leaf showed noticeable inhibitory activity against HSV-1 which indicated its antiviral activity probably unique to HSV-1 (Akanitapichat et al., 2002). Hexane extracts from forty traditional Asian medicinal plants were investigated against HIV-1 reverse transcriptase. Among these, crude extracts of seven plants, including P. indica roots, showed strong HIV-1 RT inhibitory effect that was validated by their IC50 values (Silprasit et al., 2011). Chavan et al. (2016) investigated anti-influenza activities of crude root extracts of P. indica. Cell cytotoxicity 50% (CC50) values were selected for the antiviral assay that was based on percent reduction in hemagglutination activity. Cold extract and 15 h Soxhlet extracts showed 100% reduction at 10–1 mg/mL concentrations, indicating inhibition of influenza A (H1N1) pdm09 virus infection by inhibiting the viral nucleoprotein synthesis and polymerase activity.

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16.3.3 ANTIPYRETIC ACTIVITY

The antipyretic activity of methanolic extract P. indica was studied, which showed remarkable reduction in the yeast-induced pyrexia in mice over the experimental period that was equivalent to the standard drug paracetamol (Ibrahim et al., 2018). 16.3.4 ANTICANCER/ANTITUMOR/CYTOTOXIC ACTIVITY Green synthesis of silver nanoparticles (AgNPs) synthesized by aqueous P. indica root extract was attempted to evaluate its potential against Dalton’s lymphoma cells. Administration of AgNPs synthesized aqueous P. indica root extract showed dose-dependent cytotoxicity against Dalton’s lymphoma ascitic (DLA) cell line. Significant increase of survival time in the mice model was observed with decrease in the volume of ascitic fluid bearing mice, and reduction in packed cell volume and viable tissue cell count, which is a prime action of an anticancer agent (Kumar et al., 2013). Appadurai and Rathinasamy (2015) isolated plumbagin from the roots of P. indica and complexed with Colloidal silver nanoparticles (AgNPs) to study the anticancer activity of plumbagin and plumbagin-AgNPs in the human cervical cancer cell line (HeLa cells). Plumbagin blocked the cell cycle at mitosis, induced apoptosis, and inhibited the proliferation of the cancer cell. The encapsulation of plumbagin with AgNPs led to the enhancement in the internalization of PLB and AgNPs, which can be possibly used as drug delivery system. Their work endorsed plumbagin as a potential compound as an anticancer agent that can be used either alone or in combination with other anticancer drugs. Malaiyandi et al. (2020) reported the anti-proliferative effects of plumbagin of field grown and in vitro grown P. indica. Serial maceration extraction method was used for isolating plumbagin from P. indica and was screened for its antiproliferative activity using stomach cancer cell lines (AGS) and breast cancer cell lines (MDA-MB-231) which demonstrated significant antiproliferative activity for both cell lines. Also, apoptotic cell death by nucleus staining was confirmed using different types of extracts of P. indica. Genotoxic effect of ethanolic root extract of P. indica was examined using sister chromatid exchange (SCE) assay in human lymphocytes. Results showed that the extract was genotoxic in human lymphocytes at concentrations 12.5–100 µg/mL and cytotoxic at concentrations of ≥500 µg/mL in vitro. On comparing the results with the potent genotoxic doxorubicin, the conclusion implied that the ethanolic root extract of P. indica can work effectively with a chemotherapeutic agent by increasing the anticancer potential in the

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cancer cells, at the same time letting the cell cycle to buy time for restoration (Thitiorul et al., 2013). Further, Ratanavalachai et al. (2015) explored the genotoxic potency and cell cycle modulations induced the pretreatment by ethanolic root extract of P. indica at various concentrations in combination with a standard chemotherapeutic agent doxorubicin, in human lymphocytes using in vitro sister chromatid exchange (SCE) assay. The combination of ethanolic root extract of P. indica at proper concentrations with doxorubicin was suggested to be useful for more effective cancer treatment with less doxorubicin toxicity. Ruangnoo et al. (2012) investigated cytotoxic activity of a Thai Traditional medicine preparation “Benjakul” that comprises of five plants, one of which is P. indica. Cytotoxic activity was tested against human cancer cell lines, namely, large lung carcinoma cell line (COR-L23), liver cancer cell line (HepG2), and cervical cancer cell line (Hela), and compared with normal human lung fibroblast cell (MRC-5) using SRB assay. Plumbagin isolated as a pure compound from Benjakul preparation showed highest cytotoxic activity against all the studied cell lines at 72 h exposure time. The cytotoxic and antiproliferative effect of ethanolic root extract of P. rosea and purified plumbagin from P. rosea on the SK-MEL 28 melanoma cell lines and human lymphocytes was studied. Growth inhibition in a dosedependent manner was observed in the MEL 28 cells and lymphocytes when treated with plumbagin. A substantial synergy of cytotoxicity toward cancer cells was observed when P. rosea extract was used, and this could be due to the interactions between plumbagin and other components present in the plant. The study inferred that ethanolic root extract of P. rosea exhibited selective cytotoxic and antiproliferative effects in human skin cancer SK MEL-28 cells (Anuf et al., 2014). Tumor-inhibitory and anti-leishmanial activities were investigated using synthesized plumbagin derivatives such as 1,4-dihydroxy-5-methoxy 2-methylnaphthalene (hydroquinone derivative of plumbagin methyl ether), 6-nitroplumbagin, and 2-cyanoplumbagin. The synthetic modification of plumbagin did not show any significant results for the antitumor and antileishmanial activities (Hazra et al., 2002). 16.3.5 ANTIOXIDANT ACTIVITY Ethanolic extract of Plumbago indica root showed highest scavenging in DPPH radical assay, that is 82.34% at 200 µg/mL with an IC50 value of 0.018 mg/mL (Nahak and Sahu, 2011). Chatuphonprasert et al. (2015) examined

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the effects of methanolic extract of P. indica and plumbagin on hepatic cytochrome P450 2e1 (Cyp2e1) and lung cytochrome P450 2f2 (Cyp2f2) in seven-week-old male ICR mice. The P. indica extract and plumbagin activated surplus formation of ROS and oxidative stress was mediated in the livers and lungs of the mice. Their results indicated that P. indica and/ or plumbagin can be used as an alternative medication because of its hepatotoxicity and lung toxicity by inducing oxidative stress and toxicity associated with Cyp2e1 and Cyp2f2 activation. Sukkasem et al. (2016) assessed the effect of hepatotoxic impacts of the oral administration of plumbagin and methanolic crude extract of P. indica by means of increased levels of transaminases in plasma and modification of antioxidative system in the mouse livers, the increase in lipid peroxidation, the modulatory activities of antioxidative enzymes (SOD, CAT, and GPx), and related GSH profiles with lowering level of the GSH/GSSG ratio. Plumbagin and methanolic crude extract of P. indica initiated the unbalancing in the redox defense system leading to hepatotoxic effects in the mice. 16.3.6 HEPATOPROTECTIVE ACTIVITY Investigation of hepatoprotective activity against paracetamol-induced liver damage was carried out using ethanolic root extract of P. indica (Rajasekaran and Periasamy, 2011). Blood samples of male Wistar albino rats were subjected to biochemical studies of serum namely serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, serum bilirubin, and total protein. Elevated levels in serum markers were recorded in animals treated with paracetamol (acetaminophen) which resulted in significant hepatic damage. On the other hand, pretreatment of P. indica ethanolic root extract (200 and 400 mg/kg doses) significantly reduced the increased levels of the serum markers, indicating that the extract has the potential to condition the hepatocytes and protect its membrane integrity against acetaminophen- induced leakage of marker enzymes into the circulation. 16.3.7 ANTI-INFLAMMATORY ACTIVITY Ibrahim et al. (2018) assessed anti-inflammatory activity of methanolic extract of P. indica using protein denaturation and membrane stabilization assay, which inhibited protein denaturation by 34.55% and 29.55% respectively as compared to the standard drug acetyl salicylic acid, indicating potent anti-inflammatory activity.

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16.3.8 ANTIFERTILITY ACTIVITY Savadi and Alagawadi (2009) evaluated the antifertility activity of ethanolic extract of roots of Plumbago indica using three modes of antifertility studies, namely, anti-implantation, abortifacient, and motility of rat spermatozoa (in vitro) models. Oral administration of ethanolic P. indica root extract at 200 and 400 mg/kg b/w exhibited highest significant activity in all the three modes of antifertility studies performed. Preimplantation losses of 40% and 50% were observed in the antiimplantation model, 60% and 70% of pregnancy failure were observed in abortifacient activity and no motility of rat spermatozoa at a time duration of 60 s at 10% concentration. 16.3.9 ANTI-HELICOBACTER PYLORI ACTIVITY Paul et al. (2013) studied the Anti-Helicobacter pylori activity using inhibitory-zone testing for three Plumbago sp. Ethanolic root extract of P. indica showed substantial results as compared to the other species. 16.3.10 MACROFILARICIDAL ACTIVITY In vitro macrofilaricidal activity of methanolic root extracts of P. indica/rosea was screened against a nematode Setaria digitata, a filarial parasite of cattle. Crude extract with a concentration of as low as 0.02 mg mL−1 inhibited the motility of all the worms exposed for 100 min, whereas purified fractions of 0.002 mg mL−1 immobilized all the worms exposed for 100 min, indicating 10 times more effectivity. Identification and characterization of the active principle responsible for the antifilarial activity was 5-hydroxy-2-methyl-1, 4-naphthalenedione known as plumbagin (Mathew et al., 2002). 16.3.11 ANTIMALARIAL ACTIVITY Twenty-seven medicinal plants and five herbal formulations commonly used in Thai traditional medicine were screened for antimalarial activity against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) Plasmodium falciparum clones. Ethanolic extracts of 19 medicinal plants and herbal formulation showed antimalarial activity against K1 and 3D7 P. falciparum clones. Among these, ethanolic extract of P. indica root showed significant antimalarial potency against chloroquine-resistant K1 (IC50, 3 μg/mL) and chloroquine-sensitive 3D7 (IC50, 6.2 μg/mL) clones with the highest selectivity (SI = 44.7 and 21.6) respectively (Thiengsusuk et al., 2013). Thirty-two

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plants were screened for antimalarial activity. P. indica showed significant activity against K1 chloroquine resistant (IC50 3 µg/mL) and 3D7 chloroquine sensitive (IC50 6.2 µg/mL) clones, having highest selectivity index (44.7 and 21.6) respectively. The in vitro screening demonstrated that crude ethanolic extract of P. indica exhibited class III antimalarial activity. In vivo antimalarial activity was examined in Plasmodium berghei-infected mouse model with a 4-day suppressive test, where moderate to weak antimalarial activity was seen when plumbagin dose of 25 mg/kg body weight was given for 4 days (Sumsakul et al., 2014; Sumsakul, 2015). 16.3.12 ANTHELMINTIC ACTIVITY Atjanasuppat et al. (2009) screened 32 Thai indigenous plant species for in vitro anthelmintic activity against three species of worms, Caenorhabditis elegans (nematode), Paramphistomum epiclitum (digeneans), and Schistosoma mansoni (cercariae). Plumbagin, a pure compound from P. indica, had the strongest anthelmintic activity against Caenorhabditis elegans with an IC50 of 9.71 µg/mL. 16.3.13 CNS DEPRESSANT ACTIVITY Effect of chloroform soluble extract of P. indica in the Open field test revealed that the intraperitoneal administration reduced the number of open field square crossing remarkably as compared to the control, suggesting the CNS depressant activity of P. indica extractives, those exhibiting accordance with the traditional medicinal use as narcotics (Ibrahim et al., 2018). 16.3.14 ANTIATHEROGENIC ACTIVITY Antiatherogenic effect of Caps HT2, a herbal formulation, was assessed in rats. The formulation comprised of methanolic extracts of nine plants’ parts, one of which was P. indica stem. In this investigation, the formulation Caps HT2 showed a substantial reduction in total cholesterol, LDL cholesterol, triglycerides, and phospholipids with a simultaneous upsurge in HDL cholesterol. The results validated the efficacy of Caps HT2 as an antiatherogenic agent that can avert coronary artery diseases (Mary et al., 2003).

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16.3.15 THROMBOLYTIC ACTIVITY Chloroform-soluble extract of P. indica exhibited highest of 27.56% of clot lysis in red blood cell clot lysis test, compared to the reference drug streptokinase, indicating the potential for thrombolytic activity (Ibrahim et al., 2018). 16.3.16 WOUND-HEALING ACTIVITY Saraswathy et al. (2006) studied wound-healing activity of plumbagin and chloroform extract of P. rosea root by means of excision and incision wound models in rats followed by topical application. Obtained results were compared with a standard drug Framycetin sulfate cream (1% w/w) which showed that chloroform extract of P. rosea root and plumbagin exhibited significant response. Histological studies confirmed woundhealing activity on the basis of the recovery process by the formation of fibro-vascular tissues, epithelization, and increased collagenization as compared to the control. Sujin et al. (2013) examined wound-healing activity of ethanolic, chloroform, and hexane extracts of P. indica roots using the excision wound model. Rapid epithelization, improved wound closure, and reduction of infection was recorded in the ethanolic root extract as compared to the chloroform and hexane extracts and commercial wound-healing agent Burnol. KEYWORDS • • • • • • •

Plumbago indica L. plumbagin Chitrak anticancer antioxidant CNS depressant antimicrobial

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REFERENCES

Akanitapichat, P.; Kurokawa, M.; Tewtrakul, S.; Pramyothin, P.; Sripanidkulchai, B.; Shiraki, K.; Hattori, M. Inhibitory Activities of Thai Medicinal Plants Against Herpes Simplex Type 1, Poliovirus Type 1, and Measles Virus. J. Tradit. Med. 2002, 19 (5), 174–180. Anuf, A. R.; Ramachandran, R.; Krishnasamy, R.; Gandhi, P. S.; Periyasamy, S. Antiproliferative Effects of Plumbago rosea and Its Purified Constituent Plumbagin on SK-MEL 28 Melanoma Cell Lines. Pharmacogn. Res. 2014, 6 (4), 312–319. Appadurai, P.; Rathinasamy, K. Plumbagin-Silver Nanoparticle Formulations Enhance the Cellular Uptake of Plumbagin and Its Antiproliferative Activities. IET Nanobiotechnol. 2015, 9 (5), 264–272. Ariyanathan, S.; Saraswathy, A.; Rajamanickam, G. V.; Connolly, J. D. Polyphenols from the Roots of Plumbago rosea. Indian J. Chem. 2010, 49B, 386–389. Atjanasuppat, K.; Wongkham, W.; Meepowpan, P.; Kittakoop, P.; Sobhon, P.; Bartlett, A.; Whitfield, P. J. In Vitro Screening for Anthelmintic and Antitumour Activity of Ethnomedicinal Plants from Thailand. J. Ethnopharmacol. 2009, 123 (3), 475–482. Chatuphonprasert, W.; Tatiya-Aphiradee, N.; Jarukamjorn, K. Effect of Plumbago indica Linn. and Plumbagin on the Expression of Hepatic Cytochrome P450 2e1 and Lung Cytochrome P450 2f2 in Mice. J. Sci. Technol. Mahasarakham Univ. 2015, 34 (6), 692–696. Chavan, R. D.; Shinde, P.; Girkar, K.; Madage, R.; Chowdhary, A. Assessment of AntiInfluenza Activity and Hemagglutination Inhibition of Plumbago indica and Allium sativum Extracts. Pharmacogn. Res. 2016, 8 (2), 105–111. Dinda, B.; Chel, G. 6-Hydroxyplumbagin, a Naphthoquinone from Plumbago indica. Phytochemistry 1992, 31 (10), 3652–3653. Dinda, B.; Chel, G.; Achari, B. A Dihydroflavonol from Plumbago indica. Phytochemistry 1994, 35 (4), 1083–1084. Dinda, B.; Das, S. K.; Hajra, A. K.; Bhattacharya, A.; De, K.; Chel, G.; Achari, B. Chemical Constituents of Plumbago indica Roots and Reactions of Plumbagin: Part II. Indian J. Chem. 1999, 38B, 577–582. Dinda, B.; Hajra, A. K.; Das, S. K. Chemical Constituents of Plumbago indica Roots. Indian J. Chem. 1998, 37B, 672–675. Dissanayake, D. M. I. H.; Peiris, L. D. C. Phytochemical Analysis and Anti–Oxidant Activity of Plumbago Indica L. Root Bark. In Proceedings of the 23rd International Forestry and Environment Symposium 2018 of the Department of Forestry and Environmental Science; University of Sri Jayewardenepura: Sri Lanka, 2018, pp 46. Dissanayake, D. M. I. H.; Perera, D. D. B. D.; Keerthirathna, L. R.; Heendeniya, S.; Anderson, R. J.; Williams, D. E.; Peiris, L. D. C. Antimicrobial Activity of Plumbago indica and Ligand Screening of Plumbagin Against Methicillin-Resistant Staphylococcus aureus. J. Biomol. Struct. Dyn. 2020, 1–12. DOI: https://doi.org/10.1080/07391102.2020.1846622. Eldhose, B.; Notario, V.; Latha, M. S. Evaluation of Phytochemical Constituents and In Vitro Antioxidant Activities of Plumbago indica Root Extracts. J. Pharmacogn. Phytochem. 2013, 2 (4), 157–161. Harborne, J. B. Comparative Biochemistry of the Flavonoids-IV. Phytochemistry 1967, 6 (10), 1415–1428. Hazra, B.; Sarkar, R.; Bhattacharyya, S.; Ghosh, P. K.; Chel, G.; Dinda, B. Synthesis of Plumbagin Derivatives and Their Inhibitory Activities Against Ehrlich Ascites Carcinoma

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In Vivo and Leishmania donovani Promastigotes In Vitro. Phytother. Res. 2002, 16 (2), 133–137. http://www.plantsoftheworldonline.org/taxon/urn:lsid:ipni.org:names:687077-1 Ibrahim, M.; Hossain, M. A.; Shajib, M. S.; Rashid, M. A. Preliminary Phytochemical and Pharmacological Screenings of Plumbago indica L. and Alpinia conchigera Griff. Dhaka Univ. J. Pharm. Sci. 2018, 17 (1), 73–79. Kaewbumrung, S.; Panichayupakaranant, P. Antibacterial Activity of Plumbagin DerivativeRich Plumbago indica Root Extracts and Chemical Stability. Nat. Prod. Res. 2014, 28 (11), 835–837. Kaur, D.; Prasad, S. B. Anti-Acne Activity of Acetone Extract of Plumbago indica Root. Asian J. Pharmaceut. Clin. Res. 2016, 9 (2), 285–287. Kumar, T. S. J.; Balavigneswaran, C. K.; Packiaraj, R. M.; Veeraraj, A.; Prakash, S.; Hassan, Y. N.; Srinivasakumar, K. P. Green Synthesis of Silver Nanoparticles by Plumbago indica and Its Antitumor Activity Against Dalton’s Lymphoma Ascites Model. BioNanoSci. 2013, 3 (4), 394–402. Malaiyandi, J.; Anandapadmanaban, G.; Perumalsamy, H.; Kilankajae, A.; Chellappan, K. D.; Dua, K.; Shanmugam, G.; Balusamy, S. R. Plumbagin from Two Plumbago Species Inhibits the Growth of Stomach and Breast Cancer Cell Lines. Ind. Crops Prod. 2020, 146, 112147. Mary, N. K.; Babu, B. H.; Padikkala, J. Antiatherogenic Effect of Caps HT2, a Herbal Ayurvedic Medicine Formulation. Phytomedicine 2003, 10 (6–7), 474–482. Mathew, N.; Paily, K. P.; Vanamail, A. P.; Kalyanasundaram, M.; Balaraman, K. Macrofilaricidal Activity of the Plant Plumbago indica/rosea In Vitro. Drug Dev. Res. 2002, 56 (1), 33–39. Nahak, G.; Sahu, R. K. Antioxidant Activity of Plumbago zeylanica and Plumbago rosea Belonging to Family Plumbaginaceae. Nat. Prod. Indian J. 2011, 7 (2), 51–56. NMPB, 2008 www.medicinalplants.in Paul, A. S.; Islam, A.; Yuvaraj, P. Anti-Helicobacter pylori and Cytotoxic Activity of Detoxified Root of Plumbago auriculata, Plumbago indica and Plumbago zeylanica. J. Phyto Pharmacol. 2013, 2 (4), 4–8. Rafa, Z. T.; Ashrafudoulla, M.; Fuad, F.; Islam, R.; Hasan, M.; Kafi, M. A. H.; Islam, M. S.; Parvin, S. Phytochemical and Pharmacological Investigation of Plumbago indica L. J. Med. Plants Stud. 2016, 4 (2), 115–118. Rajasekaran, A.; Periasamy, M. Protective Effect of Ethanolic Root Extract of Plumbago indica L. on Paracetamol Induced Hepatotoxicity in Rats. Afr. J. Pharm. Pharmacol. 2011, 5 (20), 2330–2334. Ratanavalachai, T.; Thitiorul, S.; Tanuchit, S.; Itharat, A.; Sakpakdeejaroen, I. In Vitro Enhancement of Doxorubicin Genotoxic Activities and Interference with Cell Cycle Delay by Plumbago indica Root ethanolic Extract in Human Lymphocytes. J. Med. Assoc. Thai. 2015, 98 (2), S38–S44. Ruangnoo, S.; Itharat, A.; Sakpakdeejaroen, I.; Rattarom, R.; Tappayutpijarn, P.; Pawa, K. K. In Vitro Cytotoxic Activity of Benjakul Herbal Preparation and Its Active Compounds Against Human Lung, Cervical and Liver Cancer Cells. J. Med. Assoc. Thai. 2012, 95 (1), S127–S134. Saha, D.; Paul, S. Pharmacognostic Studies of Aerial Part of Methanolic Extract of Plumbago indica L. Asian J. Res. Pharm. Sci. 2012, 2(3), 88–90. Saraswathy, A.; Chandran, R. V.; Manohar, B. M.; Vairamuthu, S. Wound Healing Activity of the Chloroform Extract of Plumbago rosea Linn. and Plumbagin. Nat. Prod. Sci. 2006, 12 (1), 50–54.

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Savadi, R. V.; Alagawadi, K. R. Antifertility Activity of Ethanolic Extracts of Plumbago indica and Aerva lanata on Albino Rats. Int. J. Green Pharm. 2009, 3 (3), 230–233. Silprasit, K.; Seetaha, S.; Pongsanarakul, P.; Hannongbua, S.; Choowongkomon, K. Anti-HIV-1 Reverse Transcriptase Activities of Hexane Extracts from some Asian Medicinal Plants. J. Med. Plants Res. 2011, 5 (19), 4899–4906. Sujin, J. K. T.; Balavigneswaran, C. K.; Prakash, S.; Natheer, H. Y.; Srinivasakumar, K. P. Excision Wound Healing and Antioxidant Activity of Different Root Extract of Plumbago indica. Med. Plant Res. 2013, 3 (3), 13–19. Sukkasem, N.; Chatuphonprasert, W.; Tatiya-Aphiradee, N.; Jarukamjorn, K. Imbalance of the Antioxidative System by Plumbagin and Plumbago indica L. Extract Induces Hepatotoxicity in Mice. J. Intercult. Ethnopharmacol. 2016, 5 (2), 137–145. Sumsakul, W. Antimalarial Activity, Toxicity, Pharmacokinetics and Metabolic Drug Interaction of Plumbago indica Linn. Doctoral Dissertation, Faculty of Allied Health Sciences, Thammasat University, 2015. Sumsakul, W.; Plengsuriyakarn, T.; Chaijaroenkul, W.; Viyanant, V.; Karbwang, J.; Na-Bangchang, K. Antimalarial Activity of Plumbagin In Vitro and in Animal Models. BMC Complement. Altern. Med. 2014, 14 (1), 1–6. Thiengsusuk, A.; Chaijaroenkul, W.; Na-Bangchang, K. Antimalarial Activities of Medicinal Plants and Herbal Formulations Used in Thai Traditional Medicine. Parasitol. Res. 2013, 112 (4), 1475–1481. Thitiorul, S.; Ratanavalachai, T.; Tanuchit, S.; Itharat, A.; Sakpakdeejaroen, I. Genotoxicity and Interference with Cell Cycle Activities by an Ethanolic Extract from Thai Plumbago indica Roots in Human Lymphocytes In Vitro. Asian Pac. J. Cancer Prevent. 2013, 14 (4), 2487–2490.

CHAPTER 17

Biomolecules and Therapeutics of Terminalia bellirica Roxb. VINOD S. UNDAL Department of Botany, Ghulam Nabi Azad College, Barshitakali Dist-Akola, Maharashtra, India E-mail: [email protected]

ABSTRACT Terminalia bellirica (Gaertn.) Roxb. is a tree belonging to the family Combretaceae. The phytochemicals isolated from various parts of the plant include alkaloids, coumarins, flavones, steroids, lignans, tannins, glycosides, terpenoids, saponins. Tannins, β-sitosterol, gallic acid, ellagic acid, ethyl gallate, chebulic acid and many more phytochemicals have been isolated from the fruits. The present chapter gives a concise review on traditional uses, bioactives and pharmacological activities of T. bellerica. 17.1 INTRODUCTION Terminalia bellirica (Gaertn.) Roxb. belongs to the Combretaceae family. It is distributed in Indian Subcontinent, Thailand, China, Indonesia, Malaysia, Cambodia, and Vietnam. It is known as Beleric Myrobalan. The plant is a big deciduous tree attaining a tallness of 20 and 30 m. The fruits are ovoid, gray drupes. The bark is thick, brownish gray with shallow longitudinal fissures (Choudhary, 2008). The leaves are crowded around the terminal part of the branches, alternately arranged, elliptic-obovate, rounded tip or subacute, midrib prominent, pubescent when immature and develop into glabrous Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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while maturity. Flowers are pale greenish-yellow, born in axillary spikes bigger than the petioles but smaller than the leaf. It is a category of conventional Tibetan remedy named “Maohezi” in Chinese and “Pilile” in Tibetan. The fruit is bitter, pain reliever, astringent, brain stimulant, expectorant, and laxative (Choudhary, 2008). The fruits are utilized as aphrodisiac and oil isolates from the seed pulp are used in the healing of rheumatism (Deb et al., 2016). It is valuable in the remedial of asthma, bronchitis, hepatitis, diarrhea, piles, dyspepsia, eye abnormalities, hoarseness of tone, and scorpion-sting and also used as hair tonic (Rastogi and Mehrotra, 2004; Saroya, 2011). 17.2 BIOACTIVES A range of phytochemicals are extracted from different pieces of the plant which comprised of alkaloid, coumarin, flavones, steroids, lignans, tannins, glycosides, terpenoid, saponin etc (Abraham et al., 2014). The fruit has tannin, β-sitosterol, gallic acid, ellagic acid, ethyl gallate, chebulic acid etc. in various proportions (Sharma et al., 2010). Its fruit is prosperous in bioactive elements and has been utilized for the management of diverse ailments in the indigenous systems of medicine (Jadon et al., 2007). The fruit residues trigger the discharge of insulin and improve its action and inhibit starch digestion (Violet et al., 2010). However the plant fruit is one of the main ingredients of the well-known research “Triphala,” which is utilized for the management of the general cold, pharyngitis, constipation, headache, leucorrhoea, liver abnormality, gastrointestinal trouble, and hair loss (Saroya, 2011). It is a powerful adaptogenic plant fruit that nourishes the lungs, eyes, throat, voice, and hair (Nadkarni, 2002). It expels stones or other kapha-type gathering in the urinary, digestive, and respiratory tracts (API, Govt. of India, 2001). It contains termilignan, thannilignan, 7-hydroxy-3′,4′-(methylenedioxy) flavone, anolignan B, gallic acid, ellagic acid, corilagin, ß-sitosterol, arjungenin, belleric acid, bellericoside, and cannogenol 3-O-ß-Dgalactopyranosyl(1→4)-O-α-L rhamnopyranoside (Lobo et al., 2010). Three hydrolysable tannins, four flavonol glycoside, one flavone, and two flavonolaglycone were documented (Fig. 17.1). The detection of the structures of extracted elements was done by using 1D- and 2D-NMR, UV, and MS. Compounds 3–10 were documented for the first time from T. bellirica leaves (Ayoob et al., 2014).

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FIGURE 17.1 Structure of Hydrolysable tannins, Flavonol glycoside, Flavone, and Flavonolaglycone.

Besides above a bioactivity-guided fractionation of residues of T. bellirica fruit rind led to the extraction of two novel lignans identified as termilignan (1) and thannilignan (2), together with 7-hydroxy-3′,4′-(methylenedioxy) flavan (3) and anolignan B (4) (Fig. 17.2). All four compounds possessed confirmable anti-HIV-1, antimalarial, and antifungal activity in the laboratory (Valsaraj et al., 1997). Other investigations on chloroform-ethyl acetate fraction of T. bellirica fruit rind powder displayed greatest antimicrobial action. This fraction on additional purification by column chromatography gave a distinct spot compound, which after characterization was found to be epigallocatechin gallate (Fig. 17.3) Additionally, the elemental analysis and spectral data revealed the compound structurally to be Epigallocatechin gallate (Meshram et al., 2011). Moreover, the aqueous methanolic extract was subject to column chromatography and was identified by TLC, by which the Rf value was found

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to be 0.59. The extracted compound was established by IR, GC, and MS (Kumudhavalli et al., 2010). The extracted compound was 2, 3, 7, 8-Tetraoxychromeno[5,4,3-cde]chromene-5,10-dione, having molecular formula C14H2O8 and molecular mass is 298.19 g/mol (Fig. 17.4). Compound isolated from fraction TB5 of T. bellirica and reported as 3,4,5-trihydroxy benzoic acid (gallic acid) was assessed for its hepatoprotective actions versus CCl4 elevated physiological and biochemical modification in the liver (Anand et al., 1997). Additionally, a bioassay guided fractionation and chemical examinations of the T. bellirica; resulted in the isolation of benzoic acid derivative which is identified as 4-hydroxy-(2-methylbutanol) benzoic acid (Fig. 17.5) with reducing power activity (1.25) (Laila and Amal, 2014). Furthermore, it was evaluated the consequences of the constituents of T. bellirica and T. chebula fruit residues on PPARα and PPARγ (Peroxisome proliferator-activated receptors) signaling/expression, cellular glucose uptake and adipogenesis (Yang et al., 2013). Out of the 20 compounds, 2 ellagitannins, chebulagic acid (1), corilagin (2), and 3 gallotannins, 2,3,6-tri-O-galloyl-β-D-glucose (3), 1,2,3,6-tetra-O-galloyl-β-D-glucose (4), and 1,2,3,4,6-penta-O-galloyl-βD-glucose (5) (Fig. 17.6), showed the enhancement of PPARα and/or PPARγ signaling. Two of the gallotannins (4 and 5) also enlarged PPARα and PPARγ protein expression, while all three (3–5) enhanced insulin-stimulated glucose uptake into HepG2 cells. Compound 1,2,3,6-tetra-O-galloyl-β-D-glucose (4) was mainly powerful in growing cellular glucose assimilations (9.92-fold increase at 50 μM). Also thirty-four polyphenolic substances in methanol residues of the fruits of T. bellirica, T. chebula, and T. horrida, three plants utilized in Egyptian folk remedy, were originally reported by HPLC–ESI-MS and quantitated by analytical HPLC after column chromatography on Sephadex

FIGURE 17.2 Structure of Termilignan (1), Thannilignan (2), together with 7-hydroxy3′,4′-(methylenedioxy)flavan (3) and anolignan B.

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FIGURE 17.3

Structure of Epigallocatechin gallate.

FIGURE 17.4

Structure of 2, 3, 7, 8-Tetraoxy-chromeno[5,4,3-cde]chromene-5,10-dione.

FIGURE 17.5

Structure of 4-hydroxy-(2-methylbutanol) benzoic acid.

FIGURE 17.6

1,2,3,4,6-penta-O-galloyl-β-D-glucose.

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LH-20. After purification by semi-preparative HPLC, the compounds were recognized by their mass and fragmentation patterns using ESI-MS–MS. For numerous compounds, comprehensive 1H/13C NMR analysis at 600 MHz was conducted (Pfundstein et al., 2010). With T. bellirica, the major glucose components were 1,3,4,6-tetra-O-galloyl-β-D-Glc (80 g/kg) and 1,6-di-Ogalloyl-β-D-Glc (70 g/kg), followed by 3,4,6-tri-O-galloyl-β-D-Glc (20 g/ kg) and penta-O-galloyl-β-D-Glc (4.4 g/kg). Only traces of tri-O-galloylshikimic acid were found (0.4 g/kg). T. bellirica species gave the highest concentrations of free gallic acid (14.6 g/kg) and methyl gallate (3.3 g/kg). 17.3

PHARMACOLOGY

17.3.1 ANTIMICROBIAL ACTIVITY The experiments were conducted for antimicrobial activity of T. bellirica against nine human microbial pathogens. The water extract of dry fruit at 4 mg concentration displayed peak zone of inhibition against S. aureus. These pathogens were extremely susceptible to the methanol residues also, with the exception of E. coli and P. aeruginosa. The negligible MICs of crude and methanol residues were determined by broth intensity method that ranged from 300 to >2400 pg/mL and 250 pg to >2000 pg/mL respectively, indicating that plant was extremely valuable against S. aureus with lesser MIC values (Elizabeth, 2005). The antibacterial work of the T. bellirica fruit residues was also screened against 16 strains multidrug-resistant (MDR) bacteria with 12 solvent extracts. Entire water and methanol residues showed antibacterial action (MIC 0.25–4 mg/mL) against all strains of methicillinresistant Staphylococcus aureus (MRSA), MDR Acinetobacter spp., and P. aeruginosa. The consecutive water extracts (MIC, 4 mg/mL) restricted extensive spectrum β-lactamase (ESBL) producing-E. coli. It also showed maximum DPPH radical scavenging action (EC50, 6.99 ± 0.15 ppm) and TPC substance (188.71 ± 2.12 GAE mg/g). The IC50 values of the most effective antibacterial residues on BHK-21 cells were 2.62 ± 0.06 and 1.45 ± 0.08 mg/ mL with 24 and 48 h exposure, correspondingly (Dharmaratne et al., 2018). Furthermore, MeOH, EtOAc, and n-BuOH T. bellirica fruit extract have restricted activity for the entire check bacteria. EtOAc extracts displayed elevated action against S. aureus, E. coli, and P. aeruginosa (zone of inhibition 30.00 ± 0.25, 28.67 ± 0.15, and 27.50 ± 0.65 mm, respectively). MeOH residues exhibited restricted activity against the entire screened bacteria (zone of inhibition range 8.39 ± 1.75–24.14 ± 1.67 mm). S. aureus and E.

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coli, the mainly sensitive bacteria, displayed the inconsistent MIC ranges of (0.312–2.5 mg/mL) and (0.625–5.0 mg/mL), respectively. Ethyl acetate fractions showed highest antibacterial effect against S. aureus with zone of restrictions 30.00 ± 0.25 mm (Alam et al., 2011). Also the antimicrobial prospective of diverse residues of leaves and stem of T. bellirica was investigated against five Gram +ve, five Gram −ve, and four fungi. The residues displayed additional antibacterial action than antifungal action and antibacterial action was high toward Gram −ve bacteria than Gram +ve bacteria. The residues were particularly superior against Gram +ve bacteria like C. rubrum and S. epidermidis and Gram −ve bacteria like K. pneumoniae, E. coli, and S. typhimurium (Chanda et al., 2013). Additionally, aqueous fruit extract of T. bellirica has displayed actions against several pathogenic bacteria, namely, E. coli, P. aeruginosa, K. pneumoniae, S. flexneri, and S. typhi using agar well diffusion method (Devi et al., 2014). Aqueous extract exhibited significant activity against the tested bacterial and fungal isolates, compared with chloroform and petroleum ether extracts. All the bacterial and fungal isolates tested showed significant activity against the aqueous extract and the zone of inhibition ranged from 15 to 23 mm. The highest zone of inhibition was found against K. pneumoniae (23 mm) and A. fumigatus (22 mm) with aqueous extract and least inhibition against S. typhi (8 mm) and A. niger (9 mm) with petroleum ether extract (Nithya et al., 2014). Moreover, the work was conducted on green synthesis of metal oxides of zinc, iron, and copper by means of the water residues of T. bellirica as a reductant and stabilizer. Nanoparticles were characterized, a sequence of procedures were employed. It used nanoparticles to display their antibacterial efficiency against several general standard bacterial pathogens including S. aureus, B. subtilis, E. coli, K. pneumoniae, and S. enterica (Akhter et al., 2019a). Furthermore, the ethanolic extract of T. bellirica was tested against Streptococcus mutans. It was established to considerably reduce biofilm development. The study found that the residues displayed efficient actions against Streptococcus mutans. Yadav et al. (2012) also reported that herbal preparation inhibits the biofilm formation by streptococci, an oral pathogen. Madani and Jain (2008) also reported the effect of T. bellirica against Salmonella typhi and S. typhimarium. In vitro cellular toxicity was also performed by them. In the investigation, petroleum ether, chloroform, acetone, alcohol, and water residues of TB fruit were used for examination. There was no cytotoxicity recorded in vitro cellular toxicity study. Moreover, the antibiotic sensitivity pattern of the various strains of S. typhi showed that B330 is resistant to ampicillin, ciprofloxacin, co-trimoxazole, nitrofurantoin, and

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tetracycline, whereas most of the other isolates were sensitive to these antibiotics. Of the 54 plant extracts tested, 36 showed activity against enteric bacteria. Both methanol and aqueous extracts of Triphal [mixture of three plants along with, T. bellirica fruit in a ratio of 1:1:1] showed strong antimicrobial activity (size of zone of inhibition ≥9–15 mm). The rest of the plant extracts did not show any activity. Methanol extracts showed better activity than the aqueous extracts (Rani and Khullar, 2004). 17.3.2 ANTIOXIDANT ACTIVITY Methanol extract of T. bellirica fruits displayed high scavenging actions with DPPH, superoxide, hydroxyl, and nitric oxide radicals. Cell- dependent antioxidant action was screened by flow cytometry with DCFH-DA as probe. The residues considerably restricted the oxidation of LDL through in vitro environment. Liquid chromatography–mass spectroscopy (LC–MS) examination showed that methanol residues of plant include ellagic acid and ascorbic acid as the chief composite correspondingly (Nampoothiri et al., 2011a). Moreover, quantitatively ethyl acetate T. bellirica fruit extract showed the occurrence of elevated substance of phenolics and flavonoids as correlated to aqueous extract. Further ethyl acetate extract displayed significant free radical scavenging capacity in DPPH and HRSA examination (up to 94%), reducing power screening and whole antioxidant control in phosphomolybdate evaluation (78 mg PGE/g). The EA residues displayed relatively improved a-amylase restricted action (IC50 43.5 mg/mL) as compared to water residues (IC50 74.8 mg/mL). The action was correlated to typical drug acarbose (Gupta et al., 2020). Also aqueous extract of T. bellirica showed superior antioxidant action as correlated to ethanolic extract of plant in nitric oxide, superoxide, ABTS radical scavenging examination in EETB correspondingly. Similar to antioxidant action, the reducing power enlarges in a dose- dependent method indicating superior absorbance at 700 nm for AETB as correlate to EETB at 500 μg/mL. The results suggested that TPC and TFC supply considerably to the antioxidant action of the plant fruits (Lobo et al., 2010). Additionally, the antioxidant potential of T. bellirica (TB) parts was also assessed by free radical scavenging action, superoxide anion radical scavenging activity, hydroxyl radical scavenging action and correlated through indication typical quercetin. Ethanolic extract of plant fruit pulp displayed elevated phenolic substance followed by seed and bark of GAE. Fruit pulp residues displayed swallowed IC50 for FRSA, SARSA, and HRSA

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and maximum RP (3.39 ascorbic acid equivalents/mL). TBB displayed little IC50 for LPO, whereas TBS displayed lowest IC50 for FTC. The principle phyto-compounds occurred in TB residues were quinic acid, ethyl gallate, 9,12 octadecadienoic acid, and glucopyranose in unstable concentrations as assessed by GC-MS (Gupta et al., 2016). Furthermore, Tanaka et al. (2016) investigated the effect of T. bellirica extract (TBE) on LDL oxidation and inflammation in macrophages. TBE displayed DPPH radical scavenging activity and 15-lipoxygenase restricted action. In THP-1 macrophages, TBE action found in considerable reduced of the mRNA appearance of tumor necrosis factor-alpha, interleukin-1beta, and lectin-like oxidized LDL receptor-1. TBE moreover condensed matrix metalloproteinase discharge and intracellular reactive oxygen species creation in THP-1 macrophages (Tanaka et al., 2016). The administration of the extract body weight to rats increased the % restrictions of condensed glutathione, superoxide dismutase, and catalase considerably. Ethylacetate (EtOAc) fractions showed the highest DPPH scavenging activity with the IC50 value of 5.04 ± 0.08 μg/mL, followed by n-BuOH and MeOH extract with the IC50 value of 12.32 ± 0.16 and 25.11 ± 0.22 μg/mL, respectively. The whole antioxidant competence of EtOAc extract displayed maximum and was recorded to be 274.5 ± 0.45 mg/gm equivalent of ascorbic acid, followed by, MeOH, n-BuOH, aqueous fraction, and CH2Cl2 145.4 ± 0.21, 148.9 ± 0.69, 30.4 ± 0.12, and 24.0 ± 1.01 mg/gm equivalent of ascorbic acid, respectively (Alam et al., 2011). According to Fahmy et al. (2015), antioxidant supplements help in reducing the oxidative damage at cellular level. The further investigation in vitro antioxidant action of T. bellirica seed was assessed by typical antioxidant method such as DPPH radicals, hydroxyl radicals, and whole antioxidant action by the ABTS procedure. The ethylacetate seed residues were recorded to be comparatively elevated action than other residues. In judgment to another fraction, the ethyl acetate and methanolic residues recorded considerable and major antioxidant action because of the occurrence of elevated phenolic and steroid composition (Elizabeth et al., 2017). Moreover, free radical scavenging action and antioxidant probable of acetone extract of its fruit was investigated, including scavenging ability against DPPH, β-carotene bleaching restriction, reducing power, and chelating capacity on Fe2+ ions. It was recorded that ethyl acetate extract was superior than crude acetone residues in entire antioxidant examinations, excluding chelating power that was maximum in aqueous extract. The greatest antioxidant actions displayed were 14.56, 27.81, and 67.8 μg/mL in DPPH, β-carotene bleaching, and reducing power procedures, correspondingly (Guleria et al., 2010). The free radical scavenging and

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antioxidant actions of methanol fractions and its unlike solvent residues of the T. bellirica fruit pericarp were examined also, and correlated with typical antioxidant such as gallic acid, catechin, and ascorbic acid. Along with the diverse fractions examined, the EA extract showed superior antioxidant and radical scavenging actions against DPPH, superoxide, and hydroxyl radicals than the other extract, which may be recognized to its superior phenolic and flavonoid compositions, since a linear association was recorded among the phenolic composition and the antioxidant specifications (Nampoothiri et al., 2011b). Furthermore, the methanol extract of the fruit was prepared to check the antioxidant properties of the plant (Singh and Hage, 2017). 17.3.3 ANTIDIABETIC ACTIVITY Latha and Daisy (2010) investigated the antidiabetic activity of hexane, ethylacetate, and methanolic residues of T. bellirica fruit at the concentrations of 200, 300, and 400 mg/kg, p.o. for 60 days to streptozotocin-activated diabetic rats. It considerably enlarged the plasma insulin, C-peptide, and glucose tolerance range, body mass, serum whole protein. The consequence was highly marked in methanol residues handled rats. However, the TB residues considerably reduced the serum range of whole cholesterol, triglycerides, low-density lipoprotein cholesterol, urea, uric acid, and creatinine in diabetic rats. Also methanol extracts of T. bellirica were examined for their antidiabetic action through restrictions of a-amylase, a-glucosidase, and antiglycation protocols. The observations displayed that methanolic fraction of TB can act as effective a-amylase and a-glucosidase restraint. Considerable antiglycation action moreover authenticated the remedial impending of these fractions besides diabetes (Nampoothiri et al., 2011a). The antihyperglycemic action of a methanolic fraction of a preparation including of dried fruits of two species of Terminalia was investigated by means of oral glucose tolerance trials in Swiss albino mice. The fraction when orally administered to glucose-loaded mice at doses of 50–400 mg/kg body mass, dose-dependently and considerably reduced blood glucose range. Percent reducing of blood glucose range at the afore-mentioned four doses were, respectively, 35.5, 46.8, 49.2, and 51.6. A typical antihyperglycemic drug, glibenclamide, when administered orally at a dose of 10 mg/kg body mass reduced blood glucose range in mice by 62.1% (Syeda et al., 2014). Moreover, antidiabetic activity of TB fruit residues was investigated in alloxan-elevated diabetic rats by monitoring biochemical parameters up to 28 days. In diabetic rats both the

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fractions (ethyl acetate, aqueous) displayed a curative consequence on body mass and blood biomarkers. The ethyl acetate fraction moreover also showed advantage above the water residues throughout in vivo antidiabetic procedures (Gupta et al., 2020). Similarly, it investigated the effectiveness and method of action of TB applied conventionally for the management of diabetes in country. The residues did not enlarge insulin emission in depolarized cells and did not additionally enlarge insulin discharge provoked by tolbutamide or glibenclamide. At superior concentrations, the residues moreover created a 10–50% decline in starch digestion in vitro and restricted protein glycation. It exposed that ingredients in plant residues excited insulin discharges, increased insulin operation, and restricted together protein glycation and starch digestion (Violet et al., 2010). Additionally, it reported the hypoglycemic impact, lipid profile, and safety profile and therefore monitored an ethanolic residue of TB fruit in alloxan-activated diabetic rats. Diabetes was activated by intraperitoneal alloxan introduction at a quantity of 150 mg/kg body mass, and plant fraction was fed to the rats (750 mg/kg). Subsequent to measuring the quantity of blood glucose, the hypoglycemic effectiveness was reported to be correspondent to that of metformin given (500 mg/kg). Lipid report and safety outline were assessed by quantifying different parameters. Besides, both fruit extract and metformin did not extensively influence healthy individual rats, normal physiological situation. So, it could be also summarized that fraction may perhaps be applicable as a booming substitute treatment for the management of diabetes (Tahsin et al., 2021). It has been also reported that continuous administration of 75% T. bellirica methanolic extract blocks hyperglycemia in diabetic rats via its antioxidant action (Sabu and Kuttan, 2009). The other report focused remarkable decreases in free radicals, and increased glutathione, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase actions were observed in diabetic rats following T. bellirica extract treatment. The fruit water fraction activated insulin discharges from a pancreatic â-cell line to a similar extent to glibenclamide. The extract also showed insulin derivative activity, improving glucose uptake into 3T3-L1 adipocytes by 300% and declining starch absorption and protein glycation (Kasabri et al., 2010). 17.3.4 ANTICANCEROUS ACTIVITY The ethyl acetate extract of TB displayed considerable anticancer action with ZR-75-1 cells in vitro. Management of ZR-75-1 cells with 20 and 60 mg/mL of the EA fraction elicited dose-reliant apoptosis percentages at the

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beginning phase of 17.58 (0.74)% and at a delayed phase of 29.20 (1.22)%; Colo-205 cells at the identical range of EA fraction had standards of 21.33 (1.03)% and 40.55 (0.34)%, correspondingly. Western blotting recommended that ZR-75-1 and Colo-205 cells handled through the EA fraction displayed analogous rising inclination for appearance of cleaved anti-poly adenosine diphosphate ribose polymerase I (Li et al., 2018). It further showed higher cytotoxic response of 70% methanolic extract of T. bellirica (IC50 = 19.35 ìg/ mL) against the HepG-2 cell line followed by ethyl acetate (IC50 = 24.5 ìg/ mL) and butanol fractions (IC50 = 28.6 ìg/mL). The high reducing power and 50 cytotoxic activities of n-BuOH fraction encouraged the authors to subject it to chromatographic isolation (Laila and Amal, 2014). Additionally, the T. bellirica extracts have shown growth inhibitory activity, with a certain degree of selectivity against the lung (A549) and liver (HepG2) cancer cell lines. Combination of T. bellirica with cisplatin or doxorubicin also demonstrated synergistic effects in inhibiting growth of A549 and HepG2 cells (Pinmai et al., 2008). Other workers have also reported cytotoxicity of extracts against nine human cancer cell lines, including cancers of colon, lung, breast, prostate, and leukemia by using SRB and MTT assays. The study revealed that the T. bellirica extract inhibited the cell proliferation of above-mentioned cancer cell lines in a concentration-dependent manner. DNA content analysis by flow cytometry indicated that the extract was responsible for blocking G0/G1 phase of the cell cycle and thereby inhibited cell viability of leukemia (HL-60 and K562) cells. These findings suggested that plant extracts have potent anticancer activity (Kawthar et al., 2015). The investigation was also carried out on in vitro anticancer action of 70% methanolic fraction of TB against human lung and breast carcinoma and its probable method. TBME exhibited considerable cytotoxicity together with A549 and MCF-7 cells, while cytotoxicity was never reported in nonmalignant WI-38 cells. At this concentration (100 μg/mL), TBME explored DNA destruction sample of apoptosis. Bax/Bcl-2 proportion in together types of the cells was reported to be enlarged, which resulted in the commencement of caspase cascade along through the cleavage of PARP (Ghate et al., 2014). Additionally, exposure of Capan-2 cells to the water extract of Triphala for 24 h resulted in the major reduction in the survival of cells in a dose-dependent mode with an IC50 of about 50 µg/mL. By activating ERK, the Triphala induced apoptosis in other pancreatic cancer cell line BxPC-3. On the other way, Triphala was unable to induce apoptosis or trigger ERK or p53 in usual human pancreatic ductal epithelial (HPDE-6) cells. Moreover, oral administration of 50 or 100 mg/ kg Triphala in PBS, 5 days/week considerably suppressed the enlargement

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of Capan-2 pancreatic tumor-xenograft (Shi et al., 2008). Furthermore, Basu et al. (2016) investigated antioxidant and anticancer prospectives of successively fractionated diverse residues from the 70% methanolic fraction of T. bellirica fruits. Butanol and water extracts inhibited the explosion of breast, cervical, and brain cancer cells by activating G2/M hold while TBEE influenced apoptosis. Conversely, these extracts did not reduce the proliferation of lung and liver cancer cells. BrdU integration investigation also recommended the competent anticancer prospective of ethyl acetate, butanol, water extracts. Moreover, butanol and water extracts handled MCF-7, HeLa and U87 cells displayed upregulation of p53 and p21 proteins. 17.3.5 ANTIPYRETIC ACTIVITY The antipyretic action of ethanolic and fluid fraction of TB fruits was investigated in brewer’s yeast-induced fever duplicate in mice and rats. Together fractions exhibited a large restriction of superior blood warm when correlated to equivalent supervision (Jadon et al., 2007). Moreover, paracetamol as well as ethanolic extract of TB at a dose of 200 mg/kg initiated displaying successful antipyretic action after 1 h of post administration, while aqueous extract 200 mg/kg reduced temperature after 2 h, when compared with control (Sharma et al., 2010). 17.3.6

HEPATOPROTECTIVE ACTIVITY

Shukla et al. (2006) evaluated the defending result of TB fruit residues and its dynamic belief, gallic acid through CCl4 intoxication. Management with fraction and gallic acid demonstrated dose-dependent revitalization in biochemical parameters; however, the consequence was additionally prominent with gallic acid (Shukla et al., 2006). Oral management of aceclofenac in rats for 21 days formed oxidative anxiety and harmfully exaggerated liver work recommending liver damage. Handling with TB residues (ethyl acetate and water), ellagic acid, and silymarin reported for a considerable decrease in the undesirable consequence of aceclofenac on oxidative anxiety and liver work markers in blood and hepatic tissue of rats. Histopathological assessment of the liver displayed that the fractions and ellagic acid extensively reduced the extent of liver injury. The in vivo effectiveness of ellagic acid was elevated as compared to T. bellirica fruit fraction. Of these, EA residues exposed relatively superior antioxidant and hepatoprotective action (Gupta and Pandey, 2020). Furthermore, a significant hepatoprotective effect was

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observed with fruits of T. bellirica fraction as obvious from condensed hexobarbitone “sleep time” and zoxazolamine “paralysis time” when correlated through CCI, only. Before- and after-treatment of TB5 condensed, in a dose-reliant way, the superior range of blood tranaminases and bilirubin in rats, consequently representing its outcome together as a prophylactic and restorative. Its shielding impacts on microsomal lipid peroxidation and triglycerides in liver recommend a healing consequence in the procedure of CCl4-induced liver damage (Anand et al., 1994). Furthermore, therapeutic consequence of water acetone residues of fruits through CCl4 activated oxidative anxiety and liver injure in an animal representation was accounted by Kuriakose et al. (2017). At the end of the treatment with two doses (200 and 400 mg/kg), liver function markers as well as hepatic oxidative anxiety markers were assessed. Management with AATB extensively rehabilitates the specifications toward ordinary range as correlated to the superior biochemical markers in the CCl4-treated animals with reversal to normal tissue architecture. The consequences of AATB were recorded analogous with that of typical drug silymarin in every parameter. Furthermore, oral supervision of 1 gm/kg body mass of fine particles of TB fruit improved CCl4-activated liver injure. The consequences of serum and tissue biochemical parameters indicated that, fruit fine particles might reproduce liver cells and accessible safeguard through CCl4 activated hepatic injure. The surveillance of markers as well as light and electron microscope images are evidence of the renewal progression of liver parenchyma (Pingale, 2011). Likewise compound isolated from fraction TB5 of T. bellirica and recognized as 3,4,5-trihydroxy benzoic acid was investigated for its hepatoprotective activity against CCl4induced physiological and biochemical alterations in the liver (Anand et al., 1997). The chief parameters examined were hexobarbitone-restricted sleep, zoxazolamine-activated paralysis, blood range of transaminases, and bilirubin. The hepatic signs screened were lipid peroxidation, drug metabolising enzymes, glucose-6-phosphatase, and triglycerides. Management of composite led to considerable exchange of bulk of the distorted parameters. 17.3.7 ANTIOBESITY ACTIVITY Makihara et al. (2012) conducted work on the protective consequence of a hot aqueous extract of T. bellirica fruit on obesity and different metabolic abnormality, and explored its molecular mechanisms and active constituents. The extract management had a protective result on obesity, insulin

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resistance, and hyperlipidemia in spontaneously obese type 2 diabetic TSOD mice. Plant suppressed assimilation of triacylglycerol in an olive oil loading test (in vivo) and observed a strong suppressive outcome on pancreatic lipase action (in vitro). Additionally, a look for the dynamic constituents in TB discovered that gallic acid was the constituent principally accountable for the inhibition of pancreatic lipase action (Makihara et al., 2012). Another study on albino Wistar rats revealed the therapeutic action of T. bellirica fruit ethanolic fraction on atherogenic diet-activated obesity by evaluating increase in body weight, feed and aqueous eating, body hotness, body-mass index, atherogenic index (AI), organ mass, and lipid summary (Das and Devi, 2016). 17.3.8 ANALGESIC ACTIVITY The investigation was conducted on antisecretory and analgesic action of the crude fraction of TB. The residue restricted castor oil-activated intestinal fluid discharge in mice at the dose array of 300–1000 mg/kg. The extract also condensed the records of acetic acid-mediated writhes in mice. Results indicated that T. bellirica displayed antisecretory and anti-nociceptive impacts, therefore mitigating its therapeutic employ in diarrhea and pain (Khan and Gilani, 2010). Furthermore in the hot plate method, the ethanolic and aqueous extracts at a dose of 200 mg/kg displayed considerable enlarges in response instance, that is, 7.15 and 6.81 s, respectively, at 30 min. when compared to control (5.15 s). Hence, the ethanolic extract was found to be more effective compared to aqueous extract, suggesting that both extracts showed a significant analgesic effect in chemical and mechanical induced pain models (Sharma et al., 2010). 17.3.9 ANTIULCER ACTIVITY The assay contributed the validation for the application of T. bellirica as an antiulcer cause using ethanol-acid activated gastric mucosal harm model in the Swiss albino rats. Oral administration of the extract’s doses demonstrated a significant reduction in the ethanol-acid-activated gastric erosion in the entire experimental groups when compared to the normal. Methanolic extract of plant at the doses of 250 and 500 mg/kg showed considerable regeneration of the mucosal layer and significantly prevents the creation of hemorrhage and edema (Akter et al., 2019b). The antiulcer action of ethanolic extract of Baheda

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fruits an ETB was explored out in pylorus ligation and ethanol also may assist to generate ulcer models in rats. ETB at doses of 250, 500 mg/kg orally created considerable restriction of the gastric lesions activated by Pylorus ligation activated ulcer and ethanol-induced gastric ulcer. The extract (250 & 500 mg/ kg) showed considerable decline in free acidity and ulcer index as correlated to normal (Choudhary, 2012). Similarly, the 70% methanolic extract of fruits of T. bellirica was also assessed adopting ethanol-activated, aspirin-activated, cold stress restraint, and pylorus-ligated ulcer in rats. The extract (100, 250, 500, 1000 mg/kg, p.o.) extensively hold down the peptic ulcer activated by ethanol. The methanolic extract (500 mg/kg) displayed considerable decline in gastric amount, free acidity, total acidity, ulcer index, protein, and pepsin concentration and increase in mucous content in pylorus ligated rats as correlated to normal. It suggested that the plant improved fighting to necrotizing elements, contributing a direct defensive consequence on the gastric mucosa and showed antiulcer outcome (Jawanjal et al., 2012). 17.3.10 WOUND-HEALING ACTIVITY Activity of ethanol extract of T. bellirica fruit was assessed on elimination and incision wound representation, in albino rats, in the form of an ointment through two ranges of fruit residues in trouble-free ointment base. Together ranges of the ethanol fraction displayed considerable reaction in both the injure types examined, when correlated with the normal group. Nitrofurazone ointment was used as a standard drug in the experiments (Choudhary, 2008). Moreover, extract of T. bellirica paste was applied to covering incision from the dorsal part just behind the shoulders of rabbit. Considerable increase in the range of hydroxyproline, DNA, and uronic acid ingredients with enrichment on maturation, injure reduction, and epithelialization was observed within 12 days. The investigation recommended that the herbal paste ready from TC and TB superior fibroblast work, better generation of glycosaminoglycan with deposition of collagen which was essential for injury remedial and could be helpful as an adjuvant in wound-healing process (Saha et al., 2011). 17.3.11 CARDIOTOXICITY ACTIVITY Biochemical assessment of cardiac tissue adopting METB exhibited considerable reduction in CK-MB (creatine kinase-muscle/brain) action and MDA (malondialdehyde) extent and enlarge in GSH (suppressed glutathione)

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amount. Additionally, it also enlarged the action of SOD (superoxide dismutase) along with CAT (catalase). In serum, METB amplified the quantity of oxidative stress markers such as ALP (alkaline phosphatase), UA (uric acid), ALT (alanine transferase), and AST (aspartate transaminase) close to their control standards as in organized group. The application of METB furthermore suppressed the quantity of whole cholesterol and TGs (triglycerides) in serum and appreciably enlarged HDL (high-density lipoprotein) amount. Assessment with METB moreover verified a substantial return in histopathological results of myocardium (Chaudhary et al., 2020). 17.3.12 ANTIDEPRESSANT ACTIVITY Through Forced Swim test and Tail Suspension test, antidepressant activity of aqueous extract of T. bellirica fruit was demonstrated on mature male Swiss Albino mice. The plant extract showed significant reduction in immobility time of mice in both test at the doses of 9, and 36 and 9, 18 mg/kg respectively on acute administration (Manohar et al., 2014a). However in other investigations with aqueous fruit pulp extract of T. bellirica (AETB) showed significant reduction in the immobility with group IV (18 mg/kg) and group V (36 mg/kg) in comparison to the control group when subjected to tail suspension test (TST); suggesting an antidepressant-like activity in adult male Swiss Albino mice (Manohar et al., 2014b). Aqueous extract, in a dose-dependent manner, and ethanolic extract of T. bellirica fruits (100 mg/ kg) considerably declined the immobility instance of mice in together with forced swim test (FST) plus tail suspension test (TST). The efficacies of both extracts were found to be parallel to that of imipramine (15 mg/kg, po) and fluoxetine (20 mg/kg, po) administered for 10 days. Both residues change reserpine-induced extension of immobility stage of mice in FST along with TST. Prazosin, sulpiride, and p-chlorophenylalanine considerably attenuated both the residues-elevated antidepressant-like consequence in TST (Dhingra and Valecha, 2007). 17.3.13 ANTINOCICEPTIVE ACTIVITY With five categories of Swiss Albino mice, the assessment was conducted using T. bellirica fruit pulp aqueous extract as a test drug for middle and peripheral antinociceptive action. The study has shown an enlarged in response instance in every three doses (9, 18, and 36 mg/kg) at 30 min

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intermission as correlated to the normal by Eddy’s hot plate technique and moreover condensed the amount of writhes by acetic acid activated writhing reflex in Swiss Albino mice correlate to the normal. It showed central and peripheral antinociceptive activity (Manohar et al., 2016). Moreover, the petroleum ether, chloroform, ethanol, and aqueous fractions of T. bellirica and T. chebula fruits were examined for their analgesic action employing the tail immersion replica in mice. The ethanolic residues of both the plants demonstrated analgesic reaction at 200, 400, and 800 mg/kg. The report was supplementarily conducted for 15 days to assess the consequence of these residues in chronic ache and greatest analgesic reactions were observed on the 14th day in both the plants. The results indicated that fruits of plants could be considered a potential candidate for bioactivity-guided separation of usual analgesic mediator employed in the organization of chronic pain (Kaur and Jaggi, 2010). 17.3.14 DIURETIC ACTIVITY Animals were separated into five categories to evaluate potency and efficacy of T. bellirica fruit pulp water residues in Wistar albino rats. The urine amount and electrolyte composition of Na+, K+, and Cl− in the urine were measured at the ending of 5th h. The investigation exposed that TBFPAE possesses diuretic consequence with a considerable potassium-sparing outcomes equivalent to frusemide in the dose of 9, 18, and 36 mg/kg (Rai et al., 2016). 17.3.15 ANTI-DIARRHOEAL ACTIVITY The anti-diarrhoeal action was carried out using water and ethanolic extract of fruit mash of TB at the doses of 334, 200, and 143 mg/kg. Similarity of quantity protection in these models exposed that the residues have extra important antisecretory outcomes than the decrease in gastrointestinal motility (Kumar et al., 2010a). Furthermore, Pandey et al. (2017) investigated the anti-diarrheal activity of T. bellirica fruit ethyl acetate extract on castor oil-activated diarrhea in Wistar rats. Oral administration of 100 mg/ kg of dried fruit ethyl acetate extract reduced the discharge of pellets by 42% in 4 h posttreatment, while similar dose of grilled fruit ethyl acetate extract inhibited diarrhea by 72% in 4 h.

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17.3.16 ANTI-INFLAMMATORY ACTIVITY

The investigation by Akter et al. (2019b) provided the rationale for the use of T. bellirica as an anti-inflammatory mediator employing carrageenanactivated inflammation in the Swiss albino rats. Animals treated with ibuprofen (20 mg/kg, p.o.) and methanolic residues (50, 120, and 300 mg/kg p.o.) showed a significant reduction in paw thickness from 1 to 5 h. It significantly decreased carrageenan-induced paw edema, and exhibited a reduction of 50.00%, 55.88%, and 61.76% at doses of 50, 120, and 300 mg/kg, respectively. Furthermore, Jayesh et al. (2020) reported anti-inflammatory activity of 70% aqueous-acetone extract of T. bellirica fruit in LPS-induced murine macrophage cell line by analyzing nitrate, inducible nitric oxide synthase (iNOS) levels, 5-LOX, total COX activity, ROS production, mRNA level expression of COX-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). It suggested that the extract (100 μg/mL) reduced the activity of 5-LOX and total COX, while it downregulated the expression of COX-2 gene. Furthermore, LPS-treated RAW 264.7 cell lines triggered the upregulation of pro-inflammatory cytokines, such as TNF-α, IL-6, and pro-inflammatory mediator enzyme COX-2. Extract suppressed the more expressions of these genes with substantial reduction in nitrate, iNOS, and MPO level in a concentration-dependent manner. Hepatic inflammation in CCl4-intoxicated mice was suppressed by administration of fruit ethyl acetate extract (100 and 300 mg/kg) (Rashed et al., 2014) which was achieved through the inhibition of the NF-κB, p65 activation and downregulation of TNF-α and COX-2 over expression. Another report also focused anti-inflammatory activity of T. bellirica extract. A considerable restriction of paw edema as correlated to normal category was recorded at doses of 100, 200, and 400 mg/kg at 1, 3, and 5 h. Extract displayed analogous effectiveness to indomethacin at 200 mg/kg. Highest % inhibition was observed with TBE 200 mg/kg at 3 h (57.6%) (Chauhan et al., 2018b). 17.3.17 IMMUNOMODULATORY ACTIVITY Fruit methanolic extract of T. bellirica possess immunomodulatory activity was authenticated by phagocytic and lymphocyte explosion action on the mouse, where residues have been indicated to trigger the generation of superoxide anions and acid phosphatase, then it could promote the macrophage phagocytosis (Saraphanchotiwitthaya and Ingkaninan, 2014). The plant extract with cocanavalin A and pokeweek mitogen caused restricted

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action. However acetone extracts of the plant showed an increase of the Band T-cells explosion beside with enlarged IL-10 discharge, but it condensed the generation of IFN-a and IL-250 (Manjunatha et al., 2011). 17.3.18 ANTIMUTAGENIC EFFICACY Antimutagenic consequence of 2 polyphenolic fractions extracted from T. bellirica in TA98 and TA100 strains of S. typhimurium verses 2AF, NPD and 4NQNO has been characterized. Both the fractions were appreciably valuable against S9-dependent 2AF; less efficient verses NPD and roughly not efficient against 4NQNO in TA100 strain. With application of 13C-NMR spectral examination, the TB-3 fraction, which was considerably extra successful verses 2AF compared to TB-4, was found to be a combination of three tannins whereas TB-4 was non-tannin fraction (Padam et al., 1996). The investigation was undertaken to find out antimutagenic potency of aqueous, acetone, and chloroform residues of T. bellirica using the Ames Salmonella/ microsome screening. Acetone residues displayed changeable restricted action of 65.6%, and 69.7% with 4-O-nitrophenylenediamine (NPD) and sodium azide, correspondingly, and 81.4% with 2-aminofluorene, in the previous to incubation style of techniques. restriction with chloroform and aqueous residue was slightly inconsequential (Kaur et al., 2003). Conversely one more outcome demonstrated restriction of mutagenicity activated by together straight and S9-dependent mutagens with chloroform and acetone extracts. A significant inhibition of 98.7% was examined through ‘Triphala’ (with T. bellirica) acetone residues against the revertants activated by S9-dependent mutagen, 2AF, in co-incubation method of healing. Different spectroscopic methods, specifically 1H-NMR, normal 13C-NMR, distortion less augmentation by polarization transmit, UV and IR, were below mode to recognize the polyphenolic composites from an acetone fraction (Kaur et al., 2002). 17.3.19 ANTITHROMBOTIC AND THROMBOLYTIC ACTIVITY An in vitro model was adopted to ensure the clot lysis and antithrombotic consequence of T. bellirica fruits. It was found that subsequent to addition of streptokinase, clot development was postponed up to extra than 90 min while after adding of trial, the holdup in clot development also enlarged. At 0.20 mg/dL level it displayed the greatest postponement. For thrombolytic action,

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at level of 1.00 mg/dL, the clot suspension time is lowest, that is, 58 and 66 min for water and alcoholic residues correspondingly (Ansari et al., 2012). An investigation carried out by Ansari et al. (2016), revealed that the fruit ethanolic extract and benzoyl-β-D-(4→10 geranilanoxy)-xylopyranosides inhibited the collagen-mediated aggregation of platelet in a concentrationdependent manner. 17.3.20 ACUTE AND CHRONIC TOXICITY ACTION Different concentrations of T. bellirica fruit aqueous extract did not produce any signs of behavioral changes, toxicity, and mortalities in rats (Sireeratawong et al., 2013). T. bellirica fruit methanolic extract (up to 4000 mg/kg) did not exert any adverse effects on the different body systems and somato motor action (Upadhyay et al., 2015). The oral management of the fraction did not reason for death in entire groups of the investigation till 14 days of handling periods (Das and Devi, 2016). Additionally, Thanabhorn et al. (2009) investigated acute and subacute toxicity examination as per the OECD instructions. Single oral administration of the ethanolic residues of T. bellirica at a dose of 500 mg/ kg body weight was unsuccessful to generate any deadly conditions. In subacute toxicity study, frequent administration 500 mg/kg body weight of T. bellirica over 14 days did not display any alterations in terms of common attitudes, death, mass increase, hematological, or clinical blood chemistry standard. The outcome of histologic assessments displayed conventional appearance of the inner organs while correlated to those of the normal cluster. 17.3.21 ANTIFUNGAL ACTIVITY Devi et al. (2014) reported antimycotic activity of aqueous, chloroforma and petroleum ether extracts of T. bellirica fruit against Aspergillus niger, A. fumigatus, A. flavus, Mucor, and Rhizopus spp. Ayoob et al. (2014) observed significant antifungal activity of methanolic leaf extract of T. bellirica. Moreover GC-MS and Fourier-transform infrared spectroscopy recognized benzenetriol, benzoic acid and 4H-pyran-4-one as major bioactive compounds present in fruit ethanolic extract and were responsible for its antifungal activity against ten Cryptococcus neoformans isolates (Valli and Shankar, 2013).

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17.3.22 NEPHROPROTECTIVE ACTIVITY The antioxidant and anti-urolithiatic consequences on ethylene glycolactivated renal calculi in albino rats were investigated by Upadhyay et al. (2015). The trial category of animals was injected with methanolic residues (MeTB) (100, 200, and 400 mg/kg b.w. (p.o.)) one time in a day commencing 15–28 day. The MeTB (400 mg/kg b.w.) appreciably declined the ethylene glycol activated trouble in different physical and biochemical criteria in both urine and serum. The MeTB (400 mg/kg b.w.) prohibited the reduction of GSH extent and decline in the intensity of SOD in ethylene glycol activated renal damage in rats. Furthermore, MeTB also displayed considerable decline in the LPO extent telling the effective antioxidant activity. Findings suggested that T. bellirica fruits could guard the kidney from glycol activated calculi. Another data revealed that aqueous fruit extract increased the expression of antioxidant enzyme and superior kidney damage in LPS-shock mice form. These assessments make available novel impending for fresh remedial approaches employing T. bellirica-derived antioxidants in opposition to oxidative stress-mediated renal diseases (Tanaka et al., 2018). Hepatorenal toxicity induced by MTX (Methotrexate) was attributed to increased oxidative stress, biochemical liver, and kidney parameters and upregulation of caspase-3 and nuclear factor kappa B (NFkB) in Wistar albino rats. MTX-treated group observed twofold to threefold rise in aspartate amino transferase, alanine amino transferase, blood urea nitrogen, and creatinine values—138.49, 125.81 IU/L, 63.09, and 1.895 mg/dL, respectively. Groups pretreated with hydroalcoholic T. bellirica extract (TBE) (400 mg/kg) observed a significant decrease in oxidative stress and biochemical parameters. Pretreatment with TBE 400 mg/kg, histopathology of both liver and kidney tissues, showed improved architectural damage and immune histochemistry showed downregulation of increased antigens-caspase-3 and NFkB (Chauhan et al., 2018a). Another report on five groups of rats, where the first category served as a normal and injected with usual saline, the second category injected with gentamicin or silymarin 100 mg/kg p.o., the fourth and fifth group were administered with T. bellirica ethanolic or water residues plus gentamicin for 15 days. The second category displayed premature kidney dysfunction as blood urea, uric acid, and creatinine which enlarged. It indicated that GM activated nephrotoxicity. Administration of T. bellirica plus gentamicin could guard kidney tissue in opposition to nephrotoxic impacts (Fatima and Sultana, 2016).

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17.3.23 ANTIHYPERTENSIVE ACTIVITY To examine the probable process of its blood anxiety reducing impact, the report has been published by Khan and Gilani (2008). After administration of T. bellirica, a drop in the arterial BP of rats under anesthesia was observed. In lonely guinea pig atria, inhibition of force and speed of atrial contractions documented. In thoracic aorta of rabbit, relief recorded subsequent to the administration of contractions which was formed by supplying phenylephrine. These results indicated that T. bellirica reduced BP through Ca++ antagonist process and in consequence contributed a sound mechanistic condition for its therapeutic utility in hypertension (Khan and Gilani, 2008). 17.3.24 ANGIOGENESIS ACTIVITY Gelatin sponge with or without ethanolic residues ofT. belliricaleaf (EETB—0.3 and 0.5 mg, respectively) were subcutaneously administered into Swiss albino mice, and 14 days later, the implanted sponges was cut off and histologically checkout. The stained segment displayed that sponge including EETB had created supplementary vessels in gels than sponges alone. The fresh vessels were plentifully filled with intact RBCs, which designated the development of an efficient vasculature within the sponges and blood distribution in newly produced vessels by angiogenesis that was activated by EETB. Moreover, it also calculated that the hemoglobin concentration within the sponges, whereas hemoglobin in normal was nearly 0.3 µg, EETB cases the hemoglobin amount was markedly improved to about 17 µg (Prabhu et al., 2012). 17.3.25 ANTIPLATELET ACTIVITY The ethanolic extract of T. bellirica showed very good antiplatelet activity. This study was conducted by isolated compound (Tb-01), ethanolic extract, and aspirin, and tube no. 1 contains normal saline solution as blank. It was noticed that, together the Tb-01 and ethanolic fractions at the dissimilar composition displayed considerable antiplatelet action when correlated with normal category group (Ansari et al., 2016). 17.3.26 ANTI-HELMINTHIC ACTIVITY The investigation was conducted to evaluate anti-helminthic potential of ethanolic and aqueous extract of T. bellirica fruit pulp. Levimasole (0.55 mg/mL) was included as standard reference and distilled water as control,

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and Pheretima posthuma as test worms. Various bioassay methods were used. It was confirmed that plant fruit pulp possesses anti-helminthic activity (Kumar et al., 2010b). Moreover, the experiments were undertaken to determine anthelmintic action of water and ethanolic fractions of T. bellirica fruit, B. diffusa leaves, and S. granulata root against P. posthuma and E. foetida. Albendazole 20 mg/mL was employed as an indication typical medicine and common saline as control. The consequence was articulated in conditions of instance for paralysis and time for fatality. The investigation displayed considerable anthelmintic action of water along with ethanolic fraction of T. bellirica and B. diffusa (Kulkarni et al., 2014). 17.3.27 ANTIFERTILITY ACTIVITY Adult male rats were administered with benzene and ethanol extracts of T. bellirica bark orally for up to 50 days. The entire cholesterol substance was enlarged whereas protein composition and epididymal sperm measures were appreciably reduced (Patil et al., 2010). The sperm motility of cauda epididymis and sperm measures of cauda epididymis and testis reduced drastically leading to depressing fertility, while treating with the fruit extracts of T. bellirica was fed orally to male albino rats for 60 days. The reproductive organs were decreased. Investigation suggested finally that these extracts exert both antifertility and antiandrogenic activities (Venkatesh et al., 2002). KEYWORDS • • • •

Terminalia bellirica phytochemicals pharmacological activities mode of action

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Choudhary, G. P. Anti-Ulcer Activity of the Ethanolic Extract of Terminalia bellirica Roxb. Int. J. Pharm. Chem. Sci. 2012, 1, 1637–1641. Das, C. M. S.; Devi, G. S. Anti-Obesity Activity of Ethanolic Extract of Fruits of Terminalia bellirica on Atherogenic Diet Induced Obesity in Experimental Rats. J. Chem. Pharm. Res. 2016, 8, 191–197. Deb, A.; Barua, S.; Das, B. Pharmacological Activities of Baheda (Terminalia bellirica): A Review. J. Pharmacogn. Phytochem. 2016, 5 (1), 194–197. Devi, P. N.; Kaleeshwari, S.; Poonkothai, M. Antimicrobial Activity and Phytochemical Analysis of Fruit Extract of Terminalia bellirica. Int. J. Pharm. Pharma. Sci. 2014, 6, 639–642. Dhingra, D.; Valecha, R. Evaluation of Antidepressant-Like Activity of Aqueous and Ethanolic Extracts of Terminalia bellirica Roxb. Fruits in Mice. Indian J. Exp. Biol. 2007, 45 (7), 610–116. Dharmaratne, M. P. J.; Amirthasingam, M.; Thevanesam, V.; Ekanayake, A.; Kumar, N. S.; Liyanapathirana, V.; Abeyratne, E.; Bandara, B. M. R. Terminalia bellirica Fruit Extracts: In-Vitro Antibacterial Activity Against Selected Multidrug-Resistant Bacteria, Radical Scavenging Activity and Cytotoxicity Study on BHK-21 Cells. BMC Complement. Altern. Med. 2018, 18, 325. DOI: https://doi.org/10.1186/s12906-018-2382-7. Elizabeth, K. M. Antimicrobial Activity of Terminalia bellirica. Indian J. Clin. Biochem. 2005, 20 (2), 150–153. Elizabeth, A. L.; Bupesh, G.; Susshmitha, R. In Vitro Antioxidant Efficacy of Terminalia bellirica Seed Extract Against Free Radicals. Int. J. Pharm. Sci. Res. 2017, 8 (11), 4659–4665. DOI: http://dx.doi.org/10.13040/IJPSR.0975-8232.8. Fahmy, N. M.; Al-Sayed, E.; Singab, A. N. Genus Terminalia: A Phytochemical and Biological Review. Med. Aroma. Plants 2015, 4, 1–21. DOI: http://dx.doi. org/10.4172/2167-0412.1000218. Fatima, N.; Sultana, H. Evaluation of Protective Effect of Terminalia bellirica Against Gentamicin Induced Nephrotoxicity in Albino Rats. Pharm. Biol. Eval. 2016, 3 (5), 486–494. Ghate, N. B.; Hazra, B.; Sarkar, R.; Chaudhuri, D.; Mandal, N. Alteration of Bax/Bcl-2 Ratio Contributes to Terminalia bellirica—Induced Apoptosis in Human Lung and Breast Carcinoma. In Vitro Cell. Dev. Biol. Anim. 2014, 50, 527–537. DOI: https://doi.org/10.1007/ s11626-013-9726-x. Guleria, S.; Tiku, A. K.; Rana, S. Antioxidant Activity of Acetone Extract/Fractions of Terminalia bellirica Roxb. Fruit. Indian J. Biochem. Biophys. 2010, 47, 110–116. Gupta, A.; Kumar, R.; Pandey, A. K. Antioxidant and Antidiabetic Activities of Terminalia Fruit in Alloxan Induced Diabetic Rats. South Afr. J. Bot. 2020, 130, 308–315. DOI: https:// doi.org/10.1016/j.sajb.2019.12.010. Gupta, A.; Pandey, A. K. Aceclofenac-Induced Hepatotoxicity: An Ameliorative Effect of Terminalia bellirica Fruit and Ellagic Acid. World J. Hepatol. 2020, 12 (11), 949–964. DOI: http://dx.doi.org/10.4254/wjh.v12.i11.949. Gupta, R.; Singh, R. L.; Dwived, N. In Vitro Antioxidant Activity and GC-MS Analysis of the Ethanolic Extracts of Terminalia bellirica Roxb (Baheda). Int. J. Pharm. Pharm. Sci. 2016, 8, 275–282. DOI: http://dx.doi.org/10.22159/ijpps.2016v8i11.14175. Jadon, A.; Bhadauria, M.; Shukla, S. Protective Effect of Terminalia belerica Roxb. and Gallic Acid Against Carbon Tetrachloride Induced Damage in Albino Rats. J. Ethnopharmacol. 2007, 109 (2), 214–218. DOI: http://dx.doi.org/10.1016/j.jep.2006.07.033.

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Jawanjal, H.; Rajput, M. S.; Agrawal, P.; Dange, V. Pharmacological Evaluation of Fruits of Terminalia belerica Roxb. for Antiulcer Activity. J. Complement. Integr. Med. 2012, 9, 1–15. DOI: http://dx.doi.org/10.1515/1553-3840.1556. Jayesh, K.; Karishma, R.; Vysakh, A.; Prasad, G.; Latha, M. S. Terminalia bellirica (Gaertn.) Roxb. Fruit Exerts Anti-Inflammatory Effect via Regulating Arachidonic Acid Pathway and Pro-Inflammatory Cytokines in Lipopolysaccharide-Induced RAW 264.7 Macrophages. Inflammopharmacol. 2020, 28, 265–274. DOI: http://dx.doi.org/10.1007/ s10787-018-0513-x. Kasabri, V.; Flatt, P. R.; Abdel-Wahab, Y. H. Terminalia bellirica Stimulates the Secretion and Action of Insulin and Inhibits Starch Digestion and Protein Glycation In Vitro. Br. J. Nutr. 2010, 103, 212–217. DOI: http://dx.doi.org/10.1017/S0007114509991577. Kaur, S.; Arora, S.; Kaur, K.; Kumar, S. The In Vitro Antimutagenic Activity of Triphala— An Indian Herbal Drug. Food Chem. Toxicol. 2002, 40 (4), 527–534. DOI: http://dx.doi. org/10.1016/s0278-6915(01)00101-6. Kaur, S.; Arora, S.; Kaur, S.; Kumar, S. Bioassay-Guided Isolation of Antimutagenic Factors from Fruits of Terminalia bellirica. J. Environ. Pathol. Toxicol. Oncol. 2003, 22 (1), 69–76. DOI: http://dx.doi.org/10.1615/JEnvPathToxOncol.v22.i1.70. Kaur, S.; Jaggi, R. K. Antinociceptive Activity of Chronic Administration of Different Extracts of Terminalia bellerica Roxb. and Terminalia chebula Retz. Fruits. Indian J. Expt. Biol. 2010, 48, 925–930. Kawthar, A. E. D.; Guru, S. K.; Bhushan, S.; Saxena, A. K. In Vitro Anticancer Activities of Anogeissus latifolia, Terminalia bellirica, Acacia catechu and Moringa oleiferna Indian Plants. Asian Pac. J. Cancer Prevent. 2015, 16, 6423–6428. DOI: http://dx.doi.org/10.7314/ APJCP.2015.16.15.6423. Khan, A. U.; Gilani, A. H. Pharmacodynamic Evaluation of Terminalia bellerica for Its Anti-Hypertensive Effect. J. Food Drug Anal. 2008, 16, 6–14. DOI: http://dx.doi. org/10.38212/2224-6614.2355 Khan, A. U.; Gilani, A. H. Antisecretory and Analgesic Activities of Terminalia bellirica. Afr. J. Biotechnol. 2010, 9 (18), 2717–2719. Kulkarni, C. G.; Lohar, B. N.; Jadhav, S. T.; Salunkhe, S. S. Evaluation of Antihelmintic Activity of Indian Herbs. Int. J. Pharm. 2014, 4 (1), 357–362. Kumar, B.; Divakar, K.; Tiwari, P.; Salhan, M.; Goli, D. Evaluation of Anti-Diarrhoeal Effect of Aqueous and Ethanolic Extracts of Fruits Pulp of Terminalia bellirica in Rats. Int. J. Drug Dev. Res. 2010a, 2 (4), 769–779. Kumar, B.; Kalyani, D.; Hawal, L. M.; Singh, S. In Vitro Anthelmintic Activity of Ethanolic and Aqueous Fruit Extract of Terminalia bellirica. J. Pharm. Res. 2010b, 3 (5), 1061–1062. Kuriakose, J.; Helen, L. R.; Vysakh, A.; Eldhose, B.; Latha, M. S. Terminalia bellirica (Gaertn.) Roxb. Fruit Mitigates CCl4 Induced Oxidative Stress and Hepatotoxicity in Rats. Biomed. Pharmacother. 2017, 93, 327–333. DOI: http://dx.doi.org/10.1016/j.biopha.2017.06.080. Kumudhavalli, M. V.; Vyas M.; Jayakar B. Phytochemical and Pharmacological Evaluation of the Plant Fruit of Terminalia bellirica Roxb. Int. J. Pharm. Life Sci. 2010, 1 (1), 1–11. Latha, P. C. R.; Daisy, P. Influence of Terminalia bellerica Roxb. Fruits Extract on Biochemical Parameters in Streptozotocin Diabetic Rats. Int. J. Pharmacol. 2010, 6, 89–96. Li, S.; Ye, T.; Liang, L.; Liang, W.; Jian, P.; Zhou, K.; Zhang, L. Anti-Cancer Activity of an Ethyl-Acetate Extract of the Fruits of Terminalia bellirica (Gaertn.) Roxb. Through an Apoptotic Signaling Pathway In Vitro. J. Tradit. Chin. Med. Sci. 2018, 5, 370–379. DOI: https://doi.org/10.1016/j.jtcms.2018.11.006.

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Laila, A.; Amal, M. S. Characterization of Chemical Constituents, Reducing Power and Anticancer Activities of Terminalia bellirica Roxb. Acad. J. Cancer Res. 2014, 7, 117–125. DOI: https://doi.org/10.5829/idosi.ajcr.2014.7.2.83195. Lobo, V. C.; Pathak, A.; Chandra, N. Antioxidant Availability of Baheda (Terminalia bellirica (Roxb.)) in Relation to Its Medicinal Uses. Pharmacogn. J. 2010, 2, 338–344. Madani, A.; Jain, S. K. Anti-Salmonella Activity of Terminalia bellirica In Vitro and In Vivo Studies. Indian J. Exp. Biol. 2008, 46, 817–821. Makihara, H.; Shimada, T.; Machida, E.; Oota, M.; Nagamine, R.; Tsubata, M.; Kinoshita, K.; Takahashi, K.; Aburada, M. Preventive Effect of Terminalia bellirica on Obesity and Metabolic Disorders in Spontaneously Obese Type 2 Diabetic Model Mice. J. Nat. Med. 2012, 66, 459–467. DOI: https://doi.org/10.1007/s11418-011-0606-y. Manjunatha, M.; Bhalodiya, H.; Ansari, Md. A.; Vada, S.; Goli, D. Immunomodulatory Activity of Terminalia bellirica Extract in Mice. Int. J. Pharm. 2011, 2, 103–108. DOI: https://doi.org/10.13140/RG.2.2.15409.02401. Manohar, V. R.; Mohandas, S. R.; Alva, A.; DSouza, R. A.; Kateel, R. Acute Antidepressant Activity of Aqueous Extract of Terminalia bellirica Fruit in Mice in Experimental Paradigms. Int. J Ayurveda Pharm. 2014a, 5 (2), 198–200. DOI: https://doi. org/10.7897/2277-4343.05239. Manohar, V. R.; Mohandas, S. R.; Kateel, R.; Aravind, A.; Shridar, D.; Dsouza, F. Attenuation of Depression on Subacute Administration of Terminalia bellirica Fruit in Tail Suspension Test. J. Phytopharmacol. 2014b, 3 (3), 163–167. Manohar, V. R.; Mohandas, R.; Chandrashekar, R.; Sivan, S.; Kumar, B. D.; Aravind, A. Central and Peripheral Antinociceptive Activity of Terminalia bellirica Fruit Pulp Aqueous Extract in Swiss Albino Mice. Indian J. Pharm. Pharmacol. 2016, 3 (1), 13–16. DOI: https://doi.org/10.5958/2393-9087.2016.00003.0. Meshram, G.; Patil B.; Shinde, D.; Metangale, G. Effect of Epigallocatechin Gallate Isolated from Terminalia bellerica Fruit Rind on Glucoamylase Activity In Vitro. J. Appl. Pharm. Sci. 2011, 01, 115–117. Nadkarni, K. M. Indian Materia Medica; Vol. 1; Published by Ramdas Bhatkal for Popular Prakashan Pvt. Ltd.: Mumbai, 2002; pp 202–1205. Nampoothiri, S. V.; Prathapan, A.; Cherian, O. L.; Raghu, K. G.; Venugopalan, V. V.; Sundaresan, A. In Vitro Antioxidant and Inhibitory Potential of Terminalia bellirica and Emblica officinalis Fruits Against LDL Oxidation and Key Enzymes Linked to Type 2 Diabetes. Food Chem. Toxicol. 2011a, 49, 125–131. DOI: https://doi.org/10.1016/j. fct.2010.10.006. Nampoothiri, S. V.; Binil, R. S. S.; Prathapan, A.; Abhilash, P. A.; Arumughan, C.; Sundaresan, A. In Vitro Antioxidant Activities of the Methanol Extract and Its Different Solvent Fractions Obtained from the Fruit Pericarp of Terminalia bellirica. Nat. Prod. Res. 2011b, 25, 277–287. DOI: http://dx.doi.org/10.1080/14786419.2010.482053. Nithya, D. P.; Kaleeswari, S.; Poonkothai, M. Antimicrobial Activity and Phytochemical Analysis of Fruit Extracts of Terminalia bellirica. Int. J. Pharm. Pharm. Sci. 2014, 6, 639–642. Padam, S. K.; Grover, I. S.; Singh, M. Antimutagenic Effects of Polyphenols Isolated from Terminalia bellirica Myroblan in Salmonella typhimurium. Indian J. Exp. Biol. 1996, 34, 98–102.

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Shi, Y.; Sahu, R. P.; Srivastava, S. K. Triphala Inhibits Both In Vitro and In Vivo Xenograft Growth of Pancreatic Tumor Cells by Inducing Apoptosis. BMC Cancer 2008, 294, 1–16. DOI: https://doi.org/10.1186/1471-2407-8-294. Shukla, S.; Jadon, A.; Bhadauria, M. Protective Effect of Terminalia bellirica Roxb, and Gallic Acid Against Carbon Tetra Chloride Induced Damage in Albino Rats. J. Ethnopharmacol. 2006, 109, 214–218. Singh, A. V.; Hage, A. Antioxidant Activity of Terminalia bellirica (Gaertn.) Roxb. of Tawang, Arunachal Pradesh, India. J. Bioresour. 2017, 4 (2), 65–72. Sireeratawong, S.; Jaijoy, K.; Panunto, W.; Nanna, U.; Lertprasertsuke, N.; Soonthornchareonnon, N. Acute and Chronic Toxicity Studies of the Water Extract from Dried Fruit of Terminalia bellirica (Gaertn.) Roxb. in Spargue-Dawley Rats. Afr. J. Tradit. Complement. Altern. Med. 2013, 10, 223–231. DOI: http://dx.doi.org/10.4314/ajtcam. v10i2.6. Syeda, S.; Shahnaz, R.; Nusrat, A. A.; Mostafi, J. M.; Auditi, S.; Mohammed, R. Antihyperglycemic Activity Evaluation of a Formulation Consisting of Phyllanthus emblica, Terminalia bellirica and Terminalia chebula Fruits and Trigonella foenum-graecum Seeds. Adv. Nat. Appl. Sci. 2014, 8 (1), 12–15. Tahsin, Md. R.; Jannat, B.; Mostafa, A.; Purni, F. A.; Khondoker, S.; Islam, S.; Shantha, A. A.; Afrim, S.; Asadullah, Q. U.; Amran, M. S. An Evaluation of Diabetes Ameliorating Capacity of Terminalia bellirica Ethanolic Extract on Alloxan-Induced Diabetic Rat Including Safety Profile Study. J. Clin. Mol. Endocrinol. 2021, 6, 1–8. DOI: http://dx.doi. org/10.36648/2572-5432.6.1.33. Tanaka, M.; Kishimoto, Y.; Saita, E.; Suzuki-Sugihara, N.; Kamiya, T.; Taguchi, C.; Iida, K.; Kondo, K. Terminalia bellirica Extract Inhibits Low-Density Lipoprotein Oxidation and Macrophage Inflammatory Response In Vitro. Antioxidants 2016, 5 (20), 1–13. DOI: http:// dx.doi.org/10.3390/antiox5020020. Tanaka, M.; Kishimoto, Y.; Sasaki, M.; Sato, A.; Kamiya, T.; Kondo, T.; Iida, K. Terminalia bellirica (Gaertn.) Roxb. Extract and Gallic Acid Attenuate LPS-Induced Inflammation and Oxidative Stress via MAPK/NF-κB and Akt/AMPK/Nrf2 Pathways. Oxid. Med. Cell. Longev. 2018, 9364364,1–15. DOI: http://dx.doi.org/10.1155/2018/9364364. Thanabhorn, S.; Jaijoy, K.; Thamaree, S.; Ingkaninam, K. Acute and Sub-Acute Toxicities of the Ethanol Extract of Fruit of Terminalia bellirica. J. Pharm. Sci. 2009, 33, 23–30. The Ayurvedic Pharmacopoeia of India (API). Govt. of India, Ministry of Health and Family Welfare, Part-I; 1st ed., Vol. 3; The Controller of Publications, Dept. of ISM and H: New Delhi; 2001; Part-1, 1, 252.10. Valli, S.; Shankar, G. S. Terminalia bellirica—A Promising Challenge to Cryptococcosis. Int. J. Pharm. Bio. Sci. 2013, 2, 154–169. Valsaraj, R.; Pushpangadan, P.; Smitt, U. W.; Adsersen, A.; Christensen, S. B.; Sittie, A.; Nyman, U.; Nielsen, C.; Olsen, C. E. New Anti-HIV-1, Antimalarial, and Antifungal Compounds from Terminalia bellerica. J. Nat. Prod. 1997, 60 (7), 739–742. DOI: http:// dx.doi.org/10.1021/np970010m. Upadhyay, N.; Tiwari, S. K.; Srivastava, A.; Seth, A.; Maurya, S. K. Anti-Urolithiatic Effect of Terminalia bellirica Roxb. Fruits on Ethylene Glycol-Induced Renal Calculi in Rats. Indo Am. J. Pharm. Res. 2015, 5, 2031–2040. Venkatesh, V.; Sharma, J. D.; Kamal, R. A. Comparative Study of Effect of Alcoholic Extracts of Sapindus emarginatus, Terminalia bellirica, Cuminum cyminum and Allium cepa on Reproductive Organs of Male Albino Rats. Asian J. Exp. Sci. 2002, 16, 51–63.

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Violet, K.; Peter, R. F.; Yasser, H. A. A. Terminalia bellirica Stimulates the Secretion and Action of Insulin and Inhibits Starch Digestion and Protein Glycation In Vitro. Br. J. Nutr. 2010, 103, 212–217. DOI: http://dx.doi.org/10.1017/S0007114509991577. Yadav, S.; Singh, S.; Sharma, P.; Thapliyal, A.; Gupta, V. Antibiofilm Formation Activity of Terminalia bellirica Plant Extract Against Clinical Isolates of Streptococcus mutans and Streptococcus sobrinus: Implication in Oral Hygiene. Int. J. Pharm. Bio. Arch. 2012, 816–821. Yang, M. H.; Vasquez, Y.; Ali, Z.; Khan, I. A.; Khan, S. I. Constituents from Terminalia Species Increase PPARα and PPARγ Levels and Stimulate Glucose Uptake Without Enhancing Adipocyte Differentiation. J. Ethnopharmacol. 2013, 149, 490–498. DOI: http://dx.doi.org/10.1016/j.jep.2013.07.003.

CHAPTER 18

Phytochemicals and Pharmacological Activities of Tinospora cordifolia (Willd.) Miers A. NAGALAKSHMI, K. ABRAHAM PEELE, S. SIVA KUMAR, M. INDIRA, T.C. VENKATESWARULU, AND S. KRUPANIDHI* Department of Biotechnology, Vignan’s Foundation for Science Technology and Research (Deemed to be University), Vadlamudi, Andhra Pradesh 522213, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Tinospora cordifolia is a widely used shrub in folk and ayurvedic medicine for treating the various disorders. The plant belongs to the family Menispermaceae. It is commonly known as thippateega, guduchi and amrita. The bioactive compounds belong to different classes such as alkaloids, terpenoids, phenolics, diterpenoid lactones, glycosides, aliphatic compounds, steroids, polysaccharides and sesquiterpenoids. The bioactive compounds present in various parts of the plant are tinosporin, berberine, magnoflorine, palmitine, tetrahydropalmatine, syringine, tinocordiside, cordifolioside A, β-sitosterol, choline and jatrorrhizine. Due to the presence of various bioactive compounds, the plant possesses different pharmacological activities such as antidiabetic, anti-inflammatory, antioxidant, antiallergic, anticancer, immunomodulatory, antimicrobial, anti-HIV activity, neuroprotective, cardioprotective and hypoglycemic activity. The chapter deals about the geographical distribution of the plant, bioactive compounds and their structures. Further it emphasizes on pharmacological activities of the Tinospora cordifolia. Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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INTRODUCTION

Tinospora cordifolia (Wild.) Miers belongs to Menispermaceae family. It has several vernacular names in Indian languages such as Thippateega (Telugu), Guduchi (Sanskrit), Giloy (Marathi), Sindal (Tamil), Sitta-mrytu (Malayalam), Gulancha (Bengali), Gurcha (Hindi), Amritaballi (Kannada), and Galac (Gujarati). It is a deciduous, climbing shrub widely distributed with numerous elongated twinning branches. The parts of this plant exhibit different types of morphology (Upadhyay et al., 2010). The plant grows in both tropical and subtropical areas of the world. The plant is widely distributed in India, Sri Lanka, China, Madagascar, Pacific islands, Malaysia, and Australia. In India it is widely distributed throughout. It extended from northern region Kumaon to North East region Assam and West Bengal, Bihar, Deccan, Konkan, Karnataka Kerala regions, and Andaman and Nicobar island groups (Choudhary et al., 2013; Gaur et al., 2014). This plant is traditionally used for various diseases such as gastrointestinal hemorrhoids, gastritis, dyspepsia, flatulence, splenomegaly, and jaundice. It is also recommended in the treatment of metabolic disorders including kidney diseases and diabetes (Chi et al., 2016). It is now widely used to treat COVID-19 in South India. It has medicinal properties such as analgesic, antispasmodic, anti-inflammatory, anti-asthmatic, expectorant, aphrodisiac, antipyretic, and infective conditions such as typhoid, eye diseases, and skin diseases (Upadhyay et al., 2010). The therapeutic potential of the plant is due to its bioactive compounds such as phenolics, glycosides, sesquiterpenoids, diterpenoid lactones, steroids, essential oils, aliphatic compounds, polysaccharides, and fatty acids (Saha and Ghosh, 2012). The stem is green succulent in nature and surrounded by thin layer of brown bark when aged. The leaves are heart-shaped, membranous, 7-9-nerved, and 5–10 cm long with long petiole. Flowers are green-yellow, unisexual and appear when the plant is leafless. The male flowers are clustered, small and the female flowers are solitary in nature. Fruits are large pea sized, green to red in color when it ripens (Saha and Ghosh, 2012; Sharma et al., 2019). 18.2

BIOACTIVE COMPOUNDS

The phytochemical constituents present in Tinospora cordifolia are glycosides, alkaloids, sesquiterpenoids, diterpenoid lactones, steroids, essential oils, phenolics, aliphatic compounds, polysaccharides, and fatty

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acids (Sharma et al., 2019). The leaves are rich in calcium, phosphorous and proteins. The root, stem, leaf, and whole plant consist of alkaloids berberine, tinosporic acid, tinosporin, palmitine, magnoflorine, tembatarine, isocolumbin, choline, tetrahydropalmatine, and Jatrorrhizine (Panchabhai et al., 2008; Saeed et al., 2020). The whole plant consists of diterpenoid lactones, diterpenoid furanolactones, heptacosanol, octacosanol, cleodrane derivatives, tinosporin, columbin, tinosporides, Nanocosan 15-one dichloromethane, and jateorine (Panchabhai et al., 2008; Tiwari et al., 2018). The glycosides present majorly in stem part of the plant which includes tinocordifoliside, nonclerodane glycoside, glucoside, cordioside, cordifoliside—A, B, C, Dand E, palmitoside C and P, furanoid, and syringin (Panchabhai et al., 2008; Sharma et al., 2019). The steroids identified in this plant are octacosanol, β-sitosterol, δ-sitosterol, nonacosan-15-one, heptacosanol, tetrahydrofuran, hydroxy ecdysone, giloinsterol, makisterone, and ecdysterone (Panchabhai et al., 2008; Singh and Chaudhuri, 2017). The other chemical constituents are aregiloin, cordifol, tinosporidin, tinocordifolin, cordifelone, tinosporal acetate, sinapic acid, phyto ecdysones, and arabinogalactan (Panchabhai et al., 2008; Sharma et al., 2019). 18.3

PHARMACOLOGICAL ACTIVITIES

18.3.1 ANTIDIABETIC ACTIVITY Nadig et al. (2012) evaluated hyperalgesia in animal models of diabetic neuropathy. The first group was administered with normal vehicle and the second group administered with control drugs glibenclamide and metformin. The third group (100 mg/kg), fourth group (200 mg/kg), and fifth group (400 mg/kg) received T. cordifolia extract after the induction of diabetes. The initial fasting blood sugar, body weight, in-vitro aldose reductase inhibition, and reaction time were evaluated. The results found that the T. cordifolia extract prevents hyperalgesia in diabetic neuropathy. The phytochemicals palmatine and berberine upregulated the PPARα (Peroxisome proliferator-activated receptor alpha) and Glut-4 (Glucose transporter protein) expression in L6 myotubes. The PPARα regulated the glucose metabolism and also Glut-4 showed positive impact on glucose uptake. These studies reported that the plant compounds palmitine and berberine from T. cordifolia have antidiabetic activity (Sangeetha et al., 2013). The anti-dyslipidemic activity of plant extract was investigated in

Molecular formula C21H26O8 C20H18NO4+

Plant part

Phytochemical class Alkaloid Isoquinoline alkaloid

Biological activity

Reference

Aflatoxin induced nephrotoxicity Neuroprotective, Aphrodisiac, Anticancer

Stem and root

Alkaloid

Antiadipogenic, Antidiabetic.

C20H26NO4+

Stem and root

C20H24NO4+

Stem and root

Benzyl isoquinoPlant metabolite Aphrodisiac line alkaloid Aporphine alkaloid Inhibits α-glucosidase and antiglycemic Neurotransmitter,Neuroprotective Berberine alkaloid Adrenergic agent, dopaminergic antagonist

Gupta and Sharma (2011) Yuan et al. (2019), Goel and Maurya (2020), and Palmieri et al. (2019) Vasanthi and Kannan (2012) Wani et al. (2011)

Palmatine

C21H22NO4+

Tembatarine Magnoflorine

Choline C5H14NO+ Tetrahydropalmatine C21H25NO4

Stem and root Stem

Stem and root Root

Isocolumbin

C20H22O6

Root

Organic heterocyclic compound

Jatrorrhizine

C20H20NO4+

Root

Isoquinoline alkaloid

1-Octacosanol

C28H58O

Stem

Heptacosanol

C27H56O

Stem

Fatty alcohol

Neuroprotective effect Antioxidant, Aphrodisiac, Ameliorative, Hepatoprotective, Antipsychotic. Hypoglycemic activity Nutritional supplement, Tumor angiogenesis and metastasis Antinociceptive and antiinflammatory

Patel and Mishra (2012) Bairy et al. (2004) Kosaraju et al. (2014)

Gupta and Sharma (2011)

Patel and Mishra (2011) Thippeswamy et al. (2008) Kumar et al. (2017)

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Chemical constituent Tinosporin Berberine

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TABLE 18.1 Phytochemicals of T. cordifolia and Their Biological Activity.

(Continued)

Chemical constituent

Molecular formula

Plant part

Phytochemical class

Biological activity

Reference

β-Sitosterol

C29H50O

Stem and other aerial parts

Phytosterol

Cholesterol lowering

Upadhyay et al. (2010)

Ecdysterone

C27H44O7

Steroidal hormone

Immune booster Anti osteoporotic effect

Tinocordifoliside Tinocordiside Cordifolioside A

C21H32O8 C21H32O7 C22H32O13

Stem and other aerial parts Stem Stem Stem

Cardiac glycoside Cardiac glycoside Cardiac glycoside

Antioxidant activity SARS-CoV-2 infection Radioprotective, cytoprotective,

Cordioside Syringin

C26H34O12 C17H24O9

Stem Stem

Tinosporaside

C25H32O10

Whole plant

Tinosporide Tinocordifolin

C20H22O7 C15H22O3

Stem

glycoside Monosaccharide derivative Norclerodane glucoside Terpenoid sesquiterpenoid

Immunomodulatory immunomodulatory Hepatoprotective

Gao et al. (2008) and Kumar et al. (2017) Kumar et al. (2017) Balkrishna et al. (2020) Patel et al. (2013) and Sharma et al. (2012)

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TABLE 18.1

Sharma et al. (2012) Gong et al. (2014)

Protection from uterine fibroids

Li et al. (2019)

Hepatocellular carcinoma Antiseptic activity

Kumar et al. (2017) Tiwari et al. (2018)

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diabetic rats induced by alloxan 150 mg/kg body weight. The levels of glucose, lipid peroxide, glycosylated hemoglobin, and free fatty acids were evaluated and found that there is a reduction in the levels of all these plasma markers in diabetic rats treated with plant extract (Kumar et al., 2013). 18.3.2 ANTICANCER ACTIVITY The anticancer activity was investigated for T. cordifolia dichloromethane extract in transplanted mice with Ehrlich ascites carcinoma. The mice were administered with different doses of extract ranging from 25 to 100 mg/kg and it was found that the 50 mg/kg showed optimum dose for neoplastic activity in mice. The 50 mg/kg dose was evaluated for different stages of tumor development by inoculating intraperitoneally for every 3 days starts from day 1 to day 15 of tumor inoculation. The anticancer activity was observed for initial stages 1, 3, and 6 days where the long-term survivors are 33%, 25%, and 17% respectively. In addition to this the plant extract showed reduction of glutathione activity and lipid peroxidation levels. The results indicate that the extract showed cytotoxic activity on tumor cells (Jagetia and Rao, 2006). Dhanasekaran et al. (2009) investigated the anticancer activity of T. cordifolia bioactive compound epoxy clerodane diterpene in rat models. The diethyl nitrosamine was used to induce carcinoma in rats. The first group treated as control, second to fourth group administered with water for twenty weeks. The third group received 10 mg/kg of epoxy clerodane diterpene throughout the study. The fourth group received 10 mg/kg of epoxy clerodane diterpene for 8 weeks. The fifth group received 10 mg/kg of epoxy clerodane diterpene alone. The animals were sacrificed and it was found that the animals treated with epoxy clerodane diterpene showed increased levels of antioxidants and detoxification enzymes. The serum markers SGPT, SGOT, and LDH levels were decreased and reached to near normal. The tumor incidence also reduced and reached to normal and found that the compound has preventive effect against carcinoma in rats. The glioblastoma activity was evaluated for T. cordifolia. In this study the C6 glioma cells were used to evaluate the anticancer potential of plant and found that the extract reduced cell proliferation in a dose-dependent manner. The antiproliferative activity is due to enhanced expression of senescence marker. Further, it also showed antimetastatic and antimigratory potential of T. cordifolia extract using brain cells (Mishra and Kaur, 2013).

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T. cordifolia methanolic extract showed inhibitory activity against human breast cancer cell line. The cytotoxicity activity was observed against breast cancer cell line and found that the IC50 value was 59 ± 4.05 µg/mL in 0.2% of DMSO and 50 ± 2.01 µg/mL in 0.5% DMSO (Ahmad et al., 2015). In a recent study, Palmieri et al. (2019) evaluated the methanolic extract on selected 44 genes of human colon adenocarcinoma cell line (HCA-7) and the expression levels are quantified with RT-PCR. The purified berberine and crude extract of berberine from plant extract treatment resulted in downregulation of 33 genes. These findings suggest that the berberine from the plant extract has antiproliferative activity against human colon adenocarcinoma cell line. 18.3.3 ANTIOXIDANT ACTIVITY The T. cordifolia was evaluated for antioxidant activity in diabetic rats induced by alloxan. In this study, the plant extract 500 mg/kg was fed orally for 40 days. The levels of catalase, glutathione peroxidase, and superoxide dismutase in liver were decreased when compared with normal rats (Sivakumar and Rajan, 2010). In another study, the antioxidant activity was evaluated for T. cordifolia ethanolic extract in N-nitroso diethyl amine-induced liver cancer in Wistar rats. The first group was administered with normal saline (0.9%). The second and third groups were cancer-induced models administered with phenobarbital and ethanol extract of T. cordifolia, respectively. The fourth group received only ethanolic extract of T. cordifolia. The enzymic, nonenzymic, and lipid peroxidation antioxidants are normal in case of liver cancer-induced animals (Jayaprakash et al., 2015). 18.3.4 T. CORDIFOLIA ROLE IN TREATMENT OF CHRONIC BRONCHITIS The hydroalcoholic extract of T. cordifolia modulates proinflammatory mediators, redox signaling, and oxidative stress in asthma of BALB/c mice models. The mice were sensitized using ovalbumin intraperitoneally at 0 and 14 days followed by intranasal administration at 24 and 27 days to induce asthma. The mice were fed orally with T. cordifolia extract and dexamethasone from day 15 onward up to 23 days. The treated mice showed increase in oxidative stress parameters such as catalase, glutathione peroxidase, superoxide dismutase, glutathione reductase while decrease in eosinophil

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count, peroxidase, protein carbonyl content, myeloperoxidase, NO release, and IgE content. In addition to this there is a reduction in levels of pJNK, COX-2, iNOS, and ICAM-1. These results indicate that the T. cordifolia extract has therapeutic potential for the management of oxidative stress, redox signaling, and proinflammatory mediator release in asthma models (Tiwari et al., 2014). In a recent study, Kumar (2018) found that the T. cordifolia improves lung function in case of chronic bronchitis patients and also improves the quality of life. The chronic bronchitis patients with age group between 18 and 70 years were selected and a randomized, single-blind placebo-controlled study was conducted. In this clinical trial study, the patients were divided into test and placebo group and it was found that the test group showed improvement in breathlessness, expectoration, cough, and wheezing compared with the placebo group. The quality of life also improved in test compared to the placebo group. 18.3.5 NEUROPROTECTIVE ACTIVITY The neuroprotective role of T. cordifolia was investigated in Parkinson’s disease animal models. In this study the disease was induced by intracerebral injection of 6-hydroxy dopamine (8 µg). The rats were administered with 200–400 mg/kg of plant extract orally for 30 days. It was found that the dopamine and complex I activity levels were increased and also reduced oxidative stress results in neuroprotective activity in diseased model rats compared with control group (Kosaraju et al., 2014). In another study, the differentiation and senescence induced by T. cordifolia was investigated in neuroblastoma cells. Further, this study investigated the anticancer activity in human neuroblastoma cell line. The extract-treated cells showed expression of markers NeuN, MAP-2, and NF200 in neuroblastoma cells. The senescence markers Rel A and mortalin expression induced the senescence and pro-apoptosis pathway, while the expression of Bcl-xl marker was decreased (Mishra and Kaur, 2015). Sharma et al. (2020) investigated the neuroprotective role of butanol extract of T. cordifolia in both in-vitro and in-vivo model systems. The butanol extract showed activity in protecting the hippocampal neurons and prevention of cognition, anxiety, and motor deficits in glutamate-induced excitotoxicity. The compound tinosporicide isolated from T. cordifolia showed neuro-protective role in neurodegeneration umder in-vitro conditions.

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CARDIOPROTECTIVE ACTIVITY

Sharma et al. (2011) investigated the T. cordifolia cardioprotective activity in CaCl2-induced arrythmia. The animals were fed with 150–400 mg/kg body weight and a few parameters were evaluated using standard drug verapamil. The results found the normalized PQRST waves, ventricular, and atrial fibrillation were controlled in both verapamil and alcoholic extract of T. cordifolia. Apart from these, the plant extract decreased serum sodium, calcium levels and increased potassium levels in experimental rats. 18.3.7 ANTI-INFLAMMATORY ACTIVITY The extracted sample and market sample of T. cordifolia were evaluated for anti-inflammatory activity in edema models. The first group received extracted sample, the second group was administered with 50 mg/kg of market sample, and the third group received tap water. The results were compared with control and found that the first group and second group showed 33.06% and 11.71% reduction in edema (Patgiri et al., 2014). The anti-inflammatory activity of chloroform extract of Tinospora cordifolia was evaluated in LPS-induced inflammation. The macrophages RAW264.7 are preincubated with T. cordifolia and the expressions of TNF-α, COX-2, and iNOS genes were evaluated. It was found that the p38-MAPK levels were reduced and the NF-κB level was increased and thus it resulted in anti-inflammatory activity (Philip et al., 2018). The dry leaf extracts of T. cordifolia were investigated for both antioxidant and anti-inflammatory activities in THP-1 cells. The lipopolysaccharide and arachidonic acid-activated cells were used to evaluate the activities of the plant extract. The reactive oxygen species were monitored using confocal microscopy and catalase enzyme activity by quantitative RT-PCR. The protein levels and TNF-α in monocytic cells are measured by qRT-PCR. The immunoblotting and confocal microscopy were used to measure the IκB, P-IκB, and NF-κB translocation levels in cells. The water and alcohol extracts of T. cordifolia reduced ROS levels in THP-1 cells. The reduced levels of TNF-α and decreased levels of NF-κB in THP-1 cells result in anti-inflammatory activity (Reddi and Tetali, 2019).

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18.3.8 APHRODISIAC ACTIVITY The T. cordifolia aqueous extract of stem 400 mg/kg was fed to rats and it showed aphrodisiac property in Wistar albino male rats by increasing its number of mounts and mating performance (Wani et al., 2011). 18.3.9 ANDROGENIC ACTION The androgenic activity was evaluated for T. cordifolia in LNCaP prostate cancer cell line. The cell lines treated with T. cordifolia extract showed dose-dependent action on LNCaP cells and found that there is an increase of proliferation by 2.5-fold compared with dihydrotestosterone. The antiandrogen flutamide coincubated with T. cordifolia or dihydrotestosterone reversed the stimulation of prostate-specific antigen. The results showed that the extract has stimulation activity on prostate cells (Kapur et al., 2009). 18.3.10 IMMUNOMODULATORY ACTIVITY The T. cordifolia aqueous extract was evaluated for immunomodulatory activity on macrophages isolated from male albino mice (Sengupta et al., 2011). In this study, the swiss albino male animals were taken and divided into four groups. The first group was given isotonic solution (0.1 mL sterile) and the second group treated with CCl4 (0.5 mL/kg) for 7 days. The third and fourth groups were treated with 40 mg/kg T. cordifolia extract, but the fourth was treated with CCl4 for last 7 days. In case of CCl4-treated mice, there is an increase in the number of altered macrophages compared with the mice treated with T. cordifolia extract. The levels of altered macrophages, NO release, cell adhesion, DNA fragmentation, and phagocytic activity came to closer with the normal group (Sengupta et al., 2011). 18.3.11

GASTROPROTECTIVE EFFECT

The bioactive compound epoxy clerodane diterpene extracted from T. cordifolia was evaluated for the gastroprotective effect in gastric ulcer rat models. The gastric ulcer was induced by indomethacin in Wistar albino rats and the parameters ulcerative index and myeloperoxidase activities were measured. The bioactive compound was given as different doses ranging from 12.5 to 200 mg/kg for

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antiulcer activity and it was found that the 50 mg/kg showed a significant effect. The mucosal lesions were reduced by 91.8% and 77.39% in epoxy clerodane diterpene and omeprazole-treated groups, respectively. The ulcerative index and myeloperoxidase activities were reduced in the extract-treated group. The bioactive compound epoxy clerodane diterpene increased the levels of PGE2, IL-10, IL-4, EGF, and VEGF factors (Antonisamy et al., 2014). The antiulcer activity and antidiarrhoeal activity was evaluated for T. cordifolia in rat models. The castor oil and magnesium sulfate were used to induce diarrhoea and the parameters like onset of stools, number of wet stools, onset of diarrhoea, total number, and weight of the stools were evaluated. The extract showed a dose-dependent antidiarrhoeal effect by reducing the number of total stools. Further, the antiulcer activity was evaluated by inducing ethanol and pylorus ligation. The results showed that there is a reduction in ulcerative index, decrease in total acidity, gastric volume, and increase in gastric pH (Kaur et al., 2014). 18.3.12 ANALGESIC ACTIVITY The T. cordifolia was evaluated for its analgesic activity in albino rats. The animals were divided into three groups for analgesic activity. The first group was administered with 0.4 mL distilled water, the second group administered with 300 mg/kg, and the third group administered with pentazocine 10 mg/kg. The response time was increased and the number of writhes was decreased. The results showed a significant analgesic activity (Goel et al., 2014). 18.3.13 ANTIFERTILITY ACTIVITY The antifertility activity was evaluated for T. cordifolia extract using rat models. The rats were administered with plant extract 100 mg/rat/day for 60 days. The results found that the testes, ventral prostate, seminal vesicle, and epididymis weight were decreased. The male fertility (100%) was reduced due to reduction of sperm density and sperm motility (Gupta and Sharma, 2003). 18.3.14 ANTI-OSTEOPOROTIC AGENT The T. cordifolia was investigated for anti-osteoporotic potential in female Sprague Dawley rats. The benzoate: castor oil (1:4) vehicle was

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administered in female rats that are ovariectomized or sham operated. The remaining group rats were bilaterally ovariectomized and administered with estradiol (1 µg/day), Tinospora extract (10, 50 and 100 mg/kg) subcutaneously for four weeks. The bone mineral density was measured and the activity of serum markers like alkaline phosphatase, lipids, osteocalcin, and cross-laps were analyzed in serum. The T. cordifolia extract-treated rats showed an osteoprotective effect compared with ovariectomized controls. The cross-laps and osteocalcin levels were reduced and the ALP was higher in T. cordifolia extract-treated group. This study suggests that the extract has more potential as anti-osteoporotic agent (Kapur et al., 2008). 18.3.15 ANTIMALARIAL ACTIVITY The antimalarial activity was investigated for stem extracts of T. cordifolia along with root extracts of Cissampelos pareira ethanol extracts. The ethanolic extracts of both plants were administered in BALB/c mice and found that the plant extracts have inhibitory activity on propagation of rodent parasite Plasmodium berghei under in-vivo conditions compared with the control group that is untreated and devoid of extracts (Singh and Banyal, 2011). 18.3.16 HEPATOPROTECTIVE EFFECT The T. cordifolia extract and melatonin were investigated for hepatoprotective activity in experimental jaundice rat models. The jaundice in rats was induced by bile duct ligation and the parameters like microscopy, oxidative stress measurement, and lab tests were measured. The results showed that the melatonin and T. cordifolia have hepatoprotective activity and also reduce the cholestasis oxidative stress in humans (Stanca et al., 2011). 18.3.17 ANTIMICROBIAL ACTIVITY The T. cordifolia stem extract was investigated for its antibacterial activity against selected organisms. The ethanolic extract showed high antimicrobial activity against Escherichia coli, Proteus vulgaris and moderate activity was observed for Enterobacter faecalis. However, less inhibition was observed

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for Staphylococcus aureus Salmonella typhi and Serratia marcescens. The chloroform extract showed moderate activity against P. vulgaris, E. faecalis, E. coli, and less inhibition was observed for S. typhi. There is no inhibition for S. marcescens and S. aureus. The aqueous extract showed less activity against selected organisms (Jeyachandran et al., 2003). 18.3.18 ANTI-HYPERTRIGLYCERIDEMIA The biochemistry and metabolic alterations were evaluated in hypertriglyceridemia patients using T. cordifolia. The first group is administered with 3 g of T. cordifolia per day and another group administered with 850 mg of metformin per day. The study was carried out for 14 days and the blood samples were analyzed for lipid profiles. The abnormal metabolic regulation and oxidative damage were analyzed in urine samples by subjecting the sample to HPLC-QTOF-MS for quantification. The T. cordifolia extract reduced the levels of LDL, VLDL, and triglycerides to 133.25 ± 3.18, 31.85 ± 5.88, and 380.45 ± 17.44 mg/dL in hypertriglyceridemia patients. The HDL levels are increased to 47.50 ± 9.05 mg/dL. The results indicate that the plant extract reduced the levels of markers of hypertriglyceridemia in patients and it is due to modulation of amino acid, vitamin, biopterin butanoate, and antioxidative potential (Shirolkar et al., 2020). KEYWORDS • • • • • •

antimicrobial antioxidant berberine cordifolioside immunomodulatory Tinospora cordifolia

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REFERENCES

Ahmad, R.; Srivastava, A. N.; Khan, M. A. Evaluation of In-Vitro Anticancer Activity of Stem of Tinospora cordifolia Against Human Breast Cancer and Vero Cell Lines. J. Med. Plants. 2015, 3 (4), 33–37. Antonisamy, P.; Dhanasekaran, M.; Ignacimuthu, S.; Duraipandiyan, V.; Balthazar, J. D.; Agastian, P.; Kim, J. H. Gastroprotective Effect of Epoxy Clerodane Diterpene Isolated from Tinospora cordifolia Miers (Guduchi) on Indomethacin-Induced Gastric Ulcer in Rats. Phytomedicine 2014, 21 (7), 966–969. Bairy, K. L.; Rao, Y.; Kumar Das, S.; Kumar, K. B. Efficacy of Tinospora cordifolia on Learning and Memory in Healthy Volunteers: A Double-Blind, Randomized, PlaceboControlled Study. Iranian J. Pharmacol. Therapeut. 2004, 3 (2), 57–60. Balkrishna, A.; Pokhrel, S.; Varshney, A. Tinocordiside from Tinospora cordifolia (Giloy) May Curb SARS-CoV-2 Contagion by Disrupting the Electrostatic Interactions Between Host ACE2 and Viral S-Protein Receptor Binding Domain. Comb. Chem. High Throughput Screen. 2020. DOI: 10.2174/1386207323666201110 152615. Chi, S.; She, G.; Han, D.; Wang, W.; Liu, Z.; Liu, B. Genus Tinospora: Ethnopharmacology, Phytochemistry, and Pharmacology. Evid. Based Complement. Altern. Med. 2016. DOI: 10.1155/2016/9232593. Choudhary, N.; Siddiqui, M. B.; Azmat, S.; Khatoon, S. Tinospora cordifolia: Ethnobotany, Phytopharmacology and Phytochemistry Aspects. Int. J. Pharm. Sci. Res. 2013, 4 (3), 891–899. Dhanasekaran, M.; Baskar, A. A.; Ignacimuthu, S.; Agastian, P.; Duraipandiyan, V. Chemo Preventive Potential of Epoxy Clerodane Diterpene from Tinospora cordifolia Against Diethyl Nitrosamine-Induced Hepatocellular Carcinoma. Investig. New Drugs 2009, 27 (4), 347–355. Gao, L.; Cai, G.; Shi, X. β-Ecdysterone Induces Osteogenic Differentiation in Mouse Mesenchymal Stem Cells and Relieves Osteoporosis. Biol. Pharm. Bull. 2008, 31 (12), 2245–2249. Gaur, L. B.; Singh, S. P.; Gaur, S. C.; Bornare, S. S.; Chavan, A. S.; Kumar, S.; Ram, M. A Basic Information, Cultivation and Medicinal Use of Tinospora cordifolia. Pop. Kheti. 2014, 2 (3), 188–192. Goel, B.; Maurya, N. K. Aphrodisiac Herbal Therapy for Erectile Dysfunction. Archives of Pharm. Pract. 2020, 11 (1), 1–6. Goel, B.; Pathak, N.; Nim, D. K.; Singh, S. K.; Dixit, R. K.; Chaurasia, R. Clinical Evaluation of Analgesic Activity of Guduchi (Tinospora cordifolia) Using Animal Model. J. Clin. Diagnost. Res. 2014, 8 (8), 1–4. Gong, X.; Zhang, L.; Jiang, R.; Wang, C. D.; Yin, X. R.; Wan, J. Y. Hepatoprotective Effects of Syringin on Fulminant Hepatic Failure Induced by D-Galactosamine and Lipopolysaccharide in Mice. J. Appl. Toxicol. 2014, 34 (3), 265–271. Gupta, R.; Sharma, V. Ameliorative Effects of Tinospora cordifolia Root Extract on Histopathological and Biochemical Changes Induced by Aflatoxin-B1 in Mice Kidney. Toxicol. Int. 2011, 18 (2), 94–98. Gupta, R. S.; Sharma, A. Antifertility Effect of Tinospora cordifolia (Willd.) Stem Extract in Male Rats. Indian J. Exp. Biol. 2003, 41 (8), 885–889.

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Jagetia, G. C.; Rao, S. K. Evaluation of the Antineoplastic Activity of Guduchi (Tinospora cordifolia) in Ehrlich Ascites Carcinoma Bearing Mice. Biol. Pharm. Bull. 2006, 29 (3), 460–466. Jayaprakash, R.; Ramesh, V.; Sridhar, M. P.; Sasikala, C. Antioxidant Activity of Ethanolic Extract of Tinospora cordifolia on N-Nitrosodiethylamine (Diethylnitrosamine) Induced Liver Cancer in Male Wister Albino Rats. J. Pharm. Bioallied Sci. 2015, 7 (Suppl 1), S40–S45. Jeyachandran, R.; Xavier, T. F.; Anand, S. P. Antibacterial Activity of Stem Extracts of Tinospora cordifolia (Willd) Hook. f & Thomson. Anc. Sci. Life. 2003, 23 (1), 40–43. Kapur, P.; Jarry, H.; Wuttke, W.; Pereira, B. M. J.; Seidlova-Wuttke, D. Evaluation of the Anti Osteoporotic Potential of Tinospora cordifolia in Female Rats. Maturitas 2008, 59 (4), 329–338. Kapur, P.; Pereira, B. M. J.; Wuttke, W.; Jarry, H. Androgenic Action of Tinospora cordifolia Ethanolic Extract in Prostate Cancer Cell Line LNCaP. Phytomedicine 2009, 16 (6–7), 679–682. Kaur, M.; Singh, A.; Kumar, B. Comparative Antidiarrheal and Antiulcer Effect of the Aqueous and Ethanolic Stem Bark Extracts of Tinospora cordifolia in Rats. J. Adv. Pharm. Technol. Res. 2014, 5 (3), 122–128. Kosaraju, J.; Chinni, S.; Roy, P. D.; Kannan, E.; Antony, A. S.; Kumar, M. S. Neuroprotective Effect of Tinospora cordifolia Ethanol Extract on 6-Hydroxy Dopamine Induced Parkinsonism. Indian J. Pharmacol. 2014, 46 (2), 176–180. Kumar, D. V.; Geethanjali, B.; Avinash, K. O.; Kumar, J. R.; Basalingappa, K. M. Tinospora cordifolia: The Antimicrobial Property of the Leaves of Amruthaballi. J. Bacteriol. Mycol. 2017, 5, 363–371. Kumar, R. A Randomized Study of Effect of Tinospora cordifolia in Chronic Bronchitis Patients. IOSR J. Dental Med. Sci. 2018, 17 (7), 5–10. Kumar, V.; Mahdi, F.; Chander, R.; Husain, I.; Khanna, A. K.; Singh, R.; Saxena, J.; Mahdi, A.; Singh, R. K. Tinospora cordifolia Regulates Lipid Metabolism in Alloxan Induced Diabetes in Rats. Int. J. Pharm. Life Sci. 2013, 4, 3010–3017. Li, M.; Qingxiang, H.; Lingli, X.; Mei, Z.; Dan, L.; Yongwang, L. Treatment with Tinosporaside Attenuates the Uterine Fibroid by Stimulating the Apoptosis. Int. J. Pharmacol. 2019, 15 (1), 50–55. Mishra, R.; Kaur, G. Aqueous Ethanolic Extract of Tinospora cordifolia as a Potential Candidate for Differentiation-Based Therapy of Glioblastomas. PLoS One 2013, 8 (10), e78764. DOI: 10.1371/journal.pone.0078764. Mishra, R.; Kaur, G. Tinospora cordifolia Induces Differentiation and Senescence Pathways in Neuroblastoma Cells. Mol. Neurobiol. 2015, 52 (1), 719–733. Nadig, P. D.; Revankar, R. R.; Dethe, S. M.; Narayanswamy, S. B.; Aliyar, M. A. Effect of Tinospora cordifolia on Experimental Diabetic Neuropathy. Indian J. Pharmacol. 2012, 44 (5), 580–583. Palmieri, A.; Scapoli, L.; Iapichino, A.; Mercolini, L.; Mandrone, M.; Poli, F.; Gianni, A. B.; Baserga, C.; Martinelli, M. Berberine and Tinospora cordifolia Exert a Potential Anticancer Effect on Colon Cancer Cells by Acting on Specific Pathways. Int. J. Immunopathol. Pharmacol. 2019, 33, 1–10. Panchabhai, T. S.; Kulkarni, U. P.; Rege, N. N. Validation of Therapeutic Claims of Tinospora cordifolia: A Review. Phytother. Res. 2008, 22 (4), 425–441.

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Patel, A.; Bigoniya, P.; Singh, C. S.; Patel, N. S. Radioprotective and Cytoprotective Activity of Tinospora cordifolia Stem Enriched Extract Containing Cordifolioside-A. Indian J. Pharmacol. 2013, 45 (3), 237–243. Patel, M. B.; Mishra, S. M. Hypoglycaemic Activity of Alkaloidal Fraction of Tinospora cordifolia. Phytomedicine 2011, 18 (12), 1045–1052. Patel, M. B.; Mishra, S. M. Magnoflorine from Tinospora cordifolia Stem Inhibits α-Glucosidase and Is Anti Glycaemic in Rats. J. Funct. Foods. 2012, 4 (1), 79–86. Patgiri, B.; Umretia, B. L.; Vaishnav, P. U.; Prajapati, P. K.; Shukla, V. J.; Ravishankar, B. Anti-Inflammatory Activity of Guduchi Ghana (Aqueous Extract of Tinospora Cordifolia Miers.). Ayu. 2014, 35 (1), 108–110. Philip, S.; Tom, G.; Vasumathi, A. V. Evaluation of the Anti-Inflammatory Activity of Tinospora cordifolia (Willd.) Miers Chloroform Extract—A Preclinical Study. J. Pharm. Pharmacol. 2018, 70 (8), 1113–1125. Reddi, K. K.; Tetali, S. D. Dry Leaf Extracts of Tinospora cordifolia (Willd.) Miers Attenuate Oxidative Stress and Inflammatory Condition in Human Monocytic (THP-1) Cells. Phytomedicine 2019, 61, 152831. DOI: 10.1016/j.phymed.2019.152831. Saeed, M.; Naveed, M.; Leskovec, J.; Kakar, I.; Ullah, K.; Ahmad, F.; Chao, S. Using Guduchi (Tinospora cordifolia) as an Eco-Friendly Feed Supplement in Human and Poultry Nutrition. Poult. Sci. 2020, 99 (2), 801–811. Saha, S.; Ghosh, S. Tinospora cordifolia: One Plant, Many Roles. Anc. Sci. Life. 2012, 31 (4), 151–159. Sangeetha, M. K.; Priya, C. M.; Vasanthi, H. R. Anti-Diabetic Property of Tinospora cordifolia and Its Active Compound Is Mediated Through the Expression of Glut-4 in L6 Myotubes. Phytomedicine 2013, 20 (3–4), 246–248. Sengupta, M.; Sharma, G. D.; Chakraborty, B. Effect of Aqueous Extract of Tinospora cordifolia on Functions of Peritoneal Macrophages Isolated from CCl4 Intoxicated Male Albino Mice. BMC Complement. Altern. Med. 2011, 11 (1), 1–9. Sharma, A.; Kalotra, S.; Bajaj, P.; Singh, H.; Kaur, G. Butanol Extract of Tinospora cordifolia Ameliorates Cognitive Deficits Associated with Glutamate-Induced Excitotoxicity: A Mechanistic Study Using Hippocampal Neurons. Neuromol. Med. 2020, 22 (1), 81–99. Sharma, A. K.; Kishore, K.; Sharma, D.; Srinivasan, B. P.; Agarwal, S. S.; Sharma, A.; Jatav, V. S. Cardioprotective Activity of Alcoholic Extract of Tinospora cordifolia (Willd.) Miers in Calcium Chloride-Induced Cardiac Arrhythmia in Rats. J. Biomed. Res. 2011, 25 (4), 280–286. Sharma, P.; Dwivedee, B. P.; Bisht, D.; Dash, A. K.; Kumar, D. The Chemical Constituents and Diverse Pharmacological Importance of Tinospora cordifolia. Heliyon 2019, 5 (9), e02437. DOI: 10.1016/j.heliyon.2019.e02437. Sharma, U.; Bala, M.; Kumar, N.; Singh, B.; Munshi, R. K.; Bhalerao, S. Immunomodulatory Active Compounds from Tinospora cordifolia. J. Ethnopharmacol. 2012, 141 (3), 918–926. Shirolkar, A.; Yadav, A.; Mandal, T. K.; Dabur, R. Intervention of Ayurvedic Drug Tinospora cordifolia Attenuates the Metabolic Alterations in Hypertriglyceridemia: A Pilot Clinical Trial. J. Diabetes Metab. Disord. 2020, 19 (2), 1367–1379. Singh, D.; Chaudhuri, P. K. Chemistry and Pharmacology of Tinospora cordifolia. Nat. Prod. Commun. 2017, 12 (2). DOI: 10.1177/1934578X1701200240. Singh, V.; Banyal, H. S. Antimalarial Effect of Tinospora cordifolia (Willd.) Hook. f. & Thoms and Cissampelos pareira L. on Plasmodium berghei. Curr. Sci. 2011, 101 (10), 1356–1358.

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Sivakumar, V.; Rajan, M. D. Antioxidant Effect of Tinospora cordifolia Extract in AlloxanInduced Diabetic Rats. Indian J. Pharm. Sci. 2010, 72 (6), 795–798. Stanca, M. H.; Nagy, A.; Toşa, M.; Vlad, L. Hepatoprotective Effects of Orally Administered Melatonin and Tinospora cordifolia in Experimental Jaundice. Chirurgia 2011, 106 (2), 205–210. Thippeswamy, G.; Sheela, M. L.; Salimath, B. P. Octacosanol Isolated from Tinospora cordifolia Downregulates VEGF Gene Expression by Inhibiting Nuclear Translocation of NF-κB and Its DNA Binding Activity. Eur. J. Pharmacol. 2008, 588 (2–3), 141–150. Tiwari, M.; Dwivedi, U. N.; Kakkar, P. Tinospora cordifolia Extract Modulates COX-2, iNOS, ICAM-1, Pro-Inflammatory Cytokines and Redox Status in Murine Model of Asthma. J. Ethnopharmacol. 2014, 153 (2), 326–337. Tiwari, P.; Nayak, P.; Prusty, S. K.; Sahu, P. K. Phytochemistry and Pharmacology of Tinospora cordifolia: A Review. Syst. Rev. Pharm. 2018, 9 (1), 70–78. Upadhyay, A. K.; Kumar, K.; Kumar, A.; Mishra, H. S. Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi)–Validation of the Ayurvedic Pharmacology Through Experimental and Clinical Studies. Int. J. Ayurveda Res. 2010, 1 (2), 112–121. Vasanthi, H. R.; Kannan, S. M. Palmatine a Novel Anti-Adipogenic and Anti-Diabetic Alkaloid from an Indian Medicinal Plant Tinospora cordifolia. FASEB J. 2012. DOI: 10.1096/fasebj.26.1_supplement.112.8. Wani, J. A.; Achur, R. N.; Nema, R. K. Phytochemical Screening and Aphrodisiac Property of Tinospora cordifolia. Int. J. Pharm. Clin. Res. 2011, 3 (2), 21–26. Yuan, N. N.; Cai, C. Z.; Wu, M. Y.; Su, H. X.; Li, M.; Lu, J. H. Neuroprotective Effects of Berberine in Animal Models of Alzheimer’s Disease: A Systematic Review of Pre-Clinical Studies. BMC Complement. Altern. Med. 2019, 19 (1), 1–10.

CHAPTER 19

A Pharmacological View on the Medicinal Properties of the Ziziphus joazeiro Mart. RAFAEL VRIJDAGS CALADO, FELIPE LIMA PORTO,

JAMYLLE NUNES DE SOUZA FERRO,

TAYHANA PRISCILA MEDEIROS SOUZA, EMILIANO BARRETO, and

MARIA DANIELMA DOS SANTOS REIS*

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil Corresponding author. E-mail: [email protected]

*

ABSTRACT Ziziphus joazeiro is an important plant used in traditional medicine, industry, and agriculture. It is endemic of Caatinga, a Brazilian semiarid biome, known by the popular name of “juazeiro”. All parts of the plant are used to treat viral, fungal, and bacterial diseases. Phytochemical analysis indicated the presence of different types of terpenoids, flavonoids and phenolic acids in the extracts of the plant. Several studies showed the potent microbicidal effect of the juazeiro, confirming its popular use. Furthermore, extracts obtained from Z. joazeiro showed gastroprotective, antioxidant and immunomodulatory actions without exerting toxic effects. 19.1 INTRODUCTION Ziziphus joazeiro Mart. is popularly known in Brazil as “juazeiro,” “juábabão,” “juá de boi,” “joazeiro,” and “juá.” This tree of the Rhamnaceae family is an endemic of Caatinga, a Brazilian semiarid biome, which extends Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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across the northeast of Brazil to the north part of the Minas Gerais State (de Oliveira et al., 2012; Andrade et al., 2020). The Z. joazeiro produces an edible yellow fruit known as “juá,” which presents an ovoid shape with one seed surrounded by a mucilaginous and sweet white pulp; it is a rich source of fibers and phenolic compounds (de Lima Oliveira et al., 2020). In Brazilian folk medicine, the extracts of the bark, leaves, inner bark, and roots of this plant are used for the treatment of several maladies, such as stomach pain, poor digestion, constipation, gastric ulcers, cough, asthma, pneumonia, tuberculosis, throat inflammation, influenza, bronchitis, head injuries, fever, bacterial infection, general pain, caries, gingivitis, oral candidiasis, dandruff, scabies, seborrheic dermatitis, itching, skin problems, superficial mycoses, hepatic and cardiac tonic, diuretic, and other purposes (de Albuquerque et al., 2007; Cruz et al., 2007; Coelho et al., 2011; Brito et al., 2015; Santos et al., 2018; Andrade et al., 2020). Additionally, a product derived from Z. joazeiro is also used in the manufacturing of cosmetics, shampoos, and toothpaste, its barks are triturated and used for tooth brushing, and the fruits are used to feed animals mainly in periods of drought (Barbosa Junior et al., 2015; Andrade et al., 2019a). 19.2 BIOACTIVES Phytochemical analyses of the bark and stem of the Z. joazeiro indicated the abundant presence of triterpenoids saponins, betulinic acid, lupeol, caffeine, and the alkaloid amphibine-D (Schühly et al., 2000; de Albuquerque et al., 2007; Gomes et al., 2016). It was also reported that the aqueous extracts of the stem bark and leaves showed catechin, myricetin, quercetin, saponin derivatives, rutin, ramnazin, phenolic acid dihydroxybenzoic acid pentoside, and the nitrogen compound 5-allyl-1-(2,3,4-tris-O-benzoylpentafuranosyl)2,4(1H,3H)–pyrimidinedione (Andrade et al., 2019b, 2020). Moreover, other important phenolic compounds like gallic acid, chlorogenic acid, caffeic acid, ellagic acid, epicatechin, isoquercitrin, and quercitrin have been identified in the hydroalcoholic extract of the leaves Z. joazeiro using high-performance liquid chromatography (HLPC-DAD) (Brito et al., 2015). In the dichloromethane extract of the stem bark beyond already wellknown phytochemical constituents, it was identified a new lupane-type triterpene named methylbetulinate, and two ceanothane-type triterpenes named methylceanothate and epigouanic acid (Leal et al., 2010). The extract of the fruit (pulp) was identified in different types of flavanols, flavonols,

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and phenolic acids as free and conjugated phenolic compounds (de Lima Oliveira et al., 2020). 19.3 PHARMACOLOGY 19.3.1 ANTIHELMINTIC ACTION The helminticide capacity of the Z. joazeiro was observed against nematode eggs and larvae obtained from the goat faeces. The hydroethanolic, hexane, aqueous extracts, and a saponin fraction of the bark inhibited the hatching of the nematode eggs but did not interfere in the larvae motility and migration (Gomes et al., 2016). 19.3.2 ANTIOXIDANT EFFECTS The Z. joazeiro pulp had antioxidant action when evaluated by different methods, such as in ferric reducing antioxidant power (FRAP), 2,2-di-phenyl1-picrylhydrazyl (DPPH) radical scavenging, and oxygen radical absorbance capacity assays; however, the pulp’s antioxidant power drastically decreased after gastrointestinal digestion (de Lima Oliveira et al., 2020). On the other hand, the aqueous extract of the inner bark of the plant had low antioxidant capacity in vitro (Alviano et al., 2008). 19.3.3 GASTROPROTECTION The hydroalcoholic extract of the leaves prevented gastric lesions as maintained the epithelial barrier in acute gastritis murine models induced by indomethacin, absolute, or acidified ethanol (Brito et al., 2020). 19.3.4 IMMUNOMODULATORY ACTIVITY The betulinic acid extracted from the bark of the Z. joazeiro showed immunomodulatory activity on macrophages and lymphocytes. The addition of an amide in the C-28 of the lupane backbone of betulinic acid potentialized its immunomodulatory effect, with inhibition of nitric oxide and tumor necrosis factor-α production by macrophages in a mechanism associated with

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inhibition of activation of the nuclear factor kappa B. In lymphocytes, the betulinic acid alone or in synergy with dexamethasone inhibited the in vitro proliferation of lymphocytes and the secretion of pro- and anti-inflammatory cytokines (Meira et al., 2017). The authors also tested the betulinic acid effects on in vivo experiments and observed that treatment prevented the death of animals submitted to the endotoxic shock induced with LPS and reduced paw oedema in a murine model of delayed-type hypersensitivity reaction with bovine serum albumin (Meira et al., 2017). 19.3.5

MICROBICIDE ACTIVITY

The aqueous extract of the stem of Z. joazeiro had in vitro antifungal effect against Candida albicans (ATCC strain), Candida guilliermondii (both ATCC strain line and clinical isolate), Trichophyton rubrum, Fonsecaea pedrosoi, and Cryptococcus neoformans clinical isolates (Cruz et al., 2007). The infusion and the decoction of the stem bark and the leaves also inhibited the in vitro growth of the C. neoformans (Barbosa Junior et al., 2015). The aqueous extract of the stem and the leaves from Z. joazeiro also presented inhibitory effects on biofilm growth of Streptococcus mutans, Staphylococcus epidermidis, and Pseudomonas aeruginosa (Andrade et al., 2019a). It was also showed that the extract from the leaves reduced the biofilm formation of Enterococcus faecalis while the extract from the stem bark prevented the growth of C. albicans and C. tropicalis biofilms. Interestingly, the hydroethanolic extract of the leaves did not show bactericidal activity, but it had a synergistic effect when used together with the standard drugs gentamicin and amikacin against Enterobacter aerogenes and with gentamicin against Staphylococcus aureus (Brito et al., 2015). The authors suggested that the saponins present in the extract could alter the structure of the bacterial cell membrane, allowing the entrance of the drugs with proper bactericide action. In line with these findings, a saponin-rich compound isolated from the bark alone did not have a bactericidal effect on P. aeruginosa, Escherichia coli, S. aureus, Bacillus subtilis, and Salmonella choleraesuis; however, it showed antifungal activity against C. albicans and Aspergillus niger (Ribeiro et al., 2013). The antibacterial effect of the Z. joazeiro was also verified against known species involved in oral infections. Alviano et al. (2008) observed that the aqueous extract of this plant inhibited the growth of Prevotella intermedia, Porphyromonas gingivalis, Fusobacterium nucleatum, S. mutans, and

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Lactobacillus casei, but it was not effective in inducing bacterial killing and artificial biofilm formation. Leal et al. (2010) showed that the methylceanothate isolated from dichloromethane extract of the stem bark had antibacterial activity against clinical and reference strains of methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus. 19.3.6

PROTOZOCIDAL ACTIVITY

The derivatives from the betulinic acid extracted from the bark of Z. joazeiro showed activity against Trypanosoma cruzi (Y strain), by inducing trypomastigote morphology alteration leading to necrotic death and by inhibiting the macrophage infection in vitro (Meira et al., 2016). In another study, it was shown that the aqueous extract of the stem bark of this plant was effective in inhibiting in vitro the promastigote activities of Leishmania braziliensis and L. infantum; however, this effect was not related to the presence of betulinic acid in the extract (Andrade et al., 2019b). Conversely, the hydroalcoholic extract of the leaves did not show clinically relevant effects on T. cruzi epimastigotes (CLB5 clone), L. braziliensis (MHOM/ BR/75/M2903), and L. infantum ((MCAN/ES/92/BCN83) promastigotes (Brito et al., 2015). 19.3.7 TOXICITY The hydroalcoholic extract of the Z. joazeiro leaves showed low toxicity in murine fibroblasts with an IC50 of 119.34 µg/mL (Brito et al., 2015). In contrast, the aqueous extract and the saponin fraction of the bark diminished the viability of Vero cells in a concentration-dependent manner, with the IC50 values of 0.75 and 0.20 mg/mL, respectively (Gomes et al., 2016). In an acute toxicity assay in vivo, the oral administration of the aqueous extract from the inner bark (1–4 or 5 g/kg) did not cause weight loss or mortality in mice (Alviano et al., 2008). Accordingly, the acute oral treatment with the hydroalcoholic extract of the leaves (2000 mg/Kg) did not cause toxicity, mortality, or behavioral alterations in mice (Brito et al., 2020).

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KEYWORDS

• • • • •

Ziziphus joazeiro bioactive compounds juazeiro folk medicine Caatinga

REFERENCES Alviano, W. S.; Alviano, D. S.; Diniz, C. G.; Antoniolli, A. R.; Alviano, C. S.; Farias, L. M.; et al. In Vitro Antioxidant Potential of Medicinal Plant Extracts and Their Activities Against Oral Bacteria Based on Brazilian Folk Medicine. Arch. Oral Biol. 2008, 53 (6), 545–552. Andrade, J. C.; da Silva, A. R. P.; dos Santos, A. T. L.; Freitas, M. A.; de Matos, Y. M. L. S.; Braga, M. F. B. M.; et al. Chemical Composition, Antiparasitic and Cytotoxic Activities of Aqueous Extracts of Ziziphus joazeiro Mart. Asian Pac. J. Trop. Biomed. 2019b, 9 (5), 222–226. Andrade, J. C.; da Silva, A. R. P.; Freitas, M. A.; de Azevedo Ramos, B.; Freitas, T. S.; Franz de Assis, G.; et al. Control of Bacterial and Fungal Biofilms by Natural Products of Ziziphus joazeiro Mart. (Rhamnaceae). Comput. Immunol. Microbiol. Infect. Dis. 2019a, 65, 226–233. Andrade, J. C.; Dos Santos, A. T.; Da Silva, A. R.; Freitas, M. A.; Afzal, M. I.; Gonçalo, M. I.; et al. Phytochemical Characterization of the Ziziphus joazeiro Mart. Metabolites by UPLC-QTOF and Antifungal Activity Evaluation. Cell. Mol. Biol. 2020, 66 (4), 127–132. Barbosa Junior, A. M.; Mélo, D. M. D.; Almeida, F. D.; Trindade, R. Estudo comparativo da susceptibilidade de isolados clínicos de Cryptococcus neoformans (Sanfelice, 1895) frente a alguns antifúngicos de uso hospitalar e extratos vegetais obtidos de plantas medicinais da região semiárida sergipana. Rev. Bras. Plantas Med. 2015, 17 (1), 120–132. Brito, S. M. O.; AOBPB, M.; De Oliveira, M. R. C.; Vidal, C. S.; de Lacerda Neto, L. J.; Ramos, A. G. B.; et al. Gastroprotective and Cicatrizing Activity of the Ziziphus joazeiro Mart. Leaf Hydroalcoholic Extract. J. Physiol. Pharmacol. 2020, 71 (3). DOI: 10.26402/ jpp.2020.3.14. Brito, S. M.; Coutinho, H. D.; Talvani, A.; Coronel, C.; Barbosa, A. G.; Vega, C.; et al. Analysis of Bioactivities and Chemical Composition of Ziziphus joazeiro Mart. Using HPLC–DAD. Food Chem. 2015, 186, 185–191. Coelho, M. D. F. B.; Maia, S. S.; Oliveira, A. K.; Diógenes, F. E. Allelopathic Activity of Juazeiro Seed Extract. Hort. Bras. 2011, 29 (1), 108–111. Cruz, M. C. S.; Santos, P. O.; Barbosa Jr, A. M.; De Mélo, D. L. F. M.; Alviano, C. S.; Antoniolli, A. R.; et al. Antifungal Activity of Brazilian Medicinal Plants Involved in Popular Treatment of Mycoses. J. Ethnopharmacol. 2007, 111 (2), 409–412.

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De Albuquerque, U. P.; De Medeiros, P. M.; De Almeida, A. L. S.; Monteiro, J. M.; Neto, E. M. D. F. L.; de Melo, J. G.; Dos Santos, J. P. Medicinal Plants of the Caatinga (Semi-Arid) Vegetation of NE Brazil: A Quantitative Approach. J. Ethnopharmacol. 2007, 114 (3), 325–354. de Lima Oliveira, P. M.; Dantas, A. M.; dos Santos Morais, A. R.; Gibbert, L.; Krüger, C. C. H.; dos Santos Lima, M.; et al. Jua Fruit (Ziziphus joazeiro) from Caatinga: A Source of Dietary Fiber and Bioaccessible Flavanols. Food Res. Int. 2020, 129, 108745. de Oliveira, A. K. D.; Coelho, M. D. F. B.; Maia, S. S. S.; Diógenes, F. É. P.; Medeiros Filho, S. (). Atividade alelopática de extratos de diferentes partes de juazeiro (Ziziphus joazeiro Mart.—Rhamnaceae). Acta Bot. Bras. 2012, 26 (3), 685–690. Gomes, D. C.; de Lima, H. G.; Vaz, A. V.; Santos, N. S.; Santos, F. O.; Dias, Ê. R.; et al. In Vitro Anthelmintic Activity of the Zizyphus joazeiro Bark Against Gastrointestinal Nematodes of Goats and Its Cytotoxicity on Vero Cells. Vet. Parasitol. 2016, 226, 10–16. Leal, I. C. R.; dos Santos, K. R. N.; Júnior, I. I.; Antunes, O. A. C.; Porzel, A.; Wessjohann, L.; Kuster, R. M. Ceanothane and Lupane Type Triterpenes from Zizyphus joazeiro–An Anti-Staphylococcal Evaluation. Planta Med. 2010, 76 (01), 47–52. Meira, C. S.; Barbosa-Filho, J. M.; Lanfredi-Rangel, A.; Guimarães, E. T.; Moreira, D. R. M.; Soares, M. B. P. Antiparasitic Evaluation of Betulinic Acid Derivatives Reveals Effective and Selective Anti-Trypanosoma cruzi Inhibitors. Exp. Parasitol. 2016, 166, 108–115. Meira, C. S.; do Espírito Santo, R. F.; Dos Santos, T. B.; Orge, I. D.; Silva, D. K. C.; Guimarães, E. T.; et al. Betulinic Acid Derivative BA5, a Dual NF-kB/Calcineurin Inhibitor, Alleviates Experimental Shock and Delayed Hypersensitivity. Eur. J. Pharmacol. 2017, 815, 156–165. Ribeiro, B. D.; Alviano, D. S.; Barreto, D. W.; Coelho, M. A. Z. Functional Properties of Saponins from Sisal (Agave sisalana) and Juá (Ziziphus joazeiro): Critical Micellar Concentration, Antioxidant and Antimicrobial Activities. Colloids Surf. A Physicochem. Eng. Asp. 2013, 436, 736–743. Santos, M. O.; Ribeiro, D. A.; Macêdo, D. G.; Macedo, M. J.; Macedo, J. G.; Lacerda, M. N. S.; et al. Medicinal Plants: Versatility and Concordance of Use in the Caatinga Area, Northeastern Brazil. Anais da Academia Brasileira de Ciências, 2018, 90 (3), 2767–2779. Schühly, W.; Heilmann, J.; Çalis, I.; Sticher, O. Novel Triterpene Saponins from Zizyphus joazeiro. Helv. Chim. Acta, 2000, 83 (7), 1509–1516.

CHAPTER 20

Phytochemistry and Pharmacological Potentialities of Syzygium caryophyllatum (L.) Alston KARUPPA SAMY KASI1, ANJANA SURENDRAN2, and RAJU RAMASUBBU1* Department of Biology, The Gandhigram Rural Institute (Deemed to be University) Gandhigram, Dindigul, Tamil Nadu, India

1

Department of Botany Arulmigu Palani Andavar Arts College for Women, Palani, Tamil Nadu, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Syzygium caryophyllatum L. is traditionally used to treat various diseases including diabetes mellitus, diarrhoea, dysentery, leucorrhoea, menorrhagia, piles, fever, skin diseases, and general debility. It is also used as antiemetic, anthelmintic, laxative, antioxidant and anti-inflammatory agent. The major chemical compounds isolated from the leaves were caryophyllene oxide, α-pinene, 4,8,13-duvatrene-1,3-diol, and cadin-4-en-10-ol, γ-gurjunenepoxide-(1), α-cadinol, 3,5,9-trimethyldeca-2,4,8-trien-1-ol, β-pinene and cis-lanceol, δ-cadinene and τ-muurolol. The fruits were reported titrable acidity of acids, total sugars, reducing sugars, non-reducing sugars, vitamin C, proteins, total anthocyanin. The essential oil of stem and leaves have been reported with considerable antimicrobial activities. The higher concentration of leaf extract has significant inhibitory action of DPPH radical scavenging activity. The volatile leaf oil was reported to possess antiinflammatory and anticarcinogenic activity. The bark extract possessed good antihyperglycaemic activity and the leaf essential oil and methanolic crude Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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extracts of bark, leaf, fruit pulp and the seed exhibited potential larvicidal activity against Aedes aegypti and Culex quinquefasciatus. 20.1

INTRODUCTION

Syzygium caryophyllatum is a medium-sized tree or larger shrub that belongs to the family Myrtaceae. This is usually growing up to 3–5-m-tall along the margin of evergreen forests or in open formations from 10 to 1500 asl elevations of the Western Ghats, India (Stalin and Swamy, 2018). This tree has also been reported in tropics and subtropics of the world including Africa, Asia, Australia, Malaysia, New Zealand, Sri Lanka, and western pacific regions (Biffin, 2005). Van Rheede (1678–1703) has recorded its name as njara in the Hortus Malabaricus (Manilal, 2003). The species has locally called as clovescented plum (English), jamun (Hindi), kshudra jambu (Sanskrit), bhumi jambu, kuru naval (Tamil) (Suma et al., 2020). The fruits of the species were reported as small, globose, and purple with higher pulpy juice. The ripened fruits were served as the principal diet for some birds such as red vented bulbul, red-whiskered bulbul, and green barbet (Stalin and Swamy, 2018). The seeds were used for making wine by fermentation (Geethika and Sabu, 2017). Various parts of this tree including bark, leaves, and fruits were used to cure various diseases, such as diabetes mellitus, diarrhea, leucorrhea, and skin diseases (Kala et al., 2016). Rice flakes were prepared by incorporating S. caryophyllatum fruit pulp which contained high antioxidant activity with the mucilage extracted from Neolitsea cassia had better physical, chemical, and organoleptic properties (Kasunmala et al., 2020). Harsha et al. (2005) reported that the bark extract of S. caryophyllatum was used in veterinary medicine to treat tympanitis in cattle. S. caryophyllatum is traditionally used to treat diabetes mellitus, diarrhea, dysentery, leucorrhea, menorrhagia, piles, fever, skin diseases, and general debility (Shilpa and Krishnakumar, 2018). It is also used as antiemetic, anthelmintic, laxative, antioxidant, and anti-inflammatory agent and also acted as antihyperglycaemic antibacterial and anticancer activities (Shilpa and Krishnakumar, 2018). The fruits and seeds of this tree have been utilized as edible and to provide energy by Paniya tribes of Waynad district, Kerala, India (Narayanan et al., 2011). The antidiabetic potentialities of fruits and seeds were recorded in the Ayurvedic system of medicine (Raj et al., 2016). The fruits of S. caryophyllatum consumed as fresh and used for making wine (Mundaragi et al., 2017). Savinaya et al. (2016) have reported that raw fruit and bark decoction of S. caryophyllatum was used for diabetes. The immature leaves of this tree were traditionally used by folklore practitioners to treat diarrhea, ulcers, stools

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with blood and mucous, wound, stomatitis (Parvathy et al., 2018). The decoction of seeds and bark was used in the ketoacidosis (DKA) (Ediriweera and Ratnasooriya, 2009). The root extract of S. caryophyllatum was used to treat inflammation in Sri Lankan traditional medicine (Heendeniya et al., 2018). 20.2

BIOACTIVES

Stalin and Sudhakar (2018) isolated essential oils from the leaves in two seasons (summer and winter), in which the winter season yielded 0.35% of oil with 55 compounds and the summer season yielded 0.2% with 129 compounds. In summer the major chemical compounds are caryophyllene oxide (10.72%), α-pinene (10.55%), 4,8,13-duvatrene-1,3-diol (10.44%), and cadin-4-en-10-ol (8.27%) followed by γ-gurjunenepoxide-(1) (5.93%), α-cadinol (4.6%), 3,5,9-trimethyldeca-2,4,8-trien-1-ol (4.11%), τ-muurolol, cis-lanceol β-pinene, and δ-cadinene and dominant phytocompounds recorded along with β-caryophyllene, α-muurolol, β-cis-ocimene, β-elemene, and calarene epoxide. The chemical compounds reported from winter (myristicin, α-cadinol) were used in essence industries and cosmetic preparation and also used for inducing aroma in confectionary industry. In addition, myristicin isolated from the essential oil of S. caryophyllatum has an efficient role in the treatment of nausea, cholera, diarrhea, stomach cramps, and anxiety (Martins et al., 2011). Bhuiyan et al. (2010) reported that the main compounds were cadinol, eugenol, caryophyllene, and eucalyptol from essential oil. Stalin and Swamy (2013) analyzed the chemical composition of volatile oil ofS. caryophyllatumin which 55 compounds were identified including α-cadinol (18.3%), myristicin (12.02%), δ-cadinene (8.4%), α-cadinol (6.65%), τ-cadinol (5.11%), β-caryophyllene (5.33%), β-cis-ocimene (2.53%), β-elemen-(2) (2.52%), diepi-alpha-cedrene epoxide (2.31%), β-cubebene (1.9%), ledol (1.81%), globulol (1.83%), germacrene d (1.77%), epicubenol (1.69%), (−)-isolongifolol (1.54%), methyl docosanoate (1.4%), α-caryophyllene (1.38%), viridiflorol (1.37%), cubenol (1.3%), linoleic acid ethyl ester (1.21%), germacrene b (1.15%), α-bulnesene (1.11%), cedrol (1.1%), α-curcumene (1.01%), bicyclogermacrene (1.02%), α-muurolene (1.5 β-Trans-oclrnene (0.34%), cubeban-11-ol (0.4%), copaene (0.64%), germacrene b (0.64%), rosifoliol (0.56%), α-eudesmol (0.51%), δ-guajene (0.52%), junipercamphor (0.5%), cycloheptane, 4-methylene-1-methyl-2-(2-methyl-1-propen-1-yl)-1vinyl-(0.47%), methyl ether ethyl oleate (0.45%), a-bergamotene (0.42%), spathulenol (0.37%), ledol (0.35%), β-cadinene (0.18%), methyl lignocerate (0.97%), α-amorphene (0.7%), methyl 18-ethylnonadecanoate (0.77%), n-caryophyllene oxide (0.3%), heptadecanoate (0.29%), α-cubebene (0.28%),

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α-muurolen (0.27%), globulol (0.25%), viridiflorol (0.23%), cubebol (0.21%), cadina-1,4-diene (0.19%), and linolenate-emethyl-e-phytol (0.3%) Soni and Dahiya (2014) investigated the phytocompounds of essential oil that consists of steroids, alkaloids, flavonoids, cardiac glycosides, tannins, saponins. Stalin and Swamy (2018) examined the phytoconstituents of fruit, leaves, bark, and seeds with higher content of phenol, flavonoids, and tannin. The methanol and water extract of leaf and barks of S. caryophyllatum reported with steroids, phenols, saponins, glycosides, and tannins (Shilpa and Krishnakumar, 2018). The tender leaves of S. caryophyllatum were reported to contain alkaloids, flavonoids, saponins, and carboxylic acid (Parvathy et al., 2018). Phytochemical investigation of leaves of S. caryophyllatum with different extracts indicated the presence of terpenoids, flavonoids, carbohydrates, phenolics, glycosides, amino acids, and flavonol (Subramanian et al., 2014). The fruits of S. caryophyllatum were reported titratable acidity of acids (0.770 mg/100 g), total sugars reducing sugars (37.70 mg/100 g), nonreducing sugars (30.40 mg/100 g), vitamin C (50 mg/100 g), proteins (3.37%), total anthocyanin (240.36 mg/L). Methanolic and aqueous extracts of fruit have 75.16 and 33.55 mg/100 g phenolics (Shilpa and Krishnakumar, 2015). Kala et al. (2016) identified both primary and secondary metabolites from fruit and seeds of S. caryophyllatum. The fructose was identified from the pulp, whereas sucrose and deoxyribose were detected from seeds. Asparagine was reported in pulp, and cystine, serine was obtained from seeds and dopaxanthin identified from seeds. The seed extract has been reported to contain linolenic acid, linoleic acid, and hexanoic acid. Whereas alpha licanic acid, stearic acid, alpha-linolenic acid, and decanoic acid were reported from the pulp. Likewise, the secondary metabolites including terpenoids, carotenoids, alkaloids, and carboxylic acid were isolated from pulp and seeds. From the pulp and seeds of S. caryophyllatum beta citronellal, betulin, lupulone, friedelin alpha vetivone, phytol, and isodonal were reported (Kala et al., 2016). Crocetin, a type of carotenoid has been reported from the pulp of S. caryophyllatum along with nicotine, and nornicotine, hydroquinidine, and ambellin reported from the seed. S. caryophyllatum was reported with various kinds of flavonoids with biological efficiencies (Kala et al., 2016). Parahydroxy benzoic acid, hydroxymethyl benzoic acid, ferulic acid, caffeic acid, gallic acid, and ferulic acid were isolated from pulp and seeds of S. caryophyllatum. Coumarins, a plant derived natural products have anticancer, anticonvulsant anti-inflammatory, and antibacterial activities, etc. (Jain and Joshi, 2012). Wedelolactone, xanthotoxol, xanthotoxin and anthatoxin, xanthatoxol and scopoletin were isolated from the pulp of S. caryophyllatum (Kala et al., 2016). They have expectorant, an antiinflammatory

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activity that prevents cholesterol deposition, and also recorded with several other pharmacological potentialities (Oakenfull, 1982; Ezeabara et al., 2014). Alkaloids, reducing sugars, flavanoids, tannins, saponins, steroids, triterpenoids, phenols, and glycosides were reported in S. caryophyllatum (Savithri et al., 2018). Mundaragi et al. (2017) reported that fruits of S. caryophyllatum have minerals phosphorus (42.14 mg), potassium (42.14 mg), copper (0.12 mg), iron (1.04), magnesium (19.83 mg), and zinc (0.15). The seeds of S. caryophyllatum contain serine, palmitic acid, and stearic acid, whereas fruits were reported with asparagine, cystine, aminobutyric acid, palmitic acid, and linolic acid (Suma et al., 2020). 20.3

PHARMACOLOGY

20.3.1 ANTIMICROBIAL ACTIVITY The essential oil of the stem and leaves of S. caryophyllatum have been reported with considerable antimicrobial activities (Hartwell, 1982). The essential oil isolated was proved with antibacterial efficiencies against six bacterial strains Bacillus cereus, Staphylococcus aureus, S. hominis, B. licheniformis, Aerococcus viridans, and Escherichia coli with a different zone of inhibition. Minimum inhibitory concentration was observed in A. viridans, B. cereus, and S. aureus (Stalin and Sudhakar, 2018). Ethyl acetate extract of S. caryophyllatum has been reported as an effective agent against four bacterial strains (Aeromonas hydeophila, S. aureus, Bacillus substillus, and Entercoccus faecalis) and three fungal strains (Aspergillus niger, Alternaria alternata, and Penicillium chrysogenum) (Annadurai et al., 2012). Saeed and Tariq (2008) revealed the antimicrobial activity of S. caryophyllatum essential oil against all bacterial isolates tested and maximum activity has recorded against Gram-positive and Gram-negative bacteria. Also, the essential oil was reported with higher activity against few plant and animal fungal pathogens (Rana et al., 2011). 20.3.2 ANTIOXIDANT ACTIVITY The higher concentration (400 µg/mL) of leaf extract has significant inhibitory action of DPPH radical scavenging activity in Syzygium cumini and Syzygium aromaticum (Annadurai et al., 2012). The flower buds of S. caryophyllatum have been reported to possess higher antioxidant activity (Gupta and Sharma, 2006). Soni and Dahiya (2014) revealed that the commercial essential oil of S. cayophyllatum confirmed good antioxidants through

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catalase (CAT), and reduced glutathione (GSH). Superoxide dismutase and glutathione-s-transferase. The extract isolated from fruit in methanol was used to determine the total antioxidant and free radical scavenging activities on 2,2-diphenyl-1-picrylhydrazyl (DPPH) with significant free radical scavenging ability (IC50 = 70.47 ± 2.0 μg/mL) and the antioxidant activity were reported as 454 ± 28.4 mg/g of ascorbic acid equivalent (Stalin and Swamy, 2013). 20.3.3 ANTICANCER ACTIVITY The volatile oil of S. caryophyllatum was reported to possess anti-inflammatory and anticarcinogenic activity (Zheng et al., 1992). Anticancer activity of leaf extract of S. caryophyllatum was tested against human liver carcinoma cell lines (HEP2) by using 3-(4, 5-dimethyl thiazol-2yl)-2, 5-diphenyl tetrazolium bromide (MTT) which showed maximum cell inhibition at higher concentration (1000 µg/mL) and the extract of S. caryophyllatum showed higher inhibition rate on HEP2 cell line compared to AML cells exhibited by S. cumini (Annadurai et al., 2012; Afify et al., 2011). 20.3.4 ANTIARTHRITIC POTENTIAL ACTIVITY Methanolic leaf extract of S. caryophyllatum was reported with antiarthritic potential due to its polyphenolic compounds, alkaloids, flavonoids, tannins, steroids, and phenols (Heendeniya et al., 2018). 20.3.5 ANTIHYPERGLYCAEMIC ACTIVITY The bark extract of S. caryophyllatum possess good antihyperglycaemic activity when the extract was subjected to alloxan-induced diabetic rats from the improvement of glucose tolerance in alloxan-induced diabetic rats to 1.00 g/kg (Anoja et al., 2013). 20.3.6

LARVICIDAL ACTIVITY

The leaf essential oil and methanolic extracts reported from fruit pulp, leaf, seed, and bark have showed efficient larvicidal activity against two mosquito vectors such as Aedes aegypti and Culex quinquefasciatus (Stalin and Swamy, 2013). The leaf essential oil of S. caryophyllatum has shown 100% mortality against fourth instar larvae at 400 ppm, whereas 200 ppm, 95%

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mortality recorded. The larvicidal activity was recorded as higher at higher concentration of leaf essential oil. Methanolic fruit pulp extract exhibited poor larvicidal activities when compared to the other three parts studied (Stalin and Swamy, 2013). Different chemical compound and their chemical structures isolated from S. caryophyllatum

α-cadinol

α-pinene

β-cisocomene

β-elemene

Calarene epoxide

Caryophyllene oxide

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Caryophyllene

Eugenol

τ Muurolol

Myrceti

KEYWORDS

• • • • • •

Syzygium caryophyllatum Evergreen tree Myrtaceae Menorrhagia Flavonoids Antioxidant

REFERENCES Afify, A. M.; Fayed, S. A.; Shalaby, E. A.; El Shemy, H. A. Syzygium cumini (pomposia) Active Principles Exhibit Potent Anticancer and Antioxidant Activities. Afr. J. Pharm. Pharmacol. 2011, 5 (9), 48–56. Annadurai, G.; Masilla, B. R. P.; Shekar, S. J.; Palanisami, E.; Puthiyapurayil, S.; Parida, A. K. Antimicrobial, Antioxidant, Anticancer Activities of Syzygium caryophyllatum (L.) Alston. Int. J. Green Pharm. 2012, 285–288. DOI: 10.4103/0973-8258.108210.

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Anoja, P.; Attanayake Kamani, A. P. W. J.; Chitra, P.; Lakmini, K. B. M. Study of Antihyperglycaemic Activity of Medicinal Plant Extracts in Alloxan-Induced Diabetic Rats. Anc. Sci. Life. 2013, 32 (4), 193–198. Bhuiyan, N. I.; Begum, J.; Nandi, N. C.; Akter, F. Constituents of the Essential Oil from Leaves and Buds of Clove [Syzygium caryophyllatum (L.) Alston]. Afr. J. Plant Sci. 2010, 4 (11), 451–454. Biffin, E. Sorting Out the Confusion: Phylogenetics of Large Genera and the Lessons from Syzygium (Myrtaceae). Aust. Biol. Resour. Study Biol. 2005, 30. Canberra: CSIRO Plant Industry. Ediriweera, E. R. H. S. S.; Ratnasooriya, W. D. A. Review on Herbs Used in the Treatment of Diabetes Mellitus by Sri Lankan and Traditional Physicians. Ayu. 2009, 30 (4), 373–391. Ezeabara, A. C.; Okeke, C. U.; Aziagba, B. O.; Ilodibia, C. V.; Emeka, A. N. Determination of Saponin Content of Various Parts of Six Citrus Species. Int. Res. J. Pure Appl. Chem. 2014, 4 (1), 137–143. Geethika, K.; Sabu, M. Pollination Biology of Syzygium caryophyllatum (L.) Alston (Myrtaceae). Int. J. Plant. Reprod. Biol. 2017, 9 (1), 69–72. DOI: 10.14787/ijprb.2017 9.1.69-72. Gupta, V. K.; Sharma, S. K. Plants as Natural Antioxidants. Nat. Prod. Rad. 2006, 5 (4), 326–334. Harsha, V. H.; Sripathy, V.; Hedge, G. K. Ethnoveterinary Practices in Uttara Kannada District of Karnataka. Indian J. Tradit. Knowl. 2005, 4, 253–258. Hartwell, J. L. Plant Used Anticancer; Quaterman Pub: M.A., 1982. Heendeniya, S. N.; Ratnasooriya, W. D.; Pathirana, R. N. In Vitro Investigation of Anti-Inflammatory Activity and Evaluation of Phytochemical Profile of Syzygium caryophyllatum. J. Pharmacogn. Phytochem. 2018, 7 (1), 1759–1763. Jain, P. K.; Joshi, H. Coumarin: Chemical and Pharmacological Profile. J. Appl. Pharm. Sci. 2012, 2 (6), 236–240. Kala, K.; Antony, V. T.; Sheemole, M. S.; Asha, S. Analysis of Bioactive Compounds Present in Syzygium caryophyllatum (L.) Alston Fruit. Int. J. Pharm. Sci. Rev. Res. 2016, 36 (1), 239–243. Kasunmala, I. G. G. Navaratne, S. B.; Wickramasinghe, I, Development of Syzygium caryophyllatum fruit Pulp Incorporated Rice Flakes, Vidyod. J. Sci. 2020, 23 (02), 31–41. Manilal K. S. Van Rheed’s Hortus Malabaricus English Edition with Annotation and Mordern Botanical Nomenclature; Vol. 5; University of Kerala, 2003; pp 99–101. Martins, C.; Doran, C.; Laires, A.; Rueff, J.; Rodrigues, A. S. Genotoxic and Apoptotic Activities of the Food Flavourings Myristicin and Eugenol in AA8 and X., RCC1 Deficient EM9 Cells. Food Chem. Toxicol. 2011, 49, 385–392. Mundaragi, A.; Devarajan, T.; Jeyabalan, S.; Bhat, S.; Hospet, R. Unexploited and Underutilized Wild Edible Fruits of Western Ghats in Southern India. Sci. Pap. Ser. A. Agron. 2017, 60, 326–339. Narayanan, M. K. R.; Anilkumar, N.; Balakrishnan, V.; Sivadasan, M.; Ahmed Alfarha, H.; Alatar, A. A. Wild Edible Plants Used by the Kattunaikka, Paniya and Kuruma Tribes of Wayanad District, Kerala, India. J. Med. Plant Res. 2011, 5, 3520–3529. Oakenfull, D. Saponins in Food—A Review. Food Chem. 1982, 6, 19–40. Parvathy S; Mohammed, F; Suchitra P. Pharamacognostic and Experimental Evaluationm of Tender Leaf of Bhumijambu-Syzygium caryophyllatum (L.) Alston in Ulcerative Colitis. J. Ayurveda Med. Sci. 2018, 3, 294–295.

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Raj, R.; Chandrashekar, K. S.; Maheshwari, R.; Polu, P. R.; Pai, V. Pharmacognostical Study of Syzygium caryophyllatum L. Res. J. Pharm. Tech. 2016, 9 (10), 1653–1657. Rana, I. S.; Rana, A. S.; Rajak, R. C. Evaluation of Antifungal Activity in Essential Oil of the Syzygium aromaticum (L.) by Extraction, Purification and Analysis of Its Main Component Eugenol. Braz. J. Microbiol. 2011, 42 (4), 1269–1277. Saeed, S.; Tariq, P. In Vitro Antibacterial Activity of Clove Against Gram Negative Bacteria. Pak. J. Bot. 2008, 40, (5), 2157–2160. Savinaya, M. S.; Sangamesh, S.; Patil Narayana, J.; Krishna, V. Traditional Medicine Knowledge and Diversity of Medicinal Plants in Sharavathi Valley Region of Central Western Ghats. Int. J. Herb. Med. 2016, 4 (6), 124–130. Savithri, A. S.; Chacko, N.; Shetty, P.; Shilpa, K. In-Vitro Anti-Arthritic Potential of Syzygium caryophyllatum (L) Alston Leaf Extract. Saudi J. Med. Pharm. Sci. 2018, 4, 95–101. Shilpa, K. J.; Krishnakumar, G. Nutritional, Fermentation and Pharmacological Studies of Syzygium caryophyllatum (L.) Alston and Syzygium zeylanicum (L.) DC Fruits. Cog. Food Agri. 2015, 1–13. DOI: http://dx.doi.org/10.1080/23311932.2015.1018694. Shilpa, K. J.; Krishnakumar, G. Phytochemical Screening, Antibacterial and Antioxidant Efficacy of the Leaf and Bark Extracts of Syzygium caryophyllatum (L.) Alston. Int. J. Pharm. Pharm. Sci. 2018, 4, 198–202. Soni, A.; Dahiya, P. Phytochemical Analysis, Antioxidant and Antimicrobial Activity of Syzygium Caryophyllatum Essential Oil. Asian. J. Pharm. Clin, Res. 2014, 7 (2), 202–205. Suma, H. R; Shrikanth, P; Niveditha Shetty. Comparative Phyto-Pharmacognostic Evaluation of Jambu (Eugenia jambolana Lam.) and Kshudra Jambu (Syzygium caryophyllatum (L.) Alston.). Ann. Ayurved. Med. 2020, 9 (3), 148–161. Stalin, N.; Swamy, P. S. Scientific Basis of Herbal Medicine; Daya Publishing House: New Delhi, 2013; pp 15–126. Stalin, N.; Swamy, P. S. Screening of Phytochemical and Pharmacological Activities of Syzygium caryophyllatum (L.) Alston. Clin. Phytosci. 2018, 4, (3), 1–13. DOI: 10.1186/ s40816-017-0059-2. Stalin, N; Sudhakar, P. S. Phenological Patterns of an Endangered Tree Species Syzygium caryophyllatum in Western Ghats, India: Implication for Conservation. Proc. Natl. Acad. Sci. India Sect. B Biol. Sci. 2018. DOI: https://doi.org/10.1007/s40011-018-1044-3. Subramanian, C. R.; Subbramaniyan, P.; Raj, V. Phytochemical Screening, Total Phenolic Contents and Antioxidant Activity of Syzygium caryophyllatum and Syzygium densiflorum. J. Biol. Act. Prod. Natu. 2014, 4 (3), 224–235. Zheng, G.; Kennedy, P. M.; Lam, L. K. T. Sesquiterpenes from Clove (Eugenia caryophyllata) as Potential Anticarcinogenic Agents. J. Nat. Prod. 1992, 55, 999–1003.

CHAPTER 21

Phytochemistry and Biological Activities of Crepidium acuminatum (D. Don) Szlach.: A Systematic Review SEBASTIAN JOHN ADAMS1,2*, THIRUPPATHI SENTHIL KUMAR3, and GNANAMANI MUTHURAMAN1 Department of Phyto-Pharmacognosy, Research, and Development,

Sami Labs Ltd., 19/1 & 19/2, 1st main, 2nd Phase,

Peenya Industrial Area, Bangalore 560058, India

1

National Center for Natural Products Research, School of Pharmacy,

University of Mississippi, University, MS 38677, USA

2

Department of Botany, Bharathidasan University,

Tiruchirappalli 620024, India

3

Corresponding author. E-mail: [email protected]

*

ABSTRACT Ashtavarga, a group of rasayana herbs consists of eight plants. One among them is Crepidium acuminatum, an Orchid commonly known as jeevaka. This orchid is traditionally used in the famous formulation Chyawanprash. The phytochemistry and pharmacological studies are very limited due to the unavailability of genuine pseudobulbs. This chapter is composed of the available scientific evaluation of phytochemistry and its therapeutical values. The major phytochemical constituents of essential oil contain limonene, eugenol, citronellal,1-8- cineole, piperitone, and p-cymene. Secondary metabolites were ß-sitosterol, ceryl alcohol, two sugars, namely glucose and rhamnose, pyromeconic acid, 3′-O- methybatatasin-III, Gigantol, Coelonin, Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Batatasin-III, Lusianthridin. and the alkaloid choline (in trace amount). The major pharmacological use of pseudobulb of Crepidium acuminatum is antiaging and aphrodisiac properties. 21.1 INTRODUCTION Crepidium acuminatum (D. Don) Szlach. (family: Orchidaceae) synonyms of the plant include Microstylis wallichii Lindl. and Malaxis acuminata D. Don. Plant traditionally used in folk and Ayurvedic medicine is the pseudobulb (the aerial stem of the plant). It is used under an essential Rasayana group, Ashtavarga, as Jeevaka. This species is native to India, Bangladesh, Cambodia, China, Indonesia, Laos, Myanmar, Nepal, Philippines, Thailand, and Vietnam (Wu and Hong, 2009). The recent study discussed the distribution and its taxonomical identity in morpho-anatomical evidence (Adams et al., 2018a). There are substantial market problems in meeting the demands for pseudobulb of C. acuminatum, as it is very short in supply; thus it leads to adulteration/substitution by other orchids like Malaxis cylindrostachya, Malaxis mackinnonii, Pueraria tuberosa, Centaurea behen, Dioscorea bulbifera, and Tinospora cordifolia (Balkrishna, 2012). This orchid plant is highly dynamic in its chemical characters and its phytochemicals. The pseudobulb is sweet in taste, cold in potency, reduces Vata, and provokes Kapha (Singh, 2006). The ethanolic extract of pseudobulbs exhibits antiproliferative activity (Singh et al., 2017). This form is a useful therapy when formulated with other ayurvedic plants and formulations like Astavarg Churna, Jevaniyo Dashko Mahakshay, and Chyawanprash Linctus formulated drug, with this plant (Kaushik, 1983; Bose et al., 1999; Chinmay et al., 2011). This chapter highlights the phytochemicals present in the pseudobulbs and their pharmacological importance in detail. 21.2 BIOACTIVE COMPOUNDS The chemical studies of C. acuminatum known from the earlier 1980s by the studies were done by Bhatnagar et al. (1971), followed by Gupta et al. (1978) and both researchers reported that the essential oil contains as limonene, eugenol, citronellal,1-8- cineole, piperitone, and p-cymene. Bhatnagar et al. (1971) reported the presence of ß-sitosterol, ceryl alcohol, two sugars, namely glucose and rhamnose, and the alkaloid choline (in trace amount)

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also pyromeconic acid, 3′-O- methybatatasin-III, Gigantol, Coelonin, Batatasin-III, Lusianthridin. Sharma et al. (2007, 2009) reported certain chemical constituents by TLC using different mobile phases. Chinmay et al. (2011) made a phytochemistry study of this plant to distinguish the genuine sample from market samples. Lohani et al. (2013) examined the fatty acids contents and heavy metal in the whole plant. Recently, 11 compounds and three steroids were isolated and characterized by HPLC-ESI-QTOF-MS/ MS analysis in this plant (Singh et al., 2017). They listed out the authenticating phytochemical features, so that future researchers and industries can use these data to standardize their authentication process. The analysis of pseudobulbs of C. acuminatum (Syn.: M. acuminata) by gas chromatography–mass spectrometry (GC–MS) reveled the presence of long-chain saturated and unsaturated fatty acids (Rajurkar and Gaikwad, 2014). Adams et al. (2017a) reported the percentage of minerals and heavy metals present in the powder sample of pseudobulbs for its formulation criteria. Arora et al. (2018a, 2018b) said two kinds of saponins, three bitter compounds, two steroidal compounds, two aromatic essential oils, one anthraquinones, two coumarin compounds, and five flavonoid compounds in methanol extract of pseudobulbs of this plant and confirmed their sample authenticity before experimenting for propagation studies. 21.3 PHARMACOLOGICAL ACTIVITIES The pseudobulb of C. acuminatum has the following therapeutic activities: cooling effect, febrifuge, spermopiotic, antiaging, aphrodisiac, refrigerant, and treat bleeding diathesis, burning sensation, dipsia, haematemesis, fever, semen related weakness, emaciation, tuberculosis, general debility, and phthisis. C. acuminatum is one of the eight plants in the formulation used to prepare rejuvenating drug “Chyavanprash” (Govindarajan et al. 2007). The other formulations like Astavarg Churna, Jevaniyo Dashko Mahakshay, and Himvana agada, also used C. acuminatum pseudobulbs (Adams et al., 2017b). The crude extracts of C. acuminatum pseudobulbs were used to rejuvenate the tissues and organs. Ayurveda used this plant for this purpose for many thousands of years. C. acuminatum showed the antioxidant and antiaging properties. The leaf and stem of C. acuminatum with methanolic extract showed anti-inflammatory potential, photoprotective, and skinaging-related enzyme inhibitory activities on in vitro cell lines. The nonpolar extracts of leaf of in-vitro cultured plants and wild plants were compared for

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their antioxidant activity, that shown in vitro cultured plant with 42.66 ± 1.8 μg/mL (IC50) in comparison to the standard ascorbic acid [38.24 ± 2.5 μg/ mL (IC50)]. However, in vitro derived plant stem extracts showed moderate DPPH activity. The radical scavenging potential was observed in aqueous stem extracts of the wild plant (178.56 ± 2.9 μg/mL) (Bose et al., 2017). In vitro assays of antiaging shows the methanolic extract of leaf is good in anticollagenase with the IC50 of 32.52 ± 1.6 μg/mL compared to standard EDTA (IC50 = 35.45 ± 1.7 μg/mL); and again the extracts exhibited antielastase activity with the IC50 = 32.24 ± 1.7 μg/mL as compared to standard oleanolic acid (IC50 = 30.56 ± 1.8 μg/mL) while aqueous stem extract of wild plants revealed least inhibitory effect (IC50 = 145.36 ± 3.1 μg/mL). Since collagen and elastin mainly maintain skin structural integrity and elasticity, the studies support the ayurvedic usage of this plant for antiaging properties. The methanolic leaf extract of in-vitro cultured C. acuminatum showed the highest tyrosinase inhibitory activity (IC50 175.812 ± 2.1 μg/mL) against the standard Kojic acid (IC50 52.24± 2.5 μg/mL). Xanthine oxidase inhibition assay using methanolic leaf extract of in-vitro derived plantlets showed significant value, that is, 22.88 ± 1.9 μg/mL (IC50) in comparison to standard allopurinol which is a xanthine oxidase inhibitor prescribed for chronic gout (Bose et al., 2017). And the same team also studied the sun protection factor and UV-A blocking the activity of C. acuminatum (Syn.: M. acuminata) extracts which showed promising UV-A blocking potential. The pseudobulbs extracts of C. acuminatum showed antiproliferative activity against the human cancer cell lines A549, DU145, DLD1, and MCF-7 by the SRB assay against. This study reported moderate activity of ethanol and butanol extracts. The ethyl acetate extract showed a potent antiproliferative activity when compared with standard doxorubicin against cancer cell lines (Singh et al., 2017). Arora et al. (2017) studied to confirm the antimicrobial activities of chloroform extracts with the zone of inhibition studies. Sharma et al. (2014) proved that plant extraction could treat tuberculosis and improve the aphrodisiac effect. The pseudobulbs of this plant are used to treat the diseases like bleeding diathesis, burning sensation in the stomach, inflammation, and lung diseases and are also used to treat insect bites and rheumatism (Cheruvathur et al., 2010; Chinmay et al., 2011). The pseudobulb extract by ethanol was reported for analgesic and anti-inflammatory activity studies by in-vivo analysis (Chinmay et al., 2011). Indian Nagaland tribals used the decoction of pseudobulbs to cure common diseases (Rajurkar and Gaikwad, 2014). Sharma et al. (2007) examined the ethanolic (50% v/v)

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extracts of C. acuminatum (Syn.: M. wallichii) for anti-inflammatory and analgesic activities in experimental animals. The formulated drugs using C. acuminatum, such as chavanprash, Bramha Rasayana, and Haritak Kyadiyoga, are used as rejuvenating and improving overall human health (Govindarajan et al. 2007). C. acuminatum (50–200 mg/kg) inhibits the swelling caused by carrageenin significantly in rats. The author of this chapter has done in-vivo aphrodisiac studies (Adams et al., 2018b) using the crude extracts of the pseudobulbs. The male mice administrated with the aqueous ethanol extract of 400 mg/kg bw showed the mounting frequency and mounting latency very similar to the standard observed in Sildenafil citrate. These are 16 times on the first day of administration and take just 50 s to start mating. The second efficient extract is the alkaloid layer which is present in the aqueous extract. The chloroform layer is also an efficient aphrodisiac. Aqueous ethanol extract shows total cholesterol of 114.33 mg/dL compared to the standard (114.67 mg/dL); nitric oxide level is 69.17 µmol/L compare to the standard (71.3 µmol/L), and the testosterone is about 3.45 ng/mL, and the average value is 3.57 ng/mL. Studies involving in vivo assay of aphrodisiac activity using the mice model proved that the pseudobulb of this plant is an effective aphrodisiac, promoting virility, and improving health. The aqueous ethanolic extract of the pseudobulb and the alkaloid extract (both aqueous and chloroform layer) showed significant or equivalent effects compared to that obtained with the standard Sildenafil citrate. The results pertained to mounting frequency, mounting latency, reduction in total cholesterol content, increase in nitric oxide, testosterone levels, etc. Thus, the aphrodisiac potential of the pseudobulb of this plant, as indicated in tribal and Ayurvedic medicines, is proved by investigators carried out here. 21.4 CONCLUSION This chapter complied with the phytochemical and pharmacological potential of the plant C. acuminatum, which helps the researcher to focus on this plant in the future. Few studies use the pseudobulbs due to their very short supply of raw material in the herbal market. There are market problems in meeting the demands for C. acuminatum, giving scope for possible adulteration/substitution by other orchids like M. cylindrostachya, M. mackinnonii, P. tuberosa, C. behen, D. bulbifera, and T. cordifolia (Balkrishna, 2012). In southern India, it is likely that other plants like Malaxis rheedii and some

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Hebenaria sp., merely out of wrong identification during collection in place of C. acuminatum. There are many therapeutical similarities to the genuine C. acuminatum with its substitutes, but there are not many studies to distinguish the difference between them (Adams et al., 2017b). In the future, this plant and its therapeutical values will interest many scholars in doing research. KEYWORDS • • • • • •

anti-aging aphrodisiac Ashtavarga Orchid rasayana secondary metabolites

REFERENCES Adams, S. J.; Senthil Kumar, T.; Muthuraman, G.; Majeed, A.; Majeed. M. Mineral Elements and Their ICP-MS Validation in Crepidium acuminatum (D. Don) Szlach. An Ashtavarga Plant. Asian J. Biochem. Pharmaceut. Res. 2017a, 4 (7), 38–46. 10.24214/AJBPR/7/4/3846 Adams S. J.; Senthil Kumar T.; Muthuraman G.; Majeed A. Ashtavarga Plants. A Review. In The Ethnobotany of India, Vol. 4: Western and Central Himalayas; Pullaiah T., Krishnamurthy K. V., Bahadur B.; Eds.; Apple Academic Press: USA, 2017b; pp 293–312. Adams, S. J.; Senthil Kumar, T.; Muthuraman, G. Botanical, Pharmacognostic and Pharmacological Studies on Crepidium acuminatum (D. Don) Szlach. An Ashtavarga Plant. Ph.D Thesis; Bharathidasan University: Tamil Nadu, India, 2018b. Adams, S. J.; Senthil Kumar, T.; Muthuraman, G.; Majeed, A. Distribution, Morphology, Anatomy, and Histochemistry of Crepidium acuminatum. Modern Phytomorphol. 2018a, 12, 15–32. https://doi.org/10.5281/zenodo.1195691 Arora, M.; Kaur, G.; Kahlon, P. S.; Mahajan, A.; Sembi, J. Pharmacognostic Evaluation and Antimicrobial Activity of Endangered Ethnomedicinal Plant Crepdium acuminatum (D. Don) Szlach. Pharmacogn. J. 2017, 9 (6), s56–s63. Arora, M.; Kaur,G.; Singh, S.; Mahajan, A.; Sembi, J. K. Quantification of Phytochemicals in the Pseudobulbs of Crepidium acuminatum (D. Don) Szlach-a Critically Endangered Medicinal Plant. Curr. Trends Biotechnol.Pharm. 2018a, 13 (4), 366–375. Arora, M.; Mahajan, A.; Sembi, J. K. Fingerprint Profile of an Important Therapeutic Plant of Astavarga Crepidium acuminatum (D. DOn) Szlach by HPTLC. Curr. Trends Biotechnol. Pharm. 2018b, 12 (3), 257–264.

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Balkrishna A. Secrets of Astavarga Plants (for Vitality and Antiaging); Divya Prakashan, Patanjali Yogpeeth, Haridwar, Uttarakhand, India, 2012. Bhatnagar, J. K.; Handa, S. S.; Duggal, S. C. Chemical Investigations on Microstylis wallichii. Planta Med. 1971, 20, 156–161. Bose T. K.; Bhattacharjee S. K.; Das P.; Basak U. C. Orchids of India, 2nd ed.; Naya Prakash: Calcutta, 1999; pp 325–332. Bose, B.; Choudhury, H.; Tandon, P.; Kumaria, S. Studies on Secondary Metabolite Profiling, Anti-Inflammatory Potential, In Vitro Photoprotective and Skin-Aging Related Enzyme Inhibitory Activities of Malaxis acuminata, a Threatened Orchid of Nutraceutical Importance. J. Photochem. Photobiol. B: Biol. 2017, 173, 686–695. https://doi. org/10.1016/j.jphotobiol.2017.07.010 Cheruvathur, M. K.; Abraham, J.; Mani, B.; Thomas, T. D. Adventitious Shoot Induction from Cultured Internodal Explants of Malaxis acuminata D. Don, a Valuable Terrestrial Medicinal Orchid. Plant Cell Tiss. Organ Cult. 2010, 101, 163–170. Chinmay, R.; Kumari, S.; Bishnupriya, D.; Mohanty, R. C.; Renu, D.; Padhi, M. M.; Ramesh, B. Phyto-Pharmacognostical Studies of Two Endangered Species of Malaxis (Jeevak and Rishibhak). Phcog. J. 2011, 3, 77–85. https://doi.org/10.5530/pj.2011.26.13 Govindarajan, R.; Singh, D. P.; Rawat, A. K.S. High-Performance Liquid Chromatographic Method for the Quantification of Phenolics in ‘Chyavanprash’a Potent Ayurvedic Drug. J. Pharm. Biomed. Anal. 2007, 43, 527–532. Gupta, R.; Agarwal, M.; Baslas, R. K. Chromatographic Separation and Identification of Various Constituents of Essential Oil from the Bulb of M. accuminata. Indian Perfume. 1978, 22 (4), 287–288. Kaushik, P. Ecological and Anatomical Marvels of the Himalayan Orchids; Today and Tomorrow’s Printers and Publishers: New Delhi, India, 1983; pp.101–113. Lohani, N.; Tewari, L. M.; Kumar, R.; Joshi, G. C.; Kishor, K.; Kumar, S.; Tewari, G.; Joshi, N. Chemical Composition of Microstylis wallichii Lindl. from Western Himalaya. J. Med. Plants Res. 2013, 7 (31), 2289–2292. Rajurkar, N. S.; Gaikwad, K. N. Identification and Quantification of Amino Acids from Medicinally Important Plants by Using High Performance Thin-Layer Chromatography. J. Liq. Chromatogr. Relat. Technol. 2014, 37, 2197–2205. Sharma, A.; Rao, C. V.; Tiwari, R. K.; Tyagi, L. K.; Kori, L.; Shankar, K. Comparative Study on Physico Chemical Variation of Microstylis walichii: A Drug Used in Ayurveda. Acad. J. Plant Sci. 2009, 2 (1), 4–8. Sharma, A.; Reddy, G. D.; Kaushik, A.; Shanker, K.; Tiwari, R. K.; Mukherjee, A.; Roa, Ch.V. Analgesic and Anti-Inflammatory Activity of Carissa carandas Linn Fruits and Microstylis wallichii Lindl Tubers. Nat. Prod. Sci. 2007, 13 (1), 6–10. Sharma, Y. P.; Rani, J.; Raina, R.; Bandana, K. New Insights Into the Morphology of Malaxis acuminata D. Don. Intern. J. Farm Sci. 2014, 4 (4), 136–146. Singh, A. P. Ashtavarga-Rare Medicinal Plants. Ethnobot. Leaflets 2006, 10, 104–108. Singh, D.; Kumar, S.; Pandey, R.; Hasanain, M.; Sarkar, J.; Kumar, B. Bioguided Chemical Characterization of the Antiproliferative Fraction of Edible Pseudobulbs of Malaxis acuminata D. Don by HPLC-ESI-QTOF-MS. Med. Chem. Res. 2017, 26 (12), 3307–3314. https://doi.org/10.1007/s00044–017–2023–6 Wu, Z.; Hong, D. (Eds.) Flora of China; Missouri Botanical Garden Press: St. Louis, 2009; pp 25, 1–570.

CHAPTER 22

Phytochemistry and Bioactive Potential of Tiririca (Cyperus esculentus L.) JOSÉ FRANCISCO DOS SANTOS SILVEIRA JUNIOR* Department of Food Science and Technology, Federal University of Santa Catarina, Florianópolis 88034-001, Santa Catarina, Brazil Corresponding author. E-mail: [email protected]

*

ABSTRACT Cyperus esculentus is a perennial sedge plant widely distributed across the globe. Their popular names (amêndoa-da-terra, junça-doce, junça, juncinha e cípero-comestível, Tiger nut, earth almond, rush nut, yellow nutsedge, nutgrass, zulu nut, and ground almond), vary according to the popular culture of each geographic region. It has a wide range of applications in folk medicine, as in the alternative treatment of heart disease, gastric ulcer, thrombosis, and arthritis. As an anxiolytic agent, in treating diarrhea, fever, pain, and vomiting, as a promoter of blood circulation activation, and in controlling female problems, such as menstrual irregularities and amenorrhea. It also reduces colon cancer risk, acting as an analgesic, sedative, antispasmodic, and antiinflammatory. Tubers of C. esculentus have a wide range of compounds with bioactive potentials, such as phenolic acids, flavonoids, alkaloids, tannins, steroids, terpenes, triterpenes, and sesquiterpenes. They also have karyophyllan, eudesman, patchoulan, cyperene, αcyperone, and cyperotundone. They usually have several natural antioxidants, such as phydroxybenzoic acid, vanylic acid, p-hydroxybenzaldehyde, vanillin, p-trans-cumearic transferulic acid, p-cis-cumaric acid, cis-ferulic acid, and among others. Pharmacological studies show promising results in terms of antimicrobial, antioxidant, antiinflammatory, antidiabetic, antidiarrheal, anticancer, antihyperlipidemia, neuroprotective, and fertility promoting activities. Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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22.1 INTRODUCTION Cyperus esculentus L. is a perennial sedge and is considered as one of the most cosmopolitan members of the Cyperaceae family. It has a wide range of global distribution and presence in about 92 countries (Silveira junior and De francisco, 2020). The average height of C. esculentus is 20–90 cm, and it has inflorescences grouped in spikelets, which support one or more flowers as its basic reproductive unit. The structure, arrangement, quantity of male, and female flowers are essential for the group’s systematic (Pascual et al., 2000). The fruits are of the achene type, with laminar leaves and basal linear leaves of bright green color with paralelinérervea innervation. It has a triangular stem with very rigid aerial branches and an underground stem (rhizomes) with roots that end in yellow, brown, or black oval tubers that vary according to the species’ varieties (Moreira and Bragança, 2011). Several popular names are attributed to C. esculentus and vary according to nationality. For example, tiririca, bibi, tiririca-amarela, capim coco, cotufa, tamascal, amêndoa-da-terra, junça-doce, junça, juncinha e cípero-comestível (Brazil); chufa (Spain); Tiger nut, earth almond, rush nut, yellow nutsedge, nutgrass, zulu nut, and ground almond (English-speaking countries); erd mandel (Germany); coquilo, tulle, and tutillo (Mexico); hab-elsamar (Saudi Arabia); yang di li and shat-tsan (China); velvet junquinha (Portugal); jordmandel (Denmark); aardmnandel (Netherlands); choufa, lover of land, and edible souchet (France); chichoda (India); kwentti (Ethiopia); zigolo Dulce, doldichini, and babbagiggi (Italy); and moskoi sitnik (Russia) (Defelice, 2002; Lorenzi and Kinupp, 2014). In almost all countries where C. esculentus grows, it is used in the alternative treatment of heart disease, gastric ulcer, thrombosis, and arthritis. As an anxiolytic agent, in the treatment of diarrhea, fever, pain, and vomiting, as a promoter of blood circulation activation and in the control of female problems, such as menstrual irregularities and amenorrhea. It also reduces colon cancer risk, acting as an analgesic, sedative, antispasmodic, and antiinflammatory (Kurian, 2012; Gambo and Da’u, 2014). 22.2 BIOACTIVES Tubers of C. esculentus have a wide range of compounds with bioactive potentials, such as phenolic acids, flavonoids, alkaloids, tannins, steroids, terpenes, triterpenes, and sesquiterpenes. They also have karyophyllan, eudesman, rotund and patchoulan, cyperene, α-cyperone, and cyperotundone. They usually have several natural antioxidants, such as p-hydroxybenzoic

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acid, vanillic acid, p-hydroxybenzaldehyde, vanillin, p-trans-coumaric trans-ferulic acid, p-cis-coumaric acid, cis-ferulic acid, and among others (Chukwuma et al., 2010; Ezeh et al., 2014). Vega-morales et al. (2019) investigated the chemical composition of ethanolic extract of C. esculentus tubers and found significant quercetin, stigmasterol, and levels of oleic and linoleic fatty acids, along with 4-chlorobutyloleate, oleamide, myrrine, tyramine, and N-feruloiltiramine. However, no alkaloids were detected and the presence of flavonoids and sterols was moderate. According to a study by Stary (1991), the variety of C. esculentus with brown tubers showed a higher content of alkaloids, saponins, flavonoids, and glycosides than the variety with yellow tubers. However, the variety in which the tubers are yellow showed higher levels of tannins, steroids, and reducing sugars. Eskander et al. (2020) investigated the phytochemical composition of methanolic and chloroform extracts and its oil from the tuber of C. esculentus. The methanolic fraction resulted in the identification of the terpenes oleanolic acid, α-amyrin 3-O-glucopyranoside, and β-amyrin 3-O-glucopyranoside, reported for the first time for this plant. The chloroform extract revealed the presence of the following compounds: 9,12-octadecadienoic acid (Z, Z)-, 9-octadecenoic acid (Z)-, hexadecanoic acid, octadecanoic acid, 9-octadecenoic acid, (E)-, tetracosanoic acid, eicosanoic acid stigmasterol, and betasitosterol. While in the oil, the compounds hexylene glycol, 9-octadecenoic acid (Z)—methyl ester, hexadecanoic acid-methyl ester, methyl stearate, 9,12-octadecadienoic acid (Z, Z)—methyl ester, eicosanoic acid-methyl ester, octadecanoic acid-9,10-dihydroxy-methyl ester, 2,3-dihydroxypropyl elaidate, hexadecanoic acid, 2,3-dihydroxypropyl ester, 9-octadecenoic acid (Z)-, 2-hydroxy-1-(hydroxymethyl) ethyl ester, octadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester, -octadecenoic acid (Z)-, 2,3-dihydroxypropyl ester have been recorded. Hu et al. (2018) investigated the phytochemicals in the oil of tubers of C. esculentus. They identified phenolic compounds α-tocopherol, β-carotene, phospholipids, phytosterols, β-sitosterol, stigmasterol, and campesterol. In another research, Hu et al. (2020) addressed other experimental conditions and identified the same compounds. Daniel and Edigeal (2019) identified in the extracts of tubers of C. esculentus obtained with methanol and ethyl acetate, phenolic compounds, flavonoids, and alkaloids in addition to vitamins A, C, and E. Chukwuma et al. (2010) investigated the phytochemical content of raw and roasted C. esculentus tubers. In the raw tubers, they identified alkaloids, cyanogenic glycosides, flavonoids, resins, tannins, sterols, and saponins, while in the roasted tubers, only sterols, and resins.

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Maduka and Ire (2018) investigated the phytochemical composition of tubers of C. esculentus and identified tannins, polyphenols, phytate, oxalate, alkaloids, and saponin.

22.3

PHARMACOLOGY

22.3.1 ANTIMICROBIAL ACTIVITY Tubers extracts of C. esculentus elaborated with the solvents chloroform, petroleum ether, acetone, and 50% ethanol showed efficacy against several human pathogens Staphylococcus aureus, Escherichia coli, Salmonella sp.,

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Pseudomonas aeruginosa, Klebsiella pneumoniae, Citrobacter freundii, and Proteus vulgaris. The activity of extracts was compared with conventional antibiotics in an in vitro test, using 20 µL of each extract in agar plates, inoculated with the cultures, and incubated at 37°C for 48 h. The chloroform extract inhibited the maximum growth of S. aureus while the petroleum ether extract showed positive results against Salmonella sp., respectively. Acetone extract showed the highest inhibitory activity against S. aureus, P. vulgaris, and K. pneumoniae while the ethanol extract showed maximum activity against Salmonella sp., S. aureus, and E. coli. All extracts were sensitive to C. freundii (Prakash and Ragavan, 2009). Moral-Anter et al. (2021) found that tuber flour from C. esculentus protected against infection by S. enteritidis in Caco-2 cell cultures. The cells were preincubated for 24 h with 2.5 mg/mL of the aforementioned flour and then incubated with S. enteritidis (multiplicity of infection 10, for 3 h), or TNF (300 mg/mL, for 48 and 72 h), or H2O2 (350 µmol/L, for 3 h). The results revealed that the protective effect is associated with the phytochemicals present in the flour, which have the ability to reduce reactive oxygen species in H2O2, agglutinating the pathogen and consequently reducing bacterial invasion. Daniel and Edigeal (2019) evaluated the effect of methanol and ethyl acetate extracts from tubers of C. esculentus against the microorganisms E. coli, S. aureus, and K. pneumoniae, which cause human urinary tract infection. The microorganisms were subcultured and then incubated for 24 h at 37 °C. Different extracts (12.5, 25, 50, and 100 mg/mL) were prepared and kept in corked test tubes. The extracts obtained with both solvents showed significant effects against the microorganisms investigated in the study. However, methanol extract exhibited greater activity against E. coli, while the ethyl acetate extract showed maximum efficacy against K. pneumoniae. 22.3.2 ANTIOXIDANT ACTIVITY Tuber oil from C. esculentus was tested on 20 adult male Wistar albino rats, weighing between 270 and 300 g for antioxidant properties. The rats were randomly distributed into four groups (five rats per group). Rats in group A received distilled water and served as a control. Group B rats were administered daily doses of 5 mg/kg (body weight—bw) of hydroxamic fatty acid (oleic, linoleic, and palmitic acids) (FHA) isolated from oils. The rats in Groups C and D were submitted to daily doses of FHA in the proportions of 15 mg/kg and 50 mg/kg bw, respectively. Treatments were performed orally,

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daily, for 1 week. The results indicate that FHA exerts antioxidant activity, in addition to eliminating free radicals (Adewuyi et al., 2015). Hexanolic and methanolic extracts from tubers of C. esculentus were tested in vitro for antioxidant properties and considered effective compared to hydroxylanisole (BHA), ascorbic acid, and α-tocopherol. The results are related to the presence of alkaloids, flavonoids, phenols, and glycosides (Abimbade et al., 2014). Jing et al. (2013) investigated the fatty acid content of C. esculentus oil, and the antioxidant effect was tested in 5-week-old Kunmin female mice. Five concentrations (0.1, 0.2, 0.4, 0.6, and 0.8 mg/mL) of C. esculentus oil, vitamin C, and TBHQ were prepared with 95% ethanol and used for measurement of the reducing power as well as OH • and DPPH • scavenging activities and in vitro antioxidant activity. It was found that most of the lipid composition is formed by unsaturated fatty acids, of which oleic acid was responsible for the highest content, followed by linoleic acid and palmitic acid. The results indicate a significant reduction in hydroxyl radicals according to the increase in oil concentration. 22.3.3 ANTI-INFLAMMATORY ACTIVITY Udefa et al. (2020) studied the anti-inflammatory activity of the hydroethanolic extract of tubers of C. esculentus (500 mg/kg bw) in testicular dysfunction induced by lead acetate in Wistar rats. There was a significant decrease in testicular oxidative stress, inflammation, and apoptosis resulting from testicular dysfunction. The tubers extract of C. esculentus (500 mg/ kg/day) for 6 weeks attenuated the deficiency of testicular function caused by a salt-rich diet induced in Wistar rats and reduced oxidative stress and inflammation improving testicular steroidogenesis. The antioxidants present in the extract, such as quercetin, vitamin C, vitamin E, and zinc, are identified as responsible for enhancing male reproductive function (Nwangwa et al., 2020). 22.3.4 ANTIDIABETIC ACTIVITY A plantain-based diet enriched with defatted soybeans and C. esculentus rhizome flour was used to reduce the glucose content in the blood of diabetic rats. The results were positive and associated with the low glycemic index of plantains and soy protein but mainly related to the functional activity exerted

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by the phytochemical compounds of the C. esculentus rhizome flour that exercise pronounced biological activity (Oluwajuyitan and Ijarotimi, 2019). Udogadi and Onyenibe (2019) investigated the influence of C. esculentus oil (CEO) in male diabetic Wistar rats induced by a combination of a high-fat diet and low-dose streptozotocin (35 mg/kg) for 30 days. The animals treated daily with 5 mL of CEO showed a rapid clearance in the blood, as well as a significant reduction in the levels of the atherogenic index, triglycerides, and VLDL. 22.3.5 ANTIDIARRHEAL ACTIVITY Shorinwa and Dambani (2020) studied the antidiarrheal activity of ethanol extract from tubers of C. esculentus administered in dosages of 250, 500, and 1000 mg/kg in albino rats induced with castor oil and charcoal flour. The percentage inhibition of defecation was 46.7% and 40% at 500 and doses of 1000 mg/kg of the extract. The result was attributed to the therapeutic effect of steroids, carbohydrates, alkaloids, and saponins verified in the chemical composition of the extract. As a result, it was also found that the extract appears to have an antisecreting effect but has no antimotility impact. 22.3.6 ANTICANCER ACTIVITY Achoribo and Ong (2019) evaluated the cytotoxic effect of the respective bioactive compounds found in the aqueous and ethanol extracts of C. esculentus tubers in MCF7 and MDAMB-231 cancer cell lines. The results showed that the aqueous extract was more effective against the cells used in the cancer study when compared to the ethanol extract. The aqueous extract markedly reduced the percentage of cell viability at a concentration of 6.25µg/mL within 24 h after treatment for MDAMB-231 cells and 48 h for MCF7 cells. The presence of flavonoids, phenols, and sterols may be involved in the cytotoxicity effect of the extracts on cancer cells used in the study. 22.3.7 ANTIHYPERLIPIDEMIA ACTIVITY Moon et al. (2012) evaluated the effect of adding defatted tubers of C. esculentus (DTCE) on diet-induced obesity and lipid metabolism in C57BL/6J

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mice. The mice were separated into groups and fed four different diets, including the control with a regular diet, high-fat diet, a high-fat diet with 5% DTCE and diet, and 10% DTCE for 7 weeks. Supplementation with the diet added 10% DTCE significantly reduced body weight gain, adipose tissue weight, and adipocyte size and reduced cholesterol and triglycerides. The results suggest that DTCE may be helpful in the prevention of obesity induced by a hyperglycemic diet. 22.3.8

NEUROPROTECTIVE ACTIVITY

Jing et al. (2020) investigated the neuroprotective action of the flavonoid Orientin present in 30% EtOH extracts from C. esculentus leaves against ischemia/reperfusion injury in rats with induced occluded middle cerebral artery. Doses of 125 mg/kg and 500 mg/kg were administered for 7 days. Significant effects have been found against brain damage, possibly caused by the reduction of lipid peroxidation and protein oxidation and the formation of reactive oxygen species. It was also possible to see that Orientin can decrease the neurological deficit score, attenuate the brain’s water content, and reduce the volume of cerebral infarction. Umukoro et al. (2020) investigated the influence of the aqueous extract of tubers of C. esculentus in the treatment of cognitive disorders and the underlying changes in acetylcholinesterase action and oxidative stress biomarkers in mice subjected to scopolamine. In the study, six male mice were used, which were treated with 50–200 mg/kg of extract for 7 days and submitted to cognitive evaluation through Y-maze and object recognition. The results showed that the extract improved cognitive function and reduced scopolamine-induced amnesia. There was also a marked reduction in the content of acetylcholinesterase, malondialdehyde, and nitrite, in addition to the attenuation in the unregulated GSH content in the brain of the mice. Therefore, regular consumption of C. esculentus tubers can provide positive results in memory-related disturbance. Arogundade et al. (2018) studied the effect of C. esculentus consumption on neurochemical, behavioral, and cellular parameters in the prefrontal and hippocampal regions of the rat brain. Twenty-four adult male Wistar rats were used, divided into four groups. Three groups were treated with different concentrations of aqueous extract of tubers of C. esculentus (10, 20, and 30 mg/kg). The fourth group served as a control receiving distilled water for 14 days. The assessment of the cortico-hippocampal neural circuit of rats

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treated with the extracts showed an increase in memory than the control. The neural levels of malondialdehyde were significantly reduced while the catalase and superoxide dismutase concentrations increased as the dose used increased. 22.3.9

FERTILITY PROMOTER

The consumption of water-soluble rhizome extract of C. esculentus produced an increase in the fertility of male rats. Stimulation of the biosynthesis of the hormone testosterone increased spermatogenesis, improved quality and motility were observed, as well as reduced mortality of sperm. The results can be attributed to the animals’ seminal pH stabilization after ingesting the extract (Ogbuagu and Airaodion, 2020). KEYWORDS • • • • •

Cyperus esculentus tiger nut tiririca bioactive compounds natural antioxidants

REFERENCES Abimbade, S. F.; Oloyede, G. K.; Nwabueze, C. C. Antioxidant and Toxicity Screenings of Extracts Obtained from Cyperus esculentus. Academia Arena 2014, 6 (1), 77–83. Achoribo, E. S.; Ong, M. T. Antioxidant Screening and Cytotoxicity Effect of Tigernut (Cyperus esculentus) Extracts on Some Selected Cancer-Origin Cell Lines. Euro Mediterranean Biomed. J. 2019, 14 (1), 01–06. Adewuyi, A.; Otuechere, C. A.; Oteglolade, Z. O.; Bankole, O.; Unuabonah, E. I. Evaluation of the Safety Profile and Antioxidant Activity of Fatty Hydroxamic Acid from Underutilized Seed Oil of Cyperus esculentus. J. Acute Dis. 2015, 4 (3), 230–235. Arogundade, T. T.; Yawson, E. O.; Gbadamosi, I. T.; Abayomi, A. T.; Tokunbo, O. S.; Lambe, E.; Bamisi, O. D.; Alabi, A. S. Behavioural Cellular and Neurochemical Alterations in Rat Prefrontal Cortex and Hippocampus Exposed to Tigernut (Cyperus esculentus) Treatment. J. Environm. Toxicol. Public Health, 2018, 3, 38–46.

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Chukwuma, E. R.; Obioma, N.; Christopher, O. I. The Phytochemical Composition and Some Biochemical Effects of Nigerian Tigernut (Cyperus esculentus L.) Tuber. Pak. J. Nutr. 2010, 9 (7), 709–715. Daniel, I. E.; Edigeal, D. E. Nutraceutical Composition and Antimicrobial Activity of Cyperus Esculentus (Tiger Nut) Against Urinary Tract Infection Pathogens. J. Agroalimentary Processes Technol. 2019, 25 (3), 127–136. Defelice, M. S. Yellow Nutsedge Cyperus esculentus L.—Snack Food of the Gods 1. Weed Technol. 2002, 16 (4), 901–907. Eskander, D. M.; Nassar, M. I.; Mohamed, R. A.; Farrag, A. R. H. Isolation, Characterization of Phytochemical Compounds and Hepatoprotective Activity Evaluation in Rats of Various Extracts from Cyperus esculentus L. Tubers. Egypt. J. Chem. 2020, 63 (12), 4867–4873. Ezeh, O.; Gordon, M. H.; Niranjan, K. Tiger Nut Oil (Cyperus esculentus L.): A Review of Its Composition and Physico-Chemical Properties. Eur. J. Lipid Sci. Technol. 2014, 116 (7), 783–794. Gambo, A.; Da’u, A. Tiger nut (Cyperus esculentus): Composition, Products, Uses and Health Benefits—A Review. Bayero J. Pure Appl. Sci. 2014, 7 (1), 56–61. Hu, B.; Li, Y.; Song, J.; Li, H.; Zhou, Q.; Li, C.; Zhang, Z.; Liu, Y.; Liu, A.; Zhang, Q.; Liu, S.; Luo, Q. Oil Extraction from Tiger Nut (Cyperus esculentus L.) Using the Combination of Microwave-Ultrasonic Assisted Aqueous Enzymatic Method-Design, Optimization and Quality Evaluation. J. Chromatogr. A 2020, 1627, e461380. Hu, B.; Zhou, K.; Liu, Y.; Liu, A.; Zhang, Q.; Han, G.; Liu, S.; Yang, Y.; Zhu, Y.; Zhu, D. Optimization of Microwave-Assisted Extraction of Oil from Tiger Nut (Cyperus esculentus L.) and Its Quality Evaluation. Ind. Crops Prod. 2018, 115, 290–297. Jing, S. Q.; Wang, S. S.; Zhong, R. M.; Zhang, J. Y.; Wu, J. Z.; Tu, Y. X.; Pu, Y.; Yan, L. J. Neuroprotection of Cyperus esculentus L. Orientin Against Cerebral Ischemia/Reperfusion Induced Brain Injury. Neural Regen. Res. 2020, 15 (3), 548–556. Jing, S.; Ouyang, W.; Ren, Z.; Xiang, H.; Ma, Z. The In Vitro and In Vivo Antioxidant Properties Of Cyperus esculentus Oil from Xinjiang, China. J. Sci. Food Agric. 2013, 93 (6), 1505–1509. Kurian, J. C. Ethno-Medicinal Plants of India, Thailand and Vietnam. J. Biodiversity 2012, 3 (1), 61–75. Lorenzi, H.; Kinupp, V. F. Plantas alimentícias não convencionais (PANC) no Brasil; Instituto Plantarum: São Paulo, 2014; p 768. Maduka, N.; Ire, F. S. Tigernut Plant and Useful Application of Tigernut Tubers (Cyperus esculentus)—A Review. Curr. J. Appl. Sci. Technol. 2018, 29 (3), 1–23. Moon, M. K.; Ahn, J.; Lee, H.; Ha, T. Y. Anti-Obesity and Hypolipidemic Effects of Chufa (Cyperus esculentus L.) in Mice Fed a High-Fat Diet. Food Sci. Biotechnol. 2012, 21 (2), 317–322. Moral-Anter, D.; Campo-Sabariz, J.; Ferrer, R.; Martín-Venegas, R. Cyperus esculentus L. Tubers (Tiger Nuts) Protect Epithelial Barrier Function in Caco-2 Cells Infected by Salmonella enteritidis and Promote Lactobacillus plantarum Growth. Nutrients 2021, 13 (1), e71. Moreira, H. J. C.; Bragança, H. B. N. Manual de identificação de plantas infestantes; FMC Agricultural Products: São Paulo, 2011; p 1017. Nwangwa, J. N.; Udefa, A. L.; Amama, E. A.; Inah, I. O.; Ibrahim, H. J.; Iheduru, S. C.; Okorie, N. E.; Ogar, J. A.; Madaki, F. N.; Owai, P. O.; Karawei, E. V. Cyperus esculentus L. (Tiger Nut) Mitigates High Salt Diet-Associated Testicular Toxicity in Wistar Rats by

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Targeting Testicular Steroidogenesis, Oxidative Stress and Inflammation. Andrologia 2020, 52 (11), e13780. Ogbuagu, E. O.; Airaodion, A. I. Tiger Nut (Cyperus esculentus L.) Boosts Fertility in Male Wistar Rats. Asian Res. J. Gynaecol. Obstetr. 2020, 3 (3), 8–18. Oluwajuyitan, T. D.; Ijarotimi, O. S. Nutritional, Antioxidant, Glycaemic Index and Antihyperglycaemic Properties of Improved Traditional Plantain-Based (Musa AAB) Dough Meal Enriched with Tigernut (Cyperus esculentus) and Defatted Soybean (Glycine max) Flour for Diabetic Patients. Heliyon 2019, 5 (4), e01504. Pascual, B.; Maroto, V. J.; López-Galarza, S.; Sanbautista, A.; Alagarda, J. Chufa (Cyperus esculentus L. var. sativus Boeck.): Unconventional Crop. Studies Related to Applications and Cultivation. Econ. Bot. 2000, 54 (4), 439–448. Prakash, N.; Ragavan, B. Phytochemical Observation and Antibacterial Activity of Cyperus esculentus L. Ancient Sci. Life 2009, 28 (4), 16–20. Shorinwa, O. A.; Dambani, D. T. Antidiarrheal Activity of Aqueous Ethanol Extract of Cyperus esculentus Tuber in Albino Rats. J. Appl. Biol. Biotechnol. 2020, 8 (3), 47–50. Silveira Junior, J. F. S.; de Francisco, A. Unconventional Food Plants as an Alternative in Starch Production. Cereal Foods World 2020, 65 (2), 1–10. Stary, F. The Natural Guide to Medicinal Herbs and Plants; Tiger Bark Institute: Twickenham, 1991; p 224. Udefa, A. L.; Amama, E. A.; Archibong, E. A.; Nwangwa, J. N.; Adama, S.; Inyang, V. U.; Inyaka, G. U.; Aju, G. J.; Okpa, S.; Inah, I. O. Antioxidant, Anti-Inflammatory and AntiApoptotic Effects of Hydro-Ethanolic Extract of Cyperus esculentus L. (Tigernut) on Lead Acetate-Induced Testicular Dysfunction in Wistar Rats. Biomed. Pharmacother. 2020, 129, e110491. Udogadi, N. S.; Onyenibe, N. S. Ameliorative Potentials of Cyperus esculentus Oil on Type 2 Diabetes Induced by High Fat Diet and Low Dose Streptozotocin in Male Wistar Rats. Intern. J. Diabetes Res. 2019, 2 (1), 33–39. Umukoro, S.; Okoh, L.; Igweze, S. C.; Ajayi, A. M.; Ben-Azu, B. Protective Effect of Cyperus esculentus (Tiger Nut) Extract Against Scopolamine-Induced Memory Loss and Oxidative Stress in Mouse Brain. Drug Metabol. Personal. Ther. 2020, 35 (3), e0112. Vega-Morales, T.; Mateos-Diaz, C.; Perez-Machin, R.; Wiebe, J.; Gericke, N. P.; Alarcon, C.; Lopez-Romero, J. M. Chemical Composition of Industrially and Laboratory Processed Cyperus esculentus Rhizomes. Food Chem. 2019, 297, e124896.

CHAPTER 23

Phytochemistry and Pharmacological Properties of Justicia betonica L. CH. SRINIVASA REDDY1, K. AMMANI2,*, and M. SANTOSH KUMARI2 Department of Botany, SRR & CVR Government Degree College, Vijayawada, India

1

Department of Botany and Microbiology, Acharya Nagarjuna University, Guntur, India

2

*Corresponding author. E-mail: [email protected]

ABSTRACT Justicia betonica L., family Acanthaceae, is an important traditional folk medicinal herb. Traditionally, it is used for various fevers, stomach pain, constipation, diarrhea, malaria, pain, snake bite, vomiting etc. It has external wound healing and ulcer healing property. The important phytoconstituents in the whole plant is steroids, triterpenoids, alkaloids, saponins, glycosides, carbohydrates, gum and mucilage, proteins, fixed oils and fat, phenolics and tannins. It showed anti-malarial, antiviral, antioxidant, anti-inflammatory, analgesic and antimalarial activities. The present review gives the traditional uses, phytoconstituents and Pharmacology of Justicia betonica. 23.1

INTRODUCTION

Justicia betonica L. belonging to the family Acanthaceae is an under shrub. This plant is native to tropical Africa and tropical Asia. J. betonica is present throughout Sri Lanka and India. Synonyms of the plant include Justicia Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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trinervia Vahl, Justicia uninervis S. Moore, Dicliptera lupulina C. Presl, Adhatoda betonica (L.) Nees, and Adhtoda lupulina Nees. It is commonly called Tella-addasaramu, Tellarantu, Velimungilu (Telugu), Venkurinni, Vellakurunji (Malayalam), and Velimungil (Tamil). The plant is a glabrous shrub; branchlets green, striate; leaves ovate-lanceolate, acuminate; flowers white with pink or rose spots in terminal spikes; bracts scarious with green nerves; calyx-lobes obovate-lanceolate; corolla tube cylindric; stamens 2; and capsule clavate. J. betonica has been extensively investigated for its biological attributes. It is a traditional medicinal plant used mainly for treating gastrointestinal complaints. Also used to cure pain, constipation, orchitis, diarrhea, malaria, snake bite, vomiting, etc. Lou tribe of Tanzania used whole plant infusion for gastrointestinal complaints (Kokwaro and Johns, 1998). In India, inflorescence extract is given orally to treat vomiting and constipation (Rao et al., 2006). Leaf and flower ash is used for the treatment of cough, diarrhea, and orchitis by the Nandi community of Kenya (Jeruto et al., 2008). In Uganda, leaves are used to treat HIV/AIDS (Lamorde et al., 2008). Stem, leaf, and inflorescence are used for curing diarrhea and inflammation and swelling (Gangabhavani and Ravishankar, 2013). Root paste is used to treat muscular pains (Satyavathi et al., 2014). In Kenya, a leaf decoction is used for vomiting and headache by Kipsigis people (Pacifica et al., 2018). The leaves of this plant consist of jusbetonin, a unique compound that yield bluish purple dye (Shinwari et al., 2017). The present review aims to enlighten the bioactive compounds and pharmacology of least explored J. betonica. 23.2 PHYTOCHEMICALS The phytochemical screening of J. betonica revealed the presence of several phytochemical constituents such as alkaloid glycosides, triterpenoids, phenolics, and tannins. Four triterpenoidal glycosides were isolated from the aerial portion of plant (justiciosides A–D). By using NMR spectroscopy, structural elucidation was carried out and established as olean-12-ene-1beta, 3beta, 11alpha, 28-tetraol 28-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside, olean-12-ene-1beta,3beta,11alpha,28-tetraol 28-O-β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside, 11alpha-methoxyolean-12-ene-1beta,3beta,28-triol28-O-β-D-glucopyranosyl-(1→2)--D-glucopyranoside, 11alpha-methoxy-olean-12-ene-1beta,3beta,28-triol 28-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside, respectively (Kanchanapoom et al., 2004 ). From the leaves of J. betonica,

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Jusbetonin, a new indolo[3,2-b]quinoline alkaloid glycoside and three known alkaloids, namely, 10H-quindoline, 6H-quinindoline, and 5H,6Hquinindolin-11-one have been isolated (Subbaraju et al., 2004). From the aerial portion of J. betonica, three new triterpenoidal glycosides, justiciosides E, F, and G, were isolated. Through chemical and spectroscopic analysis, the structures were established. An unusual A-nor-B-homo oleanan-12-ene skeleton type for the aglycone moiety as A-nor-B-homo-oleanan-10, 12-diene-3β, 11α, 28-triol 28-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside, A-nor-Bhomo-oleanan-10, 12-diene-3β, 11α, 28-triol 28-O-β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside, and 11α-methoxy-A-nor-B-homo-oleanan-10,12-diene-3β, 11α, 28-triol 28-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-(1→2)-β-Dglucopyranoside, respectively, were identified (Kanchanapoom et al., 2005). Andy et al. (2007) isolated 10H-indolo [3, 2-b] quinolone, a potent brine shrimp toxin from J. betonica. The standard phytochemical procedures reveal that all plant parts consist of flavonoids, alkaloids, proteins, carbohydrates, glycosides gum and mucilage, fixed oils and phenolics, tannins, and fats (Bbosa et al., 2013). John et al. (2013) evaluated the total flavonoids and phenolics in methanolic extracts of root, stem, and leaf of J. betonica. Total phenolic content in different parts of the plants was found to be 26.85 mg GAE (root), 29.60 mg GAE (stem) 30.90 mg GAE (leaf), respectively. Total flavonoid content was found to be 2.3.mg QE (root), 2.1 mg QE (stem), 2.86 mg QE (leaf), respectively. Sini et al. (2018) estimated the total phenolic content of stem (2.57 and 2.22 mg GAE), root (2.11 and 1.77 mg GAE), leaf (9.31 and 4.95 mg GAE) using water and methanol as solvent, respectively. 23.3 PHARMACOLOGICAL USES 23.3.1 ANTIMICROBIAL ACTIVITY Antibacterial activity of J. betonica leaves was studied using aqueous, methanol, benzene, petroleum ether, chloroform, and ethyl acetate extracts against, Escherichia coli, Salmonella typhi, Aeromonas hydrophila, Staphylococcus aureus, Vibrio cholerae, and Vibrio parahemolyticus. The plant showed moderate activity against all the tested microorganisms (Sasikumar et al., 2007). Fresh leaf infusion of J. betonica tested against S. aureus showed a maximum inhibition zone (15.5 mm) (Ssenyondo et al., 2020).

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23.3.2 ANTHELMINTIC ACTIVITY To study the anthelmintic activity, different solvent extracts of the whole plant were evaluated against Pheretima posthuma. Significant anthelmintic activity was observed with methanolic extract compared to other solvent extracts. The worm was paralyzed at 32 min and with increased concentration of methanolic extract from 2.5 to 10 mg mL the time decreased to 21 min (Prathibha and Jayaramu, 2019). 23.3.3 ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES Ethanolic extract of the whole plant showed significant anti-inflammatory activity equivalent to standard drug, diclofenac sodium in HRBC & carrageenan induced paw edema models (Gangabhavani and Ravishankar, 2013).

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23.3.4 ANTI-PLASMODIUM FALCIPARUM ACTIVITY Ether leaf extracts of J. betonica were tested for anti-Plasmodium falciparum activity using chloroquine diphosphate as the positive control. Significant schizonts suppression was noticed per 200 WBC with EC50 of 13.36 μg/mL (Bbosa et al., 2013). 23.3.5 ANTIOXIDANT ACTIVITY Odongo et al. (2018) studied the antioxidant activity of whole plant methanolic extract. The percent inhibition among various concentrations tested is 31.1% and the inhibitory concentration is 50 μg/mL. 23.3.6 ANTITUMOR ACTIVITY Compounds isolated from J. betonica, namely, 5H, 6H-Quinindolin-11-one (Caprio et al., 2000), 10H-Quindoline, Jusbetonin, Cilinaphthalide A (Subbaraju et al., 2004), and tuberculatin showed antitumor activity (Lu et al., 2008) 23.3.7 BRONCHODILATOR AND ANTIPLATELET AGGREGATION ACTIVITY 6H-Quinindoline and Cilinaphthalide-B from the plant have bronchodilatory and antiplatelet aggregation activity, respectively (Subbaraju et al., 2004). KEYWORDS • • • • •

Justicia betonica phytoconstituents antitumor activity antiplasmodial activity antioxidant activity

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REFERENCES Andy, A.; Ramani, M. V.; Subbaraju, G. V. 10H-Indolo [3, 2-b] Quinolone, a Potent Brine Shrimp Toxin from Justicia betonica. Asian J. Chem. 2007, 19 (1), 539–542. Bbosa, G.; Kyegombe, D. B.; Lubega, A.; Musisi, N.; Ogwal-Okeng, J.; Odyek, O. AntiPlasmodium falciparum Activity of Aloe dawei and Justicia betonica. African J. Pharma. Pharmacol. 2013, 7 (31), 2258–2263. Caprio, V.; Guyen, B.; Opoku-Boahen, Y.; Mann, J.; Gowan, A. M.; Kelland, L. M.; Readd, M. A.; Neidled, S. A Novel Inhibitor of Human Telomerase Derived from 10H-Indolo [3, 2-b] quinoline. Bioorg. Med. Chem. Lett. 2000, 10, 2063–2066. Gangabhavani, K.; Ravishankar, K. Evaluation of Analgesic and Anti-Inflammatory Activities of Ethanolic Extract of Whole Plant Justicia betonica. World J. Pharm. Pharma. Sci.2013, 2 (6), 5218–5228. Jeruto, P.; Lukhoba, C.; Ouma, G.; Otieno, D.; Mutai, C. Herbal Treatments in Aldai and Kaptumo Division in Nandi District, Rift Valley Province. African J. Trad. Complem. Altern. Med. 2008, 5 (1), 103–105. John, B.; Reddy, V. R. K.; Sulaiman, C. T. Total Phenolics and Flavonoids in Selected Justicia Species. J. Pharmacog. Phytochem. 2013, 2 (4), 72–73. Kanchanapoom, T.; Noiarsa, P.; Kasai, R.; Otsuka, H.; Ruchirawat, S. Justiciosides E-G, Triterpenoidal Glycosides with an Unusual Skeleton from Justicia betonica. Tetrahedron 2005, 61, 2583–2587. Kanchanapoom, T.; Noiarsa, P.; Ruchirawat, S.; Kasai, R.; Otsuka, H. Triterpenoidal Glycosides from Justicia betonica. Phytochem. 2004, 65, 2613–2618. Kokwaro, J. O.; Johns, T. Luo Biological Dictionary; East African Education Publishers: Nairobi, 1998. Lamorde, M.; Tabuti, J. R. S.; Obua, C.; Kukunda-Byobona, C.; Lanyero, H.; ByakikaKibwika, P. Medicinal Plants Used by Traditional Medicine Practitioners for the Treatment of HIV/AIDS and Related Conditions in Uganda. J. Ethnopharmacol 2008, 130, 43–53. Lu, Y. H.; Wei, B. L.; Ko, H. H.; Lin, C. N. DNA Strand-Scission by Phloroglucinols and Lignans from Heartwood of Garcinia subelliptica Merr. and Justicia Plants. Phytochemistry 2008, 69, 225–233. Odongo, E. N.; Mungai, P.; Mutai, E.; Karumi, J.; Mwangi, J.; Omale. Ethnobotanical Survey of the Medicinal Plants Used in Kakamega County, Western Kenya. Appl. Med. Res. 2018, 4, 22–40. Pacifica, B. C.; Nyanchongi, B.; Masai, R. Ethnobotanical Survey of Medicinal Plants Used for Treatment of Malaria by Kipsigis People in Kericho County, Kenya. J. Pharma. Bio. Sci. 2018, 13, 24–30. Prathibha, M.; Jayaramu, S. C. Phytochemical Screening and In Vitro Anthelmintic Properties of Justicia betonica L. Intern. J. Pharma Bio. Sci. 2019, 9 (1), 1426–1430. Rao, D. M.; Rao, U. V. U. B.; Sudharshanam, G. Ethno-Medico-Botanical Studies from Rayalaseema Region of South Eastern Ghats, Andhra Pradesh, India. Ethnobot. Leaflets 2006, 10, 198–207. Sasikumar, J. M.; Thayumanavan, T.; Subashkumar, R.; Janardhanan, K.; Lakshmanaperumalsamy, P. Antibacterial Activity of Some Ethnomedicinal Plants from the Nilgiris, Tamil Nadu, India. Nat. Prod. Radiance 2007, 6 (1), 34–39.

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Satyavathi, K.; Satyavani, S.; Padal, T. S.N.; Padal, S. B. Ethnomedicinal Plants Used by Primitive Tribal of Pedabayalu Mandalam, Visakhapatnam District, A.P, India. Intern. J. Ethnobiol. Ethnomed. 2014, 1, 1–7. Shinwari, Z. K.; Jan, S. A.; Khan, I.; Al, M.; Khan, Y.; Kumar, T. Ethnobotany and Medicinal Uses of Folklore Medicinal Plants Belonging to Family Acanthaceae: An Updated Review. MOJ Biol. Med. 2017, 1 (2), 34–38. Sini, S.; Prashy, P.; George, S. Preliminary Phytochemical Investigation and Estimation of Polyphenolics in Different Parts of Selected Species of Justicia. Eur. J. Biomed. Pharma. Sci. 2018, 5, 460–464. Ssenyondo, K. A.; Tibyangye, J.; Mivule A. Kinene, M. A.; Christopher, E.; Stephen,K.; Winnie, N.; Mongosho, D.; Hillary, K. Anti-Microbial Activity of Vernonia amygdalina, Justicia betonica, Leonatis nepetaefolium and Mormadica foetilda to Staphylococcus aureus. J. Pharm. Bio Sci.2020, 15 (2), 6–10. Subbaraju, G. V.; Kavitha, J.; Rajasekhar, D.; Jimenez, J. I. Jusbetonin, the First Indolo [3,2-b] Quinoline Alkaloid Glycoside from Justicia betonica. J. Nat. Prod. 2004, 67 (3), 461–462.

CHAPTER 24

A Review on Phytochemistry and Pharmacology Profile of Pendant Amaranth (Amaranthus caudatus L.) NAYAN KUMAR SISHU1, PARTHASARATHI THEIVASIGAMANI2, and CHINNADURAI IMMANUEL SELVARAJ2* Department of Biotechnology, School of Biosciences and Technology, VIT, Vellore 632014, Tamil Nadu, India

1

VIT School for Agricultural Innovations and Advanced Learning (VAIAL), Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Amaranthus caudatus L. is commonly known as “Tassel flower” or “foxtail Amaranth”. Its seed and leaf are considered to be very useful because of their high nutritional value. The plant is rich in vitamin C, vitamin A, riboflavin, iron, magnesium, and calcium. The plant is a diuretic, blood purifier; strangury; used to treat piles, anasarca and dropsy. Phytochemical studies show the presence of flavonoids, alkaloids, proteins, β-sitosterol, α-tocopherol, squalene, glucosinolates, lycopene, unsaturated fatty acids, beta-carotene, polyphenols (such as rutin, isoquercitrin, and nicotoflorin) in A. caudatus which are proved to be very crucial for treating diseases like constipation, diarrhoea, and hyperlipidaemia. The low molecular weight bioactive peptides found in this species of Amaranth play a crucial role in neutralizing free radicals, enhancing the activities of essential enzymes. In contrast, the high Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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molecular weight peptides help to inhibit the growth of colon cancer cells by enhancing the cytotoxicity of immune cells. Betalains extracted from the plant help to prevent the oxidation of low-density lipoprotein. Therefore, they are preferred widely in the food and pharmaceutical industries. Various studies indicate that the plant possesses antioxidant, anticancer, antidiabetic, cardio-protective, antimicrobial and antipyretic activities. 24.1 INTRODUCTION Amaranthus caudatus L. is an annual herb that is believed to be originated from tropical America, and it is widely distributed in Africa, Europe, and Asia. It is commonly known as “love-lies-bleeding” or “Tassel flower” or “foxtail Amaranth” in English. In Ayurveda, it is known as “Raam-daanaa.” In Siddha or Tamil, it is known as Sirukeerai. This species is a grainy amaranth. The grains deviate in color from red to white to brown. They are admired as an ornamental plants due to their majestic red inflorescence, they have dense spikes. The plant can reach up to 160–165 cm and is sun-loving (Ogwu and Chidozie, 2020). The leaf of the plant is ovate to rhomboid-ovate or ovate-elliptic in shape and has a long petiole. The flowers are axillary and formed of cymose clusters. It is an economically important crop that can be grown quickly. It has a remarkable ability to resist heat, pest infections, and water scarcity. Its seed and leaf are considered to be very useful because of their high nutritional value. Products of A. caudatus do not cause any allergic reaction in the intestine of celiac disease people (Joshi and Verma, 2020). The plant is a rich source of vitamin C, vitamin A, riboflavin, iron, magnesium, and calcium. Amaranth seed can produce pseudo cereals which can be an effective supplement to prevent malnutrition in developing countries with low income and food deficiency. The plant is a diuretic, blood purifier; strangury; used to treat piles, anasarca and dropsy; hydro infusion has been used to reduce pneumonic conditions; given in scrofula and applied to scrofulous abscesses. Antimicrobial peptides have been isolated from seeds (Khare, 2008). In western traditional medicine, love-lies-bleeding is compared with Amaranthus hypochondriacus and is used to treat diarrhea, ulcers, soreness of the throat and mouth. Preliminary indication suggests that amaranth seeds can decrease LDL and total cholesterol while boosting HDL. However, amaranth biscuits failed to lessen cholesterol levels in hypercholesterolemic men and women beyond the results achieved by a low-fat diet. (Natural Medicines Comprehensive Database, 2007). The approximate composition

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of A. caudatus plant consists of moisture-content, ash, fat, protein, crude fiber, calorific value (K. cal/100 g), dry matter content, and lipid as 74.8, 64, 10, 14, 8, 200.40, 7.2, and 5.5 percentages, respectively. The nutritive value of A. caudatus seeds, reported to possess 261, 261, 322.4, 14.3, 21.2, 0.2, 0.5, 0.9 of Ca, Mg, K, Fe, Na, thiamine, riboflavin, and niacin, respectively (Ogwu and Chidozie, 2020). 24.2 BIOACTIVITES Phytochemical studies show the presence of flavonoids, alkaloids, proteins, β-sitosterol, α-tocopherol, squalene, glucosinolates, lycopene, unsaturated fatty acids, beta-carotene, polyphenols (such as rutin, isoquercitrin, and nicotoflorin) in A. caudatus which are proved to be very crucial for treating diseases like constipation, diarrhea, and hyperlipidaemia (De la Rosa et al., 2009). The amino acids such as isoleucine, lysine, tryptophan, methionine, and threonine are abundantly found in A. caudatus (Bressani, 1989; Mota et al., 2016). The low molecular weight bioactive peptides (such as YESGSQ, GGEDE, and NRPET) found in this species of Amaranth play a crucial role in neutralizing free radicals, enhancing the activities of essential enzymes. In contrast, the high molecular weight (such as STNYFLISCLLFVLFNGCMGEG and GLTEVWDSNEQEF) peptides help in inhibit the growth of colon cancer cells by enhancing the cytotoxicity of immune cells (Vilcacundo et al., 2019). Various phenolic compounds are isolated from the seed and leaves of A. caudatus; they are generally flavonoids and polyphenol compounds, such as salicylic acid, ferulic acid, quercetin, gentisic acid, ellagic acid, protocatechuic acid, rutin, caffeic acid, chlorogenic acid, gallic acid, vanillic acid, kaempferol-3-rutinoside, and 2,4-dihydroxybenzoic acid (Karamać et al., 2019; Conforti et al., 2005; Li et al., 2015; Jimoh et al., 2019). Studies related to the shoot extract of this plant show the presence of components such as ferulic acid, p-coumaric acids, betalains, amaranthin, amaricin, amaranthoside, carotenoids, and flavonoids (De la Rosa et al., 2009; Martirosyan et al., 2004; Oboh et al., 2008). Squalene is an essential phytosterol isolated from the plant in an unsaponifiable fraction, which is associated with lowering LDL. Betalains extracted from the plant help to prevent the oxidation of low-density lipoprotein. Therefore, they are preferred widely in the food and pharmaceutical industries (Li et al., 2015; Tesoriere et al., 2004). The important bioactive compounds found in A. caudatus are shown in Figures 24.1 and 24.2.

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FIGURE 24.1 Important bioactive compounds found in A. caudatus.—1. squalene, 2. β-carotene, 3. lycopene, 4. β-sitosterol, 5. α-tocopherol, 6. betalains, 7. chlorogenic acid, 8. vanillic acid, 9. gallic acid, and 10. protocatechuic acid (Marvin 17.21.0, ChemAxon tool was used for drawing chemical structures).

FIGURE 24.2 Important bioactive compounds found in A. caudatus.—11. salicylic acid, 12. rutin, 13. quercetin, 14. caffeic acid, 15. ferulic acid and 16. ellagic acid (Marvin 17.21.0, ChemAxon tool was used for drawing chemical structures).

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PHARMACOLOGY

24.3.1 ANTIOXIDANT ACTIVITY Various phenolic and polyphenol compounds have been investigated in A. caudatus which act as antioxidants that can neutralize ROS’s effect and reduce oxidative stress conditions and tissue damage. Several studies have been done to identify and quantify the type and amount of antioxidants present in A. caudatus. It was reported that A. caudatus methanol extract contains 48% of the total phenolic component, and these components have a substantial antioxidant property (Kumar et al., 2011; Peiretti et al., 2017; Martinez-Lopez et al., 2020). In addition, it was reported that the leaves of A. caudatus contain tannin, which possess nutraceutical values and exhibits a good level of antioxidant activity (Jo et al., 2015). It was reported by Kumar et al. (2011) that A. caudatus methanol extract exhibits substantial antioxidant property, which was confirmed by ABTS assay where the extract was found to be effective against ABTS radical with an IC50 value of 48.75 ± 1.1 mg/mL. 24.3.2 ANTIDIABETIC PROPERTY The significant antidiabetic activity was observed in streptozotocin-induced diabetic rats when administered with methanolic extract of A. caudatus for 21 days. It was observed by Girija et al. (2011) that there was a significant decrease of 59.60% in serum glucose level in the STZ-induced rat treated with methanolic extract of A. caudatus at 400 mg/kg at the end of 21 days of treatment. It was reported that health improvement was observed in patients suffering from obesity and diabetes after taking amaranthus seed-based food containing important bioactive peptides for 3 months (Gómez-Cardona et al., 2017). Based on the model of type II diabetes, it was reported that administration of 2000 mg hydro-ethanolic extract of A. caudatus per kg body weight of Goto-Kakizaki Rats and Wistar rats had shown significant improvement in glucose tolerance by increasing the serum insulin level of the body (Zambrana et al., 2018). 24.3.3

CARDIO-PROTECTIVE PROPERTY

It has been reported that various components found in the seeds of A. caudatus help regulate our body’s anticholesterolemic activity (MartinezLopez et al., 2020). Oil extracted from A. caudatus has been proved to be

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effective in preventing hypertension and cardiovascular disease. Consumption of amaranth regularly can effectively reduce the level of cholesterol and blood pressure (Bruni et al., 2001). There was seen a significant change in the lipid profile of a diabetic rat after administration of methanolic extract of A. caudatus which includes a reduction in the level of cholesterol (25.7%), high-density lipoprotein (3.57%), low-density lipoprotein (31.7%), very low-density lipoprotein (41.7%) at 400 mg/kg of extract over 21 days (Girija et al., 2011). Squalene isolated from A. caudatus shows antiatherogenic and antihypercholesterolemic activity by reducing the level of serum lipids and biomarkers of oxidative stress condition in rabbits fed with high cholesterol diet (Kabiri et al., 2010). It was reported that A. caudatus seed possesses hypoglycemic, antineoplastic, and anticholesterol properties and enhances the functioning of the immune system (Caselato-Sousa and Amaya-Farfan, 2012). However, few studies suggest that the use of seed and leaves extract of A. caudatus can be proved to be a potential compound against the hypercholesterolemia effect associated with coronary heart diseases in some patients (Martinez-Lopez et al., 2020). 24.3.4 ANTIHELMINTHIC PROPERTY The extract obtained from A. caudatus is proved to be a potent antihelminthic agent with effective vermifugal properties due to the presence of polyphenol compounds (Jimoh et al., 2019). Kumar et al. (2010) comparatively studied the vermifugal effect of methanolic extract of A. caudatus with a notable worm expeller, piperazine. It was reported that, unlike piperazine which has only a paralytic effect on worms, the plant extract resulted in the death of an adult Pheretima posthuma (which is structurally similar to human annelids) after paralyzing it. 24.3.5 ANTIMICROBIAL ACTIVITY Ac-AMP1 and Ac-AMP2 are the two effective antibacterial bioactive peptides isolated from A. caudatus seed extract that inhibit the growth of different bacterial strains thus, and it possesses antibacterial property. In addition, the peptides possess antifungal activity (Broekaert et al., 1992). Therefore, the consumption of A. caudatus extracts as medicine prevents the annexation of Escherichia coli into epithelial cells of the urinary tract (Mohanty et al., 2018). Ethanolic extract of A. caudatus has a practical

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antibacterial effect on Gram-negative and Gram-positive bacteria compared to the compounds derived from petroleum and chloroform (Maiyo et al., 2010). Ethyl acetate, methanol, dichloromethane, and hexane leaf extracts obtained from Amaranthus hybridus, Amaranthus spinosus, and A. caudatus exhibited a broad range of antibacterial activity. The MIC value for A. spinosus extracts was 129 mg/mL against Salmonella typhi, the MIC value for A. hybridus extracts against S. typhi ranged from 200 to 755 mg/mL, whereas the MIC value for A. caudatus ranged between 162.2 and 665 mg/ mL (Maiyo et al., 2010). Zinc oxide nanoparticle synthesized from aqueous extract of A. caudatus possesses antibacterial property against Gram-positive Staphylococcus epidermidis (MTCC9040) and Gram-negative Enterobacter aerogenes (MTCC8100) by forming an inhibition zone of 14 and 9 mm, respectively (Jeyabharathi et al., 2017). 24.3.6 HEPATO-PROTECTIVE PROPERTY The extract from A. caudatus induces resistance against infections resulting from disease-causing agents by regulating the liver’s host immune system (Kumar et al., 2010). A. caudatus can increase the hepatoprotective activity in Wistar rats treated with paracetamol-induced liver damages at 200 and 400 mg/kg doses of methanolic extract of plant (Kumar et al., 2011). Amaranthin, a lectin isolated from A. caudatus is a potent component of A. caudatus agglutinin (ACA), an identifier for both NeuAcα2–3Galβ1– 3GalNAcα-Oand Galβ1–3GalNAcα-O- is an essential glycoprotein conjugate regarded as pancarcinoma antigens which can detect and prevent the exacerbation of hepatocellular carcinoma in humans (Kumar et al., 2011; Jimoh et al., 2019). 24.3.7 ANTICANCER ACTIVITY Pretreatment of white albino Wistar rats with aqueous extract of A. caudatus and A. hybridus before the exposure of NaAsO2 significantly decrease the GGT activity to about 1.9 and 1.6 folds and ALP activity to about 1.4 and 1.04 folds, respectively, in comparison with the sodium arsenite-treated group (Adewale and Olorunju, 2013). Lectin derived from A. caudatus possesses high activity antiproliferative and anticancer activity, and inhibits the growth of the UMR106 cell line with an IC50 = 0.08 mg/mL. The study concludes that amaranth lectin is five times stronger than refined lectin (Quiroga et al., 2015). The TF-binding lectins derived from A. caudatus may be used as

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biomarkers to study malignant gastrointestinal epithelial cells proliferation and help diagnose intestinal cancer (Yu et al., 2001). In addition, a study indicates that the lectin isolated from A. caudatus can prevent hepatocellular carcinoma (Jimoh et al., 2019). 24.3.8 ANTIPYRETIC ACTIVITY The methanol extract of three Amaranthus species, namely Amaranthus viridis, A. spinosus, and A. caudatus exhibited a significant antipyretic activity by yeast-induced elevated body temperature in rats at a dose of 200 and 400 mg/kg, when compared with standard antipyretic drug paracetamol (Bagepalli et al., 2011). Furthermore, the methanol extract of A. caudatus exhibits antipyretic activity in the rat by lowering the elevated body temperature, which resulted from Brewer’s yeast-induced pyrexia at different doses (Kumar et al., 2010). KEYWORDS • • • • • •

Amaranthus caudatus a-tocopherol betalain glucosinolate amaranthin quercetin

REFERENCES Adewale, A.; Olorunju, A. E. Modulatory of Effect of Fresh Amaranthus caudatus and Amaranthus hybridus Aqueous Leaf Extracts on Detoxify Enzymes and Micronuclei Formation After Exposure to Sodium Arsenite. Pharmacogn. Res. 2013, 5 (4), 300. Bagepalli, S. A. K.; Kuruba, L.; Jayaveera, K. N. Comparative Antipyretic Activity of Methanolic Extracts of Some Species of Amaranthus. Asian Pac. J. Trop. Biomed. 2011, 1 (1), 47–50. Bressani, R. The Proteins of Grain Amaranth. Food Rev. Int. 1989, 5 (1), 13–38. Broekaert, W. F.; Marien, W.; Terras, F. R.; De Bolle, M. F.; Proost, P.; Van Damme, J.; Dillen, L.; Claeys, M.; Rees, S. B. Antimicrobial Peptides from Amaranthus caudatus Seeds with

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Sequence Homology to the Cysteine/Glycine-Rich Domain of Chitin-Binding Proteins. Biochem.1992, 31 (17), 4308–4314. Bruni, R.; Medici, A.; Guerrini, A.; Scalia, S.; Poli, F.; Muzzoli, M.; Sacchetti, G. Wild Amaranthus caudatus Seed Oil, a Nutraceutical Resource from Ecuadorian Flora. J. Agric. Food Chem. 2001, 49 (11), 5455–5460. Caselato-Sousa, V. M.; Amaya-Farfán, J. State of Knowledge on Amaranth Grain: A Comprehensive Review. J. Food Sci. 2012, 77 (4), 93–104. Conforti, F.; Statti, G.; Loizzo, M. R.; Sacchetti, G.; Poli, F.; Menichini, F. In Vitro Antioxidant Effect and Inhibition of α-Amylase of Two Varieties of Amaranthus caudatus Seeds. Biol. Pharm. Bull. 2005, 28 (6), 1098–1102. De la Rosa, A. B.; Fomsgaard, I. S.; Laursen, B.; Mortensen, A. G.; Olvera-Martínez, L.; Silva-Sánchez, C.; Mendoza-Herrera, A.; González-Castañeda, J.; De León-Rodríguez, A. Amaranth (Amaranthus caudatus) as an Alternative Crop for Sustainable Food Production: Phenolic Acids and Flavonoids with Potential Impact on Its Nutraceutical Quality. J. Cereal Sci. 2009, 49 (1), 117–121. Girija, K.; Lakshman, K.; Udaya, C.; Sachi, G. S.; Divya, T. Anti–Diabetic and Anti– Cholesterolemic Activity of Methanol Extracts of Three Species of Amaranthus. Asian Pac. J. Trop. Biomed. 2011, 1 (2), 133. Gómez-Cardona, E. E.; Hernández-Domínguez, E. E.; Huerta-Ocampo, J. Á.; Jiménez-Islas, H.; Díaz-Gois, A.; Velarde-Salcedo, J.; Barrera-Pacheco, A.; Goñi-Ochoa, A.; Barba de la Rosa, A. P. Effect of Amaranth Consumption on Diabetes-Related Biomarkers in Patients with Diabetes. Diabetes Obes. Metab. Disord. 2017, 3, 5–10. Jeyabharathi, S.; Kalishwaralal, K.; Sundar, K.; Muthukumaran, A. Synthesis of Zinc Oxide Nanoparticles (ZnONPs) by Aqueous Extract of Amaranthus caudatus and Evaluation of Their Toxicity and Antimicrobial Activity. Mater. Lett. 2017, 209, 295–298. Jimoh, M. O.; Afolayan, A. J.; Lewu, F. B. Therapeutic Uses of Amaranthus caudatus L. Trop. Biomed. 2019, 36, 1038–1053. Jo, H. J.; Chung, K. H.; Yoon, J. A.; Lee, K. J.; Song, B. C.; An, J. H. Radical Scavenging Activities of Tannin Extracted from Amaranth (Amaranthus caudatus L.). J. Microbiol. Biotechnol. 2015, 25 (6), 795–802. Joshi, N.; Verma, K. C. A Review on Nutrition Value of Amaranth (Amaranthus caudatus L.): The Crop of Future. J. Pharmacogn. Phytochem.2020, 9 (4), 1111–1113. Kabiri, N.; Asgary, S.; Madani, H.; Mahzouni, P. Effects of Amaranthus caudatus L. Extract and Lovastatin on Atherosclerosis in Hypercholesterolemic Rabbits. J. Med. Plant Res. 2010, 4 (5), 354–361. Karamać, M.; Gai, F.; Longato, E.; Meineri, G.; Janiak, M. A.; Amarowicz, R.; Peiretti, P. G. Antioxidant Activity and Phenolic Composition of Amaranth (Amaranthus caudatus) During Plant Growth. Antioxidants 2019, 8 (6), 173. Khare, C. P. Indian Medicinal Plants: An Illustrated Dictionary; Springer Science & Business Media, 2008 Apr 22. Kumar, A.; Lakshman, K.; Jayaveera, K. N.; Sheshadri Shekar, D.; Narayan Swamy, V. B.; Khan, S.; Velumurga, C. In Vitro α-Amylase Inhibition and Antioxidant Activities of Methanolic Extract of Amaranthus Caudatus Linn. Oman Med. J. 2011, 26 (3), 166. Kumar, B. S. A.; Lakshman, K.; Jayaveera, K. N.; Velmurugan, C.; Manoj, B.; Sridhar, S. M. Anthelmintic Activity of Methanol Extract of Amaranthus caudatus Linn. Int. J. Food Safet. 2010, 12, 127–129.

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Kumar, B. S. A.; Lakshman, K.; Jayaveera, K. N.; Shekar, D. S.; Murugan, C. S. V. Antinociceptive and Antipyretic Activities of Methanol Extract Amaranthus caudatus Linn. Lat. Am. J. Pharm. 2010, 29 (4), 635–639. Li, H.; Deng, Z.; Liu, R.; Zhu, H.; Draves, J.; Marcone, M.; Sun, Y.; Tsao, R. Characterization of Phenolics, Betacyanins and Antioxidant Activities of the Seed, Leaf, Sprout, Flower and Stalk Extracts of Three Amaranthus Species. J. Food Compost. Anal. 2015, 37, 75–81. Maiyo, Z. C.; Ngure, R. M.; Matasyoh, J. C.; Chepkorir, R. Phytochemical Constituents and Antimicrobial Activity of Leaf Extracts of Three Amaranthus Plant Species. Afr. J. Biotechnol. 2010, 9 (21), 3178–3182. Martinez-Lopez, A.; Millan-Linares, M. C.; Rodriguez-Martin, N. M.; Millan, F.; Montserrat-de la Paz, S. Nutraceutical Value of Kiwicha (Amaranthus caudatus L.). J. Funct. Foods 2020, 65, 103735. Martirosyan, D. M.; Kadoshnikov, S. I.; Bil, K. Y.; Tchernov, I. A.; Kulikov, Y. A. Carotenoids Accumulation in the Amaranth and its Role in Cancer Prevention. In Phytotherapy with Biological Active Substrates on the Basis of Natural Sources; Chernogolovka: Russia, 2004; pp 100–112. Mohanty, S.; Zambrana, S.; Dieulouard, S.; Kamolvit, W.; Nilsén, V.; Gonzales, E., Östenson, C. G.; Brauner, A. Amaranthus caudatus Extract Inhibits the Invasion of E. coli Into Uroepithelial Cells. J. Ethnopharmacol. 2018, 220, 155–158. Mota, C.; Santos, M.; Mauro, R.; Samman, N.; Matos, A. S.; Torres, D.; Castanheira, I. Protein Content and Amino Acids Profile of Pseudocereals. Food Chem. 2016, 193, 55–61. Natural Medicines Comprehensive Database. Therapeutic Research Facility; Stockton, CA-95208, 2007. www.naturaldatabase.com Oboh, G.; Raddatz, H.; Henle, T. Antioxidant Properties of Polar and Non-Polar Extracts of Some Tropical Green Leafy Vegetables. J. Sci. Food Agric. 2008, 88 (14), 2486–2492. Ogwu,; Chidozie. M. Value of Amaranthus [L.] Species in Nigeria. In Nutritional Value of Amaranth; IntechOpen, 2020. Peiretti, P. G.; Meineri, G.; Gai, F.; Longato, E.; Amarowicz, R. Antioxidative Activities and Phenolic Compounds of Pumpkin (Cucurbita pepo) Seeds and Amaranth (Amaranthus caudatus) Grain Extracts. Nat. Prod. Res. 2017, 31 (18), 2178–2182. Quiroga, A. V.; Barrio, D. A.; Añón, M. C. Amaranth Lectin Presents Potential Antitumor Properties. LWT-Food Sci. Technol. 2015, 60 (1), 478–485. Tesoriere, L.; Allegra, M.; Butera, D.; Livrea, M. A. Absorption, Excretion, and Distribution of Dietary Antioxidant Betalains in LDLs: Potential Health Effects of Betalains in Humans. Am. J. Clin. Nutr. 2004, 80 (4), 941–945. Vilcacundo, R.; Martínez-Villaluenga, C.; Miralles, B.; Hernández-Ledesma, B. Release of Multifunctional Peptides from Kiwicha (Amaranthus caudatus) Protein Under In Vitro Gastrointestinal Digestion. J. Sci. Food Agric. 2019, 99 (3), 1225–1232. Yu, L. G.; Milton, J. D.; Fernig, D. G.; Rhodes, J. M. Opposite Effects on Human Colon Cancer Cell Proliferation of Two Dietary Thomsen-Friedenreich Antigen-Binding Lectins. J. Cell. Physiol. 2001, 186 (2), 282–287. Zambrana, S.; Lundqvist, L. C.; Veliz, V.; Catrina, S. B.; Gonzales, E.; Östenson, C. G. Amaranthus caudatus Stimulates Insulin Secretion in Goto-Kakizaki Rats, a Model of Diabetes Mellitus Type 2. Nutrients 2018, 10 (1), 94.

CHAPTER 25

Bioactives and Therapeutic Potential of Blood Amaranth (Amaranthus cruentus L.) NAYAN KUMAR SISHU1, BABU SUBRAMANIAN2, and CHINNADURAI IMMANUEL SELVARAJ1,* School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632 014, India

1

School of Agricultural Innovations and Advanced Learning, Vellore Institute of Technology, Vellore, Tamil Nadu 632 014, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Amaranthus cruentus L. (Amaranthaceae) is an endemic plant species of Mesoamerica. It is a pseudo-cereal of low gluten content with excellent protein content and quality. It controls cholesterol, glycemic condition, and increased oxidative stress. It has cardioprotective, anticancer, and hepatoprotective properties. Its constituents combine essential amino acids (lysine, tryptophan), protein (globulins, albumins), fatty acids (squalene), micronutrients (minerals and vitamins), and tocopherols. It is abundant in vitamins, namely, vitamin B6, β-carotene, riboflavin, vitamin C, and folic acid, and dietary minerals. A. cruentus is abundant in lysine, an essential amino acid, lysine, which is found lacking in cereals and tubers. Various reports suggest that A. cruentus is rich in bioactive compounds, including alkaloids, flavonoids, polyunsaturated fatty acids, steroids, bioactive peptides, phenols, and polyphenols. The plant is rich in coumaric acid, gallic acid, p-hydroxybenzoic acid, squalene, and tannins. The most abundant phytosterol found in A. cruentus is spinasterol (46–54%), Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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D7-stigmasterol (15–18%), ergosterol (12–15%), and 10–13% stigmasterol. The most abundant flavonoids were rutin, isoquercetin, and nicotiflirin. In general, the plant possesses antioxidant, anticancer, cardioprotective, hypocholesterolemic and antidiabetic activity. 25.1

INTRODUCTION

Amaranthus cruentus L. (Amaranthaceae) is a regional plant species of Mesoamerica. It grows in tropical Africa, Southeast Asia, Mexico, Ecuador, and Colombia, and is believed to be first cultivated in Central America to produce pseudo-cereals. Leaves are ovate to rhombic-ovate in shape and are arranged spirally, simple, without stipules. The annual herb is with a cluster of dark red flowers on the terminal part of the plant. The inflorescence is axillary and provided with racemes and spikes. The plant gets consumed as a substitute for spinach due to its good nutrition value. It is rich in protein, carbohydrates, and vitamins. It is a pseudo-cereal of low gluten content with excellent protein content and quality (Cáceres and Cruz, 2019). It is a herbaceous seasonal leafy vegetable grown for fresh market in 28–42 days subsequent after planting. It is a generally dispersed species occurring primarily in tropical and temperate zones. It is helpful in the control of cholesterol, raised glycemia, and increased oxidative stress. It has cardioprotective, anticancer, and hepatoprotective properties (Peter and Gandhi, 2017). Its constituents combine essential amino acids (lysine, tryptophan), protein (globulins, albumins), fatty acids (squalene), micronutrients (minerals and vitamins), and tocopherols (Loaiza et al., 2016; Musa et al., 2011; Venskutonis and Kraujalis, 2013). It is abundant in vitamins, namely, vitamin B6, β-carotene (precursor of vitamin A), riboflavin, vitamin C, and folic acid, and dietary minerals, namely, iron, calcium, phosphorus, magnesium, zinc, potassium, manganese, and copper (Makus, 1984; Stallknecht and Schulz-Schaeffer, 1993). A. cruentus is abundant in lysine, an essential amino acid, lysine, which is found lacking in cereals and tubers (Schipper, 2000). In Nigeria, amaranthus leaves combined with condiments are used to prepare the sauce (Mepba et al., 2007). The ascorbic acid, cyanide content, total and soluble oxalates content in A. cruentus increased significantly during the heading stage. β-carotene and nitrate levels significantly decreased during heading; besides that, the decrease in β-carotene was not significant in plants administered with nitrogenous fertilizer. Furthermore, the results indicate that magnesium, zinc, calcium, and potassium levels were not significantly influenced by heading. However, the Fe concentration was increased (Musa et al., 2011). In Senegal, this plant’s roots are boiled with honey and used

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as a laxative for infants. In Ghana, the plant’s aqueous extract is used as a painkiller by people suffering from limbs and joints pain. In Ethiopia, A. cruentus is used as an expellant against tapeworm infestation. In Sudan, the plant stem is dried and burnt to obtain the ash used in dressing wounds. In Gabon, the leaves are heated and used to treat skin tumors (Grubben, 2004). A moderate to a high level of oxalic acid in leaves of Amaranthus sps. represses the retention of calcium and additional minerals, leading to electrolyte imbalance and kidney stone formation (Robertson, 2010). A. cruentus, under specific circumstances, raised nitrate content surpassing the tolerable limit (Macrae et al., 1997). The plant is prescribed for children, lactating mothers, and people suffering from constipation, fever, hemorrhage, and kidney complaints due to its high medicinal importance (Grubben, 2004). The approximate composition of A. cruentus plant (leaf and stem) consists of carbohydrates, moisture-content, ash, fat, protein, crude fiber, calorific value, and lipid content as 9.8%, 63.8%, 7.2%, 1.6%, 8.1%, 6.4%, and 5.5%, respectively. The nutritive value of A. cruentus plant, reported to possess 175, 244, 290, 17.4, 37.0, 0.1, 0.2, 1.2, and 4.5 mg of Ca, Mg, K, Fe, Na, thiamin, riboflavin, niacin, and vitamin C, respectively (Ogwu and Chidozie, 2020). 25.2 BIOACTIVES A. cruentus have a high-fat content more than cereal grains because the oil consists principally of unsaturated fatty acids (linolenic, oleic, and linoleic). The unsaturated fatty acid and linolenic acid are exogenous fatty acids vital for the human body. Relevant components of the fatty acid fraction include tocotrienols, squalene, and tocopherols. In addition, these compounds are valuable due to their antioxidant properties (Skwaryło-Bednarz et al., 2020). Many reports suggest that A. cruentus is rich in bioactive compounds, including alkaloids, flavonoids, polyunsaturated fatty acids, steroids, bioactive peptides, phenols, and polyphenols. Products derived from A. cruentus are suitable for a person with celiac disease and diabetic patients (Guerra-Matias and Arêas, 2005). A. cruentus seeds are rich in protein, namely albumins (48.9–65%), globulins (13.7–18.1%), prolamins (1.0–3.2%), and glutelins content (22.4–42.3%), since it has a low percentage of gluten prolamins and is used a pseudo-cereal (Januszewska-Jozwiak and Synowiecki, 2008). As there is a high concentration of globulin and glutenin in the seed extract of A. cruentus, it is a potential source of antihypertensive compounds (Wolosik and Markowska, 2019). A. cruentus contains a 43 amino acid, potent bioactive protein “Lunasin” with the conserved region for chromatin-binding protein, and Arg-Gly-Asp cell adhesion motif (Januszewska-Jozwiak and Synowiecki,

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2008; Wolosik and Markowska, 2019). The plant is rich in coumaric acid, gallic acid, p-hydroxybenzoic acid, squalene, and tannins. The plant’s tannins content is known to be 1.57 mg/100 mg of dry aerial material. It has medicinal importance as it possesses antidiarrheal activity and helps to prevent hemorrhages (Nana et al., 2012). The most abundant phytosterol found in A. cruentus is spinasterol (46–54%), D7-stigmasterol (15–18%), ergosterol (12–15%), and 10–13% stigmasterol (Schnetzler and Breene, 1994; Marcone et al., 2003; Venskutonis and Kraujalis, 2013). The plant extract contains 47% of linoleic acid, 24% of oleic acid, and 23.4% of palmitic acid out of the total fatty acid percentage (Wolosik and Markowska, 2019). Total flavonoid content is highest in A. cruentus followed by Amaranthus hybridus, Amaranthus hypochondriacus, and Amaranthus caudatus, the value ranging from 8.91 to 9.93 mg CE/100 g (Akin-Idowu et al., 2017). Furthermore, the most abundant flavonoids were rutin, isoquercetin, and nicotiflirin (Nana et al., 2012). In A. cruentus, the betacyanin and betaxanthin contents are 40.42 mg amaranthin equivalent per 100 g dry weight and 19.34 mg indicaxanthin equivalent per 100 g dry weight, respectively (Nana et al., 2012). Structures of a few important bioactive compounds found in A. cruentus are depicted in Figure 25.1.

FIGURE 25.1 Structures of some important bioactive compounds found in A. cruentus; 1. gallic acid, 2. 4-hydroxybenzoic acid, 3. coumaric acid, 4. vanillic acid, 5. isoquercetin, 6. rutin, 7. linoleic acid, 8. stigmasterol, 9. spinasterol, 10. betacyanin, 11. amaranthin (Marvin 17.21.0, ChemAxon tool was used for drawing chemical structures).

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25.3.1 ANTIOXIDANT PROPERTY A study was conducted in A. cruentus to protect DNA damage against provoked mycotoxin aflatoxin B1 (AFB1) and oxidative strain using the comet assay. In addition, the antioxidant activity was examined using electron paramagnetic resonance spectroscopy (EPR) and an ARE/Nrf2 reporter gene assay in vitro in HepG2 cell lines. Ethanolic leaf extracts repressed both AFB1 and oxidative stress-provoked DNA damage in a concentration-reliant mode with the highest effect of 81% and 57%. Moreover, oxidative stress triggered utilizing ferrous sulfate was prevented up to 38.0% (EPR); the potential to influence antioxidant enzymes with ARE/Nrf2-interfered gene expression was established (Odongo et al., 2018). Escudero et al. (2011) reviewed the antioxidant activity of the bioactive compounds in A. cruentus (Ac) seed protein concentrate (PCAc) and flour (FAc). They studied the effect of treatment on the liver of Wistar rats. Total phenols content (mg gallic acid eq/100 g dry weight) was 190.23 ± 1.50 for PCAc and 73.78 ± 1.70 for FAc. The antioxidant activity was determined by: β-carotene bleaching technique (β-carotene), 1, 1-diphenyl-2-picrylhydrazyl (DPPH), and nitric oxide scavenging action (NO). The values expressed as percentage represent to PCAc and FAcs, sequentially. β-carotene: 44.60 ± 1.5 and 83.00 ± 1.8; DPPH: 88.83 ± 1.2 and 86.30 ± 1.1; NO: 48.75 ± 1.7 and 29.38 ± 1.9. The histological investigation shows that casein-fed animals exhibit average fat infiltration in the liver, whereas in PCAc-fed rats, the liver maintained its anatomical integrity. The presence of phenols might stimulate enhanced antioxidant defenses and might protect the liver (Escudero et al., 2011). To understand the antioxidant property of A. cruentus, major scientific work was done using methanol, ethanol, hydro-acetone, and aqueous extract of leaf, stem, and root of the plant. Reports indicate that the methanol and hydro-acetone extract of A. cruentus exhibited remarkable antioxidant properties. The hydro-acetone extract exhibited the highest free-radical scavenging activity in DPPH assay with an IC50 value of 75.6 ± 0.5 μg/mL (Nana et al., 2012). During DPPH assay, aqueous extract of A. cruentus leaves exhibited antiradical activity with an IC50 value of 548 µg/mL (Samarth et al., 2008). A study to determine the antioxidant capacity using ABTS assay, A. cruentus extract exhibited the highest free radical scavenging activity (179.3 mmol TE/100 g) compared to other species (Akin-Idowu et al., 2017). The extract of A. cruentus shows considerable xanthine oxidase inhibitory activity with

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an inhibition percentage of 3.18 ± 1.10% (Nana et al., 2012). The conclusion is that the plant’s antioxidant property is due to the presence of flavonoids and polyphenols. In ultrasound and the SCE-CO2 method, reports indicate that alpha-tocopherol, gamma-tocotrienol, delta-tocotrienol, and beta-tocotrienol are present in the extract of A. cruentus. These compounds mainly inhibit new free radicals’ production and enhance antioxidant capacity (Venskutonis and Kraujalis. 2013). 25.3.2 ANTICANCER ACTIVITY A bioactive peptide Lunasin found in A. cruentus possesses anticarcinogenic properties. It can inhibit the mechanism of acetylation of histone protein (H3 and H4) and exhibits an epigenetic mechanism for preventing carcinoma. The protein plays an essential role in chromatin modification during cell cycle control and promotes tumor suppressors during carcinogenesis (Jeong et al., 2002; Maldonado-Cervantes et al., 2010). Squalene present in A. cruentus believed to reduce the risk of skin, colon, and breast cancer. It can suppress tumor cell growth and enhance antineoplastic agents′ functioning, such as 5-fluorouracil, bleomycin, Adriamycin, and omega-3 fatty acids. Hence, it improves the immune system naturally (Grajeta, 2000). Trypsin hydrolysate isolated from the grain of A. cruentus exhibited a robust anticancer activity against MCF-7, A549, and HEK 293 cell lines confirmed by MTT cytotoxicity assay, caspase 3/7 activity, and Annexin V-FITC flow cytometry which exhibited significant apoptosis of cancer cells (Ramkisson et al., 2020). The aqueous extract of A. cruentus has antiproliferative activity against human peripheral lymphocytes. It could be an inexpensive, biocompatible antiproliferative therapeutics (Gandhi et al., 2011). 25.3.3 ANTHELMINTHIC ACTIVITY The extract of A. cruentus shows tapeworm expellant property. Further, the plant’s anthelminthic activity, confirmed by Torane et al. (2017) for various concentration (0.1 and 0.25 mg/mL) of aqueous and chloroform extract of A. cruentus. Each extract was compared with standard albendazole with the same set of concentrations. The extracts resulted in paralysis followed by the death of Eicinia feotida (experimental model) at all tested levels. The aqueous extract exhibit significant vermicide activity similar to the standard albendazole (0.25 mg/mL) concentration.

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25.3.4 ANTIDIABETIC ACTIVITY A study indicated that in type 2 diabetic patient, hyperglycemia results from hydrolysis of starch by pancreatic alpha-amylase and absorption of the high amount of glucose by intestinal alpha-glucosidases. A significantly higher inhibitory activity of fresh ethanol leaf extract of A. cruentus (0.32 mg/mL) was observed against alpha-amylase than blanched A. cruentus (0.72 mg/ mL). Similarly, the ethanol leaf extract of fresh A. cruentus (0.21 mg/mL) exhibits significantly higher inhibitory activity against alpha-glucosidase than blanched extract (0.29 mg/mL). This activity is due to antioxidant molecules, which decreases the blood glucose level in diabetic condition (Oboh et al., 2013). 25.3.5

HYPOCHOLESTEROLEMIC ACTIVITY

A study to find out the antihypocholesterolemic activity of A. cruentus in hamsters, fed with a diet containing 20% of A. cruentus grains and a total of 5% amaranth oil, exhibited a low level of non-HDL cholesterol. Thus, it confirms that phytosterols and the antioxidant molecules present in A. cruentus have hypocholesterolemic activity. It regulates the function by enhancing the activity of tocopherols (Berger et al., 2003). Squalene obtained from A. cruentus can decrease LDL level by replacing it with highdensity lipoprotein cholesterol to improve hypercholesterolemic patients’ blood cholesterol levels (Wolosik and Markowska, 2019). The extracts of A. cruentus can reduce the low-density lipoprotein-cholesterol and regulate the lipoprotein lipase enzyme since it is rich in alpha-tocopherol, which has high antioxidant potential (León-Camacho et al., 2001). It was recognized lately that the in-vitro hydrolysis of A. cruentus proteins with trypsin and pepsin made the peptides VGVL, GGV, and IVG actively repressed the activity of a key enzyme in cholesterol biosynthesis, namely, 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), inferring a possible hypocholesterolemic effect (Soares et al., 2015). 25.3.6 TOXICITY STUDIES A. cruentus seed extract was examined for the concentrations of four triterpene saponins using high-performance liquid chromatography. The concentration of saponins in seeds was 0.09–0.10% of dry matter. The highly purified

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extracts from the seeds were tested for their toxicity against hamsters. The seeds were extracted with methylene chloride. The hydrophobic fraction revealed no toxicity; the response of tested animal models was comparable to the hamster groups administered with an equivalent measure of rapeseed oil. However, a crude saponin portion comprising approximately 70% of pure saponins in the test animals exhibited moderate toxicity; the relative lethal dose was determined to be 1100 mg/kg of body weight. Therefore, it is inferred that moderate contents of saponins in A. cruentus seeds and their moderately low toxicity ensure that amaranth-originated commodities generate no significant risk for the buyers (Oleszek et al., 1999). 25.3.7

CARDIOPROTECTIVE ACTIVITY

Cardiovascular diseases are the most significant cause of death globally, and dyslipidemia is emerging as one of the most critical risk determinants. Bile acids (BAs) binding has been hypothesized as a possible mechanism by which dietary fibers decrease blood cholesterol levels. Further, the fibers and other ingredients in the A. cruentus seeds might be associated with the hypocholesterolemic effect. The amaranth protein concentrate (APC) and defatted amaranth flour (DAF) from A. cruentus were evaluated for BA’s binding capability. The alkaline residue, rich in fibers (8.6%), displayed the weakest binding action for the BAs examined, except for glycocholic acid. DAF showed intermediary binding activity for all the BAs tested, comparable to the amaranth protein hydrolysate for taurocholic acid and APC for deoxycholic acid. In addition, the APC and DAF confirmed binding activity for secondary BAs poisonous to the duodenal mucus (Tiengo et al., 2011). KEYWORDS • • • • • •

A. cruentus antiproliferative squalene β-sitosterol hepatoprotective lysine

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REFERENCES

Akin-Idowu, P. E.; Ademoyegun, O. T.; Olagunju, Y. O.; Aduloju, A. O.; Adebo, U. G. Phytochemical Content and Antioxidant Activity of Five Grain Amaranth Species. Am. J. Food Technol. 2017, 5 (6), 249–255. Berger, A.; Gremaud, G.; Baumgartner, M.; Rein, D.; Monnard, I.; Kratky, E.; Geiger, W.; Burri, J.; Dionisi, F.; Allan, M.; Lambelet, P. Cholesterol-Lowering Properties of Amaranth Grain and Oil in Hamsters. Int. J. Vitam. Nutr. Res. 2003, 73 (1), 39–47. Cáceres, A.; Cruz, S. M. Edible Seeds, Leaves and Flowers as Maya Super Foods: Function and Composition. Intern. J. Phytocosmetics Natural Ingredients 2019, 6 (1), 1–5. Escudero, N. L.; Albarracin, G. J.; Lucero Lopez, R. V.; Giménez, M. S. Antioxidant Activity and Phenolic Content of Flour and Protein Concentrate of Amaranthus cruentus Seeds. J. Food Biochem. 2011, 35 (4), 1327–1341. Gandhi, P.; Khan, Z.; Niraj, K. In Vitro Assay of Anti-Proliferative Potential of Amaranthus cruentus Aqueous Extract on Human Peripheral Blood Lymphocytes. Curr. Trends Biotechnol. Chem. Res. 2011, 1 (1), 42–48. Grajeta, H. 2000. Hipolipemiczne dzialanie ekspandowanych nasion szarlatu [Amaranthus cruentus] u szczurow doswiadczalnych. Bromatologia i Chemia Toksykologiczna 2000, 1 (33), 7–13. Grubben, G. J. H. Amaranthus cruenthus In Plants Resources of Tropical Africa 2; Grubben, G. J. H., Denton, O. A., Eds.; Vegetables PROTA Foundation: Wageningen, Netherlands, 2004. Guerra-Matias, A. C.; Arêas, J. A. Glycemic and Insulinemic Responses in Women Consuming Extruded Amaranth (Amaranthus cruentus L). Nutr. Res. 2005, 25 (9), 815–822. Januszewska-Jozwiak, K.; Synowiecki, J. Characteristics and Suitability of Amaranth Components in Food Biotechnology. Biotechnologia 2008, 3, 89–102. Jeong, H. J.; Lam, Y.; de Lumen, B. O. Barley Lunasin Suppresses Ras-Induced Colony Formation and Inhibits Core Histone Acetylation in Mammalian Cells. J. Agric. Food Chem. 2002, 50 (21), 5903–5908. León-Camacho, M.; García-González, D.L; Aparicio, R. A Detailed and Comprehensive Study of Amaranth (Amaranthus cruentus L.) Oil Fatty Profile. Eur. Food Res. Technol. 2001, 213 (4), 349–355. Loaiza, M. A. P. P.; López-Malo, A.; Jiménez-Munguía, M. T. Nutraceutical Properties of Amaranth and Chia Seeds. In Functional Properties of Traditional Foods; Kristbergsson, K.; Ötles, S., Ed.; Springer: Boston, MA, 2016; pp 189–198. Macrae, R.; Robinson, R. K.; Sadler, M. J. Encyclopaedia of Food Science, Food Technology and Nutrition, Vol. 5; Academic Press: New York, 1997; 3240–3249. Makus, J. D. Evaluation of Amaranth as a Potential Green Crop in the Mid-South. HortSci. 1984, 19, 881–883. Maldonado-Cervantes, E.; Jeong, H. J.; León-Galván, F.; Barrera-Pacheco, A.; De LeónRodríguez, A.; De Mejia, E. G.; Ben, O.; De La Rosa, A. P. B. Amaranth Lunasin-Like Peptide Internalizes Into the Cell Nucleus and Inhibits Chemical Carcinogen-Induced Transformation of NIH-3T3 Cells. Peptides 2010, 31 (9), 1635–1642. Marcone, M. F.; Kakuda, Y.; Yada, R. Y. Amaranth as a Rich Dietary Source of β-Sitosterol and Other Phytosterols. Plant Foods Hum. Nutr. 2003, 58 (3), 207–211.

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Mepba, H. D.; Eboh, L.; Banigo, D. E. B. Effects of Processing Treatments on the Nutritive Composition and Consumer Acceptance of Some Nigerian Edible Leafy Vegetables. Afr. J. Food Agric. Nutr. Dev. 2007, 7 (1), 2–18. Musa, A.; Oladiran, J. A.; Ezenwa, M. I.; Akanya, H. O.; Ogbadoyi, E. O. Effect of Heading on Some Micronutrients, Anti-Nutrients and Toxic Substances in Amaranthus cruentus Grown in Minna, Niger State, Nigeria. Am. J. Food Nutr. 2011, 1 (4), 147–154. Nana, F. W.; Hilou, A.; Millogo, J. F.; Nacoulma, O. G. Phytochemical Composition, Antioxidant and Xanthine Oxidase Inhibitory Activities of Amaranthus cruentus L. and Amaranthus hybridus L. Extracts. Pharmaceuticals 2012, 5 (6), 613–628. Oboh, G.; Akinyemi, A. J.; Ademiluyi, A. O.; Bello, F. O. Inhibition of-Amylase and-Glucosidase Activities by Ethanolic Extract of Amaranthus cruentus Leaf as Affected by Blanching. Afr. J. Pharm. Pharmacol. 2013, 7 (17), 1026–1032. Odongo, G. A.; Schlotz, N.; Baldermann, S.; Neugart, S.; Ngwene, B.; Schreiner, M.; Lamy, E. Effects of Amaranthus cruentus L. on Aflatoxin B1-and Oxidative Stress-Induced DNA Damage in Human Liver (HepG2) Cells. Food Biosci. 2018, 26, 42–48. Ogwu,; Chidozie. M. Value of Amaranthus [L.] Species in Nigeria. In Nutritional Value of Amaranth; IntechOpen, 2020. Oleszek, W.; Junkuszew, M.; Stochmal, A. Determination and Toxicity of Saponins from Amaranthus cruentus Seeds. J. Agric. Food Chem. 1999, 47 (9), 3685–3687. Peter, K.; Gandhi, P. Rediscovering the Therapeutic Potential of Amaranthus Species: A Review. Egypt J. Basic Appl. Sci. 2017, 4 (3), 196–205. Ramkisson, S.; Dwarka, D.; Venter, S.; Mellem, J. J. In Vitro Anticancer and Antioxidant Potential of Amaranthus cruentus Protein and Its Hydrolysates. Food Sci. Tech. 2020, 40, 634–639. Robertson, W. G. The Scientific Basis of Urinary Stone Formation. Scientific Basis of Urology, 3rd ed.; Informa UK Ltd: Colchester, 2010; pp 162–81. Samarth, R. M.; Panwar, M.; Kumar, M.; Soni, A.; Kumar, M.; Kumar, A. Evaluation of Antioxidant and Radical-Scavenging Activities of Certain Radioprotective Plant Extracts. Food Chem. 2008, 106 (2), 868–873. Schippers, R. R. African Indigenous Vegetables: An Overview of the Cultivated Species; University of Greenwich: Kent, UK, 2000; pp 193–205. Schnetzler, K. A.; Breene, W. M. Food Uses and Amaranth Product Research: A Comprehensive Review; CRC Press: Boca Raton, FL, 1994; pp 155–184. Skwaryło-Bednarz, B.; Stępniak, P. M.; Jamiołkowska, A.; Kopacki, M.; Krzepiłko, A.; Klikocka, H. Amaranth Seeds as a Source of Nutrients and Bioactive Substances in Human Diet. Acta Scientiarum Polonorum-Hortorum Cultus, 2020, 19 (6), 153–164. Soares, R. A. M.; Mendonça, S.; De Castro, L. Í. A.; Menezes, A. C. C. C. C.; Arêas, J. A. G. Major Peptides from Amaranth (Amaranthus cruentus) Protein Inhibit HMG-CoA Reductase Activity. Intern. J. Mol. Sci. 2015, 16 (2), 4150–4160. Stallknecht, G. F.; Schulz-Schaeffer, J. R. Amaranth Rediscovered. In New Crops; Janick, J., Simon, J. E., Eds.; Wiley: New York, 1993. Tiengo, A.; Motta, E. M. P.; Netto, F. M. Chemical Composition and Bile Acid Binding Activity of Products Obtained from Amaranth (Amaranthus cruentus) Seeds. Plant Foods Hum. Nutr. 2011, 66 (4), 370–375. Torane, R.; Gaikwad, S.; Ahuja, V.; Kamble, S. Comparative In Vitro Anthelmintic Activity of a Medicinal Plant Amaranthus cruentus. Int. J. Chemtech. Res. 2017, 10 (9), 173–176.

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Venskutonis, P. R.; Kraujalis, P. Nutritional Components of Amaranth Seeds and Vegetables: A Review on Composition, Properties, and Uses. Compr. Rev. Food Sci. Food Saf. 2013, 12 (4), 381–412. Wolosik, K.; Markowska, A. Amaranthus Cruentus Taxonomy, Botanical Description, and Review of Its Seed Chemical Composition. Nat. Prod. Commun. 2019, 14 (5), 1–10.

CHAPTER 26

Bioactive Compounds and Pharmacological Activity of Beta vulgaris L. RAGHVENDRA DUBEY1*, KUSHAGRA DUBEY2, SIBBALA SUBRAMANYAM3, and K. N. JAYAVEERA4 Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, SAGE University, Indore, Madhya Pradesh, India 1

Department of Pharmaceutical Chemistry, Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India

2

Department of Pharmaceutical Sciences, Vignan’s Foundation for Science, Technology and Research (VFSTR) - (Deemed to be University), Vadlamudi, Guntur, India

3

Department of Chemistry, Jawaharlal Nehru Technological University, Anantapur 515002, India

4

Corresponding author. E-mail: [email protected]

*

ABSTRACT Beta vulgaris, commonly known as beet root, has been utilised in traditional medicine for a variety of purposes. The red color of the beet root is due to the presence of the betaine, a betacyanin pigment. Various parts of the plant have been shown to exhibit antioxidant, cyotoxic, antifungal, antimicrobial, wound healing, antidiabetic, antidepressant, anti-inflammatory, diuretic, carminative, and expectorant effect. Numerous phytochemicals have been extracted from B. vulgaris, including flavonoids, polyphenols, alkaloids, carbohydrates, glycosides, proteins, amino acids, vitamins, and folic acid. Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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INTRODUCTION

Beet root, scientifically known as Beta vulgaris, belongs to Chenopodiaceae family and popularly known as “chukandar.” There are four different varieties of the beet root, crimson globe, detroit dark red, and two Crosby Egyptian which are generally erect annual herb with tuberous root stocks. There are number of subspecies of B. vulgaris that are cultivated for the source of dietary supplement as a rich source of the sugar, mineral, nutrients, and vitamin. The beet root is also rich in phytoconstituents that have potent medicinal and pharmaceutical value. The various plant parts have been reported to have antioxidant, cyotoxic, antifungal, antimicrobial, wound healing, antidiabetic, antidepressant, anti-inflammatory, diuretic, carminative, and expectorant action. The beet root contains natural red color, which is observed due to the presence of the betaine, a betacyanin pigment. A number of the phytochemicals such as flavonoids, polyphenols, alkaloids, carbohydrates, glycosides, proteins, amino acids, vitamins, and folic acids have been isolated from the various extracts of B. vulgaris. 26.2

BIOACTIVES

B. vulgaris is a rich source of starch, carbohydrates, proteins, vitamins (A, B, C E, K), and fibers. The roots are rich in vitamins B and consist of thiamine (B1), riboflavin (B2), niacin (B3), pathothetic (B5), pyridoxine (B6), folates (B9), and cyancoblamin(B12) (Clifford et al., 2015; Agarwal and Varma, 2014). There are a number of minerals found in beet root, some are magnesium, potassium, sodium, manganese, phosphorous, iron, copper, silica, zinc, boron, and selenium (Yashwant, 2015). The main amino acids found in the beet roots are leucine, isoleucine, threonine, cysteine, valine, arginine, glutamic acid, methionine, phenylalanine, tyrosine, proline, and histidine. The roots are also rich in flavonoids such as kaempferol, rhamnocitrin, rhamnetin, astragalin and tiliroside, coumains, carotenoids, sesquiterpenoids, triterpenes, phenolic compounds, and betalains. Some alkaloids such as ipomine and calystegine (B1, B2, B3, and C1), polyphenols, tannins, and saponins have been identified in beet root. The chemical composition and different phytochemicals are varied in different parts and different varieties of the plant. The beet root contains carotenoids (Ninfali and Angelino, 2013), such as lutein, α- and β-carotene, β-cryptoxanthin, violaxnthin, neopxanting, zeaxanthin which were found to be rich in green parts of the plant. It also consists of high levels of nitrates

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which are more than 600 mg/kg and ranges to 1800 mg/kg (Lidder and Webb, 2013). The beet root is rich source of water-soluble betalains (Guldiken et al., 2016) which are synthesized from amino acid tyrosine and are highly rich in nitrogen. The betalains fall in two structural categories known as betacyanins and betaxanthins. The betalains are important chromo alkaloid secondary metabolite of beet root which are beneficial to human health especially and have antiviral, antifungal, antitumor, and anti-inflammatory and antioxidant activity. The betacyanins are betalamic acids that are observed in condensed form with cyclo-dihydroxyphenylalanine (cyclo-DOPA) (Hatlestad et al., 2012) and which show characteristic purple color with maximum absorptionin UV-visible spectrophotometer at 540 nm, while the betaxanthins are ammonium derivative of the betalamic acid with different amino acids and amines, which are yellow in color with maximum absorption at 480 nm in UV-visible spectrophotometer. The color of the betalains is highly influenced by pH and temperature. The betalains degrades to betalamic acid and cyclo-DOPA, under influence of pH and temperature resulting the change in the color of extract. The betaxanthin is more susceptibile than betacyanin for stability concerns. Ascorbic acid some time protects the degradation by its antioxidant effect. Due to the high intense color of betalains, it is widely accepted as coloring additives in the food industry, such as sauces, soups, jams, jellies, sweets, and ice-creams. It is also used for avoiding food discoloration. The extract of beet root is approved as red food colorant by European Union. The choice of the beet root colorant is more than other flavonoids because of its excellent bioavailability, stability, and antioxidant potential. Betacyanins and betaxanthins reported in red beet root are amaranthin, lampranthin I, lampranthin II, cyclodopa glycoside, N formylcyclodopa glycoside, betalamic acid, p coumaric acid, ferulic acid, and indicaxanthin (Strack et al., 2003). Beet root contains the highest concentration of total phenolic content. It was reported that it consists of about 50–60 µmol/g dry weight (Karthiravan et al., 2014). The phenolic isolates obtained from various parts of beet roots are dimer of 5,6-dihydroxyindolecarboxylic acid, 5,50,6,60-tetrahydroxy3,30-biindolyl, and betalains (comprises betanidin, isobetanidin, isobetanin, neobetanin, prebetanin, vulgaxanthin I, vulgaxanthin II). It also consists of phenolic amides N-transferuloylhomovanillylamine and N-trans-feruloyltyramine (Nemzer et al., 2011; Strack et al., 2003).

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Betaxanthin

Vulgaxanthin-I

Vulgaxanthin-II

Betacyanin

Betanin

Isobetanin

Rhamnetin

Betagarin

Betavulgarin

Betalamic acid

Betanidin

Indicaxanthin

FIGURE 26.1 The structure of the phytochemicals isolated from B. vulgaris L.

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Two major classes of phenolic acids, hydroxybenzoic acid and hydroxycinnamic acid are also found in beet root. Some other phenolic acids found in beet root are betalamic acid, p coumaric acid, ferulic acid, epicatechin, vanillic, caffeic acid, indicaxanthin, and syringic acids (Maraie et al., 2014). Different varieties of beet root are highly rich in the flavonoids that have significant medicinal properties. The beet root leaves and other parts contain flavonoids such as cohliophilin A, betagarin (5,2-dimethoxy-6,7-methylenedioxyflavanone), betavulgarin (2′-hydroxy-5-methoxy-6,7-methylenedioxyisoflavone), 3,5-dihydroxy-6,7-methylenedioxy flavanone, 5-hydroxy-6,7-methylenedioxyflavone, 7-methylenedioxyisoflavone, and dihydro-isorhamnetin. The triterpene oleanolic acid derivatives, saponins are found in the beet roots. It was found that about 26 triterpenes saponins were characterized from root and leaves which also includes some novel triterpenes. The identified saponins are Betavulgarosides I, II, III, IV, V, VI, VII, VIII, IX, and X (Mroczek et al., 2012; Mikolajczyk-Bator et al., 2016; Chhikara et al., 2019). 26.3 PHARMACOLOGY 26.3.1 ANTIOXIDANT ACTIVITY The free radical is generated in the body cells as by-products by oxidation metabolism of the oxygen. These free radicals damage the enzymes, cells walls, DNA, lipids, proteins, and affect the normal defense mechanisms. To protect such destruction, the antioxidants are used as dietary supplement or medicine. The betalain which is obtained from beet root has potent antioxidant potential reported in the number of in vitro studies (Kanner et al., 2001; Reddy et al., 2005; Tesoriere et al., 2008; Wootton-Beard and Ryan, 2011). In experimental evaluation, it was reported that the linoleate damage induced by cytochrome C oxidase and lipid membrane oxidation induced by peroxide-activated metmyoglobin was reduced by betanin and betanidin. The betanin has a high antioxidant activity found in beet root (300–600 mg per kg) due to its exceptional electron-donating capacity and ability to defuse highly reactive radicals targeting cell membrane. The antioxidant potential in beet root is synergistically increase by the some more bioactive molecules, such as caffeic acid, epicatechin, and rutin (Frank et al., 2005; Manach et al., 2005). The nitrates in the beet root also possess antioxidant potential as they act by damaging free radicals such a hydrogen peroxide and superoxide

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suppressing radical formation and direct scavenge potential (Lundberg et al., 2011; Wink et al., 2001). The in-vivo evaluation of the protective effect of the beet root extract against the oxidative stress induced by N-nitrosodiethylamine (NDEA) and carbon tetrachloride (CCl4) has confirmed its antioxidant potential (Kujwaska et al., 2009). 26.3.2 ANTI-INFLAMMATORY ACTIVITY The betalains usually increase the resistance to oxidation which enriches human metmyoglobin and low-density lipoproteins. In combination with phenolic compounds, the betalains decrease the oxidative damage of lipids. It also helps to reduce the inflammation in joints, bones, and blood vessels. This in turn helps the patient suffering from asthma and osteoporosis (Clifford et al., 2015; Adhikari et al., 2017; Zaho et al., 2018; Craig, 2004; Detapoulou et al., 2008; Slow et al., 2008). 26.3.3

CYTOTOXIC ACTIVITY

The betalains show antimutagenic effect in humans. It acts against the directacting mutagen, Methyl-Nitro-Nitrosoguanidine. The mutagenic action is due to its action to methyl group donation (trasmethylation) and action as an osmolytes. The osmolyte effect of betalains helps and protects the vital cells, enzymes, and protein by maintaining high intracellular osmotic concentration from environmental stress which may occur due to extreme temperature, increase in salinity, and reduction in water. The betanin manages the oxidative stress involved in the origin and aggravation of the cancer by which it elicit chemoprotective and antitumor effect. Betaine also possesses antiproliferative action with the induction of cell apoptosis. The beet root extracts are also used in combination with doxorubicin and showed significant synergistically potential in the treatment of drug toxicity and cytotoxicity (Klewicka, 2010; Lechner and Stoner, 2019). 26.3.4 ANTIMICROBIAL ACTIVITY The beet root extract contains the betalains that were evaluated for antibacterial potential against Gram-positive and Gram-negative bacteria by agar well diffusion method. The zone of inhibition was observed with a minimum

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concentration of 1 mg of betalain. The extracts were active against Enterococcus feacalis and Klebsiella pneumoniae. The betalains were observed to be active natural antibacterial agents against extended-spectrum β-lactamase producing isolates (Vijaya and Thangaraj, 2019). 26.3.5 ANTIFUNGAL ACTIVITY The antifungal potential of two proteins isolated from the leaves of the beet roots was evaluated. The antifungal activity is concentration dependent and found active against Cercospora beticola (Kargh et al., 1995). 26.3.6 ANTICOCCIDIAL ACTIVITY The anticoccidial activity is performed to control the avian coccidosis. The methanolic extract of B. vulgaris was subjected for anticoccidial activity in broiler chicks. As beet root has antioxidant potential and hence showed remarkable anticoccidial activity. The coccidian oocysts are ubiquitous in nature and begin to sporulate which further gives rise to millions of new oocysts. The beet root extract inhibits the sporulation and stop its growth (Abbas et al., 2017). 26.3.7 ANTIDIABETIC ACTIVITY The in-vitro and preclinical studies have shown that the extracts of beet root possess antidiabetic potential (Murthy and Manchali, 2013). The pharmacological action is associated with the most potent free radical scavenging ability of the bioactive molecules of the beet root extracts, which directly or indirectly plays an important therapeutic role in various disease or ailments. The betanin form beet root extract was subjected to in-silico and in-vitro studies against aldose reductase, alpha-amylase, protein tyrosine phosphate, alpha-glucosidase, and dipetidyl peptidase. It was observed that betanin is active against all the four enzymes, which plays important role in diabetes and its complication (Dubey et al., 2019). 26.3.8 RADIO-PROTECTIVE EFFECT The betalains extracted from the beet root have been found to have radioprotective action (Babrykin et al., 2019). The experimental investigation was made on betalains containing extract (5–80 mg/kg) treated mice, which were

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irradiated by gamma rays (60Co). The white blood cells (WBC), Karyota of femur, and micronuclei in bone marrow in mice were determined. In addition, superoxide dismutase, thymus index, catalase, gluctathione peroxidase, and spleen index were also determined. The results indicate the radio-protective action of the extract (Lu et al., 2009). 26.3.9 ANTIULCER ACTIVITY The beet root extracts showed antiulcer activity. In ethanol-induced ulcer model, cold restraint stress induce model, and pylorus ligated model, the albino rats showed a significant antiulcer potential by action of beet root extracts. The methanolic extracts have significantly reduced the ulcer score, ulcer index, free acidity, and total acidity in all the models (Jagtap and Deore, 2018; Samyuktha et al., 2017). 26.3.10 HEMATOPOEITIC ACTIVITY The laboratory investigation has provided scientific evidence of the hematopoietic effect of the extract of leaves of B. vulgaris (beet). The phenylhydrazine-induced anemia model in albino rats has developed and the hematopoietic effect was evaluated on different dilutions of B. vulgaris leaf extract. The extracts in dose and time-dependent manner have significantly restored the level of WBC, red blood cells, hemoglobin, and hematocrit. The erythropoietin level was maintained and malondialdehyde (erythrocytic membrane oxidation biomarker) level reduces significantly as compared to untreated anemic group (Gheith and El-Mahmoudy, 2018). 26.3.11 HEPATOPROTECTIVE ACTION The in-vitro and in-vivo studies of various extracts of B. vulgaris leaves showed hepatoprotective action against ethanol-mediated hepatotoxicity rat models. The serum marker enzymes were evaluated as compared to standard silymarin which clearly indicated n-butanol extract to be the most potent hepatoprotective extract against ethanol-induced hepatic toxicity (Jain and Singhai, 2012).

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KEYWORDS

• • • • •

Beta vulgaris Beet root bioactive compounds phytoconstituents pharmacology

REFERENCES Abbas, A.; Iqbal, Z.; Abbas R. Z.; Khan, M. K.; Khan, J. A.; Sindhu, Z. U. D.; Mahmood, M. S.; Saleemi, M. K. In Vivo Anticoccidial Effects of Beta vulgaris (Sugar Beet) in Broiler Chickens. Microb. Pathog. 2017, 111, 139–144. Adhikari A.; Saha A.; Raina, I.; Sur, T. P.; Das, A. K. Evaluation of Antiinflamatory Effect of Beet Root Extract in Animal Models. Int. J. Basic Clin. Pharmcol. 2017, 6, 2853–2858. Agarwal, K.; Varma, R. Biochemical Screening of Beetroot Leaves. Int. J. Pharm. Sci. Rev. Res. 2014, 1, 127–134. Babrykin, D.; Sminrnova, G.; Pundinsh, I.; Vasiljeva, S.; Krumina, G.; et al. Red Beet (Beta vulgaris) Impact on Human Health. J. Biosci. Med. 2019, 7, 61–79. Chhikara, N.; Kushwaha, K.; Sharma, P.; Gat, Y.; Panghal, A. Bioactive Compounds of Beetroot and Utilization in Food Processing Industry: A Critical Review. Food Chem. 2019, 272, 192–200. Clifford, T.; Howatson, G.; West, D. J.; Stevenson, E. J. The Potential Benefits of Red Beetroot Supplementation in Health and Disease. Nutrients 2015, 7, 2801–2822. Craig, S. A. Betaine in Human Nutition. Am. J. Clin. Nutr. 2004, 80, 539–549. Detapoulou, P.; Panagiotakos, D. B.; Antonopoulou, S.; Pitsavos, C.; Stefanadis, C. Dietary Choline and Betaine Intakes in Relation to Concentrations of Inflammatory Markers in Healthy Adults: The ATTICA Study. Am. J. Clin. Nutr. 2008, 87, 424–430. Dubey, K.; Dubey, R.; Gupta, R.; Gupta, A. In-Silico Reverse Docking Studies for the Identification of Potential of Betanin on Some Enzymes Involved in Diabetes and Its Complications. J. Drug Deliv. Ther. 2019, 92(2-A), 72–74. Frank, T.; Stintzing, F. C.; Carle, R.; Bitsch, I.; Quaas, D.; Strass, G. et al. Urinary Pharmacokinetics of Betalains Following Consumption of Red Beet Juice in Healthy Humans. J. Pharmacol. Res. 2005, 52, 290–297. Gheith, I.; EI-Mahmoudy, A. Laboratory Evidence for the Hematopoietic Potential of Beta vulgaris Leaf and Stalk Extract in Phenylhydrazine Model of Anemia. Braz. J. Med. Biol. Res. 2018, 51 (11), e7722. Guldiken, B.; Toydemir, G.; Nur Memis, K.; Okur, S.; Boyacioglu, D.; Capanoglu, E. HomeProcessed Red Beet Root (Beta vulgaris L.) Products: Change in Antioxidant Properties and Bioaccessibility. Int. J. Mol. Sci. 2016, 17, 858.

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Hatlestad, G. J.; Sunnadeniya, R. M.; Akhavan, N. A.; Gonzalez, A.; Goldman, I. L.; Mc Grath, J. M.; Lloyd, A. M. The Beet R Locus Encodes a New Cytochrome P450 Required for Red Betalain Production. Nat. Genet. 2012, 44, 816–820. Jagtap, M. J.; Deore, A. B. Antiulcer Activity of Methanolic Extract of Roots of Beta vulgaris, Chenopodiaceae. Int. J. Pharm Sci. Drug Res. 2018, 10 (06), 454–459. Jain, N. K.; Singhai, A. J. Protective Role of Beta vulgaris L. Leaves Extract and Fractions on Ethanol-Mediated Hepatic Toxicity. Acta Pol. Pharm. 2012, 69 (5), 945–950. Kanner, J.; Harel, S.; Granit, R. Betalains a New Class Ofdietary Cationized Antioxidants. J Agri. Food Chem. 2001, 49, 5178–5185. Kargh, K. M.; Nielsen, J. E.;Nielsen, K. K.; Dreboldt, S.; Mikkelsen, J. D. Characterization and Localization of New Antifungal Cysteine-Rich Proteins from Beta vulgaris. Mol. Plant Micr. Intera. 1995, 8 (3), 424–434. Karthiravan, T.; Nandansabapathi, S.; Kumar, R. Standardization of Process Condition in Batch Thermal Pasteurization and Its Effect on Antioxidant, Pigments and Antimicrobial Inactivation of Ready to Drink (RTD) Beet Root (Beta vulgaris L.) Juice. Int. Food Res. J. 2014, 21 (4), 1305–1312. Klewicka, E. Fermented Beetroot Juice as a Factor Limiting Chemical Mutations Induced by MNNG in Salmonella typhimurium TA98 and TA100 Strains. Food Technol. Biotechnol. 2010, 48 (2), 229–233. Kujwaska, M.; Ignatowicz, E.; Murias, M.; Ewertowska, M.; Mikolajczyk, K.; JodynisLiebert, J. Protective Effect of Red Beetroot Against Carbon Tetrachloride and N-Nitrosodiethylamine Induced Oxidative Stress in Rats. J. Agric. Food Chem. 2009, 57 (6), 2570–2575. Kumar, S.; Vishwakarma, V.; Yadav, Bharti.; Gupta, R.; Aggarwal, N. K.; Yadav A. Evaluation of Antigenotoxic Potential of Beet Root Extract Against Hair Dye Induced Genotoxicity. IJPSR, 2020, 11 (4), 1874–1878. Lechner, J. F.; Stoner, G. D. Red Beetroot and Betalains as Cancer Chemopreventative Agents. Rev. Mol. 2019, 24, 1602. Lidder, S.; Webb, A. J. Vascular Effects of Dietary Nitrate (as Found in Green Leafy Vegetables and Beet Roots) via the Nitrate-Nitrite-Nitiric Oxide Pathway. Brt. J. Clin Pharm. 2013, 73, 677–696. Lu, X.; Wang, Y.; Zhang, Z. Radioprotective Activity of Betalains from Red Beets in Mice Exposed to Gamma Irradiation. Eur. J. Pharmcol. 2009, 615 (1–3), 223–227. Lundberg, J. O.; Carlstrom, M.; Larsen, F. J.; Weitzberg, E. Roles of Dietary Inorganic Nitrate in Cardiovascular Health and Disease. J. Cardiovasc. Dis. Res. 2011, 89, 525–532. Manach, C.; Williamson, G.; Morand, C.; Scalbert, A.; Remesy, C. Bioavailability and Bioefficacy of Polyphenols in Humans, I. Review of 97 Bioavailability Studies. Am. J. Clin. Nutr. 2005, 81, 230–242. Maraie, N. K.; Abdul-Jalil, T. Z.; Alhamdany, A. T.; Janabi, H. A. Phytochemical Study of the Iraqi Beta vulgaris Leaves and Its Clinical Application for the Treatment of Different Dermatological Diseases. World J. Pharm. Pharm. Sci. 2014, 3, 5–19. Mikolajczyk-Bator, K.; Blaszczyk, A.; Czyzniejewski, M.; Kachlicki, P. Identification of Saponins from Saponins from Sugar Beet (Beta vulgaris) by Low and High-Resolution HPLC-MS/MS. J. Chromatography B. 2016, 1029, 36–47. Mroczek, A.; Kapusta, I.; Janda, B.; Janiszowska, W. Triterpene Saponin Content in the Roots of Red Beet (Beta vulgaris L.) Cultivars. J. Agri. Food Chem. 2012, 60, 12397–12402.

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Murthy, K. N.C.; Manchali, S. Anti-Diabetic Potentials of Red Beet Pigment and Other Constituents. In Red Beet Biotechnology; Neelwarne, B., Ed.; Springer: Boston, MA, 2013. Nemzer, B.; Pietrzkowski, Z.; Sporna, A.; Stalica, P.; Thresher, W.; Michalowski, T.; Wybraniec, S. Betalainic and Nutritional Profiles of Pigment–Enriched Red Beet Root (Beta vulgaris L.) Dried Extracts. Food Chem. 2011, 127, 42–53. Ninfali, P.; Angelino, D. Nutritional and Functional Potential of Beta vulgaris cicla and rubra. Fitoterpia, 2013, 89, 188–199. Reddy, M. K.; Lindo, R. L.; Nair, M. G. Relative Inhibition of Lipid Peroxidation, Cyclooxygenase Enzymes, and Human Tumour Cell Proliferation by Natural Food Colours. J. Agri. Food Chem. 2005, 53, 9268–9273. Samyuktha, K.; Chinnala, K. M.; Prathiba, G.; Rajendhar, D.; Reddy, S. P. Evaluation of Antiulcer Activity of Ethanolic Root Extract of Beta vulgaris in Rats. Int. J. Basic Clin. Pharmacol. 2017, 6 (02), 359–364. Slow, S.; Elmslie, J.; Lever, M. Dietary Betaine and Inflammation. Am.J. Clin. Nutr. 2008, 88, 247–248. Strack, D.; Vogt, T.; Schliemann, W. Recent Advances in Betalain Research. Phytochemistry 2003, 62, 247–269. Tesoriere, L.; Fazzari, M.; Angileri, F.; Gentile, C.; Livrea, M. A. In Vitro Digestion of Betalainic Foods. Stability and Bioaccessibility of Betaxanthins and Betacyanins and Antioxidative Potential of Food Digesta. J. Agri. Food Chem. 2008, 56, 10487–10492. Vijaya, D.; Thangaraj, N. Extraction of Betalins from Red Beet Root (Beta vulgaris L.) and to Evaluate Its Antibacterial Potential Against Spectrum Beta-Lactamase Producing Isolates. J. Pharm. Sci. Res. 2019, 11 (6), 2422–2425. Wink D. A.; Miranda, K. M.; Espey, M. G.; Pluta, R. M.; Hewett,S. J.; Colton, C. et al. Mechanisms of the Antioxidant Effects of Nitric Oxide. J. Antioxid. Redox Signal. 2001, 3, 203–213. Wootton-Beard, P. C.; Ryan, L. A Beetroot Juice Shot Is a Significant and Convenient Source of Bioaccessible Antioxidants. J. Funct. Foods, 2011, 3, 329–334. Yashwant, K. Beetroot: A Super Food. Int. J. Eng. Stud. Tech. Appr. 2015, 1, 20–26. Zaho, G.; He, F.; Wu, C.; Li, P.; Li, N. et al. Betaine in Inflammation: Mechanistic Aspects and Application. Front. Immunol. 2018, 9, 1070.

CHAPTER 27

Phytoconstituents and Pharmacological Properties of Enicostemma axillare Raynal JAISHREE VAIJANATHAPPA School of Life Sciences, JSS Academy of Higher Education and Research, Avenue Droopnath Ramphul, Bonne Terre 73103, Vacaos, Mauritius E-mail: [email protected]

ABSTRACT The chapter is aimed to provide a summary of the reported phytoconstituents and pharmacological properties of Enicostemma axillare Raynal. It includes a collection of vernacular names in India, distribution of the plant and information, and synonyms. The chapter also draws attention of the extracts and phytoconstituents reported for different biological properties. 27.1 INTRODUCTION Enicostemma axillare (Poir. ex Lam.) Raynal belongs to the family Gentianaceae and it is also called as Enicostemma littorale non-Blume. Other vernacular names in India are Mamajaka, Nagajivha, Nayi (Sanskrit), Chhotakirayata (Hindi), Vallari (Tamil), Nelaguli (Telugu), and Kadavinayi (Marathi). The plant is distributed throughout the greater part of India, more frequent near the sea and widespread in tropical Africa and Asia. This is a herb up to 50 cm in height and the leaves are linear or linear-oblong, variable,

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3.2–6.3 cm by 3–16 mm. Flowers are white color sessile all along the stem. The plant is known for its bitter taste, contributed by several constituents (Kirtikar and Basu, 1999; Patel et al., 2018). Synonyms of the plant include Enicostema hyssopifolium (Willd.) I. Verd. and Gentiana axillaris Lam. Traditionally, E. axillare is being used in the treatment of jaundice, stomach ulcers, diabetes, rheumatism, insect poisoning, and inflammation. Additionally, antimalarial, antipyretic, antidiabetic, antimicrobial, and antiinflammatory activities have been confirmed (Nwafor et al., 2012). Various parts of the E. axillare plant are used for specific functions. For example, the roots are utilized in the treatment of leprosy, skin diseases, malaria, and diabetes. The leaves have been reported for antioxidant, hepatoprotective, hepatomodulatory, and hypoglycemic properties and be able to restructure the obesity (Gite et al., 2010). 27.2

BIOACTIVES

Screening of E. axillare for the phytoconstituents revealed that a major percentage of iridoids and other biochemicals, such as flavonoids, phenols, tannins, and steroids were confirmed. Several biomolecules were reported from the entire aerial part of the plant E. axillare. A secoiridoid glycoside swertiamarin has been isolated from the leaf and stem of the E. axillare (Desai et al., 1966; Vishwakarma et al., 2004), it is one of the major chemical constituents in E. axillare. Six phenolic acids, namely, p-hydroxy benzoic acid, syringic acid, protocatechuic acid, vanillic acid, ferulic acid, and p-coumaric acid (Daniel and Sabnis, 1978) and seven flavonoids isovitexin, apigenin, genkawanin, swertisin, saponarin, and swertiamarin (Ghosal and Jaiswal, 1980) were isolated from E. axillare. Five alkaloids, volatile oil, and two sterols (Garad et al., 2012) in E. littorale were identified. Enicoflavin and gentiocrucine are monoterpene alkaloids that were isolated from the alcoholic extract of E. littorale (Ghosal et al., 1974). Triterpenoids, saponins, sapogenin, catechins, steroids, xanthones and flavonoids, and a C-glucoside named as Verticilliside were isolated (Jahan et al., 2009). Swertiamarin was also isolated from E. littorale by using alcoholic extract. From methanol extract of E. littorale, different amino acids like tryptophane, serine, aspartic acid, L-glutamic acid, alanine, L-proline, threonine, L-histidine, L-tyrosine, phenylalanine, monohydrochloride, methionine, L-arginine monohydrochloride, iso leucine, DOPA, L-Glycine, valine, and 2-amino butyric acid were reported (Ghosal et al., 1974; Chaudhuri et al., 1975).

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FIGURE 27.1 Phenolic acids isolated from Enicostemma axillare plant and characterized.

FIGURE 27.2 Flavonoids and secoiridoids isolated from E. axillare plant and characterized.

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PHARMACOLOGY

27.3.1 ANTIOXIDANT ACTIVITY The successive extracts of the E. axillare plant were evaluated for antioxidant activity. Several different methods such as 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt method, hydrogen peroxide method, 2,2′-diphenyl-1-picryl hydrazyl scavenging method, hydroxyl radical using deoxyribose, superoxide radical with alkaline dimethyl sulphoxide, and lipid peroxidation method were assayed and calculated the IC50 values. All the extracts have shown potent antioxidant activity. The extracts were also estimated for total antioxidant activity and posed high antioxidant capacity. The plant merits for good antioxidant activity (Vaijanathappa et al., 2008). 27.3.2 HEPATOPROTECTIVE AND ANTIOXIDANT ACTIVITY The ethyl acetate extract of E. axillare was examined for in vivo hepatoprotective and antioxidant activity against carbon tetrachloride-induced hepatotoxicity in rats. The protective activity of extract at 100 and 200 mg/ kg was assessed by histological damage and changes in serum enzymes and biochemical parameters. The results showed the recovery in histological damage and ameliorated serum enzyme. The study supports the ethnomedical use of E. axillare in India (Jaishree et al., 2010). 27.3.3 ANTIFERTILITY ACTIVITY The ethanolic extract of E. axillare was examined for antifertility activity in adult male Wistar albino rats. In the study results, at all the doses of ethanolic extract, the body weight of rats was not decreased, whereas seminal vesicles and weight of testes were reduced. It also found a decrease in sperm motility, viability, and counts. At the higher dose, it was observed that a marked increase in testicular cholesterol, sperm morphological abnormalities, and ascorbic acid contents were considerably increased. The outcome of the study affirms that the ethanolic extract of E. axillare inhibited spermatogenesis and steroidogenesis revealing its antifertility activity which could support the traditional use of this plant as a male contraceptive (Dhanapal et al., 2012).

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27.3.4 ANTI-INFLAMMATORY ACTIVITY

The methanol extract of E. axillare whole plant was examined for in vitro anti-inflammatory activity by various methods such as antilipoxygenase activity, proteinase inhibitory activity, albumin denaturation assay, and at different concentrations membrane stabilization. To compare the study, standard drugs diclofenac sodium, aspirin, and indomethacin were used. The results showed that the methanol extract of E. axillare at a concentration range of 100–500 µg/mL highly protected the heat-induced protein denaturation. In proteinase inhibitory action, methanol extract of E. axillare at 400 and 500 µg/mL concentration has shown significant inhibition. The extract also inhibited heat-induced hemolysis of erythrocyte at 400 and 500 µg/mL concentration. The methanol extract at 400 and 500 µg/mL concentration has significantly inhibited lipoxygenase activity. The results of the study affirmed that methanol extracts of E. axillare can be a natural source of antiinflammatory action (Leelaprakash and Dass, 2011). 27.3.5 ANTIMICROBIAL ACTIVITY Antimicrobial activity of chloroform, ethyl acetate, methanolic, hydroalcoholic, and aqueous extracts of E. axillare was evaluated against six bacterial species and two fungal species Bacillus subtilis, Proteus vulgaris, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Shigella sonni, Aspergillus niger, and Candida albicans. In the study, chloroform, ethyl acetate, and hydroalcoholic extract have shown better antimicrobial activity against all microorganisms (Praveena and Sudarsanam, 2011). 27.3.6

CARDIAC ANTIHYPERTROPIC ACTIVITY

E. littorale aqueous extract was evaluated for antihypertrophic potential against isoproterenol-induced cardiac hypertrophy in male albino Wistar rats and biochemicals were investigated. The aqueous extract was administered for 12 days orally at 100 mg/kg b. w. The cardiac hypertrophy in low dose isoproterenol at 60 mg/kg and high dose isoproterenol at 100 mg/kg was given for 12 days, subcutaneously. The extract-treated groups were compared with the standard group with losartan treated (10 mg/kg b.w. administered for 12 days, orally). The antihypertrophic activity of E. littorale was determined by analyzing the morphometric indices of the heart and amended blood

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biochemical parameters, namely, serum total protein, serum albumin, serum glucose, lipid profile, cardiac-specific enzymes (SGPT, SGOT, and LDH), and ECG tracings. The histopathological investigation of the heart tissue was carried out and the results explored that the extract-treated group significantly changed cardiac hypertrophy in experimental rats. The biochemical investigations of this study emphasized the correlation between the hypertrophic β-adrenergic receptor signaling and the 5′-adenosine monophosphateactivated protein kinase (Doss and Kuberapandian, 2019). 27.3.7 ANTIULCER AND ANTI-INFLAMMATORY ACTIVITY The E. littorale aerial parts were studied for antiulcer activities against pyloric ligation, ethanol, and aspirin-induced ulcers in rats. The in vitro antiinflammatory study by bovine serum albumin denaturation was evaluated. The extract was at doses of lower and higher (200 and 400 mg/kg po) that were administered to the overnight fasted rats, 1 h prior to ethanol/pyloric ligation/aspirin administration. The ulcer index parameters such as lipid peroxidation and tissue glutathione levels were estimated in all the ulcer models, and the volume of gastric secretion, pH, and acidity was estimated in the pyloric ligation ulcer model. The extract has shown a dose-dependent reduction in all the tested ulcer models (against aspirin, ethanol challenge, pyloric ligation). Pretreatment of the extract also decreased the free acidity, total acidity, and elevated the gastric pH and volume of gastric secretion. In addition, the extract also prevented the serum albumin denaturation in a concentration-dependent manner. Therefore, it was confirmed that the methanolic extract exhibited antiulcer and anti-inflammatory activities (Roy et al., 2010). 27.3.8

HYPOLIPIDEMIC AND ANTIOXIDANT ACTIVITY

The E. littorale aqueous extract was administered to rats along with hypercholesterolemic diet for 6 weeks and evaluated for hypolipidemic and antioxidant activities. Due to the consumption of cholesterol, it was found that increased serum triglycerides, serum cholesterol, VLDL, LDL, and decreased HDL levels when compared to normal diet-fed rats. The aqueous extract treated group increased HDL levels and decreased serum triglyceride, cholesterol, VLDL, LDL, and LDL/HDL ratio. Lovastatin was used as a standard drug. In addition, the extract-treated group showed a decrease

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in activities of superoxide dismutase, catalase, and lipid peroxidation levels with an increase in glutathione levels as compared to control group rats (only cholesterol-fed rats). The triglyceride levels and cholesterol levels of the liver and kidney were also decreased and also observed that the hepatic enzyme HMG CoA reductase activity was decreased in the extract-streated hypercholesterolemic rats (Vasu et al., 2005). 27.3.9 ANTIMICROBIAL ACTIVITY The chloroform, methanol, and acetone extracts of leaf, stem, and root parts of E. littorale were assessed for antimicrobial activity by the disc diffusion method. Some Gram-negative bacteria such as P. aeruginosa, E. coli, Klebsiella pnemoniae, Salmonella typhi and some Gram-positive bacteria such as Bacillus cereus, S. aureus, B. subtilis, and two fungal species, namely, Aspergillus flavus and Aspergillus fumigatus. In the outcome of the study, the chloroform extract showed better antibacterial activity. Among leaf, stem, and root extracts of chloroform, stem extract has shown the highest antibacterial activity. All of the other tested extracts had not shown any significant antifungal activity against A. flavus and A. fumigatus. The chloroform stem extract has maximum antimicrobial activity and shown inhibition zone upto 20 mm against B. subtilis at concentration of 500 mg/mL. Whereas the methanolic stem extract also exhibited highest activity against the same organism. The acetone leaf extract has shown the lowest antibacterial activity against E. coli at 8 mm inhibition zone. In conclusion, the study results indicated that E. littorale can be a novel natural source for inventing antibiotics (Abirami et al., 2012). 27.3.10 ANTICANCER ACTIVITY The methanolic extract of E. littorale was investigated for antitumor activity against Dalton’s ascitic lymphoma in Swiss albino mice. The survival time of methanolic extract treated mice bearing tumor was significantly enhanced upon comparison with the control group. The methanolic extract of E. littorale treatment has increased the peritoneal cell counts and the treated animals underwent i.p. inoculation with DAL cells, the extract inhibited tumor cell growth. The methanolic extract was able to reverse the changes in the hematological parameters, protein, and PCV consequent after 14 days of inoculation (Kavimani and Manisenthlkumar, 2000).

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27.3.11 ANTIDIABETIC ACTIVITY The aqueous extract of E. littorale was assessed for antidiabetic activity against a single dose of streptozotocin (70 mg/kg; i.p. injection) to the 5-dayold pups induced neonatal noninsulin-dependent diabetes mellitus (NIDDM). The animals were confirmed as diabetic after 3 months of streptozotocin injection, to diabetic animals aqueous extract of E. littorale was administered orally for 6 weeks. After 6 weeks, the animals were tested for glucose and insulin levels in fasting and fed NIDDM. The glucose and insulin levels were significantly higher than in control rats and they were significantly decreased in the aqueous extract E. littorale treated groups. The study suggests that E. littorale aqueous extract is an effective antidiabetic herb. It increases insulin sensitivity and regularizes dyslipidaemia and reveals nephroprotection in diabetic rats (Murali et al., 2002). A single dose of E. littorale aqueous extract was given to alloxan-induced diabetic rats and estimated blood glucose lowering ability. The 15 g/kg dry plant equivalent extract of E. littorale has shown a significant increase in the serum insulin levels in alloxan-induced diabetic rats after 8 h. Rat pancreatic islets were used to confirm insulinotropic action of extract. The aqueous extract has the capability to improve glucose-induced insulin release from isolated rat pancreatic islets and was able to change the effect of diazoxide. The study results suggest that glucose-lowering effect of aqueous extract of E. littorale was correlated with the potentiation of glucose-induced insulin release (Maroo et al., 2002). The aqueous extract of E. littorale was used as dose-dependent blood glucose lowering effect in alloxan-induced diabetic rats. Among several doses, 1.5 g dry plant equivalent extract/100 g body wt. was found to be an efficient dose. This dose caused a major decrease in liver glucose-6-phosphatase activity, glycosylated hemoglobin, and significant increase in serum insulin levels of the diabetic rats. No considerable changes were noticed in the toxicity parameters of extract-treated diabetic rats as compared to diabetic control rats. The study suggests that E. littorale is an effective antidiabetic herb without any toxic effect at this particular dose (1.5 g) (Maroo et al., 2003). 27.3.12 ANTIPLASMODIAL AND ANTIPYRETIC ACTIVITY The whole plant extract and fractions of E. axillare evaluated for the antiplasmodial and antipyretic activities for determining the traditional use of its antimalarial and antipyretic activities. The crude extract of E. axillare and fractions of chloroform and water were evaluated for antiplasmodial activity

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against chloroquine-resistant Plasmodium berghei infections in mice and for antipyretic activity against amphetamine, dinitrophenol, and yeast-induced pyrexia. The extract and fractions have shown dose-dependent results with decreased parasitaemia in prophylactic, suppressive, and curative models of mice. The effects of extract/fractions were equivalent to that of the standard drugs pyrimethamine and artesunate, respectively. The plant extracts of E. axillare exhibited significant antiplasmodial and antipyretic properties (Nwafor et al., 2012). KEYWORDS • • • • •

Enicostemma axillare phytoconstituents Gentianaceae Swertiamarin bioactives

REFERENCES Abirami, P.; Gomathinayagam, M.; Panneerselvam, R. Preliminary Study on the Antimicrobial Activity of Enicostemma littorale Using Different Solvents. Asian Pacific J. Trop. Med. 2012, 5 (7), 552–555. Chaudhuri, R. K.; Singh, A. K.; Ghosal S. Chemical Constituents of Gentianaceae. XVIII. Structure of Enicoflavine. Monoterpene Alkaloid from Enicostimma hyssopifolium. Chem. Ind. (London) 1975, 3, 127–128. Daniel, M.; Sabnis, S. D. Chemical Systematics of Family Gentianaceae. Curr. Sci. 1978, 20, 109–111. Desai, P. D.; Ganguly, A. K.; Govindachari, T. R.; Joshi, B. S.; Kamat, V. N.; Manmade, A. H. et al. Chemical Investigation of Some Indian Medicinal Plants: Part II. Indian J. Chem. 1966, 4, 457–459. Dhanapal, R.; Ratna, J. V.; Gupta, M.; Sarathchandran, I. Preliminary Study on Antifertility Activity of Enicostemma axillare Leaves and Urena lobata Root Used in Indian Traditional Folk Medicine. Asian Pacific J. Trop. Med. 2012, 5 (8), 616–622. Doss, V. A.; Kuberapandian, D. Evaluation of Anti-Hypertrophic Potential of Enicostemma littorale Blume on Isoproterenol Induced Cardiac Hypertrophy. Indian J. Clin. Biochem. 2019, 22, 1–10. Garad, M. C.; Upadhya, M. A.; Kokare, D. M.; Itankar, P. R. Aerial Parts of Enicostemma littorale Blume Serve as Antipyretic and Antacid: In Vivo and In Vitro Evaluations. Pharmacogn. Commun. 2012, 2 (3), 42–45.

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Ghosal, S. S.; Sharma, A. K.; Chaudhuri, P. V. Chemical Constituents of Gentianaceae IX: Natural Occurrence of Erythrocentaurin in Enicostemma hissopifolium and Swertia lawii. J. Pharm. Sci. 1974, 63, 944–945. Ghosal, S.; Jaiswal, D. K. Chemical Constituents of Gentianaceae XXVIII: Flavonoids of Enicostemma hyssopifolium (Willd.) Verd. J. Pharmaceut. Sci. 1980, 69 (1), 53–56. Gite, V. N.; Pokharkar, R. D.; Chopade, V. V.; Takate, S. B. Hepatoprotective Activity of Enicostemma axillare in Paracetamol Induced Hepatotoxicity in Albino Rats. Int. J. Pharm. Life Sci. 2010, 1 (2), 50–53. Jahan, E.; Perveen, S.; Malik, A. Verticilliside, a New Flavones C-Glucoside Form Enicostemma verticillatum. J. Asia. Nat. Prod. Res. 2009, 11, 257–260. Jaishree, V.; Badami, S.; Krishnamurthy, P. T. Antioxidant and Hepatoprotective Effect of the Ethyl Acetate Extract of Enicostemma axillare (Lam). Raynal Against CCl4-Induced Liver Injury in Rats. Indian J. Exp. Biol. 2010, 48, 896–904. Kavimani, S.; Manisenthlkumar, K. T. Effect of Methanolic Extract of Enicostemma littorale on Dalton’s Ascitic Lymphoma. J. Ethnopharmacol. 2000, 71 (1–2), 349–352. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants, 2nd ed.; Bishen Singh Mahendrapal Singh: Dehradun, 1999; pp 1655–1656. Leelaprakash, G.; Dass, S. M. In Vitro Anti-Inflammatory Activity of Methanol Extract of Enicostemma axillare. Intern. J. Drug Dev. Res. 2011, 3 (3), 189–196. Maroo, J.; Vasu, V. T.; Aalinkeel, R.; Gupta, S. Glucose Lowering Effect of Aqueous Extract of Enicostemma littorale Blume in Diabetes: A Possible Mechanism of Action. J. Ethnopharmacol. 2002, 81 (3), 317–320. Maroo, J.; Vasu, V. T.; Gupta, S. Dose Dependent Hypoglycemic Effect of Aqueous Extract of Enicostemma littorale Blume in Alloxan Induced Diabetic Rats. Phytomedicine. 2003, 10 (2–3), 196–199. Murali, B.; Upadhyaya, U. M.; Goyal, R. K. Effect of Chronic Treatment with Enicostemma littorale in Non-Insulin-Dependent Diabetic (NIDDM) Rats. J. Ethnopharmacol. 2002, 81 (2), 199–204. Nwafor, P. A.; Abia, G. O.; Bankhede, H. K. Antipyretic and Antimalarial Activities of Crude Leaf Extract and Fractions of Enicostema littorale. Asian Pacific J. Trop. Dis. 2012, 2 (6), 442–447. Patel, N.; Tyagi, R. K.; Tandel, N.; Garg, N. K.; Soni, N. The Molecular Targets of Swertiamarin and Its Derivatives Confer Anti-Diabetic and Anti-Hyperlipidemic Effects. Curr. Drug Targets. 2018, 19 (16), 1958–1967. Praveena, P.; Sudarsanam, D. In vitro antimicrobial activity studies on Enicostemma littorale (Lam), Raynal whole plants. Int. J. Curr. Res. 2011, 11 (3), 123–124. Roy, S. P.; Niranjan, C. M.; Jyothi, T. M.; Shankrayya, M. M.; Vishawanath, K. M.; Prabhu, K.; Gouda, V. A.; Setty, R. S. Antiulcer and Anti-Inflammatory Activity of Aerial Parts Enicostemma littorale Blume. J. Young Pharmacists 2010, 2 (4), 369–373. Vaijanathappa, J.; Badami, S.; Bhojraj, S. In Vitro Antioxidant Activity of Enicostemma axillare. J. Health Sci. 2008, 54 (5), 524–528. Vasu, V. T.; Modi, H.; Thaikoottathil, J. V.; Gupta, S. Hypolipidaemic and Antioxidant Effect of Enicostemma littorale Blume Aqueous Extract in Cholesterol Fed Rats. J. Ethnopharmacol. 2005, 101 (1–3), 277–282. Vishwakarma, S. L.; Rajani, M.; Bagul, M. S.; Goyal, R. K. A Rapid Method for the Isolation of swertiamarin from Enicostemma littorale. Pharmaceut. Biol. 2004, 42, 400–403.

CHAPTER 28

Phytochemical and Pharmacological Potential of Ornamental Bougainvillea (Bougainvillea spectabilis) SINOY SUGUNAN1,*, RAKESH BARIK1, G. SHIVA KUMAR1, and K. N. JAYAVEERA2 Gitam School of Pharmacy, GITAM Deemed To Be University, Hyderabad Campus, Rudraram 502329, Telangana, India

1

Department of Chemistry, Jawaharlal Nehru Technological University, Anantapur 515002, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Bougainvillea spectabilis belonging to the family Nyctaginaceae has high ornamental value due to its elegant colour, protracted florescence, and high strength. Various scientific publications have revealed that B. spectabilis consists of bioactive ingredients such as flavonoids, phytosterols, alkaloids, saponins, triterpenoids, tannins, anthraquinones, furanoids, and phenols. In the traditional system of medicine, numerous parts of B. spectabilis are used as anti-inflammatory, antiulcer, anticancer, antimicrobial, antihyperlipidaemic, antifertility, thrombolytic, antioxidant, and hepatoprotective agents. Spectrometric analytical studies on different parts of this plant showed mainly the presence of essential oils including methyl salicylate (21.8%), terpinolene (8.2%), and α-E-ionone (9.8%). Preclinical studies have revealed that B. spectabilis exhibits better protective effects against diabetes, inflammation, microbial infections and neurodegeneration. Further, this plant has shown a significant effect on haematological indices and fertility in animal experiments. Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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INTRODUCTION

The genus Bougainvillea belongs to family Nyctaginaceae. Bougainvillea has 18 species, amongst which Bougainvillea spectabilis, Bougainvillea glabra, and Bougainvillea peruviana are having a high ornamental worth (Wang et al., 2019). Their bracts have exquisite color, extended florescence, and strong endurance, which are of high value in urban landscape greening and ornamental horticulture. Further, more than 400 varieties of Bougainvillea have been recorded by the international authority (Wang et al., 2019). Among the different species of Bougainvillea, various scientific studies have highlighted the medicinal value of B. spectabilis (Ghogar and Jiraungkoorskul, 2017; Bhat et al. 2011; Do et al., 2018; Chauhan et al., 2016). By tradition, various parts of this plant are being used as anti-inflammatory, antiulcer, anticancer, antimicrobial, antihyperlipidaemic, antifertility, thrombolytic, antioxidant activity, and hepatoprotective agent (Bhat et al., 2011; Chaires-Martinez et al., 2009; Dhankhar et al., 2013; Do et al., 2018; Ferdous et al., 2020; Ghogar and Jiraungkoorskul, 2017; Malairajan et al., 2007; Venkatachalam et al., 2012; Joshi, et al., 1984; Mishra et al., 2016). In the present chapter, we summarize the paramount research findings related to the pharmacological activities of B. spectabilis and highlight the potential of B. spectabilis as a source of innovative phytotherapeutics to treat various debilitating diseases. 28.2 PHYTOCONSTITUENTS Previous analytical studies on B. spectabilis demonstrated the presence of flavonoids, phytosterols, alkaloids, saponins, triterpenoids, tannins, anthraquinones, furanoids, and phenols (Fawad et al., 2012; Ferdous et al., 2020). In a different study, the composition of the essential oil produced from the aerial parts of Bougainvillea spectabilis was examined by gas chromatography (GC) and GC–mass spectroscopy (Vukovic et al., 2013). The important constituents characterized in this study were methyl salicylate, terpinolene, and α-(E)-ionone. Older research also found that the leaves of B. spectabilis consisted of 3-O-methyl-chiroinositol (Ferdous et al., 2020; Geethan and Prince, 2008). Further, the existence of numerous flavones including bougainvinones (Compound 1-8), 20-hydroxydemethoxymatteucinol (Compound 6), 5,7,30,40-tetrahydroxy-3-methoxy-6,8-dimethylflavone (Compound 7), and 5,7,4′-trihydroxy-3-methoxy-6,8-dimethylflavone (Compound 8) have been established in the bark of B. spectabilis (Do et al., 2018; Ferdous et al., 2020). Additionally, spectrometric analysis of various

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parts of B. spectabilis consists of essential oils including methyl salicylate (21.8%), terpinolene (8.2%), and α-e-ionone (9.8%) (Ferdous et al., 2020; Vukovic et al., 2013). Due to these varied phytoconstituents present in this plant, researchers validated the pharmacological properties of the same. d-pinitol (6-methoxycyclohexane-1,2,3,4,5-pentol) Methyl Salicylate.

General Structure of Bougainvinones

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PHARMACOLOGICAL ACTIVITIES

28.3.1 ANTIDIABETIC The administration of aqueous extract of B. spectabilis for 28 days resulted in a significant reduction in hyperglycaemia as evident from the restoration of relevant biochemical markers through in vivo experimentation (Chauhan et al., 2016). The aforementioned study successfully demonstrated the antihyperglycemic effect of B. spectabilis leaves in streptozotocin-induced diabetes in Wistar rats. Interestingly, in an another study conducted, the antihyperglycemic effect of 16 plants (including B. spectabilis) and four algae, commonly used in Egypt for the treatment of diabetes mellitus, was researched (AbouZid et al., 2014). This study revealed that extracts prepared from B. spectabilis (leaves), Sonchus oleraceus, Plantago psyllium (seeds), Morus nigra (leaves), and Serena repens (fruits) were found to have antihyperglycemic potentials in diabetic mice (AbouZid et al., 2014). They recommended further studies to identify the active constituent responsible for the antidiabetic effect. The glucose lowering effect of B. spectabilis could be attributed to a key constituent present in the plant, primarily, d-pinitol (3-O-methyl-chiroinositol). Older research by group of scientists determined that D-pinitol can wield an insulin-like effect to increase glycaemic control in hypoinsulinaemic streptozotocin (STZ)-diabetic mice (Bates et al., 2000). They showed that in STZ-diabetic mice, 100 mg/kg oral administration, D-pinitol highly reduced the hyperglycaemia (by 22% at 6 h). A comparable reduction in plasma glucose (by 21%) was detected after 100 mg/kg intraperitoneal D-pinitol (Bates et al., 2000). It was mentioned by them that D-pinitol may act via a postreceptor pathway of insulin action affecting glucose uptake (Bates et al., 2000). It is noteworthy that two older experimental works established the potency of B. spectabilis against hyperglycaemia, mainly its constituent the D-pinitol (Narayanan et al., 1984, 1987). Furthermore, various studies have corroborated the hypoglycaemic effect of constituents from the leaves, stem barks, and roots of B. spectabilis (Jawla et al., 2012, 2013; Saikia and Das, 2009; Mahajan et al., 2015). 28.3.2 ANTI-INFLAMMATORY ACTIVITY A group of researchers demonstrated that the methanolic extract of B. spectabilis leaves has substantial anti-inflammatory and immunoregulatory activity (Mandal et al., 2015). Their experiments revealed that methanolic

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extract of B. spectabilis leaves (20 and 50 mg/kg) elicited significant antiinflammatory effects 20.6% and 67.6%, respectively, on carrageenan-induced acute inflammatory models. In dextran-induced edema, the impact was 30% and 66%, respectively (Mandal et al., 2015). Although the standard drug indomethacin (87.3% and 91.5%, respectively) exhibited a better inhibitory response in both models (Mandal et al., 2015). Similarly, in arthritic model 50 mg/kg of the extract displayed a significant chronic anti-inflammatory effect (38.46%) in contrast to the standard drug dexamethasone (84.6%). In turn, this study suggested to find the exact mechanism through which the B. spectabilis produced these effects. The next research from a different group showed that methanolic extract of B. spectabilis leaves suppressed inflammation and nociception in vivo (Ferdous et al., 2020). Their results exhibited that the extract at 50, 100, and 200 mg/kg doses were not effective enough to contain centrally mediated pain in the hot plate and tail immersion models. However, the extract was effective (at 100 and 200 mg/kg doses) in reducing peripheral nociception in the acetic acid-induced writhing and inflammatory phase of the formalin tests (Ferdous et al., 2020). Additional analyses revealed that the extract could interfere with glutamatergic system, cGMP and ATP-sensitive K+ channel pathways to produce its antinociceptive properties (Ferdous et al., 2020). Furthermore, they carried out the GC/MS–MS analysis of the extract which revealed the presence of 35 different phytochemicals with potent anti-inflammatory and antinociceptive properties including phytol, neophytadiene, 2,4-Di-tert-butylphenol, fucoxanthin, and Vit-E (Ferdous et al., 2020). Another group of scientists was successful in identifying seven bioactive components from the methanolic extract of B. spectabilis leaves (Ahmed and Abd Elkarim, 2020). They revealed that the leaves of this plant consist of secologanin dimethyl acetal, α- and β-amyrin, α- and β-amyrin acetate, Kaempferol, and kaempferol-3-O-rhamnoside (Ahmed and Abd Elkarim, 2020). These seven phytochemicals isolated from the methanolic extract of B. spectabilis leaves exhibited strong antirheumatoid arthritis activity (Ahmed and Abd Elkarim, 2020). 28.3.3 CYTOTOXIC ACTIVITY Initial interest in cytotoxic activity of B. spectabilis was generated through an appealing experiment whereby, Bouganin, a type I ribosome-inactivating protein was isolated from the plant leaves (Cizeau et al., 2009). Later on,

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it was mutated and was genetically linked to an antiepithelial cell adhesion molecule (EpCAM) Fab moiety via a peptidic linker comprising a furin proteolytic site to create the fusion construct VB6-845 (Cizeau et al., 2009). Interestingly, this construct selectively destroyed EpCAM-positive cell lines with a superior potency to various commonly used chemotherapeutic agents (Cizeau et al., 2009). Another experimental study extracted and characterized eight new peltogynoids, named bougainvinones A–H from the stem bark of B. spectabilis (Do et al., 2016). These isolated compounds were assessed for their cytotoxic effects against five cancer cell lines, mainly, KB, Hela S-3, HT-29, MCF-7, and HepG2. Among them, three compounds showed cytotoxicity against five cancer cell lines with IC50 values in the 6.6–9.7 μM range (Do et al., 2016). The same group extracted five new flavones from the bark of B. spectabilis and among these flavones, a constituent named as Compound 5 elicited cytotoxic activity against the KB and HeLa S-3 cell lines, with IC50 values of 7.44 and 6.68 µM (Do et al., 2018). 28.3.4 ANTIMICROBIAL ACTIVITY In a curious experimental work, the methanolic extracts of B. spectabilis flowers (5 different colors) were screened biologically by performing four bioassays: antibacterial, antifungal, brine shrimp lethality, and phytotoxicity (Ali et al., 2005). The methanolic extract of white flowers exhibited high antibacterial activity among all the tested extracts (Ali et al., 2005). Further, various studies indicated that the constituents from B. spectabilis could act against different forms of microbes and these phytochemicals have the potential to be precursors for various novel antimicrobial agents (Dhankhar et al., 2013; Hajare et al., 2015; Kumara Swamy et al., 2012; Kumar et al., 2011; Rashid et al., 2013; Umamaheswari, et al., 2008). 28.3.5 ANTIFERTILITY EFFECT The research conducted by Mishra et al. (2009) evaluated the effect of the 800 mg/kg/day of oral administration of B. spectabilis leaves on reproductive organs and fertility of male and female Swiss albino mice for 30 days, and it was found to reduce the caudal epididymal sperm count. This finding was corroborated by other researchers (Ghogar and

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Jiraungkoorskul, 2017). In addition to these findings, another group also demonstrated improved seminal quality through the administration of extracts from B. spectabilis in mice (Hembrom et al., 2011, 2014). Contrary to these findings, a study identified the harmful effect of the extract from B. spectabilis on spermatogenic pathways in rat (Ikpeme et al., 2015). 28.3.6

LARVICIDE ACTIVITY

The aqueous extract of B. spectabilis is inexpensive larvicide against A. aegypti and can be used as an efficient, easy-to-use, and eco-friendly control alternatives for management of A. aegypti, the vector of dengue/chikungunya (Sharma et al., 2019). 28.3.7 EFFECT ON HAEMATOLOGICAL INDICES The extract from the leaves of B. spectabilis was effective in serum cholesterol concentration reduction in rat with a caveat that it also possesses the potential of unfavorably affecting hematological indices (Adebayo et al., 2005). Interestingly, a different study indicated that alcoholic extract of B. spectabilis leaves was effective in lowering total cholesterol, triglyceride, low-density lipoprotein, very low-density lipoprotein levels, and significant increase in high-density lipoproteins in hypercholesteromic rats (Saikia and Lama, 2011). Another research finding revealed that concentrations of leaf extract improved the percentage of clot lysis in dose-dependent manner but it was not effective as streptokinase SK, a reference standard used in the experiment (Sherwani et al., 2013). 28.3.8 NEUROPROTECTIVE EFFECT The extract from the flowers of B. spectabilis was able to protect the brain cells against the rotenone-induced toxicity in rats (Abdel-Salam et al., 2017). Administration of rotenone increased lipid peroxidation marker malondialdehyde (MDA) and reduced glutathione in vivo (Abdel-Salam et al., 2017). However, flowers extracts exerted a protective effect against the toxic effects of rotenone on rat brains (Abdel-Salam et al., 2017).

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KEYWORDS

• • • • • • •

Bougainvillea spectabilis phytoconstituents terpenoids flavonoids diabetes antimicrobial cytotoxic

REFERENCES Abdel-Salam, O. M. E.; Youness, E. R.; Ahmed, N. A.; El-Toumy, S. A.; Souleman, A. M. A.; Shaffie, N.; Abouelfadl, D. M. Bougainvillea spectabilis Flowers Extract Protects Against the Rotenone-Induced Toxicity. Asian Pacific J. Tropical Med. 2017, 10 (5), 478–490. https://doi.org/10.1016/j.apjtm.2017.05.013 AbouZid, S. F.; Ahmed, O. M.; Ahmed, R. R.;, Mahmoud, A.; Abdella, E.; Ashour, M. B. Antihyperglycemic Effect of Crude Extracts of Some Egyptian Plants and Algae. J. Med. Food 2014, 17 (3), 400–406. https://doi.org/10.1089/jmf.2013.0068 Adebayo, J. O.; Adesokan, A. A.; Olatunji, L. A.; Buoro, D. O.; Aoladoye, A. O. Effect of Ethanolic Extract of Bougainvillea spectabilis Leaves on Haematological and Serum Lipid Variables in Rats. Biochemistry 2005, 17, 45–50. Ahmed, A. H.; Abd Elkarim, A. S. Bioactive Compounds with Significant Anti- Rheumatoid Arthritis Effect Isolated for the First Time from Leaves of Bougainvillea spectabilis. Curr. Pharma. Biotech. 2020. https://doi.org/10.2174/1389201021666201229111825 Ali, M. S.; Ibrahim, S. A.; Ahmed, F.; Pervez, M. K. Color Versus Bioactivity in the Flowers of Bougainvillea spectabilis (Nyctaginaceae). Natural Product Res. 2005, 19 (1), 1–5. https://doi.org/10.1080/14786410310001630609 Bates, S. H.; Jones, R. B.; Bailey, C. J. Insulin-Like Effect of Pinitol. British J. Pharmacol. 2000, 130 (8), 1944–1948. https://doi.org/10.1038/sj.bjp.0703523 Bhat, M.; Kothiwale, S. K.; Tirmale, A. R.; Bhargava, S. Y.; Joshi, B. N. Antidiabetic Properties of Azardiracta indica and Bougainvillea spectabilis: In Vivo Studies in Murine Diabetes Model. Evidence-Based Complement. Altern. Med. 2011, 2011, 561625. https:// doi.org/10.1093/ecam/nep033 Chaires-Martinez, L.; Monroy-Reyes, E.; Bautista-Bringas, A.; Jimenez-Avalos, H. A.; Sepulveda-Jimenez, G. Determination of Radical Scavenging Activity of Hydroalcoholic and Aqueous Extracts from Bauhinia divaricata and Bougainvillea spectabilis Using the DPPH Assay. Pharmacognosy Res. 2009, 1, 238–244. Chauhan, P.; Mahajan, S.; Kulshrestha, A.; Shrivastava, S.; Sharma, B.; Goswamy, H. M.; Prasad, G. B. K. S. Bougainvillea spectabilis Exhibits Antihyperglycemic and Antioxidant

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Activities in Experimental Diabetes. J. Evidence-Based Complem. Altern. Med. 2016, 21 (3), 177–185. https://doi.org/10.1177/2156587215595152 Cizeau, J.; Grenkow, D. M.; Brown, J. G.; Entwistle, J.; MacDonald, G. C. Engineering and Biological Characterization of VB6-845, an Anti-EpCAM Immunotoxin Containing a T-Cell Epitope-Depleted Variant of the Plant Toxin Bouganin. J. Immunother. (Hagerstown, MD: 1997), 2009, 32 (6), 574–584. https://doi.org/10.1097/CJI.0b013e3181a6981c Dhankhar, S.; Sharma, M.; Ruhil, S.; Balhara, M.; Kumar, M.; Chhillar, A. K. Evaluation of Antimicrobial and Antioxidant Activities of Bougainvillea spectabilis. Int. J. Pharm. Pharm. Sci. 2013, 5, 178–182. Do, L. T. M.; Aree, T.; Siripong, P.; Pham, T. N. K.; Nguyen, P. K. P.; Tip-Pyang, S. Bougainvinones A-H, Peltogynoids from the Stem Bark of Purple Bougainvillea spectabilis and Their Cytotoxic Activity. J. Nat. Prod. 2016, 79 (4), 939–945. https://doi.org/10.1021/ acs.jnatprod.5b00996 Do, L. T. M.; Aree, T.; Siripong, P.; Vo, N. T.; Nguyen, T. T. A.; Nguyen, P. K. P.; Tip-Pyang, S. Cytotoxic Flavones from the Stem Bark of Bougainvillea spectabilis Willd. Planta Medica 2018, 84 (2), 129–134. https://doi.org/10.1055/s-0043-118102 Fawad, S. A.; Khalid, N.; Asghar, W.; Suleria, H. A. R. In Vitro Comparative Study of Bougainvillea spectabilis “Stand” Leaves and Bougainvillea variegata Leaves in Terms of Phytochemicals and Antimicrobial Activity. Chinese J. Nat. Med. 2012, 10 (6), 441–447. https://doi.org/10.1016/S1875-5364 (12)60085-5 Ferdous, A.; Janta, R. A.; Arpa, R. N.; Afroze, M.; Khan, M.; Moniruzzaman, M. The Leaves of Bougainvillea spectabilis Suppressed Inflammation and Nociception In Vivo Through the Modulation of Glutamatergic, cGMP, and ATP-Sensitive K (+) Channel Pathways. J. Ethnopharmacol. 2020, 261, 113148. https://doi.org/10.1016/j.jep.2020.113148 Geethan, P. K. M. A.; Prince, P. S. M. Antihyperlipidemic Effect of D-Pinitol on StreptozotocinInduced Diabetic Wistar Rats. J. Biochem. Mol. Toxicol. 2008, 22 (4), 220–224. https://doi. org/10.1002/jbt.20218 Ghogar, A.; Jiraungkoorskul, W. Antifertility Effect of Bougainvillea spectabilis or Paper Flower. Pharmacogn. Rev. 2017, 11 (21), 19–22. https://doi.org/10.4103/phrev.phrev_44_16 Hajare, C. N.; Inamdar, F. R.; Patil, R. V.; Shete, C. S.; Wadkar, S. S.; Patil, K. S.; et al. Antibacterial Activity of the Leaves of Bougainvillea spectabilis Against E. coli NCIM 2832 and M. aureus NCIM 5021. Int. J. Pharm. Sci. Rev. Res. 2015, 34, 194–196. Hembrom, A. R.; Pragya, S.; Kumar, J.; Singh, V. N. Effects of Aqueous Leaf Extract of Bougainvillea spectabilis on Seminal Quality of Mice. J. Adv. Zool. 2011, 32, 119–122. Hembrom, A. R.; Pragya, S.; Singh, V. N. Selective and Directional Influence of Bougainvillea spectabilis on Anodic Electrophoretic Proteins and M-Isozymes of LDH in Semen of Mice in Relation to Fertility Control. Int. Res. J. Pharm. 2014, 5, 576–577. Ikpeme, E. V.; Ekaluo, U. B.; Udensi, O. U.; Ekerette, E. E.; Pius, M. Phytochemistry and Reproductive Activities of Male Albino Rats Treated with Crude Leaf Extract of Great Bougainvillea (Bougainvillea spectabilis) Asian J. Sci. Res. 2015, 8, 367–373. Jawla, S.; Kumar, Y.; Khan, M. S. Hypoglycemia Activity of Bougainvillea spectabilis Stem Bark in Normal and Alloxan-Induced Diabetic Rats. Asian Pac. J. Trop. Biomed. 2012, 2, 919–23. Jawla, S.; Kumar, Y.; Khan, M. S. Isolation of Phytoconstituents and Antihyperglycemic Activity of Bougainvillea spectabilis Root Bark Extracts. Lat. Am. J. Pharm. 2013, 32, 1389–1395.

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Joshi, D. D.; Mujumdar, A. M.; Narayanan, C. R. Antiinflammatory Activity of Bougainvillea spectabilis Leaves. Indian J. Pharm. Sci. 1984, 46, 187–188. Kumar, D. J.; Sonia, K.; Madhan, R.; Selvakumar, K. Antiyeast, Antioxidant and Anticancer Activity of Tribulus terrestris Linn and Bougainvillea spectabilis Linn. Res. J. Pharm. Technol. 2011, 4, 1483–1489. Kumara Swamy, M.; Sudipta, K. M.; Lokesh, P.; Neeki, M. A.; Rashmi, W.; Bhaumik, S. H. et al. Phytochemical Screening and In Vitro Antimicrobial Activity of Bougainvillea spectabilis Flower Extracts. Int. J. Phytomed. 2012, 4, 375–379. Mahajan, M. M.; Dudhgaonkar, S.; Deshmukh, S. N. Anti-Diabetic and Hypolipidemic Effects of the Aqueous Leaf Extract of Bougainvillea Species. Int. J. Basic Clin. Pharmacol. 2015, 4, 596–597. Malairajan, P.; Gopalakrishnan, G.; Narasimhan, S.; Jessi, K. V. Antiulcer Activity of Crude Alcoholic Extracts of Bougainvillea spectabilis Willd. Jundishapar J. Nat. Pharm. Prod. 2007, 2, 1–6. Mandal, G.; Chatterjee, C.; Chatterjee, M. Evaluation of Anti-Inflammatory Activity of Methanolic Extract of Leaves of Bougainvillea spectabilis in Experimental Animal Models. Pharmacogn. Res. 2015, 7 (1), 18–22. https://doi.org/10.4103/0974-8490.147194 Mishra, N.; Joshi, S.; Tandon, V. L.; Munjal, A. Evaluation of Antifertility Potential of Aqueous Extract of Bougainvillea spectabilis Leaves in Swiss Albino Mice. Int. J. Pharm. Sci. Drug Res. 2009, 1, 19–23. Mishra, N.; Tandonn, V. L.; Dhama, K.; Khandia, R.; Munjal, A. Does Bougainvillea spectabilis Protect Swiss Albino Mice from Aflatoxin-Induced Hepatotoxicity? Adv. Anim. Vet. Sci. 2016, 4 (5), 250–257. Narayanan, C. R.; Joshi, D. D. Mujumdar, A. M.; Dhekne, V. Pinitol a New Antidiabetic Compound from the Leaves of Bougainvillea spectabilis. Curr. Sci. 1987, 56, 139–141. Narayanan, C. R.; Joshi, D. D.; Mujumdar, A. M. Hypoglycemic Action of Bougainvillea spectabilis Leaves. Curr. Sci. 1984, 53, 579–581. Rashid, F.; Sharif, N.; Ali, I.; Sharif, S.; Nisa, F. U.; Naz, S. Phytochemical Analysis and Inhibitory Activity of Ornamental Plant (Bougainvillea spectabilis). Asian J. Plant Sci. Res. 2013, 3, 1–5. Saikia, H.; Das, S. Antidiabetic Action of Bougainvillea spectabilis (Leaves) in Normal and Alloxan Induced Diabetic Albino Rats. Indian Drugs 2009, 46, 391–397. Saikia, H.; Lama, A. Effect of Bougainvillea spectabilis Leaves on Serum Lipids in Albino Rats Fed with High Fat Diet. Int. J. Pharm. Sci. Drug Res. 2011, 3, 141–145. Sharma, A.; Tilak, R.; Sisodia, N. Evaluation of Bioactivity of Aqueous Extracts of Bougainvillea spectabilis, Saraca asoca, and Chenopodium album Against Immature Forms of Aedes aegypti. Med. J. Armed Forces India 2019, 75 (3), 308–311. https://doi. org/10.1016/j.mjafi.2018.07.013 Sherwani, S. K.; Khan M. M.; Zubair, A; Shh, M. A.; Kazmi S. U. Evaluation of In Vitro Thrombolytic Activity of Bougainvillea spectabilis Leaf Extract. Int. J. Pharm. Sci. Rev. Res. 2013, 21, 6–9. Umamaheswari, A.; Shreevidya, R.; Nuni, A. In Vitro Antibacterial Activity of Bougainvillea spectabilis Leaves Extracts. Adv. Biol. Res. 2008, 2, 1–5. Venkatachalam, R. N.; Singh, K.; Marar, T. Bougainvillea spectabilis a Good Source of Antioxidant Phytochemicals. Res. J. Pharm. Biol. Chem. Sci. 2012, 3, 605–613.

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Vukovic, N.; Kacaniova, M.; Hleba, L.; Sukdolak, S. Chemical Composition of the Essential Oil of Bougainvillea spectabilis from Montenegro. J. Essential Oil Bearing Plants 2013, 16 (2), 212–215. https://doi.org/10.1080/0972060X.2013.794014 Wang, N.; Qiu, M.-Y.; Yang, Y.; Li, J.-W.; Zou, X.-X. Complete Chloroplast Genome Sequence of Bougainvillea spectabilis (Nyctaginaceae). Mitochondrial DNA. Part B, Resour. 2019, 4 (2), 4010–4011. https://doi.org/10.1080/23802359.2019.1688716

CHAPTER 29

Bioactives and Pharmacology of Couroupita guianensis Aubl. S. RAJASHEKARA1* and M. MUNIRAJU2 Centre for Applied Genetics, Department of Studies in Zoology, Bangalore University, Jnana Bharathi Campus, Off Mysuru Road, Bengaluru 560056, India

1

Department of Studies in Botany, Bangalore University, Jnana Bharathi Campus, Off Mysuru Road, Bengaluru 560056, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Couroupita guianensis Aubl. is generally identified as cannonball tree having a place with the flowering plant family Lecythidaceae. It has gained worldwide attention because of its immense therapeutic values including antibiotic, antiseptic, anti-inflammatory, antimicrobial, antimycobacterial, analgesic, antiarthritic, anti-biofilm, antidiarrheal, antifertility, antipyretic, antistress, antitumor, antiulcer, antidermatophytic, wound healing, and immunomodulatory activities. Almost all parts of the tree have been used traditionally for treating various ailments since C. guianensis is a rich source of bioactive compounds, specifically the presence of isatin, tryptanthrin, and indirubin noteworthy. This review attempts to summarize information related to the medicinal value of C. guianensis to date to provide baseline knowledge for future work.

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INTRODUCTION

The conventional type of giving improvement to a few sicknesses and diseases can be utilized from the herbal plants. Couroupita guianensis Aubl. is generally identified as cannonball tree having a place with the flowering plant family Lecythidaceae. It is local to the tropical woodland of Central and South America, and it is developed in numerous other tropical regions all through the world due to its wonderful, fragrant flowers and huge, intriguing fruits. There are therapeutic practices for many parts of C. guianensis and, this tree has social and sacred implication in India. Common or regional names in different vernaculars include Abricodemacaco (Portuguese), Cocosachapura (Colombia, Panama), Kaman Gola, Nagkeshar (Bengali), Nagalinga, Shiv Kamal, Shivalinga, Tope Gola (Hindi), Lingada Mara, Nagalingam, Nagalinga Pushpa (Kannada), Shivalingam (Marathi), Naagalingam (Tamil), Nagamalli, Mallikarjuna (Telugu). It is extensively planted as ornamental tree in India, Thailand, and United States Couroupita guianensis is broadly used in Indian customary medications to treat stomach hurts, toothaches, cold, skin illnesses, microbial and parasitic contaminations (Sirisha and Jaishree, 2018). Pulp of the fruit color is white, acidic, and not agreeable. The fruits are palatable, vinous, and charming and are once in a while eaten as well as used to feed animals such as chickens, ducks, muscovy, and pigs (Kumar et al., 2017). The flowers of Kailashpati tree can be used to manufacture scent, perfumes, and cosmetics due to its wonderful smell in nature (Kumar et al., 2017). Amazonian basin people used the infusion or tea obtained from leaves, flower, and bark of C. guianensis to treat hypertension, growths, torment, and incendiary cycles (Sanz-Biset et al., 2009). The scent of flowers is utilized for treating asthma and the outer layer of fruits is used as a utensil. The current survey covers inside and out writing overview concerning nature, morphology, ethnopharmacology, phytochemistry, and toxicological data of C. guianensis. This survey endeavors to sum up data identifying with the restorative worth of C. guianensis to date to give standard information for future work. 29.2 BIOACTIVES Ethanolic extract of the plant leaves samples was investigated by GC-MS for optional metabolites (the bioactive mixtures) in C. guianensis uncovering absolutely eight mixtures tops occurred in GC-MS spectrum (Narasimhan, 2020). That one significant top with maintenance time of 18.88 min and their separate

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region rate is 81.84%. The metabolites/compounds was 10-octadecenoic methyl esters, that is available in the C. guianensis which has more drug properties; consequently, this plant plays more indispensable part in drug disclosure and consists of particular bioactive substances, for example, isatin, eugenol, farnesol, beta sitosterol, nerol, benzyl alcohol, trypthantrin, indirubin, indigo, alpha amyrin, beta amyrin, stigmasterol, and campesterol (Narasimhan, 2020).

The phytochemical investigation of extracts of stem of C. guianensis and secondary metabolite screening by TLC analysis revealed alkaloids, flavonoids, phenols, saponins, and triterpenoids in petroleum ether extracts; alkaloids, amino acids, flavonoids, saponins, steroids, and triterpenoids in benzene extracts; alkaloids, flavonoids, phenols, steroids, and triterpenoids in ethanol extracts; and amino acids, flavonoids, phenols, steroids, and triterpenoids in water extracts (Regina and Rajan, 2012). The fundamental examinations on the phytochemical constituents showed the occurrence of alkaloids, saponin, flavonoids, phenol, tannin, and terpenoids in the methanolic extract of the leaves of C. guianensis structures an intense cell reinforcement, unrestricted radical sifting movement, and inhibitory activity against α-amylase and α-glucosidase activity. The amount of terpenoids, alkaloids, tannins, and saponins was originated to show an ascending trend with 1.7 ± 0.09 × 102, 2.4 ± 0.12 × 102, 10.4 ± 0.52 × 102, and 18.1 ± 0.91 × 102 mg/g, respectively (Ilangovan and Thavasumani, 2021). Wong and Tie (1995) analyzed the volatile constituents of C. guianensis flowers using the capillary GC and GC/MS followed by the solvent

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extraction and isolation methods. Among the identified 41 compounds, eugenol (41.6%), linalool (14.9%), (E, E)- farnesol (10.3%), and nerol (9.8%) were predominant ones. Sirisha and Jaishree (2018) evaluated the phytochemical constituents, cancer prevention agent, and antiproliferative exercises of progressive extracts of leaves, stem, and unrefined methanolic extract of flowers of C. guianensis. These extracts were assessed for their cancer prevention agent action by 1,1’- diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity action, nitric oxide free revolutionary searching action, hydrogen peroxide searching, lipid peroxide inhibitory action, hydroxyl radical by deoxyribose strategy and absolute cell reinforcement limit of extracts and cytotoxic property of extracts just as complete phenolic content. The methanolic leaf extract showed most noteworthy all-out phenol content. Ethyl acetic acid derivation and methanol extracts were found to have astounding cancer prevention agent movement in the greater part of the tried strategies. Thus, the cytotoxicity studies revealed that ethyl acetic acid derivation leaf and rough methanolic flower extracts have better movement. Bergman et al. (1985) pull out the dehydrated biological substances from the cannon ball tree and yielded 6, 12-dihydro-6,12-dioxoindolo[2,1-b]quinazoline (tryptanthrin), indigo, indirubin, isatin and furthermore, synthesized the isatoic anhydride in pyridine by reduction of isatin. The chemical examination of the bark of C. guianensis furnishes a new ketosteroid, couropitone in addition to 13-amyrin, Oamyrone, p-amyrin acetate, stigmasterol, ergosta-4,6,8(14), 22-tetraen-3-one, 13- sitosterol, and its glycoside. The structure of couropitone is established as stigmasta4,23(E)-dien-3-one 1 (Anjaneyulu and Rao, 1998). The n-hexane and carbon tetrachloride solvent parts of a methanolic extract of the stem bark of the C. guianensis furnished three compounds, identified as β-amyrin (1), betulin-3β-caffeate (2), and lupeol-3β-caffeate (3). The designs of the disconnected mixtures were found by a broad spectroscopic investigation just as by correlation with distributed qualities. Compounds 1–3 were exposed to cancer prevention agent screening through free radical searching movement by DPPH (1,1-diphenyl-2-picrylhydrazyl), where compound 2 showed moderate cell reinforcement action with an IC50 value 108.0 μg/mL (Begum et al., 2009). The seeds of C. guianensis contain 32% oil and 19.0% protein. The seed oil has an iodine value of 126.1, a saponification value of 185.7, a peroxide value of 0.8, and an acid value of 2.4 (Dave et al., 1985).

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Kaneria et al. (2017) exhibited the most extreme phenol and best DPPH free revolutionary searching movement and ferric decreasing cell reinforcement power. They characterized the active metabolites and identified in total 39 compounds. Therefore, high correlations, between phenolic pieces and cell reinforcement exercises of different extracts. Also, cold permeation extraction strategy demonstrated the best extraction of cell reinforcement from C. guianensis. The fruit of the cannonball tree contains a small amount of essential oil, made out of a phenolic substance and acids, which has the characteristic odor of the fruit. A red color is present, which is evidently a carotenoid pigment. The acids chiefly consist of citric acid with small amounts of malic and isocitric acids (Nelson and Wheeler, 1937). The fruits, flowers, and the stem bark of the cannonball tree comprise a couroupitine determined alkaloid structure (Sen et al., 1974). Pandurangan et al. (2018) extracted the phytochemical and biological activities of different extracts of leaf, flower, and fruit. Also, silver nanoparticles were manufactured from these parts, described for its antibacterial action. Their study revealed that aside from the fluid extracts, any remaining extracts have great cancer prevention and antibacterial activity in this manner communicating the existence of bioactive combinations. Flower intervened nanoparticles showed preferred outcomes over others which may be because of the presence of certain phytochemical compounds answerable for the decrease and covering of silver nanoparticles. These outcomes showed the capability of C. guianensis and further examination to seclude such pharmacologically dynamic mixtures that can be utilized in the creation of novel medications for different infections. Martínez et al. (2012) inspected the hydroalcoholic leaf extracts of C. guianensis for the cancer prevention agent action, phytochemical and complete phenolic piece, incitement of human skin fibroblast (HSF) multiplication, and UV ingestion. The revolutionary rummaging limit, decreasing force, and assurance compared to the joint oxidation of linoleic acid and—carotene dying oxidation in emulsion were utilized to assess the cancer prevention agent movement. They emphatically demonstrated in vitro cell reinforcement action, which may be because of the presence of a highly complete phenolic content. To discriminate active values, the extracts were acquiesced to fractionation and the mixtures confined were the flavonoids 20,40-dihydroxy-60-methoxy-30,50-dimethylchalcone (1), 7-hydroxy-5-methoxy-6,8-dimethylflavanone (2), and the phenolic acid, 4-hydroxybenzoic acid (3). Likewise, an undeniable degree of incitement of

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HSF multiplication and critical assimilation of UV radiation were additionally noticed. Along these lines, hydroalcoholic leaf extracts of C. guianensis have promising healthy skin properties. Manimegalai et al. (2014) assessed the cell reinforcement potential and antibacterial action of alcoholic extract of flowers of C. guianensis. In vitro cell reinforcement movement was surveyed by 1, 1-diphenyl-2-picryl hydrazyl (DPPH) rummaging examine and estimated the hydrogen peroxide radical searching action. Ascorbic acid was utilized as the standard cell reinforcement for examination. Phytochemical investigation of the extract showed the presence of significant classes of phytochemicals alkaloids, phenolic mixtures like flavonoids, tannins, and saponins. C. guianensis methanolic extract showed the most elevated lessening limit. The antibacterial action of plant extract was found critical. Thus, the flowers of C. guianensis have intense antibacterial movement and are a decent wellspring of regular cancer prevention agents. Prabhu and Ravi (2017) isolated the flower for consecutive extraction utilizing oil ether, chloroform, ethyl acetic acid derivation, and methanol solvents. Cycloart-24-en-3-ol-4’-exomethylene heptadeconate along with stigmasterol, p-coumaric acid, o-coumaric acid, caffeic acid, and quercetin have been detached by section chromatography and described utilizing IR, 1H, and 13C NMR and MS unearthly information. Accordingly, C. guianensis is utilized broadly as a fixing in numerous Ayurveda arrangements that fix gastritis, scabies, demanding stacks, diarrhoea, and scorpion venomous. Khan et al. (2014) analyzed the composition of volatile components in C. guianensis flowers utilizing the headspace-strong stage miniature extraction (HS-SPME), trailed by narrow gas chromatography and mass spectrometry (GC-MS) detachment and distinguishing proof. Taking all things together, 75 mixtures were distinguished representing 96.32% of the absolute volatiles present. The significant gatherings of mixtures present were oxygenated terpenoids (35.66%), alcohols (26.92%), esters (17.36%), mono-and sesquiterpenoids (8.64%), aldehydes and ketones (4.71%), hydrocarbons (1.68%), phenols (0.18%), acids (0.754%), and heterocyclic mixtures (0.42%) establishing a little extent of the unstable profile. The most bountiful distinct component was eugenol (18.95%) trailed by nerol (13.49%), (E,E) farnesol (12.88%), (E,E)- farnesyl acetic acid derivation (6.68%), trans ocimene (6.02%), nootkatone (4.64%), geraniol (2.94%), 2-isopropenyl-5-methyl4-hexenyl acetic acid derivation (2.69%), cedr-8-en-13-ol (2.58%), (E,Z)farnesyl acetic acid derivation (2.40%), and methyl (11E)- 11-hexadecenoate (2.041%). Logical correlation of arrangement of volatiles in the flowers,

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acquired by various techniques for extraction, viz., dissolvable extraction, miniature synchronous extraction, and headspace-strong stage microextraction, uncovered explicit varieties in relative convergences of the constituent synthetic compounds. Linalool was the significant synthetic (21.5% and 14.9%) in dissolvable extract and miniature synchronous extract, separately. Shivashankar et al. (2013) assessed the phytochemicals for the existence of high substance of complete cell reinforcement action (598.4 µg/mL), phenol content action of (417.52 µg/mL) and phytosterols of (133.92 µg/ mL) in cold hydromethanolic extract contrasted with the hot hydromethanolic extract. The presence of high flavonoid content (417.52 µg/mL) was recorded in hot extract. Hot extract forms the good antimicrobial activity with IC50 esteem (33.5 µg/mL). ABTS radical scavenging activity movement was observed to be more in cool extract with IC50 esteems (24 µg/mL). Antimicrobial estimation showed activity with B. cereus (13.00 ± 0.00 mm) and S. aureus (15.00 ± 0.00 mm) microbes showed greatest zone of interference contrasted with the hot extract while C. albicans (13.00 ± 0.00 mm) showing most extreme zone of inhibition contrasted with the virus extract and was not delicate to some other parasitic structures tried. Hence, C. guianensis with exceptionally expected cell reinforcement and antimicrobial parts can be utilized in drug organizations for the improvement of phytomedicine for the treatment and medicines. 29.3

PHARMACOLOGY

Couroupita guianensis has numerous restorative uses in the act of customary medication. Cannonball tree has acquired overall consideration as a result of its massive remedial qualities. Almost all pieces of the tree have been utilized generally for treating different illnesses. C. guianensis is a rich wellspring of bioactive mixtures; explicitly, the presence of isatin, tryptanthrin, and indirubin is critical. Cannonball tree has acquired overall consideration in light of its tremendous helpful values including antimicrobial, sterile, mitigating, antimycobacterial, pain relieving, antiarthritic, against biofilm, antidiarrheal, antifertility, antipyretic, antistress, antitumor, antiulcer, antidermatophytic, wound mending, and immunomodulatory activities. Very nearly all standard parts of the tree have been used traditionally for treating different ailments. Cannonball tree has gained worldwide attention because of its immense therapeutic values including antibiotic, antiseptic, anti-inflammatory,

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antimicrobial, antimycobacterial, analgesic, antiarthritic, anti-biofilm, antidiarrheal, antifertility, antipyretic, antistress, antitumor, antiulcer, antidermatophytic, wound healing, and immunomodulatory activities. Almost all parts of the tree have been used traditionally for treating various ailments. It has been reported that C. guianensis is a rich source of bioactive compounds, specifically the presence of isatin, tryptanthrin, and indirubin is noteworthy. 29.3.1 ANTIMICROBIAL ACTIVITY The Kailashpati tree components have numerous restorative properties like antibacterial and antifungal actions (Kavitha et al., 2011). The antimicrobial activities of extracts from C. guianensis tissues were estimated against 12 g positive, 12 g negative, and one protozoan. Methanol extracts of leaves, flowers, fruits, stem and root barks, and stem and root heartwood of the plant restrained development of the microorganisms, a marvel that was upgraded by additional fractionation of the methanol extracts into petroleum, dichloromethane, ethyl acetic acid derivation, and butanol solvent portions. Most movement was found in the petroleum parts of the flowers, fruits, and stem bark; the ethyl acetic acid derivation part of the flowers, and stem and root bark; and the dichloromethane parts of the stem and root barks; likewise, a few parts of the stem bark and flowers displayed antifungal action (Khan et al., 2003). The antimicrobial action of CGEE was examined against Gram-positive (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli). Extraction of flavonoids from different parts of C. guianensis exhibited the flavonoids from a wide scope of biochemical and pharmacological impacts and its efficacy owing to scavenge the free radicals, oxidative damage of cell during different stresses including pathogenic bacterial infections (Akther et al., 2017). The trichloromethane extract of the fruits of C. guianensis presented the great antimicrobial and antibiofilm-shaping actions; though, it exhibited low antimycobacterial action. The zones of restraint by chloroform extract went from 0 to 26 mm. Trichloromethane extract displayed successful antibiofilm action against Pseudomonas aeruginosa beginning from 2 mg/mL of biofilm inhibitory fixation (BIC), with 52% restraint of biofilm development. At the point when the chloroform extract was exposed to elite fluid chromatography strategy with diode cluster discovery (HPLC-DAD) examination, alongside Indirubin standard, in similar chromatographic conditions, it was

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discovered that Indirubin was single of the significant combinations in this plant (0.0918% dry mass premise) (Al-Dhabi et al., 2012). The C. guianensis flowers are utilized to treat microbial diseases in customary restorative acts of India. The methanolic extract of C. guianensis flowers was found to be active against both Gram-negative E. coli (24 mm) and Gram-positive methicillin-sensitive and methicillin-resistant S. aureus strains (16) when exposed to the antimicrobial activity by the agar well diffusion method with MIC values of 25 mm and 13 mm of zone of inhibition for the standard strains. This was primarily owing to the existence of biochemical group of compounds such as glycosides, tannins, and phenolics that exhibited the antimicrobial effects (Majumder et al., 2014). Raghavendra et al. (2017) made the analyses on antimicrobial, radical scavenging, and insecticidal action of leaf and flower of C. guianensis by maceration measure utilizing methanol. Antibacterial and antifungal activities of extracts were completed by the agar well-dissemination strategy and harmed food procedure separately. Revolutionary rummaging movement of extracts was controlled by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) radical scavenging assays. Insecticidal action of extracts was assessed as far as larvicidal and pupicidal impacts against Aedes aegypti. Leaf extracts showed checked antibacterial movement when contrasted with flower extracts. Most elevated and least inhibitory movement of extracts was seen against Staphylococcus epidermidis and E. coli, individually. The two extracts showed antifungal action with most noteworthy movement. Most elevated and least weakness were shown by Curvularia sp. also, Fusarium sp., individually. The two extracts scavenged DPPH and ABTS radicals portion conditionally. Leaf extract (IC50 = 19.61 g/mL) marked DPPH radical scavenging potentiality compared to the flower extract ((IC50= 257.13 g/mL). IC50 worth of ABTS radical hindrance of leaf and flower extract was observed to be 7.63 and 53.34 g/mL, individually. The vulnerability of hatchlings and pre-adult to extract was in the request: second instar hatchlings > fourth instar hatchlings > pupae. Leaf extract showed noticeable insecticidal action when contrasted with flower extract as uncovered by lower LC50 esteems. Thus, leaf extract displayed noticeable bioactivities than flower extract. The plant can be utilized to treat microbial contaminations and oxidative harm and to oversee parasitic sicknesses. The plant can be utilized against mosquito vectors that communicate arboviral illnesses. Shah et al. (2012–2013) powdered the dried mash of C. guianensis and fine powder was extracted with alcohol (95%) by maceration technique.

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Alcoholic extract was evaluated for antibacterial action by tube-shaped cup plate technique utilizing four standard bacterial communities—E. coli, S. aureus, B. subtilis, and P. aeruoginosa. The main action was found against B. subtilis at observed 4 mg when contrasted with other tried life forms. Ramalakshmi et al. (2013) assessed the methyl alcohol extract of the flowers of C. guianensis for its antimicrobial activity and phytochemical substance. The antimicrobial activity showed effective inhibitory activity against Staphylococcus aureus, Plesiomonas shigelloides, Vibrio mimicus, and Proteus vulgaris. Moderate antimicrobial action was recorded against E. coli, Salmonella typhi, and Klebsiella pneumoniae. An important phytochemical investigation of the flower extract of this plant showed the presence of phytoconstituents like starches, protein, alkaloids, terpenoids, phenolic compounds, lessening sugar, and triterpenoids. The alkaloids present in the rough rose extracts of this plant C. guianensis are significantly expected for its likely antimicrobial activity. Shete et al. (2013) manufactured a residue sample from the fruits dried shell by the maceration method. The phytochemical constituents displayed the occurrence of tannins, sugars, and polyphenolic compounds. Alcoholic extract was estimated for antibacterial action by round and hollow cup plate strategy utilizing four standard bacterial communities like E. coli, S. aureus, B. subtilis, and P. aeruoginosa. Bacillus subtilis was the most significant activity that was found at concentration 4 mg when compared with the other tested organism. Costa et al. (2017) evaluated the antimicrobial activity of ethanolic (EtOH) extract and fractions of C. guianensis flowers and segregation of bioactive part. These were exposed to agar diffusion, MIC, TLC, and bioautography to microorganisms, filamentous growths, and yeasts. Among the negligible portions of EtOH extract, the DCM division was the most dynamic, especially against Methicillin-resistant Staphylococcus aureus (MRSA) with MIC of 156 μg/mL. The dynamic compound in this division was recognized as Tryptanthrin, which showed promising antibacterial action for MRSA showing MIC of 62.5 μg/mL. Ultrastructural investigation of MRSA hatched within the sight of Tryptanthrin by transmission electron magnifying lens showed critical modifications in the cell structure. Cytotoxicity tests exhibited that DCM division and Tryptanthrin showed low poisonousness. Along these lines, C. guianensis structures a promising possibility for elective treatments to control and battle sicknesses.

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29.3.2 ANTIMALARIAL ACTIVITY The most potent antimalarial activity was obtained from the ethyl acetate extract of C. guianensis flowers and was discovered as stigmasterol which was isolated and characterized this compound responsible for activity by HPTLC fingerprint analysis, UV, FTIR, H-NMR, and Mass Spectroscopy. Malaria is the most well-known irresistible sickness, due to multi-drug resistance parasites and the limited number of effective drugs available in this situation is stigmasterol with the concentration of 412.69 g/mL as new antimalarial drugs (Shwetha et al., 2020). Desai et al. (2003) evaluated the larvicidal property of various extracts of C. guianensis against late-third or mid-fourth instar hatchlings of Culex quinquefasiatus. The petrol ether and chloroform extract of flowers displayed great larvicidal action and the chloroform extract of its fruits likewise showed promising larvicidal action. Maheswaran et al. (2019) assessed the bioefficacy of unrefined extract and divisions from the leaves of C. guianensis used the second and fourth instar fledglings of Culex quinquefasciatus Say and Aedes aegypti L. Larval poisonousness examination was done with water containing the rough extract ranged 125 to 1000 ppm and parts of powerful unrefined extract was tried from 25 to 200 ppm fixations against C. quinquefasciatus and A. aegypti. Out of three dissolvable raw extracts, hexane extract of C. guianensis exhibited hopeful larvicidal activity against the two vector mosquitoes trailed by chloroform and ethyl acetic acid derivation. Chromatographically eluted part 3 showed promising larvicidal movement followed by portions 2 and 8 contrasted and the unrefined extract. Consequently, C. guianensis extract can possibly control C. quinquefasciatus and A. aegypti without hurting nontarget fish. 29.3.3 ANTIFUNGAL ACTIVITY The extract inhibited Candida albicans with a base inhibitory concentration worth of 12.5 mg/mL when Time-kill assay was made with C. guianensis flower extract had totally inhibited C. albicans development and furthermore showed delayed anti-yeast action. This may be because of the presence of major classes of phytochemicals like alkaloids, phenolic compounds such as flavonoids, tannins, steroids, glycosides, and saponin. The extract shows cell reinforcement action with an Inhibitory Concentration (IC50) value of 93.2 ± 0.011 μg/mL. Therefore, the extract of C. guianensis flower with great anticandidal and cell reinforcement exercises could be a powerful specialist to treat the C. albicans infection (Gothai et al., 2018).

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29.3.4 ANTIOXIDANT ACTIVITY Ethyl acetate fraction of water extract of C. guaianensis flowers (EAFWE) was investigated by Bafna et al. (2011) for in vitro antioxidant action utilizing the DPPH test, superoxide rummaging impact, lessening power, and in-vitro lipid peroxidation. EAFWE was observed to be amazingly successful in searching DPPH (EC50 =24.41 μg/mL) and superoxide radical (EC50=10.65 μg/mL) though restraint of lipid peroxidation was moderate (EC50=199.70). This share also exhibited cell reinforcement activity as far as critical decreasing force. In this manner, C. guaianensis flowers are utilized to fix chilly, digestive gas arrangement, and stomachache (Bafna et al., 2011). The clinical methodologies of cell reinforcements expanded multifold during the new ideal opportunity for the administration and restorative ramifications of neurodegenerative issues, maturing and ongoing degenerative illnesses. Gupta et al. (2014) evaluated the impact of development measure on in vitro cell reinforcement movement of C. guianensis flower and fruit. The cell reinforcement exercises of methanolic extracts of flower and product of youthful and developed stages were researched spectrophotometrically against DPPH, ABTS, H2O2, NO, superoxide, hydroxyl radical, and lipid peroxidation, alongside ferric decreasing force, metal chelating, and β-carotene blanching examine. Complete phenols, flavonoids, ortho-dihydric phenols, and anthocyanin still up in the air. The methanolic extract got from youthful fruit was found to have more elevated level of phenolic content, flavonoids just as ortho-dihydric phenol content. The youthful stages were seen with profoundly potential free radical searching action in contrast with that of the developed one. The development cycle significantly affected the cell reinforcement action and polyphenol content of C. guianensis flower just as fruit; additionally, the youthful stages are proposed as the best reap stage for therapeutic purposes. Subsequently, there was a positive correlation between the polyphenolic substance and the cancer prevention agent movement of the methanolic extracts. 29.3.5 ANTIULCER ACTIVITY Ramalakshmi et al. (2014) reported that the ulcer protection was 86.82% in experimental Wistar rats treated with methanol extract of flower of C. guianensis (MECG) 400 mg/mL and the ulcer score level was observed to be 4.93 ± 0.22 %. The complete acridity reaches and free sharpness level was noted 88.50 ± 5.09 and 61.83 ± 4.71 separately at the convergence of 400 mg/mL. The biochemical marker protein pepsin level was decreased to 15.36 μg/mL when compared with the ulcer encouraged control cluster (24.62 μg/mL).

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Gothai et al. (2019) evaluated the potential of C. guinensis cytotoxicity on salt water shrimp nauplii and Vero cell feasibility, while genotoxicity movement was evaluated on the DNA of Vero cells. In vivo cytotoxicity was performed utilizing salt water shrimp lethality examine (LC50), while in vitro cytotoxicity measure was performed using Vero cells by the MTT test (CV50). The genotoxicity test be that as it may, was performed utilizing comet examine and the quantity of feasible cells were counted depending on the grouping of (CV50). The LC50 focus estimated for brackish water shrimp lethality examined was 513.22 μg/mL. Thus, no significant evidence of DNA damage was observed with treated comet assay tail DNA (1.21 ± 1.676%) at which cell viability was recorded at 75 ± 5%. 29.3.7 ANTI-TUBERCULAR ACTIVITY The anti-tubercular activity of entire extracts of C. guianensis was assessed against Mycobacterium tuberculosis H73Rv strain utilizing Microplate Alamar Blue Assay (MABA) and recognized within MIC from 0.8 to 100 μg/ mL. The results of MABA exhibited that both ethanol and dichloromethane extract demonstrated substantial anti-tubercular action. Thus, C. guianensis possess remarkable anti-tubercular activity (Aravind et al., 2017). 29.3.8 WOUND-HEALING ACTIVITY Umachigi et al. (2007) reported the wound-healing activity in the ethanolic extract of entire plant of C. guianensis (CGEE) (barks, leaves, flowers, and fruits) on extraction and cut injury models. Different boundaries like epithelization period, scar region, elasticity, and hydroxyproline estimations alongside wound constriction were measured to evaluate the effect of CGEE on wound healing. Nitrofurazone ointment was utilized as a positive control. CGEE likewise displayed a possible inhibitory impact on every one of the microorganisms analyzed, in the accompanying request: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and E. coli MIC being 0.56, 0.78, 0.89, 1.33 mg mL–1, respectively. The significant antimicrobial effect of CGEE against all the four microbes affirmed that the mixtures present in the unrefined extract are answerable for the powerful antimicrobial movement.

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29.3.9 ANTICOAGULANT ACTIVITY Uppala et al. (2016) inspected the anticoagulant action of the chloroform and aqueous extracts of the leaves of C. guianensis. The aqueous and chloroform extracts of leaves of C. guianensis exhibited the improved anticoagulant action at a dose of 0.1 mL quantified by time taken for clotting. Thus, the C. guianensis plant possesses significant anticoagulant activity when compared with the conventionally used drug. 29.3.10 ANTI-INFLAMMATORY ACTIVITY Sumathi and Anuradha (2016) studied the medical applications of C. guianensis flower for in vitro anti-inflammatory activity utilizing human red platelet film adjustment. The level of film stabilization for CGEF (C. guianensis ethanolic flower) extract, CGMF (C. guianensis methanolic flower) extract, and diclofenac sodium (as a standard medication) was done at various fixations. The most extreme layer adjustment of CGMF extract was observed to be 70.58 ± 7.1 at a portion of 500 µg/mL contrasted and CGEF extract and standard medication. Geetha et al. (2004) anticipated to recognize the pain releasing and extenuating action of different extracts of flowers and bark of C. guianensis. The intensities of different extracts of flower and bark were contrasted and (i) paracetamol (200 mg/kg) for pain relieving and (ii) indomethacin (10 mg/ kg) for anti-inflammatory actions. Every one of the extracts of C. guianensis showed pain relieving and calming action. The pinnacle pain relieving impact of flower was seen after 1 h, while bark extracts showed top impact after 2 h. Most extreme decrease in aggravation by the extracts was seen after 3 h. Henceforth, C. guianensis is practically equipotent to paracetamol in its pain-relieving action and to indomethacin in its calming action. Pinheiro et al. (2013) assessed the ethanol extract and hexane and ethyl acetic acid derivation portions (10, 30, or 100 mg/kg, p.o.) in models of incendiary agony (formalin-incited licking) and intense irritation (carrageenan-actuated peritonitis). The focussed drugs dexamethasone (5 mg/kg), morphine (5 mg/kg, s.c.), and acetylsalicylic acid (100 mg/kg, p.o.) were tried in formalin-prompted licking reaction and carrageenan-incited peritonitis. Each of the three portions from C. guianensis portions fundamentally diminished the time that the creature spent licking the formalin-infused paw in first and second stages. Nonetheless, just higher dosages (30 and 100 mg/ kg) had the option to hinder the leukocyte movement into the peritoneal cavity after carrageenan infusion. In this model, the 100 mg/kg portion

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nearly nullified the cell movement. The protein fixation came about because of extravasation to the peritoneum and nitric oxide (NO) creations were essentially decreased. Cytokines creation was distinctively influenced by the treatment. TNF-a creation was diminished after ethanol extract and ethyl acetic acid origin part pretreatment; however, hexane part had influence just with 100 mg/kg portion. IL-1b creation was restrained solely after hexane division pretreatment. The inhibitory impact noticed was not because of a direct cytotoxic impact on cells nor to a NO-scrounger movement. The impact was because of an immediate hindrance on NO creation by the cells. In this way, C. guianensis extracts have calming impact, somewhat because of a reduce on cell transfer and an interference on cytokines and fiery arbiters creation (Reshma and Sunilkumar, 2018). 29.3.11 ANTHELMINTIC ACTIVITY The trichloromethane, dimethyl ketone, and alcoholic flower extracts of C. guianensis were assessed for in vitro anthelmintic activity on grown-up worm, Pheretima posthuma. The activity was surveyed by the worm motility test that included assurance of season of loss of motion and demise of worms. The alcoholic extract was observed as the most compelling than the mixture of chloroform and acetone extract and the action was contrasted and the standard drug piperazine citrate (Rajamanickam et al., 2008). 29.3.12 IMMUNE MODULATORY ACTIVITY Flower extracts of this plant were screened for the immune modulatory activity (Pradhan et al., 2009). The successive methanol extract was found to show a portion-related expansion in the excessive touchiness response, to the SRBC antigen, at dose of 100 and 200 mg/kg. The progressive methanol extract was found to invigorate cell intervened and counter acting agent interceded safe reactions in rodents. It likewise upgraded the phagocytic capacity of the human neutrophils, in vivo. 29.3.13 ANTIUROLITHIATIC ACTIVITY Panchal et al. (2018) reported the aqueous extract of C. guianensis with the capabilities to break up calcium oxalate precious stone under in vitro conditions when it is contrasted and cystone as a norm. The antiurolithiatic action of C. guianensis leaves is likely intervened through the restraint of calcium

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oxalate crystallization. Notwithstanding its free revolutionary rummaging and cell reinforcement exercises, it goes about as an incredible specialist for the counteraction of urolithiasis. 29.3.14 HEPATOPROTECTIVE ACTIVITY Elumalai et al. (2018) reported the hepatoprotective function of C. guianensis leaf extract against CCl4-induced liver damage in Wistar albino rats. The assessment of liver marker enzymes at doses of 150 mg/kg body weight and 300 mg/kg body weight uncovered critical hepatoprotective movement. 29.3.15 NEUROPHARMACOLOGICAL ACTIVITY Gupta et al. (2012a) examined the impacts of the methanolic extract of C. guianensis and revealed the neuropharmacological activities such as unconstrained engine action, rota-pole execution, and phenobarbital resting time in mice. The extract (100, 250, and 500 mg/kg) in a portion subordinate way showed a huge decrease in unconstrained engine movement yet had no effect and influence on engine organization as uttered by the performance on rotarod. These extracts additionally delivered decrease of the beginning and length of pentobarbitone actuated spellbinding. Consequently, the plant extract confined an expert with its neuropharmacological action on both focal and fringe sensory system. 29.3.16 ANTIDEPRESSANT ACTIVITY Kulkarni et al. (2011) carried out the phytochemical and pharmacological investigations on the leaves of C. guianensis. Fractionation of petrol ether extract of these leaves yielded three mixtures like aliphatic hydrocarbon with melting point (m.p.) of 79–81°C, compound 2 with m.p. of 95–97°C was acquired in little yields and triterpene alcohol with m.p. of 273–375°C as indicated by its physicochemical and phantom information. Its lipid solvency and complex design incited the authors to attempt psychopharmacological investigations in mice. Conduct investigations of compound 3 (1, 2.5, 5 mg/ kg) utilizing tail suspension test and hopelessness swim test, proposed its potential upper action. Hence, adequacy of triterpene liquor at all dosages was practically alike to the typical restorative suppository, imipramine (25 mg/kg).

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Gupta et al. (2012b) assessed the fluid and methanolic extracts of C. guianensis flower for its upper like action. The plant extract at a higher concentration showed huge decrease in idleness in tail interruption and forced swim model of despair analogous to imipramine. 29.3.17 ANTIDIABETIC ACTIVITY Morankar et al. (2013) tested for antidiabetic effects in normoglycemic and alloxan-induced diabetic mice utilizing the unrefined methanolic extract of the C. guianensis flowers. Antidiabetic action was seen to be timesubordinate. The watery and methanolic extracts of C. guianensis flowers were measured for its antidiabetic activity in alloxan-induced diabetic mice. Day-by-day oral dosing of the two extracts (100 mg/kg body weight) and metformin (100 mg/kg body weight) as standard in diabetic mice show altogether decrease in blood glucose level. 29.3.18 ANTICANCER ACTIVITY Premanathan et al. (2013) examined the anticancer exercises of isatin, isolated from the flower of C. guianensis against human promylocytic leukemia (HL60) cells. Isatin isolated from the dynamic division showed cancer prevention agent action with the EC50 value of 72.80 μg/mL. It additionally displayed cytotoxicity against human promylocytic leukemia HL60 cells in a portion subsidiary way with the CC50 value of 2.94 μg/mL. The isatintreated cells went through apoptosis and DNA discontinuity. Apoptosis was affirmed by the FACS examination utilizing FITC-annexin V markers. In this way, Isatin showed cancer prevention activity and was cytotoxic to the HL60 cells because of acceptance of programmed cell death. The isatin can be additionally assessed to be utilized as a prophylactic specialist to forestall the free radical instigated disease and as a chemotherapeutic specialist to kill the malignancy cells. 29.3.19 ANTIOBESITY AND ATHEROSCLEROTIC ACTIVITY Ramyasai et al. (2013) made investigation on the antiobesity and atherosclerotic activity of C. guianensis flower extract on elevated cholesterol diet rodents. Stoutness was actuated in rodents by giving elevated cholesterol diet (coconut oil, grains, sugar, and so on) for 7 days in standard rodent chow

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diet. The methanolic extract of C. guianensis flowers (100, 200 mg/kg body weight) was orally controlled once per day to rodents being taken care of with an elevated cholesterol diet for 15 days. Elevated cholesterol took care of diets; rodents displayed huge development in all out serum cholesterol, fatty oils, low thickness lipoproteins, exceptionally low density lipoproteins and critical diminishing in high density lipoproteins. Treatment with methanolic extract of C. guianensis flowers altogether reduced complete serum cholesterol, fatty substances, low density lipoproteins, very low density lipoproteins and expanded the high density lipoproteins in fat rodents and was practically identical to that of standard Atorvastatin. After the completion of experiment rats were anesthetized with Isoflurane and sacrificed and the atherosclerotic lesions in the aorta were assessed. The attained outcomes of the examination of all five groups were compared. Thus, a significant inhibition of atherosclerotic plaque formation, while a pure concentrationdependent association was found at the practical dosages. Therefore, it was determined that important antiobesity and atherosclerotic actions of C. guianensis flowers might be because of the presence of starches, tannins, phenols, flavonoids, proteins, amino acids, and saponins occurred in the fundamental phytochemical screening. KEYWORDS • • • • •

anticancer activity antimicrobial activity antioxidant activity antiarthritic activity immunomodulatory activity

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Anjaneyulu, A. S. R.; Rao, S. S. A New Ketosteroid from the Bark of Couroupita guianensis Aubl. Indian J. Chem. 1998, 37 (4), 382–386. Aravind, D. S.; Karthikeyan, R.; Babu, P. S. In Vitro Anti Tubercular Activity of Flowers of Couroupita guanensis L. J. Appl. Pharm. Res. 2017, 5 (1), 27–29. Bafna, A. R.; Mishra, S. H.; Deoda, R. S.; Bafna, P. A.; Kale, R. H. In Vitro Antioxidant Activity of Ethyl Acetate Fraction of Water Extract of Flowers of Couroupita guaianensis. Intl. J. Pharm. Pharm. Sci. 2011, 3 (4), 110–112. Begum, R.; Rahman, M. S.; Chowdhury, A. M. S.; Hasan, C. M.; Rashid, M. A. Secondary Metabolites (Triterpenes) from Couroupita guianensis. Orient. Pharm. Exp. Med. 2009, 9 (2), 200–205. Bergman, J.; Egestad, B.; Lindström, J. O. The Structure of Some Indolic Constituents in Couroupita guianensis Aubl. Tetrahedron Lett. 1977, 18, 2625–2626. Costa, D. C. M.; Azevedo, M. M. B.; Silva, D. O. E.; Romanos, M. T. V.; Souto-Padron, T.; Alviano, C. S. et al. In Vitro Anti-MRSA Activity of Couroupita guianensis Extract and Its Component Tryptanthrin. Nat. Prod. Res. 2017, 31 (17), 2077–2080. Dave, G. R.; Patel, R. M.; Patel, R. J. Characteristics and Composition of Seeds and Oil of Couroupita guianensis Aubl. from Gujarat, India. Fette Seifen Anstrichmittel. 1985, 87 (3), 111–112. Desai T.; Golatakar, S. G.; Rane, J. B.; Ambaye, R. Y.; Kamath, V. R. Larvicidal Property of Couroupita guianensis Aubl. Indian Drugs 2003, 40, 484–486. Elumalai, A.; Bargavi, K.; Krishna, S.; Chinnaeswaraiah, M. Evaluation of Anti-Oxidant and Hepatoprotective Activity of Couroupita guianensis Leaves. J. Cell Tissue Res. 2013, 13 (2), 3745–3748. Geetha, M.; Saluja, A. K.; Shankar, M. B.; Mehta, R. S. Analgesic and Anti-Inflammatory Activity of Couroupita guianensis Aubl. J. Nat. Remed. 2004, 4 (1), 52–55. Gothai, S.; Vijayarathna, S.; Chen, Y., Kanwar, J. R.; Wahab, H. A., Sasidharan, S. In VitroScientific Evaluation on Anti-Candida albicans Activity, Antioxidant Properties, and Phytochemical Constituents with the Identification of Antifungal Active Fraction from Traditional Medicinal Plant Couroupita guianensis Aubl. Flower. J. Comple. Med. Res. 2018, 8 (2), 85–101. Gothai, S.; Vijayarathna, S.; Chen, Y., Lai, N. S.; Wahab, H. A., Firdaus, H.; Sreeramanan, S.; Sasidharan, S. In Vitro and In Vivo-Scientific Evaluation on Cytotoxicity and Genotoxicity of Traditional Medicinal Plant Couroupita guianensis Aubl. Flower. Pharmacol. Online 2019, 2, 24–38. Gupta, S. K.; Ghosal, M.; Choudhury, D.; Mandal, P. Assessment of Antioxidant Activity and Polyphenolic Content of Couroupita guianensis During Flower and Fruit Maturation. Int. J. Recent Sci. Res. 2014, 5 (5), 940–947. Gupta, V. H.; Gunjal, M. A.; Wankhede, S. S.; Deshmukh, V. S. Neuropharmacological Evaluation of the Methanolic Extract of Couroupita guianensis Aubl. Flower in Mice. Intl. J. Pharma. Pharmacol. Res. 2012a, 1 (5), 242–246. Gupta, V. H.; Wankhede, S. S.; Gunjal, M. A.; Juvekar, A. R. Antidepressant Like Effect of Couroupita guianensis Aubl. Flowers in Animal Model of Depression. Intl. J. Toxicol. Pharmacol. Res. 2012b, 4 (2), 12–16. Ilangovan, S.; Thavasumani, P. Preliminary Screening of Phytochemical Constituents, Antioxidant and Antimicrobicidal Activities in the Methanolic Leaf Extract of Couroupita guianensis. Asian J. Pharm. Clin. Res. 2021, 14 (1), 203–206.

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Kaneria, M.; Rakholiya, K.; Jakasania, R.; Dave, R.; Chanda, S. Metabolite Profiling and Antioxidant Potency of Couroupita guianensis Aubl. Using LC-QTOF-MS Based Metabolomics. Res. J. Phytochem. 2017, 11 (3), 150–169. Kavitha, R.; Kamalakannan, P.; Deepa, T.; Elamathi, R.; Sridhar, S.; Kumar, J. S. In Vitro Antimicrobial Activity and Phytochemical Analysis of Indian Medicinal Plant Couroupita guianensis Aubl. J. Chem. Pharma. Res. 2011, 3 (6), 115–121. Khan, A. M.; Shivashankara, K. S.; Roy, T. K. Determining Composition of Volatiles in Couroupita guianensis Aubl. Through Headspace-Solid Phase Micro-Extraction (HS-SPME). J. Hortic. Sci. 2014, 9 (2), 161–165. Khan, M. R.; Kihara, M.; Omoloso, A. D. Antibiotic Activity of Couroupita guianensis, J. Herbs, Spices Med. Plants 2003, 10 (3), 95–108. Kulkarni, M.; Wakade, A.; Ambaye, R.; Juvekar, A. Phytochemical and Pharmacological Studies of the Leaves of Couroupita guianensis Aubl. Pharmacol. Online 2011, 3, 809–814. Kumar, V.; Tiwari, A.; Ashwin, S. Couroupita guianensis: A Potential Medicinal Tree. Van Sangyan 2017, 4 (10), 30–34. Maheswaran, R.; Baskar, K.; Ignacimuthu, S.; Packiam, S. M.; Rajapandiyan K. Bioactivity of Couroupita guianensis Aubl. Against Filarial and Dengue Vectors and Non-Target Fish. South Afr. J. Bot. 2019, 125, 46–53. Majumder, S.; Elango, E. M.; Hoebe, J. P. A. C.; Rahmatullah, M. Antibacterial Studies with Methanol Extract of Couroupita guianensis Flowers Against Methicillin-Resistant Staphylococcus aureus. World J. Pharm. Pharm. Sci. 2014, 3 (9), 543–550. Manimegalai, S.; Sridharan, T. B.; Rameshpathy, M.; Rajeswari, V. D. Antioxidant, Phytochemical Screening and Antimicrobial Activity of Couroupita guianensis Flower Extract. Der Pharm. Lett. 2014, 6 (6), 251–256. Martínez, A.; Conde, E.; Moure, A.; Domínguez, H.; Estévez, R. J. Protective Effect Against Oxygen Reactive Species and Skin Fibroblast Stimulation of Couroupita guianensis Leaf Extracts. Nat. Prod. Res. 2012, 26 (4), 314–322. Morankar, P. G.; Dhake, A. S.; Kumbhare, M. R.; Ushir, Y. V.; Surana, A. R.; Patil, S. D. An Evaluation of the Antidiabetic Effects of Couroupita guianensis Aubl. Flowers in Experimental Animals. Indo Am. J. Pharm. Res. 2013, 3 (4), 3114–3122. Narasimhan, G. In Silico Screening of Active Constituent of Couroupita guianensis Against Mycobacterium. Int. J. Pharm. Chem. Analy. 2020, 7 (3), 125–134. Nelson, E. K.; Wheeler, D. H. Some Constituents of the Cannonball Fruit (Couroupita guianensis, Aubl.). J. Am. Chem. Soc. 1937, 59 (12), 2499–2500. Panchal, H. N.; Desai, S. D.; Soni, M. K.; Mishra, P.; Meshram, D. B. In Vitro Antiurolithiatic and Antioxidant Activity of Couroupita guianensis Aubl Leaves. Der Pharmacia Sinica 2018, 9 (1), 1–6. Pandurangan, P.; Sahadeven, M.; Sunkar, S.; Dhana, S. K. Comparative Analysis of Biochemical Compounds of Leaf, Flower and Fruit of Couroupita guianensis and Synthesis of Silver Nanoparticles. Pharmacogn. J. 2018, 10 (2), 315–323. Pinheiro, M. M.; Fernandes, S. B.; Fingolo, C. E.; Boylan, F.; Fernandes, P. D. AntiInflammatory Activity of Ethanol Extract and Fractions from Couroupita guianensis Aublet Leaves. J. Ethnopharmacol. 2013, 146 (1), 324–330. Prabhu, V.; Ravi, S. Isolation of Phytoconstituents from the Flowers of Couroupita guianensis. Indian J. Chem. 2017, 56, 709–713.

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Pradhan, D.; Panda, P. K.; Tripathi, G. Evaluation of Immunomodulatory Activity of Methanolic Extract of Couroupita guianensis Aublet. Flowers in Rats. Nat. Prod. Radiance 2009, 8 (1), 37–42. Premanathan, M.; Radhakrishan, S.; Kulangiappar, K.; Singaravelu, G.; Thirumalaiarasu, V.; Sivakumar, T.; Kathiresan, K. Antioxidant and Anticancer Activities of Isatin (1H-indole2,3-dione), Isolated from the Flowers of Couroupita guianensis Aubl. Indian J. Med. Res. 2012, 136 (5), 822–826. Raghavendra, H. L.; Kekuda, T. R. P.; Pushpavathi, D.; Shilpa, M.; Petkar, T.; Siddiqha, A. Antimicrobial, Radical Scavenging, and Insecticidal Activity of Leaf and Flower Extracts of Couroupita guianensis Aubl. Intl. J. Green Pharmacy 2017, 11 (3), 171–179. Rajamanickam, V.; Rajasekaran, A.; Quine, S. D.; Jesupillai, M.; Sabitha, R. Anthelmintic Activity of the Flower Extract of Couroupita guianensis. Internet J. Altern. Med. 2008, 8 (1), 1–3. Ramalakshmi, C.; Kalirajan, A.; Ranjitsingh, A. J. A.; Kalirajan K. Bioprospecting of Medicinal Plant Couroupita guianensis for Its Potential Anti-Ulcer Activity. Intl. J. Appl. Biol. Pharm. Technol. 2014, 5 (3), 226–232. Ramalakshmi, C.; Ranjitsingh, A. J.; Kalirajan, K.; Kalirajan, A.; Athinarayanan, G.; Mariselvam, R. A Preliminary Screening of the Medicinal Plant Couroupita guianensis for Its Antimicrobial Potential Against Clinical and Fish-Borne Pathogens. Elixir. Appl. Biol. 2013, 57, 14055–14057. Ramyasai, M.; Babu, S. M.; Vadivel, K. Anti-Obesity and Atheroscelerotic Activity of Methanolic Extract of Couroupita guianensis Aubl. Flowers in Rats Fed with High Fat Diets. Int. J. Univ. Pharm. BioSci. 2013, 2 (6), 288–300. Regina, V.; Rajan, K. M. U. Phytochemical Analysis, Antioxidant and Antimicrobial Studies of Fruit Rind of Couroupita guianensis (AUBL). Intl. J. Curr. Sci. 2012, 262–267. Reshma, Y.; Sunilkumar, T. Phytochemical Analysis of Fruit Pulp of Couroupita guianensis Aubl. J. Pharmacogn. Phytochem. 2018, 7 (2), 877–879. Sanz-Biset, J.; Campos-de-la-Cruz, J.; Epiquién-Rivera, M. A.; Cañigueral, S. A First Survey on the Medicinal Plants of the Chazuta Valley (Peruvian Amazon). J. Ethnopharmacol. 2009, 122 (2), 333–362. Sen, A. K.; Mahato, S. B.; Dutta, N. L. Couroupitine A, a New Alkaloid from Couroupita guianensis. Tetrahedron Lett. 1974, 7, 609–610. Shah, G. N.; Shete, S. A.; Walke, S. S.; Patil, V. S.; Patil, K. D.; Killedar, S. G. Standardization and Antibacterial Activity of Couroupita guianensis Fruit Pulp Extract. Int. J. Pharmacogn. Phytochem. Res. 2012–2013, 4 (4), 185–189. Shete, S. A.; Shah, G. N.; Walke, S. S.; Patil, V. S.; Patil, K. D.; Killedar, S. G. Standardization and Antibacterial Activity of Couroupita guianensis Fruit Shell Extract. Int. J. Biol. 2013, 2 (1), 360–364. Shivashankar, M.; Rajeshwari, S.; Nagananda, G. S.; Rajath, S.; Chandan, N. Comparative Antioxidant and Antimicrobial Studies of Cold and Hot Bark Hydromethanolic Extract of Couroupita guianensis Aubl. Res Pharm. 2013, 3 (6), 6–13. Shwetha, R.; Roopashree, T. S.; Das, K.; Prashanth, N.; Kumar, R. HPTLC Fingerprinting of Various Extracts of Couroupita guianensis Flowers for Establishment of In Vitro Antimalarial Activity Through Isolated Compound. Ann. Phytomed. 2020, 9 (1), 133–140. Sirisha, M.; Jaishree, V. Phytochemical Screening, Antioxidant and Antiproliferative Activities of Successive Extracts of Couroupita guianensis Aubl. Plant. Indian J. Nat. Prod. Resour. 2018, 9 (1), 22–27.

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Sumathi, S.; Anuradha. R. In Vitro Anti-Inflammatory Activity of Flower Extract of Couroupita guianensis Aubl. Int. J. Herb. Med. 2016, 4 (5), 5–8. Umachigi, S. P.; Jayaveera, K. N., Ashok Kumar, C. K.; Kumar, G. S. Antimicrobial, Wound Healing and Antioxidant Potential of Couroupita guianensis in Rats. Pharmacol. Online 2007, 3, 269–281. Uppala, P. K.; Krishna, B. M.; Kumar, K. A.; Ramji, D. J. V. Evaluation of Anti-Coagulant Activity of the Chloroform and Aqueous Extracts of the Leaves of Couroupita guianensis. Int. J. Pharm. Pharm. Res. 2016, 6 (4), 189–199. Wong, K. C.; Tie, D. Y. Volatile Constituents of Couroupita guianensis Aubl. Flowers. J. Essent. Oil Res. 1995, 7 (2), 225–227.

CHAPTER 30

Review on Pharmacological Activities of Gentiana scabra Bunge C. V. JAYALEKSHMI and V. SURESH* Department of Botany, Government Victoria College, Palakkad, Kerala, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Gentiana scabra is widely used in traditional Chinese and Japanese medicine. In Chinese medicine G. scabra is used as bitter tonic for promoting digestive secretions and for the treatment of liver diseases. Dried roots of the plant are commonly used as medicine for the treatment of jaundice, eczema, conjunctivitis, urinary system infections, hypertension etc. Dried roots are rich in secoiridoid glycosides which is the primary bioactive component in this plant. The plant possesses anti-inflammatory, anti-tumor, antidiabetic, antioxidant, hepatoprotective, anticoagulant, immunomodulatory, insecticidal properties. These pharmacological properties are contributed by various bioactive compounds present in this plant. Various bioactive compounds reported from G. scabra are secoiridoids, triterpenoids, flavonoids, essential oils, polysaccharides, alkaloids and phenolic compounds. The present review chapter aimed to combine all recent research studies on pharmacological properties of G. scabra. 30.1 INTRODUCTION Gentiana scabra Bunge belongs to the family Gentianaceae. It is a semi evergreen flowering plant with violet- or purple-colored star-shaped Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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flowers and ovate leaves. It is mainly distributed in China, Russia, and Japan. The plant is used in traditional medicine for anti- inflammatory, antitumour, and antioxidant properties. The plant is commonly called Japanese gentian or Long dan cao. Dried roots of G. scabra are commonly called Long dan cao in traditional Chinese medicine (Cai et al., 2016). The root extract of the plant is used for the treatment of Diabetes mellitus in traditional Korean medicine (Suh et al., 2015). The roots of the plant are traditionally used for stimulation of gastric secretion, appetite and to treat inflammatory diseases in Korea. The drug is called Gentianae Scabrae Radix (Kim et al., 2009). 30.2

BIOACTIVE COMPOUNDS

G. scabra is rich in bioactive compounds which contribute to its pharmacological properties. The plant contains secoiridoids, triterpenoids, flavonoids, essential oils, polysaccharides, alkaloids, and phenolic compounds. Methanol extract of rhizome and roots of G. scabra var. buergera possessed acylsecoiridoid glucoside called rindoside and iridoid glucoside called loganic acid (Ikeshiro et al., 1990). Triterpenoids like (20S)-dammara-13(17)24dien-3-one, (20R)-dammara-13(17)24-dien-3-one, chirat-17(22)-en-3-one, chirat-16-en-3-one, 17β,21β-epoxyhopan-3-one, chi hop-17(21)-en-3β-ol, lupeol, and α-amyrin were isolated from roots and rhizomes of G. scabra (Kakuda et al., 2002). Roots and rhizome of G. scabra contain secoiridoid glycosides like 4‴-O-β-D-glucopyranosyl trifloroside, 4‴-O-β-D-glucopyranosyl scabraside, trifloroside, scabraside, and gentiopicroside (Ikeshiro and Tomita, 1983; Kim et al., 2009). Polyphenols like kaempferol, ellagic acid, and quercetin were isolated from aqueous extract of G. scabra (Ko et al., 2011). 2,3-deacetyl trifloroside, 3-deacetyl trifloroside, and 2-deacetyl trifloroside were isolated from methanol extract of rhizome and roots of G. scabra (Li et al., 2015). Seventeen secoiridoid glycosides like 6′-O-(3″-hydroxy benzoyl)-8epikingiside, 6′-O-(4″-hydroxy benzoyl)-8-epikingiside, 6′-O-(2″,3″dihydroxybenzoyl)-8-epikingiside, 2′-O-benzoyl kingiside, 2′-O-(2″,3″dihydroxybenzoyl) kingiside, 2″dehydroxytrifloroside, 6β-hydroxy-3epi-swertiajaposide A, gentiopicroside, 6β-hydroxy swertiajaposide A, 2′-O-(3″-hydroxy benzoyl) kingiside, 4‴-O-β-D-Glucopyranosyl trifloroside, 4‴-O-β-D-Glucopyranosyl scabraside, gelidoside, trifloroside, macrophylloside A, scabraside, and deglucosyltrifloroside were isolated from chloroform extract of G. scabra (He et al., 2015).

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Structure of (1) Rindoside (Redrawn from Ikeshiro et al. 1990); (2) 4‴-O-β-D-Glucopyranosyl trifloroside, (3) Trifloroside (Redrawn from Kim et al. 2009); (4) Loganic acid (Redrawn from Suh et al. 2015); (5) Gentiopicroside, (6) 4‴-O-β-D-Glucopyranosyl scabraside, (7) Scabraside (Redrawn from Kim et al. 2009); (8) 6′-O-(3″-hydroxy benzoyl)-8-epikingiside, (9) 6′-O-(4″-hydroxy benzoyl)-8-epikingiside, (10) 6′-O-(2″,3″-dihydroxybenzoyl)-8epikingiside, (11) 2′-O-benzoyl kingiside, (12) 2′-O-(2″,3″-dihydroxybenzoyl) kingiside, (13) 2″dehydroxytrifloroside, (14) 6β-hydroxy-3-epi-swertiajaposide A, (15) 6β-hydroxy swertiajaposide A (Redrawn from He et al. 2015).

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PHARMACOLOGY

G. scabra possessed various pharmacological activities like antidiabetic, anti-inflammatory, hepatoprotective, antitumor, antioxidant activities, etc. 30.3.1 ANTIDIABETIC ACTIVITY Aqueous extract of G. scabra activates GLP-1 (Glucagon like peptide 1) in enteroendocrine NCI- H716 cells. GLP-1 secretion in these cells is mediated through the GPCR pathway. The molecular mode of action of ethyl acetate fraction of aqueous extract was studied by microarray experiment. Microarray data showed that ethyl acetate fraction activated GPCR signaling pathway in NCI- H716 cells. The extract upregulated two types of G-protein-coupled receptors GPR68 and CCKBR. The extract also downregulated voltage gated potassium channels. The GLP-1 secretion through GPCR signaling pathway finally leads to insulin secretion at the β cell of islets (Shin et al., 2012). Treatment of root extract of G. scabra stimulated the secretion of GLP-1 in human enteroendocrine NCI- H716 cells. Oral glucose tolerance test (OGTT) was also performed in db/db mice to study the glucose-lowering effect of the plant extract. Mouse plasma was collected during the OGTT test to measure GLP-1 and insulin levels. The plant extract produced a dose-dependent GLP-1 secretion effect on NCI- H716 cells. The GLP-1- secreting effect was mediated by G protein βγ subunit and by inositol triphosphate. The extract at a dose between 100 and 750 µg/mL increased the GLP-1 secretion in NCI- H716 cells. The EC50 value was 113.3 µg/mL. The mice group treated with 100 mg/kg of plant extract reduced blood glucose levels at 90 and 120 min. The mice group treated with 300 mg/kg of plant extract reduced blood glucose levels at 40, 90, and 120 min. In the treated mouse, the blood glucose lowering was due to GLP-1 secretion. From this study they found that loganic acid contributed to the GLP-1 secretion effect of plant extract (Suh et al., 2015). 30.3.2 ANTIOXIDANT ACTIVITY Water-soluble polysaccharides isolated from G. scabra possessed antioxidant activities. In vitro studies on antioxidant activity on polysaccharides indicated that polysaccharides have high scavenging activity to DPPH radicals and lower reducing power and scavenging activity to superoxide anions and

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hydroxyls. The superoxide scavenging rate of the polysaccharide was low. The maximum hydroxyl scavenging activity of polysaccharide is about 37% at concentration 1500 mg/L. The polysaccharide showed scavenging activity toward DPPH radicals in a concentration-dependent manner at a concentration range of 10–15 mg/L. The scavenging activity increased insignificantly at concentration 50–3750 mg/L. The EC50 value of polysaccharides for DPPH scavenging activity was 11.25 mg/L which is similar to the EC50 value of control ascorbic acid (11.5 mg/L) (Wang et al. 2014a). Aqueous extract of G. scabra possessed antilipid peroxidation, DPPH, and superoxide radical scavenging activities with IC50 values 45.84, 183.38, and 56.25 µ/ mL respectively (Ko et al., 2011). GSP1-a (G. scabra polysaccharide 1-a) and GSP1-b (G. scabra polysaccharide 1-b), polysaccharide isolated from G. scabra roots possessed radical scavenging activity to DPPH radicals. GSP1-b possessed stronger radical scavenging activity than GSP1-a. At a concentration of 0–100 mg/L GSP1-b showed marked DPPH scavenging activity in a concentration-dependent manner. The maximum scavenging rate was 79% at concentration 200 mg/L. The EC50 value of GSP1- b was 12.5 mg/L. Both polysaccharide exhibited relatively low reducing powers and scavenging activities toward superoxide anions and hydroxyl radicals (Wang et al., 2014b). Polysaccharide extracted from G. scabra, showed potent antioxidant activity. The antioxidant activity of crude polysaccharide was studied by DPPH radical scavenging assay, hydroxyl radical scavenging assay, and ferric-reducing power assay. The polysaccharide showed a concentration-dependent DPPH radical scavenging activity. At concentration from 0.2 to 1.2 mg/mL of the polysaccharide DPPH radical scavenging rate increased from 17.80% to 80.81%. The hydroxyl scavenging rate of polysaccharides was 29.53% at 5.5 mg/mL. The polysaccharide possesses poor hydroxyl radical scavenging activity compared to ascorbic acid. At concentration 0.2–1.2 mg/mL of polysaccharide, the scavenging rate for superoxide anion radicals increased from 5.075 to 46.84%. The reducing power of polysaccharide to ferric ion increased with increase in concentration from 0.2 to 1.2 mg/L (Cheng et al., 2016). 30.3.3

HEPATOPROTECTIVE ACTIVITY

Treatment of aqueous extract of G. scabra extract in carbon tetrachloride intoxicated mice showed hepatoprotective activity. Oral administration of 500 and 1000 mg/kg of the extract daily inhibited the elevation of glutamic

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pyruvic transaminase and thiobarbituric acid reactive substance levels and enhanced the level of antioxidant enzymes like superoxide dismutase, catalase, and glutathione peroxidase. 1000 mg/kg of the extract was effective as 100 mg/kg of silymarin (Ko et al., 2011). Treatment of G. scabra in Paragonimus skrjabini rats with liver fibrosis reduced the content of hepatic type one and type three collagen proteins. Changes of contents of hepatic type one and three proteins were studied by the immunohistochemical technique. The expression of hepatic type one and type three collagen proteins was decreased in the treated group, which indicated that the G. scabra can be used against liver fibrosis (Qu et al., 2015). 30.3.4 ANTITUMOR ACTIVITY In vivo antitumor activity of water-soluble polysaccharide isolated from G. scabra was studied in male BALB/c mice induced with sarcoma 180 cells. The mice were treated with 0.2 mL 25, 50, and 100 mg/kg of polysaccharide. Significant tumor inhibition was observed in polysaccharide-treated groups compared to control. The polysaccharide showed a maximum inhibition ratio of 65.76% at a dose of 100 mg/kg and also increased organ weight of thymus and spleen of tumor-bearing mice (Wang et al. 2014a). 30.3.5 ANTI-INFLAMMATORY ACTIVITY Seventeen secoiridoids isolated from chloroform extract of G. scabra were tested for their anti-inflammatory activity through the assay of inhibitory effect against NO, IL-6, and TNF-α production in LPS- stimulated RAW 264 macrophage cells. Compounds 1-6 and 10 exhibited inhibitory activity on IL-6 production with IC50 values of 51.70–63.80 µM. Compounds 12, 13, 15, 16, 17 showed inhibitory activity on both NO and IL-6 production with IC50 values of 64.74–94.95 µM and 48.91–75.45 µM, respectively. All compounds showed weak inhibition on TNF- α production (He et al., 2015). The anti-inflammatory activity of 20 iridoid and secoiridoid glycosides isolated from methanolic extract of G. scabra roots on lipopolysaccharide (LPS) stimulated bone marrow-derived dendritic cells (BMOCs) were studied. The effects of various concentrations of compounds 1, 2, 5, and 10 µM on secretion of cytokines IL-6, IL-12, p40 and TNFα were studied. Significant inhibitory effects were shown by compounds 6, 10, and 20 on LPS-induced IL-12, p40and IL- 6 production with IC50 values of

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1.62–14.29 µM. Compound 10 with an IC50 value of 10.45 µM exhibited a strong inhibitory effect on LPS- stimulated TNF- α production (Li et al., 2015). Ethanol extract of G. scabra root and rhizome inhibited contact dermatitis in mice induced by 1- fluoro- 2, 4- dinitrofluorobenzene (DNFB). Topical application of ethanolic extract reduced skin lesions and prevented skin enlargement and lowered erythema and melanin index. The extract also prevented hyperkeratosis and epidermal hyperplasia. Treatment with 60 µg/day of ethanolic extract reduced the production of proinflammatory cytokines such as TNF-α, INF- γ, IL-6, and MCP-1 (Yang et al., 2019). 30.3.6 ANTICOAGULANT ACTIVITY In vitro anticoagulant activity of water-soluble polysaccharide GSP and fractions GSP-1, GSP-2, and GSP-3 isolated from roots of G. scabra were studied by activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT) assays. The clotting assays were performed using normal human plasma collected from blood of healthy volunteers. 50 µL of GSP and its fractions were mixed with human plasma. GSP, GSP-1, GSP-2, and GSP-3 could prolong APTT and TT. GSP-3 exhibited strong anticoagulant properties when compared to GSP and other two polysaccharide fractions. The blood clotting time of GSP-3 in APTT assay was 33.17 s at 1.5 mg/mL, which was 1.3-fold longer than normal saline. The blood clotting time of GSP-3 in TT assay was increased by 1.14 compared to saline control group at 1.5 mg/mL (Cai et al., 2016). 30.3.7 IMMUNOLOGICAL ACTIVITY Polysaccharide isolated from G. scabra roots GSP1-a and GSP1-b significantly increased lymphocyte proliferation in spleen cells from BALB/c mice. Lymphocyte proliferation was evaluated using MTT-based colorimetric assay. Both polysaccharides significantly increased lymphocyte proliferation when lipopolysaccharide was used as a mitogen for lymphocytes. GSP1-b significantly increased lymphocyte proliferation when concanavalin A was used as mitogen. Lymphocyte proliferation activity of GSP1-b was stronger than GSP1-a (Wang et al. 2014b).

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30.3.8 ANTIOBESITY ACTIVITY Genticopicroside isolated from G. scabra inhibited adipogenesis in 3T3-L1 cells and also reduced body weight in diet-induced obese mice. Gentiopicroside was dissolved in DMSO and 3T3L1 cells were treated with 5 and 10 µM concentrations of the compound during adipocyte differentiation. At concentration 5 and 10 µM gentiopicroside reduced intracellular lipid droplet accumulation by 62% and inhibited adipocyte differentiation by 72% when compared with differentiated adipocytes. Molecular level studies showed that the compound significantly down regulated expression of key adipogenic transcription factors like PPARγ, C/EBPα, SREBP-1c and inhibited the lipid uptake-related gene LPL, fatty acid synthesis- related genes FAS and SCD1. Gentiopicroside also inhibited inflammatory markers during adipocyte differentiation. The mRNA expression of NFkB1, TNF α, and IL6 was reduced in gentiopicroside-treated adipocytes. Oral administration of the compound at a dose 50 mg/kg in diet induced obese mice for 12 weeks resulted in reduced body weight and visceral fat mass (Choi et al., 2019). 30.3.9

PROKINETIC ACTIVITY

In vivo studies on effects of aqueous and ethanolic extract of rhizomes and roots of G. scabra on gastrointestinal motor function by measuring the gastric emptying rate and intestinal transit rate in mice showed that the water extract was a potential prokinetic agent. Water extract at a dose of 1 g/ kg significantly increased the gastric emptying rate. Both water extracts at doses of 0.1 and 1 g/kg and ethanol extract at a dose of 1 g/kg significantly increased intestinal transit rate in a dose-dependent manner (Lee, 2019). 30.3.10 ANTI-ATHEROGENIC ACTIVITY In a study conducted on 30 types of Chinese herbs, screened against atherosclerosis using oxidized LDL uptake and cell toxicity assay, G. scabra reduced oxidized LDL uptake effectively in THP-1 macrophages. The extract dose-dependently inhibited oxidized LDL uptake. Treatment with G. scabra resulted in decreased expression of scavenger receptor –A (SR-A) in THP-1 macrophages. Molecular analysis revealed that G. scabra decreased the expression of SR-A by regulating ERK signaling pathways. The results indicated that G. scabra can be used as a potential therapeutic agent for treating atherosclerosis (Lin et al., 2016).

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30.3.11 ANTIPARASITIC EFFECT Methanolic extract of the trunk of G. scabra inhibited the growth of Trichomonas vaginalis. At a concentration of 0.7 mg/mL of the extract, the growth inhibition against T. vaginalis became optimal. After incubation at 12, 24, 36, and 48 h, the number of cells in the group decreased by 5 × 105, 1 × 105, 1 × 105 and none respectively. Electron microscopic studies on the experimental group treated with 100 µL/mL extract showed that nucleus, karyosomes, and chromatin were weaker than the control group after 1 h of incubation. The treated group after 3 h of incubation was destroyed abruptly (Ryang et al., 2001). KEYWORDS • • • • •

Secoiridodis anti-tumor Gentiana Chinese anti-oxidant

REFERENCES Cai, W.; Xu, H.; Xie, L.; Sun, J.; Sun, T.; Wu, X.; Fu, Q. Purification, Characterization and in Vitro Anticoagulant Activity of Polysaccharides from Gentiana scabra Bunge Roots. Carbohydr. Polym. 2016, 140, 308–313. Cheng, Z., Zhang, Y.; Song, H.; Zhou, H.; Zhong, F.; Hu, H.; Feng, Y. Extraction Optimization, Characterization and Antioxidant Activity of Polysaccharide from Gentiana scabra Bge. Intern. J. Biol. Macromol. 2016, 93, 369–380. Choi, R.-Y.; Nam, S.-J.; Lee, H.-I.; Lee, J.; Leutou, A. S.; Ham, J. R.; Lee, M.-K. Gentiopicroside Isolated from Gentiana scabra Bge. Inhibits Adipogenesis in 3T3-L1 Cells and Reduces Body Weight in Diet-Induced Obese Mice. Bioorg. Med. Chem. Lett. 2019, 29, 1699–1704. He, Y.-M.; Zhu, S.; Ge, Y.-W.; Kazuma, K.; Zou, K.; Cai, S.-Q.; Komatsu, K. The AntiInflammatory Secoiridoid Glycosides from Gentianae scabrae Radix: The Root and Rhizome of Gentiana Scabra. J. Natural Med. 2015, 69, 303–312. Ikeshiro, Y.; Mase, I.; Tomita, Y. A Secoiridoid Glucoside from Gentiana scabra var. buergeri. Planta medica 1990, 56, 101–103.

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Ikeshiro, Y.; Tomita Y. A New Bitter Secoiridoid Glucoside from Gentiana scabra var. buergeri. Planta Medica 1983, 48, 169–173. Kakuda, R., Iijima, T.; Yaoita, Y.; Machida, K.; Kikuchi, M. Triterpenoids from Gentiana scabra. Phytochemistry 2002, 59, 791–794. Kim, J.-A.; Son, N. S.; Son, J. K.; Jahng, Y.; Chang, H. W.; Jang, T. S.; Na, M.; Lee, S.-H. Two New Secoiridoid Glycosides from the Rhizomes of Gentiana scabra Bunge. Arch. Pharmacol. Res. 2009, 32, 863–867. Ko, H.-J., Chen, J.-H.; Ng, L.-T. Hepatoprotection of Gentiana scabra Extract and Polyphenols in Liver of Carbon Tetrachloride-Intoxicated Mice. J. Environ. Pathol. Toxicol. Oncol. 2011, 30. Lee, H.-T. Prokinetic Activities of Extracts from the Dried Rhizomes and Roots of Gentiana scabra Bunge in Mice. J. Life Sci. 2019, 29, 735–739. Li, W., Zhou, W.; Kim, S.; Koo, J.-E., Kim, Y.; Koh, Y.-S.; Shim, S. H.; Ma, J. Y.; Ho Kim, Y. Three New Secoiridoid Glycosides from the Rhizomes and Roots of Gentiana scabra and Their Anti-Inflammatory Activities. Nat. Prod. Res. 2015, 29, 1920–1927. Lin, C.-S., Liu, P.-Y.; Lian, C.-H.; Lin, C.-H.; Lai, J.-H.; Ho, L.-J.; Yang, S.-P.; Cheng S.-M. Gentiana scabra Reduces SR-A Expression and Oxidized-LDL Uptake in Human Macrophages. Acta Cardiologica Sinica 2016, 32, 460. Qu, Z.-X.; Li, F.; Ma, C.-D.; Liu, J.; Wang, W.-L. Effects of Gentiana scabra Bage on Expression of Hepatic Type I, III Collagen Proteins in Paragonimus skrjabini Rats with Liver Fibrosis. Asian Pacific J. Trop. Med. 2015, 8, 60–63. Ryang, Y.-S.; Im, J.-A.; Kim, I.-S.; Cho, Y.-K.; Sung, H.-J.; Park, J.-Y.; Min, D.-Y.; Ha J.-Y. Antiparasitic Effects of a Herb Extract from Gentiana scabra var. buergeri on Trichomonas vaginalis. Biomed. Sci. Lett. 2001, 7, 53–58. Shin, M.-H.; Suh, H.-W.; Lee, K.-B.; Kim, K.-S.; Yang, H. J.; Choi, E.-K.; Cho, Y. J.; Song, M.-Y.; Ahn, K. S.; Jang, H.-J. Gentiana scabra Extracts Stimulate Glucagon-Like Peptide-1 Secretion via G Protein-Coupled Receptor Pathway. BioChip J. 2012, 6, 114–119. Suh, H.-W.; Lee, K.-B.; Kim, K.-S.; Yang, H. J.; Choi, E.-K.; Shin, M. H.; Park, Y. S.; Na, Y.-C.; Ahn, K. S.; Jang, Y. P. A Bitter Herbal Medicine Gentiana scabra Root Extract Stimulates Glucagon-Like Peptide-1 Secretion and Regulates Blood Glucose in db/db Mouse. J. Ethnopharmacol. 2015, 172, 219–226. Wang, C.; Wang, Y.; Zhang, J.; Wang, Z. Optimization for the Extraction of Polysaccharides from Gentiana scabra Bunge and Their Antioxidant In Vitro and Anti-Tumor Activity In Vivo. J. Taiwan Inst. Chem. Eng. 2014a, 45, 1126–1132. Wang, Z.; Wang, C.; Su, T.; Zhang J. Antioxidant and Immunological Activities of Polysaccharides from Gentiana scabra Bunge Roots. Carbohydr. Polym. 2014b, 112, 114–118. Yang, B.; Kim, S.; Kim, J.-H.; Lim, C.; Kim, H.; Cho, S. Gentiana scabra Bunge Roots Alleviates Skin Lesions of Contact Dermatitis in Mice. J. Ethnopharmacol. 2019, 233, 141–147.

CHAPTER 31

Pharmacological Importance and Chemical Composition of Mallotus roxburghianus Müell.Arg. MARY ZOSANGZUALI, MARINA LALREMRUATI, C. LALMUANSANGI, F. NGHAKLIANA, and ZOTHANSIAMA* Department of Zoology, Mizoram University (A Central University), Aizawl 796004, Mizoram, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Mallotus roxburghianus Müell.Arg. is a traditional medicine widely used to cure various ailments in different parts of the world. Traditionally, M. roxburghianus has been used as a dietary supplement and herbal remedy for diabetes, ulcer, liver disorders, and hepatitis. The treatment of jaundice, hepatomegaly, hypertension, snake bite, and malaria are among the conditions for which it is well-known to be beneficial. Phenols, alkaloids, saponins, terpenes, tannins, triterpenoids, steroids, reducing sugars, coumarin, berginin, gallic acid, gentisic acid, gums, and a variety of other natural substances, particularly flavonoids like chrysin, hesperidin, naringenin, quercetin, and rutin, are the main phytochemicals found in M. roxburghianus. Various types of extracts derived from this plant have been found to exhibit biological activities including antioxidant, anti-inflammatory, hepatoprotective, gastroprotective, anti-hemolytic, antidiabetic, anti-pathogenic, and recovery of testicular activity from the damaging influence of scrotal hyperthermia. The present review reveals that M. roxburghianus is a valuable source of naturally occurring compounds with interesting pharmacological activities. Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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31.1 INTRODUCTION Among innumerable medicinal plants studied Mallotus roxburghianus Müell.Arg. (common name: Mallotus), a member of the Euphorbiaceae family, is a traditional medicine locally used for the treatment of various ailments. It is a tropical/subtropical plant widely distributed in Vietnam, South of China, Bangladesh, Myanmar, hilly parts of the Himalayas, and Northeast India. M. roxburghianus is a shrub to small tree; deciduous, stem whitish-brown, rough; bark gray, rough; young part softly pubescent; leaves alternate; flowers racemes, terminal; fruits 3-lobed and sub-globose (Lalramnghinglova, 2003). M. roxburghianus has been used traditionally by the tribal people of Mizoram in Northeast India as a dietary supplement and herbal remedies for diabetes, ulcer, liver disorders, and hepatitis. It is also known to be effective for the treatment of jaundice, hepatomegaly, hypertension, and even snake bite (Rai and Lalramnghinglova, 2010; Lalhlenmawia et al., 2007). The Chakma tribes in Bangladesh also used M. roxburghianus as an effective herbal remedy against malaria (Rahman et al., 2007). Considering M. roxburghianus as rich resources of ingredients, this review aims to provide an overview on scientific investigations on the pharmacological properties and chemical compositions for an optimal valuation. 31.2 BIOACTIVES Chemical screening of the leaf of M. roxburghianus revealed that the methanolic extract contain phytochemicals including flavonoids, alkaloids, saponins, terpenes, tannins, triterpenoids, reducing sugars, and gums and the aqueous extract possessed phenolic and flavonoid contents (Lalhlenmawia et al., 2013; Sagun et al., 2017; Zothansiama et al., 2018). Rana et al. (2005) reported the chemical constituents from the alcoholic extract of the leaves of M. roxburghianus. Two new compounds 3-(1-C-β-Dglucopyranosyl)-2,6-dihydroxy-5-methoxybenzoic acid and 2,4,8,9,10pentahydroxy-3,7-dimethoxyanthracene-6-O-β-D-rhamnopyranoside are isolated and identified. The pharmacologically active compounds Stigmasterol, Betulinic acid, and Berginin were identified with direct comparison of mixed melting points, super-imposable IR, and co-TLC with authentic samples. Other major compounds including β-sitosterol, 4-hydroxybenzoic acid, and β-sitosterol-β-D-glucoside were also isolated by comparison of chemical, physical, and spectral data.

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FIGURE 31.1 Chemical structures of isolated compounds from the leaf extract of M. roxburghianus: (A) β-sitosterol; (B) Stigmasterol; (C) Betulinic acid; (D) 4-hydroxybenzoic acid; (E) β-sitosterol-β-D-glucoside; (F) 3-(1-C-β-D-glucopyranosyl)-2,6-dihydroxy-5methoxybenzoic acid; (G) 2,4,8,9,10-pentahydroxy-3,7dimethoxyanthracene-6-O-β-Drhamnopyranoside; and (H) Bergenin (Rana et al., 2005).

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LC-MS/MS chromatogram profile of methanolic extract of M. roxburghianus reported by Sagun et al.(2017) also revealed the presence of several phytocompounds such as bergenin, betulinic acid, chlorogenic acid, coumarin, chrysin, ellagic acid, gallic acid, genistein, gentisic acid, hesperidin, hesperitin, kaempferol, luteolin, myrcetin, naringenin, protocatechuic acid, quercetin, rutin, and tannic acid. The most abundant phytocompounds are tannic acid, bergenin, betulinic acid, myricetin, hesperidin, and gallic acid. Futhermore, from GC-MS analysis, the leaf extract of M. roxburghianus comprised of several pharmacologically active constituents of diverse chemical classes. 25 phytochemicals were characterized and identified from the methanolic extract and are grouped into six main classes: fatty acids (7.16%), flavonoids (1.99%), esters (3.19%), phenols (45.36%), terpenes (40.23%), and others (1.11%). The major phytochemicals were found to be betulinic acid (40.05%) and bergenin (45.21%) and at a retention time of 23.418 min and 21.072 min respectively (Roy et al., 2015). Meanwhile, α-tocopherol, 2-propyl tridecyl ester, betulin, dihydrostachysterol, ethyl palmitate, phytol, squalene, and sulfurous acid are identified in the ethanolic extract of M. roxburghianus (Hnamte et al., 2019). The retention time and relative area of the identified phytochemicals present in the methanolic and ethanolic extract of M. roxburghianus are given in Tables 31.1 and 31.2, respectively. TABLE 31.1 List of Phytochemical Compounds Isolated and Identified in Methanolic Fractions of M. roxburghianus by GC-MS Analysis with Their Biological Activity (Roy et al., 2015). Compounds

Biological activity

References

4-(3-Hydroxybutyl) Phenol 3,4-dihydroxy-5methoxybenzoic acid, 3-O-methyl gallic acid p-hydroxybenzoic acid Diethylphthalate 9Z,12E-octadecadienoic acid Hexadecanoic acid ethyl ester Phytol

Antioxidant Antioxidant

Tapiero et al. (2002) Tapiero et al. (2002)

Antioxidant Antimicrobial Anti-inflammatory, hepatoprotective Antioxidant

Riviere et al. (2009) Janu and Jaynthy (2014) Riviere et al. (2009)

Anticancer, antioxidant, anti-inflammatory, diuretic, antimicrobial

Pejin et al. (2015)

Riviere et al. (2009)

Mallotus roxburghianus Müell.Arg. TABLE 31.1 (Continued) Compounds Octadecanoic acid (Stearic acid) Caryophyllene oxide

1-iodo-2-methylundecane Squalene β-Eudesmol Rottlerin/mallotoxin Myricetin Octadecanoic acid, ethyl ester Bergenin/cuscutin

Betulinic acid 3-O-α-L-rhamnosyl kaempferol

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Biological activity

References

Antioxidant

Riviere et al. (2009)

Antitermitic, antifungal, antiinflammatory, anticarcinogenic activity Enhancing reproductive activity, pheromone Antioxidant, antitumor, cancer preventive Apoptosis inducer Antimicrobial, antioxidant Cancer-preventive, cosmetic, nematicide Antioxidant

Fidyt et al. (2016)

Antioxidant, anti-inflammatory, antifungal, hepatoprotective, antimicrobial Antibacterial, antimalarial, anti-inflammatory, anthelmintic Antileukemic, anti-inflammatory

Hikino et al. (1978)

Achiraman et al. (2010) Kim and Karadeniz, (2012) Narahara et al. (2020) Maioli et al. (2009) Jiang et al. (2019), Bano et al. (2020) Riviere et al. (2009)

Moghaddam et al. (2012) Riviere et al. (2009)

TABLE 31.2 List of Phytochemicals Present in the Ethanolic Crude Extracts of M. roxburghianus Using GC-MS Analysis with Their Biological Activity (Hnamte et al., 2019). Compounds Phytol Squalene Dihydrotachysterol α- tocopherol Betulin

31.3

Biological activity Anti-inflammatory, anti-QS activity Antioxidant, anticancer activity For treatment of hypocalcemia and hypothyroidism Antioxidant, hepatoprotective activity Immunomodulatory activity

References Pejin et al. (2015) Kim and Karadeniz (2012) Pfarr et al. (2015) Palipoch et al. (2014) Pfarr et al. (2015)

PHARMACOLOGY

31.3.1 ANTIOXIDANT ACTIVITY The antioxidant potential of different extracts of M .roxburghianus was investigated by using various in vitro standard methods. The methanolic extract showed high radicals scavenging for ABTS (2,2’-azino-

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bis-(3- ethylbenzothiazoline- 6- sulfonic acid), DPPH (1, 1-diphenyl-2-picrylhydrazyl), superoxide anion, hydroxyl radical, nitric oxide, hydroxyl radical, hydrogen peroxide with strong reducing power ability in a dose-dependent manner. Chloroform and aqueous extract also inhibited the generation of ABTS, DPPH, and superoxide anions in a concentration-dependent manner (Lalhlenmawia et al., 2013; Zothansiama et al., 2018; Sagun et al., 2017). Rana et al. (2005) showed that chloroform soluble portions and compounds isolated from M. roxburghianus such as 3-(1-C-β-D-glucopyranosyl)-2, 6-dihydroxy-5-methoxybenzoic acid, betulinic acid, berginin, and β-sitosterol possess antioxidant activities. 31.3.2 ANTI-INFLAMMATORY ACTIVITY The production of secondary metabolites in M. roxburghianus involves some mechanisms for the treatment of inflammation. In vitro anti-inflammatory activities of total methanolic extracts showed inhibition for lipoxygenase (LOX,1.426 µg quercetin equivalents/mL) and Xanthine oxidase (XO, 1.593 µg quercetin equivalents/ mL) (Sagun et al., 2017). 31.3.3

HEPATOPROTECTIVE EFFECT

The aqueous crude extract of M. roxburghianus possesses hepatoprotective activities in Swiss albino mice by elevating doxorubicin-induced reduction in various antioxidants. Intraperitoneal injection of doxorubicin significantly reduces the level of liver antioxidants, which was however elevated by the administration of aqueous extract of M. roxburghianus at a dose of 100, 150, and 200 mg/kg administered for seven consecutive days (Zothansiama et al., 2018). 31.3.4

GASTRO-PROTECTIVE PROPERTY

In the in vivo studies carried out by Sagun et al. (2017), the gastro-protective effect was observed from the methanolic extract of M. roxburghianus against ethanol-induced GM hemorrhagic lesions in Wistar rats. 31.3.5 ANTI-HEMOLYTIC ACTIVITY Ex-vivo studies performed by Zothansiama et al. (2018) reported the potent anti-hemolytic activity of various extracts of M. roxburghianus at

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the concentration of 0.5 mg/mL by measuring the inhibition of erythrocyte hemolysis. The aqueous extract showed the highest inhibition activity (95.39%) followed by methanolic and chloroform extract with the inhibition rate of 90.66% and 85.66%, respectively. 31.3.6

RECOVERY OF TESTICULAR ACTIVITY

The administration of methanolic extract of M. roxburghianus at a dose of 100mg/kg and 400 mg/kg for 28 days accelerates testicular recovery in Wistar albino rats from the damaging influence of scrotal hyperthermia. It significantly restored the antioxidant enzyme and testosterone levels, suppressed lipid peroxidation, revived spermatogenesis, and increased cell proliferation activity (Roy et al., 2016). 31.3.7 ANTIDIABETIC PROPERTY The oral administration of methanolic extract of M. roxburghianus (100 and 400 mg/kg) and glibenclamide (0.1 mg/kg) to the diabetic rats for 28 days caused degenerative changes by improving the seminiferous tubule structure and increasing the number of spermatogenic cells when compared with the alloxan-induced diabetic group. Bergenin and Betulinic acid were the main compounds that show antidiabetic activities related to testicular impairment (Roy et al., 2015). The methanolic extract of M. roxburghianus leaves also has antioxidant and anti-hyperglycaemic potential that could modulate pancreatic architecture and physiology by restoring the antioxidant enzyme system and rejuvenates the islets mass in alloxan-induced diabetic rats (Roy et al., 2016). 31.3.8 ANTI-PATHOGENIC AGENTS In vitro studies of M. roxburghianus followed by in silico analysis showed the efficacy in downregulating bacterial virulence by inhibiting the binding of natural ligand with LasR and thereby altering production of P. aeruginosa virulence phenotypes. In silico analysis of M. roxburghianus, comprising several phytochemicals, revealed that phytol exhibited a docking score of -7.042 kcal/mol, whereas sulfurous acid and 2-propyl tridecyl ester with a score of -6.669 kcal/mol suggested its affinity for LasR (Hnamte et al., 2019).

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KEYWORDS

• • • • • •

Mallotus roxburghianus traditional medicine antioxidant anti-inflammatory antidiabetic pharmacological activities

REFERENCES Achiraman, S.; Archunan, G.; Ponmanickam, P.; Rameshkumar, K.; Kannan, S.; John, G. 1-Iodo-2 Methylundecane [1I2MU]: An Estrogen-Dependent Urinary Sex Pheromone of Female Mice. Theriogenology 2010, 74 (3), 345–353. Bano, S., Iqbal, E. Y., Lubna, Zik-ur-Rehman, S.; Fayyaz, S.; Faizi, S. Nematicidal Activity of Flavonoids with Structure Activity Relationship (SAR) Studies Against Root Knot Nematode. Meloidogyne incognita. Eur. J. Plant. Pathol. 2020, 157, 299–309. Fidyt, K.; Fiedorowicz, A.; Strządała, L.; Szumny, A. β-caryophyllene and β-caryophyllene Oxide-Natural Compounds of Anticancer and Analgesic Properties. Cancer Med. 2016, 5 (10), 3007–3017. Hikino, H.; Tamada, M.; Yen, K. Y. Mallorepine, Cyano-γ-Pyridone from Mallotus repandus. Planta Med. 1978, 33, 385–388. Hnamte, S.; Subhaswaraj, P.; Ranganathan S. K.; Ampasala, D. P.; Muralitharan, G.; Siddhardha. B. Anti-Quorum Sensing and Anti-Biofilm Potential of Anogeissus acuminata and Mallotus roxburghianus Muell. Against Pseudomonas aeruginosa PAO1. J. Microbiol. Biotech. Food Sci. 2019, 8 (5), 1135–1140. Janu, N. P.; Jaynthy, C. Antimicrobial activity of diethyl phthalate: An in silico approach. Asian. J. Pharm. Clin. Res. 2014, 7 (4), 141–142. Jiang, M.; Zhua, M.; Wang, L.; Yua, S. Anti-Tumor Effects and Associated Molecular Mechanisms of Myricetin. Biomed. Pharmacother. 2019, 120, 109506. Kim, S. K.; Karadeniz, F. Biological Importance and Applications of Squalene and Squalane. Adv. Food Nutr. Res. 2012, 65, 223–233. Lalhlenmawia, H.; Kumarappan, C. T.; Bhattacharjee, B. B.; Mandal, S. C. Antidiabetic Activity of Mallotus roxburghianus Leaves in Diabetic Rats Induced by Streptozocin. Pharmacol. Online. 2007, 3, 244–254. Lalhlenmawia, H.; Mandal, S. C.; Lalremruata, V.; Lalhriatpuii, T. C.; Zothanpuia. In Vitro Antioxidant Activity Study of Traditionally Used Plant Mallotus roxburghianus Muell. Int. J. Pharm. Sci. Res.2013, 3 (1), 93–104. Lalramnghinglova, H. Ethno-Medicinal plants of Mizoram. Bishen Singh Mahendra Pal Singh, Dehradun, India. 2003, 193–199.

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Maioli, E.; Greci, L.; Soucek, K.; Hyzdalova, M.; Pecorelli, A.; Fortino, V.; Valacchi, G. Rottlerin Inhibits ROS Formation and Prevents NFkappaB Activation in MCF-7 and HT-29 Cells. J. Biomed. Biotechnol. 2009, 742936. Moghaddam, M. F.; Ahmad, F. B. H.; Samzadeh-Kermani, A.; Biological Activity of Betulinic Acid: A Review. Pharmacol. Pharm. 2012, 3, 119–123. Narahara, C.; Saeheng, T.; Chaijaroenkul, W.; Dumre, S. P.; Na-Bangchang, K.; Karbwang, J. β-Eudesmol Induces the Expression of Apoptosis Pathway Proteins in Cholangiocarcinoma Cell Lines. J. Res. Med. Sci. 2020, 25, 7. Palipoch, S.; Punsawad, C.; Koomhin, P.; Suwannalert, P. Hepatoprotective Effect of Curcumin and Alpha-Tocopherol Against cisplatin induced Oxidative Stress. BMC Compl. Alternative Med. 2014, 14, 111. Pejin, B.; Ciric, A.; Glamoclija, J.; Nikolic, M.; Sokovic, M. In Vitro Anti-Quorum Sensing Activity of Phytol. Nat. Prod. Res. 2015, 29 (4), 374–377. Pfarr, K.; Danciu, C.; Arlt, O.; Neske, C.; Dehelean, C.; Pfeilschifter, J. M.; Radeke, H. H. Simultaneous and Dose Dependent Melanoma Cytotoxic and Immune Stimulatory Activity of Betulin. PLOS One. 2015, 10 (3), e0118802. Rahman, M. A.; Uddin, S. B.; Wilcock, C. C. Medicinal Plants Used by Chakma Tribe in Hill Tracts Districts of Bangladesh. Indian J. Tradit. Knowl. 2007, 6 (3), 508–517. Rai, P. K.; Lalramnghinglova, H. Lesser Known Ethnomedicinal Plants of Mizoram, North East India: An Indo-Burma Hotspot Region. J. Med. Plant Res. 2010, 4 (13), 1301–1307. Rana, V. S.; Rawat, M. S. M.; Pant, G.; Nagatsu, A. Chemical Constituents of Antioxidant Activity of Mallotus roxburghianus Leaves. Chem. Biodivers. 2005, 2, 792–798. Riviere, C.; Nguyen, T. H. V.; Tran, H. Q.; Chataigne, G.; Nguyen, H. N.; Dejaegher, B.; Tistaert, C.; Thi, N. K. T.; Vander Heyden, Y.; Chau, V. M.; Quetin-Leclercq, J. Mallotus Species from Vietnamese Mountainous Areas: Phytochemistry and Pharmacological Activities. Phytochem. Rev. 2009, 9, 217. Roy, V. K.; Chenkual, L.; Gurusubramanian, G. Protection of Testis Through Antioxidant Action of Mallotus roxburghianus in Alloxan-Induced Diabetic Rat Model. J. Ethnopharmacol. 2015, 176, 268–280. Roy, V. K.; Chenkual, L.; Gurusubramanian, G.. Mallotus roxburghianus Modulates Antioxidant Responses in Pancreas of Diabetic Rats. Acta Histochemica 2016. Sagun, K.; Roy, V. K.; Kumar, R. S.; Ibrahim, K. S.; Parimelazhagan, T.; Kumar, N. S.; Gurusubramanian, G.Antioxidant Potential,Anti-InflammatoryActivity and Gastroprotective Mechanisms of Mallotus roxburghianus (Muell.) Against Ethanol-Induced Gastric Ulcers in Wistar Albino Rats. J. Funct. Food. 2017, 36, 448–458. Tapiero, H.; Tew, K. D.; Ba, G.N; Mathé, G. Polyphenols: Do They Play a Role in the Prevention of Human Pathologies? Biomed. Pharmacother. 2002, 56, 200–207. Zothansiama.; Lalmuansangi, C.; Zosangzuali, M.; Tochhawng, L.; Jagetia, G. C. Assessment of Free Radical Scavenging Activity and Antioxidant Mediated Hepatoprotective Effects of Mallotus roxburghianus Muell. in Doxorubicin Induced Oxidative Stress in Swiss Albino Mice. Int. J. Pharm. Sci. Res.2018, 9 (10), 4138–4150.

CHAPTER 32

Phytochemistry and Pharmacology of Phytolacca dodecandra L. HIRPASA TERESSA* Department of Biology, Wolkite University, Wolkite, Ethiopia E-mail: [email protected]

*

ABSTRACT Phytolacca dodecandra L. is a woody, perennial climber, commonly known as “soapberry.” It extensively inhabits parts of Sub-Saharan Africa, Asia, and South America. P. dodecandra is used in the treatment of different diseases including gonorrhoea, skin diseases, abortion, otitis, intestinal worms, pneumonia, emetics, edema, laxatives, diuretics, diarrhea, stomach pain, anthrax, and rabies. Phytochemical analysis from extracts of P. dodecandra leaves, fruits, stem, and roots showed the presence of several compounds such as alkaloids, flavonoids, saponins, steroids, total phenols and tannins, triterpenoid, terpenoids, an oleanolic acid glycoside, named Lemmatoxin, leuco-anthocyanins, and anthocynins. As a result, P. dodecandra is proved as a potential molluscicidal, insecticidal and larvacidal agent, and have antibacterial, antiviral, antifungal, antioxidant, and hypotensive and cardio depressant properties. In addition, the plant also has anti-hyperglycemic, hepatoprotective, and anti-inflammatory activities. 32.1 INTRODUCTION Phytolacca dodecandra L. is a woody climber with stems reaching 10 m in length, dioecious flowering stalks with red or pinkish berries. It is commonly known as “soapberry,” called “endod” (Amharic) or “handoodee” (Afan Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Oromo) in Ethiopia. The plant is extensively distributed over parts of Sub-Saharan Africa, Asia, and South America (Lemma, 1965). It is a perennial plant growing in Ethiopian highlands (1600–3000 m.a.s.l.) (Lemma and Wolde-Yohannes, 1979; Karunamoorthi et al., 2008). In Ethiopia, P. dodecandra have been used as soap for washing clothes, and control of schistosomiasis. Medicinal uses of endod include treatment of gonorrhoea, skin diseases, abortion, otitis, intestinal worms, leeches, pneumonia, stomach pain, anthrax, and rabies (El-Kamali, 2009; Esser et al., 2003; Lemma, 1965). 32.2 BIOACTIVES Phytochemical analysis done in benzene, aqueous, ethanol, and CCl4 extracts of P. dodecandra leaves, fruits, and stem showed the presence of alkaloids, proteins and amino acids, flavonoids, saponins, steroids, total phenols and tannins, and triterpenoid (Ganesan et al., 2016). In addition, P. dodecandra root was examined to be positive for saponins, tannins, terpenoids, and polyphenols (Meharie and Tunta, 2021). Chemical studies of the P. dodecandra berries have led to the discovery of a new compound, an oleanolic acid glycoside, named Lemmatoxin. Chromatographic separations of the crude saponins in P. dodecandra demonstrated the presence of a dozen compounds similar to Lemmatoxin (Esser et al., 2003). Other study done on phytochemical screening of P. dodecandra also revealed the presence of various secondary metabolites namely polyphenols, tannins, saponins, alkaloids, leuco-anthocyanins, anthocynins, steroids, and triterpenoids (Mekonnen et al., 2012). Moreover, study done by Iteku et al. (2019) revealed the presence of secondary metabolites such as phenolic compounds in the leaves of P. dodecandra. The analysis of the chromatographic systems showed the presence of phenolic acids and flavonoids in the plant. Analysis of the chromatogram also revealed the presence of anthocyanins and terpenoids in the leaves of P. dodecandra. Furthermore, Matebie et al. (2019) identified the chemical composition of essential oils of this plant, while Tura et al. (2017) reported the presence of saponins, tannins, and flavonoids in the fruit of P. dodecandra. Vithya et al. (2018) also reported the presence of alkaloids, tannins, flavonoids, amino acids, phenols, steroids, terpenoids, saponins, and glycosides in the leaves.

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32.3 PHARMACOLOGY

32.3.1 MOLLUSCICIDAL PROPERTIES P. dodecandra is proved as a potential molluscicidal agent that kills the intermediate host (snails) of schistosome worms which cause schistosomiasis (Semagn et al., 2004). In Ethiopia, high mortality of snails was observed in freshwater where people use P. dodecandra to wash their clothes. Lemma (1970) studied and confirmed to have molluscicidal activities. The snails exposed to 19–25 ppm after 24 h and 6–7 ppm concentration proved to show 100% mortality (Baalawy, 1972). Among 65 known varieties, the type E44 Ethiopian Phytolacca contained 25% of saponins in which Lemmatoxin, a potential molluscicide, was identified (Esser et al., 2003; Lemma et al., 1972). This species contains structurally related triterpenoid saponins in which the most potent one has been identified as ‘Lemmatoxin (an oleanolic acid glycoside). The potential molluscicide activity of P. dodecandra extracts in Ethiopia was isolated using organic solvents for the first time by Lemma and Wolde-Yohannes (1979). In addition to snail, Schistosome cercariae and miracidia mortality was also increased when exposed to aqueous extract of P. dodecandra berries (type 44) with increased concentration and time of exposure (Birrie et al., 1998). 32.3.2 INSECTICIDAL AND LARVACIDAL ACTIVITY Zeleke et al. (2017) revealed that exposures of Anopheles arabiensis larvae to the seed extracts of endod showed significant mortality of the insect larvae. A considerable larvicidal effect of both powder and extract of the seed against third instars larvae of A. arabiensis was observed. In this study, for both forms of the seed products, the larval mortality rate increased with increasing concentration. Similarly, Getachew et al. (2016) showed that fresh and aged endod berry’s solutions had a significant mortality effect against fourth instars larvae of A. arabiensis. Other study reported that the crude seed products of P. dodecandra revealed significant larvicidal and pupicidal effect against C. quinquefasciatus (Nurie et al., 2012). Study also identified that butanol extract was found to be highly toxic to the second and third instar larvae of Aedes aegypti, Culex pipiens, and Anopheles quadrimaculatus (Spielman and Lemma, 1973). A study done by Spielman and Lemma (1973) showed that leaves extracts of P. dodecandra have insecticidal activity against bedbugs.

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32.3.3 ANTIBACTERIAL ACTIVITY Alkaloids, anthocyanins, polyphenols, saponins, flavonoids, steroids, tannins, and triterpenes in plants confer antibacterial activity (Kuete, 2010). Researchers also identified antibacterial activity in P. dodecandra extracts though it is low. It was observed that the extracts of P. dodecandra have low antibacterial activity against three bacterial strains, namely S. aureus, E. coli, and P. aeruginosa (Iteku et al., 2019). Taye et al. (2011) also found a similar result. Moreover, Tadeg et al. (2005) reported that methanol extract of P. dodecandra has a low activity on S. aureus, E. coli, P. aeruginosa. Iteku et al. (2019) also observed that only the dichloromethane and aqueous extracts of P. dodecandra showed a relatively low antibacterial activity (Iteku et al., 2019). Furthermore, crude extracts of P. dodecandra exhibited bacterial growth inhibition up to 25% (Taye et al., 2011). P. dodecandra root showed strong antibacterial activity against P. aeuruginosa and S. pyogens. Likewise, its petroleum ether extract was active against gram-positive bacteria (Nastro et al., 2000). The methanol extract of endod stem bark was effective against P. aeruginosa and Salmonella typhi (Ogutu et al., 2012). 32.3.4 ANTIVIRAL ACTIVITY In mice inoculated with CVS-11 rabies virus strain, root extract of P. dodecandra revealed a potential anti-rabies activity at 5000 mg/kg (Zewde et al., 2019). 32.3.5 ANTIFUNGAL ACTIVITY Methanolic crude extracts of P. dodecandra berries exhibited most effective antifungal activity against Sclerotium rolfsii, Rhizoctonia solani, Botrytis cinerea, Fusarium oxysporum, Pythium ultimum, and Botryosphaeria dothidea, using an agar diffusion method (Tegegne and Pretorius, 2007). However, aqueous extract of P. dodecandra had moderate activity against Trichophyton mentagrophytes and Microsporum gypseum, and mild activity against Candida albicans. Similarly, aqueous extract of P. dodecandra had moderate activity against Microsporum gypseum and Trichophyton mentagrophytes and mild activities against Candida albicans. It was observed that n-butanol extract of P. dodecandra demonstrated effective antifungal activity (Mekonnen et al., 2012), while ethyl acetate extract of the plant

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roots had very mild antifungal property (Ogutu et al., 2012) and the study by Woldeamanuel et al. (2005) showed that the crude extract of P. dodecandra could be an important natural source of antifungal substance for topical. 32.3.6 ANTIOXIDANT PROPERTY 80% methanol extract of P. dodecandra root showed free radical scavenging activity. Secondary metabolites found in the P. dodecandra root extract including polyphenols, saponins, flavonoids, tannins, and terpenoids were found to have principal antioxidant activities (Ganesan et al., 2016; Meharie and Tunta, 2021). These phenolic compounds have many biological properties including antioxidant capacities (El Gharras, 2009; Perron and Brumaghim, 2009; Imene, 2013). 32.3.7 HYPOTENSIVE AND CARDIO DEPRESSANT PROPERTIES Study showed that saponins, secondary metabolites present in the P. dodecandra root extract, have hypotensive and cardio depressant properties (Olaleye, 2007), which are helpful for the treatment of congestive heart failure and cardiac myopathy (Ugochukwu et al., 2013). The occurrence of saponins in aqueous and ethanol extracts of leaves, stem, and fruits of soapberry plays a role in the cardioprotective potential (Ganesan et al., 2016). 32.3.8 ANTI-HYPERGLYCEMIC EFFECT Tannins and alkaloids that are present in P. dodecandra extracts have the potential of hypoglycemic activities. Moreover, the terpenoids have also been revealed to decrease blood sugar level (Augusti and Cherian, 2008). 32.3.9 HEPATOPROTECTIVE ACTIVITY 80% methanol extract of P. dodecandra root possessed comparable hepatoprotective activities. Mice treated with the extracts showed decrease in derangement of hepatocytes, hepatocyte ballooning, cytoplasmic vacuolization, and infiltration of hepatocyte membrane with inflammatory cells and collagen fibers. Furthermore, the study showed that CCl4 mediated oxidative

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damage was reversed by the administration of the plant extract (Meharie and Tunta, 2021). 32.3.10 ANTI-INFLAMMATORY ACTIVITY Studies revealed that phenolic compounds, alkaloids and tannins, which are present in P. dodecandra extracts, have several anti-inflammatory activities (Brian et al., 1985; Hong et al., 2013; Bernard et al., 2018). A recent study also identified that crude leaf extract of P. dodecandra possesses an antiinflammatory activity (Nakalembe et al., 2019). 32.3.11

OTHER MEDICINAL USES

The medicinal values of P. dodecandra are well documented. Various medicinal uses documented worldwide include purgatives, antihelmintics, antimalaria, emetics, edema, laxatives, diuretics, abdominal pains, diarrhea, and intestinal problems (Bizimana, 1994; Schemelzer and Gurib-Fakim, 2008; Mesfin et al., 2009). It is also used in the treatment of wound, abortion induced by young leaves, skin diseases like ringworms, scabies, itching, dandruff, headache, emesis, rheumatism, otitis, pneumonia, stomach pain, skin irritation, and intestinal roundworms (Fonnegra and Jimenez, 2007; Schemelzer and Gurib-Fakim, 2008; EL-Kamali, 2009). Polyphenols (metabolites of P. dodecandra) are known to have antitumor, antiallergic, and other activities and useful in the preventive management of cardiovascular and neurodegenerative diseases, diabetes, and obesity (Vauzour et al., 2008). KEYWORDS • • • • •

bioactives molluscicidal properties phytochemicals Phytolacca dodecandra secondary metabolites

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REFERENCES Augusti, K. T.; Cherian, S. Insulin Sparing Action of Leucopelargonidin Derivative Isolated from Ficus bengalesis Linn. Indian J. Exp. Biol. 2008, 33, 608–611. Baalawy, S. S. Laboratory Evaluation of the Molluscicidal Potency of a Butanol Extract of Phytolacca dodecandra (Endod) Berries. Bull. World Health Org. 1972, 47 (3), 422–425. Bernard, N.; Emmerance, N.; Ingabire, A. Comparative Bacterial Inhibition by Bioactive Extracts from Datura stramonium and Phytolacca dodecandra. Virol Res J. 2018, 2 (1), 1–5. Birrie, H.; Balcha, F.; Erko, B.; Bezuneh, A.; Gemeda, N. Investigation in to the Cercariacidal and Miracidiacidal Properties of Endod (Phytolacca dodecandra) Berries (Type 44). East Afr. Med. J. 1998, 75, 311–314. Bizimana, N. Traditional Veterinary Practice in Africa; Eschborn: Germany, 1994. Brian, F. H.; Thomas-Bigger, J.; Goodman, G. The Pharmacological Basis of Therapeutics; Macmillan: New York, 1985. El Gharras, H. Polyphenols: Food Sources, Properties and Applications—A Review. Intern. J. Food Sci. Technol. 2009, 44 (12), 2512–2518. El-Kamali, H. H. Medicinal Plants in East and Central Africa: Challenges and Constraints. Ethnobot. Leaflets 2009, 13, 364–369. Esser, K. B.; Semagn, K.; Wolde-Yohannes, L. Medicinal Use and Social Status of the Soap Berry endod (Phytolacca dodecandra) in Ethiopia. J. Ethnopharmacol. 2003, 85, 269–277. Fonnegra, G. R.; Jimenez, R. S. L. Approved as Medicinal Plant in Colombia, 2nd ed.; Universidad de Antioquia: Medellin, Colombia, 2007. Ganesan, K.; Nair, S. K. P.; Letha, N.; Gani, S. B. Phytochemical Screening of Different Solvent Extracts of Soap Berry (Phytolacca dodecandra L’herit.)- A Native Ethiopian Shrub. Intern. J. Pharm. Pharma. Sci. 2016, 5 (2), 100–109. Getachew, D.; Balkew, M.; Gebre-Michael, T. Evaluation of Endod (Phytolacca dodecandra: Phytolaccaceae) as a Larvicide Against Anopheles arabiensis, the Principal Vector of Malaria in Ethiopia. J. Am. Mosq. Control Assoc. 2016, 32 (2), 124–129. Hong, S. Y.; Roze, L. V.; Linz, J. E. Oxidative Stress-Related Transcription Factors in the Regulation of Secondary Metabolism. Toxins 2013, 5 (4), 683–702. Imene, R. Etude in vitro de l’activite anti Leishmanienne de certaines plantes medicinales locales: cas de la famille des lamiacées. These en vue d’obtention du diplome: Magister en Biologie Appliquee. Universite Constantine 1’Algerie, 2013. Iteku, J. B.; Mbayi, O.; Bongo, G. N.; Mutwale, P. K.; Wambale, J. M.; Lengbiye, E.; Inkoto, C. L.; Ngunde1, S. N.; Ngbolua, K. Phytochemical Analysis and Assessment of Antibacterial and Antioxidant Activities of Phytolacca dodecandra L. Herit Leaf Extracts (Phytolaccaceae). Intern. J. Biomed. Eng. Clin. Sci. 2019, 5 (3), 31–39. Karunamoorthi, K.; Adane, M.; Fantahun, W. Laboratory Evaluation of Traditional Insect/ Mosquito Repellent Plants Against Anopheles arabiensis, the Predominant Malaria Vector in Ethiopia. Parasitol. Res. 2008, 103, 529–534. Kuete, V. Potential of Cameroonian Plants and Derived Products Against Microbial Infections: A Review. Planta Med. 2010, 76 (14), 1479–1491. Lemma, A. A Preliminary Report on the Molluscicidal Property of endod (Phytolacca dodecandra). Ethiopian Medical J. 1965, 3, 187–190. Lemma, A. Laboratory and Field Evaluation of the Molluscicidal Properties of Phytolacca dodecandra. Bull. World Health Org. 1970, 42, 597–612.

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Lemma, A. G.; Brody, G. W.; Newell, R. M.; Parkhurst; Skinner, W. A. Endod (Phytolacca dodecandra), a Natural Product Molluscicide: Increased Potency with Butanol Extraction. J. Parasitol. 1972, 58, 104–107. Lemma, T.; Wolde-Yohannes, L. Selected Stage for Endod Berry Harvesting. In Studies on the Molluscicidal and other Properties of the Endod Plant, Phytolaca dodecandra; Lemma, A., Heyneman, D., Kloos, H., Eds.; University of California: San Francisco, 1979; pp 241–245. Matebie, W. A.; Zhang, W.; Xie, G. Chemical Composition and Antimicrobial Activity of Essential Oil from Phytolacca dodecandra Collected in Ethiopia. Molecules 2019, 24 (342), 1–8. Meharie, B. G.; Tunta, T. A. Phytolacca dodecandra (Phytolaccaceae) Root Extract Exhibits Antioxidant and Hepatoprotective Activities in Mice with CCl4- Induced Acute Liver Damage. Clin. Exp. Gastroenterol. 2021, 14, 59–70. Mekonnen, N.; Makonnen, E.; Aklilu, N.; Amen, G. Evaluation of Berries of Phytolacca dodecandra for Growth Inhibition of Histoplasma capsulatum var. farciminosum and treatment of Cases of Epizootic Lymphangitis in Ethiopia. Asian Pacific J. Trop. Biomed. 2012, 2 (7), 505–510. Mesfin, F.; Demissew, S.; Tekelehaymanot, T. An Ethnobotanical Study of Medicinal Plants in Wonago Woreda, SNNPR, Ethiopia. J. Ethnobiol. Ethnomed 2009, 5, 28. Nakalembe, L.; Kasolo, J. N.; Nyatia, E.; Lubega, A.; Bbosa, G. S. Analgesic and AntiInflammatory Activity of Total Crude Leaf Extract of Phytolacca dodecandra in Wistar albino rats. Neurosci. Med. 2019, 10, 259–271. Nastro, A.; Germano, M. P. A.; D’Angelo, V.; Marino, A.; Cannatelli, M. A. Extraction Methods and Bioautography for Evaluation of Medicinal Plant Antimicrobial Activity. Lett Appl Microbiol. 2000, 30, 379–384. Nurie, M.; Shiferaw, M.; Muche, T.; Mamaye, T.; Tigab, T.; Nagappan, R. Evaluation of Multi Potential Bioactive Endod, Phytolacca dodecandra (L’ Herit) Berries Extracts Against Immature Filarial Vector Culex quinquefasciatus (Diptera: Culicidae). Res. J. Environ. Earth Sci. 2012, 4 (7), 697–703. Ogutu, A. I.; Lilechi, D. B.; Mutai, C.; Bii, C. Phytochemical Analysis and Antimicrobial Activity of Phytolacca dodecandra, Cucumis aculeatus and Erythrina excelsa. Int. J. Biol. Chem. Sci. 2012, 6 (2), 692–704. Olaleye, M. T. Cytotoxicity and Antibacterial Activity of Methanolic Extract of Hibiscus sabdariffa. J. Med. Plants Res. 2007, 1, 9–13. Perron, N. R.; Brumaghim, J. L. A Review of the Antioxidant Mechanisms of Polyphenol Compounds Related to Iron Binding. Cell Biochem. Biophys. 2009, 53 (2), 75–100. Schemelzer, H. H.; Gurib-Fakim, A. Plant Resources of Tropical Africa-Medicinal Plants; Backhuys Publishers: Wageningen, Netherlands, 2008. Semagn, K.; Stedje, B.; Bjornstad, A. Patterns of Phenotypic Variation in Endod (Phytolacca dodecandra) from Ethiopia. Afr. J. Biotechnol. 2004, 3 (1), 32–39. Spielman, A.; Lemma, A. Endod Extract, Plant Derived Molluscicide: Toxic for Mosquitoes. Am. J. Trop. Med. Hyg. 1973, 22, 802–804. Tadeg, H.; Mohammed, E.; Asres, K.; Gebre-Mariam, T. Antimicrobial Activities of Some Selected Traditional Ethiopian Medicinal Plants Used in the Treatment of Skin Disorders. J. Ethnopharmacol. 2005, 100 (1–2), 168–175. Taye, B.; Giday, M.; Animut, A.; Seid, J. Antibacterial Activities of Selected Medicinal Plants in Traditional Treatment of Human Wounds in Ethiopia. Asian Pacific J. Trop. Biomed. 2011, 1 (5), 370–375.

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Tegegne, G.; Pretorius, J. C. In Vitro and In Vivo Antifungal Activity of Crude Extracts and powdered Dry Material from Ethiopian Wild Plants Against Economically Important Plant Pathogens. BioControl 2007, 52, 877–888. Tura, G. T.; Eshete, W. B.; Tuchi, G. T. Antibacterial Efficacy of Local Plants and Their Contribution to Public Health in Rural Ethiopia. Antimicrob. Resist. Infect. Control 2017, 6, 76. Ugochukwu, S. C.; Uche, I. A.; Ifeanyi, O. Preliminary Phytochemical Screening of Different Solvent Extracts of Stem Bark and Roots of Dennetia tripetala G. Baker. Asian J. Plant Sci. Res. 2013, 3 (3), 10–13. Vauzour, D.; Vafeiadou, K.; Rodriguez-Mateos, A.; Rendeiro, C.; Spencer, J. P. E. The Neuroprotective Potential of Flavonoids: A Multiplicity of Effects. Genes Nutr. 2008, 3 (3–4), 115–126. Vithya, E. D.; Maleeka, B. S. F.; Ravikumar, K. Evaluation of Phytochemical and Antimicrobial Property of Phytolacca octandra. Intern. J. Res. Ayurveda Pharm. 2018, 9 (6), 111–115. Woldeamanuel, Y.; Abate, G.; Chryssantou, E. In Vitro Activity of Phytolacca dodecandra (Endod) Against Dermatophytes. Ethiop. Med. J. 2005, 43. Zeleke, A. J.; Shimo, B. A.; Gebre, D. Y. Larvicidal Effect of Endod (Phytolacca dodecandra) Seed Products Against Anopheles arabiensis (Diptera: Culicidae) in Ethiopia. BMC Res. Notes 2017, 10, 449. Zewde, D.; Dawo, F.; Hurisa, B.; Mengesha, A.; Tadele, A. Determination of Anti-Rabies Virus Activities of Crude Extracts from Some Traditionally Used Medicinal Plants in East Wollega, Ethiopia. Intern. J. Basic Appl. Virol. 2019, 8 (2), 28–37.

CHAPTER 33

Phytochemical and Pharmacological Aspects of “Arogyapacha,” Trichopus zeylanicus Gaertn. THADIYAN PARAMBIL IJINU1,2*, THOMAS ASWANY3, MANIKANTAN AMBIKA CHITHRA1, MAHESWARI PRIYA RANI4, VARUGHESE GEORGE1, and PALPU PUSHPANGADAN1 Amity Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India

1

Naturæ Scientific, Kerala University Business Innovation and Incubation Centre, Karyavattom Campus, Thiruvananthapuram 695581, Kerala, India

2

Department of Biotechnology, Malankara Catholic College, Kanyakumari 629153, Tamil Nadu, India

3

Phytochemistry and Pharmacology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram 695562, Kerala, India

4

Corresponding author. E-mail: [email protected]

*

ABSTRACT Trichopus zeylanicus Gaertn. is a perennial herb, belongs to the family Dioscoreaceae. It is endemic and mainly seen in the evergreen and semi-evergreen forests. It is found in the Southern Western Ghats of peninsular India. The Kani tribe of the Southern Western Ghats region of India traditionally uses this plant as an anti-fatigue and stamina-boosting herbal drug. Preliminary chemical investigations have resulted in the identification of glycolipids, flavonoids, Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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chromones, etc. from the aerial parts. Scientific investigations into the tribal therapeutic claims of this plant have resulted in the finding of this plant as an adaptogenic, antifatigue, immunoenhancing, cardioprotective, anticancer, antidiabetic, hepatoprotective, antinociceptive, and anti-inflammatory. 33.1

INTRODUCTION

Trichopus zeylanicus Gaertn. (Syn.: Podianthus arifolius Schnizl., Steireya angustifolia (Lindl.) Raf., Steireya cordata (Lindl.) Raf., Steireya media Raf., Trichopodium angustifolium Lindl., Trichopodium cordatum Lindl., Trichopodium intermedium Lindl., Trichopodium travancoricum Bedd., Trichopodium zeylanicum (Gaertn.) Thwaites, Trichopus malayanus Ridl., Trichopus zeylanicus subsp. angustifolius (Lindl.) Sivar., Pushp. & P.K.R. Kumar) belongs to the family Dioscoreaceae. Kani tribe of Southern Western Ghats region of India traditionally are using this plant as an antifatigue and stamina-boosting herbal drug. Despite the fact that the plant is not mentioned in classical Ayurveda, it has been tentatively equated as Varahi, a group of divine drugs by Ayurvedic scholars. Kani tribes claim that by eating the fruits of T. zeylanicus, one can go days without eating and yet be active and perform even very strenuous physical work or exercise. Another claim was that eating fresh fruits of T. zeylanicus on a daily basis can keep you healthy, agile, young, and immune to different ailments and infections (Pushpangadan et al., 1988). The drug Jeevani is a formulation containing T. zeylanicus as a major component and has been in the market since 1996 (Anilkumar et al., 2002; George et al., 2016). It is a perennial herb, rhizome slender. Leaves ovate-lanceolate, acute or obtuse, apiculate, base deeply cordate, to 12 × 7 cm; five to sevenribbed, petiole to 5 cm. Flowers fascicled at the base of the petiole. Perianth dark brown, campanulate, lobes lanceolate. Stamens 6, anthers apiculate. Fruit triquetrous, purple-brown; seeds dorsally grooved. It is endemic and mainly seen in the evergreen and semi-evergreen forests (Sivarajan et al., 1990; Anilkumar et al., 2002; Sasidharan, 2004, 2012; Pushpangadan et al., 2016). The plant is distributed in the southern Western Ghats of peninsular India at altitudes to an elevation of 1100 m. Locally, it is also known as saasthankizhangu, arogyapacha (Malayalam), arogyapachai, arogyapachilai (Tamil) and ginseng of Kerala, ginseng of Kani tribe (English) (Sasidharan, 2004, 2012; Pushpangadan et al., 2016; George et al., 2016). 33.2

PHYTOCHEMICAL CONSTITUENTS

It is reported that the seeds and leaf extracts of T. zeylanicus are rich in saponins and the leaves also contain flavonoids, glycosides, and some other

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nonsteroidal constituents. Chacko et al. (2002) isolated 6-acetyl-7-hydroxy, 8-methoxy-2,2-dimethyl-3,4-dihydro-1H-1-benzopyran; β-sitosterol; triacontanol; apigenin-8-C-glucoside (vitexin) and apigenin-6,8-di-C-glucoside (vicenin-2) from the aerial parts of T. zeylanicus (Chacko et al., 2002).

33.3 PHARMACOLOGICAL STUDIES T. zeylanicus exhibited a diverse set of pharmacological activities, which are detailed below. 33.3.1 IMMUNOMODULATORY ACTIVITY Bachhav and Sambathkumar (2016) found that T. zeylanicus alkaloid fraction improved the percentage of neutrophils adherence to the nylon fiber in a dose-dependent manner (75, 150, and 300 mg/kg). The delayed type

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hypersensitivity reaction generated by sheep red blood cells was also potentiated by the alkaloid fraction. Administration of alkaloid fraction increased the white blood cells, red blood cells, and hemoglobin counts. The extract also prevented myelosuppression in cyclophosphamide (30 mg/kg)-induced mice. Pushpangadan et al. (1995) found that the Swiss albino mice treated with 0.5 mL of 2% T. zeylanicus water suspension for 7 days increased the number of thymocytes, white blood cells, lymphocyte production in the spleen, and macrophages in the peritoneal cavity. But there is no effect on hemoglobin content and body weight. Treatment with T. zeylanicus leaf inhibited antigen-induced degranulation of sensitized peritoneal mast cells in mice and also decreased the peritoneal exudate mast cell proportion (Subramoniam et al., 1999). 33.3.2 ANTITUMOR ACTIVITY Pushpangadan et al. (1995) found that the treatment of mice with 0.5 mL of 2% T. zeylanicus water suspension for 7 days before and 20 days after tumor induction with Ehrlich Ascitic carcinoma cells (0.5 million / mouse) significantly protected 60% of mice from tumor cell growth. 33.3.3 GASTROPROTECTIVE ACTIVITY Pushpangadan et al. (1995) found that the T. zeylanicus water suspension reduced the gastro-intestinal motility, tested by observing the movement of charcoal (5% suspension of finely ground charcoal in 50% gum acacia) as a marker. At a higher dose (1 mL/mouse) there was about 30% decrease in the movement of charcoal whereas at a lower dose (0.5 mL/mouse) there was a slight decrease. 33.3.4 ANTIOXIDANT ACTIVITY There is an improved liver mitochondrial antioxidant status observed in aged BALB/c mice treated with T. zeylanicus extract (50 and 250 mg/kg). Up on treatment with the extract, level of glutathione, superoxide dismutase, and catalase were increased and level of malondialdehyde was decreased. T. zeylanicus extract also showed significant free radical scavenging (2,2-diphenyll-picrylhydrazil and 2, 2′-azinobis [3-ethylbenzothiazolin-6-sulphonic

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acid]), ferric reducing antioxidant power, and antilipid peroxidation activities (Cherian et al., 2009). Tharakan et al. (2005) also studied the antioxidant properties of T. zeylanicus. 33.3.5 ANTIFATIGUE ACTIVITY The whole plant powder of T. zeylanicus at doses of 250 and 500 mg/kg showed antifatigue property in young Sprague-Dawley rats up on forced swim test. In aged mutant and normal mice, oral administration of T. zeylanicus at a dose of 500 mg/kg for 2 weeks considerably enhanced mobility time and dramatically increased swim time (Tharakan et al., 2005, 2006). Pushpangadan et al. (1995) found that the methanol and acetone extracts (200 mg/kg) of T. zeylanicus showed 54 and 40%, respective increase in the swimming performance as compared to control group. T. zeylanicus administration raised the corticosterone level in male albino mice, and the physical endurance (survival time) of swimming was also increased (Singh et al., 2000). 33.3.6

CARDIOPROTECTIVE ACTIVITY

Pretreatment with T. zeylanicus leaves at a dose of 500 mg/kg for 28 days significantly prevented the isoproterenol-induced cardiac alterations in Wistar rats. T. zeylanicus improved the reduction in cardiac markers, elevated lipid peroxidation, and decreased glutathione level (Velavan et al., 2009). 33.3.7 ANTIDIABETIC ACTIVITY Rajan et al. (2015) found that the ethanolic extract of T. zeylanicus leaves (400 mg/kg, 15 days) significantly lowered the blood glucose in streptozotocininduced diabetic rats. 33.3.8 ADAPTOGENIC ACTIVITY Rishikesh et al. (2012) found that the saponin fraction of T. zeylanicus at a dosage of 75, 150, and 300 mg/kg has shown promising anxiolytic and antidepressant activities in mice. Sharma et al. (1989) found that T. zeylanicus at a dose of 100 mg/kg possess potent antistress properties as tested in rats and mice using a variety of stress models. The glyco-peptido-lipid fraction (12.5–100 mg/kg) obtained from the alcoholic extract of T. zeylanicus

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showed adaptogenic activity in mice (Singh et al., 2001, 2005). The glycopeptido-lipid fraction also exhibited significant antistress activity in various stress-induced models tested. Sharma et al. (1989) found the adaptogenic and antistress properties of ethanolic extract of T. zeylanicus seed (100 and 200 mg/kg) and fresh seed paste suspension (100, 200 and 300 mg/kg) in rodent models. The alcohol extract of T. zeylanicus leaves (100 mg/kg) decreased plasma glucose levels (1 h after the administration) and increased the swimming performance of mice. In resting mice, the extract (100 mg/kg) reduced the plasma glucose level and elevated the free fatty acid content, and there is no significant change in the levels of pyruvic acid and lactic acid. In comparison with the control group, the extract treated group showed higher level of glucose and reduced levels of free fatty acid, lactic acid and pyruvic acid after 90 min swimming performance (Evans et al., 2001). 33.3.9 HEPATOPROTECTIVE ACTIVITY The alcoholic extract of seed, leaf and rhizome of T. zeylanicus showed potent hepatoprotective activity in different animal models (Pushpangadan et al., 1995). The methanol extract (100 mg/kg) and leaf suspension (1000 mg/kg, wet weight) of T. zeylanicus showed potent antihepatotoxic effect against paracetamol induced toxicity in rats (Subramoniam et al., 1998). 33.3.10 APHRODISIAC PROPERTY In male mice, administration of ethanolic leaf extract of T. zeylanicus enhanced sexual behavior, as demonstrated by an increase in the number of mounts and mating performance (Subramoniam et al., 1997). A single dose of 200 mg/kg orally administered was found to be effective, and daily dosing for 6 days was more effective. All the pups delivered are found to be normal with reference to foetal growth, litter size and sex ratio, after mating with extract treated male mice. 33.3.11 ANTINOCICEPTIVE AND ANTI-INFLAMMATORY ACTIVITIES Kumar et al. (2012) found that the alkaloid fraction of T. zeylanicus (75, 150, and 300 mg/kg) dose dependently inhibited the acetic acid induced

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writhing in mice and increased the mean baseline reaction time in the hot plate analgesic method. Further, the alkaloid fraction of T. zeylanicus (75, 150, and 300 mg/kg) significantly decreased the paw edema volume and granulomatous tissue weight in carrageenan and cotton pellet-induced inflammatory models. 33.3.12 TOXICITY STUDIES There is no mortality observed in mice after 72 h of treatment with 3 g/ kg body weight of T. zeylanicus seed extract. However, a dose of 4 g/kg produced 10% mortality after 48 h (Sharma et al., 1989). The alkaloid fraction of T. zeylanicus obtained from methanolic extract up to the dose of 2000 mg /kg b.w. p.o. did not show any mortality or toxicity (Kumar et al., 2012). It was observed that ethanolic extract of T. zeylanicus leaves was nontoxic up to 5 g/kg body weight (Rajan et al., 2015). ACKNOWLEDGMENTS The authors express their sincere thanks to Dr. Ashok K. Chauhan, Founder President, Ritnand Balved Education Foundation (RBEF) and Amity Group of Institutions, and Dr. Atul Chauhan, Chancellor, Amity University Uttar Pradesh (AUUP) for facilitating this work. Thadiyan Parambil Ijinu is receiving Young Scientist Fellowship from the Department of Science and Technology, Government of India (SP/YO/413/2018). KEYWORDS • • • • • •

traditional medicinal use arogyapacha Kani tribe antifatigue stamina-boosting adaptogenic

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REFERENCES Anilkumar, E. S.; Dan, M.; Navas, M.; Rajasekharan, S.; Pushpangadan, P. Pharmacognostic Studies on Trichopus zeylanicus ssp. travancoricus. J. Trop. Med. Plants. 2002, 3, 239–245. Bachhav, R. S.; Kumar R. S. Evaluation of Immunomodulatory Activity of the Alkaloid Fraction of Trichopus zeylanicus Gaertn on Experimental Animals. Indian J. Pharm. Sci. 2016, 78, 161–166. Chacko, S.; Sethuraman, M. G.; George, V.; Pushpangadan, P. Phytochemical Constituents of Trichopus zeylanicus ssp. travancoricus. J. Med. Aromat. Plant Sci. 2002, 24, 703–706. Cherian, E.; Sudheesh, N. P.; Janardhanan, K. K.; Patani, G. Free-Radical Scavenging and Mitochondrial Antioxidant Activities of Keishi—Ganoderma lucidum (Curt: Fr) P. Karst and Arogyapacha—Trichopus zeylanicus Gaertn extracts. J. Basic Clin. Physiol. Pharmacol. 2009, 20, 289–307. Evans, D. A.; Subramoniam, A.; Rajasekharan, S.; Pushpangadan, P. Effect of Trichopus zeylanicus Leaf Extract on the Energy Metabolism in Mice During Exercise and at Rest. Indian J. Pharmacol. 2001, 34, 32–37. George, V.; Ijinu, T. P.; Chithra, M. A.; Pushpangadan, P. Can Local Health Traditions and Tribal Medicines Strengthen Ayurveda? Case Study 2. Trichopus zeylanicus ssp. travancoricus Burkill ex Narayanan. J. Trad. Folk Practices. 2016, 4, 3–16. Kumar R. S.; Perumal, P.; Shankar, B. R. Antinociceptive and Anti-Inflammatory Activity of Alkaloid Fraction of Trichopus zeylanicus Gaertn. Int. J. Pharm. Pharm. Sci. 2012, 4, 632–635. Pushpangadan, P.; George, V.; Sreedevi, P.; Ijinu, T. P.; Anzar, S.; Bincy, A. J. Plants for Health and Nutritional Security; Amity Institute for Herbal and Biotech Product Development, Thiruvananthapuram, India, 2016; pp 427–429. Pushpangadan, P.; Rajasekharan, S.; Ratheshkumar, P. K.; Jawahar, C. R.; Velayudhan Nair, V.; Lakshmi, N.; Sarada Amma, L. ‘Arogyappacha’ (Trichopus zeylanicus Gaertn), the ‘Ginseng’ of Kani Tribes of Agashyar Hills (Kerala) for Ever Green Health and Vitality. Anc. Sci. Life. 1988, 8, 13–16. Pushpangadan, P.; Rajasekharan, S.; Subramaniam, A.; Latha, P. G.; Evans, D. A.; Valsa Raj, R. Further on the Pharmacology of Trichopus zeylanicus. Anc. Sci. Life. 1995, 14, 127–135. Rajan, S. T.; Velmurugan, V.; Arunkumar, S. Antidiabetic Activity of Ethanolic Extract of Trichopus zeylanicus in Streptozotocin Induced Diabetic Rats. World J. Pharm. Sci. 2015, 4, 734–740. Rishikesh, B.; Kumar R. S.; Perumal, P. Anxiolytic and Antidepressant Activity of Saponin Fraction of Trichopus zeylanicus Gaertn, in Mice. Int. J. Phytopharmacol. 2012, 3, 1–6. Sasidharan, N. Biodiversity Documentation for Kerala, Part 6: Flowering Plants; Kerala Forest Research Institute: Kerala, India, 2004. Sasidharan, N. Flowering Plants of Kerala, Ver. 2.0 (DVD), Serial Number 698329520, Kerala Forest Research Institute: Thrissur, Kerala, India, 2012. Sharma, A. K.; Pushpangadan, P.; Chopra, C. L. Adaptogenic Activity of Seeds of Trichopus zeylanicus Gaertn, the Ginseng of Kerala. Anc. Sci. Life. 1989, 8, 212–219. Singh, A.; Saxena, E.; Bhutani, K. K. Adrenocorticosterone Alterations in Male, Albino Mice Treated with Trichopus zeylanicus, Withania somnifera and Panax ginseng Preparations. Phytother. Res. 2000, 14, 122–125.

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Singh, B.; Chandan, B. K.; Sharma, N.; Singh, S.; Khajuria, A.; Gupta, D. K. Adaptogenic Activity of Glyco-Peptido-Lipid Fraction from the Alcoholic Extract of Trichopus zeylanicus Gaerten (Part II). Phytomedicine 2005, 12, 468–481. Singh, B.; Gupta, D. K.; Chandan, B. K. Adaptogenic Activity of a Glyco-Peptido-Lipid Fraction from the Alcoholic Extract of Trichopus zeylanicus Gaertn. Phytomedicine. 2001, 8, 283–291. Sivarajan, V. V.; Pushpangadan, P.; Ratheesh Kumar, P. K. A Revision of Trichopus (Trichopodaceae). Kew Bull. 1990, 45, 353–360. Subramoniam, A.; Evans, D. A.; Rajasekharan, S.; Pushpangadan, P. Hepatoprotective Activity of Trichopus zeylanicus Extract Against Paracetamol Induced Hepatic Damage in Rats. Indian J. Exp. Biol. 1998, 36, 385–389. Subramoniam, A.; Evans, D. A.; Valsaraj, R.; Rajasekharan, S.; Pushpangadan, P. Inhibition of Antigen-Induced Degranulation of Sensitized Mast Cells by Trichopus zeylanicus in Mice and Rats. J. Ethnopharmacol. 1999, 68, 137–143. Subramoniam, A.; Madhavachandran, V.; Rajasekharan, S.; Pushpangadan, P. Aphrodisiac Property of Trichopus zeylanicus Extract in Male Mice. J. Ethnopharmacol. 1997, 57, 21–27. Tharakan, B.; Dhanasekaran, M.; Brown-Borg, H. M.; Manyam, B. V. Trichopus zeylanicus Combats Fatigue Without Amphetamine-Mimetic Activity. Phytother. Res. 2006, 20, 165–168. Tharakan, B.; Dhanasekaran, M.; Manyam, B. V. Antioxidant and DNA Protecting Properties of Anti-Fatigue Herb Trichopus zeylanicus. Phytother. Res. 2005, 19, 669–673. Velavan, S.; Selvarani, S.; Adhithan, A. Cardioprotective Effect of Trichopus zeylanicus Against Myocardial Ischemia Induced by Isoproterenol in Rats. Bangladesh J. Pharmacol. 2009, 4, 88–91.

CHAPTER 34

Pharmacological Activities of Manilkara hexandra (Roxb.) Dubard: A Comprehensive Review NEHA MISHRA1, YASHASWANI CHOUHAN2, EKTA MENGHANI2, and ARVIND PAREEK3* Vardhman Mahaveer Open University, Kota 324010, India

1

Department of Biotechnology, JECRC University, Jaipur 303905, India

2

Maharshi Dayanand Saraswati University, Ajmer 305009, India

3

Corresponding author. E-mail: [email protected]

*

ABSTRACT An evergreen tree species in the Sapotaceae family, Manilkara hexandra (Roxb.) Dubard, has a long history of traditional medicinal applications in south Asia, particularly in western and central India. The plant has long been used as a remedy for a variety of illnesses, including arthritis, bronchitis, jaundice, ulitis, fever, hyperdypsia, and gastrointestinal ailments. According to a review of the literature, this plant’s extracts and metabolites have antiinflammatory, antiulcer, aphrodisiac, alexipharmic, anthelmintic, antibacterial, and free radical scavenging activities. This species has yielded a variety of chemical substances that have been isolated, including sterols, starches, terpenoids, anthraquinone glycoside, cardiac glycoside, saponin, and tannins. The information on the pharmacological properties of M. hexandra is compiled in the review that is being given.

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INTRODUCTION

Manilkara hexandra (Roxb.) Dubard. is a plant of family Sapotaceae. This plant is known for its medicinal properties. Synonyms of this plant include Mimusops hexandra Roxb. and Manilkara emarginata H. J. Lam. It is a socioeconomic important species of India (Malik et al., 2012; Mishra and Pareek, 2014). This evergreen plant grows in tropical and temperate forests of India and is a comparatively slow growing plant. It is a native of South Asian region. Its common name in English is Obtuse Leaved Mimusops while in Hindi this plant is known as Khirni and Rayan. Tamil people called this Ulakkaippalai and Palai. In Telugu this plant is called Patla, Pola, and Kirni. In old Sanskrit texts this plant is mentioned as Rajadanah (Nambiar and Warrier, 2002). Presence of milky sap and reddish-brown hairs on plant surfaces are characteristic features of family Sapotaceae. M. hexandra is a tall tree having black-gray bark that is deeply furrowed. Plant has oblong or elliptic leaves that are glabrous and dark green in color. Flowers are bisexual, white, calyx 6-lobed, corolla 16 or 24-lobed in two or three series, stamens 6, ovary 12-celled and hairy; fruit berry, ovoid shape, shining yellow, and one-seeded which is endospermic seed. Its oily seeds have light brown or blackish seed coats. Bark, leaves, and fruits contain sticky and white latex (Gopalkrishnan et al., 2017). Flowering occurs in the month of October to December and fruiting occurs during April–May (Dwivedi and Bajpai, 1974). 34.1.1

ETHNO-MEDICINAL USES

M. hexandra found a natural wild plant of India. In Rajasthan, Gujarat, Madhya Pradesh, and Maharashtra it is most common (Malik et al., 2012). In Western and central India this plant has been used as one of the important medicinal plants for a long time. Ripened fresh and sweet fruits of M. hexandra are of high economic value and also a good source of minerals, sugars, proteins, carbohydrates, and vitamin A (Nautiyal, 2013). For the treatment of ailments like helminthiasis colic dyspepsia, odontopathy, common fever, hyper dyspepsia, jaundice, and burning sensation M. hexandra is used in traditional medicinal herbal drugs (Goswami and Ram, 2017). To cure some of the digestive disorders its fruit pulp is used (Patil and Patil, 2012). It is also useful for arthritis and jaundice, heat burning, and wormicide (Bakare, 2014). In few districts of Madhya Pradesh (Ratlam,

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Dhar, Jhabua, and Khargone) and surrounding states like Rajasthan, Maharashtra, and Gujarat, Bhils are inhabitants with large number and they utilize bark of M. hexandra as remedy of various ailments (Meeta and Jindal, 1994). 34.2

BIOACTIVES

A number of phytochemicals have been extracted and isolated from various plant parts of M. hexandra. Mishra and Pareek (2018) observed that the plant contains rich contents of carbohydrate and protein via quantitative analysis of extracts from bark and leaf of M. hexandra. Secondary metabolites, namely, sterols, alkaloids, and flavonoids were identified in extracts of both leaf and bark using the technique thin-layer chromatography (TLC). Presence of sterols, volatile oil, tannin, cinnamic acid, hentriacontane, triterpene ketone, triterpenic hydrocarbon, taraxerol, and quercitol in leaves of M. hexandra was observed by Madhak et al. (2013). Monisha and Vimala (2018) reported phytoactive compounds in its stem bark and isolated flavan-3-ol. The triterpene acid isolated from the mesocarp of fruit also recognized as ursolic acid. Cinnamic acid ester of α- and β-amyrins along with taraxerol, α-spinasterol, quercitol, and β-d-glucoside of β-sitosterol from the roots were isolated by Misra and Mitra (1968). Presence of cinnamic acid, quercitol, taraxerol, and hentriacontane was also reported in aqueous and alcoholic extracts of leaves (Misra and Mitra, 1968). Presence of a triterpene ketone, taraxerol, alpha and beta-amyrin, cinnamates, alpha-sipnasterol, beta-sitosterol, its beta-D-glucoside, quercitol, quercetin and its dihydro derivatives and ursolic acid was also observed from various parts of the plant (Mitra and Misra, 1965; Misra and Mitra, 1966, 1968). Srivastava and Singh (1994) isolated a triterpenoid saponin, 1β 2α, 3β, 19α-tetrahydroxyursolic acid 28-O-β-D-glucopyranoside along with β-sitosterol were also reported in the stem bark of this plant. They also elucidated their structures on the basis of chemical and spectral evidence. The unsaponifiable lipids, triterpene alcohols, and sterols were also investigated from seed oil of M. hexandra by gas liquid chromatography. Some seed oils contained large amounts of α-amyrin, β-amyrin, and cycloartenol (Saeed et al., 2010, Annamalai et al., 2018). The chemical analysis of fresh fruits showed that it is a rich source of proteins, lipids and carbohydrates (Daripkar and Jadhav, 2010). Misra et al. (1974) proved the presence of esters of fatty acid and some triterpene alcohols in fruit pulp, which was first ever reported from the family Sapotaceae. Three known phenolic compounds quercetin, myrecetin, and gallic acid were reported for the first time from M. hexandra.

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The structure elucidation of the isolated saponins has been determined by using spectral techniques. The acetone fraction with crude saponin mixture has a significant anti-inflammatory effect (Eskander et al., 2013). 34.3

PHARMACOLOGY

34.3.1 ANTIMICROBIAL ACTIVITY Leaf extracts of M. hexendra in various solvents have been tested against different bacteria (Gram positive and Negative both) as well as in yeasts and moulds also. These extracts exhibited antimicrobial potency. These antimicrobial studies were performed using the agar disc diffusion method (Chanda and Parekh, 2010, 2014; Sisodiya and Shrivastava, 2018). Chanda and Parekh (2010, 2014), concluded that among three extracts of leaf, methanol extract showed higher antimicrobial activity than the acetone extract. The antimicrobial activity was better at higher concentration, that is, 500 μg/disc. The MIC range was from 250 to 32,000 μg/mL. In a different set of experiments they observed that methanolic extract showed maximum antimicrobial potency (Chanda and Parekh, 2010, 2014). In the study conducted by Sisodiya and Shrivastava (2018), MIC range was 25–100 mg/mL. Antibacterial potency of M. hexandra leaf extracts in a gel was carried out against strains of Klebsiella pneumoniae, Enterobacter aerogenes, E. coli, Proteus mirabilis, and P. vulgaris. It was found to have better stability and antibacterial potency (Pingiliet al., 2018). Patel et al. (2015) observed antibacterial activity in the seed extract of M. hexandra. They reported significant bactericidal activity against Streptococcus mutans. 34.3.2 ANTIFERTILITY ACTIVITY Seeds of M. hexandra have been evaluated for its antifertility properties in male albino rats. It was also proved that extracts of seed markedly decreased the sperm count of the albino rats. Manilkara hexandra seed concentrate caused decline in weight of testicles, epididymis, fundamental vesicle, vas deferens, and ventral prostate that might be because of low plasma level of testosterone caused by seed extracts of this plant (Devangi and Gopalkrishan, 2016). 34.3.3 ANTIOXIDANT ACTIVITY Parikh and Patel (2017) observed the antioxidant properties in methanolic extract of fruits and seeds of the plant. Six different assays, that is, FRAP,

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DPPHRSA, ABTSRSA, HRSA, and NORSA, were used for this study. They observed that fruits are a better source of antioxidants than the seeds. Presence of some phenolic compounds (gallic acid, kaempferol, quercetin, and vanillic acid), which have excellent antioxidant properties, was also reported in these fruits. In a different study antioxidant activity infractions of leaf extract of this plant were also observed (Dutta and Ray 2015). Monisha and Vimala (2019) extracted the flavan-3-ol from the stem of the plant and reported its antioxidant potential. 34.3.4 ANTIULCER ACTIVITY It was observed that the ethyl acetate extract of the M. hexendra significantly reduced the lipid peroxidation in experimental animals and also inhibited the increase in vascular permeability. It was also observed that the pretreatment of ethyl acetate extract significantly increases the production of mucus and elevates the level of glycoprotein when administered as there was an increase in the mucin contents (Shah et al., 2004). The maximum antiulcer activity was observed in ethyl acetate extract as it is responsible for decreasing gastric acid secretory activity and also strengthening the mucosal defence mechanisms (Modi et al., 2012; Shah et al., 2004). 34.3.5 ANTIDIABETIC PROPERTY Antidiabetic property of M. hexendra was observed in a study conducted by Dasi et al. (2016). Non-insulin-dependent diabetes mellitus (NIDDM) was induced for the time being in rodents by an intraperitoneal infusion. Ethanolic concentrate of M. hexandra was managed orally to these rodents and blood glucose level was surveyed. A noteworthy decrease in the blood glucose level was observed. Similar findings were there in histopathological assessment also. 34.3.6 ANTI–INFLAMMATORY/ IMMUNOMODULATORY EFFECT Crude polysaccharides were extracted from the bark of M. hexandra to evaluate stimulating effects of polysaccharides on immune system and it was found that the polysaccharides from M. hexandra bark stimulate the immune activity as it has a stimulating effect on macrophage function (Gomathi,

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2012). Treatment of macrophages by plant polysaccharides was also reported to modulate expression of various cell surface receptors that recognize plant polysaccharides. Eskander et al. (2013) observed that acetone fraction of this plant with crude saponin mixture has significant anti-inflammatory activity. KEYWORDS • • • • •

Manilkara hexandra Sapotaceae medicinal properties phytochemical constituents pharmacological activities

REFERENCES Annamalai, T.; Ganadoss, J. J.; Manikandan, A.; Prince, A. A. M. Secondary Metabolites from the Plant Manilkara hexandra Roxb. Intern. J. Green Herbal Chem. 2018, 7 (4), 715–724. Bakare, S. S. Ethnomedicinal Plants Diversity Around Nawargaon Village of Chandrapur District, Maharashtra, India. Wkly. Sci. Res. J. 2014, 1 (24), 1–10. Chanda, S.; Parekh, J. Assessment of Antimicrobial Potential of Manilkara hexandra. Pharmacogn. J. 2010, 2 (12), 448–455. Chanda, S.; Parekh, J: Antimicrobial Potential of Manilkara hexandra leaf. World J. Pharm. Pharma. Sci. 2014, 3 (2), 2503–2511. Daripkar, N.; Jadhav, B. L. Technology Development for Ethanol Production from the Wild Fruits of Mimusops hexandra. Res. J. Biotechnol. 2010, 5 (3), 63–67. Dasi, T.; Das, B.; Saha, B.; Bhushan, M. S. Anti-Hyperglycemic Activity of Hydro-Alcoholic Bark Extract of Manilkara hexandra (Roxb.) in Streptozotocin Induced Diabetic Rats. Intern. J. Pharm. Pharma. Sci. 2016, 8 (4), 185–188. Devangi, C.; Gopalkrishnan, B. Antifertility Activity of Manilkara hexandra (Roxb.) Dubard Seed Extract on Male Albino Rates. Intern. J. Appl. Biol. Pharmaceut. Technol. 2016, 7 (3), 71–76. Dutta, S.; Ray, S. Evaluation of In-Vitro Free Radical Scavenging Activity of Leaf Extracts Fractions of Manilkara hexandra (Roxb) Dubard in Relation to Total Phenolic Contents. Intern. J. Pharm. Pharma. Sci. 2015, 7 (10), 296–301. Dwivedi, R. M.; Bajpai, P. N. Studies on the Blossoms and Fruiting of Manilkara hexandra. Progress. Hortic. 1974, 6 (2/3), 17–20. Eskander, J.; Haggag, E.; El–Gindi, M.; Mohamedy, M. A Novel Saponin from Manilkara hexandra Seeds and Anti–Inflammatory Activity. Med. Chem. Res. 2013, 23 (2), 717–724.

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Gomathi, P.; Kumar, A.; Prameela, R.; Kishorekumar, K.; Gnananath, K. Stimulation of Immune System Function by Polysaccharides of Manilkara hexandra (Roxb.) Bark. Intern. J. Pharmaceut. Sci. 2012, 4 (3), 430–432. Goswami, H.; Ram, H. Ancient Food Habits Dictate That Food Can Be Medicine But Medicine Cannot Be “Food”!. Medicines 2017, 4 (4), 82–105. Madhak, S. A.; Savsani, J. D.; Pandya, D. J. Comparative Pharmacognostical and Phytochemical Study of Leaves of Different Species of Mimusops. Intern. J. Pharma. Sci. Res. 2013, 4 (3), 1074–1078. Malik, S.; Choudhary, R.; Kumar, S.; Dhariwal, O.; Deswal, R.; Chaudhury, R. Potential of Khirni [Manilkara hexandra (Roxb.) Dubard]: A Promising Underutilized Fruit Species of India. Genet. Resour. Crop Evol. 2012, 59 (6), 1255–1265. Meeta, M.; Jindal, K. Diseases of Ornamental Plants in India; Daya Publishing House: Delhi, 1994. Mishra, N.; Pareek, A. Phytochemical Analysis of Leaf and Bark Extracts of M. hexandra (Roxb.)—A Valuable Medicinal Plant. J. Phytolog. Res. 2018, 31 (1–2), 17–22. Mishra, N.; Pareek, A. Traditional Uses, Phytochemistry and Pharmacology of Mimusops hexandra Roxb. Adv. Pharma Ethnomed. 2014, 2 (2), 32–35. Misra, G.; Mitra, C. R. Mimusops hexandra–III. Constituents of Root, Leaves and Mesocarp. Phytochemistry 1968, 7 (12), 2173–2176. Misra, G.; Mitra, C. R.; Nigam, S. K. Studies on Mimusops spp. Planta Medica. 1974, 26 (6), 155–165. Misra, G.; Mitra, C. R.: Mimusops hexandra-II: Constituents of Bark and Seed. Phytochemistry 1966, 5 (3), 535–538. Mitra, C. R.; Misra, G: Mimusops hexandra-I: Constituents of Fruit and Seed. Phytochemistry 1965, 4 (2), 345–348. Modi, K. P.; Lahiri, S. K.; Goswami, S. S.; Santani, D. D.; Shah, M. B. Evaluation of Antiulcer Potential of Mimusops hexandra in Experimental Gastro Duodenal Ulcers. J. Complem. Integr. Med. 2012, 9 (1), 18–22. Monisha, S. I.; Vimala, J. R. Extraction, Identification and Pharmacological Evaluation of Phyto-Active Compound in Manilkara hexandra (Roxb.) Dubard Stem Bark. Biosci. Biotech. Res. Asia. 2018, 15 (3), 687–699. Monisha, S. I.; Vimala, J. R. Phytocompounds Investigation, Isolation of Flavan-3-ol from the Stem of Manilkara hexandra (Roxb.) Dubard and Its Potential in Antioxidant. Intern. J. Sci. Technol. Res. 2019, 8 (8), 1482–1488. Nambiar, V. P. K.; Warrier, P. K. Indian Medicinal Plants; Orient Longman: Madras, 2002. Nautiyal, S.; Rao, K.; Kaechele, H.; Raju, K.; Schaldach, R. Knowledge Systems of Societies for Adaptation and Mitigation of Impacts of Climate Change; Springer Science & Business Media: Berlin, 2013. Parikh, B.; Patel, V. H. Quantification of Phenolic Compounds and Antioxidant Capacity of an Underutilized Indian Fruit: Rayan [Manilkara hexandra (Roxb.) Dubard]. Food Sci. Human Wellness 2017, 6 (1), 10–19. Patel, K; Ali, A. K.; Nair, N; Kothari, V: In-Vitro Antibacterial Activity of Manilkara hexandra (Sapotaceae) Seed Extracts and Violacein Against Multidrug Resistant Streptococcus mutans. J. Natural Rem.2015, 15 (1), 1–11. Patil, K. J.; Patil, S. V. Biodiversity of Vulnerable and Endangered Plants from Jalgaon District of North Maharashtra. Asian J. Pharm. Life Sci. 2012, 2 (2), 144–150.

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Pingili, D.; Amminbavi, D.; Awasthi, A.; Khan, F. M. S. Formulation, Evaluation and In Vitro Antibacterial Screening of Herbal Gel Containing Manilkara hexandra (Roxb.) Dubard Leaf Extract. Int. J. Pharm. Sci. Res. 2018, 9 (2), 702–707. Saeecd, M. T.; Agarwal, R.; Khan, M. W. Y.; Salkind, N. J. Encyclopedia of Research Design; SAGE Publication: London, 2010 Shah, M. B.; Goswami, S. S.; Santani, D. D. Effect of Manilkara hexandra (Roxb.) Dubard Against Experimentally-Induced Gastric Ulcers. Phytother Res. 2004, 18 (10), 814–818. Sisodiya, D.; Shrivastava, P. Antimicrobial Activity of Euphorbia thymifolia and Manilkara hexandra (Roxb.). Intern. J. Curr. Adv. Res. 2018, 7 (2), 9660–9663. Srivastava, M.; Singh, J. A New Triterpenoid Saponin from Mimusops hexandra. Pharma. Biol. 1994, 32 (2), 197–200.

CHAPTER 35

Rhinacanthus nasutus (L.) Kurz: Prehistory to current uses to humankind JAYA PREETHI PEESA* and B. SIVA SAI KIRAN Department of Pharmaceutical Sciences, Krishna University, Machillipatnam, Andhra Pradesh, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Rhinacanthus nasutus (L.) Kurz, had made a pivotal role in phytopharmaceuticals from ancient times. It is an erect, much-branched shrub grows mostly in moist well-drained soils and plains. It was reported to contain napthoquinone (rhinacanthin), flavonoids, lignans, steroids and terpenoids. Rhinacanthins present in the roots of R. nasutus showed promising antimalarial activity. Rhinacanthin-C exhibited antidiabetic activity whereas, rhinacanthin- C, D and N showed anti-allergic activity. Phenols had antioxidant property. R. nasutus exhibited anti-proliferative, anti-viral, anti-microbial, anti-inflammatory, immunomodulatory, neuroprotection, hypolipidemic, and hepatoprotective activities. This objective of this chapter was to provide insights on the introduction, bioactive molecules and the pharmacology of R. nasutus. 35.1 INTRODUCTION Rhinacanthus nasutus (L.) Kurz, belonging to the family Acanthaceae, grows mostly in moist well-drained soils and plains of India, Java, Madagascar, and Sri Lanka. It is an erect, much-branched shrub of 2–3 m. Leaves are acute Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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at both ends, elliptic and crenulate, minutely pubescent, nerves 7–10 pairs. Cymes terminal, panicled. Flowers sessile; bracts and bracteoles similar, 2 mm long, hispid; five sepals, 5 mm long, linear-lanceolate, hispid; corolla white, tube 25 mm long, slender, hispid; upper lip entire, oblong, acuminate; lower lip broad, three-lobed, obtuse; stamens 2, inserted near the throat of the tube, equal; one anther lobe lower than other, glabrous; cell 2-ovuled, style slender. Capsule 2 cm long, clavate, with a lower solid slender stalk, glabrous; seeds 1 or 2 in each cell, rugose (Sasidharan, 2021). Synonyms include Rhinacanthus rottlerianus Nees., Justicia gendarussa Macrae ex Nees, Rhinacanthus osmospermus Bojer ex Nees, Justicia macilenta E.Mey., Rhinacanthus macilentus C.Presl, Justicia nasuta L., Pseuderanthemum connatum Lindau, Justicia odoratissima Bojer ex Nees, Justicia sylvatica Vahl, Justicia rottleriana Wall., Justicia silvatica Nees. It is commonly known as Dainty Spurs, Snake Jasmine while vernacular names include Nagamalle (Telugu) Nagamalli, Uragamalli (Tamil), Gajkarni (Marathi), Yudhikaparni, Yoodhikaparni (Sanskrit), Vellakkurunji, Nagamulla, Puzhukkolli, Orukaalmudanthi, Purukolli, Pushpakedal (Malayalam), Doddapatike, Nagamallige (Kanada), and Juipana (Bengali). It has been used traditionally to treat eczema, herpes, ringworm, scurf, skin diseases, allergies, pulmonary tuberculosis, hepatitis, diabetes, and hypertension. Additionally, the leaves and root extract of Rhinacanthus nasutus were utilized in folklore as an antidote to the snake venom and detoxicant (Rao et al., 2013). 35.2

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Rhinacanthus nasutus was reported to contain anthraquinones, flavonoids, lignans, steroids, and terpenoids. Leaves and roots contain rhinacanthin-A, B, C, D, F, H, I, J, K, M, N, O, and P (Fig. 35.1) dihydroxy-a-lapachone, wogonin, p-hydroxy benzaldehyde, lupeol, methyl vanillate, oroxylin, syringaldehyde, praeruptorin, allantoin, 4-acetonyl-3,5-dimethoxy-p-quinol, 2-methylanthraquinone, β-amyrin, glutinol, lupeol, stigmasterol with sitosterol, stigmast-4-en-3-one with stigmasta-4,22-dien-3-one, stigmast-22-en3-one with stigmastan-3-one, 6β-hydroxystigmasta-4, 22-dien-3-one with 6β-hydroxystigmast-4-en-3-one, 2-methoxy-4-propionylphenol, methyl pheophorbide-a, umbelliferone, 2,6-dimethoxybenzoquinone, sitosterol-β-Dglucopyranoside, stigmasterol-β-D-glucopyranoside, 3,4-dimethoxyphenolβ-D-glucopyranoside, 3,4,5-trimethoxyphenol-β-D-glucopyranoside, syringic acid, vanillic acid, and methyl-a-D-galactopyranoside (Wu et al., 1988).

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(Continued)

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FIGURE 35.1 Rhinacanthin- C, D, F, H, I, K, N, and 2,6-dimethoxybenzoquinone structures.

By bioassay-directed fractionation of the methanolic extract of dried leaves and stem of Rhinacanthus nasutus, 4-acetonyl-3,5-dimethoxy-pquinol (Fig. 35.2) along with triterpenoids, anthraquinone, steroids, benzenoids, quinone, carbohydrate, glycosides, chlorophyll, and coumarin were isolated (Wu et al., 1995).

FIGURE 35.2

Structure of 4-acetonyl-3,5-dimethoxy-p-quinol.

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Two naphthoquinones, rhinacanthin-A, B and Q (Fig. 35.3), lupeol, β-sitosterol, stigmasterol, glucosides of stigmasterol, and β-sitosterol were isolated by bioassay-directed fractionation from the roots by methanolic extraction (Wu et al., 1998).

FIGURE 35.3

35.3

Structure of rhinacanthin-A, B, and Q.

PHARMACOLOGY

35.3.1 ANTIMALARIAL ACTIVITY Petroleum ether, methanolic and ethanolic root extract of Rhinacanthus nasutus were evaluated for larvicidal activity against late-third and earlyfourth instar larvae of Aedes aegypti, Anopheles dirus, Culex quinquefasciatus, and Mansonia uniformis. Petroleum ether extract showed promising activity against Aedes aegypti, Anopheles dirus, Culex quinquefasciatus, and Mansonia uniformis with LC50 values as 3.93, 7.91, 9.98, and 11.52 mg/L. Methanolic extract displayed potent activity against Aedes aegypti, Anopheles dirus, Culex quinquefasciatus, and Mansonia uniformis with LC50 values as 8.11, 14.51, 8.57, and 14.73 mg/L. But, significant activity was obtained from ethanolic extract against A aegypti with LC50 values as 16.04 mg/L (Komalamisra et al., 2005).

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Methanolic root extract of Rhinacanthus nasutus was formulated into tablets (5% and 10% concentration) by the wet granulation method using lactose, PVP, and stearic acid as the excipients. These tablets were evaluated for mosquito larvicidal activity against Aedes aegypti and Culex quinquefasciatus. Tablets of both concentrations showed similar larvicidal activity and they were also not toxic to male and female fish, Poecilia reticulata (Rongsriyam et al., 2006). Chloroform, ethyl acetate, methanolic, and petroleum ether extracts of R nasutus were tested against 5–6 days old adult Aedes aegypti and Culex quinquefasciatus female mosquitoes. Among these, ethanolic extract was most potent with LC50 and LC90 values 69.27, 73.47 ppm and 138.49 and 145.57 ppm, respectively, against Aedes aegypti and Culex quinquefasciatus (Jayapriya and Griselda, 2015). Rhinacanthin-B, C, D, E, G, N, Q, and H isolated from the whole plant of Rhinacanthus nasutus were evaluated for in-vitro CYP6AA3 and CYP6P7 inhibitory activity on benzyloxyresorufin-O-debenzylation; synergistic activity of rhinacanthins against CYP6AA3/ CYP6P7 inhibition and P450expressing Spodoptera frugiperda cells cypermethrin toxicity. Rhinacanthins successfully inhibited CYP6AA3 and CYP6P7 enzymes and revealed synergistic activity with cypermethrin toxicity (Kotewong et al., 2015). 35.3.2 ANTIDIABETIC ACTIVITY Methanolic leaves extract of Rhinacanthus nasutus 200 mg/kg daily for 30 days reestablished overall metabolism and liver functioning in streptozotocininduced diabetic rats by significantly reducing aspartate aminotransferase (AST), carbohydrate, protein, glycogen, and alanine aminotransferase (ALT) levels (Rao et al., 2013). Rhinacanthins-rich leaves extract from Rhinacanthus nasutus manifested noncompetitive α-glucosidase inhibitory activity with an IC50 value of 25 µg/mL and when combined with acarbose or rhinacanthin-C at low doses it exhibited a synergistic inhibitory effect (Shah et al., 2017). Rhinacanthins-rich extract of Rhinacanthus nasutus was evaluated for antidiabetic activity in nicotinamide-streptozotocin-induced diabetes. After 28 days of treatment, rhinacanthins-rich extract significantly lowered food intake, fasting blood glucose level, and HbA1c, whereas it increased insulin level and body weight of the animals. Extract also reestablished islets of langerhans and normalized the lipid, kidney, and liver profiles in the diabetesinduced rats (Shah et al., 2019).

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35.3.3 ANTI-ALLERGIC ACTIVITY

Rhinacanthin- C, D, and N isolated from the leaves of Rhinacanthus nasutus ethyl acetate extract were assessed for anti-allergic activity against antigeninduced β-hexosaminidase, TNF-a and IL-4 release in RBL-2H3 cells, and β-hexosaminidase inhibitory activity. All the three compounds showed promising anti-allergic properties on both the early-phase and the late-phase reactions because of octadienoic acid, benzodioxo carboxylic acid ester, and naphthalene carboxylic acid ester in their structures (Tewtrakul et al., 2009). 35.3.4 ANTIOXIDANT ACTIVITY Phenols from Rhinacanthus nasutus ethanolic root extract exhibited antioxidant activity by significantly inhibiting pro-inflammatory mediators (IFN-γ/ TNF-a) produced apoptosis in huma keratinocyte HaCaT cells (Thongrakard and Tencomnao, 2010). Ethanolic root extract of Rhinacanthus nasutus (0.1 and 10 µg/mL) has a protective effect via the activation of antioxidant pathways in HT-22 cells by significantly reducing the oxygen radical buildup. This activity was studied using MTT, trypan blue exclusion, LDH, and H2DCFDA assays. Hypoxia was induced in the study by the anaeropack method in HT-22 cells. Rhinacanthus nasutus, at higher concentrations, also showed cytoprotective, antiproliferative, and neuroprotective activity in HT-22 cells (Brimson and Tencomnao, 2011). Diabetes leads to excessive oxidative stress and was measured by glutathione peroxidase, lipid peroxidation, catalase, and superoxide dismutase levels in the liver. Rhinacanthus nasutus methanolic leaf extract (200 mg/ kg) exhibited a protective role in oxidative stress by the significant reduction of lipid peroxidation levels and significant increase in superoxide dismutase, glutathione peroxidase, and catalase levels than control (Rao et al., 2012). Rhinacanthus nasutus leaves ethanolic extract showed 92.58 GAE/mg of dry extract phenols. Ethanolic extract displayed a concentration-dependent manner of increasing DPPH and ABTS radical scavenging activity. Extract also exhibited antihemolytic activity with 77.88 ± 6.13% inhibition (Thephinlap et al., 2013). 35.3.5 ANTIPROLIFERATIVE ACTIVITY Rhinacanthin- A, B, C, D, G, H, I, K, M, N, and Q extracted from the roots of Rhinacanthus nasutus exhibited cytotoxic activity against P-388, A-549,

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HT-29, and HL-60 cell lines. Rhinacanthin- A, B, C, D, G, H, I, K, M, and wogonin displayed antiplatelet activity by significantly inhibiting the arachidonic acid-induced plasma platelet aggregation, whereas Rhinacanthin- A, B, C, and wogonin inhibited the collagen-induced plasma platelet aggregation (Wu et al.,1998). Rhinacanthus nasutus root extract (ethanolic) and leaves extract (aqueous) manifested in-vitro antiproliferative activity against HeLa, Hvr100-6, PC-3, and T24 cell lines and in-vivo using sarcoma 180-bearing mice (Gotoh et al., 2004). Rhinacanthin-M, N, and Q and 39 novel naphthoquinone esters were synthesized by esterification with benzoic or naphthoic acids as substituents and evaluated for cytotoxicity against KB, HeLa, and HepG2 cell lines. Among them, naphthoquinone esters with hydroxy group on C-3 and two methyl substituents on the C-2′ propyl chain of the esters showed promising cytotoxicity (Kongkathip et al., 2004). Rhinacanthin- C, N, and Q isolated from the roots of Rhinacanthus nasutus were formulated to liposomes and evaluated for in-vitro and in-vivo antiproliferative activity. All three compounds showed significant in-vitro antiproliferative activity against HeLaS3 cell lines, whereas rhinacanthin- N was potent in Meth-A sarcoma-bearing BALB/c mice (Siripong et al., 2006b). Aqueous and chloroform extract of Rhinacanthus nasutus was evaluated for in-vitro and in-vivo antiproliferative activity. Both the extracts showed notable activity against KB, Hep-2, MCF-7, HepG2, HeLa, SiHa, C-32, LLC, Colon-26, P388, and vero cell lines and Meth-A sarcoma-bearing BALB/c mice (Siripong et al., 2006a). Rhinacanthone isolated from the roots of Rhinacanthus nasutus showed significant in-vitro activity against HeLa cell lines by inhibiting the proliferation in a dose-dependent manner and induction of apoptosis through mitochondrial dependent signaling pathway manifested by the presence of inter-nucleosomal DNA fragmentation, chromatin condensation, externalization of annexin-V, and increase in the proportion of sub-G1 apoptotic cells (Siripong et al., 2009). Methanolic extract of the aerial parts and roots of Rhinacanthus nasutus were evaluated for antitumor activity by performing MTT assay. Among them, methanolic extract of the root proved potent. N-butanol fraction from the root (methanolic extract) triggered nitric oxide production by RAW264.7 cells and inhibited the lipopolysaccharide stimulated nitric oxide production. But, ethylacetate fraction inhibited NF-κB ligand (RANKL)-stimulated osteoclastogenesis of RAW264.7 cells (Horii et al., 2011).

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Rhinacanthin- C, G, N, Q, N, and rhinacanthone isolated from the roots of Rhinacanthus nasutus were evaluated for in-vitro antitumor activity by performing MTT assay. Among them, rhinacanthin- C showed promising tumor specificity by inhibiting the RANKL-stimulated osteoclastogenesis and did not influence either caspase-3 or internucleosomal DNA fragmentation activation, implicating non-apoptotic cell death (Horii et al., 2013). Rhinacanthin- C isolated from the roots of Rhinacanthus nasutus exhibited in-vitro anti-osteoclastogenic activity by the inhibition of RANKL-stimulated nuclear factor of activated T cells c1 expression and TRAF6-TAK1 complex formation, subsequently activating MAPKs/NF-κB. But, in-vivo reduced RANKL-induced osteoclast formation and bone resorption in calvaria of the experimental animals (Tomomura et al., 2015). 35.3.6 ANTIMICROBIAL ACTIVITY Naphthopyran isolated from Rhinacanthus nasutus (stems and leaves) displayed antifungal activity against Pyricularia oryzae by inhibiting the spore germination (Kodama et al., 1993). Ethanolic extract of leaves of Rhinacanthus nasutus demonstrated antifungal activity in a dose-dependent manner against Candida albicans and Tricophyton mentagorphytes and notable activity against Candida tropicalis and Candida parapsilosis. Ethanolic extract was also effective against grampositive bacteria (Bacillus cereus, Bacillus globigii, and Bacillus subtilis), whereas it was ineffective against gram-negative bacteria (Sattar et al., 2004). Prabakaran and Pugalvendhan (2009) reported that leaves ethanolic extract and aqueous extract exhibited antibacterial activity. They reported that the antibacterial activity of the extract showed better antibiotic disc than standard chloramphenicol. Rhinacanthins isolated from Rhinacanthus nasutus leaves (methanolic extract) exhibited potent antimicrobial activity by microdilution assay against Streptococcus mutans, Propionibacterium acnes, Helicobacter pylori, Staphylococcus aureus, and S. epidermidis, but it was inactive against Candida albicans. Rhinacanthins was stable for 1 week when exposed to light, stable for 8 weeks under accelerated stability conditions, and stable at pH 5.5 (Puttarak et al., 2010). Silver nanoparticles of Rhinacanthus nasutus leaf extract showed potential for in-vitro antimicrobial activity by the disc diffusion method against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa,

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Klebsiella pneumoniae, Escherichia coli, Aspergillus niger, and Aspergillus flavus with zone of inhibition values as 10.33, 8.33, 12.66, 13.33, 11.33, 9.66, and 12.66 mm (Rao et al., 2013). Rhinacanthus nasutus n-hexane extract (1000 μg/ml) displayed antibacterial activity against Micrococcus luteus, Escherichia coli, Klebsiella pneumoniae, and Bacillius licheniformis with 16, 17, 17, and 20 mm as zone of inhibition (Preethi et al., 2013). Ethanolic extract of the leaves of Rhinacanthus nasutus exhibited antifungal activity by acting on the cell wall of dermatophytes such as Trichophyton mentagrophytes var. mentagrophytes, Trichophyton mentagrophytes var. interdigitale, Trichophyton rubrum, Microsporum gypseum, and Microsporum canis. The extract showed a minimum inhibitory concentration of 136.6 mg/ml for all the above-specified species (Darah and Jain, 2001). 35.3.7 ANTIVIRAL ACTIVITY Rhinacanthin – C and D isolated from Rhinacanthus nasutus whole plant were evaluated for in-vitro antiviral activity using viral cytopathic effect assay, plaque-neutralization assay, and hemadsorption-inhibition assay. The results of the assay showed that both the compounds exhibited potent inhibitory activity against both murine and human strains of cytomegalovirus with EC50 values of 0.02 and 0.22 µg/mL, respectively. But, no activity was noticed against herpes simplex virus type-2, influenza A virus, and respiratory syncytial virus (Sendl et al., 1996). Rhinacanthin – E and F isolated from the aerial parts of Rhinacanthus nasutus were evaluated for antiviral activity using viral cytopathic effect assay and hemadsorption-inhibition assay. Both the isolated compounds demonstrated outstanding antiviral activity against influenza A virus by inhibiting the formation of the microtubule (Kernan et al., 1997). Trans O-coumaric acid, 2,3-bis[(4-hydroxy-3,5-dimethoxyphenyl) methyl]-1,4-butanediol, 2,4-dihydroxycinnamic acid, 3,4-dimethoxyphenylO-β-D-glucopyranoside, 8,8′-bisdihydrosiringenin glucoside, p-hydroxy phenethyl trans-ferulate, dehydrodiconiferyl alcohol-4-β-D-glucoside, and (-)-dehydrodiconiferyl alcohol were isolated from the methanolic extract of the branches and leaves of Rhinacanthus nasutus were evaluated for Neuraminidase inhibition using Amplex Red Neuraminidase Assay. Among them, 2,3-bis[(4-hydroxy-3,5-dimethoxyphenyl)methyl]-1,4-butanediol and 8,8′-bisdihydrosiringenin glucoside displayed significant activity with IC50 values as 30.7 ± 2.1 and 33.7 ± 5.3 μM (Kwak et al., 2018).

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Rhinacanthins- C, D, N, Q, and E, rhinacanthone, and heliobuphthalmin isolated from the roots of Rhinacanthus nasutus were in-vitro evaluated for antiviral activity against PR8, HRV1B, and CVB3-infected vero cells. Among them, rhinacanthins- C, D, N, and Q exhibited promising activity with IC50 values within the range from 0.03 to 23.7 μM (Ngoc et al, 2019). 35.3.8 ANTI-INFLAMMATORY ACTIVITY Rhinacanthus nasutus n-hexane extract (100 and 200 mg/kg) exhibited dosedependent anti-inflammatory activity by significantly inhibiting the paw volume of the right hind paw of the experimental animal in which inflammation is induced by the pholistic agent, carrageenan, and analgesic activity by the hot plate method, where the experimental animals (mice) showed increase in the resistance to nociceptive response (Preethi et al., 2013). 35.3.9 IMMUNOMODULATORY ACTIVITY Rhinacanthus nasutus leaves and stems (ethanol extract) alone and in combination with bacterial lipopolysaccharide (LPS) were studied on the immunomodulatory activity by the production of nitric oxide (NO) and tumor necrosis factor-a (TNF-a) in J774.2 mouse macrophages. Ethanol extract of Rhinacanthus nasutus alone had no effect on NO and TNF-a, but there is stimulation in production when administered along with LPS (Punturee et al., 2004). Water and ethanol extracts of Rhinacanthus nasutus exhibited its immune modulatory activity by significantly increasing the proliferation and production of IL-2 and TNF-α in human peripheral blood mononuclear cells. Rhinacanthus nasutus also displayed immunomodulatory activity on both nonspecific cellular and humoral immune responses by generating higher amounts of secondary antibodies against bovine serum albumin (Punturee et al., 2005). 35.3.10 NEUROPROTECTION Rhinacanthin isolated from the ethanolic extract of roots of Rhinacanthus nasutus exhibited promising neuroprotection activity by preventing amyloid β-peptide-induced toxicity in hippocampal neurons, whereas, in glia,

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reduced LPS-activated nitric oxide production inceased nitric oxide synthase expression and NF-κB signaling. Thereby, it can be used to treat Alzheimer’s disease (Chuang et al., 2017). 35.3.11 HYPOLIPIDEMIC ACTIVITY Rhinacanthus nasutus dried leaves methanolic extract (200 mg/kg) was studied for hypolipidemic activity in streptozotocin-induced diabetes in experimental animals for 30 days. Post treatment, it was observed that the extract-treated animals showed significant reduction in serum total cholesterol, triglycerides, phospholipids, LDL, and increased HDL levels (Rao et al., 2011). 35.3.12 HEPATOPROTECTIVE ACTIVITY Suja et al. (2003) reported hepatoprotective effect of Rhinacanthus nasutus root extracts. KEYWORDS • • • • • •

Rhinacanthus nasutus Rhinacanthin hepatoprotective diabetes 4-acetonyl-3,5-dimethoxy-p-quinol immunomodulatory activity

REFERENCES Brimson, J. M.; Tencomnao, T. Rhinacanthus nasutus Protects Cultured Neuronal Cells Against Hypoxia Induced Cell Death. Molecules 2011, 16 (8), 6322–6338. Chuang, K. A.; Li, M. H.; Lin, N. H.; Chang, C. H.; Lu, I.; Pan, I.; Takahashi, T.; Perng, M. D.; Wen, S. F. Rhinacanthin C Alleviates Amyloid-β Fibrils’ Toxicity on Neurons and attenuates Neuroinflammation Triggered by LPS, amyloid-β, and Interferon-γ in Glial Cells. Oxidative. Med. Cell. Longev. 2017, 5414297.

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Darah, I.; Jain, K. Efficacy of the Rhinacanthus nasutus Nees Leaf Extract on Dermatophytes with Special Reference to Trichophyton mentagrophytes var. mentagrophytes and Microsporum canis. Nat. Prod. Sci. 2001, 7 (4), 114–119. Gotoh, A.; Sakaeda, T.; Kimura, T.; Shirakawa, T.; Wada, Y.; Wada, A.; Kimachi, T.; Takemoto, Y.; Iida, A.; Iwakawa, S.; Hirai, M.; Tomita, H.; Okamura, N.; Nakamura, T.; Okumura, K. Antiproliferative Activity of Rhinacanthus nasutus (L.) Kurz Extracts and the Active Moiety, Rhinacanthin C. Biol. Pharm. Bull. 2004, 27 (7), 1070–1074. Horii, H.; Suzuki, R.; Sakagami, H.; Tomomura, M.; Tomomura, A.; Shirataki, Y. New Biological Activities of Rhinacanthins from the Root of Rhinacanthus nasutus. Anticancer Res. 2013, 33 (2), 453–459. Horii, H.; Ueda, J.-Y.; Tamura, M.; Sakagami, H.; Tomomura, M.; Tomomura, A.; Shirataki, Y. New Biological Activity of Rhinacanthus nasutus Extracts. In Vivo. 2011, 25 (3), 367–373. Jayapriya, G.; Griselda, S. F. Adulticidal and Repellent Activities of Rhinacanthus nasutus Leaf Extracts Against Aedes aegypti Linn and Culex quinquefasciatus Say. J. Entomol. Zool. Stud. 2015, 3 (1), 154–9. Kernan, M. R.; Sendl, A.; Chen, J. L.; Jolad, S. D.; Blanc, P.; Murphy, J. T.; Stoddart, C. A.; Nanakorn, W.; Balick, M. J.; Rozhon, E. J. Two New Lignans with Activity Against Influenza Virus from the Medicinal Plant Rhinacanthus nasutus. J. Nat. Prod. 1997, 60 (6), 635–637. Kodama, O.; Ichikawa. H.; Akatsuka, T.; Santisopasri, V.; Kato, A.; Hayashi, Y. Isolation and Identification of an Antifungal Naphthopyran Derivative from Rhinacanthus nasutus. J. Nat. Prod. 1993, 56 (2), 292–294. Komalamisra, N.; Trongtokit, Y.; Rongsriyam, Y.; Apiwathnasorn, C. Screening for Larvicidal Activity in Some Thai Plants Against Four Mosquito Vector Species. Southeast Asian J. Trop. Med. Public Health. 2005, 36 (6), 1412. Kongkathip, N.; Luangkamin, S.; Kongkathip, B.; Sangma, C.; Grigg, R.; Kongsaeree, P.; Prabpai, S.; Pradidphol, N.; Piyaviriyagul, S.; Siripong, P. Synthesis of Novel Rhinacanthins and Related Anticancer Naphthoquinone Esters. J. Med. Chem. 2004, 47 (18), 4427–4438. Kotewong, R.; Pouyfung, P.; Duangkaew, P.; Prasopthum, A.; Rongnoparut, P. Synergy Between Rhinacanthins from Rhinacanthus nasutus in Inhibition Against Mosquito Cytochrome P450 Enzymes. Parasitol. Res. 2015, 114 (7), 2567–79. Kwak, H. J.; Park, S.; Kim, N.; Yoo, G.; Park, J. H.; Oh, Y.; Nhiem, N. X.; Kim, S. H. Neuraminidase Inhibitory Activity by Compounds Isolated from Aerial Parts of Rhinacanthus nasutus. Nat. Prod. Res. 2018, 32 (17), 1–5. Ngoc, T. M.; Phuong, N. T.; Khoi, N. M.; Park, S.; Kwak, H. J.; Nhiem, N. X.; Trang, B. T.; Tai, B. H.; Song, J. H.; Ko, H. J.; Kim, S. H. A New Naphthoquinone Analogue and Antiviral Constituents from the Root of Rhinacanthus nasutus. Nat. Prod. Res. 2019, 33 (3), 360–366. Prabakaran, G.; Pugalvendhan, R. Antibacterial Activity and Phytochemical Standardization of Rhinacanthus nasutus (White Crane). Recent Res. Sci. Technol. 2009, 1 (5), 199–201. Preethi, P. J.; Sree, K. B.; Sirisha, A.; Kumar, P.; Ruby, S.; Sivakumar, T. Isolation, Characterization of Rhinacanthus nasutus L. Kurz and Its Biological Evaluation. Res. Rev. A J. Pharmacol. 2013, 3 (1), 9–15. Punturee, K.; Wild, C. P.; Kasinrerk, W.; Vinitketkumnuen, U. Immunomodulatory Activities of Centella asiatica and Rhinacanthus nasutus Extracts. Asian. Pac. J. Cancer. Prev. 2005, 6 (3), 396–400.

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Punturee, K.; Wild, C. P.; Vinitketkumneun, U. Thai Medicinal Plants Modulate Nitric Oxide and Tumor Necrosis Factor-α in J774.2 Mouse Macrophages. J. Ethnopharmacol. 2004, 95 (2–3), 183–189. Puttarak, P.; Charoonratana, T.; Panichayupakaranant, P. Antimicrobial Activity and Stability of Rhinacanthins-Rich Rhinacanthus nasutus Extract. Phytomedicine 2010, 17 (5), 323–327. Rao, P. V.; Madhavi, K.; Naidu, M. D. Hypolipidemic Properties of Rhinacanthus nasutus in Streptozotocin Induced Diabetic Rats. J. Pharmacol. Toxicol. 2011, 6 (6), 589–595. Rao, P. V.; Sujana, P.; Vijayakanth, T.; Naidu, M. D. Rhinacanthus nasutus—Its Protective Role in Oxidative Stress and Antioxidant Status in Streptozotocin Induced Diabetic Rats. Asian Pacific J. Trop. Dis. 2012, 2 (4), 327–330. Rao, P. V.; Prasad, T. N. V. K. V.; Shiekh, R. A.; Balam, S. K.; Narasimhulu, G.; Reddy, C. S.; Rahman, I. A.; Gan, S. H. Biogenic Silver Nanoparticles Using Rhinacanthus nasutus Leaf Extract: Synthesis, Spectral Analysis, and Antimicrobial Studies. Int. J. Nanomed. 2013, 8, 3355–3364. Rongsriyam, T.; Trongtokit, Y.; Komalamisra, N.; Sinchaipanich, N.; Apiwathnasorn, C.; Mitrejet, A. Formulation of Tablets from the Crude Extract of Rhinacanthus nasutus (Thai Local Plant) Against Aedes aegypti and Culex quinquefasciatus Larvae: A Preliminary Study. Southeast Asian J. Trop. Med. Public Health 2006, 37 (2), 265–271. Sasidharan, D. Rhinacanthus nasutus (L.) Kuntze. [Online] India Biodiversity Portal, Species Page. https://indiabiodiversity.org/biodiv/species/show/230906 (accessed May 2, 2021). Sattar, M. A.; Abdullah, N. A.; Khan, A. H.; Noor, A. M. Evaluation of Anti-Fungal and AntiBacterial Activity of a Local Plant Rhinacanthus nasutus (L.). J. Biol. Sci. 2004, 4 (4), 498–500. Sendl, A.; Chen, J. L.; Jolad, S. D.; Stoddart, C.; Rozhon, E.; Kernan, M.; Nanakorn, W.; Balick, M. Two New Naphthoquinones with Antiviral Activity from Rhinacanthus nasutus. J. Nat. Prod. 1996, 59 (8), 808–811. Shah, M. A.; Khalil, R.; Ul-Haq, Z.; Panichayupakaranant, P. α-Glucosidase Inhibitory Effect of Rhinacanthins-Rich Extract from Rhinacanthus nasutus Leaf and Synergistic Effect in Combination with Acarbose. J. Funct. Foods. 2017, 1 (36), 325–31. Shah, M. A.; Reanmongkol, W.; Radenahmad, N.; Khalil, R.; Ul-Haq, Z.; Panichayupakaranant, P. Anti-hyperglycemic and Anti-Hyperlipidemic Effects of Rhinacanthins-Rich Extract from Rhinacanthus nasutus Leaves in Nicotinamide-Streptozotocin Induced Diabetic Rats. Biomed. Pharmacother. 2019, 113, 108702. Siripong, P.; Hahnvajanawong, C.; Yahuafai, J.; Piyaviriyakul, S.; Kanokmedhakul, K.; Kongkathip, N.; Ruchirawat, S.; Oku, N. Induction of Apoptosis by Rhinacanthone Isolated from Rhinacanthus nasutus Roots in Human Cervical Carcinoma Cells. Biol. Pharm. Bull. 2009, 32 (7), 1251–1260. Siripong, P.; Kanokmedakul, K.; Piyaviriyagul, S.; Yahuafai, J.; Chanpai, R.; Ruchirawat, S.; Oku, N. Antiproliferative Naphthoquinone Esters from Rhinacanthus nasutus Kurz. Roots on Various Cancer Cells. J. Trad. Med. 2006a, 23, 166–172. Siripong, P.; Yahuafai, J.; Shimizu, K.; Ichikawa, K.; Yonezawa, S.; Asai, T.; Kanokmedakul, K.; Ruchirawat, S.; Oku, N. Antitumor Activity of Liposomal Naphthoquinone Esters Isolated from Thai Medicinal Plant: Rhinacanthus nasutus Kurz. Biol. Pharm. Bull. 2006b, 29 (11), 2279–2283.

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CHAPTER 36

Chemical Composition and Bioactivities of Great Mullein [Verbascum thapsus L. (Family: Scrophulariaceae)] SHREEDHAR S. OTARI and SAVALIRAM G. GHANE* Plant Physiology Laboratory, Department of Botany, Shivaji University,

Kolhapur, 416 004, Maharashtra, India

Corresponding author.

E-mail: [email protected]; [email protected]

*

ABSTRACT Verbascum thapsus L. (Family: Scrophulariaceae) is also known as Mullein. It is found along the roadside, meadows, or pasture lands. Verbascum is an annual or biennial, herbaceous, erect, stout weed. In the homoeopathic system of medicine, leaves are used to treat headache and its ointment found effective in curing burns. Oil collected from leaves used to treat wound healing, gastric problems, and skin infections. Active ingredients found in the various plant parts showed its significant ethnomedicinal potential. In phytoconstituents profiling, a variety of compounds produced by the plant include iridoid glycosides, sterones, sesquiterpenes, phenylethanoides, verbascosides, and lignan glycosides. These substances possess a variety of potent biological actions. It also exhibit antioxidant, antimicrobial, antihelminthic, antibacterial, antiviral, cytotoxic, and insecticidal properties. In the chapter, secondary metabolites, several bioactivities and traditional use of great Mullein is thoroughly discussed.

Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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INTRODUCTION

Verbascum thapsus L. is usually referred to as mullein and located in Asia, Europe, and North America. The plant is known by many synonyms viz. Leiosandra cuspidal Raf., Thapsus linnaei (Opiz) Opiz, Thapsus schraderi (G.Mey.) Opiz, Verbascum alatum Lam., Verbascum angustius Schrank, Verbascum bracteatum J. Kickx f. ex Dumort., Verbascum kickxianum Dumort., Verbascum lanatum Gilib., Verbascum linnaei Opiz, Verbascum majus Bubani, Verbascum mas Garsault, Verbascum neglectum Guss., Verbascum officinarum Crantz, Verbascum pallidus Nees, Verbascum plantagineum Moris, Verbascum schraderi G.Mey., Verbascum seminigrum francium., Verbascum spectabile Salisb., Verbascum subalpinum Schur, Verbascum tapsus Neck. and Verbascum thapsum St.-Lag. (POWO, 2019). It is found along the roadside, meadows, or pasture lands (Mihailovic et al., 2016). Verbascum is an annual or biennial, herbaceous, erect and stout weed with few common names such as white mullein, velvet plant, flannel plant, jungle tambako etc. Leaves are oblong or obovate, alternately arranged, densely arranged flowers with yellow color containing each five sepals, petals, and stamens with two celled ovary. Fruits are found in the form of capsule that divides into two valves at maturity. Ovoid-shaped capsule near about 3–6 cm long shows the star-shaped structure. It shows the deep tap root system (Riaz et al., 2013). V. thapsus has great ethnomedicinal importance due to the active principles present in the different plant parts. In the homeopathic system of medicine, leaves of this plant are used in the treatment of headaches and its ointment is found effective against burns. In some countries, dried roots and flowers are used in the form of cigarettes for reducing asthma attacks. Flower oil is used in the treatment of piles, bruises, and frostbites (Turker and Gurel, 2005; Mack and Erneberg, 2002). Oil isolated from leaves is used in the treatment of skin infection, gastrointestinal problems, and wound healing (Viegi et al., 2003; Manganelli et al., 2001). It is also used extensively for treating the internal and external infections (Meurer-Grimes et al., 1996). Several potent biological activities like antioxidant, antimicrobial, antihelmenthic, antibacterial, antiviral, cytotoxic, and insecticidal have been reported (Riaz et al., 2013, Angeloni et al., 2021, Mahadavi et al., 2020). 36.2 BIOACTIVES Phytoconstituent profiling revealed presence of several compounds such as iridoid glycosides, sterones, sesquiterpene, phenylethanoid, verbascoside,

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and lignan glycosides (Khuroo et al., 1988; Mehrotra et al., 1989; Warashina et al., 1991). Mehrotra et al. (1989) isolated a new triglycoside of luteolin, verbascoside, from the entire plant and based on the spectral and chemical studies compound was identified as luteolin 5-O-α—rhamnopyranosyl (1→3)-{β-D-glucuronopyranosyl(1→6)}- β -D-glucopyranoside. Air-dried methanolic extract was obtained by maceration and further fractionated using n-hexane and ethyl acetate. Extracts then subjected to HPLC analysis showed presence of protocatechuic acid (0.12 mg/g), gentisic acid (0.17 mg/g), p-coumaric acid (0.11 mg/g), ferulic acid (1.33 mg/g), salicylic acid (2.49 mg/g), rosmarinic acid (0.41 mg/g), rutin (2.90 mg/g), quercetin (1.35 mg/g) along with trace amount of harpagoside (Selseleh et al., 2020). Recently, phytochemical profiling carried out by liquid chromatography coupled mass spectrometry (LC–MS) revealed presence of number of compounds such as ajugol, luteolin, rhamnetin, hesperetin, verbascoside, cynaroside, apigenin, martinoside, apigetrin, and chrysin (Selseleh et al., 2020). Methanol extract of air-dried plant was further fractionated using n-hexane, ethyl acetate, chloroform, and methanol afforded number of minor compounds including iridoid glycosides (laterioside, harpagoside, ajugol, picroside IV), one phenylethyl glycoside (verbascoside), three iridoids {(+)-genipin, α-gardiol, β-gardiol}, two sesquiterpenes (buddlindeterpene A, -B), one diterpene (buddlindeterpene C), and one biflavonoid (amentoflavone) (Hussain et al., 2009). Among all the detected compounds, iridoid glycosides such as laterioside and harpagoside have been reported earlier (Warashina et al., 1991). Whole plants of V. thapsus yielded three known phenylethanoid glycosides and four lignans, five new phenylethanoid glycosides, and one new lignan glycoside. Structures of the detected compounds were elucidated by spectroscopic methods and chemical evidence (Warashina et al., 1992). GC-MS analysis of ethanolic extract revealed presence of 1-hexzanol (2.11%), 2-hexene (1.95%), chloroacetic acid (3.70%), palmitate (16.96%), 9-octadecenoic acid (4.67%), linoleic acid ethyl ester (19.07%), 15,12,9-octadecenoic acid (39.81%), and phytol (11.73%) (Mahdavi et al., 2020). Extraction and analysis of saponins using HPLC have been carried out from field-grown, in vitro grown biomass, commercially obtained leaves, and field-grown capsules (Turker et al., 2014). In the same study, ilwensisaponin A and digitoxin were used as external and internal standards. Among all the samples tested, commercially obtained leaves had the highest saponin content (0.215 mg/g) than leaves (0.081–0.198 mg/g tissue) and capsule (0.016 mg/g tissue). For the separation of saponins,

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they had used C18 reverse phase column with 15 cm × 4.6 mm I.D, gradient elution of acetonitrile with 0.1% orthophosphoric acid and water with 0.1% orthophosphoric acid, 10 µL injection volume,1 mL/min flow rate, 30 min run time, and 210 nm wavelength. Further, several researchers also reported verbascoside, caffeoyl phenylethanoid glycoside using LC-MS and HPLC (Selseleh et al., 2020; Mihailovic et al., 2016; Temporiti et al., 2020). Fresh leaves of the plant collected from cultivated land from Etnean area, Belpasso town were subjected to extraction using distilled water (at 80°C for 5 h under stirring). Aqueous extract was then subjected to HPLC-DADMS analysis that revealed presence of several phenylethanoid glycosides such as samioside, verbascoside, iso-verbascoside, alyssonoside, eucosceptoside, martynoside, and leucosceptoside A. Detected phenylethanoid glycosides have been further confirmed using NMR (Frezza et al., 2019). Brownstein et al. (2017) investigated methanolic extracts of different plant parts using ultra-performance liquid chromatography and found highest harpagoside content from the roots. From the whole plant, bioactive compounds such as verbascoside, isoverbascoside, leucosceptoside A, martynoside, samioside, alyssonoside, and leucosceptoside B have been identified (Frezza et al., 2019; Hussain et al., 2009; Brownstein et al., 2017). Aerial parts were extracted with 70% aqueous acetone for 24 h at room temperature, dissolved in water, and partitioned with ethyl acetate. Study revealed the presence of new iridoid compound named verbathasin A along with ten known compounds. Among all the detected compounds, luteolin and 3-O-fucopyranosylsaikogenin F showed promising antiproliferative activities (Zhao et al. 2011). Ethanolic root extract showed presence of iridoid glycosides such as lateroside, harpagoside, ajugol, and aucubin (Pardo et al., 1998). LC-MS analysis also confirmed presence of a number of compounds like apigetrin, hyperoside, chrysin, apigenin, cynaroside, hesperetin, rhamnetin, luteolin, ajugol, and martinoside (Selseleh et al., 2020). In addition, Mihailovic et al. (2016) also confirmed phenolics such as vanilic acid, luteolin, and caffeic acid from the whole plant using HPLC. Structural details of the compounds is given in Figure 36.1. 36.3

PHARMACALOGY

36.3.1 ANTIOXIDANT ACTIVITY Antioxidant activity was assessed from different parts of plants (root, stem, and leaves) extracted with methanol. The highest DPPH activity was found in

Verbascum thapsus L.

FIGURE 36.1

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Bioactive compounds from Verbascum thapsus.

root and leaf extracts (IC50 26.46 ± 0.009 μg/mL each) followed by stem (IC50 27.46 ± 0.009 μg/mL). Stem extract showed the highest phenolic content (0.166 ± 0.003 mg/g DW) followed by leaf (0.124 ± 0.009 mg/g DW) and root (0.100 ± 0.009 mg/g DW). Similarly, total flavonoid content was highest in leaf (0.024 ± 0.001 mg/g DW) followed by root (0.018 ± 0.001 mg/g DW) and stem (0.009 ± 0.002 mg/g DW). It could be due to the variation in the bioactive metabolites, season, and age of the genotype (Kogje et al., 2010).

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DPPH activity was evaluated by using different concentrations (50–300 mg/L) of ethanolic extract of whole plant. Results showed 91.31% inhibition of DPPH free radicals at 300 mg/L concentration of extract. Further, increase in the concentration up to 1 g/mL showed little increase (93.7%) in the percent inhibition of DPPH-free radicals. At the same time, synthesized antioxidant called BHT showed 94.20 and 95.11% inhibition of radicals at 300 and 1000 mg/L concentrations, respectively. The authors also reported that the extract contains some compounds responsible for potent antioxidant, anticarcinogenic and antimicrobial activities (Mahdavi et al., 2020). 36.3.2 ANTHELMINTIC ACTIVITY Plant parts (leaf, stem, and root) were soaked in methanol for fifteen days and further dried to get a gummy mass. All the extracts were investigated for anthelmintic activity using earthworm (Pheretima posthuma, 4–8 cm length and 0.2–0.3 cm width). In the same study, different extract concentrations (5, 10, 25, 50, 75, and 100 mg) along with distilled water (negative control) and Yomesan® (positive control) were used and time required for paralysis and death of earthworm was measured. Fruit extract (100 mg) showed total paralysis and death of the animals after five and 60 min of treatment. Similarly, administration of extract (100 mg) revealed paralysis and death of earthworms after 30 and 60 min, respectively. Leaves and fruit extracts exhibited promising anthelmintic activity and death of worms was observed after 35–40 min. Highest concentration of stem and leaf extracts exhibited mild responses. It was also confirmed that leaves extract had greater anthelmintic activity as compared to stem and root extract. These results confirmed the presence of bioactive metabolites that are found responsible for promising anthelmintic activity (Riaz et al., 2013). 36.3.3 ANTIBACTERIAL ACTIVITY In vitro antibacterial activity was analyzed using methanolic and acetone leaf extracts against various pathogens like Listeria monocytogenes, Pseudomonas aeruginosa, Yersinia pestis, Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus by using the agar-well diffusion method. All the tested organisms were treated with different concentrations of plant extracts (25, 50, 75, and 100%) and zone of inhibition (mm) was measured. Results revealed that 100% methanolic extract showed maximum growth inhibition against E. coli, Y. pestis, P. aeruginosa,

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B. cereus, L. monocytogenes, and S. aureus (20.43 ± 0.47, 22.00 ± 0.00, 16.10 ± 1.82, 12.30 ± 0.06, 22.45 ± 1.65 20.35 ± 1.33 mm zone of inhibition, respectively). Similarly, higher concentration of acetone extract (100%) exhibited 16.25 ± 0.76 17.75 ± 2.03 17.10 ± 0.98, 10.00 ± 1.56, 18.55 ± 0.24, 21.50 ± 2.54 mm zone of inhibition against E. coli, Y. pestis, P. aeruginosa, B. cereus, L. monocytogenes, and S. aureus, respectively. In general, methanol extract found the most effective as compared to acetone extract. Among all the pathogenic bacteria, B. cereus found to be the most sensitive. The authors also stated that these activities could be due to the presence of alkaloids, tannins, saponins, terpenes, and flavonoids in the leaves of Verbascum thapsus (Prakash et al., 2016). Ghasemi et al. (2015) also studied antibacterial activity of different extracts (ethanol, methanol, and aqueous) obtained from aerial parts using disc diffusion and micro dilution assay. In the same study, pathogenic bacteria viz. Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli were used. Results revealed that methanolic extract represented the highest (7–16.83 mm) inhibition zone against all the microorganisms studied (MIC 31.25 μg/mL). Similarly, ethanol extract exhibited maximum inhibition zone (5.83–11.00 mm) with an MIC value of 62.5–125 μg/mL. All these findings confirmed the antibacterial potential of the plant. 36.3.4 ANTIVIRAL ACTIVITY Methanol extracts of aerial part were assessed against Pseudorabies Virus Strain RC/79 using virus plaque reduction assay. Extracts revealed a clear dose-dependent response in viral infection. After 72 h incubation, extract showed promising responses against PrV infection and it was increased from 40.5 to 99.4% at 25 to 300 mg/mL concentration. Methanolic extract (IC50 35 mg/mL) showed 50% inhibition of pseudorabies virus production. These results revealed that methanolic extract of aerial part had antiviral potential (Escobar et al., 2012). 36.3.5

CYTOTOXIC ACTIVITY

Cytotoxic potential was investigated using Neutral Red Uptake (NRU) and MTT {(3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide} assay (Borenfreund and Puerner, 1985; Mosmann, 1983) assay. In the same study, basal cytotoxicity or assessing cell metabolic activity was noted. Methanol extract of aerial part was used to analyze cytotoxic activity against Vero cells using MTT and NRU assay. Growth of Vero cells was depending

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on the concentration of methanolic extract. Cytotoxic concentration (CC50) was recorded at 1100 and 1426 mg/mL for NRU and MTT assay, respectively. Maximum non-cytotoxic concentration (MNCC) was recorded at 850 mg/ mL with the percent survival rate of 64 (NRU) and 99 (MTT), respectively. It was also observed that methanolic extract (300 mg/mL) showed no effect on cell growth and cell survival rate which was close to 100%. The authors also recommended the use of < 300 mg/mL methanol extracts for further investigations (Escobar et al., 2012). 36.3.6 ANTIPROLIFERATIVE ACTIVITY Antiproliferative activity of total eleven compounds isolated from 70% aqueous acetone extract of dried aerial parts was studied (Zhao et al., 2011). Among all, luteolin and 3-O-fucopyranosylsaikogenin F revealed antiproliferative activity up to certain extent by inducing apoptosis of A549 lung cancer cells. 36.3.7 ANTI-INFLAMMATORY ACTIVITY Speranza et al. (2010) investigated the anti-inflammatory action of verbascoside isolated from the aerial parts Verbascum thapsus. The authors investigated status of antioxidant enzymes, iNOS expression, and activity in whole cell preparations via NF-kb. Inflammation was induced by treating THP-1 cells (human myelomonocytic leukemia) with pro-inflammatory stimuli (LPS and IFN-γ) showing upregulation in the expression and activity of iNOS. Treatment of verbascoside (100 μM) significantly reduced the activity of iNOS. Cell viability was noted up to 91–95% after 24 h treatment (Speranza et al., 2010). KEYWORDS • • • • •

Verbascum thapsus iridoids bioactive metabolites antioxidant anti-viral

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REFERENCES

Angeloni, S.; Zengin, G.; Sinan, K. I.; Gunes, A. K.; Maggi, F.; Caprioli, G., Kaplan, A.; Bahs, M.; Çakilcioglu, U.; Bouyahya, A.; Jugreet, S.; Mahomoodally, M. F. An Insight Into Verbascum bombyciferum Extracts: Different Extraction Methodologies, Biological Abilities and Chemical Profiles. Ind. Crops. Prod. 2021, 161. https://doi.org/10.1016/j. indcrop.2020.113201. Borenfreund, E.; Puerner, J. A. Toxicity Determined In Vitro by Morphological Alterations and Neutral Red Absorption. Toxicol. Lett. 1985, 24, 119–124. Brownstein, K. J.; Mahmoud, G; William, R. F.; David, R. G. Iridoid and Phenylethanoid/ Phenylpropanoid Metabolite Profiles of Scrophularia and Verbascum Species Used Medicinally in North America. Metabolomics 2017, 13, 133–141. Escobar, F. M.; Sabinia, M. C.; Zanona, S. M.; Tonnb, C. E.; Sabinia, L. I. Antiviral Effect and Mode of Action of Methanolic Extract of Verbascum thapsus L. on Pseudorabies Virus (Strain RC/79). Nat. Prod. Res. 2012, 26 (17), 1621–1625. Frezza, C.; Bianco, A.; Serafini, M.; Foddai, S.; Salustri, M.; Reverberi, M.; Gelardi, L.; Bonina, A.; Bonina, F. A. HPLC and NMR Analysis of the Phenylethanoid Glycosides Pattern of Verbascum thapsus L. Cultivated in the Etnean Area. Nat. Prod. Res. 2019, 33 (9), 1310–1316. Ghasemi, F.; Rezaei, F.; Araghi, A.; Tabari, A. M. Antimicrobial Activity of AqueousAlcoholic Extracts and the Essential Oil of Verbascum thapsus L. Jundishapur J. Nat. Pharm. Prod. 2015, 10 (3), 1–5. DOI: 10.17795/jjnpp-23004. Hussain, H.; Shahid, A.; Ghulam, A. M.; Viqar, U. A.; Anwar, S.; Ishtiaq, A. Minor Chemical Constituents of Verbascum thapsus. Biochem. Syst. Ecol. 2009, 37, 124–126. Khuroo, M. A.; Qureshi, M. A.; Razdan, T. K.; Nicholas, P. Sterones, Iridoids and a Sesquiterpene from Verbascum thapsus. Phytochemistry 1988, 27, 3541–3544. Kogje, K. K.; Jagdale, V. K.; Dudhe, S. S.; Phanikumar, G.; Bader, R. S. Antioxidant Property and Phenolic Compounds of Few Important Plants from Trans-Himalayan Regions of North India. Int. J. Herb. Med. 2010, 4 (2), 145–151. Mack, R. N.; Erneberg, M. The United States Naturalized Flora: Largely the Product of Deliberate Introductions. Ann. Missouri Bot. Gard. 2002, 89, 176–189. Mahdavi, S.; Amiradalat, M.; Babashapour, M.; Sheikhlooei, H.; Miransari, M. The Antioxidant, Anticarcinogenic and Antimicrobial Properties of Verbascum thapsus L. Med. Chem. 2020, 16, 991–995. Manganelli, R. U.; Camangi, F.; Tomei, P. Curing Animals with Plants: Traditional Usage in Tuscany (Italy). J. Ethnopharmacol. 2001, 2, 171–191. Mehrotra, R.; Ahmed, B.; Vishwakarma, R. A.; Thakur, R. S. Verbascoside: A New Luteolin Glycoside from Verbascum thapsus. J. Nat. Prod. 1989, 52 (3), 640–643. Meurer-Grimes, B.; Mcbeth, D. L.; Hallihan, B. D. S. Antimicrobial Activity in Medicinal Plants of the Scrophulariaceae and Acanthaceae. Int. J. Pharmacogn. Phytochem. 1996, 34, 243–248. Mihailovic, V.; Kreft, S.; Benkovic, T. E.; Lvanovic, N.; Stankovic, M. S. Chemical Profile, Antioxidant Activity and Stability in Stimulated Gastrointestinal Tract Model System of Three Verbascum Species. Ind. Crops. Prod. 2016, 89, 141–151. Mosmann, T. Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. J. Immunol. Methods. 1983, 85, 55–63.

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Pardo, F.; Perich, F.; Torres, R.; Monache, F. D. Phytotoxic Iridoid Glucosides from the Roots of Verbascum thapsus. J. Chem. Ecol. 1998, 24 (4), 645–654. POWO. Plants of the World Online. Facilitated by the Royal Botanic Gardens, Kew. 2019. Published on the Internet. http://www.plantsoftheworldonline.org/ (accessed 02 Feb 2021). Prakash, V.; Rana, S.; Sagar, A. Studies on Antibacterial Activity of Verbascum thapsus. J. Med. Plants Stud. 2016, 4 (3), 101–103. Riaz, M.; Rahman, N.; Haq, M. Z. U. Anthelmintic and Insecticidal Activities of Verbascum thapsus L. Pak. J. Zool. 2013, 45 (6), 1593–1598. Selseleh, M.; Ebrahimib, S. N.; Aliahmadic, A.; Sonbolic, A.; Hossein, M.; Mirjalilia, M. H. Metabolic Profiling, Antioxidant and Antibacterial Activity of Some Iranian Verbascum L. Species. Ind. Crops. Prod. 2020, 153, 1–12. https://doi.org/10.1016/j.indcrop.2020.112609. Speranza, L.; Franceschelli, S.; Pesce, M.; Reale, M.; Menghini, L.; Vinciguerra, I.; Delutiis, M. A.; Felaco, M., Grilli, A. Antiinflammatory Effects in THP-1 Cells Treated with verbascoside. Phytothe. Res. 2010, 24 (9), 1398–1404. Temporiti, M. E. E.; Frezza, C.; Beccaccioli, M.; Luca, G.; Bianco, A.; Francesco, P. B.; Nielsen, E. Production of Verbascoside and Its Analogues in In Vitro Cultures of Verbascum thapsus L. Plant Cell. Tissue Organ Cult. 2020, 140, 83–93. https://doi.org/10.1007/ s11240–019–01712–5. Turker, A. U.; Camper, N. D.; Gurel, E. High-Performance Liquid Chromatographic Determination of a Saponin from Verbascum thapsus L. Biotechnol. Biotechnol. Equip. 2014, 18 (1), 54–59. Turker, A. U.; Gurel, E. Common Mullein (Verbascum thapsus L.) Recent Advances in Research. Phytother. Res. 2005, 9, 733–739. Viegi, L.; Pieroni, A.; Guarrera, P. M.; Vangelisti, R. A Review of Plants Used in Folk Veterinary Medicine in Italy as Basis for a Databank. J. Ethnopharmacol. 2003, 2, 221–244. Warashina, T.; Miyase, T.; Ueno, A. Iridoid Glycosides from Verbascum thapsus L. Chem. Pharm. Bull. 1991, 39, 3261–3264. Warashina, T.; Miyase, T.; Ueno, A. Phenylethanoid and Lignan Glycosides from Verbascum thapsus. Phytochemistry 1992, 31, 961–965. Zhao, Y. N.; Wang, S. F.; Li, Y.; He, Q. X.; Liu, K. C.; Yang, Y. P.; Li, X. L. Isolation of Chemical Constituents from the Aerial Parts of Verbascum thapsus and Their Antiangiogenic and Antiproliferative Activities. Arch. Pharm. Res. 2011, 34 (5), 703–707.

CHAPTER 37

A Brief Review on Biological Properties and Pharmacological Activities of Litsea cubeba SUPARNA LODH* Asian Institute of Nursing Education, Guwahati, Assam, India Corresponding author. E-mail: [email protected]

*

ABSTRACT Litsea cubeba (Lour.) Pers., is an evergreen, aromatic tree or shrub, attains a height of about 8 meters. Different parts of L. cubeba such as root, stem, leaf, flower, and fruits contain various secondary metabolites, basically essential oils and many others biologically active compounds. The essential oils are a complex mixture of monoterpenes, phenols, and sesquiterpenes. Literature survey revealed that essential oils are mainly used as antidepressant, antiinflammation, antioxidant, pesticide, antimicrobial, anticancer, antiparasitic activity. Alkaloids have pharmaceutical properties like antioxidant, antitumor, anticonvulsant etc and flavonoids also have therapeutic properties like anti-inflammatory, antioxidant, and hepatoprotective activities. 37.1 INTRODUCTION Litsea cubeba (Lour.) Pers. is an evergreen, aromatic tree or shrub; this plant is about a height of 8 m. In India Litsea cubeba is mainly available in tropical and subtropical regions (Madhu et al., 2019). It belongs to the family Lauraceae (Bhuinya et al., 2010). Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Litsea cubeba contain dioecious flower, small pepper like fruit, and aromatic leaves. Young shoots are silky and it contains naked leaf buds. Leaves are alternate, simple, and size is about 5.2–13.5 × 1.4–3.9 cm (Bhuinya et al., 2010). This plant is cultivated for various purposes such as for feeding muga silk worms (Antheraea assamensis), production of timber, and treatment for various diseases. Essential oils (EO) are highly aromatic and it is used in the production of cosmetics and food products as an enhancer of aroma (Madhu et al., 2019; Bhuinya et al., 2010). The common names of Litsea cubeba are Mountain Pepper, Aromatic Litsea, and May Chang. The other names are Mejankeri (Assamese), Sil timur (Nepali), Usingsa (Manipuri), Sernam (Mizo). Synonyms of Litsea cubeba (Lour.) Pers. are Litsea piperita Mirb., Laurus cubeba Lour., Tetranthera cubeba (Lour.) Meisn, and many more. The extracts from the different parts of the L. cubeba have been used as traditional medicine in China to treat various diseases (Madhu et al., 2019). In China, the seeds are used to increase digestion, to treat cough and bronchitis (Bhuinya et al., 2010). The fruits are edible and used in various medicinal purposes such as carminative; it relieves flatulence (Madhu et al., 2019; Bhuinya et al., 2010), used to treat dizziness (Bhuinya et al., 2010), also used as diuretic means it increases production of urine, antidysentric, and antiseptic. It also relieves stomach ache (Madhu et al., 2019). Literature review revealed that the extract of L. cubeba has some biological properties such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, antioxidant, and anti-HIV (Aminah et al., 2018; Hsin et al., 2016; Madhu et al., 2019). 37.2 BIOACTIVES Studies revealed that L. cubeba contains various biologically active compounds. Different parts of L. cubeba comprise secondary metabolites basically essential oils (EO) and many other biologically active compounds. Monoterpenes, phenols, and sesquiterpenes are the constituents of essential oils L. cubeba. The composition of essential oils varies in leaf, flower, fruits, root, and stem of L. cubeba (Madhu et al., 2019). This plant contains small and pepper-like fruits that contain essential oil with an intensely lemon-like, fresh, sweet odor and the oil is rich in citral (Ying et al., 2012). Studies revealed that citral was the main cause of the antimicrobial activity (Yu and Chen, 2016). Chemical structure of citral is depicted in Figure 37.1.

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FIGURE 37.1 Chemical structure of citral.

Research revealed that essential oils are mainly used as antidepressant, anti-inflammation, antioxidant, pesticide, antimicrobial, anticancer, antiparasitic activity and also used in neuropharmacology. It was found that essential oils also have insecticidal activity and can be used against various insects (Aminah et al., 2018; Madhu et al., 2019). Studies revealed that the biologically active compounds like amides, fatty acids, lignans, alkaloids, monoterpene, flavonoids, sesquiterpenes, and diterpenes present in this plant have anticancer, antidiabetic, anti-inflammatory, antimicrobial, antioxidant, and anti-HIV properties, and therefore these compounds are highly potential for treatment of various diseases (Aminah et al., 2018; Hsin et al., 2016; Madhu et al., 2019). Literature survey revealed that essential oil of L. cubeba has an immunosuppressive effect also. Evidence revealed that essential oil of Litsea cubeba may be a promising agent for the treatment of inflammation and autoimmune diseases (Hsin et al., 2016). It was found that EO of L. cubeba is available in all parts of the plant like leaf, fruit, flower, stem, as well as in the root (Linlin et al., 2012). 37.2.1 ALKALOIDS Madhu et al. (2019) said that almost 63 alkaloid compounds were identified in the genus Litsea cubeba and most of these compounds have pharmaceutical properties like antioxidant, antitumor, and anticonvulsant. These alkaloid compounds can be used to cure various diseases. 37.2.2 ESSENTIAL OILS L. cubeba is a valuable EO-producing plant species. It was reported that EO of L. cubeba has been used as a traditional medicine to treat several diseases

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and the oil is intense yellowish in color, fresh and has a sweet aromatic flavor (Bhagavathi et al., 2020). It was reported that essential oil present in L. cubeba has antibacterial, antifungal, antioxidant, anticancer, insecticidal properties and is also used for food preservation (Linlin et al., 2012; Kai et al., 2014). Studies found that essential oils are widely used in antibacterial and food preservation (Liqun et al., 2019). Linlin et al. (2012) Identified 59 compounds from essential oil of L. cubeba by gas chromatography–mass spectrometry (GC-MS). It was reported that the dominant components of L. cubeba are monoterpenes. It is constituted mainly by two chemical components like neral and geranial (Linlin et al., 2012; Nor et al., 2016; Madhu et al., 2019). Apart from these the other chemical compounds present in EO are α-pinene, β-pinene, methyl heptenone, β-myrcene, d-limonene, cineole, linalool, isopulegone, α-terpineol (R)-citronellol, piperitone, β-caryophyllene, and caryophyllene oxide etc. (Linlin et al., 2012). It was found that EO extracted from different parts of the plant such as leaves, stem bark, and flowers may vary in composition. Literature studies revealed that citral is the major compound found in fruits of L. cubeba while leaves contain 1,8-cineole than citral. EO obtained from leaves of L. cubeba contain two compounds like sabinene and α-pinene (Madhu et al., 2019; Yu et al., 2010). 37.2.2.1 Monoterpenes Monoterpenes (citral, limonene, citronellal, etc.) are one of the most important compounds present in the EO of L. cubeba. Monoterpenes are responsible for the bioactivities of oil (Bhagavathi et al., 2020). According to literature survey approximately 90% of essential oils contain monoterpenes. Many monoterpene compounds with varying structures have been reported in the EO of L. cubeba. Monoterpenes have different biological properties like antiasthmatic, antioxidant, antifungal, and antianaphylactic. Menthane and cineole are the two broad categories of monoterpenes found in this plant (Madhu et al., 2019). 37.2.3 FLAVONOIDS AND PHENOLIC ACID Another important compound present in Litsea species are flavonoids. Literature review said that flavonoids also have therapeutic properties like antioxidant, anti-inflammatory, and hepatoprotective properties (Madhu et

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al., 2019). In another study it was found that flavonoids also act as anticancer agent (Tapan et al., 2020). Previous literature revealed that various flavonoids have been reported in L. cubeba. Some of these are anthocyanidins, flavanols, flavanones, flavanonols, chalcones, flavan-3-ols, etc. (Madhu et al., 2019). Tapan et al. (2020) performed HPLC to extract various phenolics and polyphenolic compounds from methanolic extract of fresh fruits of L. cubeba; the compounds included caffeic acid, gallic acid, catechin, protocatechuic acid, gentisic acid, salicylic acid, p-hydroxy benzoic acid, vanillic acid, ellagic acid, syringic acid, p-coumaric acid, ferulic acid, sinapic acid, rutin, naringin etc. They also said that these phenolics and polyphenolic compounds have high antioxidant activity (Tapan et al., 2020). 37.2.4

FATTY ACIDS

Litsea species also contain fatty acids. Some of the major fatty acids present in this plant include cinnamic acid, linolenic acid, octanoic acid, decenoic acid, dodecenoic acid, myristic acid, canoic acid, oleic acid (Madhu et al., 2019). In another study it was reported that Litsea cubeba kernel oil extract contains five kinds of saturated fatty acids and five types of unsaturated fatty acids. The major saturated fatty acid includes lauric acid, capric acid, and the major unsaturated fatty acid includes oleic acid (Pengying et al., 2019). 37.3

PHARMACOLOGY

Studies reported that L. cubeba contains a wide range of structurally diverse biologically potential compounds and the major groups of these compounds include flavonoids, alkaloids, steroids, monoterpenes, amides, sesquiterpenes, diterpenes, lignans, and fatty acids. These compounds have some medicinal properties like anti-HIV, antidiabetic, anticancer, anti-inflammatory, antimicrobial, and antioxidant (Madhu et al., 2019). 37.3.1 ANTIFUNGAL ACTIVITY Liqun et al. (2019) reported that essential oils of L. cubeba extracted from fruits can inhibit the growth of Botrytis cinere. It was found that at a concentration of 1.0%, essential oils of L. cubeba could inhibit the growth of fungus like Botrytis cinere. It was also found that essential oils of L. cubeba can

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inhibit potential fungal infections in fruits and vegetables, extending the shelf life of various vegetables as well as fruits. 37.3.2 ANTIBACTERIAL ACTIVITY Wei et al. (2019) found the inhibiting effect of essential oils of L. cubeba against methicillin-resistant Staphylococcus aureus that leads to intracellular biological macromolecules leakage. Literature revealed that the antibacterial mechanisms of essential oils extracted from fruits showed multiple actions (Liqun et al., 2019). Researcher found the highest antimicrobial activity based on OH. scavenging activity test against three bacteria namely Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium in the EO obtained from fruits of L. cubeba (Qi et al., 2020). 37.3.3 ANTIOXIDANT ACTIVITY Ying et al. (2012) analyzed the chemical composition of EO L. cubeba using the GC-MS method. They reported thirty-eight components in the EO. Among these components they reported that relatively high contents of citral (47.87% of total oil) present in the EO act as potentially major antioxidant components. This result revealed that EO could be used as an easily accessible source of natural antioxidant for food industry. 37.3.4 ANTICANCER ACTIVITY Studies found that the EO obtained from the fruits of L. cubeba has a cytotoxic effect on different human cancer cells (oral, lung, and liver cancer cells) (Bhagavathi et al., 2020; Chen et al., 2010; Madhu et al., 2019). Literature review revealed that the vapor of seed oil of Litsea cubeba showed an effect on apoptosis and cell cycle arrest in lung carcinoma cells (Blowman et al., 2018). Piyapat et al. (2014) identified a diterpene compound called cubelin from methanolic extract of fruits of L. cubeba and they found that this compound induced apoptosis in HeLa cells viability and proliferation by promoting activation of initiators caspase-8 and -9. Another study found that the EO of L. cubeba contain citral as a major compound that showed an anticancer activity against chronic myelogenous erythroleukemia (K562) cells of human (Basma et al., 2019).

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37.3.5 ANTIDIABETIC ACTIVITY

In vitro antidiabetic activity of powder fruits extract of Litsea cubeba in different solvents was performed by α-amylase and α-glucosidase inhibitory assays. They found that methanolic extract exhibited highest antidiabetic activity in α-amylase and α-glucosidase inhibition assay followed by ethanol extract (Rakhi and Vivekananda, 2018). KEYWORDS • • • • • •

Litsea cubeba monoterpenes phenols antidepressant anti-inflammation pesticide

REFERENCES Aminah, D.; Poppy, A. Z. H.; Jansen, S.; Denny, S. Antioxidant Activity of Alkaloid Fractions of Litsea cubeba Lour. Fruits. Asian J. Pharm. Clin. Res. 2018, 11 (1), 31–32. Basma, N.; Jorge, E. S.; Luisa, P.; Joseph, B. Chemical Composition and In Vitro Cytotoxic Screening of Sixteen Commercial Essential Oils on Five Cancer Cell Lines. Chem. Biodivers. 2019, 17 (1). DOI: 10.1002/cbdv.201900478. Bhagavathi, S. S.; Periyanaina, K.; Chaiyavat, C. The Composition, Pharmacological and Economic Importance of Essential Oil of Litsea cubeba (Lour.) Pers. Food Sci. Technol. 2020. https://doi.org/10.1590/fst.35720. Bhuinya, T.; Singh, P.; Mukherjee, S. K. Litsea cubeba—Medicinal Values—Brief Summary. J. Trop. Med. Plants. 2010, 11 (2), 179–183. Blowman, K.; Magalhaes, M.; Lemos, M. F. L. Cabral, C.; Pires, I. M.; Anticancer Properties of Essential Oils and Other Natural Products. Evid. Based Complement. Alternat. Med. 2018, 2018, 3149362. Chen, L. H.; Ou J. P.; Yao, C. L.; Chien, P. H.; Ming, C. T.; Pei, C. L.; Eugene, I. C. W.; Yi, L. C.; Yu, C. S. Compositions and In Vitro Anticancer Activities of the Leaf and Fruit Oils of Litsea cubeba from Taiwan. Nat. Prod. Commun. 2010, 5 (4), 617–620. Hsin, C. C.; Wen, T. C.; You, C. H.; Hsing, Y. C.; Cheng, H. C.; Chi, C. L.; Meng, S. L.; Ming, K. L. Immunosuppressive Effect of Litsea cubeba L. Essential Oil on Dendritic Cell and Contact Hypersensitivity Responses. Int. J. Mol. Sci. 2016, 17 (8), 1319. DOI: 10.3390/ ijms17081319.

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Kai,Y.; Cheng, F. W.; Chun, X. Y.; Zhu, F. G.; Rui, Q. S.; Shan, S. G.; Shu, S. D.; Zhi, L. L.; Zhi, W. D. Bioactivity of Essential Oil of Litsea cubeba from China and Its Main Compounds Against Two Stored Product Insects. J. Asia Pac. Entomol. 2014, 17 (3), 459–466. Linlin, S.; Yicun, C.; Xiaojiao, H.; Zhiyong, Z.; Shengping, T.; Qinqin, C.; Yangdong, W. Chemical Composition of Essential Oils of Litsea cubeba Harvested from Its Distribution Areas in China. Molecules 2012, 17 (6), 7057–7066. Liqun, W.; Wei, H.; Jiao, D.; Xin, L.; Jun, Z.; Xiangzhou, L. Antibacterial Activity of Litsea cubeba Essential Oil and Its Mechanism Against Botrytis cinerea. Roy. Soc. Chem. 2019, 9, 28987–28995. Madhu, K.; Dipendra, K. M.; Kyung, E. L.; Vivek, K. B.; Padam, R. G.; Kang, S. G.; Pradeep, K. Ethnopharmacological Properties and Medicinal Uses of Litsea cubeba. Plants (Basel) 2019, 8 (150), 1–13. Nor, A. M. A.; Malina, J.; Abd, Majid, J.; Saidatul, H. S.; Sahrim, L., Noorsiha, A., Mohammad, F. Z. P.; Chung, R. C. K.; Azrina, A., Kamaruddin, S.; Christine, S. A. B.; Nurliyana, A. L. Chemical Composition of Litsea cubeba Essential Oils from Cameron Highlands. 2016. https://www.researchgate.net/publication/311576040. Pengying, L.; Yidan, H.; Jilie, L.; Zhihong, X.; Aihua, Z.; Optimization of Process Conditions for Extracting Litsea cubeba Kernel Oil By Microwave-Assisted Water Method. IOP Conf Ser Earth Environ Sci. 2019, 332 (2019) 022051. DOI: 10.1088/1755–1315/332/2/022051 Piyapat, T.; Akihiko, S.; Hisashi, N.; Hirotoshi, T. A New Diterpene from Litsea cubeba Fruits: Structure Elucidation and Capability to Induce Apoptosis in HeLa Cells. Molecules 2014, 19, 6838–6850. DOI: 10.3390/molecules19056838. Qi, H. S.; Wen, S. L.; Yuan, Y. J.; Yi, C. W.; Yong, H. Z.; Li, Z. Chemical Composition, Antimicrobial Activity and Antioxidant Activity of Litsea cubeba Essential Oils in Different Months. Nat. Prod. Res. 2020, 34 (22), 3285–3288. Rakhi, C.; Vivekananda, M. In Vitro Hypoglycemic and Antioxidant Activities of Litsea cubeba (Lour.) Pers. Fruits, Traditionally Used to Cure Diabetes in Darjeeling Hills (India). Pharmacogn J. 2018, 10 (6), s119–s128. Tapan, S.; Kausik, C.; Basundhara P.; Shrabana, C.; Tanmoy, M.; Biswajit, A. Evaluation of Antioxidant Activities, Toxicity Studies and the DNA Damage Protective Effect of Various Solvent Extracts of Litsea cubeba Fruits. Heliyon. 2020, 6. https://doi.org/10.1016/j. heliyon.2020.e03637 Wei, H.; Changzhu, L.; Jinming, D.; Haiying, C.; Lin, L. Antibacterial Activity and Mechanism of Litsea cubeba Essential Oil Against Methicillin-Resistant Staphylococcus aureus (MRSA). Ind. Crops Prod. 2019, 130, 34–41. Ying, W.; Zi, T. J.; Rong, L. Antioxidant Activity, Free Radical Scavenging Potential and Chemical Composition of Litsea cubeba Essential Oil. J. Essent. Oil-Bear. Plants 2012, 15 (1), 134–143. DOI: 10.1080/0972060X.2012. Yu, C. S.; Chen, L. H. Essential Oil Compositions and Antimicrobial Activities of Various Parts of Litsea cubeba from Taiwan. Nat. Prod. Commun. 2016, 11 (4), 515–518. Yu, Y.; Jiazheng, J.; Luobu, Q.; Xiaojing, Y.; Junxia, Z.; Huizhu, Y.; Zhaohai, Q.; Mingan, W. The Fungicidal Terpenoids and Essential Oil from Litsea cubeba in Tibet. Molecules 2010, 15 (10), 7075–7082.

CHAPTER 38

Phytochemistry and Pharmacology of Calotropis procera L. and C. gigantea R.Br. PAYAL SOAN Department of Botany, St. Wilfred College for Girls, Mansarover, Jaipur, Rajasthan 302020, India E-mail: [email protected]

ABSTRACT Apocynaceae or milkweed family is a group of plants having latex in almost all parts. Calotropis is one such genus; possess two common species C. procera and C. gigantea in India. Both species are rich in flavonoids, phytosterols, alkaloids, cardiac glycosides etc. Strong anti-inflammatory activity of Calotropis is due to presence of latex. Many other phytochemical properties have been reported by many researchers in both plant species. These species showed hepatoprotective activity, antimicrobial activity, antifertility, anticancer activity, antioxidant and local anesthetic activity. 38.1 INTRODUCTION Calotropis belongs to the family Apocynaceae or Milkweed family which is commonly known as Aak family. This genus is rich in phytochemicals, such as primary and secondary metabolites, which exhibit potential pharmacological activities. The presence of latex in whole plant is a conspicuous feature of this family. Plants of Calotropis procera are generally found on the road

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sides, in dumping areas, and in wastelands. In India, two species of the genus Calotropis are commonly found viz., C. procera and C. gigantea. C. procera has been mentioned as “Raktha Arka” in ancient ayurvedic medicine system, while C. gigantea as “Shwait Arka.” The botanical characters as well as the pharmacological impacts of both plants are similar. In traditional medicinal system, Calotropis genus has a significant space (Rastogi and Mehrotra, 1993) with many pharmacological properties (Oudhia and Tripathi, 1999). Caius (1986) reported that Calotropis was effective alone or when combined with other medicines for the treatment of common diseases, such as cough, cold, fevers, asthma, eczema, elephantiasis, indigestion, rheumatism, diarrhea, vomiting, etc. The milky exudate can cause blindness if it gets into the eyes. It is corrosive. It is also reported to have mercury like effects on the human body (Das, 1996). 38.2

BIOACTIVES

C. procera has been reported to possess several types of phytocompounds, such as flavonoids, phytosterols, alkaloids, cardiac glycosides, triterpenoids, tannins in adequate concentration, while cardenolide, anthocyanins, α- and β amyrinl, etc. are present in trace amounts (Al-Yahya et al., 1990). All these compounds were screened out by Yoganarasimhan (1996) in the whole plant. α-amyrin, β sitosterol, and lupeol are the major compounds of root and root bark (Saber et al., 1969), β-amyrin was also extracted by Saxena and Saxena (1979), some unique sterols, such as akundarol isovalerate, mundarol isovalerate, calotropterpenyl ester, calotropfridelenyl acetate, and flavonoid like quercetin-3-rutinoside (Lal et al., 1985; Ansari and Ali, 2001; Akhtar and Malik, 1998) were also reported. Leaves are rich in calotropin, calotropagenin, β-sitosterol, amyrin, amyrin acetate, cardenolides, and ursolic acid (Abbas et al., 1992). Flowers contain glucose, glucosamine, L-rhamnose terpenes, multiflavenol, and cyclisadol (Al-Yahya et al., 1990), giganteol, glactuceryl acetate, calotropagenin, calotoxin, quercetin-3-rutinoside, sterol, calactin, calotoxin, calotropin polysaccharides, D-arabinose, isogiganteol, uzarigenin, and voruscharina-calotropeol (Ansari and Ali, 1999). Latex is having caloptropaine (Kishore and Chopra, 1997), voruscharin, caoutchouc, syriogenin, calactin, calotropin, uzarigenin, calotoxin, uscharin trypsin, and proceroside (Atef et al., 1999). Various chemical constituents have been reported from different parts of C. gigantea (Murti and Seshadri, 1945; Kumar et al., 2012). Large quantity of latex is produced by Calotropis (Watkins et al., 2005). C. gigantea has been

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screened for various secondary metabolites, such as steroids, flavonoids, triterpenoids, glycosides, etc. (Habib and Karim, 2012; Jaiswal et al., 2013). Seniya et al. (2011) conducted investigation for similar phytoconstituents in C. gigantea. Balamurugan et al. (2009) had reported that the leaf contains ascorbic acid, o-pyrocatechic acid, and also contains β-sitosterol, taxasterol, tarasterol, and β-amyrin. Cardenolides, 19-Nor, and 18, 20-epoxy-cardenolides were two new compounds isolated from C. gigantea leaves. The plant latex is rich in uscharidin, calotropin, lupeol, and calotoxin (Sharma and Tripathi, 2009). Kirtikar and Basu (1999) had reported that the cardiac glycosides, gigantin uscharidin, calotopin, calotoxin, uscharin, and calactin are major compounds of flowers of C. gigantea. Calotropin FI and FII and calotropin DI and DII protease are also present in flowers. Roots of C. gigantea having cardenolide glycosides, such as calotropin, 4-0-beta-D glucopyranosylfrugoside and frugoside (Balamurugan et al., 2009). 38.3 PHARMACOLOGICAL STUDIES C. procera has many medicinal properties. Different plant parts used as medicine from ancient time (Mukherjee et al., 2010). Different pharmacological activities of various plant parts of C. procera and C. gigantea are as follows. 38.3.1 ANTI-INFLAMMATORY ACTIVITY The latex of the plant C. procera exhibited potent anti-inflammatory activity against carrageenan and formalin. It has been reported by histological analysis that the extracts were more potent than phenylbutazone for the inhibition of cellular infiltration and subcutaneous edema induced by carrageenan. The anti-inflammatory effects of the extracts of DL exert is mainly by inhibiting histamine and BK and partly by inhibiting prostaglandin E2 (Kumar and Arya, 2006). Roots (Parrotta, 2001), leaves (Kapur and Sarin, 1984), and flowers (Rastogi and Mehrotra, 1993; Pathak and Argal, 2007) were also reported to possess anti-inflammatory activity. C. gigantea was evaluated for anti-inflammatory activity in using carrageenan-induced, kaolin-induced rat paw edema for acute and cotton-pellet granuloma for chronic inflammation adjuvant-induced arthritis model. Variable anti-inflammatory activity was exhibited by test compounds. Alkaloid fraction showed high initial anti-inflammatory activity (Adak and Gupta, 2006).

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HEPATOPROTECTIVE ACTIVITY

Flower extract of C. procera was prepared with 70% ethanol and tested for its hepatoprotective activity against paracetamol-induced hepatitis in rats. Both treated and untreated groups were screened for ALP, SGOT, SGPT, HDL, cholesterol and tissue glutathione (GSH). It was reported that HDL and GSH were decreased due to paracetamol (2 g/kg), while SGOT, SGPT, ALP, cholesterol and bilirubin levels were increased. Flower extract of C. procera in hydro-ethanolic extract provides normal levels (Setty et al., 2007). Hepatoprotective activity in male Wistar rats were studied with ethanolic extract (50 %) doses of 250 and 500 mg kg-1 of C. gigantea stem were given for liver damage-induced using carbon tetrachloride, 2 mL kg-1 twice a week. Standard drug was Silymarin. Biochemical parameters, such as catalase (CAT), superoxide dismutase (SOD), amino transferase (AST), glutathione peroxidase (GPx), alanine amino transferase (ALT), lipid peroxide (LPO), and glutathione (GSH) were evaluated. AST, ALT, and lipid peroxide levels were decreased by C. gigantea extract while catalase, GSH, SOD, and GPx levels were enhanced (Lodhi et al., 2009). 38.3.3 ANTIMICROBIAL ACTIVITY The antimicrobial activity of different organic solvent extracts and flavonoids of C. procera was evaluated by Nenaah (2013). He used the agar well diffusion method for this bioassay. Crude flavonoid fraction of methanolic extract exhibited maximum antimicrobial activity. This fraction was further fractionated to isolate four flavonoid glycosides. The diameter of inhibition zones ranged between 15.5 and 28.5 mm. The maximum zone of inhibition was reported against the fungus Candida albicans, that is 30 mm. The Grampositive bacteria (Bacillus subtilis and Staphylococcus aureus) were more susceptible than the Gram-negative (Salmonella enteritidis and Pseudomonas aeruginosa) bacteria and the filamentous fungi were less susceptible than the yeast species. C. gigentea was found to be effective against Streptococcus mutans and Lactobacilli casei (Sharma et al, 2015), S. aureus, Escherichia coli, Bacillus cereus, P. aeruginosa, Micrococcus luteus, and Klebsiella pneumoniae (Kumar et al, 2010).

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38.3.4 ANTIFERTILITY ACTIVITY Methanolic extract of C. gigantea exhibits potential antifertility activity. This study was carried out by Chandrawat and Sharma (2018). For this study, four groups of rats were made, each having 10 Wistar rats. Control group (I) rats received vehicle alone. The second and third (II and III) group animals were administered the root extract daily for the study. Recovery group (IV) of rats were treated with 100 mg dose for 60 days. It was further kept of 30 days recovery. Male reproductive organs were significantly observed. Testicular sperm count, epididymal sperm count and motility, number of fertile males were observed. Ratio between delivered and inseminated females and number of pups were also listed. Decreased value of luteinizing hormone and testosterone were also observed. However, FSH did not show any marked change. All results indicate the antifertility activity of Calotropis extracts on Wistar rat. Querashi and Quereshi (1991) had also studied different parts of C. procera for antisperm activity. Ethanolic extract of roots of C. procera has been studied by Kamath and Rana (2002) in albino rats for its antifertility and hormonal efficacy. 38.3.5 ANTICANCER ACTIVITY The methanolic extract of C. procera was evaluated for its anticancer activity against MCF7 breast cancer cell line by performing MTT assay. Also, antibacterial activity was carried out against S. aureus using disc diffusion method. Methanolic fraction exhibited significant activity against the MCF7 cell line and growth of MRSA significantly decreased. Results reveal the methanolic extract of C. procera as potential antimicrobial agent (Alzahrani et al., 2017). Nalini et al. (2016) used electrochemical methods for anticancer efficacy of C. procera against glioblastoma cell lines (LN-18). The polyphenol contents in the leaf of C. procera were extracted using Soxhlet-assisted extraction (SAE) method. Electrochemical characteristics were studied of the proposed Gr/NT-G/LN-18 cytosensor toward the plant extract. Scanning electron microscopy (SEM) and energy-dispersive analysis of x-ray were used for physical characterization of the Gr/PAH/NT-G/PPy/DNA. The plant extract can be used as a potential source against LN-18 cancer cells.

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38.3.6 ANTIOXIDANT ACTIVITY Antioxidant effects of leaves of C. procera in different solvents, such as methanol, chloroform, hot water and ethyl acetate were tested by Mohanraj and Usmani (2012) for the scavenging property of the free radical DPPH, reducing power, and nitric oxide radical inhibition. C. procera extract in chloroform exhibited the highest antioxidant activity. Rathod et al. (2009) studied C. gigantea leaf and flower extracts in chloroform for antioxidant and free radical scavenging activity. He also worked on lipid profile in streptozocin-induced diabetic rats. The liver homogenate was examined for lipid peroxidation, superoxide dismutase, and catalase and blood serum were analyzed for lipid profile, serum glutamic pyruvic transaminase, alkaline phosphatase, and glutamic oxaloacetic transaminase. Single dose of streptozocin (55 mg/kg, i.p.) was given which caused significant decrease in the levels of superoxide dismutase and catalase. But, enhanced the level of serum glutamic pyruvic transaminase, triglyceride levels, lipid peroxidation, alkaline phosphatase, serum glutamic oxaloacetic transaminase, and cholesterol. 38.3.7 LOCAL ANESTHETIC ACTIVITY Milky latex of C. procera was studied for the local anesthetic activity. The milky latex with dilution ratio of 1:10, exhibited potential local anesthetic activity. The work was performed with epinephrine in Guinea pig for the local anesthetic activity. For the study, milky latex was obtained from C. procera. Results reveal that the latex and epinephrine are more effective than the latex alone (Pathyusha, 2012). KEYWORDS • • • • •

Apocynaceae Calotropis C. procera C. gigantea pharmacological characters

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REFERENCES

Abbas, B.; El Tayeb, A. E.; Sulleiman, Y. R. Calotropis procera: Feed Potential for Arid Zones. Vet. Record 1992, 131 (6), 132. Adak, M.; Gupta, J. K. Evaluation of Anti-Inflammatory Activity of Calotropis gigantea (Akanda) in Various Biological System. Nepal Med. Coll. J. 2006, 8 (3), 156–161. Akhtar, N.; Malik, A. Proceragenin, an Antibacterial Cardenolide from Calotropis procera. Phytochemistry 1998, 31 (8), 2821–2824. Al-Yahya, M. A.; Al-Meshal, I. A.; Mossa J. S.; Al-Badr A. A.; Tarig M. Saudi Plants: A Phytochemical and Biological Approach; King Saud University Press: Riyadh, 1990; pp 31–34. Alzahrani, H. S.; Mutwakil, M.; Sabir, J; Saini, K. S.; Alarif, W. M.; Rizgallah, M. R. Anticancer and Antibacterial Activity of Calotropis procera Leaf Extract. J. Basic. Appl. Sci. Res. 2017, 7 (12), 18–25. Ansari, S. H.; Ali, M. New Oleanene Triterpenes from Root Bark of Calotropis procera. Med. Arom. Plant Sci. 1999, 21 (4), 978–981. Ansari, S. H.; Ali, M. Norditerpenic Ester and Pentacyclic Triterpenoids from Root Bark of Calotropis procera (Ait) R. Br. Pharmazie. 2001, 56 (2), 175–177. Atef, G. H.; Elgamal, M. H. A.; Morsy, N. A. M.; Duddeck H.; Kovacs, J.; Toth, G. Two Cardenolides from Calotropis procera. J. Magn. Reson. Chem.1999, 17, 754–757. Balamurugan, G.; Muralidharan, P.; Selvarajan, S. Antiepileptic Activity of Poly Herbal Extract from Indian Medicinal Plants. J. Sci. Res. 2009, 1 (1), 153–159. Caius, J. F. The Medicinal and Poisonous Plants of India; Scientific Publ.: Jodhpur, India, 1986. Chandrawat, P.; Sharma, R. A. Antifertility Effect of Methanolic Extract of Aerial Plant Parts of Calotropis gigantea L. in Male Albino Wister Rats. J. Pharmacogn. Phytochem. 2018, 7 (5), 1671–1675. Das, B. B. Rasraj Mahodadhi; Khemraj Shri Krishnadas Prakashan: Bombay, 1996. Habib, M. R.; Karim, M. R. Antitumour Evalution of di- (2- ethylhexyl) Phthalate (DEHP) Isolated from Calotropis gigantea L. Flower. Acta Pharm. 2012, 62, 607–615. Jaiswal, J.; Srivastava, S.; Gautam, H.; Sharma, S. Phytochemical Screening of Calotropis gigantea (Madar) seeds extracts. Intern. J. Pharmaceut. Res. Scholars. 2013, 2 (2), 235–238. Kamath, J. V.; Rana, A. C. Preliminary Study on Antifertility Activity of Calotropis procera Roots in Female Rats. Fitoterapia 2002, 73 (2), 111–115. Kapur, S. K.; Sarin, Y. K. Medico-Botanical Survey of Medicinal and Aromatic Plants of Katra Valley (J. K. State), India. Indian Drugs 1984, 22 (1), 4–10. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants, 2nd ed., Vol. III, International Book Distributors, Dehradun, 1999; pp 191–192, 420–422, 993–994, 2045–2047. Kishore, N.; Chopra, A. K. Antimicrobial Properties of Calotropis procera Ait. in Different Seasons: A Study In Vitro. Biol. Memoirs.1997, 23 (2), 53–57. Kumar, G.; Karthik, L.; Rao, K. V. B. Antibacterial Activity of Aqueous Extract of Calotropis gigantea Leaves—An In Vitro Study. Intern. J. Pharma. Sci. Rev. Res. 2010, 4 (2), 141–144. Kumar, S. S.; Sivamani, P.; Baskaran, C.; Mohamad, M. J. Evaluation of Antimicrobial Activity and Phytochemical Analysis of Organic Solvent Extracts of Calotropis gigantea. IOSR J. Pharm. 2012, 2 (3), 389–394.

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Kumar, V. L.; Arya, S. Medicinal Uses and Pharmacological Properties of Calotropis procera. In Recent Progress in Medicinal Plants; Govil, J. N., Ed.; Studium Press: Texas. 2006, 11, pp. 373–388. Lal, S. D.; Kumar, P.; Pannu, D. S. Quercetin-3-Rutinoside in Calotropis procera. J. Sci. Res. 1985, 7 (1), 141–142. Lodhi, G,; Singh, H. K.; Pant, K. K.; Hussain, Z. Hepatoprotective Effects of Calotropis gigantea Extract Against Carbon Tetrachloride Induced Liver Injury in Rats. Acta Pharm. 2009, 59 (1), 89–96. Mohanraj, R.; Usmani, M. S. Antioxidant Activity of the Leaf Extracts of Calotropis procera. Intern. J. Adv. Biotechnol. Res. 2012, 2 (1), 47–52. Mukherjee, B.; Bose, S.; Dutta, S. K. Phytochemical and Pharmacological Investigation of Fresh Flower Extract of Calotropis procera Linn. Int. J. Pharmaceut. Sci. Res. 2010, 1 (2), 182–187. Murti, P.; Seshadri, T. R. Chemical Composition of Calotropis gigantea: Part VI. Flowers. A Comparison of the Composition of the Various Parts of the Plant. Proc. Ind. Acad. Sci.1945, 18 (3), 304–309. Nalini, S.; Nandini, S.; Suresh, G. S.; Melo, J. S.; Neelagund, S. E.; Kumar, H. N. N.; Sanetuntiku, J.; Shanmugam, S. An Electrochemical Perspective Assay for Anticancer Activity of Calotropis procera Against Glioblastoma Cell Line (LN-18) Using Carbon Nanotubes- Graphene Nano- Conglomerate as a Podium. Adv. Mater. Lett. 2016, 7 (12), 1003–1009. Nenaah, G. E. Antimicrobial Activity of Calotropis procera Ait. (Asclepiadaceae) and Isolation of Four Flavonoid Glycosides as the Active Constituents. World J. Microbiol. Biotechnol. 2013, 29 (7), 1255–1262. Oudhia, P.; Tripathi, R. S. Medicinal Weeds of Raipur and Durg (Madhya Pradesh) Region. Proceedings of the National Conference on Health Care and Development of Herbal Medicines, IGAU, Raipur, India, 1999, pp 71–78. Parrotta, J. A. Healing Plants of Peninsular India; CAB International: Wallingford and New York, 2001. Pathak, A. K.; Argal, A. Analgesic Activity of Calotropis gigantea Flower. Fitoterapia 2007, 78, 40–42. Pathyusha, R. J. B. Potential of Local Anesthetic Activity of Calotropis procera Latex with Epinephrine and pH in Guinea Pig, 2012. http//www.pharmatutor.org/articles/ Pharmatutor-art-1043 Qureshi, M. A.; Qureshi, N. M. A Study on the Antisperm Activity in Extracts from Different Parts of Calotropis procera. Pakistan J. Zool. 1991, 23 (2), 161–166. Rastogi, R. P.; Mehrotra, B. N. Compendium of Indian Medicinal Plants; CDRI: Lucknow, 1993, 2, 174–551. Rathod, N. R.; Raghuveer, I.; Chitme, H. R.; Chandra, R. Free Radical Scavenging Activity of Calotropis gigantea on Streptozotocin-Induced Diabetic Rats. Indian J. Pharm. Sci. 2009, 71 (6), 615–621. Saber, A. H.; Maharan, G. H.; Rizkallah, M. M. Sterols and Pentacyclic Triterpenes of Calotropis procera. Bull. Fac. Pharm. Cairo Univ. 1969, 7 (1), 91–104. Saxena, V. K. Saxena, Y. P. Isolation and Study of Triterpenoids from Calotropis procera. J. Res. Indian Med. Yoga Homeopathy 1979, 14, 152–154. Seniya, C.; Trivedia, S. S.; Verma, S. K. Antibacterial Efficacy of Calotropis gigantea. J. Chem. Pharm. Res. 2011, 3 (6), 330–336.

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CHAPTER 39

A Review on Bioactive and Pharmacological Activities of Adansonia digitata L.: A Majestic and Universal Remedy Plant PULICHERLA YUGANDHAR1*,

CHENNAREDDY MARUTHI KESAVA KUMAR2, SADE ANKANNA2,

and NATARU SAVITHRAMMA2

Survey of Medicinal Plants Unit, Regional Ayurveda Research Institute, Itanagar 791111, Arunachal Pradesh, India

1

Department of Botany, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India

2

Corresponding author. E-mail: [email protected]

*

ABSTRACT Adansonia digitata L. is an iconic tree of African countries and is sparsely distributed in tropical countries. Almost all parts of the plant have either dietary or medicinal value. Due to this, the plant is being praised as “Kalpavriksha” in India. In this review, A. digitata has been selected to explore different bioactive, and pharmacological activities reported so far from this medicinal plant. For this, an extensive literature survey was conducted to collect the various pharmacological activities published up to 2021 through different databases or search engines like Google Scholar, Pubmed, ScienceDirect, Scopus, SpringerLink, Web of Science, etc. The relevant literature was extracted from the different databases using keywords like pharmacological activities, biological activities, and evaluation of particular activity by its Phytochemistry and Pharmacology of Medicinal Plants, Volume 1: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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name. The search results manifest around 17 types of biological activities like antibacterial, antifungal, antioxidant, anti-inflammatory, analgesic, antidepressant, antihyperlipidemic, antiulcer, antidiabetic, antigiardial, antihyperlipidemic, antitrypanosomal, hypoglycemic, antilarvicidal & repellent, neuroprotective effect, hepatoprotective and antitumor activities. Along with these, Traditional/Ethnomedicinal uses, Phytochemical analyses, and Isolation of bioactive principles were discussed in this review. 39.1

INTRODUCTION

Adansonia digitata L. commonly called as “baobab” and no one knows about the origin of this name and most of the researchers envisaged that it was derived from the Arabic word “buhibab,” indicates numerous seeds (Kaboré et al., 2011). The genus “Adansonia” was named in privilege of “Adanson” who brought the seeds from West Africa and introduced them in Paris in 1479. He was the first to describe the taxonomical description of the genus Adansonia with illustrations (Esterhuyse et al., 2001). The species “digitata” was named with reference to the shape of the leaves of this plant. Based on the geographical location, different names have been acquired by this plant like, chemist tree, magic tree, monkey bread of Africa, symbol of the earth and upside-down tree, which are the most popular ones among numerous other names (Wickens, 1982; Kaboré et al., 2011; Vermaak et al., 2011). This plant has synonyms, such as Adansonia bahobab L., Adansonia baobab Gaertn., Adansonia somalensis Chiov., Adansonia sphaerocarpa A. Chev., Adansonia sulcata A. Chev. and Baobabus digitata (L.) Kuntze. In India, the Ayurvedic texts described this plant name as Gorakshi (Yadav et al., 2017) and commonly called as Kalpavriksha, Khursani imli and Mandav imli (Singh, 2015). The native tribal people of African countries use the products of this plant as food, fiber, and medicine. The leaves of this plant have higher levels of proteins, sugars, and different mineral constituents. Ascorbic acid was reported to be present in higher quantities in pulp part of the fruit (Wickens, 1982; Sidibe and Williams, 2002; Chadare et al., 2009; Caluwe et al., 2009). The fundamental focus of the geographical distribution of the genus Adansonia is emigrated from Madagascar to Africa through West Gondwana in cretaceous period. The tree is in bottle shape, the branches are irregularly arranged with reddish brown-colored bark. When the entire leaves drop off in the autumn season, the green color layer exactly beneath the external bark can perform photosynthesis. The plant has lateral

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root structure that ends with tubers. In juvenile stage, the tree trunk is conical in shape and turned gradually into bottle-shaped structure at mature stage (Yushau et al., 2010). A. digitata is an iconic tree of African countries and is sparsely distributed in tropical countries. Different parts of the plant (stem bark, fruits, leaves, and seeds) provide livelihood to the aboriginals of African countries and this plant is the main source of fiber, food, and medicine (Codjia et al., 2001; Sidibe and Williams, 2002; Caluwe et al., 2009; Chadare et al., 2009). The major reports on the applications of this plant include, augmentation of the immune system (Rahul et al., 2015), analgesic properties of the extracts (Khan et al., 2006), anti-inflammatory, and antioxidant activities (Ibrahim, 2015), treated for dysentery and diarrhea (Kamatou et al., 2011), has pesticidal (Caluwe et al., 2010) larvicidal and insect repellent properties (Krishnappa et al., 2012). Due to the medicinal importance, the exports of baobab products are commercialized and increasing the pressure on this plant day by day. This plant has several vernacular names, such as tartar cream (taste like tartar cream), dead rat tree (appearance of fruits), monkey bread tree (dry edible and soft fruit), and upside-down tree (resemblance of branches like roots). It can reach up to a height of 5–25 meters and girth up to 10–14 meters. The trunk of the plant is in bottle shape, smooth, shiny brown/ gray in color and the bark is scaly in texture. The branches are wide, strong, and short when compared with the trunk. Leaves are alternatively arranged and have 2–3 foliate structures with deciduous nature and are completely shed down in spring season. Flowers are mushy and whitish yellow-colored, blooming begins between 08 and 23 years. Flowers are large, have 24 h. of life span after blooming, 12 cm in size, nocturnal, sepals 5, cup-shaped, united to form cleft, petals 5, leathery and hairy inside, stamens numerous, stigmas 7–10. The fruit surface is gritty in nature and the seeds are covered with yellow-colored pulp. Glittering black or brownish colored homogenous sized seeds covered with hard coat of testa. The trees grow leafless up to 9 months in a year, they are large, apparent, grow individually in the savannah or scrub forests and have nearly thousand years of life span (Varmah and Vaid, 1978). The tree holds a large number of immense white flowers. These pretentious pendulous flowers have numerous stamens, disperse the carrion scent to attract bats, which helps in pollination. After pollination, the tree bears large-sized fruits having a huge quantity of dried pulp with numerous seeds, the pulp appears like chunks of bread powder.

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39.2 TRADITIONAL/ETHNOMEDICINAL USES Almost all parts of this plant registered their medicinal uses for curing more than 300 types of ailments (Buchmann et al., 2010). In India, the tender leaf paste is used for external application in relieving swellings. Whereas the extractions or different forms of the matured leaves are used for the treatment of urinary tract infections, infestation of guinea worms, internal pains and as a tonic. West African countries used dried leaf powder as insect repellent, oral intake of capsule form of the leaf acts as astringent and reduce the excessive sweating (Denloye et al., 2006). In Ghana, decoction of stem bark has been used to treat different types of fevers (Shukla et al., 2001). The seed oil is used for the treatment of diarrhea and it reduces the continuous hiccoughs (Caluwe et al., 2009). In Africa, the tribals chew the dried stem bark to get relief from malaria and related fevers (Wickens and Lowe, 2008). The fruit pulp has been used for the treatment of dysentery and diarrhea (Sidibe and Williams, 2002). In Mali, the external application of fruit pulp is used for the treatment of joint pains (Wickens and Lowe, 2008). The Sub-Saharan African people utilized stem, leaf, fruit and seeds for the treatment of various types of diseases, such as anemia, diarrhea, dysentery, malaria, microbial infections, toothache, and tuberculosis (Caluwe et al., 2010; Kaboré et al., 2011; Vermaak et al., 2011). In Nigeria, the leaves are used for the treatment of fever and the fruit pulp is used to boost the immune system (Caluwe et al., 2009). The roots, stem bark, leaves, fruit pulp, and seeds are best resource for different types of phytochemicals. There are number reports available on phytochemical analysis of different parts of the pant. 39.3

PHYTOCHEMICAL ANALYSIS

Different types of phytochemical analysis were carried out by different researchers. Talari and Nanna (2015) extracted floral parts, fruit wall, leaves, seeds, and stem bark of A. digitata with acetone, distilled water, methanol, and petroleum ether for analyzing phytochemicals in vitro. About 11 types of tests were performed to know the presence of different types of phytochemicals. The results reveal that all the plant parts possess high concentrations of alkaloids, glycosides, flavonoids, tannins, saponins, phenols, lignins, and lower concentrations of quinones and sterols. Based on the results, authors specified that the subjected plant is the store house for different types of phytochemicals. Mumtaz et al. (2016) used butanol, distilled water, ethyl acetate, and n-hexane for the extraction of phytochemicals from plant leaves. The qualitative phytochemical analysis revealed the presence of different types of phytochemicals.

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Among all the extracts, aqueous extract showed a number of phytochemicals when compared with the other solvents. Ogbaga et al. (2017) analyzed the presence of phytochemicals, such as alkaloids, flavonoids, glycosides, resins, saponins, steroids, and tannins from stored, sun-dried and shade-dried leaves. All the analyzed plant parts revealed the presence of glycosides, saponins, steroids, flavonoids, and the absence of alkaloids, tannins, and resins from the above-specified different types of leaves. Kamanula et al. (2018) extracted root tubers with distilled water and performed the phytochemical screening to know the presence of phytochemicals, suh as alkaloids, flavonoids, saponins, and terpenoids. The analysis revealed the presence of only saponins and terpenoids in the sample. Arowora et al. (2019) quantified different concentrations of alkaloids, anthraquinone, cardiac glycosides, flavonoids, phenols, phlobatanins, saponins, steroids, tannins, and terpenoids using standard protocols. From the results, highest concentration of phenols was present in the leaves when compared with other types of phytochemicals. Aliyu et al. (2020) extracted plant leaves with ethanol to analyze the presence of different types of phytochemicals, such as alkaloids, flavonoids, glycosides, phenols, saponins, tannins, and terpenoids. The analysis revealed the presence of flavonoids, glycosides, terpenoids, and phenols in the extract. 39.4

ISOLATION OF BIOACTIVE PRINCIPLES

Shahat (2006) extracted A. digitata fruit pericarp with 80% aqueous methanol and concentrated with rotary evaporator, defatted by extracting two times with petroleum ether and four times with EtOAc. The obtained solid material was dissolved in methanol, chromatographed with Sephadex LH-20 column, and monitored with TLC. The extraction procedure was repeated and the obtained fractions were subjected to column chromatography. The analyses of obtained fractions from column chromatography using NMR revealed the presence of five compounds, such as (-)-epicatechin, epicatechin-(2β→O→7, 4β→8)-epicatechin, epicatechin-(4β→6)-epicatechin, epicatechin-(4β→8)epicatechin, and epicatechin-(4β→8)-epicatechin-(4β→8)- epicatechin (Fig. 39.1). Li et al. (2017) tried to isolate different types of compounds from dried fruit pulp of A. digitata and characterize those fractions with HRMS, 1H and 13C NMR and 2D experiments. The dried plant powder was extracted with 70% EtOH-H2O (v/v) for three times and dissolved it into 750 mL of H2O and partitioned into ethyl acetate and n-butanol. The obtained ethyl acetate fraction was subjected to UHPLC-DAD-HRMS-MS, 1H and 13C NMR analyses. The obtained results confirm the presence of nearly 13 types of compounds.

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All of these compounds were categorized into different types of glycosides, such as hydroxycinnamic acid glycosides, iridoid glycosides, and phenylethanoid glycosides (Fig. 39.1). Braca et al. (2018) collected leaf and fruit part of A. digitata from Mali for the extraction, isolation, and antioxidant analysis of phenolic compounds. For this, the plant material was extracted with n-hexane followed by methanol and partitioned into n-butanol and water fractions. The n-butanol fraction was dissolved in methanol, centrifuged, and the supernatant was subjected to analyze using HPLC coupled with PDA-UV-ESI-MS/ MS. The results reveal that a total of 26 procyanidin and flavonol glycosides were isolated. Among all the compounds, tiliroside was considered as major constituent (Fig. 39.1). The fruit pulp extract showed higher antioxidant activity against DPPH than the leaves, and was similar to that of Trolox which was used as a standard control.

FIGURE 39.1 digitata.

Different types of bioactive compounds isolated from different parts of A.

Source: Structures were drawn with the help of chemdraw and pubchem online software tools.

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Ismail et al. (2019a) focused on quantification, isolation, and antioxidant activity of compounds from fruit pulp of the plant. The phenols and flavonoids were quantified according to the standard methods using gallic acid and rutin as standard compounds with different combinations of solvents. The isolation of compounds were carried out with HPLC, LC-MS/QTOF, and finally antioxidant activity was carried out against DPPH and ferric reducing antioxidant power. From the results, 30% and 80% acetone are the best suitable solvent for the extraction of higher quantities of phenols and flavonoids, respectively. From the HPLC and LC-MS/QTOF analyses, the plant revealed the presence of nearly 46 compounds. The obtained compounds were categorized into flavonols, phenolic acids, proanthocyanidins, and saponins. The acidic acetone has significant DPPH inhibitory activity and 50% and 80% methanol showed highest ferric reducing antioxidant power. Ismail et al. (2019b) focused on the isolation of different types of compounds from fruit shells and analyzed the fractions through LC-MS/QTOF analysis. Along with these, antioxidant and antidiabetic tests were carried out in this study. The analysis revealed the presence of nearly 45 types of compounds. Among them, quercetin, kaempferol, proanthocyanidins, and phenolic acids were considered as main constituents and the extracts showed significant antioxidant and antidiabetic activities. Ibraheem et al. (2021) investigated the phytochemical profile and biological activities of A. digitata fruit pulp that has grown in Sudan. The fruit pulp was extracted with methanol and subjected to LC-MS and 1H-NMR analyses, then analyzed the antioxidant, alpha-glucosidase, and nitric oxide inhibitory activities. The detailed analysis of methanolic fruit fractions revealed the presence of nearly 52 types of compounds. It includes different types of compounds, such as adenosine, flavonoids, iridoids, lipids, organic acids, phenols, scopoletin, sugars, and taraxerone. The fruit pulp extract inhibited the generation of NO at 36.55 μg/ mL and IC50 value in the stimulated RAW264.7 cells with 98.45% inhibition and α-glucosidase enzyme activity at 58.59 μg/mL IC50 value with 97.94% inhibition. 39.5 PHARMACOLOGICAL ACTIVITIES 39.5.1 ANTIBACTERIAL ACTIVITY Abiona et al. (2015) analyzed the antimicrobial activity of aqueous leaf extract against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, Salmonella typhi, Klebsiella pneumoniae,

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Candida albicans, Aspergillus niger, Rhizopus stolonifer, Penicillium notatum using well diffusion method. For this, 6.25, 12.5, 25, 50, 100, and 200 mg/mL concentration of plant extract, 10 μg/mL concentrations of gentamycin, and tioconazole were used as standard drugs for bacteria and fungi, respectively. From the results, it is known that 200 mg/mL concentration of the leaf extract showed higher antimicrobial activity against S. aureus and C. albicans of bacteria and fungi, respectively. Singh (2015) tried to establish the callus by using A. digitata leaves and studied the antibacterial activity against Staphylococcus aureus. For this, methanolic and aqueous extracts of both the leaves and callus were prepared. Equal volumes of the extracts, 1 mg/mL concentration of ampicillin were loaded in 6 mm agar wells and incubated at 37°C temperature up to 24 h. The results revealed that the methanolic and aqueous leaf extracts showed highest zone of inhibition against S. aureus when compared with callus extract. Abdoulaye et al. (2018) extracted A. digitata leaves with methanol and evaluated the antibacterial activity against Escherichia coli (CIP) 54127AF, Pseudomonas aeruginosa (CIP) 103,467, Staphylococcus aureus ATCC 25923, Staphylococcus aureus (CIP) 4.83, and Staphylococcus aureus were sensitive to penicillin using agar well method according to the standard protocol. About 50 μL of 1500 μg/mL concentration of methanolic plant extract and 25 μg/mL concentrations of tetracycline and gentamycin were taken as positive controls that were dissolved in DMSO. The prepared aliquots were poured in agar wells and incubated up to 18 h. at 37°C temperature. Among the tested different types of bacterial strains S. aureus sensitive to penicillin and S. aureus (CIP) 4.83 showed highest zone of inhibition. Abdallah and Ali (2019) extracted the stem bark and leaves with water, ethanol, and chloroform to evaluate the antibacterial activity against Escherichia coli and Salmonella typhi using agar well diffusion method. From the extracts, the ethanolic leaf extract showed highest antimicrobial activity against E. coli when compared with the remaining extracts. It is due to the leaf part of the plant having more number of phytochemicals when compared with the stem bark. Hussein and Hamad (2020) extracted the seed oil using hexane and analyzed the antimicrobial activity against Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans using surface viable counting technique. The 100 mg/mL concentration of seed oil extract, gentamycin and clotrimazole were used for checking the activity. From the results, seed oil extract showed highest antimicrobial activity against C. albicans when compared with the other microorganisms.

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39.5.2 ANTIFUNGAL ACTIVITY

Samatha et al. (2018) extracted leaf, flower, fruit wall, seed, and stem bark with methanol and analyzed their antifungal activity against Aspergillus and Penicillium stains using agar well diffusion method. For this, 100 μL of crude extract was poured into the wells and incubated at 37°C temperature up to 72 h. From the results, stem bark extract showed highest zone of inhibition against both the species when compared with the other parts of the plant. 39.5.3 ANTIOXIDANT ACTIVITY Vertuani et al. (2002) analyzed the antioxidant capacity of aqueous and methanolic extracts of leaf and fruit pulp. Photochemiluminescence method was used by photochemical generation of free radicals and antioxidant inhibition with luminal, it works as photosensitizer and oxygen radical detecting reagent. The Trolox was taken as reference compound and analyzed the different concentrations of extracts with Trolox calibration curve. From the results, fruit pulp extracts showed highest antioxidant activity when compared with leaf extracts. Ibrahim et al. (2014) tried to isolate polysaccharides from the fruit pulp of A. digitata with gel permeation chromatography. The HPLC analysis revealed that the isolated fraction contains fructose and glucose. Thereafter, they evaluated the in vitro antioxidant activity against free radical scavenging, metal chelating, superoxide anion scavenging, hydrogen peroxide scavenging, and nitric oxide radical scavenging activities with 75, 150, 300, and 600 μg/mL concentrations. The results revealed that 300 and 600 μg/mL concentrations showed 100% chelating effect against free radical, metal, superoxide anion, hydrogen peroxide, and 96% of nitric oxide scavenging activities. The polysaccharides of A. digitata fruit pulp have significant antioxidant activity when compared with the standard antioxidants. Samatha et al. (2017) extracted flowers, fruit wall, leaves, seeds, and stem bark powders with methanol to evaluate the in vitro antioxidant activity using DPPH assay. For this 2 mL of 200, 400, 600, 800, 1000 μg/mL of concentrations of all the extracts were prepared and analyzed against 4 mL of DPPH solution at 517 nm with Spectrophotometer. From all the parts, seed extract showed highest antioxidant activity when compared with the remaining parts. From this study, they concluded that the presence of highest concentrations of phenols and flavonoids in the seed extract directly contributed for highest free radical scavenging potential. Singh and Shashi (2017)

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extracted the stem bark and fruit pulp with distilled water and methanol to analyze the antioxidant activity. For this, phosphomolybdenum method was used and ascorbic acid was taken as a standard control. The results showed that methanolic fruit pulp extract showed highest antioxidant activity when compared with stem bark extract. It may be due to that the fruit pulp extract has higher concentrations of phenols and flavonoids. Josiane et al. (2020) taken different granulometric classes, that is, 100 μm sized fruit pulp particles of A. digitata to study the content of phenolic compounds and its effect on antioxidant activities against DPPH, ABTS and power reducing tests. The results proved that the granulosites 250 mg/dL blood glucose level were selected for further studies. The petroleum ether and ethyl acetate extracts were administered orally at the dose of 100 and 300 mg/kg, respectively. Metformin was given as a stan­ dard drug at a dose of 50 mg/kg. The fasting (FBS) and postprandial blood glucose (PLBS) levels were estimated through glucose-oxidase assay. FBS and PLBS levels from the animals treated with petroleum ether seed extract (300 mg/kg) were 270.83 ± 4.36 and 148.95 ± 1.38 mg/dL as compared to the control (94.4 ± 3.80 and 132.5 ± 2.5 mg/dL, respectively). A marked decrease in the level of serum cholesterol, triglycerides, LDL, HDL, and a decrease in VLDL levels was found in diabetic rats treated with petroleum ether seed extract of H. laurifolia. The treatment of the extract (100 mg/kg) exhibited a significant decrease in the level of serum cholesterol (122.82 ± 1.52 mg/dL), triglycerides (97.38 ± 1.00 mg/dL), HDL (37.4 ± 0.51 mg/dL), and LDL (84.5 ± 3.19 mg/dL). It was also observed that the VLDL levels increased (27.5 ± 0.43 mg/dL) significantly and the values were almost near to the normal rats (23.5 ± 0.43 mg/dL). Similarly, the extract at the dose of 300 mg/kg also showed a significant reduction in the level of serum cholesterol (106.93 ± 1.48 mg/dL), triglycerides (87.85 ± 1.22 mg/ dL), LDL (81.17 ± 2.70 mg/dL), and HDL (43.7 ± 1.04 mg/dL). A potent hypolipidaemic effect of the extract at 100 mg/kg was also evident by a significant reduction in the serum cholesterol, triglycerides, LDL, and VLDL levels in diabetic rats and also by the marked increase in the HDL levels in the extract-treated rats (Rao and Mohan, 2014). Antihyperglycemic activity of petroleum ether and ethyl acetate extracts of H. laurifolia seeds were evaluated using male Wistar rats (Rao et al., 2014). Diabetic animals treated with petroleum ether seed extract (300 mg/ kg p.o.) showed the highest (148.31 ± 1.49 mg/100 mL) reduction in the blood sugars after 4 h of treatment. Similar trend was recorded for the ethyl acetate seed extract wherein blood sugar was 155.83 ± 6.54 mg/100 mL. Reddy et al. (2005) studied α-glucosidase inhibitory activity of the acetone extract and isolated fractions (luteolin and isohydnocarpin) from the shadedried seed hulls of H. wightiana. Among all the samples, the α-glucosidase inhibitory potentiality was reported in the isolated hydnocarpin (IC50 21.55 µM), luteolin (IC50 23.52 µM), and isohydnocarpin (23.9 µM). α-Glucosidase inhibitory potential for luteolin was stronger than the extract followed by

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isohydnocarpin. Isolated luteolin and isohydnocarpin have the equal poten­ cies to inhibit the enzyme. Flavonolignans such as hydnocarpin, neohydno­ carpin, and hydnowightin isolated from H. weightiana also demonstrated the potential hypolipidemic activity in mice by lowering serum cholesterol and triglyceride levels (Sharma, 1991). 45.3.4 LARVICIDAL POTENTIAL The leaf extract of H. pentandrus showed potential larvicidal activity against II and IV instar larvae of Aedes aegypti in a dose-dependent manner. The susceptibility of stage II instar larvae was high against leaf extract when compared to stage IV. All the concentrations of extract (0.25–2.0 mg/mL) effectively caused the mortality of II instar larvae, while the extract at 0.25 mg/mL did not cause any effects to IV instar larvae. However, it was observed that the extract at 1 and 2 mg/mL caused the highest mortality (>50%) in II and IV instar larvae. Mortality of larvae was recorded highest (96.66 ± 05.77%) in II instar larvae as compared to IV (70.00 ± 10.00%) at 2 mg/mL concentration. The LC50 values of extract were 0.79 and 1.37 mg/mL recorded against II and IV instar larvae, respectively (Kekuda et al., 2017). A significant insecticidal activity of fatty acid rich fraction obtained from the petroleum ether extract of H. laurifolia seeds was found against rice bug, Leptocorisa acuta with LC50 8 mg/mL (Sini et al., 2005). Sivaraman et al. (2014) carried out the larvicidal activity of H. pentandra seed extracts against third instar larvae of Culex quinquefasciatus Say and A. aegypti L. mosquito species. The median lethal concentration values (LC50 and LC90) were found least in the chloroform extract, proving its efficacy in the treatment. The LC50 and LC90 values of chloroform extract were 248.28 and 731.62 ppm, respectively for A. aegypti, whereas for C. quin­ quefasciatus, they were 89.52 and 678.48 ppm, respectively. LC50 and LC90 values of hexane extract were 853.45 and 1538.83 (A. aegypti) as well as 130.74 and 1062.34 ppm (C. quinquefasciatus), respectively. Ethyl acetate extract against C. quinquefasciatus showed 543.72 and 1035.46 ppm LC50 and LC90 values, respectively. Similarly, methanol extract showed LC50 and LC90 values of 936.29 and 1776.32 ppm against A. aegypti. Comparatively higher LC50 and LC90 values (1144.76 and 2202.70 ppm) were noted for C. quinquefasciatus. The larvicidal activity was also found to be concentration dependent.

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45.3.5 ANTIOXIDANT ACTIVITY Acetone seed extract of H. wightiana possessed strong DPPH radical scavenging activity (RSA) (Reddy et al., 2005). Fractionation of the extract resulted in the isolation of hydnocarpin (1.4% w/w), luteolin (1.4% w/w) and isohydnocarpin (0.17% w/w). Hydnocarpin and isohydnocarpin failed to exhibit antioxidant activity. The strongest DPPH RSA was reported from the acetone extract that might be due to the higher concentration of luteolin present in it. All the tested compounds including extract revealed promising ABTS RSA. The highest activity was reported from luteolin (1.32 µM) followed by extract (2.21 µg/mL) and isolated fractions, such as isohydno­ carpin (6.12 µM) and hydnocarpin (7.5 µM) (Reddy et al., 2005). Krishnan et al. (2013) investigated free radical scavenging activities of ethyl acetate, hexane, and methanol extracts of H. pentandrus whole plant, through 1,1-diphenyl-2-picryl-hydrazyl (DPPH), thiobarbituric acid (TBA), and ferric thiocyanate (FTC) methods. RSA at a concentration of 160 µg/mL recorded the highest for ethyl acetate extract (66%) followed by methanolic extract (44%) when compared with standard alpha-tocopherol (84%). The superoxide dismutase activity was conducted for both the extracts, where ethyl acetate extract (0.402) found to have appreciable activity compared to α-tocopherol (0.632). Similar trend was recorded for metal chelating activity. It was observed from the dose-dependent response curve that the ethyl acetate extract showed higher DPPH RSA over methanol and hexane extracts. Based on these findings, the ethyl acetate extract of H. pentandrus proved its excellence in free radical scavenging activities. Yuvaraja et al. (2018) carried out in-vitro antioxidant activity of H. lauri­ folia chloroform extract through DPPH, total reduction capability, superoxide anion, hydroxyl free radicals, and lipid peroxidation assays using standard protocols. The extract exhibited the strongest in-vitro antioxidant activity as confirmed by the scavenging of DPPH (IC50 320 µg/mL), reduction of Fe3+ to Fe2+ (EC50, 320 µg/mL), hydroxyl (IC50 290 µg/mL) radicals, superoxide anion (IC50 280 µg/mL), and inhibition of lipid peroxidation (IC50 230 µg/ mL). 45.3.6 ANTI-INFLAMMATORY ACTIVITY Anti-inflammatory activity of flavonolignan compounds (hydnowightin, hydnocarpin, and neohydnocarpin) obtained from H. wightiana seeds was studied in mice in vivo (Sharma, 1991). Male mice (ca. 25 g) were

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administered with test drugs at 8 mg/kg dissolved in 0.05% Tween 80. Hydnocarpin at 8 mg/kg demonstrated anti-inflammatory activity by 42% lowering the induced edema, comparable to phenylbutazone (50 mg/kg) but not as effective as indomethacin. The compounds hydnowightin and neohyd­ nocarpin responded poorly as compared to hydnocarpin, phenylbutazone, and indomethacin. Hydnowightin and neohydnocarpin showed a decrease in the induced edema by 24 ± 3 and 6 ± 2%, respectively (Sharma, 1991). 45.3.7 CYTOTOXICITY Sharma (1991) studied the cytotoxicity of different compounds of Hydnocarpus using murine and human tissue culture cell lines. All three compounds (hydnowightin, hydnocarpin, and neohydnocarpin) were active against colon adenocarcinoma, murine L-1210 lymphoid leukemia, HeLa-S uterine carcinoma, KB nasopharynx, and bone osteosarcoma (ED ≤ 4 µg/ mL). Hydnocarpin revealed promising activity against the reduction of Ehrlich ascites carcinoma growth in CF1 mice and demonstrated 84.75% inhibition of tumor growth. In contract, all the reported compounds were found inactive against lung bronchogenic growth. KEYWORDS • • • • •

Hydnocarpus anticancer hydnocarpin wound healing seed oil

REFERENCES Bhat, K. G. Flora of Udupi; Indian Naturalist: Udupi, 2003. David, T.; George, K. V. HPTLC Analysis of the Leaf Extract of Hydnocarpus macrocarpa (Beddome) Warb. J. Pharmacogn. Phytochem. 2014, 3 (1), 43–51. Habeeb, M. N. Preliminary Phytochemical Screening of Seeds and Leaves of Hydnocarpus wightiana Blume. Int. J. Sci. Res. 2017, 6 (4), 998–1000.

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Joshi, A. B.; Harijan, K. C. Physicochemical and Phytochemical Investigation of the Roots of Hydnocarpus pentandrus (Buch.-Ham.) Oken. Int. J. Pharm. Sci. Rev. Res. 2014, 25 (1), 260–265. Kekuda, T. R. P.; Kenie, D. N.; Chetan, D. M.; Raghavendra, H. L. Phytochemical Analysis, Antimicrobial, Insecticidal and Antiradical Activity of Hydnocarpus pentandra (Buch.-Ham.) Oken. Int. J. Phytomed. 2017, 9 (4), 576–583. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants; Vols. 1–11; Oriental Enterprises: Uttaranchal, 2001. Kishan, K. G.; Shekshavali, T.; Kuppast, I. J.; Kishan Kumar, M. A.; Patil, J. A Review on Hydnocarpus wightiana. Res. J. Pharmacol. Pharmacodyn. 2016, 8 (4), 168–170. Krishnan, M. S.; Dhanalakshmi, P.; Yamini Sudhalakshmi, G.; Gopalakrishnan, S.; Manimaran, A.; Sindhu, S.; Sagadevan, E.; Arumugam, P. Evaluation of Phytochemical Constituents and Antioxidant Activity of Indian Medicinal Plant Hydnocarpus pentandra. Int. J. Pharm. Pharm. Sci. 2013, 5 (2), 453–458. Mariyaraj, J.; Anand Gideon, V.; John Britto, S.; Francis, S. Pharmaceutical Activities of Certain Phytochemicals from the Leaf and Stem of Hydnocarpus macrocarpus. Biosci. Biotech. Res. Commun. 2019, 12 (4), 1134–1140. Oommen, S. T.; Rao, M.; Raju, C. V. N. Effect of Oil of Hydnocarpus on Wound Healing. Int. J. Leprosy. 1999, 67 (2), 154–158. POWO. Plants of the World Online. Facilitated by the Royal Botanic Gardens, Kew, 2019. Published on the Internet. http://www.plantsoftheworldonline.org/ (retrieved on Feb 02, 2021). Rajput, M.; Navneet. Antimicrobial Potential of Hydnocarpus laurifolia Seeds Utilized in Folkloric Medicine: A Possible Alternative in the Treatment of Scalp Infections. Pharm. Innov. J. 2019, 8 (1), 1–5. Rao P. S.; Krishna Mohan, G.; Prathima, S. Evaluation of Anti-Diabetic Activity of Hydnocarpus laurifolia in Streptozotocin Induced Diabetic Rats. Asian J. Pharm. Clin. Res. 2014, 7 (5), 62–64. Rao, P. S.; Mohan, G. K. Beneficial Effects of Hydnocarpus laurifolia Seed on Lipid Profile Status in Streptozotocin Induced Diabetic Rats. J. Pharm. Res. 2014, 8 (9), 1274–1278. Reddy, S. V.; Tiwari, A. K.; Sampath Kumar, U.; Rao, R. J.; Rao, J. M. Free Radical Scavenging, Enzyme Inhibitory Constituents from Antidiabetic Ayurvedic Medicinal Plant Hydnocarpus wightiana Blume. Phytother. Res. 2005, 19, 277–281. Sahoo, M. R.; Dhanabal, S. P.; Jadhav, A. N.; Reddy, V.; Muguli, G.; Babu, U. V.; Rangesh, P. Hydnocarpus: An Ethnopharmacological, Phytochemical and Pharmacological Review. J. Ethnopharmacol. 2014, 154, 17–25. Saldanha, C. J. Flora of Karnataka; Vols. 1, 2; Oxford and IBH Publishers: New Delhi, 1984. Sharma, D. K. Hypolipidemic, Anti-Inflammatory, and Antineoplastic Activity and Cytotoxicity of Flavonolignans Isolated from Hydnocarpus wightiana Seeds. J. Nat. Prod. 1991, 54 (5), 1298–1302. Shi, H. M.; Wen, J.; Jia, C. Q.; Jin, W.; Zhang, X. F.; Yao, Z. R.; Tu, P. F. Two New Phenolic Glycosides from the Barks of Hydnocarpus annamensis and Their Anti-Inflammatory and Anti-Oxidation Activities. Lett. Plant. Med. 2006, 72, 948–950. Shi, H. M.; Yao, Z. R.; Chai, X. Y.; Xu, Z. R.; Zhou, Y. H.; Wen, J.; Tu, P. F. A New Phenolic Glycoside from the Stems of Hydnocarpus hainanensis. Nat. Prod. Res. 2008, 22 (7), 633–637.

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Sini, H.; Mohanan, P. V.; Devi, K. S. Studies on the Insecticidal Activity, Cytogenecity and Metabolism of Fatty Acid Rich Fraction of Hydnocarpus laurifolia. Toxicol. Environ. Chem. 2005, 87 (1), 91–98. Sivaraman, G.; Paulraj, M. G.; Rajiv Gandhi, M.; Reegan, A. D.; Ignacimuthu, S. Larvicidal potential of Hydnocarpus pentandra (Buch.-Ham.) Oken Seed Extracts Against Aedes aegypti Linn. and Culex quinquefasciatus Say (Diptera: Culicidae). Int. J. Pure Appl. Zool. 2014, 2 (1), 109–112. Yuvaraja, K. R.; Santhiagu, A.; Jasemine, S. Antioxidant and Hepatoprotective Potential of Hydnocarpus laurifolia: An In Vitro and In Vivo Evaluation. J. Pharm. BioSci. 2018, 6 (3), 43–49.

CHAPTER 46

Chemical Principles, Bioactivity, and Pharmacology of Hedychium spicatum Sm. (Family: Zingiberaceae) SINJUMOL THOMAS1, K. J. BINIMOL1, and BINCE MANI2* 1Department

of Botany, Carmel College, Mala, Thrissur, Kerala 680732,

India 2Department

of Botany, St. Thomas College Palai, Kottayam, Kerala 686574, India *Corresponding

author. E-mail: [email protected]

ABSTRACT Hedychium spicatum is a valuable medicinal plant commonly known as spiked ginger lily. It has been used in folk and traditional medicine to treat various diseases such as cough, asthma, pain, hiccough, bronchitis, indiges­ tion, inflammation, diarrhea, vomiting, pain, liver problems, fever, etc. It has also been used as expectorant, vasodilator, stimulant, tonic, stomachic, anti­ dote, and blood purifier. The volatile oil isolated from H. spicatum is rich in 1,8-cineole, α-pinene, β-pinene, linalool, 10-epi-γ-eudesmol and β-selinene which are having pharmacological applications. Various kinds of secondary metabolites of furanoid diterpenes, labdane diterpenes, flavonoids, phenolic compounds, phytosterols, etc., were also reported from H. spicatum. Different solvent extracts and most of the compounds that have been reported have bioactivities like anticancer and cytotoxicity, anti-hyperglycemic, antioxi­ dant, antibacterial, antifungal, hair growth-promoting, and hepatoprotective properties. Moreover, this plant is widely used by horticulture growers due to its lovely flowers and foliage. Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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46.1

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

INTRODUCTION

Hedychium spicatum Sm. is an aromatic perennial herb belonging to Zinigiberaceae, listed under vulnerable category, popularly known as “shati” in Bengali and “spiked ginger lily” in English (Singh et al., 2018). H. spicatum in ayurvedic trade known as “Kapurkachri” whose aromatic rhizome stock is 3.2–3.6 cm in diameter, creamy white in color, and protected by brown scales (Thomas et al., 2017; Singh et al., 2018). It is chiefly distributed in northern India, Nepal, Bhutan, Myanmar, China, and northern Thailand (Chopra et al., 1986). Its presence has been spotted from Western Ghats of Kerala in south India too (Thomas et al., 2017). The rhizome is being used as folk and traditional ethnomedicine due to its pungent, light, bitter, strong, heating properties, and used in grime of mouth, swelling, cough, asthma, pain, and hiccough (Sravani and Paarakh, 2011b). It is being utilized in different parts of India in different formulations as rhizome powder, poultice, decoction, crushed form, fresh form, paste, roasted, etc. The rhizome is chewed by local inhabitants of Uttarakhand as mouth refresher, and the paste of fresh rhizome is given with hot water to cattle and domestic animals in case of stomach disorder (Kumari et al., 2011). The aromatic rhizome is suitable for the treatment of bronchitis, indigestion, blood purification, and inflammation (Singh et al., 2018). Dried rhizome in powder form is used to treat diarrhea, asthma, vomiting, pain, liver problem, and fever, whereas rhizome decoction is an effective expectorant, vasodilator, stimulant, tonic, stomachic (Savithramma et al., 2007; Bhatt et al., 2010; Rawat et al., 2018), and antidote (Upasani et al., 2018). In Manipur, rhizome is cooked to make chutney, in Himachal Pradesh, its leaves are used in making mats for home decor combined with wheat straw, which may enhance the durability of the product (Badola, 2009). The traditional uses of H. spicatum are given in Table 46.1.

46.2

BIOACTIVES

Nutritionally and medicinally valuable compounds are isolated and char­ acterized from the scented rootstock of H. spicatum such as volatile oils, diterpenes, saccharin, albumin, starch, mucilage, glycosides, etc. Reddy et al. (2009a) isolated and characterized seven compounds from chloroform extracts of rhizomes including two new labdane-type diterpenes. The

Hedychium spicatum Sm.

55

TABLE 46.1 Traditional Uses of H. spicatum. Sl. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Plant part

Uses

References

Rhizome powder Rhizome poultice Decoction of rhizome Fruits Dried and crushed rhizome Fresh rhizome Rhizome paste Roasted powder Rhizome powder Rhizome decoction Rhizome decoction Rhizome decoction Rhizome decoction Rhizome powder Rhizome powder

Antimicrobial, laxative to brain Various acnes and pains Tuberculosis Food Incense

Badola (2009) Badola (2009) Badoni et al. (2010) Arora and Pandey (1996) Badola (2009)

Scent Hair loss Asthma Dye Tonic to brain Expectorant, vasodilator Antidote (Snake-bite) Indigestion, high fever Vomiting, hiccough, bronchitis Asthma, laxative, inflammation

Badola (2009) Rawat et al. (2017) Badola (2009) Rawat et al. (2017) Badola (2009) Rawat et al. (2018) Upasani et al. (2018) Malla et al. (2015) Bhatt et al. (2010) Savithramma et al. (2007)

molecules such as hedychilactone D (7-hydroxy,6-oxo-7,11,13-labda­ trien-16,15-olide) and 9-hydroxy hedychenone (9-hydroxy-15,16-epoxy­ 7,11,13(16)14-labdatetraen-6-one) were two new compounds, and known compounds such as hedychilactone B, hedychilactone C, yunnacoronarin A, chrysin, and teptochrysin were also characterized. It is quite interesting that all these phytoconstituents were cytotoxic. In another study Reddy et al. (2009b) isolated eight compounds including two new labdane-type diterpenes from dichloromethane/methanol (1:1) extracts of rhizome. The compounds isolated were 7-hydroxy hedichinal (new), spicatanoic acid (new), yunnacoranarin D, coronarin-E, 8(12) drimene, 4-methoxy ethyl cinnamate, ethyl cinnamate, and chrysin. Interestingly, all these compounds showed cytotoxic potential against cancer cell lines. Reddy et al. (2009c) also isolated two new labdane-type diterpenoids and seven known compounds from hexane fraction of rhizome of H. spicatum. Molecules such as spicatanol and spicatanol methyl ether were the new compounds and known compounds such as 6-oxo-7,11,13-labdatrien­ 16,15-olide (hedychelactone D), hedychenone, 7-hydroxy hedyche­ none, yunnacoronarin D, 7-acetoxy hedychenone, 8(12) drimene, and

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hedychilactone B were also isolated. Fractionation and characterization of methanol extracts of rhizomes resulted in the identification of four known compounds first time from H. spicatum such as β-sitosterol, stigmasterolD-glucoside, β-sitosterol-D-glucoside, and lupeol (Sravani et al., 2012). A detailed account on the phytochemical diversity in H. spicatum is given in Table 46.2. TABLE 46.2 Phytochemical Constituents (Nonvolatile) Reported from H. spicatum. Sl. Class No. 1. Furanoid diterpene 2. 3.

Flavonoid Labdane diterpene

4.

Phenolic compounds

5. 6.

Carotenoids Phytosterol

Compounds

References

Hedychenone; 9-hydroxy hedychenone; 7-hydroxy hedychenone Chrysin, Teptochrysin Hedychilactone B; Hedychilactone C; Hedychilactone D; yunnacoronarin A; yunnacoronarin D; 18-spicatanol; spicatanol methyl ether, 7-hydroxy hydichinal; Coronarin E; 8(12) drimene; spicatanoic acid 4-methoxy ethyl cinnamate; ethyl cinnamate; Ethyl-trans-p-methoxy cinnamate; p-methoxy cinnamic acid; ethyl p-methoxycinnmate Xanthophyll; α-Carotene; β-Carotene β-sitosterol; stigmasterol-Dglucoside; β-sitosterol D-glucoside

Sharma et al. (1975), Reddy et al. (2009a), and Sharma et al. (1976) Reddy et al. (2009a) Reddy et al. (2009a), Reddy et al. (2009b), and Reddy et al. (2009c)

Reddy et al. (2009c), Rao et al. (2011), Verma and Padalia (2010), and Suresh et al. (2013) Reddy et al. (2009c) Sharma et al. (1976)

Studies on volatile oil composition and its biological properties in H. spicatum are elaborate. H. spicatum essential oil composition was examined by various authors from different parts of the world such as Garag et al. (1977), Dixit et al. (1977), Nigam et al. (1979), Bottini et al. (1987), Sabulal et al. (2007), Joshi et al. (2008), Verma and Padalia (2010), Prakash et al. (2010), Raina and Negi (2015), Semwal et al. (2015), Mishra et al (2015), and Arumugam et al. (2021). Rhizome contains about 4% essential oils have 1,8-cineole as major component (27–75%), followed α-pinene, β-pinene, linalool, 10-epi-γ-eudesmol and β-slinene were reported in significant quality (Joshi et al., 2008; Koundal et al., 2015). Besides its essential oil contains limonene, camphor, linalyl acetate, β-terpineol, borneol, β-caryophyllene, γ-cadinene, humulene, terpinolene, p-cymene, benzyl-cinnamate, benzyl-acetate, lindyl-acetate, γ-terpinene, β-phellandrene, methyl paracumarin acetate, cinnamic ethyl acetate, ethyl

Hedychium spicatum Sm.

57

p-methoxycinnamate, ethyl cinnamate, d-sabinene, cadinene, etc. (Joshi et al., 2008; Koundal et al., 2015; Sravani et al., 2012; Verma and Padalia, 2010). GCMS studies of volatile oil fractions by Mishra et al. (2015) from different populations of west Himalaya specimens revealed terpenoids in the following ratio in essential oil such as, α-pinene (0.00–0.53%), sabi­ nene (0.13–0.67%), limonene (0.08–0.60%), 1,8-cineole (5.00–25.78%), 4-thujanol (0.00–0.10%), linalool (0.40–4.05%), 4-terpineol (0.17– 0.51%), α-terpineol (0.35–0.87%), copaene (0.03–0.59%), α-cubebene (0.00–0.10%), β-cadinene (1.74–6.77%), β-caryophyllene (0.57–1.46%), α-muurolene (0.41–1.19%), τ-elemene (0.00–0.57%), cubenol (1.65– 8.85%), β-farnesene (0.06–0.40%), furanoid (0.00–0.93%), hedycaryol (1.10–22.38%), germacrene D (0.00–0.38%), spathulenol (1.67–13.33%), germacrene D-4-ol (0.47–3.51%), caryophyllene oxide (0.04–0.23%), aromadendrene (0.00–0.18%), τ-eudesmol (0.00–12.35%), β-eudesmol (0.00–26.57%), α-eudesmol (0.24–1.29%), τ-muurolene (0.00–0.98%), and τ-muurollol (0.00–6.63%). Almost similar results were obtained in a comprehensive study on essential oil composition of sixteen natural populations of H. spicatum growing in diverse habitats of west Himalaya (Rawat et al., 2020). Moreover, various studies showed that the essential oil obtained from H. spicatum is having various biological and pharma­ cological properties (Dixit and Varma, 1975, 1979; Nigam et al., 1979; Mishra et al., 2015; Koundal et al., 2015; Prakash et al., 2010; Bisht et al., 2006; Samuel and Tripathi, 1994; Semwal et al., 2015). Structures of important phytoconstituents of H. spicatum are given in next page: 46.3 PHARMACOLOGY The plant has diverse pharmacological significance (Table 46.3) as follows: 46.3.1 ANTICANCER AND CYTOTOXIC ACTIVITIES Reddy et al. (2009a) isolated 2 new labdane diterpenes (hedychilactone D and 9-hydroxy hedychenone) and 5 known isoflavonoids, which exhibited cytotoxicity against cancer cells lines such as Colo-205 (Colon-cancer), A-431 (skin cancer), MCF-7( breast cancer), A-549 (lung cancer), and CHO. The IC50 values of the labadne diterpenes ranged between 7.69 and 49.29 μg/mL and that of the isoflavonoids between 20.36 and 54.21 μg/

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Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

(continued)

Hedychium spicatum Sm.

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(continued)

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Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

(continued)

Hedychium spicatum Sm.

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Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

mL. In another study, Reddy et al. (2009b) isolated and characterized eight compounds (7-hydroxy hedichinal, spicatanoic acid, yunnacoranarin D, coronarin-E, 8(12) drimene, 4-methoxy ethyl cinnamate, ethyl cinnamate, and chrysin) from rhizomes of H. spicatum and tested their cytotoxic potential against A-549 (human lung carcinoma), THP-1 (human acute monocytic leukemia), A-375 (human malignant melanoma), and HL-60 (human promyelocytic leukemia) cancerous cell lines by MTT assay. The results showed that the compounds exhibited significant to moderate cytotoxic activity against tested cell lines. According to Bhatt et al. (2008) α-tocopherol, present in older rhizomes, showed antioxidant activity and also possessed other biological activities such as immune stimulation and alteration of metabolic activation of carcinogenesis. So the plant may possess inherent cancer protection (Sun, 1990) potential. Cytotoxic effect of rhizome essential oil was studied by Mishra et al. (2015) against human cancer cell lines such as the colon (DLD-1, SW-620), head and neck (FaDu), breast (MCF-7, MDA-MB-231), lung (A-549), and cervix (HeLa). The results showed that the oil exhibited significant cytotoxic effect against all the tested cell lines and the IC50 values were in the range of 26.77–94.33 mg/mL (Mishra et al., 2015). 46.3.2 ANTIOXIDANT AND RADICAL SCAVENGING PROPERTIES Rhizome of H. spicatum possess potential antioxidant and radical scavenging potential. Essential oil of the rhizome exhibits very good in vitro radical scavenging activity, reducing power, and metal ion chelating activity (Joshi et al., 2008; Koundal et al., 2015). Essential oil exhibited moderate to good Fe2+ chelating activity and exhibited-dose dependent DPPH radical scavenging profile (Joshi et al., 2008; Koundal et al., 2015). Methanol extract of the rhizome collected from different regions of Himalaya exhibited good antioxi­ dant activity such as ABTS and DPPH radical scavenging and ferric reducing antioxidant power. Moreover, antioxidant activity was varied significantly among different populations and which was correlated with total phenolic compounds (Rawat et al., 2011). Studies also showed that non-phenolic compounds such as DL-α-tocopherol, xanthophyll, α-carotene, and β-carotene were characterized from the rhizomes of H. spicatum. Therefore, various antioxidant activities of the plant might be attributed to these compounds also (Bhatt et al., 2008). Remarkably, rhizome of H. spicatum has been used for the preparation of multicomponent and multipotent traditional Tibetan herbal preparation PADMA 28 (Navab et al., 2004; Lohani et al., 2015).

Sl. Pharmacological No. properties 1. Anti-inflammatory activity

2.

Analgesic activity

3.

Ulcer protection activity

4.

Anti-asthmatic & antiallergic activity

5. 6.

Blood pressure lowering activity Hepatoprotective properties

Compound/Extract

Method

Reference

Hexane & Benzene extract

Carrageenan-induced edema and cotton pellet test Carrageen-induced hind paw edema test Hind paw up to the ankle joint measured plethysmographically by mercury displacement Writhing movement assay Writhing movement and Randall-Sellitto assay Reduction in ulcerogenic index Protection against histamine-induced gastric ulcer Recovery from recurrent paroxysmal attack of bronchial asthma Reduction in eosionophil count Protection against histamine induced broncho­ spasm by preconvulsive dyspnoea Enzymatic assays

Srimal et al. (1984)

Reduction blood pressure

Srimal et al. (1984)

In vitro activity against paracetamol-induced hepatotoxicity Recovery of serum antioxidant enzymes and biomarkers

Joshi and Mishra (2011)

Ethanolic extract Aqueous & ethanolic extracts Hexane& benzene extract Ethanolic Hexane & benzene extract Aqueous & ethanolic extracts Aqueous & ethanolic extracts Rhizome powder Aqueous & ethanolic extracts Ethyl acetate &alcohol extracts Benzene& hexane extracts reduction in blood pressure Methanol extract Hydroalcoholic extract

Tandan et al. (1997) Sharma et al. (1975)

Hedychium spicatum Sm.

TABLE 46.3 Pharmacological Properties of H. spicatum (Source: Rawat et al., 2018 with permission).

Srimal et al. (1984) Tandan et al. (1997) Srimal et al. (1984) Ghildiyal et al. (2012) Chaturvedi and Sharma (1975) Sahu (1979)

Ghildiyal et al. (2012)

Habbu et al. (2002)

Bumrela and Naik (2012)

63

64

TABLE 46.3 (Continued) Compound/Extract

Method

Reference

7.

Labdane diterpenes Volatile compounds Hexane extract, Spicatanol & hedychenone

Cytotoxic activity against cancer cell lines Cytotoxic activity against cancer cell lines Protection against Histamine induced gastric ulcers

Reddy et al. (2009a) Mishra et al. (2015) Reddy et al. (2009c)

n-Butanol fraction

Maze and double-unit mirrored chamber test

Shete and Bodhankar (2010)

Hexane extract & pentadecane Ethanolic extract Hexane & benzene extract Essential oil

Reduction in hair growth time

Rao et al. (2011) Sharma et al. (1975) Ghildiyal et al. (2012) Dixit and Varma (1979)

Essential oil

Acute toxicity Acute toxicity Reduction in secondary conditioned avoidance response (SCR) Radical scavenging activity

Solvent extract

Radical scavenging activity

Various solvent extracts

Inhibitory activity against Salmonella typhi, Escheria coli, Streptococcus aureus and others Inhibitory activity against Salmonella enterica

Anticancer and cytotoxic properties

8.

Antihyperglycaemic activity 9. Nootropic effects, memory restorative activity 10. Hair growth promoting activity 11. Toxicity studies 12. Tranquillizing activity 13. Antioxidant activity

14. Antibacterial activity

Essential oil

Rawat et al. (2011), Joshi et al. (2008), Koundal et al. (2015), and Sravani et al. (2012) Kirtikar and Basu (1999), Sravani et al. (2012), and Bhatt et al. (2008) Bisht et al. (2006) and Sabulal et al. (2007)

Joshi et al. (2008)

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

Sl. Pharmacological No. properties

Sl. Pharmacological No. properties

Compound/Extract

Method

Reference

15. Antifungal activity

Various solvent extracts

Inhibitory activity against Candida albicans, C. glabrata Inhibitory activity against Aspergillus flavus and Fusarium verticillioides Activity against Plasmodium berghei strain (NK) Inhibitory activity against Pediculus humanus capitis, Pthirus pubis, and Pediculus humanus Inhibitory activity against Earthworm, tapeworm, hookworm and nodular worms Inhibitory activity against Pheretima posthuma Inhibitory activity against Pheretima posthuma

Bisht et al. (2006) and Sabulal et al. (2007) Rajasekaran et al. (2012)

Essential oil 16. Antimalarial activity 50% methanol extract 17. Pediculicidal Essential oil activity 18. Anthelmintic Essential oil activity Ethanolic extracts Methanolic extracts

Misra (1991) Jadhav et al. (2007)

Hedychium spicatum Sm.

TABLE 46.3 (Continued)

Dixit and Varma (1975) Goswami et al. (2011) Sravani and Paarakh (2011a)

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Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

46.3.3 ANTIMICROBIAL ACTIVITY Antibacterial and antifungal activities of H. spicatum were well studied and the plant was found to be a promising one. Bisht et al. (2006) analyzed the antimicrobial potential of essential oil and different extracts (petroleum ether, benzene, chloroform, ethyl acetate, acetone, ethanol and water) of rhizome of H. spicatum against Gram-positive and Gram-negative bacteria including methicillin and vancomycin-resistant Staphylococcus aureus and various fungal species. Essential oil and all the extracts except aqueous showed potent inhibitory activity, against all the tested bacteria and fungi, which was comparable to that of the standard antibiotics used (Bisht et al., 2006). Terpe­ noid compositions of the rhizome of H. spicatum also exhibited substantial antimicrobial activity against S. aureus, Shigella flexneri, Pasteurella multo­ cida, and Escherichia coli (Joshi et al., 2008). Ethanol extract of fruits of H. spicatum was reported to possess antibacterial and antifungal properties against Salmonella sps., E. coli and filamentous fungi (Ray and Majumdar, 1976). Antibacterial activity of the essential obtained from the rhizomes of H. spicatum growing in Kumaun region of central Himalaya was tested against E. coli, Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa, and Proteus vulgaris. The study revealed that the oil exhibited significant inhibitory potential against tested pathogenic bacteria (Prakash et al., 2010). Similar results were obtained in another study done by Semwal et al. (2015). In another experiment, growth of Gram-negative bacterium Borrelia burgdor­ feri arrested at stationary growth phase when treated with 0.1% (v/v) flower essential of H. spicatum (Feng et al., 2018). Rhizome essential oil (3.15 mg/g) completely inhibited the growth of Fusarium graminearum in maize grains. However, a combinational treatment of oil along with γ-radiations also completely inhibited the growth of F. graminearum at 1.89 mg/g oil and 4.1 kGy of γ-radiation (Kalagatur et al., 2018). In another study, methanolic extracts (200–1200 μg/mL) of the rhizome tested against both Gram-positive and Gram-negative bacteria such as Shigella boydii, S. flexneri, S. soneii, Vibrio cholerae, P. aeruginosa, E. coli, Bacillus cereus, S. aureus, and Klebsi­ ella pneumoniae. The results showed that the extract had a potent antibacterial effect, which was comparable to that of the standard antibiotic ciprofloxacin (Arora and Mazumder, 2017). 46.3.4 ANTIASTHMATIC AND ANTIALLERGIC ACTIVITIES Recurrent paroxysmal attack of bronchial asthma in humans was totally relieved after 4 weeks administration of rhizome powder and 36% of

Hedychium spicatum Sm.

67

patients had no sign of bronchi. The vital capacity of the patients increased by 20% and the mean absolute count was reduced by 55.6% after the treat­ ment (Chaturvedi and Sharma, 1975). Tropical (pulmonary) eosinophilia was treated using rhizome power in other clinical trials. A daily dose of 6 g aromatic rootstock powder for 4 weeks significantly reduced the eosinophil count by 60.54% (Sahu, 1979). In another experiment, aqueous and ethanol extract of rhizome was given to guinea pigs having histamine-induced bronchospasm for 7 days. The dose dependent (100, 200, and 400 mg/kg) administration of the extract gave protection by increasing preconvulsive dyspnea (PCD) time from 39.2% to 75.1% and 25.8% to 65.1% for water and ethanol extracts, respectively. PCD time for chlorpheniramine maleate (2 mg/kg) was found to be 71.3% (Ghildiyal et al., 2012). 46.3.5 BLOOD PRESSURE-LOWERING ACTIVITY Blood pressure lowering activity of the rhizome extract in cats was studied by Srimal et al. (1984). Intravenous administration of hexane fraction (10 mg/kg) of alcohol extract reduced the blood pressure (80 mm Hg) in 16 min, whereas the administration of 25 mg/kg resulted in hypotension lasting for more than 30 min. However, the benzene fraction of the alcohol extract was effective only at higher dose (25 mg/kg) which reduced the BP by 50 mm Hg in 30 min (Srimal et al., 1984). 46.3.6 HEPATOPROTECTIVE ACTIVITY Joshi and Mishra (2011) studied the in vitro hepatoprotective activity of the diterpene isolated from methanol extract of the rhizome of H. spicatum. Total protein, glutamic pyruvic transaminase and glutamic transaminase concentrations significantly altered when rat hepatocytes were treated with paracetamol. Study showed that application of isolated diterpene effectively restored the altered parameters thus it brings effective hepatoprotection (Joshi and Mishra, 2011). In another study, various liver enzyme activity was analyzed before and after the administration of hydroalcoholic extract of the rhizome in rats having chloroform and paracetamol-induced hepato­ toxicity. The results showed that extract restored the activity and prevent the depletion of catalase, superoxide dismutase, glutathione peroxidase, alkaline phosphatase, alanine aminotransferase, aspartate transferase, etc. after chloroform and paracetamol-induced hepatotoxicity (Bumrela and Naik,

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2012). Choudhary and Singh (2018) studied the hepatoprotective efficacy of methanol, ethanol, and aqueous extracts of rhizomes in HepG2 cell lines against paracetamol-induced toxicity. Hepatoprotective activity was 16%, 13% and 9% with IC50 values were 282, 356, and 515 μg/mL for methanol, ethanol and aqueous extracts. The results showed that the extracts, especially methanol fraction, have promising activity as compared with the control silymarin (19%, IC50 = 110 μg/mL). 46.3.7 ANALGESIC ACTIVITY Srimal et al. (1984) studied the analgesic activity of the hexane and benzene fractions of alcohol extract in acetic acid-induced writhing movements in mice and Randall–Selitto assay in rats. Writhing movement assay in mice showed the ED50 of the hexane fraction in the phenylquinone writhing test was 284.53 mg/kg while that of benzene extract was 93.28 mg/kg. Periph­ eral analgesic activity of the plant was studied by Tandan et al. (1997) using ethanol extract against acetic-acid induced writhing movement and Randall–Selitto assay in mice. The study displayed extract (300 mg/kg) and aspirin (300 mg/kg) significantly decreased the pain threshold. The writhing count was 57.33 when mice were given acetic-acid. The count was reduced to 34.32 after the administration of extract (300 mg/kg) (Tandan et al., 1997). 46.3.8 ANTIHYPERGLYCAEMIC/ANTIDIABETIC ACTIVITY Antihyperglycemic activity of hexane extract of the rhizome was studied by Reddy et al. (2009c) by starch tolerance test in rats. Administration of extract prior to feeding significantly decreased the rise in blood glucose level after a starchy meal. Inhibitory potential of hexane extract was further analyzed against in vitro rat intestinal enzyme α-glucosidase using 4-nitrophenyl α-D-glucopyranoside as substrate. The hexane extract displayed 21.2% inhi­ bition of the α-glucosidase at concentrations of 100 µg/mL. Besides, nine labdane-type compounds having intestinal α-glucosidase inhibition potential were fractionated and purified from the hexane extract (Reddy et al., 2009c). Antidiabetic activity of the rhizome oil of H. spicatum in wistar rats showed that oral doses of 0.3 mL of essential oil administered for 2 weeks reduced the blood glucose and urea level as compared with positive control (Kaur and Richa, 2017).

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46.3.9 NOOTROPIC EFFECTS AND MEMORY RESTORATIVE ACTIVITY Maze and double-unit mirrored chamber test in mice using 1-butanol fraction of rhizome powder exhibited the memory restorative activity, so it can be a choice for the treatment of dementia during Alzheimer’s disease. Nootropic effect and memory restorative potential of 1-butanol extract might be due to the occurrence of saponins and its presence was confirmed by HPTLC analysis (Shete and Bodhankar, 2010). 46.3.10 ANTI-INFLAMMATORY EFFECTS The hexane fraction of the alcoholic extract of H. spicatum rhizome showed significant anti-inflammatory effect in mice and rats having hind-paw edema (carrageenan-induced). The extract reduced the inflammation to 27.2% in rats (100 mg/kg) and 42.16% in mice (200 mg/kg) compared with 27.2% of reduction by phenylbutazone (30 mg/kg) in rats and 37% of reduction by indomethacin (2 mg/kg) in mice. Hexane and benzene fractions of the alco­ holic extract inhibited the granuloma formation by 8% and 5%, respectively (200 mg/kg) compared with 25% in phenylbutazone (30 mg/kg) (Srimal et al., 1984). In another study, Carrageenan-induced hind paw edema test in mice and rats using ethanolic extract (300 mg/kg) quickly reduced the edema volume (64.2%) as comparable to 49.1% reduction when treated with acetyl salicylic acid (300 mg/kg) (Tandan et al., 1997). In other in vivo study, a single oral dose of ethanol and aqueous extracts (200 mg/kg) of rhizome showed effective anti-inflammatory effect against carrageenan-induced paw edema in rats (Ghildiyal et al., 2012). 46.3.11 TOXICITY STUDIES Different studies focused on the toxicity effect of rhizomes of H. spicatum (Srimal et al., 1984; Tandan et al., 1997). Experiments in rats using extracts of the rhizome such as hexane, benzene, and methanol did not show any significant toxic effect on CNS (Srimal et al., 1984) and any harmful effects (Tandan et al., 1997). 46.3.12 TRANQUILLIZING ACTIVITY Dixit and Varma (1979) studied the pharmacological implications of the rhizomes volatile oils H. spicatum in rats. The results showed that the oil

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impart mild tranquillizing effect for a short period. At the same time, the oil stimulated the pentobarbitone hypnosis and morphine analgesia. Addition­ ally, essential oil reduced the conditioned avoidance response and rotarod performance in rats. 46.3.13 HAIR GROWTH PROMOTING ACTIVITY Hexane extract of the rhizome of H. spicatum and pentadecane isolated from hexane extract displayed good reduction in hair growth time in female wistar rats. Reduction in hair growth time by hexane extract, pentadecane, and minoxidil (+ve control) were 33%, 30% and 47%, respectively. However, side effects of minoxidil have also been proved. Though, this plant is one of the ingredients of hair oil preparations, no accounts on compounds respon­ sible for hair growth promotion activity is not yet available (Rao et al., 2011). 46.3.14 ULCER PROTECTION ACTIVITY Ulcer protective activity of ethanol and water extracts of rhizome was well studied in histamine induced gastric ulcers in guinea pigs. The water and ethanol extracts provided 75% 62.5% protection, respectively, which was as significant as the results of chlorpheniramine maleate (87.5%) (Ghildiyal et al., 2012). In another experiment ulcerogenic activity of the hexane and benzene fractions of alcohol extract of rhizome was assayed in rats. Admin­ istration of the extracts (300 mg/kg) significantly reduced ulcerogenic index, which was 0.08 and 0.02 for hexane and benzene fractions, respectively. At the same time phenylbutazone (30 mg/kg) gave an ulcerogenic index of 0.3 (Srimal et al., 1984). 46.3.15 ANTIMALARIAL ACTIVITY The antimalarial potential of H. spicatum was experimentally proved by Misra (1991). Sporozoite of Plasmodium berghei (NK 65) infected blood of Mastomys natalensis was collected and treated with a dose of 100 μg/mL of 50% ethanol extract of the rhizome. The results showed that 64.76% of parasite infection was prevented by the extract. 46.3.16 PEDICULICIDAL ACTIVITY Jadhav et al. (2007) evaluated the pediculicidal activity of rhizome essential oil of H. spicatum in vitro against Pediculus humanus capitis. Different

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concentrations of oil such as 1%, 2%, and 5% showed effective activity in a short time. Mortality rates of 85%, 80%, and 75% were observed for 5%, 2%, and 1% of oil, respectively, after 30 min of treatment. However, 100% mortality was observed after 2 h for 5%, and 2% treated group, whereas 95% mortality detected for 1% treatment. At the same time, mortality rate of the positive control (permethrin) was 79% at 120 min. 46.3.17 ANTHELMINTIC ACTIVITY Rhizome of H. spicatum has reported anthelmintic properties. Methanol extract of rhizome showed significant anthelmintic activity than standard drug piperazine citrate (Sravani and Paarakh, 2011a). In another study, essential oil obtained from rhizome showed significant activity inhibitory than piperazine citrate against Taenia solium. However, in the same work the oil was more effective than hexylresorcinol against nodular worm (Oesopha­ gostomum columbianum) and sheep hookworm (Bunostomum trigonoceph­ alum) (Dixit and Varma, 1975). In vitro anthelmintic activity of ethanolic extract of rhizome on Pheretima posthuma (earth worm) was increasing with concentration. Death time was 146, 137.5, and 96.7 min, respectively, for 25, 50, and 100 mg/mL extract concentrations. Positive control albendazole was effective at 124.8, 95.5, and 73.8 min for 25, 50 and 100 mg/mL extract respectively (Goswami et al., 2011). Experiment using P. posthuma proved the anthelmintic activity of β-sitosterol isolated from methanol extract of rhizome. The results showed that worms were paralyzed within 6.8 min and death time was 29.2 min after treatment with 40 mg/mL β-sitosterol. At the same time positive control piperazine citrate was not as effective (9.2 and 33.4 min, respectively) as β-sitosterol with same concentration (Sravani et al., 2014). KEYWORDS • • • • •

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REFERENCES Arora, R. K.; Pandey, A. Wild Edible Plants of India: Diversity Conservation and Uses; National Bureau of Plant Genetic Resources: New Delhi, India, 1996. Arora, R.; Mazumder, A. Phytochemical Screening and Antimicrobial Activity of Rhizomes of Hedychium spicatum. Pharmacog. J. 2017, 9, s64–s68. DOI: https://doi.org/10.5530/ pj.2017.6s.159. Arumugam, I.; Krishnan, C.; Ramachandran, S.; Krishnan, S.; Das, D.; Thamankar, V. Phytochemical Investigation and In-Vitro Antimicrobial Activity of the Essential Oil from Rhizomes of Hedychium spicatum. Int. J. Pharm. Sci. Res. 2021, 12 (2), 853–858. DOI: https://doi.org/10.13040/IJPSR.0975-8232. Badola, H. K. Hedychium spicatum—A Commercial Himalayan Herb Needs Internship at Local Level. Non-Wood News 2009, 19, 26–27. Badoni, A.; Bisht, C.; Chauhan, S. Micropropagation of Hedychium spicatum Smith Using In Vitro Shoot Tips. Stem. Cell. 2010, 1, 11–13. Bhatt, I. D.; Prasad, K.; Rawat, S.; Rawal, R. S. Evaluation of Antioxidant Phytochemical Diversity in Hedychium spicatum: A High Value Medicinal Plant of Himalaya. Pharmacog. Mag. 2008, 4 (16), 202–205. Bhatt, V. P.; Negi, V.; Purohit, V. K. Hedychium spicatum Buch.-Ham.: A High Valued Skin Glowing and Curing Medicinal Herb Needs Future Attention on Its Conservation. N. Y. Sci. J. 2010, 3, 86–88. Bisht, G. S.; Awasthi, A. K.; Dhole, T. N. Antimicrobial Activity of Hedychium spicatum. Fitoterpia 2006, 77 (3), 240–242. DOI: https://doi.org/10.1016/j.fitote.2006.02.004. Bottini, A. T.; Garfagnoli, D. J.; Delgado, L. S.; Dev, V.; Duong, S. T.; Kelley, C. G.; Keyer, R.; Raffel, R.; Joshi, P.; Mathela, C. S. Sesquiterpene Alcohols from Hedychium spicatum Var. acuminatum. J. Nat. Prod. 1987, 50 (4), 732–734. DOI: https://doi.org/10.1021/ np50052a027. Bumrela, S.; Naik, S. R. Hepatoprotective Activity of Hydroalcoholic Extract of Hedychium spicatum Smith in Experimental Rat Models. Asian Pac. J. Trop. Biomed. 2012, 1, 1–7. Chaturvedi, G. N.; Sharma, B. D. Clinical Studies on Hedychium spicatum (Shati): An Antiasthmatic Drug. J. Res. Indian Med. 1975, 10, 6–8. Chopra, R. N.; Nayar, S. L.; Chopra, I. C. Glossary of Indian Medicinal Plants; CSIR: New Delhi, India, 1986. Choudhary, G. K.; Singh, S. P. In Vitro Hepatoprotective Efficacy of Extract of Hedychium spicatum Rhizome in Paracetamol Induced Toxicity in HepG2 Cell Line. Indian J. Anim. Sci. 2018, 88, 546–549. Dixit, V. K; Varma, K. C. Anthelmintic Properties of Essential Oil from Rhizome of Hedychium spicatum Koenig and Hedychium coronarium Koenig. Indian J. Pharm. 1975, 37 (6), 143–144. Dixit, V. K.; Varma, K. C. Effect of Essential Oil of Rhizome of Hedychium coronarium and Hedychium spicatum on Central Nervous System. Indian J. Pharmacol. 1979, 11, 147–149. Dixit, V. K.; Varma, K. C.; Vashisht, V. N. Studies on Essential Oils of Rhizomes of Hedychium spicatum Koenig. and Hedychium coronarium Koenig. Indian J. Pharm. 1977, 39, 58–60. Feng, J.; Shi, W.; Miklossy, J.; Tauxe, G. M.; McMeniman, C. J.; Zhang, Y. Identification of Essential Oils with Strong Activity Against Stationary Phase Borrelia burgdorferi. Antibiotics 2018, 7, 89. DOI: https://doi.org/10.3390/antibiotics7040089.

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Misra, S. B. Antimalarial Activity of Traditional Plants Against Erythrocytic Stages of Plasmodium berghei. Int. J. Pharmacog. 1991, 29, 19–23. DOI: https://doi. org/10.3109/13880209109082843. Navab, R.; Aingorn, H.; Fallavollita, L.; Sallon, S.; Mechoulam, R.; Ginsburg, I.; Vlodavsky, I.; Brodt, P. PADMA-28, a Traditional Tibetan Herbal Preparation, Blocks Cellular Responses to bFGF and IGF-I. Inflammopharmacology 2004, 12 (4), 373–389. DOI: https://doi.org/10.1163/1568560043696227. Nigam, M. C.; Siddiqui, M. S.; Misra, L. N.; Sen, T. Gas Chromatographic Examination of the Essential Oil of Rhizomes of Hedychium spicatum. Perfum Kosmet 1979, 60, 245–246. Prakash, O.; Rajput, M.; Kumar, M.; Pant, A. K. Chemical Composition and Antibacterial Activity of Rhizome Oils from Hedychium coronarium Koenig and Hedychium spicatum Buch-Ham. J. Essent. Oil Bear. Pl. 2010, 13, 250–259. DOI: https://doi.org/10.1080/0972 060X.2010.10643819. Raina, A. P.; Negi, K. S. Essential Oil Composition of Hedychium spicatum Buch.-Ham. Ex Smith. from Uttarakhand, India. J. Essent Oil Bear. Pl. 2015, 18, 382–388. DOI: https://doi. org/10.1080/0972060X.2015.1010599. Rajasekaran, K.; Sakhanokho, F. H.; Tabanca, N. Antifungal Activities of Hedychium Essential Oils and Plant Extracts Against Mycotoxigenic Fungi. J. Crop. Improv. 2012, 26 (3), 389–396. DOI: https://doi.org/10.1080/15427528.2011.649395. Rao, G. V.; Mukhopadhay, T.; Madhavi, M. S. L.; Lavakumar, S. Chemical Examination and Hair Growth Studies on the Rhizomes of Hedychium spicatum Buch.-Ham. Pharmacog. Commun. 2011, 1 (1), 90–93. DOI: https://doi.org/10.5530/pc.2011.1.7. Rawat, S, Jugran, A. K, Bhatt, I. D.; Rawal, R. S. Hedychium spicatum: A Systematic Review on Traditional Uses, Phytochemistry, Pharmacology and Future Prospectus. J. Pharm. Pharmacol. 2018, 70 (6), 687–712. DOI: https://doi.org/10.1111/jphp.12890. Rawat, S.; Bhatt, I. D.; Rawal, R. S. Total Phenolic Compounds and Antioxidant Potential of Hedychium spicatum Buch. Ham. Ex D. Don in West Himalaya, India. J. Food. Compos. Anal. 2011, 24, 574–579. DOI: https://doi.org/10.1016/j.jfca.2010.12.005. Rawat, S.; Jugran, A. K.; Bhatt, I. D.; Rawal, R. S.; Nandi, S. K. Effects of Genetic Diversity and Population Structure on Phenolic Compounds Accumulation in Hedychium spicatum. Ecol. Genet. Genom. 2017, 3–5, 25–33. DOI: https://doi.org/10.1016/j.egg.2017.06.003. Rawat, S; Bhatt, I. D.; Rawal, R.S. Variation in Essential Oil Composition in Rhizomes of Natural Populations of Hedychium spicatum in Different Environmental Condition and Habitats. J. Essent. Oil Res. 2020, 32 (4), 348–360. DOI: https://doi.org/10.1080/1041290 5.2020.1750497. Ray, P. G.; Majumdar, S. K. Antimicrobial Activity of Some Indian plants. Economic Bot. 1976, 30, 317–320. Reddy, P. P.; Rao, R. R.; Rekha, K.; Babu, K. S.; Shashikiran, G.; Lakshmi, V. V.; Rao, J. M. Two New Cytotoxic Diterpenes from the Rhizomes of Hedychium spicatum. Bioorg. Med. Chem. Lett. 2009a, 19 (1), 192–195. DOI: https://doi.org/10.1016/j.bmcl.2008.10.121. Reddy, P. P.; Rao, R. R.; Shashidhar, J.; Sastry, B. S.; Rao, J. M.; Babu, K. S. Phytochemical Investigation of Labdane Diterpines from the Rhizomes of Hedychium spicatum and Their Cytotoxic Activity. Bioorg. Med. Chem. Lett. 2009b, 19 (1), 6078–6081. DOI: https://doi. org/10.1016/j.bmcl.2009.09.032. Reddy, P. P.; Tiwari, A. K.; Rao, R. R.; Madhusudhana, K.; Rao, V. R. S.; Ali, A. Z.; Babu, K. S.; Rao, J. M. New Labdane Diterpenes as Intestinal α-Glocosidase Inhibitor from

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Antihyperglycemic Extract of Hedychium spicatum (Ham. ex Smith) Rhizomes. Bioorg. Med. Chem. Lett. 2009c, 19, 2562–2565. DOI: https://doi.org/10.1016/j.bmcl.2009.03.045. Sabulal B.; George, V.; Dan, M.: Pradeep, N. S. Chemical Composition and Antimicrobial Activities of the Essential Oils from the Rhizomes of Four Hedychium Species from South India. J. Essent. Oil Res. 2007, 19 (1), 93–97. DOI: https://doi.org/10.1080/10412905.200 7.9699237. Sahu, R. B. Clinical Trial of Hedychium spicatum in Tropical Pulmonary Eosinophilia. J. Nepal Pharm. Assoc. 1979, 7, S65–S72. Samuel, C. O.; Tripathi, S. C. Fungitoxic Properties of Essential Oil of Hedychium spicatum. Indian Perfum. 1994, 38, 105–111. Savithramma, N.; Sulochana, C.; Rao, K. N. Ethnobotanical Survey of Plants Used to Treat Asthma in Andhra Pradesh, India. J. Ethnopharmacol. 2007, 113, 54–61. DOI: https://doi. org/10.1016/j.jep.2007.04.004. Semwal, R. B.; Semwal, D. K.; Mishra, S. P.; Semwal, R. Chemical Composition and Antibacterial Potential of Essential Oils from Artemisia capillaris, Artemisia nilagirica, Citrus limon, Cymbopogon flexuosus, Hedychium spicatum and Ocimum tenuiflorum. Nat. Prod. J. 2015, 5, 199–205. DOI: https://doi.org/10.2174/2210315505666150827213344. Sharma, S. C.; Tandon J. S.; Dhar M. M. 7-Hydroxyhedychenone: A Furanoditerpene from Hedychium spicatum. Phytochemistry 1976, 15 (5), 827–828. DOI: https://doi.org/10.1016/ S0031-9422(00)94465-0. Sharma, S. C.; Tandon, J. S.; Uprety, H.; Shukla, Y. N.; Dhar, M. M. Hedychenone: A Furanoid Diterpene from Hedychium spicatum. Phytochemistry 1975, 14 (4), 1059–1062. DOI: https://doi.org/10.1016/0031-9422(75)85186-7. Shete, R. V.; Bodhankar, S. L. Hedychium spicatum: Evaluation of Its Nootropic Effect in Mice. Res. J. Pharmacog. Phytochem. 2010, 2 (5), 403–406. Singh, S.; Sharma, N.; Nageshwar, S. Hedychium spicatum: Boon for Medicinal Field in Future. Bull. Env. Pharmacol. Life Sci. 2018, 7 (11), 188–192. http://www.bepls.com/ bepls_oct_2018/30a.pdf. Sravani, T.; Paarakh, P. M. Antioxidant Activity of Hedychium spicatum Buch. Ham. Rhizomes. Indian J. Nat. Prod. Resour. 2012, 3, 354–358. Sravani, T.; Paarakh, P. M. Evaluation of Anthelmintic Activity of Rhizomes Hedychium spicatum Buch. Ham. Int. J. Res. Pharm. Sci. 2011a, 2 (1), 66–68. Sravani, T.; Paarakh, P. M. Hedychium spicatum Buch. Ham.—An Overview. Pharmacologyoneline 2011b, 2, 633–642. Sravani, T.; Paarakh, P. M.; Shruthi, S. In Silico and In-Vitro Anthelmintic Activity of β-Sitosterol Isolated from Rhizomes of Hedychium spicatum Buch.-Ham. Indian J. Nat. Prod. Resour. 2014, 5 (3), 258–261. Sravani, T.; Paarakh, P. M.; Vedamurthy, A. B. Isolation of Phytoconstituents from the Rhizomes of Hedychium spicatum Buch. Ham. J. Pharm. Res. 2012, 5, 526–527. http:// jprsolutions.info/newfiles/journal-file-56a8cab62d7492.16085926.pdf. Srimal, R. C.; Sharma, S. C.; Tandon, J. S. Anti-Inflammatory and Other Pharmacological Effects of Hedychium spicatum. Indian J. Pharmacol. 1984, 16 (3), 143–147. Sun, Y. Free Radicals, Antioxidant Enzymes, and Carcinogenesis. Free. Radic. Biol. Med. 1990, 8 (6), 583–599. DOI: https://doi.org/10.1016/0891-5849(90)90156-d. Suresh, G.; Poornima, B.; Babu, K. S.; Yadav, P. A.; Rao, M. S. A.; Siva, B.; Prasad, K. R.; Nayak, V. L.; Ramakrishna, S. Cytotoxic Sesquiterpenes from Hedychium spicatum:

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Isolation, Structure Elucidation and Structure-Activity Relationship Studies. Fitoterapia 2013, 86, 100–107. DOI: https://doi.org/10.1016/j.fitote.2013.02.004. Tandan, S. K.; Chandra, S.; Gupta, S.; Lal, J. Analgesic and Anti-Inflammatory Effect of Hedychium spicatum. Indian J. Pharm. Sci. 1997, 59 (3), 148–150. Thomas, S.; Britto, S. J.; Mani, B. First Records of Two Ginger Lilys Hedychium (Zingiberace) Species from the Western Ghats, India. J. Threat. Taxa 2017, 9 (11), 10914–10919. DOI: https://doi.org/10/11609/jot.3117.9.11.10914-10919. Upasani, M. S.; Upasani, S. V.; Beldar, V. G.; Beldar, C. G.; Gujarathi, P. P. Infrequent Use of Medicinal Plants from India in Snakebite Treatment. Integr. Med. Res. 2018, 7, 9–26. DOI: https://doi.org/10.1016/j.imr.2017.10.003. Verma, R. S.; Padalia, R. C. Comparative Essential Oil Composition of Different Vegetative Parts of Hedychium spicatum Smith. from Uttarakhand, India. Int. J. Green Pharm. 2010, 4, 292–295.

CHAPTER 47

Functional Components and Biological Activities of Kaempferia galanga L. (Chandramoolika) CHACHAD DEVANGI* and MONDAL MANOSHREE Research Laboratory, Department of Botany, Jai Hind College, Churchgate, Mumbai 400020, India *Corresponding

author. E-mail: [email protected]

ABSTRACT Kaempferia galanga L. is commonly known as Chandramulika in Sanskrit and is a well-known ayurvedic drug. It is an endemic plant to India and the rhizomes are used as a herbal remedy for Skin disorders, joint disorders etc. The plant possesses fragrant underground rhizomes, leaves and flowers. In the current work a detailed review for phytochemical and pharmacological properties of the plant is given. 47.1 INTRODUCTION Kaempferia galanga L., also known as aromatic ginger or Chandramoolika (Sanskrit), is an endemic plant to India be assumed to have originated in Myanmar. It is a perennial herbaceous plant with the underground or rhizom­ atous stem. According to most taxonomists, the plant belongs to family Zingiberaceae. It has a long history in India as an important medicinal herb that is known to be used in the treatment of a few human illnesses including cough and cold, fever, migraine, pain-related illnesses, skin-related issues, Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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etc. It is also known to cure rheumatic sicknesses, joint pain, fractures, dizzi­ ness, wounds, and gastritis. It is a known traditional remedy for snakebites, aggravation, blood vomiting, mouth bruises, and tongue blisters in newborn children. Besides, this plant is very fragrant especially the rhizomes and have been utilized generally as flavors, in food enhancing, pickles, and beauty care products and in perfumery items. 47.2

BIOACTIVES

Kaempferia galanga rhizomes have been extensively studied for phyto­ chemistry. The rhizomes are rich in essential oil (2–4%). Regional variations may impact the secondary metabolites, to assess this possibility, essential oil extracted from rhizomes was screened from various geographical regions namely Vietnam, India, China, and Malaysia. The chief constituents of the oils were found to be esters and terpenoids. The major constituents detected in all the oils were ethyl cinnamate and ethyl p-methoxycinnamate; 3-carene, pentadecane, borneol, bornyl acetate, δ-selinene, camphor, and α-pinene (Luger et al., 1996; Srivastava et al., 2019). Most researchers have success­ fully isolated esters from methanolic extracts; Chowdhury et al. (2014) used a combination of supercritical fluid extraction and high-speed countercurrent chromatographic techniques, whereas Hakim et al. (2018) depended on soxhlet extraction using ethanol and recrystallization were achieved using n-hexane. A new monoterpene ketone now known as 3-caren-5-one was isolated along with p-methoxycinnamic acid from rhizomes by Kiuchi et al. (1987). Wang et al. (2013) isolated two new sulfonated diarylheptanoid epimers, namely, kaempsulfonic acids A and B. Ningombam et al. (2018) isolated the 13th diterpenoid, that is, kaemgalangol A from the rhizome of K. galanga along with 12 earlier identified diterpenoids, namely, boesenberol I, boesenberol J, (−)-sandaracopimaradiene, sandaracopimaradiene-9α-ol, kaempulchraol I, kaempulchraol E, 8(14),15-sandaracopimaradiene­ 1α,9α-diol, kaempulchraol L, 2α-acetoxy sandaracopimaradien-1α-ol, 1,11-dihydroxypimara-8(14),15-diene, 6β-hydroxypimara- 8(14),15-diene1-one, and sandaracopimaradien-6β,9α-diol-1-one. Apart from the essential oils, the rhizome also contains bioactive flavonoids (kaempferol and kaempferide); polysaccharides (fructose, arabinose, xylose, galactose, glucose, rhamnose, mannose, glucuronic acid, and galacturonic acid) (Yang et al., 2018) and diarylheptanoids (1,5-epoxy-3-hydroxy-1-(3,4­ dihydroxyphenyl)-7-(3,4-dihydroxyphenyl) heptane; 1-(4-hydroxy-3-

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methoxyphenyl)-7-(4-hydroxyphenyl) heptane1,2,3,5,6-pentaol and 1,5-epoxy-3-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl) heptane 3-O-β-d-glucopyranoside, 3,5-dihydroxy-1-(3,4-dihydroxyphenyl)7-(4-hydroxyphenyl)heptane, phaeoheptanoxide, hedycoropyran B, ethyl trans-p-methoxycinnamate, ferulic acid, trans-p-hydroxy-cinnamic acid, trans-p-methoxycinnamic acid, methyl-2,3-dihydroxy-3-(4-methoxyphenyl) propanoate, ethyl-2,3-dihydroxy-3-(4-methoxyphenyl)propanoate, p­ hydroxybenzoic acid, p-methoxybenzoic acid, vanillic acid, methyl 3,4-dihy­ droxybenzoate) (Yao et al., 2018).

47.3 PHARMACOLOGY The plant has been screened by many researchers to validate the pharmacological claims in ancient and recent texts. 47.3.1 ANTIMICROBIAL ACTIVITY Essential oil from rhizomes was found to possess significant antifungal activity against Aspergillus fumigatus when assessed by broth microdilution (Jantan et al., 2003) and antibacterial activity against Streptococcus faecalis, Staphylococcus aureus, Bacillus subtilis, Salmonella typhi, Escherichia coli, Shigella flexneri, and Candida albicans employing agar disc diffusion method (Tewtrakul et al., 2005). Ethanolic extracts form leaves and rhizomes showed fungicidal activity against Saprolignea parasitica (Udomkusonsri et al., 2007).

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47.3.2 ANTIOXIDANT ACTIVITY Antioxidant claims of essential oils from rhizomes were confirmed by DPPH and hydrogen peroxide scavenging activities keeping ascorbic acid as stan­ dard (Sahoo et al., 2014); methanolic extract of the rhizome was also found to possess promising activity in DPPH, NO scavenging assays, and ABTS using catechin as a standard (Ali et al., 2018; Rahman et al., 2019). 47.3.3 ANTI-INFLAMMATORY ACTIVITY Aqueous extracts of the leaves produced anti-inflammatory activity against a modified 0.1% carrageenan-induced paw-edema test in mice (Balb/C) and rats (Sprague-Dawley) (Sulaiman et al., 2008). Ethanolic extracts of rhizomes showed significant activity against carrageenan induced paw edema (acute inflammation), whereas chloroform extracts were potent against cotton pellet-induced granuloma (chronic inflam­ mation) models in Wistar rats (Chachad and Shimpi, 2008; Vittalrao et al., 2011; Umar et al., 2012, 2014). Ethyl p-methoxycinnamate isolated from the oil also showed anti-inflammatory activity against (carrageenan induced) acute inflammation and (adjuvant-induced) chronic inflamma­ tion in rats. 47.3.4 ANALGESIC ACTIVITY Stress tolerance capacity, in Wistar rats, was significantly increased when treated with alcoholic extract of K. galanga and was assessed using the hot plate technique and tail-flick model (Vittalrao et al., 2011). 47.3.5 AMEBICIDAL ACTIVITY Nonpolar extracts of the rhizomes possessed amoebicidal activity against the three species of Acanthamoeba, namely, A. polyphaga, A. castellanii, and A. culbertsoni (Chu et al., 1998). 47.3.6 ANTIDENGUE EFFECT Kitani et al. (2018) showed that dengue virus protease inhibitory activity was demonstrated by the isolated compound cystargamide B.

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47.3.7 ANTITUBERCULOSIS ACTIVITY The in-vitro antituberculosis activity of isolate ethyl p-methoxycinnamate from K. galanga rhizome was assessed by Lakshmanan et al. (2011) on the two strains of Mycobacterium tuberculosis, that is, H37Ra and H37Rv strains having Rifampicin 1 μg/mL (0.0012 mM) as control. The results confirmed that the compound exhibited a potent antituberculosis activity. 47.3.8 ANTITHROMBOTIC EFFECT Ethanolic extract of the rhizome was proved to possess antithrombotic potential by bleeding time assay in a mouse thrombotic model by Saputri and Avatara (2018) keeping aspirin as the positive control. 47.3.9 ANTINOCICEPTIVE ACTIVITY Ridtitid et al. (2008) checked the in-vivo antinociceptive efficacy of metha­ nolic extract of the rhizomes in (male Swiss albino) mice and (Wistar) rats by using the acetic acid-induced writhing test, formalin test, hot plate, and tail-flick test. The results clearly indicated that the methanolic extract exhib­ ited significant antinociceptive activity. 47.3.10 CHEMO-PREVENTIVE AND ANTICANCER ACTIVITY He et al. (2012) used a zebrafish angiogenic assay to assess the in-vivo anti­ angiogenic effects of ethanol extract and its subfractions (purified isolates) trans-ethyl-p-methoxycinnamate and kaempferol from the rhizome. They proved that both the crude extracts and isolates exhibit strong antiangiogenic effects. Ali et al. (2018) demonstrated in-vitro and in-vivo antineoplastic activity of methanolic extract of K. galanga on Swiss albino mice. Purified ethyl p-methoxycinnamate from the rhizome was investigated by Liu et al. (2010) in human hepatocellular liver carcinoma HepG2 cells using MTT assay showing it could induce cells into an apoptotic pathway which in turn causes the inhibition in proliferation of HepG2 cells. 47.3.11 HYPOLIPIDEMIC ACTIVITY Significant hypolipidemic activity in adult male Wistar rats upon oral admin­ istration of 70% ethanolic extract of rhizome of K. galanga was demonstrated by Achuthan and Padikkala (1997).

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47.3.12 HYPOPIGMENTARY EFFECT B16F10 murine melanoma cells when stimulated by α-melanocyte stimu­ lating hormone are known to synthesize melanin, this activity was found to significantly reduced by an isolated compound (ethyl p-methoxycinnamate) from K. galanga (Ko et al., 2014). 47.3.13 OSTEOLYSIS INHIBITORY EFFECT Kaempferide, a flavonoid from the rhizomes, was checked for its inhibitory effect on titanium particle induced osteolysis (in vivo) and to understand its mode of action (in vitro). The results showed that kaempferide is potent enough to prevent titanium particle induced osteolysis in vivo and it inhibits osteoclast genesis in vitro (Jiao et al., 2017). 47.3.14 LARVICIDAL, INSECTICIDAL AND MOSQUITO REPELLENT ACTIVITIES Metahnolic extract of the rhizome exhibited significant larvicidal activity against Aedes aegypti, Ochlerotatus togoi (Aedes togoi), Culex pipiens pallens, whereas hexane fraction of the rhizome was found to be potent against Culex quinquefasciatus (Yang et al., 2004; Choochote et al., 1999). 47.3.15

NEMATOCIDAL ACTIVITY

Essential oil and methanolic extract of the rhizomes show 100% mortality against pine wood nematode, that is, Bursaphelenchus xylophilus (Choi et al., 2006; Li et al., 2017). 47.3.16

SEDATIVE ACTIVITY

Hexane extract of K. galanga along with ethyl trans-p-methoxycinnamate and ethyl cinnamate was tested for in-vivo sedative activity by Huang et al. (2008) using spontaneous locomotor assay in mice. The extract showed considerable sedative activity. Ali et al. (2015) screened the in-vivo sedative effects of acetone extracts of the rhizome and leaves by using thiopental

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sodium induced sleeping time test, hole cross test, and open field test in Swiss albino mice against Diazepam as a standard drug. The results indicated that the acetone extracts of both leaf and rhizome possessed remarkable sedative effects. 47.3.17 VASORELAXANT ACTIVITY Dichloromethane extract of K. galanga along with its isolates, ethyl cinna­ mate, and ethyl p-methoxycinnamate was evaluated for vasorelaxant effi­ ciency by Othman et al. (2002, 2006) by employing different concentrations of the brine shrimp lethality bioassay. The crude DCM (dichloromethane) extract showed the potent vasorelaxant effect. 47.3.18 WOUND HEALING ACTIVITY Shanbhag et al. (2006) assessed the wound healing activity of ethanolic extract of K. galanga, in vivo by using incision, excision, and dead space wound models in Wistar rats and proved that the ethanolic extract of the plant showed a significant wound healing potential. KEYWORDS • • • •

Kaempferia galanga Chandramulika phytochemistry pharmacology

REFERENCES Achuthan, C. R.; Padikkala, J. Hypolipidemic Effect of Alpinia galanga (Rasna) and Kaempferia galanga (Kachoori). Indian J. Clin. Biochem. 1997, 12 (1), 55–58. DOI: https://doi.org/10.1007/BF02867956. Ali, M. S.; Dash, P. R.; Nasrin, M. Study of Sedative Activity of Different Extracts of Kaempferia galanga in Swiss Albino Mice. BMC Compl. Altern. Med. 2015, 15, 158. DOI: https://doi.org/10.1186/s12906-015-0670-z. Ali, H.; Yesmin, R.; Satter, A.; Habib, R.; Yeasmin, T. Antioxidant and Antineoplastic Activities of Methanolic Extract of Kaempferia galanga Linn. Rhizome Against Ehrlich Ascites Carcinoma Cells. J. King Saud Univ. Sci. 2018, 30 (3), 386–392. DOI: https://doi. org/10.1016/j.jksus.2017.05.009.

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Chachad, D.; Shimpi, S. Anti-Inflammatory Activity of Kapurkachari. Electron. J. Pharmacol. Ther. 2008, 1, 25–27. Choi, I.-H., Park, J. Y., Shin, S. C., Park, Il-K. Nematicidal Activity of Medicinal Plant Extracts and Two Cinnamates Isolated from Kaempferia galanga L. (Proh Hom) Against the Pine Wood Nematode, Bursaphelenchus xylophilus. Nematology 2006, 8 (3), 359–365. Choochote, W.; Kanjanapothi, D.; Panthong, A.; Taesotikul, T.; Jitpakdi, A.; Chaithong,U.; Pitasawat, B. Larvicidal, Adulticidal and Repellent Effects of Kaempferia galanga. Southeast Asian J. Trop. Med. Publ. Health 1999, 30 (3), 470–476. Chowdhury, M. Z.; Mahmud, Z.; Ali, M. S.; Bachar, S. C. Phytochemical and Pharmacological Investigations of Rhizome Extracts of Kaempferia galanga. Int. J. Pharmacogn. 2014, 1 (3), 185–192. DOI: https://doi.org/10.13040/IJPSR.0975-8232. Chu, D. M.; Miles, H.; Toney, D.; Chi, N. Y.; Cabral, F. M. Amebicidal Activity of Plant Extracts from Southeast Asia on Acanthamoeba spp. Parasitol. Res. 1998, 84 (9), 746–752. DOI: https://doi.org/10.1007/s004360050480. Hakim, A.; Andayani, Y.; Rahayuan, B. D. Isolation of Ethyl p-Methoxycinnamate from Kaempferia galanga L. IOP Conf. Ser. J. Phys. Conf. 2018, 1095, 012039. DOI: https://doi. org/10.1088/1742-6596/1095/1/012039. He, J. H.; Yue, G. G.; Lau, C. B.; Ge, W.; But, P. P. Antiangiogenic Effects and Mechanisms of Trans-Ethyl p-Methoxycinnamate from Kaempferia galanga L. J. Agric. Food Chem. 2012, 60 (45), 11309–11317. DOI: https://doi.org/10.1021/jf304169j. Huang, L.; Yagura, T.; Chen, S. Sedative Activity of Hexane Extract of Kaempferia galanga L. and Its Active Compounds. J. Ethnopharmacol. 2008, 120 (1), 123–125. DOI: https:// doi.org/10.1016/j.jep.2008.07.045. Jantan, M. S. I. B.; Yassin, M.; Chin, C. B.; Chen, L. L.; Sim, N. L. Antifungal Activity of the Essential Oils of Nine Zingiberaceae Species. Pharm. Biol. 2003, 41 (5), 392–397. DOI: https://doi.org/10.1076/phbi.41.5.392.15941. Jiao, Z.; Xu, W.; Zheng, J.; Shen, P.; Qin, A.; Zhang, S.; Yang, C. Kaempferide Prevents Titanium Particle Induced Osteolysis by Suppressing JNK Activation During Osteoclast Formation. Sci. Rep. 2017, 7, 16665. DOI: https://doi.org/10.1038/s41598-017-16853-w. Kitani, S.; Yoshida, M.; Boonlucksanawong, O.; Panbangred, W.; Anuegoonpipat, A.; Kurosu, T.; Nihira, T. Cystargamide B, a Cyclic Lipodepsipeptide with Protease Inhibitory Activity from Streptomyces sp. J. Antibiot. 2018, 71 (7), 662–666. DOI : https://doi.org/10.1038/ s41429-018-0044-0. Kiuchi, F.; Nakamura, N.; Tsuda, Y. 3-Caren-5-One from Kaempferia galanga. Phytochemistry 1987, 26 (12), 3350–3351. DOI: https://doi.org/10.1016/s0031-9422(00)82505-4. Ko, H. J.; Kim, H. J.; Kim, S. Y.; Yun, H. Y.; Baek, K. J.; Kwon, N. S.; Wan, K. W.; Choi, H. R.; Park, K. C.; Kim, D. S. Hypopigmentary Effects of Ethyl p-Methoxycinnamate Isolated from Kaempferia galanga. Phytother. Res. 2014, 28, 274–279. DOI: https://doi. org/10.1002/ptr.4995. Lakshmanan, D.; Werngren, J.; Jose, L.; Suja, K. P.; Nair, M. S.; Varma, R. L.; Mundayoor, S.; Hoffner, S.; Kumar, R. A. Ethyl p-Methoxycinnamate Isolated from a Traditional Anti-Tuberculosis Medicinal Herb Inhibits Drug Resistant Strains of Mycobacterium tuberculosis In Vitro. Fitoterapia 2011, 82 (5), 757–761. DOI: https://doi.org/10.1016/j. fitote.2011.03.006. Li, Y. C.; Ji, H.; Li, X. H.; Zhang, H. X.; Li, H. T. Isolation of Nematicidal Constituents from Essential Oil of Kaempferia galanga L Rhizome and Their Activity Against Heterodera

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avenae Wollenweber. Trop. J. Pharm. Res. 2017, 16 (1), 59–65. DOI: https://doi. org/10.4314/tjpr.v16i1.8. Liu, B.; Liu, F.; Chen, C.; Gao, H. Supercritical Carbon Dioxide Extraction of Ethyl Pmethoxycinnamate from Kaempferia galanga L. Rhizome and Its Apoptotic Induction in Human HepG2 Cells. Nat. Prod. Res. 2010, 24 (20), 1927–1932. DOI: https://doi.org/10.1 080/14786419.2010.490913. Luger, P.; Weber, M.; Dung, N. X.; Tuyet, N. T. B. Ethyl p-Methoxycinnamate from Kaempferia galanga L. in Vietnam. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 1996, 52 (5), 1255–1257. DOI: https://doi.org/10.1107/S0108270195016027. Ningombam, S.; Takehiro, T.; Abdelsamed, E.; Mahmoud, A. A. I.; Elamir, H. M.; Singh, B.; Midori, C. S.; Hiroshi, I.; Masaaki, N.; Akemi, U. Kaemgalangol A: Unusual SecoIsopimarane Diterpenoid from Aromatic Ginger Kaempferia galanga. Fitoterapia 2018, 129, 47–53. DOI: https://doi.org/10.1016/j.fitote.2018.06.010. Othman, R.; Ibrahim, H.; Awang, M.; Ali, Md. K.; Giiani, A. U.; Mustafa, Md. R. Vasorelaxant Effects of Ethyl Cinnamate Isolated from Kaempferia galanga on Smooth Muscles of the Rat Aorta. Lett. Plant. Med. 2002, 68, 655–657. Othman, R.; Ibrahim, H.; Mohd, M. A.; Mustafa, M. R.; Awang, K. Bioassay-Guided Isolation of a Vasorelaxant Active Compound from Kaempferia galanga L. Phytomedicine 2006, 13 (1–2), 61–66. DOI: https://doi.org/10.1016/j.phymed.2004.07.004. Rahman, I.; Kabir, M. T.; Islam, M. N.; Muqaddim, M.; Sharmin, S.; Ullah, M. S.; Uddin, M. S. Investigation of Antioxidant and Cytotoxic Activities of Kaempferia galanga L. Res. J. Pharm. Technol. 2019, 12 (5), 2189–2194. DOI: https://doi. org/10.5958/0974-360X.2019.00365.2. Ridtitid, W.; Sae-Wong, C.; Reanmongkol, W.; Wongnawa, M. Antinociceptive Activity of the Methanolic Extract of Kaempferia galanga Linn. in Experimental Animals. J. Ethnopharmacol. 2008, 118 (2), 225–230. DOI: https://doi.org/10.1016/j.jep.2008.04.002. Sahoo, S.; Parida, R.; Singh, S.; Padhy, R. N.; Nayak, S. Evaluation of Yield, Quality and Antioxidant Activity of Essential Oil of In Vitro Propagated Kaempferia galanga Linn. J. Acute Dis. 2014, 124–130. DOI: https://doi.org/10.1016/S2221-6189(14)60028-7. Saputri, F. C.; Avatara, C. Antithrombotic Effect of Kaempferia galanga L. and Curcuma xanthorrhiza Roxb. on Collagen-Epinephrine Induced Thromboembolism in Mice. Pharm. J. 2018, 10 (6), 1149–1153. DOI: https://doi.org/10.5530/pj.2018.6.196. Shanbhag, T. V.; Chandrakala, S.; Sachidananda, A.; Kurady, B. L.; Smita, S.; Ganesh, S. Wound Healing Activity of Alcoholic Extract of Kaempferia galanga in Wistar Rats. Indian J. Physiol. Pharmacol. 2006, 50 (4), 384–390. Srivastava, N.; Singh, S. R.; Gupta, A. C.; Shanker, K.; Bawankule, D. U.; Luqman, S. Aromatic Ginger (Kaempferia galanga L.) Extracts with Ameliorative and Protective Potential as a Functional Food, Beyond Its Flavor and Nutritional Benefits. Toxicol. Rep. 2019, 6, 521–528. DOI: https://doi.org/10.1016/j.toxrep.2019.05.014. Sulaiman, M. R.; Zakaria, Z. A.; Daud, I. A.; Ng, F. N.; Ng, Y. C.; Hidayat, M. T. Antinociceptive and Anti-Inflammatory Activities of the Aqueous Extract of Kaempferia galanga Leaves in Animal Models. J. Nat. Med. 2008, 62, 221–227. DOI: https://doi. org/10.1007/s11418-007-0210-3. Tewtrakul, S.; Yuenyongsawad, S.; Kummee, S.; Atsawajaruwan, L. Chemical Components and Biological Activities of Volatile Oil of Kaempferia galanga Linn. Songklanakarin J. Sci. Technol. 2005, 27 (2), 503–507.

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Udomkusonsri, P.; Trongvanichnam, K.; Klangkaew, M. L. N.; Kusucharit, N. In Vitro Efficacy of the Antifungal Activity of Some Thai Medicinal-Plants on the Pathogenic Fungus, Saprolegnia parasitica H2, from Fish. Kasetsart J. (Nat. Sci.) 2007, 41, 56–61. Umar, M. I.; Asmawi, M. Z.; Sadikun, A.; Atangwho, I. J.; Yam, M. F.; Altaf, R.; Ahmed, A. Bioactivity-Guided Isolation of Ethyl-p-Methoxycinnamate, an Anti-Inflammatory Constituent from Kaempferia galanga L. Extracts. Molecules 2012, 17, 8720–8734. DOI: https://doi.org/10.3390/molecules17078720. Umar, M. I.; Asmawi, M. Z.; Sadikun, A.; Majid, A. M.; Suede, F. S. A.; Hassan, L. E.; Altaf, R.; Ahamed, M. B. Ethyl-p-Methoxycinnamate Isolated from Kaempferia galanga Inhibits Inflammation by Suppressing Interleukin-1, Tumor Necrosis Factor-a, and Angiogenesis by Blocking Endothelial Functions. Clinics (Sao Paulo) 2014, 69 (2), 134–144. DOI: https:// doi.org/10.6061/clinics/2014(02)10. Vittalrao, A. M.; Shanbhag, T.; Kumari, K. M.; Bairy, K. L.; Shenoy, S. Evaluation of AntiInflammatory and Analgesic Activities of Alcoholic Extract of Kaempferia galanga in Rats. Indian J. Physiol. Pharmacol. 2011, 55 (1), 13–24. Wang, F. L.; Luo, J. G.; Wang, X. B.; Kong, L. Y. A Pair of Sulfonated Diarylheptanoid Epimers from Kaempferia galanga. Chin. J. Nat. Med. 2013, 11 (2), 171–176. DOI: https:// doi.org/10.1016/s1875-5364(13)60045-x. Yang, Y. C.; Park, I. K.; Kim, E. H.; Lee, H. S.; Ahn, Y. J. Larvicidal Activity of Medicinal Plant Extracts Against Aedes aegypti, Ochlerotatus togoi, and Culex pipiens pallens (Diptera: Culicidae). J. Asia Pac. Entomol. 2004, 7 (2), 227–232. DOI: https://doi.org/10.1016/ s1226-8615(08)60220-4. Yang, X.; Ji, H.; Feng, Y.; Yu, J.; Liu, A. Structural Characterization and Antitumor Activity of Polysaccharides from Kaempferia galanga L., Oxidative Medicine and Cellular Longevity. Oxid. Med. Cell. Longev. 2018, Article ID 9579262. DOI: https://doi. org/10.1155/2018/9579262. Yao, F.; Huang, Y.; Wang, Y.; He, X. Anti-Inflammatory Diarylheptanoids and Phenolics from the Rhizomes of Kencur (Kaempferia galanga L.). Ind. Crop. Prod. 2018, 125, 454–461. DOI: https://doi.org/10.1016/j.indcrop.2018.09.026.

CHAPTER 48

Bioactive Compounds and Pharmacological Activities of Terminalia pallida Brandis PASUPULETI SIVARAMAKRISHNA1*, PULICHERLA YUGANDHAR1,2, and NATARU SAVITHRAMMA1 1Department

of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh 517502, India

2Survey

of Medicinal Plants Unit, Regional Ayurveda Research Institute, Itanagar, Arunachal Pradesh 791111, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Terminalia pallida, an endemic threatened medicinal plant is widely used by the tribal people to cure cold, cough, fever, diabetes, dysentery, diar­ rhea, jaundice, peptic ulcers and venereal diseases. Quantitative analysis of leaf, stembark, fruit extracts of T. pallida possess the high concentration of phenols and flavonoids than other secondary metabolites. Pharmacological investigations proved the efficacy of T. pallida fruit extracts, for their antimi­ crobial, anti-diabetic, hepatoprotective, cardioprotective, antihyperlipidemic, antiulcer and anti-pyretic properties. Bioactive compounds of T. pallida are of great importance to use in modern medicine for the human wellbeing. 48.1 INTRODUCTION Terminalia pallida (Combretaceae), commonly called as Tella karakkaya in Telugu, is endemic to Sesachalam hill range of Eastern Ghats, Andhra Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Pradesh, India (Raju et al., 2012). This plant grows on rocky hilly areas of Chittoor, Kadapa, and Kurnool districts in Andhra Pradesh, India. Saha et al. (2015) assessed and categorized this plant under vulnerable category according to IUCN red data. Since long time leaves, stem bark, and fruit parts of the plant have been widely used by the tribal people as a source of medicine for treating various ailments. T. pallida leaves are used for the preparation of indigenous drugs to treat skin blisters and skin diseases. The stem bark and leaves are highly useful to treat cold, cough, fever, diabetes, dysentery, and diarrhea, and have antiinflammatory and analgesic activities. Fruit powder is given orally twice for a period of 25 days to treat diabetes by the tribal people of Tirumala forest (Thammanna et al., 1990; Nagaraju and Rao, 1997). Different forms of leaves have been used for the treatment of fever, hypertension, leprosy, jaundice, peptic ulcers, fissures, dysentery and diabetes. Whereas the fruits are used in the treatment of ulcers, diarrhea, and venereal diseases by the tribal people of Tirumala hills (Pullaiah and Sandhya Rani, 1999; Chetty et al., 2018). 48.2 PHYTOCHEMICAL STUDIES AND BIOACTIVE COMPOUNDS Preliminary phytochemical analysis on T. pallida leaf, stem bark, root, and fruits revealed the presence of different types of phytochemicals. Rajasekhar et al. (2014) reported that T. pallida revealed 14 types of phytochemicals. Kadam et al. (2015) studies revealed the presence of nearly 9 types of phytochemicals in methanolic extract. T. pallida whole plant extract showed alkaloids, flavonoids, glycosides, terpenoids, saponins, and volatile oils (Bhakshu et al., 2016). Paul et al. (2017) extracted the stem bark and fruit parts of the plant with methanol to determine the presence of different types of phytochemicals. The qualitative phytochemical analysis revealed the presence of carbohydrates, flavonoids, indoles, lignins, phenols, proteins, saponins, and tannins in both parts of the plant. Whereas leucoanthocyanins, steroids, and steroidal nucleus were present only in stem bark of the plant along with above said phyto­ chemicals. Guguloth et al. (2021) extracted plant leaves with chloroform, ethyl acetate, hydro alcohol, methanol, and petroleum ether for identification of different types of phytochemicals and performed different phytochemical screening analyses in the obtained extracts. The results revealed the presence of alkaloids, flavonoids, glycosides, proteins, saponins, steroids, and tannins. Among all the solvents ethyl acetate and hydro alcohol extracts showed more number of phytochemicals when compared with other solvents.

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Most of the preliminary phytochemical analyses revealed the presence of phenols and flavonoids in all parts of T. pallida. The extraction and isolation of stem bark and fruit extracts were reported to possess different types of bioac­ tive flavonoid compounds like Myricetin, Quercetin, Kaempferol, Luteolin, Apigenin, Orientin, and Vitexin (Paul et al., 2017; Manipal et al., 2017). The following phenolic bioactive compounds were reported from leaf and fruit extracts, such as protocatechuic acid, chlorogenic acid, α-resorcyclic acid, β-resorcyclic acid, cis-p-coumaric acid, trans-p-coumaric acid, p-hydroxy­ benzoic acid, phloretic acid, trans-ferulic acid, scopoletin, O-pyrocatechuiuc acid, vanillic acid, syringic acid, salicylic acid, cinnamic acid, gallic acid, digallic acid, and ellagic acid. Anthocyanidin-related bioactive compounds like cyanidin and delphinidin were present in stem bark, whereas Delphinidin was only obtained from fruit part of the plant (Paul et al., 2017).

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PHARMACOLOGICAL ACTIVITIES

T. pallida is reported to possess the following pharmacological properties, namely, antibacterial, antifungal, cardioprotective, hepatoprotective, anti­ pyretic, analgesic, antiulcer, antihyperlipidemic, antiatherogenic, antiadipo­ genic, thrombolytic, and antidiabetic activities. Systematic investigations on experimental organisms by administering T. pallida leaf, stem bark, and root extracts scientifically validated its pharmacological significance. 48.3.1 ANTIBACTERIAL ACTIVITY Gupta et al. (2002) evaluated antibacterial potential of methanolic extract of T. pallida fruit powder. They selected seven bacterial strains to check the antibacterial activity, among them three are Gram positive (Staphylo­ coccus aureus, Staphylococcus epidermidis, Micrococcus luteus) and four are Gram negative (Escherichia coli, Salmonella typhi, Shigella dysenteriae, Vibrio cholerae). For this 625 µg/mL, 1.25, 2.5, and 5 mg/mL concentra­ tions of T. pallida fruit extract were prepared and its potential was compared with chloramphenicol standard (10 µg/mL). E. coli, S. dysenteriae, and V. cholerae exhibited maximum antibacterial activity followed by S. aureus, S. epidermidis, and M. luteus, and the least activity was represented by S. typhi. The sensitivity of extract depends on complexity and composition of the bacterial cell wall. Due to the absence of peptidoglycan content in the Gram-negative bacteria, it is highly sensitive than Gram-positive bacteria. In another study, Paul et al. (2017) studied antibacterial activity of stem bark extracts. The concentrations of 20, 40, and 60 mg/mL were prepared to check the antibacterial activity against four bacterial strains. Among all the strains, Proteus vulgaris exhibited more susceptibility (16.5 mm) followed by Klebsiella pneumoniae (15.8 mm), Bacillus subtilis (15.4 mm), and Pseudo­ monas aeruginosa (13 mm). This study confirms the significant antibacterial potential of T. pallida stem bark. 48.3.2 ANTIFUNGAL ACTIVITY T. pallida methanolic fruit extract possess significant antifungal activity against the fungal strains like, Aspergillus niger and Candida albicans. To evaluate the activity, 625 µg/mL, 1.25, 2.5, and 5 mg/mL concentrations of plant extracts were used against above said strains. The concentrations at 2.5

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and 5 mg/mL exhibited high antifungal activity against A. niger (8 and 14 mm) than the C. albicans (7 and 11 mm). But there is no effect of 625 µg/ mL and 1.25 mg/mL concentrations on fungal stains. Similarly, ethyl alcohol extract exhibited moderate antifungal activity with 16 mm zone of inhibition (Gupta et al., 2002). 48.3.3 CARDIOPROTECTIVE ACTIVITY Shaik et al. (2012) studied the cardioprotective effect of T. pallida metha­ nolic fruit extracts against isoproterenol (ISO)-induced myocardial infarcted rats. After treatment with ISO, it elevates the lipids and lipoproteins espe­ cially LDL-C (low-density lipoprotein cholesterols) in the blood circulation and causes the blockage of arteries favoring the cardiovascular disease (Goldstein and Brown, 1984). ISO generates oxygen free radicals, cause the oxidation of low-density lipids (LDL), leads to generation of atheroscle­ rotic lesions cause the MI (myocardial infraction) (Libby, 2003) and also significantly decreases the activities of lecithin cholesterol acyl transferase (LCAT), paraoxonase, and lipoprotein lipase. It also significantly increases the activity of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCoA reductase). In ISO-treated rats, decreasing levels of cardiac marker enzymes like Creatine kinase (CK), lactate dehydrogenase (LDH), alanine transaminase (ALT), aspartate transaminase (AST), antioxidants-catalase (CAT), glutathione peroxidase (GPx), membrane-bound enzymes-Na+/K+, Ca2+, and Mg2+ ATPases (Shaik et al., 2012). The treatment of T. pallida fruit extracts to rats showed the ameliorative effect on lipids, lipoproteins (TC, TG, LDL-C, VLDL-C), and lipid metabolic enzymes. T. pallida fruit ethanolic extract doses at 100, 300, and 500 mg/kg b.w. significantly lowers the serum TC, TG, LDL-C, VLDL-C, and increased HDL-C levels in a dosedependent manner. The concentration at dose 500 mg/kg b.w. reduced the TC and LDL-C. LCAT was mainly involved in the esterification of cholesterol on HDL surface leads to growth of giant HDL particles that gives protection against MI. Pretreatment with plant extracts increased the levels of LCAT by blocking LPO, which further enhanced the levels of HDL-C. HMG­ Co-A is the rate-controlling enzyme in cholesterol biosynthesis. Enhanced activity of HMG-Co-A is found in plasma, liver, and heart of ISO-treated rats. Decreased cholesterol levels in plant extract (300 and 500 mg/kg b.w.) treated rats correlated with the decreased levels of HMG-Co-A reductase enzyme. No reduction in the levels of HMG-Co-A in case of plant extract

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dose at 100 mg/kg b.w. The extract restored the levels of cardiac marker enzymes, antioxidants, and membrane-associated enzymes CK, LDH, AlT, AST, CAT, GPx, Na+/K+, Ca2+, and Mg2+ Atpases. The change in lipid profile and the free radical scavenging activity of the extract is due to the presence of hypolipidemic and antioxidant phenolic compounds like gallic acid in the extract. 48.3.4 HEPATOPROTECTIVE ACTIVITY Palani et al. (2009) reported the hepatoprotective effect of T. pallida fruit ethanolic extracts against Acetaminophen (APAP)-induced hepatic damage in albino rats. APAP causes hepatic damage and increases the oxidative stress by releasing the lipid peroxidation molecules. Due to this loss of functional integrity of cellular membrane leads to cellular leakage of liver. Hence the marked increase in Serum glutamate oxaloacetate transaminase, Serum glutamate pyruvate transaminase, alkaline phosphatase, and total bilirubin levels. The oral administration of 250, 500 mg/kg b.w. of plant extract for a period of 7 days restored the hepatic marker enzymes to normal level. The effectiveness of hepatotrotective nature of extract was comparable to the standard drug Silymarin (25 mg/kg). Treatment with plant extract enhanced the levels of superoxide dismutase, CAT, glutathione peroxidase, and glutathione-s-transferase in Acetaminophen treated rats. 48.3.5 ANTIPYRETIC ACTIVITY Rani et al. (2016) carried out the antipyretic effect of T. pallida ethanolic fruit extracts against pyrexia-induced albino rabbits and compared its effect with aspirin, a standard antipyretic drug. Ethanolic extract at 200 mg/kg b.w. was administered orally as a single dose that significantly decreases the body temperature. A similar type of antipyretic study was carried out by Shaik et al. (2013) with T. pallida stem bark extract on experimental rat models using 250 and 500 mg/kg b.w. doses and compared the similarity results with paracetamol a standard antipyretic drug. Plant extracts exhibited antipyretic activity by reducing the temperature after 1 h of treatment and continues up to 3 h. From the results, the study emphasized that the significant antipyretic effect of plant extract is by owing rich flavonoid compounds (Brasseur, 1989).

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48.3.6 ANALGESIC ACTIVITY T. pallida stem bark extract possesses analgesic activity, which was proved by evaluating in experimental animal models. The analgesic activity was assessed using the hot plate method (Thermal stimulus-induced pain) and acetic acid-induced writhing. Doses of ethanolic extract (250 and 500 mg/ kg b.w.) of T. pallida showed significant decrease in the number of wreaths and the effect of extract was similar to the effect of Ibuprofen standard drug (40 mg/Kg b.w.). Similar dose of plant extract showed significant increase in mean reaction time to heat stimuli in hot plate method. Based on this, the extract exhibited analgesic activity, but the effect was less comparable to the effect of standard drug Pentazocine. It is due to the high concentration of flavonoids and tannins present in the plant extract exhibits analgesic activity by inhibiting the prostaglandins, which are involved in pain perception (Shaik et al., 2013). 48.3.7 ANTIULCER ACTIVITY T. pallida ethanolic leaf extracts at doses of 150, 300, and 600 mg/kg b.w. showed significant inhibition of the gastric lesions induced by the pylorus ligation and ethanol-induced gastric ulcer (Bharathi et al., 2015). The evalu­ ation of aniulcerogenic property of plant extract was compared with standard antiulcer drug ranitidine. The results of this study revealed the antiulcero­ genic as well as ulcer healing properties of T. pallida leaf extracts, it is due to the antisecretory effect of gastric cells. 48.3.8 ANTIHYPERLIPIDEMIC ACTIVITY T. pallida ethanolic fruit extract reported to possess significant effect on lowering the lipids and lipoproteins (TG, TC, LDL-C, HDL-C, and VLDL-C) in high-fat diet-induced rat models (Sampathkumar et al., 2011). This activity was proved by inducing hyperlipidemic condition in Sprague-Dawley rats by feeding with high-fat diet and investigating for a period of 30 days. In hyperlipidemic rats, total cholesterol, triglycerides, LDL-C and very LDL-C levels were elevated and high-density lipoprotein cholesterol was decreased. The rats administered with 100 mg/kg b.w. showed the reduced levels of lipids and lipoproteins.

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48.3.9 ANTIATHEROGENIC ACTIVITY Atherosclerosis happen due to the hyperlipidemia, further leads to coro­ nary heart disease. High levels of Total cholesterol (TC) and LDL-C are the predictors of atherosclerosis. AI (Atherogenic index) is the ratio of TC-HDL-C/HDL-C, which is important for assessing the atherosclerosis. The plant extract at 100 mg/kg b.w. lowers the AI, body weight gain and increases the protection against atherogenicity in HFD-fed rats evidencing its antiatherogenic activity (Sampathkumar et al., 2011). 48.3.10 ANTIADIPOGENIC ACTIVITY T. pallida fruit extract exhibited antiadipogenic activity on 3T3-L1 embry­ onic fibroblast-preadipocyte cell lines. The adipogenecity was induced with adipogenic cocktail (1 μM dexamethasone, 10 μg/mL insulin and 0.5 mM 3-isobutyl 1 methylxanthine) (Kameswara Rao, 2019). T. pallida ethanolic fruit extract at the concentrations of 10, 25, and 50 μg/mL showed antia­ dipogenic property by decreasing the proliferation and elevated apoptosis in 3T3-L1 adipocytes. The extract elicit the antiadipogenic function by regulating the preadipocyte and adipocyte cell cycle similar to the regulation effect of standard antilipidemic drug simvastatin (1 μM). 48.3.11 THROMBOLYTIC ACTIVITY In vitro thrombolytic study was carried out using T. pallida leaf extracts obtained from different solvents like methanol, hydro alcohol, petroleum ether, ethyl acetate and chloroform (Guguloth et al., 2021). After treating with plant extracts Clot lysis was observed after 72 h and streptokinase was used as positive control. Methanolic extract showed maximum clot lysis (95.4%) at the test concentration of 800 µg/mL followed by hydro alcoholic extract (90%). Other extracts such as chloroform (72.9%), ethyl acetate (70.16%), and petroleum ether (65.5%) also exhibited clot lysis, but their effects were moderate. In this study, the thrombolytic efficiency of methanolic extract of T. pallida leaf extracts was similar to the effect of streptokinase standard drug (97.26%). 48.3.12 ANTIDIABETIC ACTIVITY The ethnobotanical studies of tribal people revealed that the fruits of T. pallida control the diabetes. To confirm this property, a systematic scientific

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investigation was carried out by Kameswar rao et al. (2003) against alloxan induced diabetic rats. To confirm the hypoglycaemic effect, they were extracted the fruits with distilled water, ethanol, hexane and compared with glibenclamide standard drug. From the results, the ethanolic extract showed significant reduction of blood glucose levels than the aqueous and hexane extracts (Kameswara Rao, 2000). Ethanolic extracts at various doses (0.25, 0.5, 0.75 and 1.0 g/kg b.w.) reduced the blood glucose levels. The dose at 0.5 g/kg b.w. exhibited significant fall down of blood glucose levels by 24% in diabetic rats. 48.4

CONCLUSION

The phenols and flavonoids were occurring in large quantities when compared with other secondary metabolites of T. pallida. Many phenol and flavonoid bioactive compounds are identified based on paper chromato­ graphic technique. Antidiabetic studies and antimicrobial studies on T. pallida fruit extracts supported the ethnobotanical usage and its relevance. Other pharmacological investigations like cardioprotective activity, anti­ hyperlipidemic, and antiathergenic activities were proved the efficacy of T. pallida fruit extracts to develop natural drugs that prevent cardiovas­ cular and other related diseases. Hepatopreotective effect of T. pallida is due to the presence of strong antioxidants evidenced by its antioxidant efficacy. Whereas the flavonoids and tannin-related bioactive compounds are responsible for exhibiting the antipyretic, antianalgesic, and antiulcer activities. KEYWORDS • • • • •

endemic indigenous flavonoids anti-diabetic hepatoprotective and antipyretic

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REFERENCES Bhakshu, L. M.; Ratnam, K. V.; Raju, R. R. Anticandidal Activity and Phytochemical Analysis of Certain Medicinal Plants from Eastern Ghats, India. Indian J. Nat. Prod. Resour. 2016, 7 (1), 25–31. Bharathi, T.; Sriharsha, S. N.; Siddaiah, M. Evaluation of Anti-Ulcer Activity of Ethanolic Extract of Terminalia pallida Leaves in Experimental Rats. J. Glob. Trends Pharm. Sci. 2015, 6 (3), 2794–2797. Brasseur, T. Antiinflammatory Properties of Flavonoids. J. Pharm. Belg. 1989, 44, 235–241 Chetty, K. M.; Sivaji, Tulasi Rao, K. Flowering Plants of Chittoor District, Andhra Pradesh, India; Students Offset Printers: Tirupati, 2018. Goldstein, J. L.; Brown, M. S. Progress in Understanding the LDL Receptor and HMG-CoA Reductase, Two Membrane Proteins that Regulate the Plasma Cholesterol. J. Lipid Res. 1984, 25, 1450–1461. Guguloth, S. K.; Malothu, N.; Kulandaivelu, U.; GSN, K. R.; Areti, A. R.; Noothi, S. Phytochemical Investigation and In Vitro Thrombolytic Activity of Terminalia pallida Brandis Leaves. Res. J. Pharm. Technol. 2021, 14 (2), 879–882. Gupta, M.; Mazumder, U. K.; Manikandan, L.; Bhattacharya, S.; Haldar, P. K.; Roy, S. Antibacterial Activity of Terminalia pallida. Fitoterapia 2002, 73, 165–167. Kadam, S. D.; Sreedhar, C.; Chandrasekhar, K. B. Phytochemical Studies and Safety Evaluation of Terminalia pallida Roots and Boswelia ovalifoliolata Roots. Asian J. Pharm. Technol. Innovation. 2015, 3 (10), 21–26. Kameswara Rao, B.; Renuka Sudarshan, P.; Rajasekhar, M. D.; Nagaraju, N.; Appa Rao, Ch. Antidiabetic Activity of Terminalia pallida Fruit in Alloxan Induced Diabetic Rats. J. Ethnopharmacol. 2003, 85, 169–172. Kameswara Rao, B. Anti-Adipogenic Activity of Terminalia pallida. Exp. Biol. 2019, 33, lb42–lb42. Libby, P. Vascular Biology of Atherosclerosis: Overview and State of the Art. Am. J. Cardiol. 2003, 91, 3A–6A. Manipal, K.; Ramesh, L.; Madhava Chetty K. Quantification of Flavonoids in Barks of Selected Taxa of Combretaceae. Pharm. Pharmacol. Int. J. 2017, 5 (1), 26–29. Nagaraju, N.; Rao, K. N. 35th World Congress on Natural Medicines, Tirupati, India, AB, 300, 1997; pp 107. Palani, S.; Raja, S.; Venkadesan, D.; Karthi, S.; Sakthivel, K.; Kumar, B. S. Antioxidant Activity and Hepatoprotective Potential of Terminalia pallida. Arch. Appl. Sci. Res. 2009, 1, 18–28. Paul, M. J.; Joy, E. D.; Basha, S. K. M. Phytochemical Analysis and Antibacterial Activities of Terminalia pallida Against Bacillus subtilis, Klebsiella pneumoniae, Proteus vulgaris and Pseudmonas aeruginosa. Int. J. Sci. Res. 2017, 6 (12), 193–201. Pullaiah, T.; Sandhya Rani, S. Trees of Andhra Pradesh, India; Regency Publications, New Delhi, 1999. Rajasekhar, K.; Ramesh, S.; Raju, R. V. Preliminary Phytochemical Studies on Fruits of Terminalia Species (Combretaceae), Used by the Local Tribals of Andhra Pradesh. Int. J. Pharm. Sci. Res. 2014, 5 (1), 246–248. Raju, A. S.; Lakshmi, P. V.; Ramana, K. V. Reproductive Ecology of Terminalia pallida Brandis (Combretaceae), an Endemic and Medicinal Tree Species of India. Curr. Sci. 2012, 102, 909–917.

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Rani, S. S.; Kumar, P. V.; Kumar, M. R.; Mangilal, T. Evaluation of Antipyretic Activity of Ethanolic Extract of Terminalia pallida. Int. J. Res. Pharmacol. Pharmacother. 2016, 5 (1), 24–29. Saha, D.; Ved, D.; Ravikumar, K.; Haridasan, K. Terminalia pallida. The IUCN Red List of Threatened Species; 2015. https://dx.doi.org/10.2305/IUCN.UK.2015-2.RLTS. T50130685A50131440.en. Sampathkumar, M. T.; Kasetti, R. B.; Nabi, S. A.; Sudarshan, P. R.; Swapna, S.; Apparao, C. Antihyperlipidemic and Antiatherogenic Activities of Terminalia pallida Linn. Fruits in High Fat Diet-Induced Hyperlipidemic Rats. J. Pharm. Bioall. Sci. 2011, 3, 449–452. Shaik, A. H.; Rasool, S. N.; Reddy, A. V. K.; Kareem, M. A.; Krushna, G. S.; Devi, K. L. Cardioprotective Effect of HPLC Standardized Ethanolic Extract of Terminalia pallida Fruits Against Isoproterenol-Induced Myocardial Infarction in Albino Rats. J. Ethnopharmacol. 2012, 141, 33–40. Shaik, H. A.; Eswaraih, M. C.; Lahari, M.; Rao, B. M.; Ali, S. Evaluation of Analgesic and Antipyretic Activities of Ethanolic Extract of Terminalia pallida Stem in Experimental Animals. Sch. J. App. Med. Sci. 2013, 1 (1), 5–8. Thammanna, Rao, K. N.; Nagaraju, N. Medicinal Plants of Tirumala; T. T. Devasthanams, Tirupati, India, 1990.

CHAPTER 49

Phytochemistry and Pharmacology of an Aquatic Herb Nymphaea pubescens Willd. KIRAN KUMAR ANGADI1, AMMANI KANDRU2*, and CH. SRINIVASA REDDY3 1Biochemistry

Division, National Institute of Nutrition, ICMR, Hyderabad, Telangana, India

2Department of Botany and Microbiology, Acharya Nagarjuna University,

Guntur, Andhra Pradesh, India 3Department

of Botany, SRR & CVR Government Degree College, Vijayawada, Andhra Pradesh, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Nymphaea pubescens Willd. (Nymphaeaceae) is an important aquatic medicinal herb, widely used in traditional medicine and ethnic diets in various parts of the world. Since last few years there has been an increasing interest on ethnic and traditional use of medicinal plants and supportive experimental approach to discover novel drugs. In this context the present review attempts to assess the phytochemical and pharmacological profile of the plant. Pharmacological studies such as antibacterial, antifungal, anti-inflammatory, anticancer, hepatoprotec­ tive, antioxidant efficacy, anti-hyperglycaemic, anti-hyperlipidaemic effect, cardio protective activity, neuro protective activity of the plant are discussed at length. From different parts of the plant body many Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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bioactive compounds have been isolated and identified, such as phenolic derivatives, flavonoids, alkaloids, terpenes, sterols, tannins, and glyco­ sides. A novel compound viz., guggultetrol was isolated, purified and reported for the first time. 49.1 INTRODUCTION Nymphaea pubescens Willd., also recognized as hairy water lily or pink water lily, belongs to the family Nymphaeaceae. It is a large perennial aquatic herb with short, erect, roundish, tuberous rhizomes; leaves ovateelliptic, dentate, dark-green, glabrous above and purplish-green, and prominently veined beneath. The stem is tuberous and erect. Petioles and pedicels long. Sepals are green and ribbed outside, white inside; petals are pure white, linear oblanceolate, and obtuse. The plant’s stamens are arranged in three to four whorls, and the tip is blunt with no sterile appendage. Natural fruit formation occurs underwater, and seeds are ellipsoid, enclosed by transparent, fleshy aril (Begum et al., 2010). N. pubescens is found throughout the warmer parts of India, Sri Lanka, Thai­ land, Malaysia, Indonesia, New Guinea, Vietnam, Philippines, and Laos in tanks, ponds, and ditches. N. pubescens is used as a component of ethnic diet and traditional medi­ cine in South-East Asia. In south Borneo Island of Indonesia, N. pubescens seed flour is commonly used as a local food ingredient to prepare a cake (Nazarni et al., 2020). 49.2 PHYTOCHEMISTRY The phytochemical analysis of N. pubescens bare various bioactive composites like phenolic derivatives, flavonoids, alkaloids, terpenes, sterols, tannins, and glycosides (Table 49.1). Amongst all phytochemicals, N. pubescens has higher anthocyanidins, flavonoids, terpenoids, lipids, and amino acids. These phytochemicals have various bioactive properties, which could be of great importance in treating various human diseases. The N. pubescens seed extract oil’s fatty acids composition is similar to palm and groundnut oils. N. pubescens seed oil is unsaturated and classified in the oleic-linoleic acid group. It has great nutritional and industrial potentials (Aliyu et al., 2017).

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Phytochemicals in Nymphaea pubescens (Kumar et al., 2021).

S. Phytochemicals No. 1 Anthocyanidins: Petunidin, delphinidin, peonidin, malvidin 2 Flavonoids: Luteolin, apigenin, orientin, vitexin, rutin, myricetin, quercetin, kaempferol 3 Phenolic compounds: Iso-chlorogenic acid, caffeic acid, protocatechuic acid, phloroglucinol, chlorogenic acid, quercetin, β-resorcyclic acid, homo-protocatechuic acid, phloretic acid, o-pyrocatechuic acid, o-coumaric acid, trans-sinapic acid, p-hydroxybenzoic acid, cis-sinapic acid, trans-ferulic acid, vanillic acid, salicyclic acid, cinnamic acid 4 Amino Acids: Aspartic acid, glutamic acid, α-alanine, threonine, asparagine, lysine, histidine, arginine, cystine, γ-methylene glutamic acid, glutamine, γ-methylene glutamine, β-alanine, proline, phenylala­ nine, valine, isoleucine, leucine, norleucine 5 Lipids: Phosphatic acid, phosphatidylserine, phosphatidylinositol, phosphatidylcholine, phosphatidylethanolamine, digalactosyl­ diglyceride, phosphatidyl glycerol, unidentified galactolipid, sulphoquinovosyldiglyceride, diphosphatidyl glycerol, sterylglucoside, monogalactosyldiglyceride, sheryl glycoside 6 Saponins 7 Alkaloids 8 Terpenoids and steroids 9 Tannins 10 Indoles 11 Anthraquinones 12 Proteins 13 Carbohydrates 14 Anthocyanidins 15 Phenolic compounds 16 Coumarins 17 Quinones 18 Glycosides 19 Fixed oils and fats 20 Phytosterol 21 Lipids 22 Reducing sugars

Presence + + +

+

+

+ + + + + + + + + + + + + + + + +

Two compounds were purified and characterized from the leaf extracts of N. pubescens, namely Guggultetrol and β-sitosterol. The isolation and identification of compounds were characterized based on their U.V., I.R., 1H

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NMR, 13C NMR, and Mass spectral data. The compound guggultetrol is new and reported for the first time. Guggultetrols are evocative of the biologi­ cally vital phytosphingosine (C18 and C20), distributed in plant sphingolipids (Kumar et al., 2012).

49.3

BIOACTIVITIES

49.3.1 ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY The soxhlet extracts of N. pubescens (Hexane: petroleum ether, ethyl acetate, and methanol) have shown inhibition of bacteria such as Xanthomonas campestris (15.21 ± 1.98), Streptococcus mutans (13.81 ± 0.24), Bacillus subtilis (10.18 ± 0.42), and Staphylococcus aureus (9.08 ± 1.22). Similarly, in methanol extracts, the maximum zone of inhibition was observed in Enterococcus faecalis (9.08 ± 0.66), followed by Pseudomonas aeruginosa (8.04 ± 0.98) and B. subtilis (8.04 ± 0.88). In hexane: petroleum ether extracts, maximum zone of inhibition was observed in Pseudomonas aerugi­ nosa (10.18 ± 1.42) followed by B. subtilis (7.07 ± 0.98). However, hexane: petroleum ether extract showed moderate activity (11.34 ± 1.08) followed by ethyl acetate extract (8.04 ± 1.04) against Candida albicans. The zone of inhibition observed in the antibacterial test for the active extracts is almost equal to that of streptomycin (Kumar et al., 2012).

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Nowadays nano particle synthesis or biosynthesis of silver nanoparticles (SNPs), has accrued utmost interest. Stable SNPs were formed by treating an aqueous Ag(NO3)2 with this plant leaf extract. These nanoparticles were esti­ mated for antibacterial activity against clinically isolated bacterial pathogens like B. subtilis, S. aureus, Escherichia coli, Klebsiella pneumoniae, Pseudo­ monas aeruginosa, and Proteus vulgaris. So phytochemically synthesized SNPs has lead over conventional antibiotics (Prasad and Savithramma, 2015). 49.3.2 ANTIOXIDANT EFFICACY AND ANTI-INFLAMMATORY ACTIVITY The extract of N. pubescens revealed vigorous antioxidant activity in a dosedependent manner. The results showed that N. pubescens scavenges free radicals, enriching damage imposed by oxidative stress in different disease conditions and acts as a novel natural antioxidants source (Rajan et al., 2012). Antioxidant activity of the rhizome of N. pubescens was measured by in vitro methods, such as DPPH, superoxide, ABTS, hydroxyl, and reducing power assay using methanol extract. The methanol extract showed intense antioxidant activity, and its activity was compared with standard ascorbic acid/Trolox by in vitro assay (Mohan and Edison, 2013). 49.3.3 HEPATOPROTECTIVE ACTIVITY The hepatoprotective activity of the plant extract was estimated in rats through CCl4-induced hepatotoxicity model. Treatment with 500 mg/Kg/day of the extract for ten days attenuated CCl4 induced an increase in serum enzymes, namely, bilirubin, alanine, and aspartate aminotransferases. Also, superoxide dismutase-levels and glutathione were restored to normalcy in the liver of CCl4 treated rats, indicating the hepatoprotective role. Some of the flavonoids, phenolics, and saponin constituents might be responsible for this activity (Debnath et al., 2013). Nymphaea flowers and seeds are edible in some parts of South-East Asia. Recent studies suggest that the flower of N. pubescens is very active against the enzyme β-glucuronidase. Kaempferol, detected in the crude extract, had a 79-fold more robust activity against the enzyme β-glucuronidase than standard silymarin. After further in vivo study, the plant proved to be a novel hepatoprotective food cum medicinal plant (Acharya and De, 2016).

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49.3.4 ANTICANCER ACTIVITY N. pubescens is an interesting aquatic plant in cancer treatment, revealed in the Siddha system of medicine. The ethanolic extract of different parts such as rhizome, leaf, flower, and fruit was subjected to MTT test. The ethanolic extract of the flower part was cytotoxic against human breast carcinoma MCF cell lines and human cervical carcinoma, Hela cell lines. The IC50 value of ethanolic flower extract was 91.57 μg/mL against Hela cell lines and 99.6 μg/mL against MCF-7 cell lines. These results were significant, thereby justifying the use of the plant in the ethnic system (Selvakumari et al., 2012). Thai Nymphaea spp. extracts were assayed for antioxidative stress, cell apoptosis, and cellular migration in B16 melanoma cells. Cytotoxicity was assessed by the MTT method. In B16 melanoma cells, N. pubescens extract could inhibit B16 melanoma cell migration and invasion through low doses. Remarkably, the high doses of the extract induced melanoma cell death. At low doses, N. pubescens extract might overwhelm melanoma cells progres­ sion by interfering with cell migration and invasion capacity. Hence, N. pubescens extract induced cellular apoptosis, and it also suppressed cancer cell progression by reducing oxidative stress in B16 melanoma cells (Aimvi­ jarn et al., 2018). 49.3.5 ANTIHYPERGLYCAEMIC AND ANTIHYPERLIPIDEMIC EFFECT Selvakumari and Shantha (2010) studied antidiabetic activity in alloxan­ induced diabetic rats with the whole plant extract of N. pubescens. The ethanolic extract at 400 mg/Kg body weight significantly reduced blood glucose level up to 99.28 mg/dL. The ethanolic and aqueous flower extracts of N. pubescens were screened for antidiabetic activity. There is a signifi­ cant reduction in blood glucose levels in diabetic rats, and the percentage reductions were found to be 21.97% and 19.94% when directed with a dose of 400 mg/Kg of ethanol and aqueous extracts (Karthiyayini et al., 2011). Hyperglycaemia is the typical manifestation of patients in Diabetes, and earlier studies showed that N. pubescens reduces blood glucose by inhib­ iting the pancreatic α-glucosidases and α-amylase (Rajan et al., 2012). The antidiabetic and hypolipidemic properties of an ethanol tuber extract of N. pubescens was studied. Diabetes was induced in albino rats by administering alloxanmonohydrate (150 mg/Kg, body weight i.p.). The ethanolic tuber

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extract of N. pubescens was examined for blood parameters like serum and liver antioxidant enzymes. The ethanol extracts of N. pubescens tuber elicited significant reductions in blood glucose, lipid parameters except for HDL-C, serum enzymes, and liver antioxidant enzymes (Shakeela et al., 2012). Kumar et al. (2013b) found analogous results with methanolic leaf extract of N. pubescens. Guggultetrol isolated from N. pubescens was taken as a ligand for molecular docking. In this docking study, the assessment of guggultetrol as an inhibitor of Glucokinase (PDB ID: 1V4S), an authenticated drug target enzyme of Type-II diabetes, was taken up. Guggultetrol was found to bind at the active site of glucokinase with the lowest binding energy and RMSD values to be −9.45 kcal/mol and 2.0Å, respectively. The docking studies of the Guggultetrol with target protein disclosed that this is an appropriate molecule that docks well with target connected to Diabetes mellitus. In the preliminary studies, this compound has shown significant biological activity by targeting multiple signalling pathways. Thus, based on in silico studies, it was expected that guggultetrol displayed an inhibitory effect against diabetes (Kumar et al., 2013a). 49.3.6 CARDIOPROTECTIVE ACTIVITY N. pubescens flowers are astringent and cardiotonic. The seeds are cooling, aphrodisiac, sweet, stomachic, and restorative. Taking N. pubescens seed powder 1 gm/day for ten days showed an anti-inflammatory effect and reduced the production of free radicals, thereby preventing the damage of cardiomyocytes (Muthulingam, 2010). 49.3.7 NEUROPROTECTIVE ACTIVITY N. pubescens flower extracts displayed inhibitory activity of acetylcholin­ esterase (AChE), which is used to treat Alzheimer’s disease. Chemometric analysis revealed gallic acid, a previously reported metabolite, to be one of the contributors significantly related to the inhibition of AChE by the flower extracts. A possible synergistic action of metabolites is suggested for the AChE inhibitory property of N. pubescens flower extracts (Acharya et al., 2018).

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49.4

CONCLUSION

The traditional use of the N. pubescens by the Ayurvedic physicians for the control of Diabetes has been known since ancient times. The in silico molecular docking studies of guggultetrol with glucokinase enzyme exhib­ ited binding interactions, and further studies are required to progress a potent glucokinase inhibitor for the treatment of Type-II diabetes. This plant similarly possesses antibacterial, antifungal activity, antioxidant efficacy, anti-inflammatory, hepatoprotective, anticancerous, and cardioprotective activities. The result of these studies might support to develop plant-based natural antibiotics for curing the common diseases of humans. Also, it can be utilized as an antidiabetic herbal drug. KEYWORDS • • • • •

phytochemistry pharmacology phytoconstiuents guggultetrol novel compound

REFERENCES Acharya, J.; De, B. Bioactivity-Guided Fractionation to Identify β-Glucuronidase Inhibitors in Nymphaea pubescens Willd. Flower Extract. Food Agric. 2016, 2, 1–7. Acharya, J.; Dutta, M.; Chaudhury, K.; De, B. Metabolomics and Chemometric Study for Identification of Acetylcholinesterase Inhibitor(s) from the Flower Extracts of Nymphaea pubescens. J. Food Biochem. 2018. DOI: https://doi.org/10.1111/jfbc.12575. Aimvijarn, P.; Rodboon, T.; Payuhakrit, W.; Suwannalert, P. Nymphaea pubescens Induces Apoptosis, Suppresses Cellular Oxidants-Related Cell Invasion in B16 Melanoma Cells. Pharm. Sci. 2018, 24 (3), 199–206. Aliyu, M.; Kano, M. A.; Abdullahi, N.; Kankara, I. A.; Ibrahim, S. I.; Muhammad, Y. Y.; Abdulkadir, I. A. Extraction, Characterization, and Fatty Acids Profiles of Nymphaea lotus and Nymphaea pubescens Seed Oils. Biosci. Biotech. Res. Asia. 2017, 14 (4), 1299–1307. Begum, H. A.; Ghosal, K. K.; Chattopadhyay, T. K. Comparative Morphology and Floral Biology of Three Species of the Genus Nymphaea from Bangladesh. Bangladesh J. Bot. 2010, 39 (2), 179–183.

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Debnath, S.; Ghosh, S.; Hazra, B. Inhibitory Effect of Nymphaea pubescens Willd. Flower Extract on Carrageenan-Induced Inflammation and CCl4 Induced Hepatotoxicity in Rats. Food Chem.Toxicol. 2013, 59, 485–491. DOI: 10.1016/j.fct.2013.06.036. Karthiyayini, T.; Sindu, N. R.; Senthilkumar, K. L. Antidiabetic Activity on the Flowers of Nymphaea pubescens Willd. Res. J. Pharm. Biolog. Chem. Sci. 2011, 2, 866–873. Kumar, A. K.; Ravi, K. G.; Medicherla, V.; Jagannadham, A. K.; Ammani, K. Phytochemical Analysis and Antimicrobial Properties of Leaf Extracts of Nymphaea pubescens. Asian Pac. J. Trop. Biomed. 2012, 1–5. Kumar, A. K.; Ravi, K. G., Medicherla, V.; Jagannadham, A. K. Molecular Docking Studies of Guggultetrol from Nymphaea pubescens with Target Glucokinase (G. K.) Related to Type-II Diabetes. J. Appl. Pharm. Sci. 2013a, 3 (2), 127–131. Kumar, A. K.; Ammani, K.; Rahaman, A. Anti-Hyperlipidaemic and Antioxidant Assays (In Vivo) of Nymphaea pubescens Willd. Leaf Extract. Int. J. Pharm. Bio. Sci. 2013b, 4 (2), 624–630. Kumar, A. K.; Gurauvaiah, P.; Ammani, K. Pharmacological and In Silico Analysis of Nymphaea pubescent Leaves; Lap Lambert Academic Publishing, 2021. Mohan, V. R.; Edison, D. D. Total Phenolics, Flavonoids and In Vitro Antioxidant Activity of Nymphaea pubescens Willd. Rhizome. World J. Pharm. Pharm. Sci. 2013, 2 (5), 3710–3722. Muthulingam, M. Antihepatotoxic Efficacy of Nymphaea pubescens Willd. on AcetaminophenInduced Liver Damage in Male Wistar Rats. Int. J. Curr. Res.2010, 3, 12–16. Nazarni, R.; Khairiah, N.; Rufida.; Hidayati, S.; Muis, A. Effect of Fermentation on Total Phenolic, Radical Scavenging Activity, and Antibacterial Activity of Waterlily (Nymphaea pubescens Willd.) Seed Flour Extract. Biopropal Ind. 2020, 11 (1), 9–18. Prasad, K. S.; Savithramma, N. Tapping of Aquatic Plant Nymphaea pubescens Willd. for the Synthesis of Silver Nanoparticles and Their Antimicrobial Evaluation. Int. J. Pharm. Sci. Rev. Res. 2015, 33(2), 63–66. Rajan, R. C.; Madhavi, E.; Madhusudhanan, N.; Rao, K. V. G. In Vitro Antioxidant and Free Radical Scavenging Activity of Nymphaea pubescens Willd. J. Pharm. Res. 2012, 5 (7), 3807–3809. Selvakumari, S.; Shantha, A. Antidiabetic Activity of Nymphaea pubescens Willd. A Plant Drug of Aquatic Flora Interest. J. Pharm. Res. 2010, 3 (12), 3067–3069. Selvakumari, S.; Shantha, S.; Purushoth, P. T.; Kumar, C. S. Antiproliferative Activity of Ethanolic Flower Extract from Nymphaea pubescens Willd. Against Human Cervical and Breast Carcinoma In Vitro. Int. Res. J. Pharm. 2012, 3 (1), 124–125. Shakeela, P. S.; Kalpanadevi, V.; Mohan, V. R. Potential Antidiabetic, Hypolipidaemic and Antioxidant Effects of Nymphaea pubescens Willd. Extract in Alloxan-Induced Diabetic Rats. J. Appl. Pharm. Sci. 2012, 2 (2), 83–88.

CHAPTER 50

Phyla nodiflora (L.) Greene—Exquisite Plant with Therapeutic Effects SOMASUNDARAM RAMACHANDRAN* and VEERAMANENI ALEKHYA Department of Pharmacology, GIET School of Pharmacy, NH-16 Chaitanya Knowledge city, Rajahmundry, Andhra Pradesh 533296, India *Corresponding

author. E-mail: [email protected]

ABSTRACT Phyla nodiflora (L.) Greene of Verbenaceae family is a perennial herb with prostate stem and roots at the nodes, it is well known as poduthalai in Tamil and in English it is called as turkey tangle and cape weed. The plant is reported to have various chemical constituents like phenol compounds, flavonoids, steroids, alkaloids, resins, volatile oils and tannins. It is also reported to have therapeutic activities such as antioxidant, hepatoprotective, antibacterial, antitumour, antihyperuricemic, antiinflammatory and antidiabetic activities. 50.1 INTRODUCTION Phyla nodiflora (L.) Greene is a perennial herb, with prostrate stem and roots at the nodes which are scanty. Synonyms of the plant include Lippia nodiflora (L.) Michx, Lippia canescens Kunth, Lippia incasiomalo (Small) Tildsoan, Lippia lickiflora (L.) Michx and Lippia reptans Kunth. It is commonly known as Poduthalai in Tamil and other common names in English are: Lippia, Capeweed, carpetweed, fog fruit, mat grass, turkey-tangle; Sanskrit: VasirVasuka, Bengali: Bhuiokar, Karghas, Bakkan (Sharma and Singh, Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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2013). P. nodiflora is a medicinal plant, native of Brazil and United States. It is distributed in India, America (South and central countries), and territories of Africa (Terblanche and Kornelius, 1996). P. nodiflora is one among the family Verbenaceae. P. nodiflora is a perennial pioneer, prostate and it grows like mat forming and fast-growing plant. The plant will be 20–30 cm as a running herb (Lazarides et al., 1997). It is abundantly found in damp places or from the edges of the canal and moist places. 50.2

BIOACTIVES

P. nodiflora contains several medicinally important compounds, which are therapeutically active. Various chemical constituents were isolated such as, flavonoids, phenols, triterpenoids steroids, etc. from aerial parts. Preliminary phytochemical analysis of P. nodiflora revealed the presence of chemical constituents like phenol compounds, flavonoids, steroids, alka­ loids, quinols, resin, volatiles, and tannins (Yen et al., 2012). Rich flavo­ noids are found when compared with other constituents. From P. nodiflora plant isolated the compounds like nodifloridin A (1) & B (2), respectively, and glucose, xylose, and Fructose (Joshi, 1970). From the leaves of P. nodiflora, β-sitosterol glycoside and stigmasterol glycoside nodifloretin (3) were isolated (Barua et al., 1971). Tomas-Barberan et al. (1987) isolated 12 flavone sulfates from P. nodiflora given in Table 50.2. Other compounds isolated by Nair et al. (1973) are nepetin, batalilfolin from the flowers of P. nodiflora, two flavones’ glycosides, 6-hydroxyluteolin-7-oapioside and luteolin-7-O-glucoside, from flowers the known three flavones were isolated like 6-hydroxyluteolin, batatifolin, and nepetin were isolated (Barn­ abas et al.,1980). From the alcoholic extracts of P. nodiflora, the following compounds were isolated: acteoside (18) and 2′-O-acetylechinacoside (19), which are phenyl propanoid compounds and demethoxy centaureidin which is a flavone isolated from P. nodiflora. From the leaves of P. nodiflora acetyl derivatives isolated are halleridone and hallerone (Ravikanth et al., 2000). A new triterpenoid lippiacian (20) and new steroid 4′, 5′-dimethoxy benzoloxy stigmasterol (21) were isolated from the methanolic extracts of the aerial parts of P. nodiflora, stigmasterol and β-sitosterol known compounds were also isolated (Siddiqui et al., 2007). The extracts of P. nodiflora yielded mixture of hydro carbon and oxygenates through steam distillation. From the fraction of hydrocarbon, the major constituent was β-caryophyllene and in the oxygenated fraction the following components

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are present around 10–20% of total extract p-cymen-8-ol, linalool 1-octen­ 3-ol, phenethyl alcohol, and methyl salicylate (Elakovich and Stevens, 1985). Akhtar (1993) reported phytoconstituents from the plant like nodiflo­ ridin A & B, nod florin A&B, cornoside, α-ethyl-galactose, and 7-arabinose. Phytosterols isolated from the plant are β-sitosterol glucoside, stigmasterol glucoside, β-sitosterol, 4′,5′-dimethoxy benzoloxy stigmasterol and stigmasterol (Barua et al., 1969; Barnabas et al., 1980; Akhtar, 1993) and triterpenes like ursolic acid, lippiacian & 3 β-19α-dihydroxy-urs-1, 20-(30)diene (Akhtar, 1993; Siddiqui et al., 2009). Siddiqui et al. (2007, 2009) isolated steroidal compounds like 4′,5′-dimethoxy benzoloxy stigmasterol and beta-sitosterol; 2′-O-acetylechinacoside, arnarioside, acetoside are phenyl glycosides isolated from the plant (Khalil et al., 1995; Cheng, 2016; Cheng et al., 2015a); resin (α-copaene, β-bisabolene) (Elakovich and Stevens, 1985). From different parts of P. nodiflora several compounds were isolated which includes nodifloretin, 6-hydroxyluteolin-7-O-apioside, nodifloretin-7-sulfate, 6-hydroxy-luteolin-6-sulfate, 6-hydroxyluteolin­ 7-sulfate, jaceosidin-7-sulfate, nepetin-7-sulfate, hispidulin-4′-sulfate, hispidulin, jaceosidin, lippiacian, dimethoxy centaureidin, ganzalitosin I, 3,7,4′,5′-tetrahydroxy-3′-methoxy flavone, 4′-hydroxywogonin, and 5,7,8,4′-tetrahydroxy-3′-methoxy flavone, all these belongs to flavonoid class (Lin et al., 2014). P. nodiflora aerial parts of methanolic extract by the quantitative analysis revealed the presence of following constituents (Sudha and Srinivasan, 2013). TABLE 50.1 Quantitative Analysis of P. nodiflora Aerial Parts. S. No 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Name of the compound Phenolic compounds Total flavonoids Flavanols Total tannins Saponins Decan-4-one Stigmasterol Benzoic acid, 4-etoxyethyl ester Azacyclotridecan-2-one n-hexadecanoic acid

Quantity obtained 98.31 ± 0.003 mg GAE/g 60.88 ±0.001 mg QE/g 27.46 ± 0.002 mg QE/g 5.97 ± 0.021 mg TAE/g 3.52 ± 0.017 mg DE/g 35.75% 16.86% 13.73% 11.86% 10.13%

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From the aerial parts of P. nodiflora Priya and Ravindhran (2015) iden­ tified alkaloids, carbohydrates, phenolics, flavonoids, amino acids: 0.589, 0.411, 1.421, 0.312, 2.214, respectively.

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TABLE 50.2 List of Structures with Functional Groups. Structure number 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

50.3

Name Nodifloretin Hispidulin 7-sulfate Hispidulin 7,4′-disulfate Jaceosidin 7,4′-disulfate Nepetin 3′,4′-disulfate Nodifloretin 6,7-disulfate 6-hydroxy luteolin 6,7-disulfate Nodifloretin 7-sulfate 6-hydroxyluteolin 6-sulfate 6-hydroxyluteolin 7-sulfate Jaceosidin 7-sulfate Nepetin 7-sulfate Hispidulin 4′-sulfate Lippiflorin A Lippiflorin B

R1

R2

R3

R4

OH OCH3 OCH3 OCH3 OCH3 OSO3H OSO3H OH OSO3H OH OCH3 OCH3 OCH3 OH OH

OH OSO3H OSO3H OSO3H OH OSO3H OSO3H OSO3H OH OSO3H OSO3H OSO3H OH O-L-arabinosyl O-L-arabinosyl

OH OH OSO3H OSO3H OSO3H OH OH OH OH OH OH OH OSO3H OH OH

OCH3 H H OCH3 OSO3H OCH3 OH OCH3 OH OH OCH3 OH H OH O-L-rhamnoside

PHARMACOLOGY

50.3.1 ANTIMICROBIAL ACTIVITY Durairaj et al. (2007) examined the methanolic extract of P. nodiflora assessed for antimicrobic and lipid peroxide scavenging activity by in vitro methods. Antimicrobial action was tested by diffusion disc method. The scavenging activity using lipid peroxide is performed by making changes in the prepared concentrations (20–320 μg/mL) and its optical density. Results were compared with the standard antioxidants like BHT and BHA. The minimum inhibitory concentration for the extract and standard is given 226.52, 25.62, and 17.13 μg/mL, respectively. The results are dose dependant and satisfactory for the extract. P. nodiflora extracts were assessed for antimicrobial activity and the results are dose dependent, different extracts were tested like acetone, chlo­ roform, ethanol, and methanol against antimicrobial strains like Escherichia coli, Salmonela typhi, Escherichia aerogenes, Proteus mirabilis, and Proteus alcaligens at 200 μL concentration (Pagu et al., 2011). P. nodiflora leaves and stem extracts were assessed for antibacterial activity against Staphylococcus aureus, Micrococcus luteus, and P. mirabilis.

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Extracts were studied for antifungal activity using two fungal strains A. niger and Candida albicans. Ethanol extracts were studied for antibacterial and antifungal activity, and showed significant results with inhibition zones 3–12 mm. Inhibitory zones from fractions of pet ether 6–10 mm against all the tested organisms. The zone of inhibition produced by aqueous fraction was 10–12 mm against all tested organisms except, S. aureus and M. luteus (Ravikumar and Sudha, 2011) The methanolic extract from P. nodiflora showed antimicrobial activities against different microbial strains like E. coli, P. vulgaris, Klebsiella pneumoniae, Bacillus cereus, Bacillus subtilis, S. aureus, Pseudomonas aeruginosa, and Bacillus clausii as well as A. niger and C. albicans. All tested strains showed concentration-dependent activity. In both Gram-negative and Gram-positive bacteria tested, K. pneumoniae, P. aeruginosa, and B. subtilis displayed good sensitivity than the other tested species. Inhibition zones observed from K. pneumoniae, B. cereus and B. subtilis is 13 mm, E. coli 12 mm, Proteus vulgaris 11, P. aeruginosa, and S. aureus showed 10 mm inhibition zones in 250 μg/disc methanolic extract of P. nodiflora. Methanolic extract of P. nodiflora in concentration 500 μg/disc given highest and lowest inhibition zones exhibited from the species like Pseudomonas vulgaris, K. pneumoniae, B. cereus, and B. subtilis and B. clausii. Fungi exhibited the similar inhibition zones in A. niger and C. albicans (11 mm) at 250 g disc and for 500 μg/disc, A. niger and C. albicans showed 14 and 11 mm, respectively (Regupathi et al., 2014). N-hexane, chloroform, ethyl acetate, n-butanol and aqueous of P. nodi­ flora are examined for different microbial strains E. coli, P. aeruginosa, K. pneumoniae, S. typhi, S. epidermidis, S. aureus (MRSA) and B. subtilis. B. subtilis, Staphylococus epidermidis, and S. aureus showed dose dependent activity (Ullah et al., 2013). Arumanayagam and Arunmani (2015) also reported antibacterial activity of P. nodiflora. P. nodiflora methanolic extract of leaves and flowers showed concen­ tration-dependent antimicrobial activity against B. subtilis, B. cereus, M. luteus, S. aureus, P. aeruginosa, K. pneumoniae, K. oxytoca, and E. coli. Antifungal activity also reported against A. niger and C. albicans. All the bacterial strains are sensitive on comparison with the fungal strains and Gram-positive strains showed good inhibitory zones (Zare et al., 2012). By using human pathogenic fungi, P. nodiflora crude extracts were studied for antifungal activity using strains like A. niger, A. flavus, P. varioti, M. gypseum, and T. rubrum. All the tested extracts inhibition activity is significant (Pirzada et al., 2005).

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50.3.2 HEPATOPROTECTIVE AND ANTIOXIDANT POTENTIAL Hepatoprotective and antioxidant properties of P. nodiflora methanolic extract (MEPN) were assessed by making injury of liver using paracetamol (750 mg/kg). MEPN oral administration was for seven consecutive days. The test extract MEPN was highly effective according to the concentration gradient. By decreasing serum enzymes activity such as MEPN showed good hepatoprotective effect. On comparison with the standard silymarin 25 mg/ kg by MEPN it was found to be equal. This may be the reason P. nodiflora has significant hepatoprotective effect, antioxidant effect on hepatocytes and the of P. nodiflora methanol extract for TPC (total phenolic content) is 114.8 µg/mL for 1 mg of tested extract (Durairaj et al., 2008a, 2008b). Using in vitro methods the antioxidant, free radical scavenging assay was performed for methanolic extract (defatted) for aerial parts of P. nodiflora. DPPH, H2O2, NO scavenging assays and NBT reduction assay showed the minimum inhibitory concentration values as 799.74, 53.15, 61.51 and 45.60 μg/mL, respectively. The results are dose dependant. A total of 114.88 μg/ mL was obtained for TPC and the total phenolics equivalent to gallic acid/1 mg (Shukla et al., 2009b). Durairaj et al. (2008a, 2008b) studied methanolic extract for in vitro antioxidant methods and the results are satisfactory. By using bioassay-guided fractionation of P. nodiflora methanolic extract was studied, strong antioxidant activity was from ethyl acetate fraction, by in vitro DPPH radical-scavenging assay is due to the presence of a flavone 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxy-4H-chromen-4-one(5­ hydroxy-3′,4′,7-trimethoxyflavone) (Sudha and Srinivasan, 2014). Methanol and ethyl acetate extract for free radical scavenging activity for leaf and stems of P. nodiflora was determined using 2,2-diphenyl-1-picryl­ hydrazyl assay. The leaf extracts exhibited lower EC50 values, so they high antioxidant activity (Teoh et al., 2013). L. nodiflora whole plant extract was studied for lipid peroxide scavenging activity, the results showed that the percentage inhibition of the methanol extract is by concentration-dependent manner (Durairaj et al., 2007). 50.3.3 ANTITUMOR ACTIVITY Methanolic extract of P. nodiflora assessed for antitumor activity using Erich’s ascites carcinoma using Swiss albino mice. After tumor inoculation (24 h) for nine days mice were administered with the different concentra­ tions of the tested extract 200 and 400 μg/kg body weight. The test extract

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showed significant reduction in the volume of tumor, viable cell count and packed cell volume, increased span of life was observed. The plant was found to have significant antitumor activity, this may be due to the increased antioxidant activity (Durairaj et al., 2009). Human lung cancer cell lines (NCI-H460) are used for studying anti­ cancer activity by in vitro methods for P. nodiflora leaf extract. The leaf extracts possessed good antiproliferative activity against the tested cell lines, using MTT assays. The IC50 value was 10 μg/mL, the results are significant (Vanajothi et al., 2012). 50.3.4 ANTIDIURETIC ACTIVITY AND ANTIHYPERURICEMIC EFFECT In vivo Lipschitz test model is used in assessment for methanol and aqueous extracts of the aerial parts of P. nodiflora for diuretic using albino rats. Furo­ semide used as standard. All the extracts showed significant diuretic activity (Shukla et al., 2009a). Two phenylethanolic glycosides, and three flavonoids, are secluded from P. nodiflora methanolic extracts. The compounds exhibited xanthine oxidase activity (Cheng, 2016; Cheng et al., 2015b). The antihyper uricemic effects of the L. nodiflora methanol extract fraction, were examined for antihyper­ uricemic effect. Extracts of methanol showed decrease in the serum uric acid level. The most antihyperuricemic fraction of bioactivity-guided purifica­ tion led to separation of two phenyl ethanoid glycosides, arenarioside and verbascoside and three flavonoids, 6-hydroxyluteolin, 6-hydroxyluteolin7-O-glycoside, and nodifloretin. The isolated compounds revealed serum uric acid reduction effect (Cheng et al., 2015a) The methanol extract of P. nodiflora assessed for diuretic potential (200 and 400 mg/kg) urine output was monitored after drug administration. The dose levels for the extract were selected as 200 and 400 mg/kg, which showed substantial rise in urine volume in dose dependent manner by rise in Na+, Ca2+ and Cl− excretion together with the excretion of K+ (Ashok Kumar et al., 2008). 50.3.5 ANTI-INFLAMMATORY EFFECT P. nodiflora crude methanolic extract and cyclo-pentano phenanthrol a compound isolated were tested for anti-inflammatory potential. Extracts showed good anti-inflammatory effect (Ahmed et al., 2004). Balakrishnan et

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al. (2010) studied anti-inflammatory potential using in vitro models and the results are satisfactory. P. nodiflora methanolic extract and an isolated compound from the plant 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF) was studied for in vitro antiinflammatory methods. From the spectroscopic methods the data’s repre­ sented that quenching of intrinsic fluorescence for LOX was obtained due to the composite development of LOX-HTMF. HTMF within the LOX enzyme binding method analysis proposed the formation of hydrogen bond, hydro­ phobic interface, and π–π assembling could be the reason for the binding of HTMF. The results of molecular dynamics specified the interface of HTMF with LOX and the constancy of ligand–enzyme complex was sustained all over the simulation (Sudha and Srinivasan, 2015). 50.3.6 ANTIUROLITHIATIC ACTIVITY Dodala et al. (2010) studied the antiurolithiatic activity with P. nodiflora ethanolic extract. Antiurolithiatic effect was studied for common type of kidney stones, that is, calcium oxalate. After completion of the study the groups treated with ethanolic extract showed an increase in urinary pH of (7.0–8.0) when compared with respective control group. 50.3.7 ANTIDIABETIC AND HYPOLIPIDEMIC ACTIVITY The P. nodiflora methanolic was studied for antidiabetic effect in strepto­ zotocin-induced diabetic rats. The plant extract was given in three concentra­ tions and streptozotocin was induced as 40 mg/kg for induction of diabetes in rats for 15 days. All the three dose levels of the tested extracts showed an increase in serum insulin levels, muscle glycogen in liver and decrease of blood glucose levels in fasting, decreased levels of glycosylated haemo­ globin and serum marker enzymes. The levels of total cholesterol, serum triglycerides were significantly reduced and high-density lipoproteins were increased. Pancreas histochemical studies confirmed the biochemical results. The test extract showed significant results for antidiabetic and hypolipidemic activity in streptozotocin-induced diabetic rats (Rangachari et al., 2011). P. nodiflora methanolic extract was studied for antidiabetic effect in streptozocin induced diabetes for 15 days. Tested extracts showed raise in the of liver muscle glycogen and levels of serum insulin and a substantial reduction in levels of fasting blood glucose, glycosylated haemoglobin and serum marker enzymes and it showed significant reduction in levels of total

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cholesterol and serum triglycerides, increased high-density lipid cholesterol. Balamurugan and Ignacimuthu (2011) studied histochemical parameters for pancreas and the findings are beneficial. γ-sitosterol secluded from P. nodiflora (20 mg/kg, orally once a day for 21 day) for antidiabetic activity using streptozotocin as standard. Immuno histochemical study of pancreas also confirmed the biochemical findings (Balamurugan et al., 2011). 50.3.8 NEUROPHARMACOLOGICAL EFFECT P. nodiflora petroleum ether, chloroform and ethanolic extracts are tested for neuropharmacological profile using experimental models, like induction of sleep, motor coordination, locomotor effect, and behavior exploratory pattern, plus maze elevation, maximum electroshock convulsions. P. nodi­ flora showed remarkable results at both doses in ethanolic and chloroform extracts. But it does not show remarkable activity in pet ether extract for neuropharmacological effect because it does not contain flavonoids (Kumaresan et al., 2011). 50.3.9 EFFECT ON BLOOD CLOTTING P. nodiflora ethanolic extract significantly hastened blood clotting at dosses 100 and 200 mg/kg. Ethanolic extract showed dose dependent blood clotting effect (Al-Snafi and Faris, 2013) 50.3.10 HEPATOPROTECTIVE EFFECT Ethanolic leaf extract of P. nodiflora examined for hepatoprotective activity of (100 and 200 mg/kg/day, orally, for 15 days) was estimated for hepatic damage by induction of CCl4-in rats. The hepatoprotective activity was dose dependent (Palanisamy et al., 2008). The methanolic extract of P. nodiflora (200 and 400 mg/kg, orally) tested for hepatoprotective and antioxidant effects in acute liver injury by inducing paracetamol. Methanolic extract showed substantial hepatoprotective action in dose dependent manner (Durairaj et al., 2008a, 2008b). The crude flavonoid fractions from P. nodiflora aerial parts at test dose levels (25, 50 mg/kg) used to evaluate hepatoprotective effect for 21 days by induced oxidative stress in rats liver using ethanol. The extract is efficient and showed significant, dose dependant hepatoprotective effect by reduction in elevated liver marker enzymes lipid peroxidation marker, total bilirubin, and antioxidant levels. Sudha et al. (2013) studied P.

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nodiflora methanolic extracts for hepatoprotective effect using HepG2 cells. The tested extract results are satisfactory. Arumanayagam and Arunmani (2015) also reported hepatoprotective activity of P. nodiflora. Ethanolic extract of P. nodiflora (100 and 200 mg/kg/day, orally, for 15 days) was evaluated for hepatoprotective activity by causing hepatic damage in rats using CCl4. All the test doses are significant in restoring the high levels of total bilirubin, aspartate transaminase, alanine transaminase and alkaline phosphatase in CCl4-intoxicated rats to normal levels. The results are dose dependent (Palanisamy et al., 2008). 50.3.11 HYPOXAEMIA EFFECT Methanol extract (500 mg/kg/day for 14 days) of P. nodiflora caused signifi­ cant decrease in DOCA-Salt hypertensive Wistar rats’ systolic pressure (Gadhvi et al., 2012). The efficacy of different extracts (500 mg/kg, orally) of whole plant P. nodiflora was studied in nephrectomised DOCA-salt hypertension rats, methanol extract significantly reduced the systolic blood pressure (Gadhvi et al., 2015). 50.3.12 ANTIDANDRUFF ACTIVITY Eclipta alba and P. nodflora ethanolic extract and isolated compounds studied for antidandruff activity by disc diffusion method. The results are satisfactory (Regupathi et al., 2014). 50.3.13 EFFECT ON HAIR GROWTH Eclipta alba and P. nodiflora soluble fraction of ethyl acetate from ethanolic extract tested on instance growth of hair. The extract concentrations are selected as 5% and 10% in combination of both species and individually as 5% applied to the shaved skin topically as gel formulation for black colored mice and evaluated for 30 days. Both the test formulation in combination and individual percentage are effective in hair growth when compared with control (Regupathi and Chitra, 2015). 50.3.14 NEUROPHARMACOLOGICAL EFFECT The neuropharmacological profile of aerial parts of P. nodiflora ethanol, petroleum, and chloroform extract were evaluated in experimental

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models by induced sleeping using diazepam potentiation, locomotor activity, motor coordination, exploratory behavioral patterns, elevated plus—maze and max electroshock convulsions. Diazepam was used as a standard at doses of 1, 4, and 5 mg/kg. The results were significant for ethanolic extract of P. nodiflora at all doses (250 and 500 mg/kg orally) and higher dose of 500 mg/kg for chloroform extract produced signifi­ cant central inhibitory (sedation), anxiolytic and anticonvulsant effects on mice. Petroleum ether extract had no effect on CNS (Thirupathy et al., 2011). 50.3.15 ANTIDIARRHOEAL ACTIVITY The antidiarrhoeal activity was tested against aqueous extract of P. nodiflora. The effect in rats is by introduction of castor oil. The extract showed signifi­ cant effects (Begum et al., 2016). 50.3.16 ANTIMELANOGENIC EFFECT The antimelanogenesis properties of a methanolic extract of the aerial portion of P. nodiflora were investigated. The extract was not cytotoxic and dramatically reduced cellular melanin concentration and tyrosinase activity in a significant manner, according to the findings (Yen et al., 2012). KEYWORDS • • • • • • •

Phyla nodiflora alkaloids steroids antioxidant antitumour tannins antidiabetic

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REFERENCES Ahmed, F.; Salim, M. S. T.; Das, A. K.; Chaudhari, M. S. K. Anti-Inflammatory and Anti Neoceptive Activities of Methanolic Extract of Lippia nodiflora Linn. Die Pharm. 2004, 59 (4), 329–330. Akhtar, M. F. Chemical and Biological Investigations of Medicinal Herbs Phyla nodiflora, Ruellia patula and Ruella brittoniana. Ph.D. Thesis, University of Karachi, Pakistan, 1993. Al-Snafi, A. E.; Faris, A. N. Anti-Inflammatory and Antibacterial Activities of Lippia nodiflora and Its Effect on Blood Clotting Time. J. Thi. Qar. Sci. 2013, 4 (1), 25–30. Arumanayagam, S.; Arunmani, M. Hepatoprotective and Antibacterial Activity of Lippia nodiflora Linn. Against Lipopolysaccharides on HepG2 Cells. Pharmacogn. Mag. 2015, 11 (41), 24–31. Ashok Kumar, D.; Senthilkumar, G. P.; Mazumder, U. K.; Ray, S. K. Study on Diuretic Activity and Electrolytes Excretion of Methanol Extract of Lippia nodiflora (Verbenaceae) in Rats. Orient. Pharm. Exp. Med. 2008, 8 (1), 39–46. Balakrishnan, G.; Janakarajan, L.; Balakrishnan, A.; Lakshmi, B. S. Molecular Basis of the Anti-Inflammatory Property Exhibited by Cyclopentano Phenanthrenol Isolated from Lippia nodiflora. Immunol. Invest. 2010, 39 (7), 713–739. Balamurugan, R.; Duraipandiyan, V.; Ignacimuthu, S. Antidiabetic Activity of γ-Sitosterol Isolated from Lippia nodiflora L in Streptozotocin Induced Diabetic Rats. Eur. J. Pharmacol. 2011, 667 (1–3), 410–418. Balamurugan, R.; Ignacimuthu, S. Antidiabetic and Hypolipidemic Effect of Methanol Extract of Lippia nodiflora L. in Streptozotocin Induced Diabetic Rats. Asian Pac. J. Trop. Biomed. 2011, S30–S36. Barnabas, C.; Gunasingh, G.; Nagarajan, S. Flavonoids from the Flowers of Phyla nodiflora Linn. Indian J. Chem. Sect. B Org. Chem. Incl. Med. Chem. 1980, 19B (9), 822. Barua, A. K.; Chakrabarti, P.; Sanyal, P. K. Structure of Nodifloretin, New Flavone from Lippia nodiflora. Trans. Bose Res. Inst. 1971, 33–34 (3), 5–8. Barua, A. K.; Chakrabarti, P.; Sanyal, P. K. Nodifloretin a New Flavone from Lippia nodiflora. J. Indian Chem. Soc. 1969, 46 (3), 271–272. Begum, V. H.; Muthukumaran, P.; Suganthi, K. Evaluation of Anti-Diarrhoeal Activity of Lippia nodiflora Leaves Extracts in Experimental Rats. Int. J. Pharm. Pharm. Res. 2016, 6 (1), 140–149. Cheng, L. C. Phytochemical Studies of Lippia nodiflora L. Michx and Its Anti-Hyperuricemic Activity. Ph.D Thesis, University of Science, Malaysia, 2016. Cheng, L. C.; Murugaiyah, V.; Chan, K. L. In Vitro Xanthine Oxidase Inhibitory Studies of Lippia nodiflora and Isolated Flavonoids and Phenylethanoid Glycosides as Potential Uric Acid-Lowering Agents. Nat. Prod. Commun. 2015a, 10 (6), 945–948. Cheng, L. C.; Murugaiyah, V.; Chan, K. L. Flavonoids and Phenylethanoid Glycosides from Lippia nodiflora as Promising Antihyperuricemic Agents and Elucidation of Their Mechanism of Action. J. Ethnopharmacol. 2015b, 176, 485–493. Dodala, S.; Diviti, R.; Koganti, B.; Prasad, K V S R G. The Effect of Ethanolic Extract of Phyla nodiflora (L.) Greene Against Calculi Producing Diet Induced Urolithiasis. Indian J. Nat. Prod. Resour. 2010, 1 (3), 314–321. Durairaj, A.; Vaiyapuri, T. S.; Mazumdar, U. K.; Gupta, M. Protective Activity and Antioxidant Potential of Lippia nodiflora Extract in Paracetamol Induced Hepatotoxicity in Rats. Iran. J. Pharmacol. Ther. 2008b, 7 (1), 83–89.

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Durairaj, A.; Thamilselvan, V.; Senthilkumar, G. P.; Mazumder, U. K.; Gupta, M. Antioxidant and Free Radical Scavenging Effects of Lippia nodiflora. J. Pharm. Biol. 2008a, 46 (10–11), 762–771. Durairaj, A. K.; Mazumdar, U. K.; Gupta, M.; Selvan, V. T. Effect on Inhibition of Proliferation and Antioxidant Enzyme Level of Lippia nodiflora in EAC Cell Line Treated Mice. J. Complement. Integr. Med. 2009, 6 (1), 713–714. Durairaj, A. K.; Vaiyapuri, T. S.; Mazumdar, U. K.; Gupta, M. Antimicrobial and Lipid Peroxide Scavenging Activity of Lippia nodiflora (Verbenaceae). Pharmacol. Online 2007, 3, 177–189. Elakovich, S. D.; Stevens, K. L. Volatile Constituents of Lippia nodiflora. J. Nat. Prod. 1985, 48 (3), 504–506. Gadhvi, R.; Mishra, G.; Nagendra Reddy, M.; Nivserkar, M. Antihypertensive Efficacy of Lippia nodiflora Whole Plant on Uninephrectomized Doca Salt Hypertensive Rats. IOSR J. Pharm. 2012, 2 (6), 24–28. Gadhvi, R.; Reddy, M. N.; Joshi, S. Antihypertensive and Reno Protective Effect of Different Fractions of Whole Plant Lippia nodiflora Linn. on Uninephroctimized DOCA-Salt Hypertensive Rats. Int. J. Pharm. Bio. Sci. 2015, 6 (3), 392–399. Joshi, B. C. Chemical Examination of Lippia nodiflora. Vijnana Parishad Anusandhan Patrika. 1970, 11 (4), 214–219. Khalil, A. T.; Lahloub, M. F.; Salama, O. M. Phenolic Compounds from Lippia nodiflora. J. Pharm. Sci. 1995, 11 (2), 256–265. Kumaresan, P.; Thirupathy; Tulshkar, A.; Vijaya, C. Neuropharmacological Activity of Lippia nodiflora Linn. Pharmacogn. Res. 2011, 3 (3), 194–200. Lazarides, M.; Cowley, K. J.; Hohen, P. CSIRO Handbook of Australian Weeds; CSIRO: Australia, Collingwood, Victoria, 1997. Lin, F. J.; Yen, F. L.; Chen, P. C.; Wang, M. C.; Lin, C. N.; Lee, C. W.; Ko, H. H. HPLCFingerprints and Antioxidant Constituents of Phyla nodiflora. Sci. World J. 2014. DOI: http://dx.doi.org/10.1155/2014/528653. Nair, A. G. R.; Ramesh, P.; Nagarjan, S.; Subraimanam, S. A New Flavones Glycosides from Lippia nodiflora. Indian J. Chem. 1973, 2, 1316–1317. Pagu, M. V.; Elavarasan, P.; Jeya, K. R. In Vitro Antimicrobial Activity of Lippia nodiflora Crude Extract Against Selected Microorganisms. Biotechnol. Indian J. 2011, 5 (2), 93–95. Palanisamy, S.; Dheeba, B.; Ravichandran, V.; Veena, V.; Balakumar, S.; Shanmugasundaram. An Evaluation of Hepato Protective Efficacy of Lippia nodiflora L. Against Carbon Tetrachloride Induced Hepatic Damage in Rats. J. Cell Tissue Res. 2008, 8 (3), 1595–1598. Pirzada, A. J.; Iqbal, P.; Shaikh, W.; Kazi, T. G.; Ghani, K. V. Studies on Elemental Composition and Antifungal Activity of Medicinal Plant L. nodiflora Against Skin Fungi. J. Pak. Assoc. Derma. 2005, 15 (2), 113–118. Priya, S. E.; Ravindhran, R. Phytochemical Analysis and Antimicrobial Properties of Extracts from Aerial Parts of Phyla nodiflora (L) Greene. Int. J. Curr. Microbiol. App. Sci. 2015, 4 (2), 347–358. Rangachari, B.; Veeramuther, D.; Savarimuthu, I. G.; Macimuthu. Anti-Diabetic Activity of Y Sitosterol Isolated from Lippia nodiflora L. in Streptozotocin Induced Diabetic Rats. Eur. J. Pharmacol. 2011, 667 (1–3), 410–418. Ravikanth, V.; Ramesh, P.; Diwan, P. V.; Venkateswarlu, Y. Halleridone and Hallerone from Phyla nodiflora as Taxonomic Markers. Biochem. Syst. Ecol. 2000, 28 (9), 905–906. Ravikumar, V. R.; Sudha, T. Phytochemical and Microbiological Observations on Phyla nodiflora. Int. J. Res. Pharm. Chem. 2011, 1 (2), 117–120.

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Regupathi, T.; Chitra, K. Antidandruff Activity of Eclipta alba Hassk and Lippia nodiflora Linn. Int. J. Res. Pharm. Sci. 2015, 6 (2), 185–188. Regupathi, T.; Chitra, K.; Ruckmani, K.; Nagarajan, S.; Lalitha, K. G. Antimicrobial Potential of Lippia nodiflora Linn. Int. J. Pharm. Phytopharmacol. Res. 2014, 4 (3), 145–149. Sharma, R. A.; Singh, R. A Review on Phyla nodiflora Linn. A Wild Wetland Medicinal Herb. Int. J. Pharm. Sci. Rev. Res. 2013, 20 (1), 57–63. Shukla, S.; Patel, R.; Kukkal, R.. Study of Phytochemical and Diuretic Potential of Methanol and Aqueous Extract of Aerial Parts of Phyla nodiflora Linn. Int. J. Pharm. Pharm. Sci. 2009a, 1 (1), 85–91. Shukla, S.; Saluja, A. K.; Pandya, S. S. In-Vitro Antioxidant Activity of Aerial Parts of Lippia nodiflora Rich. Pharmacologyonline 2009b, 2, 450–459. Siddiqui, B. S.; Ahmed, F.; Sattar, F. A.; Begum, S. Chemical Constituents from the Aerial Part of L. nodiflora Linn. Arch. Pharm. Res. 2007, 30 (12), 1507–1510. Siddiqui, B. S.; Ahmed, F.; Ali, S. K.; Perwaiz, S.; Begum, S. Steroidal Constituents from the Aerial Parts of Lippia nodiflora Linn. Nat. Prod. Res. 2009, 23 (5), 436–441. Sudha, A.; Srinivasan, P. Physicochemcial and Phytochemical Profile of Aerial Parts of Lippia nodiflora L. Int. J. Pharm. Sci. Res. 2013, 4 (11), 4263–4271. Sudha, A.; Srinivasan, P. Bioassay-Guided Isolation and Antioxidant Evaluation of Flavonoid Compound from Aerial Parts of Lippia nodiflora L. Biomed. Res. Int. 2014. DOI: 10.1155/2014/549836. Sudha, A.; Srinivasan, P. In Vitro, Fluorescence-Quenching and Computational Studies on the Interaction Between Lipoxygenase and 5-Hydroxy-3′,4′,7-Trimethoxy Flavone from Lippia nodiflora L. J. Recept. Signal Transduct. Res. 2015, 35 (6), 569–577. Sudha, A.; Sumathi, K.; Manikandaselvi, S.; Prabhu, N. M.; Srinivasan, P. Anti-Hepatotoxic Activity of Crude Flavonoid Fraction of Lippia nodiflora L on Ethanol Induced Liver Injury in Rats. Asian J. Animal Sci. 2013, 7, 1–13. Terblanche, F. C.; Kornelius, G. Essential Oil Constituents of the Genus Lippia (Verbenaceae). A Literature Reviews. J. Essent. Oil Res. 1996, 8, 471–485. Teoh, P. L.; Mohd Ali, R.; Cheong, B. E. Potential Anticancer Effect of Phyla nodiflora Extracts in Breast Cancer Cell Line, MCF7. World J. Pharm. Pharm. Sci. 2013, 2 (6), 6053–6061. Thirupathy, K. P.; Tulshkar, A.; Vijaya, C. Neuropharmacological Activity of Lippia nodiflora Linn. Pharmacogn. Res. 2011, 3 (3), 194–200. Tomas-Barberan, F. A.; Harborne, J. B.; Self, R. Twelve 6-Oxygenated Flavone Sulphates from Lippia nodiflora and L. canescens. Phytochemistry 1987, 26 (8), 2281–2284. Ullah, Z.; Rehman, A.; Ullah, N.; Khan, S. A.; Khan, S. U.; Ahmad, I. Antibacterial Study of Phyla nodiflora Linn. J. Chem. Pharm. Res. 2013, 5 (3), 86–90. Vanajothi, R.; Sudha, A.; Manikandan, R.; Rameshthangam, P.; Srinivasan, P. Luffa acutangula and Lippia nodiflora Leaf Extract Induces Growth Inhibitory Effect Through Induction of Apoptosis on Human Lung Cancer Cell Line. Biomed. Prev. Nutr. 2012, 2 (4), 287–293. Yen, F. L.; Wang, M. C.; Liang, C. J.; Ko, H. H.; Lee, C. W. Melanogenesis Inhibitor(s) from Phyla nodiflora Extract. Evid. Based Complement. Altern. Med. 2012. DOI: http://dx.doi. org/10.1155/2012/867494. Zare, Z.; Ahmed, M.; Sattari, T. N.; Iranbakhsh, A.; Mehrabian, S. Antimicrobial Activity of Leaf and Flower Extracts of Lippia nodiflora L. (Verbenaceae). J. Plant Prot. Res. 2012, 52 (4), 401–403.

CHAPTER 51

Phytochemical and Pharmacological Profile of Achyranthes aspera L. (Amaranthaceae) RAJA KULLAYISWAMY1* and SAROJINI DEVI N2 1Dharmavana

Nature Ark, IDA Cherlapalli, Hyderabad, Telangana-500051, India

2Dharmavana

Nature Ark, IDA Cherlapalli, Hyderabad, Telangana-500051, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Achyranthes aspera is common herbaceous species, sometimes treated as a weed. It is medicinally important for curing many abnormalities like imma­ ture ovariectomy, allergy, cardiovascular functioning, bronchial asthma, cancer, diabetic, toothache etc. Achyranthus also showed medicinal activities against leprosy and anti-bacterial etc. These activities of Achyranthus are because of active chemical compounds like hydroquinone, benzoquinone, nerol, spathulenol, α-ionone, asarone, and Eugenol. 51.1

INTRODUCTION

Achyranthes aspera L. is Amaranthaceae herbaceous plant; it grows erect and annual. Synonyms of this species are Centrostachys aspera (L.) Standl., Centrostachys indica (L.) Standl., and Achyranthes australis R.Br. It is

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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commonly known as Devil’s horsewhip, prickly-chaff flower, burweed, pululue (English); Chirchita (Hindi); Mayur, Apamarga, Akrutihchhatra, Akshara, Adhahaghanta, Pratyanchapushpa, Kharamanjari (Sanskrit); Uttareni, Pratyak-pushpi (Telugu); Uttaraani (Kanada); Katalaati (Malay­ alam); Apamarkkam, Akatam, Naaiyuruvi, Naagarkaaimullu, Naagarkaai Mullu Naayuruvi (Tamil). Root stock stout, woody. Leaves are opposite, obovate, hairy on both the sides, margin undulate. Inflorescence a terminal spikes, about a meter long; flowers bisexual, retrorse, sessile, 180–200 per spike. Perianth segments (sepals) 5, lanceolate. Stamens 4, connate at base. Utricle (fruit) prickly 22.5 mm long. Seed 1.2–1.8 × 0.9–1.2 mm, ovoid to ellipsoid. Achyranthes aspera is used in the treatment of bronchitis, cough, asthma, hypertension, malarial fever, rheumatism, dysentery, dental problems, skin diseases, and diabetes in Indian folklore. Achyranthes aspera has many phytochemicals that show activities like anti-allergic, antiperiodic, hepatoprotective, diuretic, purgative, antiasth­ matic, laxative, and various other vital medicinal properties. This plant is commonly used in the native method of remedy as antifertility, antiarthritic, ecbolic, abortifacient, laxative, and aphrodisiac, antiviral, antihelminthic, anti-plasmodic, antihypertensive, diuretic, anticoagulant, and antitumor. It is also used to treat renal dropsy, cough, scrofula, fistula, fever, skin rash, piles, chronic malaria, nasal infection, impotence, asthma, and snake bites. This plant is also used as astringent, laxative, digestive, purgative, diuretic, and stomachic (Ghimire et al., 2015). The juice of the plant is used in the treatment of diarrhea, boils, rheumatic pains, dysentery, itches, hemorrhoids, and skin eruption. The methanolic extraction gives more yields than the ethanolic and petroleum ether (Ghimire et al., 2015). 51.2 BIOACTIVES Chemicals isolated from seeds of Achyranthes aspera (AA) are L-rham­ nopyranosyl-(1-4)-(-D-glucopyranosyluronicacid)-(1-3)-oleanolic acid, -L-rhamnopyranosyl-(1-4)-(-D-glucopyranosyluronicacid)-(1-3)-oleanolic acid-28-O—D-glucopyranoside, and -L-rhamnopyranosyl-(1-4)-(-D-gluco­ pyranosyluronicacid)-(1-3)-oleanolicacid-28-O—D-glucopyranosyl-(1-4)— D-glucopyranoside. Achyranthine, 6 Betaine, ecdysterone, hentriacontane, achyranthes saponins A, B, C, D are the major chemical constituents found in A. aspera (Dey, 2011). Volatile oil was isolated from

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Achyranthes aspera (AA) leaves and analyzed by using the G.C.M.S. method. Seven chemical compounds were detected, which are hydroquinone, benzo­ quinone, nerol, spathulenol, α-ionone, asarone, and eugenol, and 63.05% of the oil were also identified. Out of seven volatile oils hydroquinone (57.7%) was found to be important (Rameswar, 2007). Aromatic compound 3-acetoxy-6-benzoyloxyapangamide has been isolated from an ethyl acetate extract of the stem of AA. The chemical 3-acetoxy-6-benzoxyapangamide structure was established (Fig. 51.1) by using modern techniques and the formula is confirmed as C23H27NO6; it was shown by EI mass spectrum for this new compound. It has mild antibacterial activity against Bacillus cereus (Aziz et al., 2005). From the methanolic extract of the aerial parts of Achyranthes aspera (AA), two more new compounds bisdesmosidic triterpenoid saponins were isolated. Those new chemical structures were established as β-D-glucopyranosyl 3 β-[O-β-D-galactopyranosyl-(1→2)O-α-D-glucopyranuronosyloxy] machaerinate, β-D-glucopyranosyl 3 β-[O-α-L-rhamnopyranosyl-(1→3)-O-β-D-glucopyranuronosyloxy] machaerinate (Michl et al., 2000). The remaining saponins were estab­ lished as β-D-glucopyranosyl 3β-[O-β-D-glucopyranuronosyloxy] oleanolate, β-D-glucopyranosyl-3β[O-α-L-rhamnopyranosyl-[1→3)-O-βD-glucopyranuronosyloxy] oleanolate, β-D-glucopyranosyl3-β-[O-β-Dgalactopyranosyl (1→2)-O-β-D-glucopyranuronosyloxy] oleanolate (Michl et al., 2000). From the seeds of AA, a new cyclic chain aliphatic fatty acid (I) was isolated by Chauhan et al. (2002). From the methanolic extract of roots, ecdysterone a natural anabolic agent (hormone) was isolated, and from the seeds sapogenin along with oleanolic acid was isolated (Banerji et al., 1971; Banerji and Chadha, 1970; Batta and Rangaswami, 1973). Ecdysterone chemical was also isolated from the root extract by using the chromatography technique on the silca gel column, and elution with chloroform-methanol (4:1 ratio) (Ikan et al., 1971), ecdysterone also isolated from whole plant (Banerji et al., 1971). From roots of AA, oleanolic acid was isolated (Khastgir et al., 1958). A new aliphatic acid n-hexacos-14-enoic acid was isolated from the ethanalic extracts of roots. This n-hexacos-14-enoic acid is reported for the first time from natural and synthetic source. Some more phytochemi­ cals were also isolated and named as strigmasta-5, 22-dien-3-β-ol, trans13-docasenoic acid, n-hexacosanyl n-decaniate, n-hexacos-17-enoic acid, and n-hexacos-11-enoic acid. The phytosterol strignasta-5, 22-dien-3-β-ol a colorless crystalline mass was obtained by using 3:1 ratio of ether:benzene elute. It was responded to the Liebermann Burchard test for sterols (Sharma

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et al., 2009). Batta and Rangaswami (1973) isolated dihydroxy ketones as 36, 37-dihydroxyhenpentacontan-4-one and triacontanol from the shoots of AA. The plant AA was found to have chemicals in both aqueous and chloro­ form soluble base. The water-soluble chemicals included achyranthine (Basu et al., 1957a), and chloroform- soluble chemicals as a betain derivative of N-methylpyrrolidine-3-earboxylic acid (Basu et al., 1957b). Kapoor and Singh (1967) also confirmed that the water-soluble base has betain only but not achyranthin. They also confirmed chloroform-soluble basic fraction was a mixture of two uncharacterized alkaloidal entities. Kumar et al. (1990) confirmed that the ethyl alcohol extract showed alkaloids and saponins and other flavanoids, and tannins were absent. Misra et al. (1991) isolated a new aliphatic dihydroxyketone from shoots of AA and characterized as 36, 47-dihydroxyhenpentacontan-4-one together with tritriacontanol. An essen­ tial oil an aliphatic alcohol 17-pentatriacontanol which has a long chain of carbons was isolated from the shoots (Gariballa et al., 1983). Four long chain compounds were isolated and characterized as 27-cyclohexyl heptacosan­ 7-oleanolic acid, 16-hydroxy-26-methylheptacosan-2-one (Misra et al., 1993), 4-methylheptatriacont-l-en-10-ol, and tetracontanol-2 from the shoots (Misra et al., 1996). Various compounds like tetracontanol-2 (melting point76-77°C), 4-methoxyheptatriacont-1-en-10-ol, and β-sitosterol were isolated from AA (Misra et al., 1996). From the whole plant water extraction the water-soluble alkaloid betain (Melting point 292°C) was isolated and confirmed by mixed melting point detection of the hydrochlotic acid salt, picrate, and oxalate derivatives (Kapoor and Singh, 1966). Two more constituents were isolated from the fruits of AA and identified as Saponin C and Saponin D (Seshadri et al., 1981). Compounds like tritriacontane, pentatriaontane, 6-penta­ triacontanone, and hexatriacontane were isolated from the stem of AA Ali (1993). From the methanolic extract of aerial parts of AA, three chemicals called bisdesmosidic saponins (i.e., I, II, and III), 20-hydroxyecdysone, and quercetin-3-O-β-D-galactoside were isolated and their structures were established by Kunert et al. (2000) using the NMR and 2D NMR techniques. The seed proteins compared with pulses like Bengal gram and its amino acids leucine, isoleucine, phenylalanine, and valine found that the seed proteins and amino acids of AAare higher than the pulses. While its tryptophan and sulfur amino acid (methionine and cystine) contents were higher than the most of the pulses. But Achyranthes seeds have less in arginine, lysine, and threonine when compared with egg proteins (Hemalatha and Satyanarayana,

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2008). Defatted seeds have yielded 2% saponins and been identified as oleanolie acid-oligosaccharide by Khastgir and Sengupta (1958). Further research led to isolate saponins, those are saponin A as a-a-rhamnopyranosyl (1→4)-β-D-glucopyranosyl (1→4)-β-D-glucuronopyranosyl (1→3)-olea­ nolic acid and saponin B as β-D-galactopyranosyl (1→28) (Hariharan and Rangaswamy, 1970). From AA plant Sarkar and Rastogi (1960) separated triterpenoid sapo­ nins by using the partition chromatography technique. Chemicals called hentriacontane, 10-octacosane, 10-triacosanone, and 4-tritriacontanone were separated from the seeds of AA (Ali, 1993). Fatty oil from seeds contains myristic acid, stearic acid, behenic acid, lauric acid, palmitic acid, arachidie acid, oleic acid, and linoleic acid (Daulatabad and Ankalgi, 1985). Two saponins were separated from unripe fruits of AA called C and D which were named as β-D-glucopyranosyl ester of a-L—rhamno­ pyranosyl (1→4)-β—D-glucuranopyranosyl (1→3) leanolic acid and β-D-glucopyranosyl ester of a –Lrhamnopyranosyl (1→4)-p-D-glucopy­ ranosyl (1→4)-β—D-glucuranopyranosyl(l→3)oleanolic acid (Seshadri et al., 1981).

FIGURE 51.1

51.3

Structure of 3-acetoxy-6-benzoxyapangamide.

PHARMACOLOGICAL ACTIVITIES

The ethyle alcohol extracts of the leaves (Aswal et al., 1996) and whole plants (Dhar et al., 1968) were tested for preliminary biological activities. The whole plant extract showed hypoglycemic activity in rats. The extract was used to test as antibacterial, antiviral, anthelmintic, antiprotozoal, antifungal, and anticancer activities and all effects tried on isolated ileum

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of guinea pig, respiration, CNS, and CVS in experimental animals. The leaf extract of AA was confirmed in experimental studies as antiviral and antiprotozoal activities and effects on CNS, CVS, and respiration drug. The LD50 was >1000 mg/Kg i.p. in mice (Aswal et al., 1996). 51.3.1 ANTI-INFLAMMATORY ACTIVITY An alcohol extract of Achyranthes aspera (AA) showed the anti-inflamma­ tory activity in albino male rats which were carrageenin-induced hind paw edema and cotton pellet granuloma models was used for this experiment (Vetrichelvian and Jegadeesan, 2003). 100–200 mg/kg ethanolic extract of AA showed anti-inflammatory and anti-arthritic activity (Gokhale et al., 2002). The alkaloid achyranthine that is water soluble was isolated from A. aspera showing anti-inflammatory and anti-arthritic activity in rats against carrageenin-induced foot edema, formalin-induced arthritis, granuloma pouch, and adjuvant arthritis. Achyranthine also showed better anti-inflammatory activity in all the four models employed but not as good as betamethasone and phenylbutazone. Achyranthine successfully reduced adrenal gland weight, thymus weight, and spleen weight and increased the adrenal ascorbic acid and cholesterol contents; in this experiment the control was betamethasone. Achyranthine worked as good as the control. It was shown minimum effect on gastric ulcers when compared with β-methasone (Neogi et al., 1969). 51.3.2 ANTIMICROBIAL ACTIVITY The water extraction of AA and achyranthine showed antibacterial activity against Bacillus typhosus, Streptococuss heamolyticus, Staphylococcus aureus (Basu et al., 1957a). The water and the ethanolic extract of leaves showed same activity against E. coli and S. aureus (George et al., 1947). The seeds of the plants which are growing on cattle dung showed activity against Salmonella typhimurium, Pseudomonas cichorii, and Bacillus subtilis (Sushil et al., 1997). In Valsaraj et al.’s (1997) study Staphylococcus aureus and Bacillus subtilis were inhibited at 25 mg/mL of 80% ethanolic extract of stem and leaves of Achyranthes aspera.

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51.3.3 ANTIFERTILITY ACTIVITY The root of AA ethanolic extract showed antifertility activity at 200 mg/ kg body weight in pregnancy rates when given orally for 7 days. Antiimplantation activity showed 83.3% at 200 mg/kg body weight, for this study 100% root ethanolic extract was used. The ethyl alcohol extract exhibited estrogenic activity in immature ovariectomised female albino rats (Vasudeva and Sharma, 2006). The root methanolic extract showed anti-implantation activity 60% and acetone extract 50% only (Prakash, 1986). The composition of two plants extract that is the leaf of Stephania hernandifolia and the root of AA experi­ mented on sperm motility and function in a ratio of 1:3 by body weight at different concentrations, at a 0.32 g/mL concentration the extract showed better results within 20 min by complete sperm immobilization (spermicidal effect) after the application. This immobilization effect was found to be irreversible. Viability of sperm was slowly decreased and finally nonviable after 30 min at a concentration of 0.32 g/mL of composite extract (Paul et al., 2006). Methanolic extract of leaf showed antifertility activities like abortifacient, pituitary weight, estrogenesity, and ovarian hormone level and lipids profile was investigated in female rats. The leaf extract showed better abortifacient activity and increased pituitary weight and uterine wet weights in ovarectimized rats (Shibeshi et al., 2006). 51.3.4 ANTIALLERGIC ACTIVITY Petroleum ether extract of Achyranthes aspera (AA) (200 mg/kg i.p.) showed antiallergic activity in mice that were both milk-induced eosinophilia and milk-induced leukocytosis. This activity of AA was because of steroids present in the plant (Goyal et al., 2007). 51.3.5 CARDIOVASCULAR ACTIVITY Achyranthine that is aqueous soluble alkaloid, decreased blood pressure and heart rate and dilated blood vessels, and increased the rate of respiration in dogs and frogs. The alkaloid contractile effect at 0.5 mg/mL on frog rectus abdominal muscle was less than effect of acetylcholine (0.1 mg/mL) (Neogi et al., 1970). Studies on seed saponins at lower dose (1–50 pg) were blocked by pronethalol and higher dose was not blocked by pronethalol in guinea pig, rabbit, and frog (Gupta et al., 1972).

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51.3.6 HEPATOPROTECTIVE ACTIVITY Hepatotoxicity was reduced by the methanolic extract of Achyranthes aspera aerial parts in rifampicin- induced albino rats. This hepatoprotectivity showed dose-dependent decrease in the levels of SGOT, SGPT, ALKP, and total bilirubin (Bafna and Mishra, 2004). 51.3.7 ANTI-HYPERLIPIDEMIC ACTIVITY The alcoholic extract of A. aspera at 100 mg/kg dose lowered total serum cholesterol (TC) by 60% and phospholipid (PL) by 51%, triglyceride (TG) by 33%, and total lipids (TL) levels by 53% in rats that are triton-induced hyperlipidemic animals. The plant ethanolic extract was orally administrated to normal rats (without triton-induced) for 30 days; the observed TC, PL, TG, and TL levels in serum interestingly reduced hepatic lipid levels 56%, 62%, 68%, and 67% respectively (Khanna et al., 1992) 51.3.8 ANTIDIABETIC ACTIVITY The ethanolic extract (50%) of whole plant (Dhar et al., 1968) was used for preliminary biological activities and it showed hypoglycemic activity in albuminous rat. The MTD (Maximum Tolerable Dose) on the extract was found to be 1000 mg/kg body weight when giving to small rats orally (Dhar et al., 1968). Oral administration of 2–4 g/kg of whole plant powder produced a significant dose-related hypoglycemic effect in normal and also alloxan- treated diabetic rabbits. The aqueous and methyl alcohol extracts of the AA plant also reduced blood glucose levels in normal and alloxan diabetic rabbits (Akhtar and Iqbal, 1991). 51.3.9 LEPROSY Achyranthus aspera plant decoction was used orally in 19 patients who were found to have +ve stain smears at the SS Hospital, Varanasi, India. The study was conducted on 14 patients who were in the stage of reaction and 5 had active lessons, no one was in quiescent stage. The result was found in both groups (Tripathi et al., 1963). Another observation was made by conjunction with the diaminodiphenylsulphone (DDS); it was observed that reaction chances become less and improvement was faster (Ojha et al., 1966; Ojha and Singh, 1968).

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51.3.10 BRONCHIAL ASTHMA The root oil of AA socked in cow urine and smeared on betel leaf was then administered three times a day to the patients (15 No.s at the CRI, Madras). The results showed that symptoms like gasping, wheezing, dyspnea, cough, and sneezing disappeared in those 15 patients. The other patient’s diagnostic test reports include total WBC, ESR, count of eosinophil (Suresh et al., 1985). 51.3.11 ANTI-CARCINOGENIC ACTIVITY Leaves of Achyranthes aspera have been tested for chemopreventive activity. Methanolic extract non-alkaloid, alkaloid, and saponin fractions showed an inhibitory effect at 100 mg concentration on the Epstein-Barr virus early antigen activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. In this in vitro experiment the non-alkaloid fraction that contains nonpolar compounds showed the better inhibitory activity (96.9%; 60% viability). Chakraborty et al. (2002) experimented the two-stage in vivo mouse skin carcinogenesis test; the total methanolic extract possessed a pronounced anti-carcinogenic effect (76%). 51.3.12 IMMUNOMODULATORY ACTIVITY Chakrabarti and Vasudeva (2006) experimented on fish, that is, Catla catla by introducing Achyranthes aspera leaves in their artificial fish diet. There was another group of Catla fish without AA used as control. In the AAtreated group the BSA-specific antibody titers significantly improved. The efficiency of antigen clearance was also enhanced in Catla catla treated with Achyranthes (Chakrabarti and Vasudeva, 2006). 51.3.13 ANTIPARASITIC ACTIVITY The ethyl acetate extract of AA was found showing antiparasitic activity against Cattle tick Rhipicephalus (Boophilus) microplus (Acari:lxodidae), sheep internal parasite Paramphistomum cervi (Zahir et al., 2009). 51.3.14

BRONCHOPROTECTIVE ACTIVITY

As reported by Goyal et al. (2007) the ethyle alcohol extract of the AA plant showed a bronchoprotective effect in TDI-induced (Toluene di-isocyanate)

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occupational asthma in wistar rats. The result was confirmed by testing total different in leucocytes in blood and bronchoalveolar fluid (BAL). For the assessment of oxidative stress, liver homogenate was used, lung histological examination was also performed to investigate the status of airway. The results showed that treated rats did not show any abnormality in airways. 51.3.15 NEPHROPROTECTIVE ACTIVITY Aqueous extracts Achyranthes aspera roots prevented urolithiasis in which animals induced with ethylene glycol and also reduced the growth of calcium oxalate stones. The extract was effective in reducing the renal tissue injury, decreasing the crystal size and thus facilitating easy expulsion and restoring normal kidney architecture in rats (Anshu et al., 2012). Some reports say that the methanolic extract of the whole plant of Achyranthes aspera shows nephron-protective activity against lead acetate- induced nephrotoxicity in male albino rats (Jayakumar et al., 2009). 51.3.16 PHOSPHORYLASE ACTIVITY Ram et al. (1971) studied effect of AA saponins on the phosphorlase activity of the perfused rat hearts and compared with that of adrenaline. Saponins stimulated the phosphorylase enzyme activity in the heart; the effect was comparable with adrenaline. KEYWORDS • • • • •

Achyranthes herb amaranthaceae medicinal biological activities

REFERENCES Akhtar, M. S.; Iqbal, J. Evaluation of the Hypoglycaemic Effect of Achyranthes aspera L. J. Ethnopharmacol. 1991, 31 (1), 49‒57. Ali, M. Chemical Investigation of Achyranthes aspera Linn. Orient. J. Chem. 1993, 9, 84‒85.

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Anshu, A.; Surinder, K. S.; Manish, G.; Chanderdeep, T. Preventive and Curative Effects of Achyranthes aspera Linn. Extract in Experimentally Induced Nephrolithiasis. Indian J. Exp. Biol. 2012, 50, 201‒208. Aswal, B. S.; Goel, A. K.; Kulshrestha, D. K.; Mehrotra, B. N.; Patnaik, G. K. Screening of Indian Plants for Biological Activity. Part XV. Indian J. Exp. Biol. 1996, 34, 444‒467. Aziz, M. A.; Rahman, M. M.; Mondal, A. K.; Muslim, T.; Rahman, M. A.; Quader, M. A. 3-Acetoxy-6-Benzoyloxyapangamide from Achyranthes aspera. Dhaka Univ. J. Pharm. Sci. 2005, 4 (2), 113‒116. Bafna, A. R.; Mishra, S. H. Effect of Methanol Extract of Achyranthes aspera L. on Rifampicin Induced Hepatotoxicity in Rats. Ars. Pharm. 2004, 45 (4), 343‒351. Banerji, A.; Chadha, M. S. Insect Moulting Hormone from Achyranthes aspera. Phytochemistry 1970, 9, 1671. Banerji, A.; Chintalwar, G. J.; Joshi, N. K.; Chadha, M. S. Isolation of Ecdysterone from Indian Plants. Phytochemistry 1971, 10, 2225–2226. Basu, N. K.; Neogi, N. C.; Srivastava, V. P. Biological Investigation of Achyranthes aspera Linn. and Its Constituent Achyranthine. J. Proc. Inst. Chem. 1957a, 29, 161‒65. Basu, N. K.; Singh, H. K.; Aggarwal, O. P. A Chemical Investigation of Achyranthes aspera Linn. J. Proc. Inst. Chem. 1957b, 29, 55‒58. Batta, A. K.; Rangaswami. S. Angiospermae Dicotyledonae: Amaranthaceae etc. Crystalline Chemical Components of Some Vegetable Drugs. Phytochemistry 1973, 12, 214–216. Chakrabarti, R.; Vasudeva, R. Y. Achyranthes aspera Stimulates the Immunity and Enhances the Antigen Clearance in Catla catla. Int. Immunopharmacol. 2006, 6 (5), 782‒790. Chakraborty, A.; Brantner, A.; Mukainaka,T.; Nobukuni, Y.; Kuchide,M,; Konoshima, T.; Tokuda, H.; Nishino, H. Cancer Chemopreventive Activity of Achyranthes aspera Leaves on Epstein-Barr Virus Activation and Two-Stage Mouse Skin Carcinogenesis. Cancer Lett. 2002, 177 (1), 1‒5. Chauhan, A. S.; Rawat, G. S.; Singh, C. P. Phytochemical Study of Achyranthes aspera Linn. Asian J. Chem. 2002, 14 (2), 1059‒1061. Daulatabad, C. D.; Ankalgi, R. F. Minor Seed Oils. EL Fatty Acid Components of Some Seed Oils. Fette Seifen Anstrichm. 1985, 87 (5), 196‒197. Dey, A. Achyranthes aspera L: Phytochemical and Pharmacological Aspects. Int. J. Pharm. Sci. Rev. Res. 2011, 9 (2), 72‒82. Dhar, M. L.; Dhar, M. M.; Dhawan, B. N.; Mehrotra, B. N.; Ray, C. Screening of Indian Plants for Biological Activity. Part I. Indian J. Exp. Biol. 1968, 6, 232‒247. Gariballa, Y.; Iskander, G. M.; Daw, E. L.; Beit, A. Investigation of the Alkaloid Components in the Sudan Flora. Fitoterapia 1983, 54, 269‒272. George, M.; Venkataraman, P. R.; Pandalai, K. M. Investigations on Plant Antibiotics: Part II. A Search for Antibiotic Substances in Some Indian Medicinal Plants. J. Sci. Ind. Res (JSIR).1947, 6B, 42‒46. Ghimire, K.; Banerjee, J.; Amit Kumar, G.; Prasanna, D. Phytochemical Constituents and Pharmacological Uses of Medicinal Plant Achyranthes aspera: A Review. World J. Pharm. Res. 2015, 4 (1), 470–489. Gokhale, A. B.; Damre, A. S.; Kulkami, K. R., Saraf. M. N. Preliminary Evaluation of Anti-Inflammatory and Anti-Arthritic Activity of S. lappa, A. speciosa and A. aspera. Phytomedicine 2002, 9 (5), 433‒437.

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Goyal, B. R.; Mahajan, S. G.; Mali, R. G.; Goyal, R. K.; Mehta, A. A. Beneficial Effect of Achyranthes apsera Linn. in Toluene-Di-Isocyanate Induced Occupational Asthma in Rats. Glob. J. Pharmacol. 2007, 1 (1), 6‒12. Gupta, S. S.; Verma, S. C.; Ram, A. K.; Tripathi, R. M. Diuretic Effect of the Saponin of Achyranthes aspera (Apamarga). Indian J. Pharmacol. 1972, 4, 208‒214. Hariharan, V.; Rangaswamy, S. Structure of Saponins A and B from the Seeds of Achyranthes aspera. Phytochemistry 1970, 9, 409‒414. Hemalatha, K.; Satyanarayana, D. Anti-Inflammatory and Analgesic Activities of the Root Bark of Alstonia scholaris R. Br. Phcog. Mag. 2008, 4, 37‒40. Ikan, R.; Ravid, U.; Trosset, D.; Shulman, E. Ecdysterone; An Insect Moulting Hormone from Acyranthes aspera (Amaranthaceous). Experientia 1971, 27 (5), 504–505. Jayakumar, T.; Sridhar, M. P.; Bharathprasad, T. R.; Ilayaraja, M.; Govindasamy, S.; Balasubramanian, M. P. Experimental Studies of Achyranthes aspera L. Preventing Nephrotoxicity Induced by Lead in Albino Rats. J. Health Sci. 2009, 55 (5), 701‒708. Kapoor, V. K.; Singh, H. Investigation of Achyranthes aspera Linn. Indian J. Pharmacol. 1967, 29, 285–288. Kapoor, V. K.; Singh, H. Isolation of Betain from Achyranthes aspera Linn. Indian J. Chem. 1966, 4, 461. Khanna, A. K.; Chander, R.; Singh, C.; Srivastava, A. K.; Kapoor, N. K. Hypolipidemic Activity of Achyranthes aspera Linn. In Normal and Triton-Induced Hyperlipidemic Rats. Indian J. Exp. Biol. 1992, 30, 128‒130. Khastgir, H. N.; Sengupta, P. Oleanolic Acid from Achyrathes aspera Linn. J. Indian Chem. Soc. 1958, 35, 529‒530. Khastgir, H. N.; Sengupta, S. K.; Sengupta, P. The Sapogenin from Seeds of Achyranthes aspera Linn. J. Indian Chem. Soc. 1958, 35, 693–694. Kumar, S.; Singh, J. P.; Kumar, S. Phytochemical Screening of Some Plants of Manipur-I, J. Econ. Bot. Phytochem. 1990, 1, 13‒16. Kunert, O.; Haslinger, E.; Schmid, G. M.; Reiner, J.; Bucar, F.; Mulatu, E.; Abebe, D.; Debella, A. Three Saponins, a Steroid, and a Flavanol Glycoside from Achyrantes aspera. Mon. Füer Chem. 2000, 131, 195–204. Michl, G.; Abebe, D.; Bucar, F.; Debella, A.; Kunert, O.; Schmid, M. G.; Mulatu, E. New Triterpenoid Saponin from Achyranthes aspera Linn. Haslinger. Helv. Chimica Acta. 2000, 83 (2), 359‒363. Misra, T. N.; Singh, R. S.; Pandey, H. S.; Prasad, C. An Aliphatic Dihydroxyketone from Achyranthes aspera. Phytochemistry. 1991, 30, 2076‒2078. Misra, T. N.; Singh, R. S.; Pandey, H. S.; Prasad, C.; Singh, B. P. Two Long Chain Compounds from Achyranthes aspera. Phytochemistry 1993, 33, 221‒223. Misra, T. N.; Singh, R. S.; Pandey, H. S.; Prasad, C.; Singh, S. Isolation and Characterization of Two New Compounds from Achyranthes aspera Linn. India. J. Chem. 1996, 35B, 637‒639 Neogi, N. C.; Rathor, R. S.; Shreshtha, A. D.; Banerjee, B. K. Studies on the Anti-Inflammatory and Antiarthritic Activity of Achyranthine. Indian J. Pharmacol. 1969, 1, 37‒47. Neogi, N. C; Garg, R. D.; Rathor, R. S. Pharmacological and Medicinal Uses of Achyranthes aspera. Indian J. Pharm. 1970, 32 (2), 43‒46. Ojha, D.; Singh. G. Apamarga (Achyranthes aspera) in the Treatment of Lepromatous Leprosy. Lep Rev. 1968, 39, 23‒30.

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Ojha, D.; Tripathi, S. N.; Singh, G. Role of an Indigenous Drug (Achyranthes aspera) in the Management of Reactions in Leprosy. Preliminary Observations. Lep. Rev.1966, 37, 115‒120. Paul, D.; Bera, S.; Jana, D.; Maiti, R.; Ghosh, D. In Vitro Determination of the Contraceptive Spermicidal Activity of a Composite Extract of Achyranthes aspera and Stephania hernandifolia on Human Semen. Contraception 2006, 73 (3), 284‒288. Prakash, A. O. Potentialities of Some Indigenous Plants for Antifertility Activity. Int. J. Crude Drug Res. 1986, 24, 19‒24. Ram, A. K.; Bhagwat, A. W.; Gupta, S. S. Effect of the Saponin of Achyranthes aspera on the Phosphorylase Activity of Rat Heart. Indian J. Physiol. Pharmacol. 1971, 15, 107–110. Rameswar, R. D. Essential Oil Constituents of Achyranthes aspera Leaves. Indian Perfum. 2007, 51 (1), 33‒34. Sarkar, B.; Rastogi, R. P. Paper Chromatography of Triterpenoid Saponins. J. Sci. Ind. Res. 1960, 19B, 106‒107. Seshadri, V.; Batta, A. K.; Rangaswami, S. Structure of Two New Saponins from Achyranthes aspera. Indian J. Chem. 1981, 20B, 773‒775. Sharma, S. K.; Vasudeva, N.; Ali, M. A New Aliphatic Acid from Achyranthes aspera Linn. Roots. Indian J. Chem. Sect. 2009, 48B, 1164–1169. Shibeshi, W.; Makonnen, E.; Zerihun, L.; Debella, A. Effect of Achyranthes aspera L. on Fetal Abortion, Uterine and Pituitary Weights, Serum Lipids and Hormones. Afr. Health Sci. 2006, 6 (2), 108‒112. Suresh, A.; Anandan, T.; Sivanandam, G.; Veluchamy, G. A Pilot Study of Naayuruvi Kuzhi Thailam in Eraippunoi (Bronchial Asthma). J. Res. Ayur. Siddha 1985, 6, 171‒176. Sushil, K.; Bagchi, G. D.; Darokar, M. P. Antibacterial activity Observed in the Seeds of Some Coprophilous Plants. Int. J. Pharmacog. 1997, 35, 179‒184. Tripathi, S. N.; Chaturvedi, G. N.; Dube, G. P. Effect of Achyranthes aspera in the Treatment of Leprosy. J. Med. Sci. (BHU). 1963, 4, 103‒112. Valsaraj, R.; Pushpangadan, P.; Smitt, U. W.; Andersen, A.; Nyman, U. Antimicrobial Screening of Selected Medicinal Plants from India. J. Ethnopharmacol. 1997, 58, 75‒83. Vasudeva, N.; Sharma, S. K. Post-Coital Antifertility Activity of Achyranthes aspera Linn. Root. J. Ethnopharmacol. 2006, 107(2), 179‒181. Vetrichelvian, T.; Jegadeesan, M. Effect of Alcohol Extract of Achyranthes aspera Linn. on Acute and Subacute Inflammation. Phytother. Res. 2003, 17 (1), 77‒79. Zahir, A. A.; Rahuman, A. A.; Kamaraj, C.; Bagavan, A.; Elango, G.; Sangaran, A.; et al. Laboratory Determination of Efficacy of Indigenous Plant Extracts for Parasites Control. Parasitol. Res. 2009, 105 (2), 453‒461.

CHAPTER 52

Phytochemistry and Pharmacology of Garcinia mangostana (Mangosteen)— A Review ESTEFANI YAQUELIN HERNÁNDEZ-CRUZ,

OMAR N. MEDINA-CAMPOS, and JOSÉ PEDRAZA-CHAVERRI*

Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico *Corresponding

author. E-mail: [email protected]

ABSTRACT Garcinia mangostana is a tropical evergreen tree belonging to the Clusiaceae family and famous for its mangosteen fruit, which has been given the name of the “queen of fruits.” It is native to western Malaysia but has been introduced to other tropical countries. The extracts and derivatives of G. mangostana, mainly the xanthones, are known to have beneficial properties for health. They have been described as having antioxidant, anti-inflammatory, anti­ cancer, hypoglycemic, and antimicrobial properties. Furthermore, several derivatives can neutralize reactive oxygen species such as hydroxyl radical, nitric oxide, superoxide anion, and peroxynitrite. Finally, it has also been reported that both mangosteen pericarp extracts and some of its xanthones can preserve mitochondrial function. Among the most used xanthones are α-mangostin, β-mangostin, γ-magostin, gartanin, and 8-deoxygatanin. This chapter reviews the phytochemical and pharmacological properties of G. mangostana extracts and their primary isolates.

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INTRODUCTION

Garcinia mangostana is a native tropical plant of west Malaysia but has been introduced to Thailand, Indonesia, Southern India, Hawaii, Northern Australia, Brazil, Central America, and other tropical countries (Perry and Metzger, 1980) and its fruit, mangosteen, enjoys a reputation as “Queen of Fruits” not only for its special and tasty juice, but also for its extraordinary medicinal values. The name is derived from the recognition of Charles Linneaus, known as the “father of modern taxonomy,” to the work of the French naturalist Laurent Garcin (Zangger, 2014). The G. mangostana extracts and bioderivatives obtained from fruits, leaves, rind, seeds, bark, and roots have been traditionally used to alleviate wounds, diarrhea, inflammation, arthritis, tuberculosis, fever, dysentery, and ulcers in many countries (Ovalle-Magallanes et al., 2017; Rohman et al., 2019; Aizat et al., 2019b) due to its antiviral, antimicrobial, antitumor, antileishmanial, antimicrobial, antiinflammatory, antimalarial, inhibitor of advanced glyca­ tion end-products, anti-quorum sensing, antioxidant, antihypertensive, and cytotoxic activities (Pedraza-Chaverri et al., 2008; Aizat et al., 2019b) as well as tonic for low energy states and fatigue (Obolskiy et al., 2009). Additionally, the diverse bioactives of mangosteen have been employed in a wide variety of industry sectors such as control of pests (Bullangpoti et al., 2007), flavoring (Sim et al., 2016; Xiao et al., 2015), and additive for food preservation, skin care (Ohno et al., 2015), and even as supple­ ment in animal feed and natural dye in textile factories. They have also been incorporated in dye-sensitized solar cells for electricity generation, in C-dots (carbon nanospheres) of optoelectronic devices, photocatalysts, electrocatalysts, and bioimaging, and in activated carbons for contaminant removal and battery components as well as in biomedical advanced mate­ rials (Aizat et al., 2019a). 52.2

BIOACTIVES

Garcinia mangostana is a source of many bioactive compounds, such as xanthones and anthocyanins, oligomeric proanthocyanins, benzophenones, triterpenoids, depsidones, phloroglucinols (Aizat et al., 2019b; Mohamed et al., 2017) and pectin (Wathoni et al., 2019). The xanthones are the main metabolites that contribute to the pharmaceutical applications of mangosteen extracts and, to date, at least 200 xanthones have been characterized (Aizat

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et al., 2019b; Zhao et al., 2016). The xanthone structure is mainly composed of three consecutive aromatic rings differentiated by side chains (Fig. 52.1).

FIGURE 52.1

52.3

Chemical structures of the main xanthones of Garcinia mangostana.

PHARMACOLOGY

52.3.1 ANTIOXIDANT PROPERTIES Garcinia mangostana, as mentioned before, has a high content in bioactive compounds that have antioxidant and free radical scavenging properties (Ngawhirunpat et al., 2010; Wathoni et al., 2019). Examples of these abilities are described below: Antioxidant capacity. It has been indicated that consumption of bever­ ages containing mangosteen enhances human plasma antioxidant capacity, measured through oxygen radical absorbance capacity (ORAC) assay (Xie et al., 2015a, 2015b; Kondo et al., 2009). Lipoperoxidation. The use of mangosteen extracts and its bioderivatives prevents the oxidation of lipids in vivo and in vitro procedures. Malondial­ dehyde formation was inhibited in the intestine of Listeria monocytogenes­ infected mice fed with silver nanoparticles synthesized using the rind of Garcinia mangostana fruit (Alkhuriji et al., 2020) and also in the lumbar spinal cord of α-mangostin-treated rats with chronic constriction injury (Ghasemzadeh-Rahbardar et al., 2020). In an oxidant condition, due to the exposure to hydrogen peroxide, the addition of isogarcinol and α-mangostin

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to human cancerous hepatic (HepG2) cells (Liu et al., 2018b) and retinal cells (Fang et al., 2016), respectively, also prevented the increase in malondi­ aldehyde levels when compared to its respective hydrogen peroxide-treated cell groups. Finally, it has been reported that the incorporation of mangosteen rind power into chitosan-based biodegradable films for packaging applications inhibits the oxidative decomposition of soybean oil which generates alde­ hydes and ketones that were detected by the thiobarbituric acid reactive substances assay (Zhang et al., 2020). Antioxidant properties and free radicals and reactive oxygen species scavenging. G. mangostana extract and isolated xanthones exhibit anti­ oxidant capacity since it has been reported that mangosteen extracts and xanthones have the capacity of reducing ferric ion (Fe3+) which was assessed by ferric reducing antioxidant power (FRAP) assay (Alkhuriji et al., 2020; Mohammad et al., 2019; Liu et al., 2018b; Ghasemzadeh et al., 2018). In addition, they have powerful free radical scavenging power, demonstrated by neutralizing 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical (Mohammad et al., 2019; Wathoni et al., 2019; Alkhuriji et al., 2020; Rana et al., 2019), 2,2′-azino-bis-(3-ethylbenzothiazoline-6-acid sulfonic acid) (ABTS) radical (Wang et al., 2015; Mohammad et al., 2019; Liu et al., 2018b; Alkhuriji et al., 2020), hydroxyl and nitric oxide radicals (Rana et al., 2019), as well as superoxide and peroxynitrite anions (Pedraza-Chaverrí et al., 2009). Addi­ tionally, it has also been observed in some reports that hydrogen peroxideinduced reactive oxygen species generation is decreased by γ-mangostin in primary culture of rat cerebrocortical cells (Lee et al., 2019) and by isoga­ rcinol in HepG2 cells (Liu et al., 2018b). Wang et al. (2015) reported that γ-mangostin protects normal human hepatocytes (HL-7702) from tert-butyl hydroperoxide-induced oxidative injury by inactivation of free radicals, among other mechanisms. Glutathione content. Herrera-Aco et al. (2019) showed that α-mangostin increases the glutathione content in joints of collagen-induced arthritic rats and a similar effect was observed when isogarcinol was present in cultured hepatic cells exposed to hydrogen peroxide (Liu et al., 2018b) and after α-mangostin was administered to rats with chronic constriction injury (Ghasemzadeh-Rahbardar et al., 2020). Advanced glycation end-products. The glycated proteins and lipids, also known as glycotoxins, are a diverse group of highly oxidant compounds with pathogenic significance in diabetic complications. Bioderivatives of

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mangosteen, like xanthones III and IV, prevented the glycation of bovine serum albumin induced by ribose and glucose (Abdallah et al., 2016). Ohno et al. (2015) used isolated and purified compounds as garcimangosone D, eucryphin, and rhodanthenone B obtained from water extract of mangosteen pericarp and observed an inhibition of pentosidine formation during gelatin exposure to ribose. Nuclear factor erythroid 2-related factor 2 (Nrf2). This factor is the master regulator of phase II detoxifying enzyme genes through antioxidant responsive elements and studies report that its expression can be affected by Garcinia mangostana derivatives. Ibrahim et al. (2018) reported that tovophyllin A enhances the messenger RNA (mRNA) and protein expression of Nrf2 and heme oxygenase-1 in an acetaminophen-induced hepatotoxic model. Yang et al. (2016) suggest that garcinone D promotes the prolif­ eration of C17.2 neural stem cells by a mechanism related to Nrf2 activity. Other xanthones related to Nrf2 activation are γ-mangostin and α-mangostin. Wang et al. (2018) described that γ-mangostin induced Nrf2 upregulation in L02 cells and, as a consequence, an increase in the expression of heme oxygenase-1 and superoxide dismutase-2. As for α-mangostin, Fang et al. (2016) demonstrated that it activates Nrf2 pathway due to cytosolic disso­ ciation between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) and posterior nuclear translocation of Nrf2 which increases the expression of superoxide dismutase, glutathione peroxidase, and heme oxygenase-1 as well as in glutathione content. Rana et al. (2019) observed that the protective effects of G. mangostana extract and α-, β-, and γ-mangostin on acetate-induced chronic kidney disease were associated with the reduction of oxidative stress in plasma, erythrocytes, and kidney and with an increase in the renal antioxidant enzymes superoxide dismutase and catalase, through the activation of Nrf2 signaling pathway. They also inhibited the expression of molecular mediators of inflammation and apoptosis by downregulating the nuclear factor kappa-light-chain­ enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK)/ mitogen-activated protein kinase (MAPK) pathways, respectively. Antioxidant enzymes. The administration of an ethanolic extract of G. mangostana enhanced the protein expression of catalase and Cu/Zn superoxide dismutase, and the mRNA expression of manganese superoxide dismutase in the colon of rats with dextran sulfate sodium-induced colitis (Tatiya-aphiradee et al., 2021), while pretreatment with G. mangostana extract associated with silver nanoparticles increased catalase activity in

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the intestine of mice infected with Listeria monocytogenes (Alkhuriji et al., 2020). α-Mangostin pretreatment resulted in an increased activity of phase II detoxifying enzymes such as superoxide dismutase and glutathione peroxi­ dase as well as in glutathione content both in hydrogen peroxide-exposed cultured retinal cells and in light-exposed mice retinal cells (Fang et al., 2016). 52.3.2 ANTI-INFLAMMATORY EFFECTS Inflammatory diseases can develop some conditions such as allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, hepatitis, inflam­ matory bowel disease, pre-perfusion injury, transplant rejection, and ulcer­ ative colitis. Chae et al. (2017) observed that an ethanolic extract, containing 25% α-mangostin, decreases inflammatory mediators release that was asso­ ciated with the reduction of colitis symptoms. Tatiya-aphiradee et al. (2021), using also an ethanolic extract of G. mangostana, observed a reduction in myeloperoxidase activity in a dextran sulfate sodium-induced ulcerative colitis mice model, and the same effect was reached with α-mangostin pretreatment in this colitic mice model. You et al. (2017) suggested that the accumulation of α-mangostin in the colon of mice administered with this xanthone favors the relief of colitis. Tatiya-aphiradee et al. (2021) also found that the alcoholic G. mangostana extract markedly suppresses the expres­ sion of tumor necrosis factor-α mRNA and, as a consequence, restored the mRNA levels of inflammatory-associated genes following the activation of the NF-κB. Regarding data related to antiinflammatory properties of α-mangostin (a) Herrera-Aco et al. (2019) found that it decreases the activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a reactive oxygen species generating enzyme, in the joints of collagen-induced arthritic mice, (b) Gopalakrishnan et al. (1980) demonstrated that it inhibits hind paw edema in rats treated with carrageenan, cotton pellet-induced granuloma, as well as the primary and secondary responses in complete Freund’s adjuvant-induced arthritis; (c) Chairungsrilerd et al. (1996) proved that blocks histaminergic and serotonergic receptors, and (d) Chen et al. (2008) found that α-mangostin inhibits several inflammation mediators such as nitric oxide, prostaglandin E2, induced nitric oxide synthase, cyclooxy­ genase-2, tumor necrosis factor-α, and interleukin-4.

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52.3.3 MITOCHONDRIAL EFFECTS The loss of mitochondrial function and, particularly, alterations in mitochon­ drial membrane potential are strongly associated with apoptosis signaling via release of calcium, cytochrome c, and caspases activity. Some of the evidence of Garcinia mangostana on mitochondrial function are the following. Mangosteen pericarp powder prevents 3,2′-dimethyl-4-aminobiphenylinduced damage in rat prostate cells by mechanisms associated with mito­ chondrial function preservation (Tsai et al., 2020). Regarding effects of bioactives derived from G. mangostana ReyesFermín et al. (2019) found that α-mangostin preserves mitochondrial function in cisplatin-induced LLC-PK1 cell death, while Wang et al. (2015) showed that γ-mangostin significantly prevents tert-butyl hydroperoxideinduced reduction of mitochondrial membrane potential and changes in nuclei morphology of normal hepatic cells. Also, Tsai et al. (2016) reported that α-mangostin significantly improves mitochondrial membrane potential in free fatty acid-induced steatotic liver cells to avoid the decrease in calcium and cytochrome c levels as well as caspase activity. The apoptotic effect of α-, γ-mangostin, and 8-deoxygartanin on human melanoma SK-MEL-28 cell line was related to the disruption of the mito­ chondrial membrane potential (Wang et al., 2011). Similar effects were reported by Chang and Yang (2012) after adding γ-mangostin to human colon cancer cells, by Lee et al. (2017) using α-mangostin in cervical cancer cells, and by Li et al. (2020) adding β-mangostin to rat C6 glioma cells. 52.3.4 ANTICANCER EFFECTS α-Mangostin has anticancer effects on many cell types, such as gastric, cervical, colorectal, hepatocellular, breast, human lung adenocarcinoma cell line A549 cells, non-small cell lung cancer cells, bile duct cancer, and HepG2 cells (Aizat et al., 2019b) as well as human head and neck squamous carcinoma cells, leukemia, osteosarcome, and human prostate cell lines (Brito et al., 2017). The many anticancer effects of α-mangostin are related to apoptosis induction, DNAfragmentation, caspase-3 cleavage, mitochondrial membrane depolarization and cytochrome c release, cell cycle arrest, reduction in the expression of the matrix metalloproteinases and in the adhesion, invasion, and migration abilities (Brito et al., 2017; Aizat et al., 2019b). Due to that α-mangostin can also inhibit adenosine triphosphate (ATP)-binding cassette

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drug transporter activity, Wu et al. (2017) suggested its suitability for cancer chemotherapy to overcome the ability of cancer cells to survive against a wide range of anticancer drugs, and, more recently, Yokoyama et al. (2019) described the inhibition of the protein MutT homologue 1 (MTH1) as a novel strategy for the treatment of various cancers due to its role in avoiding the incorporation of oxidized nucleoside triphosphates into DNA. Garcinone E also showed potential anticancer activity against cervical, hepatoma, gastric, breast, colorectal, and hepatocellular cancer cell lines (Aizat et al., 2019b). It has been also demonstrated that garcinone E inhibits the proliferation of HEY (derived from a human ovarian cancer xenograft), A2780 (human ovarian cancer cell line), and A2780/Taxol (paclitaxel-resis­ tant cell line) cells, and particularly, this xanthone suppressed the migration and invasion properties of HEY cells (Xu et al., 2017). Yang et al. (2016) found that garcinone D inhibits tumor cell growth in HT-29, CEM-SS, KB, BC-1, and NCIH187 cancer cell lines, and according to their results they concluded that the effect of garcinone D on cell prolifera­ tion is not the same for all cell lines. Muchtaridi et al. (2018) described that gartanin exerts cytotoxicity on HeLa cervical cancer cell line and Luo et al. (2017) indicated a suppressed migration and a decrement in the viability capabilities of T98G cells, a glioblastoma cell line. Maclurin, another polyphenolic compound obtained from G. mangostana, exerted anticancer effects on PC3 human prostate cancer cells showing significant anti-metastatic effects and inhibitory effects on cell migration (Lee et al., 2018b). Other mangosteen bioactives such as mangostanin, 8-deoxygartanin, and 1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl) xanthone (Yang et al., 2016), gartanin, garcixanthone A, 7-O-methylgarcinone (Aizat et al., 2019b), and β-mangostin (Li et al., 2020) also showed anticancer activity against other cancer cells. 52.3.5 EFFECTS AGAINST DIABETES In vivo and in vitro studies have demonstrated the hypoglycemic effects and have described the molecular mechanisms of G. mangostana and its xanthones in the development of diabetes (Chen et al., 2019; Tousian et al., 2017). G. mangostana extracts have been found to improve insulin resistance in obese female patients (Watanabe et al., 2018), reduce the blood glucose levels in streptozotocin-induced diabetic rats (Taher et al., 2016), as well as

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the levels of triglycerides, total cholesterol, low-density lipoproteins, very low-density lipoproteins, serum oxaloacetic glutamic transaminase, serum pyruvic glutamic transaminase, urea, and creatinine in high-fat-fed mice (Chae et al., 2016) with an additional increase in the population of insulin producing β cells (Taher et al., 2016). It has been shown that α-mangostin has potent anti-hyperglycemic prop­ erties since it lowers blood glucose levels and stimulates insulin secretion in pancreatic INS-1 cells (Lee et al., 2018a), while it also improves insulin resistance in high fat-induced diabetic rats (Mekseepralard et al., 2015). The hypoglycemic activity of G. mangostana and its xanthones have been associ­ ated with the suppression of carbohydrate digestion, and delayed glucose uptake, due to inhibition of α-amylase (Ibrahim et al., 2019; Loo and Huang, 2007) and α-glucosidase (Ryu et al., 2011). Furthermore, polyphenols, including xanthones from G. mangostana, have been shown to decrease the accumulation of advanced glycation end products (Abdallah et al., 2016). G. mangostana extract and α-mangostin improve diabetic nephropathy. Widowati et al. (2018) reported that the extract of the G. mangostana peel and α-mangostin significantly reduce transforming growth factor beta (TGF-β) and fibronectin levels in a model of diabetic glomerulosclerosis. Also, Liu et al. (2018a) found that α-mangostin inhibits the expression of acid sphingomyelinase causing decreased endoplasmic reticulum stressrelated apoptosis in kidney cells in Goto-Kakizaki rats. On the other hand, it was found that supplementation with α-mangostin could restore ocular blood flow and retinal barrier patency in an animal model with type 2 diabetes (Jariyapongskul et al., 2015). 52.3.6 ANTIMICROBIAL (BACTERIA, FUNGI, VIRUS)/ANTI­ PROTOZOA/ANTI-HELMINTHS) EFFECTS Garcinia mangostana showed inhibitory properties against many microor­ ganisms and organisms such as bacteria (Alkhuriji et al., 2020; Zhang et al., 2020), helminths (Markowicz et al., 2019), virus (Arjin et al., 2020; Tarasuk et al., 2017), protozoan parasites (Tjahjani et al., 2019; Al-Massarani et al., 2013), and fungal (Narasimhan et al., 2017). Interestingly, it has been observed that α-mangostin has antimicrobial activity although it exerts differential effects on distinct species since it inhibits the growth of Bacillus subtilis, Staphylococcus aureus, Mycobac­ terium tuberculosis, and Helicobacter pylori; but it does not affect other

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microbes such as Escherichia coli and Candida albicans (Gutierrez-Orozco et al., 2014). However, mangosteen extracts can be used for promoting gastrointes­ tinal health since it has been observed that methanol extract of mangosteen pericarp favors the growth of probiotic bacteria Lactobacillus acidophilus (Nanasombat et al., 2018) whose health benefits include relief of some gastro­ intestinal complaints such as lactose intolerance, constipation symptoms, infantile diarrhea, travelers’ diarrhea, and also activity against Helicobacter pylori (Gopal, 2011). ACKNOWLEDGMENTS Research conducted for this publication was supported by grants from “Consejo Nacional de Ciencia y Tecnología” (CONACyT A1-S-7495) to José Pedraza-Chaverri. Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT IN200922) of Universidad Nacional Autónoma de México (UNAM) and Programa de Apoyo a la Investigación y el Posgrado (PAIP 5000-9105) of Facultad de Química, UNAM. EYHC is doctoral student from Programa de Doctorado en Ciencias Biológicas de la Universidad Nacional Autónoma de México (UNAM) and received fellow­ ship 779741 from CONACyT. KEYWORDS • • • • •

Garcinia mangostana phytochemical properties pharmacological properties reactive oxygen species mitochondria

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Taher, M.; Tg Zakaria, T. M.; Susanti, D.; Zakaria, Z. A. Hypoglycaemic Activity of Ethanolic Extract of Garcinia mangostana Linn. in Normoglycaemic and Streptozotocin-Induced Diabetic Rats. BMC Complement. Altern. Med. 2016, 16 (1), 1–12. DOI: https://doi. org/10.1186/s12906-016-1118-9. Tarasuk, M.; Songprakhon, P.; Chimma, P.; Sratongno, P.; Na-Bangchang, K.; Yenchitsomanus, P. T. Alpha-Mangostin Inhibits Both Dengue Virus Production and Cytokine/Chemokine Expression. Virus Res. 2017, 240, 180–189. DOI: 10.1016/j.virusres.2017.08.011. Tatiya-aphiradee, N.; Chatuphonprasert, W.; Jarukamjorn, K. Ethanolic Garcinia mangostana Extract and α-Mangostin Improve Dextran Sulfate Sodium-Induced Ulcerative Colitis via the Suppression of Inflammatory and Oxidative Responses in ICR Mice. J. Ethnopharmacol. 2021, 265, 113384–113394. DOI: 10.1016/j.jep.2020.113384. Tjahjani, S.; Biantoro, Y.; Tjokropranoto, R. Ethyl Acetate Fraction of Garcinia mangostana L. Rind Study as Antimalaria and Antioxidant in Plasmodium berghei Inoculated Mice. Maced. J. Med. Sci. 2019, 7 (12), 1935–1939. DOI: 10.3889/oamjms.2019.480. Tousian, S. H.; Razavi, B. M.; Hosseinzadeh, H. Review of Garcinia mangostana and Its Xanthones in Metabolic Syndrome and Related Complications. Phytother. Res. 2017, 31 (8), 1173–1182. DOI: https://doi.org/10.1002/ptr.5862. Tsai, S. Y.; Chung, P. C.; Owaga, E. E.; Tsai, I. J.; Wang, P. Y.; Tsai, J. I.; Yeh, T. S.; Hsieh, R. H. Alpha-Mangostin from Mangosteen (Garcinia mangostana Linn.) Pericarp Extract Reduces High Fat-Diet Induced Hepatic Steatosis in Rats by Regulating Mitochondria Function and Apoptosis. Nutr. Metabol. 2016, 13, 88–98. DOI: https://doi.org/10.1186/ s12986-016-0148-0. Tsai, H. H.; Chen, C. W.; Yu, P. L.; Lin, Y. L.; Hsieh, R. H. Mangosteen Pericarp Components Alleviate Progression of Prostatic Hyperplasia and Mitochondrial Dysfunction in Rats. Sci. Rep. 2020, 10, 322–331. DOI: https://doi.org/10.1038/s41598-019-56970-2. Wang, A.; Liu, Q.; Ye, Y.; Wang, Y.; Lin, L. Identification of Hepatoprotective Xanthones from the Pericarps of Garcinia mangostana, Guided with Tert-Butyl Hydroperoxide Induced Oxidative Injury in HL-7702 Cells. Food Funct. 2015, 6 (9), 3013–3021. DOI: https://doi.org/10.1039/c5fo00573f. Wang, A.; Li, D.; Wang, S.; Zhou, F.; Li, P.; Wang, Y.; Lin, L. γ-Mangostin, a Xanthone from Mangosteen, Attenuates Oxidative Injury in Liver via NRF2 and SIRT1 Induction. J. Funct. Foods 2018, 40, 544–553. Wang, J. J.; Sanderson, B. J. S.; Wei Zhang, W. Cytotoxic Effect of Xanthones from Pericarp of the Tropical Fruit Mangosteen (Garcinia mangostana Linn.) on human melanoma cells. Food Chem. Toxicol. 2011, 49 (9), 2385–2391. DOI: 10.1016/j.fct.2011.06.051. Watanabe, M.; Gangitano, E.; Francomano, D.; Addessi, E.; Toscano, R.; Costantini, D.; Tuccinardi, D.; Mariani, S.; Basciani, S.; Spera, G.; Gnessi, L.; Lubrano, C. Mangosteen Extract Shows a Potent Insulin Sensitizing Effect in Obese Female Patients: A Prospective Randomized Controlled Pilot Study. Nutrients 2018, 10 (5), 586–596. DOI: 10.3390/ nu10050586. Wathoni, N.; Yuan Shan, C.; Yi Shan, W.; Rostinawati, T.; Indradi, R. B.; Pratiwi, R.; Muchtaridi, M. Characterization and Antioxidant Activity of Pectin from Indonesian Mangosteen (Garcinia mangostana L.) Rind. Heliyon 2019, 5 (8), e02299–e02304. DOI: https://doi.org/10.1016/j.heliyon.2019.e02299. Widowati, W.; Laksmitawati, D. R.; Wargasetia, T. L.; Afifah, E.; Amalia, A.; Arinta, Y.; Rizal, R.; Suciati, T. Mangosteen Peel Extract (Garcinia mangostana L.) as Protective Agent in Glucose-Induced Mesangial Cell as In Vitro Model of Diabetic Glomerulosclerosis.

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Iran. J. Basic Med. Sci. 2018, 21 (9), 972–977. DOI: https://doi.org/10.22038/ ijbms.2018.29349.7094. Wu, C. P.; Hsiao, S. H.; Murakami, M.; Lu, Y. J.; Li, Y. Q.; Huang, Y. H.; Hung, T. H.; Ambudkar, S. V.; Wu, Y. S. Alpha-Mangostin Reverses Multidrug Resistance by Attenuating the Function of the Multidrug Resistance-Linked ABCG2 Transporter. Mol. Pharmacol. 2017, 14 (8), 2805–2814. DOI: 10.1021/acs.molpharmaceut.7b00334. Xiao, Z. B.; Liu, J. H.; Chen, F.; Wang, L. Y.; Niu, Y. W.; Feng, T.; Zhu, J. C. Comparison of Aroma-Active Volatiles and Their Sensory Characteristics of Mangosteen Wines Prepared by Saccharomyces Cerevisiae with GC-Olfactometry and Principal Component Analysis. Nat. Prod. Res. 2015, 29 (7), 656–662. DOI: 10.1080/14786419.2014.981185. Xie, Z.; Sintara, M.; Chang, T.; Ou, B. Functional Beverage of Garcinia mangostana (Mangosteen) Enhances Plasma Antioxidant Capacity in Healthy Adults. Food Sci. Nutr. 2015a, 3 (1), 32–38. DOI: 10.1002/fsn3.187. Xie, Z.; Sintara, M.; Chang, T.; Ou, B. Daily Consumption of a Mangosteen-Based Drink Improves In Vivo Antioxidant and Anti-Inflammatory Biomarkers in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Food Sci. Nutr. 2015b, 3 (4), 342–348. DOI: 10.1002/fsn3.225. Xu, X.-H.; Liu, Q.-Y.; Li, T.; Liu, J.-L.; Chen, X.; Huang, L.; Qiang, W.-A.; Chen, X.; Wang, Y.; Lin, L.-G.; Lu, J.-J. Garcinone E Induces Apoptosis and Inhibits Migration and Invasion in Ovarian Cancer Cells. Sci. Rep. 2017, 7 (1), 1–13. DOI: 10.1038/s41598-017-11417-4. Yang, X.; Wang, S.; Ouyang, Y.; Tu, Y.; Liu, A.; Tian, Y.; He, M.; Pi, R. Garcinone D, a Natural Xanthone Promotes C17.2 Neural Stem Cell Proliferation: Possible Involvement of STAT3/Cyclin D1 Pathway and Nrf2/HO-1 Pathway. Neurosci. Lett. 2016, 626, 6–12. DOI: 10.1016/j.neulet.2016.05.012. Yokoyama, T.; Kitakami, R.; Mizuguchi, M. Discovery of a New Class of MTH1 Inhibitor by X-Ray Crystallographic Screening. Eur. J. Med. Chem. 2019, 167, 153–160. DOI: 10.1016/j.ejmech.2019.02.011. You, B. H.; Chae, H.-S.; Song, J.; Ko, H. W.; Chin, Y.-W.; Choi, Y. H. α-Mangostin Ameliorates Dextran Sulfate Sodium-Induced Colitis Through Inhibition of NF-κB and MAPK Pathways. Int. Immunopharmacol. 2017, 49, 212–221. DOI: 10.1016/j.intimp.2017.05.040. Zangger, A. The Swiss in Singapore; Editions Didier Millet Pte Ltd., 2014. ISBN 10: 9814385689. Zhang, X.; Liu, J.; Yong, H.; Qin, Y.; Liu, J.; Jin, C. Development of Antioxidant and Antimicrobial Packaging Films Based on Chitosan and Mangosteen (Garcinia mangostana L.) Rind Powder. Int. J. Biol. Macromol. 2020, 145, 1129–1139. DOI: 10.1016/j. ijbiomac.2019.10.038. Zhao, Y.; Tang, G.; Tang, Q.; Zhang, J.; Hou, Y.; Cai, E.; Liu, S.; Lei, D.; Zhang, L.; Wang, S. A Method of Effectively Improved α-Mangostin Bioavailability. Eur. J. Drug Metab. Pharmacokinet. 2016, 41 (5), 605–613. DOI: 10.1007/s13318-015-0283-4.

CHAPTER 53

Bioactives and Pharmacology of Cycas beddomei Dyer B. KAVITHA1 and N. YASODAMMA2* 1Department

of Botany, Rayalaseema University, Kurnool, Andhra Pradesh 518007, India

2Department

of Botany, Sri Venkateswara University, Tirupati, India

*Corresponding

author.

E-mail: [email protected]; [email protected]

ABSTRACT Cycas beddomei Dyer, (Cycadaceae) is endemic to seshachalam hill ranges of Eastern Ghats, India and enlisted as Critically Endangered under IUCN status of red listed Gymnosperms. This review is collective information concerning the bioactives and pharmacology of C. beddomei collected from various research articles published in varies online journals, Ph.D theses from 1974 to 2019. C. beddomei is known for various medicinal properties in traditional medicinal system and use to cure wounds, narcotic agent, reju­ venating tonics, boils, sores, inflammation and arthritis. A variety of bioac­ tive compounds like phenolic, flavonoid and anthocyanidin compounds have been isolated from the various parts of the plant extracts. The extracts of the different parts of C. beddomei were subjected to antimicrobial, hepatopro­ tective, antioxidant, anthelmintic, anti-Inflammatory, antiulcer, arthritic and analgesic activities.

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INTRODUCTION

Cycas beddomei Dyer., Familly Cycadaceae, is a critically endangered and endemic species predominantly available in Seshachalam Hills of Kadapa, Nellore, and Chittoor districts of Andhra Pradesh State, in the eastern Peninsular India (Raju and Jonathan, 2010; Rao, 2013; Rao et al., 2010). This species is included in Convention on International Trade in Endangered Species of Wild Fauna and Flora Appendix I and it can be used only for scientific or conservation functions. C. beddomei which is native to India has several functions, primarily medicinal, food, and ornamental (Raju et al., 2019). Common names are Cicas di Beddome, Beddome’s cycas (English Name); Perita, Madhana—Kamakshi (Telugu); Cycad, Cycas (Trade Name). C. beddomei is a palm-like dioecious tree with a crown of leaves. Leaves are 100–200 cm long, petiole of 10–20 cm, and a few minute spines on the upper half of the petiole, leaflets are 0.5–0.75 cm broad and 9–12 cm long. Spine acuminate. The leaf bases are with rementa. The female plants are gener­ ally smaller than the male plants. The male cones are flush during April–June months, short-stalked, solitary, compact, terminal, 20 cm in diameter, and 30 cm long. Cones are oval shape. The sporophylls are attached to the central axis perpendicularly in a close spiral. Each sporophyll has two parts—the abaxial side a number of hairs—rementa—pink in color, characteristic of the species and basal part that lodges a number of sporangia over abaxial surface and sporangia are usually in 3, they form a sorus (Rao, 1974). These are woody structures with oval to pyramidal-shaped and contain a number of microsporophylls that in turn bear microsporongia (Raju and Jonathan, 2010). Female cones are formed in the terminal point of the plant. Megasporo­ phyll has two parts, they are stalk 15–20 cm long and squarish in a sectional view and are covered all over with rementa, the broad portion bearing ovules at the margins and got a number of elongated frill-like projections above the ovules and covered over by rementa. The rementa are red to pinkish in color and characteristic of this species. The ovules are green when immature and yellow to brown when mature (Rao, 1974). This species was considered a rare species (Jain and Sastry, 1980) and threatened in Indian Red Data Book (Nayar and Sastry, 1987). C. beddomei plant parts specifically male cones are used as mosquito repellent, bed bug prevention. In Ayurvedic medicine the male cones are used to treat rheumatism and joint pains and swellings in the joints

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(Latheef et al., 2008). The mature male cone is grinded with gingelly oil and ghee and the paste is applied on the swelling parts of inflammation and arthritis (Alekhya, 2015). It has been used for its apparent medicinal value, as a major ingredient in narcotic agent, rejuvenating tonics (Nayar and Sastry, 1987). The seed paste prepared with coconut oil is used as a poultice to treat skin damages such as boils, wounds, and sores (Jain and Sastry, 1980). It has shown significant pharmacological activities like antimicrobial (Alekhya et al., 2012, 2013b), anthelmintic (Alekhya et al., 2013a), anti-inflammatory (Alekhya et al., 2014), and antioxidant (Mitta et al., 2014). 53.2 BIOACTIVES Qualitative phytochemical results revealed the presence of phenolic components in leaf 13, bark 14, pith, and male cone each 11 components. Phenolic compounds were not observed in female cones and roots of C. beddomei. Phenolic compounds that exist in different parts of C. beddomei include vanillic acid, cinnamic acid, p-hydroxy benzoic acid, aesculetin, scopoletin, salicylic acid, syringic acid, caffeic acid, trans—ferulic acid, cis-p-coumaric acid, m-hydroxy benzoic acid, melilotic acid, gentisic acid, homo protocatechuic acid, trans sinapic acid, trans-p-coumaric acid, α-resorcylic acid, β-resorcylic acid, cis-sinapic acid, cis-ferulic acid, o-coumaric acid, and phloretic acid. Flavonoids were present in leaf, bark, male cone and roots include apigenin, vitexin, orientin, quercetin, luteolin, kaempferol, and myrecetin. Anthocyanidins in C. beddomei bark and roots are rosinidin, delphidin, malvinidin, petunidin, and luteolinidin (Alekhya et al., 2013c). A new amentoflavone, biflavonone, tetrahydro­ hinokiflavones are isolated from the leaves of C. beddomei (Rani et al., 1998). Other new biflavonoids have been isolated from C. beddomei which include 2,3-dihydro-4″-O-methyl amentoflavone, 2,3,2″,3″-tetrahy­ drolinokiflavone, 2,3,2″,3″-tetrahydroamentoflavone, 2,3-dihydroamento flavone from the ovules and 2″,3″-dihydrohinokiflavone was isolated from the cones (Das et al., 2005, 2006). GC-MS analysis of male cone methanol extract explored twelve phytochemical constituents. The major constituents are 1,3-propanediol, 2-(hydroxyl methyl)-2-nitro, methyl tetradeconate, hexadecanoic acid, methyl ester, and methyl cis-7-octadeconoate (Kumar et al., 2012).

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PHARMACOLOGICAL USES

53.3.1 ANTIMICROBIAL ACTIVITY The antibacterial activity of C. beddomei male and female cone extracts on four different bacterial strains Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. The male cone extracts of alcohol, methanol, cold water and hot water showed that the minimum inhibitory concentration on four bacterial strains. Ampicillin was taken as positive control. Female cone extracts have not shown any antibacterial activity. Staphylococcus aureus was more susceptible compared to other strains. The zone of inhibition was around 30.5 mm diameter, whereas the positive control activity was only 16.06 mm. The antibacterial activities of all four extracts of male cones of C. beddomei are in the order of methanol< hot water< alcohol, water (Alekhya et al., 2012, 2013b). Antifungal activity of leaf, bark, pith, female, and male cone extracts of C. beddomei on C. albicans and A. niger revealed that pith and female cones have not shown any antifungal activity. Pith and female cones have not shown any antifungal activity. Leaf, bark, and male cone extracts are

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more effective on C. albicans than that of A. niger with 20.1–26.4 mm zone of inhibition on C. albicans, 19.1–25.4 mm on A. niger at concentrations 10 mg/well. Nystatin showed 10.2–12.1 mm at concentration 10 mg/well. The above results explain that the leaf, bark, and male cones have phyto­ constituents that are antifungal in nature. Further experiments are needed to isolate the principal active constituent that is responsible for antifungal activity (Alekhya et al., 2012). Ethyl acetate and ethanol extracts of C. beddomei leaves were investi­ gated for anticandidal activity. 53.3.2 HEPATOPROTECTIVE EFFECT Hepatoprotective effects of methanol extract of C. beddomei in a rat model were studied. Primarily, they have conducted acute toxicity studies and found that up to a dosage of 2000 mg/kg weight in rats the drug is nontoxic. Hepatoprotective activity the rats were treated with carbon tetrachloride and olive oil (1:1) to induce liver damage. The damage to liver is confirmed by biochemical and histopathological studies. Methanol extracts treated rats showed healing of the damaged liver. During this healing, all the normal functions of liver have been recovered and the liver was restored back to that of control animals. The extract has hepatoprotective effects that were evidenced by biochemical, antioxidant, and histopathological analysis. The best dosage is 500 mg/kg body weight of methanol extract of C. beddomei to restore liver damage than the control drug Silymarin (David and Raja, 2015a). 53.3.3 ANTIOXIDANT ACTIVITY Antioxidant activity of C. beddomei methanol extract of whole plant on different models such as DPPH radical scavenging assay, hydroxy radical scavenging assay, lipid peroxidation assay, superoxide anion assay, nitric oxide radical inhibition assay, and thiocyanate methodology. The extract has shown superior antioxidant activity compared to ascorbic acid, rutin, curcumin, and fat-soluble vitamin E. The extract has shown activity in a dose-dependent manner. The major compounds belonging to flavonoid and phenolic group are responsible for this activity of C. beddomei (David and Raja, 2015b). The antioxidant activity of C. beddomei microsporophylls of male cones aqueous extracts by DPPH (2,2-diphenyl-1-picrylhydrazyl)

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radical scavenging assay, total antioxidant capacity (TAC), and ABTS (Azino-bis (3-ethylbanzthiazoline-6-sulphonic acid)) radical scavenging assay showed to be more effective (Mitta et al., 2014). 53.3.4 ACUTE TOXICITY Acute toxicity studies of C. beddomei in Wistar albino rats with aqueous, alcohol, and methanol extracts of leaf, bark, and male cone were carried out. There are no significant toxicity signs for first 4 h, followed by daily obser­ vations continuously up to 14 days and no mortality was observed. The drug concentrations at 100, 300, 500, 1000, 1500, 3000, and 5000 mg/kg body weight the drug usage were safe. Therefore, 5000 mg/kg body weight has been considered 1/5th (1000 mg) and 1/10th (500 mg) of the LD50 has been considered the effective doses of minimum and maximum for experimental studies according to OECD guidelines (Alekhya and Yasodamma, 2016). 53.3.5 ARTHRITIC AND ANALGESIC Analgesic activity of C. beddomei extracts was investigated in albino male Wistar rats through the acetic acid-induced writhing method. Methanol, aqueous, and alcohol extracts of male cones between 250 and 1000 mg/kg body weight were used in this study. Diazepam at 10 mg/kg body weight was used as a positive control. The extracts at the concentration of 1000 mg/ kg body weight have shown excellent activity on par with the Diazepam. Further, the extracts were also tested for anti-arthritic activity in albino male Wistar rats through complete Freund’s adjuvant (CFA)-induced arthritis method equal to that of Diclofenac as a standard drug. The anti-arthritic effect was measured by measuring the paw volume (mm) and the percentage of inhibition by methanol extract at 250 mg/kg body weight and the standard drug Diclofenac was the same as 60.71%. The male cone extracts showed effective inhibition with 3.4-mm diameter of paw with methanol and aqueous extracts at 250 mg/kg body weight equal to that of normal rats as 3.1 and 3.3 mm of paw diameter as diclofenac-treated rats and the arthritic rats showed 8.4 mm paw volume as three times that of the normal rats. The above result explains that the extracts of C. beddomei can be used as anti-arthritic drug similar to that of the standard drug Diclofenac (Alekhya and Yasodamma, 2016).

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53.3.6 ANTIULCER ACTIVITY Antiulcer activity of C. beddomei aqueous and methanol extracts of leaf at 1000, 500, and 250 mg/kg body weight on the ulcers induced albino wistar rats (male) the pylorus ligation induced ulcer method found significant reduction in ulcer index, ulcer protection percentage, gastric volume, free acidity and total acidity compared with untreated and also with Omeprazole (positive control) at 20 mg/kg body weight treated animals. Results have shown that aqueous leaf extracts are more effective than methanol extracts. Aqueous leaf extracts at concentration 1000 mg/kg body weight expressed the activity equal to or more than the standard drug Omeprazole at concen­ tration 20 mg/kg body weight. The test drug exhibited good activity in all parameters such as percentage of ulcer protection, ulcer index, and volume of gastric juice, pH of gastric juice, free acidity, and total acidity parameters. The antiulcer activity of C. beddomei is mainly in the presence of secondary metabolites such as phenols, flavonoids, and anthocyanidins in their leaf extracts (Alekhya et al., 2016). 53.3.7 ANTHELMINTIC ACTIVITY Anthelmintic activity of C. beddomei was studied on earthworms, different extracts of leaf, bark and male cones and the positive control Albendazole at 5, 10 and 15 mg/25 mL of distilled water, the earthworms were treated and observed that the death of the earthworms and the time for paralysis. The results clearly showed that the methanol extracts exhibited superior activity than the standard drug in terms of less time for death of the worms and paralysis. The time taken for paralysis showed 90.9; 9.3; 10.4; 20.8; 31.9 min with albendazole, methanol, alcohol, hot water, and cold water extracts at 5 mg of leaf respectively; further the time taken for death of worms as 110.1; 9.8; 15.5; 25.1 and 35.0 min, respectively. Anthelmintic activity was predominantly shown by leaf extracts followed by male cone extracts and then by bark extracts (Alekhya et al., 2013a). 53.3.8 ANTI-INFLAMMATORY ACTIVITY Anti-inflammatory activity of aqueous, methanol, and alcohol extracts of C. beddomei leaf and male cone was studied on induced rat paw edema model with carrageenan. Diclofenac was used as a positive control for

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anti-inflammatory activity. At 100 mg/kg body weight the standard drug diclofenac showed 3.5-mm highest activity with 63.15% inhibition, whereas the male cone alcohol extracts showed 3.7 mm with 61.05%; aqueous extracts showed 4.3 mm with 53.68% and methanol extracts showed 4.5 mm with 52.89%. There is no effect with leaf, bark, and female cone (seeds) extracts (Alekhya et al., 2014). KEYWORDS • • • • • •

Cycas beddomei cycadaceae bioactives acute toxicity hepatoprotective antiarthritic analgesic

REFERENCES Alekhya, C. In-Vivo Propagation and Pharmacognostic Studies of an Endemic Medicinal Plant Cycas beddomei Dyer. Ph.D. Thesis, S. V. University, Tirupati, 2015. Alekhya, C.; Yasodamma, N. Analgesic and Anti-Arthritic Activity of Cycas beddomei Dyer Male Cone Extracts. World J. Pharm. Res. 2016, 5 (4), 1635–1652. Alekhya, C.; Yasodamma, N.; Chaithra, D. Physicochemical Analysis and Antimicrobial Activity of Cycas beddomei Dyer Vegetative Parts. J. Pharm. Res. 2012, 5 (5), 2553–2558. Alekhya, C.; Yasodamma, N.; Chaithra, D. Anthelmintic Activity Studies on Pheretima posthuma with Cycas beddomei Dyer. Leaf, Bark, and Male Cone Extracts. Int. J. Pharm. Bio Sci. 2013a, 4 (2), 34–38. Alekhya, C.; Yasodamma, N.; Chaithra, D. Antibacterial and Physico-Chemical Studies of Cycas beddomei Dyer Male and Female Cones. Int. J. Pharm. Biosci. 2013b, 4 (2), 642–656. Alekhya, C.; Yasodamma, N.; Chaithra, D. Qualitative Analysis of Phenols, Flavonoids and Anthocyanidins of Cycas beddomei Dyer. Indo Am. J. Pharm. Res. 2013c, 3 (12), 1632–1641. Alekhya, C.; Yasodamma, N.; Chaithra, D. Anti-Inflammatory Activity of Cycas beddomei Dyer Male Cone Extracts. Indo Am. J. Pharm. Res. 2014, 4 (1), 132–137. Alekhya, C.; Yasodamma, N.; Chaithra, D. Anti-Ulcer Activity of Cycas beddomei Dyer Aqueous and Methanol Leaf Extracts. World J. Pharm. Res. 2016, 5 (4), 2040–2055.

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Bhakshu, L. M.; Ratnam, K. V.; Raju, R. R. Anticandidal Activity and Phytochemical Analysis of Certain Medicinal Plants from Eastern Ghats, India. Indian J. Nat. Prod. Resour. 2016, 7 (1), 25–31. Das, B.; Mahender, G.; Rao, Y. K.; Prabhakar, A.; Jagadeesh, B. Biflavonoids from Cycas beddomei. Chem. Pharm. Bull. 2005, 53 (1), 135–136. Das, B.; Mahender, G.; Rao, Y. K.; Thirupathi, P. A New Biflavonoid from Cycas beddomei. Indian J. Chem. 2006, 45B, 1933–1935. David, B. S.; Raja, S. Hepatoprotective and Antioxidant Effects of Cycas beddomei in Rats. Int. J. Biol. Pharm. Res. 2015a, 6 (11), 899–908. David, B. S.; Raja, S. In-Vitro Antioxidant Activity of Cycas beddomei in Rats. Int. J. Phytomed. 2015b, 7, 468–478. Jain, S. K.; Sastry, A. R. K. Threatened Plants of India: A State of the Art Report. Botanical Survey of India: Howrah; Man and Biosphere committee, DST: New Delhi, 1980. Kumar, N. R.; Reddy, J. S.; Gopikrishna, G.; Solomon, K. A. GC-MS Determination of Bioactive Constituents of Cycas beddomei Cones. Int. J. Pharm. Bio. Sci. 2012, 3 (3), 344–350. Latheef, S. A.; Prasad, B.; Bavaji, M.; Subramanyam, G. A. Database on Endemic Plants at Tirumala Hills in India. Bioinformation 2008, 2 (6), 260. Mitta, M. N.; Sankara Rao, M.; Ramesh, L.; Madhava Chetty, K. Phyto-Chemical Evaluation and Anti-Oxidant Potentiality of Cycas beddomei Dyer Male Cone Aqueous Extract. Int. J. Drug Dev. Res. 2014, 6 (2), 220–227. Nayar, M. P.; Sastry, A. R. K.; Eds. Red Data Book of Indian Plants, 1; Botanical Survey of India: Calcutta, 1987; p 359. Raju, A. J. S.; Venkata Ramana, K.; Suvarna Raju, P.; Dileepu Kumar, B.; Lakshminarayana, G.; Sravan Kumar, S. Traditional Food and Medicinal Uses of Cycas sphaerica Roxb. and Cycas beddomei Dyer (Cycadaceae). Species 2019, 20, 24–27. Raju, A. J. S.; Jonathan, K. H. Reproductive Ecology of Cycas beddomei Dyer (Cycadaceae), an Endemic and Critically Endangered Species of Southern Eastern Ghats. Curr. Sci. 2010, 99 (2), 1833–1840. Rani, M. S.; Rao, C. V.; Gunasekar, D.; Blond, A.; Bodo, B. A Biflavonoid from Cycas beddomei. Phytochemistry 1998, 47 (2), 319–321. Rao, B. R. P. Cycas beddomei. In IUCN Red List of Threatened species; IUCN, 2013. Version 2013.1 2010. Rao, B. R. P.; Babu, S.; Donaldson, J. S. A Reassessment of the Conservation Status of Cycas beddomei Dyer (Cycadaceae), an Endemic of the Tirupati-Kadapa Hills, Andhra Pradesh, India; and Comments on Its CITES Status. Encephalartos 2010, 102, 19–24. Rao, L. N. Cycas beddomei Dyer. Proc. Indian Acad. Sci. B 1974, 79, 59–67.

CHAPTER 54

Phytochemical and Pharmacological Profile of Tridax procumbens L.: An Asteraceaeous Member RAJA KULLAYISWAMY K1* and SAROJINI DEVI N2 1Dharmavana

Nature Ark, IDA Cherlapalli, Hyderabad, Telangana-500051, India

2Dharmavana

Nature Ark, IDA Cherlapalli, Hyderabad, Telangana-500051, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Tridax procumbens is an Asteraceae family herb. It grows as a weed in trop­ ical countries and it has medicinal importance, especially in blood clotting and wound healing. It shows many biological activities like antibacterial, antiviral and anti-fungal, and also against common diseases. All these activi­ ties of Tridax are because of secondary metabolites which encompass six groups flavonoids, alkaloids, carotenoids, tannins, saponins, and terpenes. 54.1 INTRODUCTION Tridax procumbens L. is a common weed in tropical or subtropical climate. It is known as coat buttons, Mexican daisy, Daisy (English). Locally, it is called Tikke gida, Kari balli (Kannada); Kurikootticheera, Odiyancheera, Muriyampachila, Kumminnippacha, Ekdandi, Railpoochedi, Sanipoovu,

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Thelkuthi (Malayalam); Dagadi Pala (Marathi); Bhumi poksungo, Bisalya karani (Oria); Seruppadithazhai, Kenathuppoondu (Tamil); Gaddi chamanthi, Kampu-chemanti, Nallaku (Telugu). Daisy is a decumbent annual ascending herb with rough hairs. Leaves are simple, toothed, lamina ovate. Peduncle is very long and strigose. Leaf shape is lanceolate-ovate having acute leaf apex, acute leaf base, and coarsely serrate leaf margins. Flowers are white or yellow heads with three-toothed ray florets and yellow-centered. Fruit is achene, seeds faintly ribbed covered with bristle hairy like feathers, called pappus. The plant flowers throughout the year. Tridax procumbens is known as noxious weed and sometimes pest in cultivation. It was introduced to tropics and subtropics, and temperate regions from tropical America. This plant is generally found in agriculture fields, roadside, waste lands, cultivated fields, and lawns. In India Tridax procumbens (TP) is known as weed and it is traditionally used as wound healing and an anticoagulant plant. Leaf juice of this plant is directly used on wounds and cuttings. Approximately 50 g of fresh leaves is boiled in coconut oil for 20 min and then the oil is used for head massage to control dandruff; this application is done due to its antifugal property. Tridax procumbens (TP) is also used to treat blisters, boils, and cuts by most of the people in parts of India (Sreeramulu et al., 2013). Dried leaves along with other herbs are used in the treatment of hemorrhages, diarrhea, diabetes, as well as hair loss and jaundice, healing of wounds, inflammation (Samantha et al., 2018). 54.2 BIOACTIVES Phytochemicals have been reported from Tridax procumbens (TP) by Verma and Gupta (1988), and Samantha et al. (2018). Those are methyl 14-oxoocta­ decanoate, methyl 14 oxononacosanoate, 3-methylnonadecylbenzene, heptacosanyl cyclohexane carboxylate, 1(2,2-dimethyl-3-hydroxypropyl)­ 2-isobutyl phthalate, 12-hydroxytetracosan-15-one, 32-methyl-30-oxotet­ ratriacont-31-en-1-ol and 30-methyl-28-oxodotriacont-29-en-1-oic acid dotriacontanol, β-amyrone, Δ12-dehydrolupen-3-one, β-amyrin, lupeol, fucosterol, 9-oxoheptadecane, 10-oxononadecane, and sitosterol. T. procumbens (TP) secondary metabolites encompass six major groups: flavonoids, alkaloids, carotenoids, tannins, saponins, and terpenes. Flavo­ noids are found in the leaves of TP and other parts (Jhariya et al., 2015); these are useful against problems of bronchial catarrh, anticoagulants, wound healing, diarrhea, dysentery, antifungal, and hair tonics (Ali et al., 2001). The presence of new flavonoid procumbenetin and other flavonoids in Tridax

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seems to reduce the deposition of calcium and oxalate in the kidneys (Sailaja et al., 2012). These secondary metabolites also help in the regeneration of damaged beta cells in the pancreas (Petchi et al., 2013); this property effected on diabetic rats showed hypoglycemic activity (flavonoids), protection against oxidative stress (due to high content of ascorbic acid), and lowering of VLDL cholesterol (due to the flavonoids) (Ikewuchi, 2012). Along with new procumbentin others like luteolin and quercetin were also isolated from Tridax procumbens (TP) (Jhariya et al.,2015). Glucoluteolin, isoquercetin, and lutein are found in the flowers of T. procumbens (Kumar et al., 2012). These two chemicals are medicinally of much importance; luteolin has anti-inflammatory, anticancer (all types of cancers), antitumor, antioxidant, free radical scavenging activity and quercetin has antioxidant, antilipid peroxi­ dation, antiulcer activity, etc. (Samantha et al., 2018). Acetone water or chlo­ roform water extract showed the presence of tannins in the leaf extracts of T. procumbens (Sawant and Godghate, 2013). Tannins are present in the pedicels and buds of T. procumbens (Ikewuchi, 2012). Carotenoids were isolated from the leaves of TP (9.41 mg/100 gm of dry leaf powder) (Ikewuchi et al., 2009). Thirty-nine alkaloids were reported in phytochemical screening of leaf aqueous extraction analysis of TP, mainly akuamidine (73.91%) and voacangine (22.33%) (Ikewuchi, 2012). The total amount of alkaloids in the pedicel was 32.25 mg/gdw and in the buds it was 92.66 mg/gdw (Jindal and Kumar, 2012). A number of active chemical constituents were isolated and reported from the Tridax procumbens (TP); they are alkaloids, flavonoids, carotenoids, β-sitosterol, linoleic acid, palmitic acid, lauric acid, myristic acid, oxoester, quercetin, fumaric acid, luteolin, arachidic acid, tannins etc (Verma and Gupta, 2004; Singh and Ahirwar, 2010). Earlier researchers reported presence of dexamethasone, luteolin (5,7-dihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one), glucoluteolin, betasitosterol, and quercetin (Subramanian et al., 1968). Linolenic acid was also reported from aerial parts of TP. Two water-soluble polysaccharides WSTPIA and WSTP-IB containing β-(1->6)-D Galactan as the main chain have been purified from the dried leaves of the TP (Raju and Davidson, 1994). A new flavonoid “Procumbenetin” has been characterized as 3,6-dimethoxy-5,7,2′,3′,4′pentahydroxyflavone 7-O-β-glucopyranoside which was isolated from aerial parts (Singh and Ahirwar, 2010). A new flavone isolated from the leaves of T. procumbens was identified as 5,7,4′-trihydroxy-6,3′-dimethoxy flavone-5-Oalpha rhamnopyranoside (glycoside) by Yadava and Saurabh (1998). Mineral composition of TP reported from leaves is calcium (20.96 mg/kg dry leaf powder (dlp)), magnesium (3.56 mg/kg dlp), potassium (31.92 mg/kg

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dlp), sodium (50.44 mg/kg dlp), and selenium (0.20 mg/kg dlp) (Ikewuchi et al., 2009). Nutritional profile and chemical profile of TP were done by Ikewuchi et al. (2009); the result showed carotenoids 9.41 mg/100 gm dlp, saponins 10.30 mg/100 gm dlp, and tannins 0.47 mg/100 mg dlp. TP can also serve as a good source of provitamin A (carotenoids), as well as plant protein and potassium supplement to the population (Chen et al., 2008; Jude et al., 2009). Four new terpenoids, bisbithiophene, taraxasteryl acetate, beta-amyrenone, lupeol, and oleanolic acid were reported from T. procumbens (Ali and Jahangir, 2002). Two new flavones, 8,3′-dihydroxy-3,7,4′-trimethoxy-6-O-β-D glucopyranosyl flavone and 6,8,3′-trihydroxy-3,7,4′-trimethoxy flavone and four more known compounds betulinic acid, oleanolic acid, esculetin, and puerarin were also isolated from TP (Xu et al., 2010). The presence of steroidal saponin and β-sitosterol-3-O-β-d-xylopyranoside in the flowers of T. procumbens was reported by Saxena and Albert (2005). A new flavone isolated from the leaves of TP was identified as 5,7,4′-trihydroxy-6,3′-dimethoxy flavone-5-O-alpha rhamnopyranoside (Glycoside) (Yadava and Saurabh, 1998). The hydrodis­ tilled essential oil of TP contains a total of 18 components that include dibutyl phthalate (19.29%), trans-(α)-caryophyllene (9.55%), biformeme (3.95%), p-cymen-7-ol (2.52%), 1,8-cineole (2.44%), and the minor compounds are trans-α-bergamotol (1.78%), 2-α-pinene (1.62%), α-selinine (1.49%), caryo­ phyllene oxide (1.39%), α-humulene (0.95%) (Poonkodi et al., 2017).

FIGURE 54.1

Chemical structures of Tridax procumbens.

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54.3 PHARMACOLOGICAL ACTIVITIES 54.3.1 REDUCED CLOTTING PROLONGATION TIME Kanungo et al. (1995) experimented on rabbits which induced reduction of normal heparin and prolongation of clotting time by giving TP extraction 200 mg/μg as IP injection. The leaf Ethanolic extract reduced clotting time by 2‒3 min in blood samples of all the subjects (Kale et al., 2008); it can be suggested that the same possesses hemostatic activity, thus affecting hemostasis (Godkar, 1994). 54.3.2 WOUND-HEALING ACTIVITY Water extract of TP leaf promoted healing and steroid depressed healing in experimental male wistar rats. The extract increased lysyl oxidase activity which is responsible for wound-healing activity. It increased reac­ tion at nucleic acid level and indicates the action at cellular level (Udupa et al., 1991). In experimented animals, fresh leaf juice showed to depress wound contraction. It involves in a complex interaction between dermal and epidermal cells, the extra cellular matrix (Bhat et al., 2007). The plant extract improves both lysyl oxidase and protein and nucleic acid content in the granulation tissue, probably as a result of increase in glycosaminoglycan content (Nia et al., 2003). 54.3.3 CARDIOVASCULAR EFFECTS/HYPOTENSIVE EFFECT The water extract from the leaf of TP was investigated on anesthetized Sprague-Dawley rat to test the cardiovascular effect. The IV administration of 9, 6, and 3 mg/kg of water extract showed the decreasion in mean arterial blood pressure in a dose-related manner. Higher doses showed significant reduction in heart rate and blood pressure. The hypotensive effect was inhib­ ited in animals that were pretreated with atropine sulfate (1 mg/kg). This mechanism was done by the activation of muscarinic cholinergic receptors (Salahdeen et al., 2004). 54.3.4 HEPATOPROTECTIVE ACTIVITY Aerial parts of TP tested on d-Galactosamine/Lipopolysaccharide (d-GalN/ LPS) induced hepatitis in rats to test the hepatoprotective activity. Acute liver failure was induced by injection of D-GalN/LPS to the experimental rats. It

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causes fulminate hepatitis within 8 h after administration (Vilwanthan et al., 2005). Hepatic damages were studied by recording morphology, metabolic, histological, and biochemical parameter in acute and chronic animals. Leaf of TP ethanolic extract justified hepatoprotective action in the liver function and also chloroform insoluble fraction exhibited the same hepatoprotection activity (Saraf and Dixit, 1991). 54.3.5 ANTI-JUVENILE HORMONE ACTIVITY Topical application of fraction of petroleum ether extract of TP showed a better effect on the metamorphosis of Dysdercus and was found to be notable in generating abnormalities in adults due to juvenile hormone activity against laboratory colonized late fourth instars larvae and adult female mosquitoes. Petroleum ether extract of TP showed growth inhibitory and juvenile hormone mimicking activity to the treated larvae of Culex quinquefasciatus. Sterilant effect could not be seen, but loss of fecundity was observed in the treated mosquitoes. Larvae that were exposed to the Tridax procumbens extracts produced better than control in shortening of egg-rafts (Saxena et al., 1992). 54.3.6 ANTI-INFLAMMATORY ACTIVITY Tridax procumbens (TP) extracts significantly reduced parameters like exudates volume leukocyte migration, edema fluid, granuloma tissue, and γ-glutamyl transpeptidase, with these properties this plant is confirmed as good anti-inflammatory drug. TP has anti-inflammatory activity through inhibiting SRs and PGs, but it has a negligible ulcerogenic property (Diwan et al., 1989). The water extract of leaves of TP was studied on the excision wound model; rat skin fibroblast and rat paw edema. TP did not significantly increase the fibroblast compared with ibuprofen. The fibroblast cell count, hydroxy­ proline/DNA ratio collagen synthesis was insignificant in the control and TP treatment, while ibuprofen and aspirin treatment had a significant effect on the above-mentioned parameters. In the carrageenan-induced edema model, inhibition of edema was comparable in 200 mg/kg TP and 50 mg/kg ibuprofen treatment and the specific activity of the enzyme gamma glutamyl transpeptidase was comparable in the TP, ibuprofen, and aspirin at 200 mg/ kg (Margaret et al., 1998).

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The anti-inflammatory activity of TP was carried out on carrageenaninduced paw edema along with standard drug, ibuprofen (Awasthi et al., 2009). Anti-inflammatory activity of T. procumbens aerial parts could be in part due to the property of COX-1 and COX-2 enzyme inhibition and free radical scavenging activities; this may be the presence of flavonoids and other polyphenols in the extract (Sanjay et al., 2011). 54.3.7 ANTIDIABETIC ACTIVITY The hypoglycemic properties of TP were evaluated in normoglycemic and alloxan-diabetic rats with the ethanolic extract (TP-1) and its fraction. The blood sugar level was reduced by 10–17% in diabetic rats, but the same extract was shown no effect on fasted blood sugar level of the normal rats. Oral administration of T. procumbens improved both oral and intraperitoneal glucose tolerance of normoglycemic rats (Kalaya et al., 1997). Dried leaf water and petroleum ether (60–80°C) and alcoholic extracts of TP were experimented on hypoglycemic activity in wister rats (with 150–200 gm body weight). The result observed that water and alcoholic extracts were significantly reduced blood glucose levels in alloxan-induced diabetic rats (Bhagwat et al., 2008). In this experiment the drug was used for 7 days orally 200 mg/kg body weight. For testing anti-hyperglycemic potential of TP ethanolic extract was used, the result showed at 250–500 mg/kg body weight, a significant reduction in fasting blood glucose levels in diabetic rats compared with the standard drug glibenclamide (10 mg/kg body weight) (Hemant et al., 2009). Petchi et al. (2013) experimented on wister rats with ethanolic extract of whole plant (250 and 500 mg/kg body weight); significant antidiabetic and antihyperlipidemic activities were observed. In this experiment standard was glibenclamide (0.25 mg/kg, p.o.) and treated for 21 days. TP extract stopped streptozotocin­ induced weight loss and significantly altered the lipid levels. Another study determined that saponins from an ethanolic extract of TP contain antidiabetic properties and it inhibited the sodium glucose co-transporter-1 (S-GLUT-1) in the intestines of male Wistar albino rats (Petchi et al., 2013). 54.3.8 ANTIOXIDANT ACTIVITY The effect of the ethanolic extract of T. procumbens (chloroform insoluble frac­ tion) was investigated against D-galactosamine/lippopolysacharide (D-galn/

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LPS)-induced hepatitis in rats. Lipid peroxidation in experimental rats was increased by giving D-galn/LPS (300 mg/kg body weight). Then liver function was observed by measuring thiobarbituric acid activity. TP was very effective in alleviating the D-galn/LPS-induced oxidative stress suggesting its antioxi­ dant property (Viluvanthan et al., 2005). Fractions of methanolic extract from the aerial part were screened for antioxidant activity by the 1,1-diphenyl-2-pic­ rylhdrazyl (DPPH) method. The n-butanol and ethyl acetate fractions showed a considerable effect that is comparable to the activity of standard antioxidant ascorbic acid (Agrawal et al., 2009). The reducing ability was analyzed for TP antioxidant activity by using the DPPH assay and for total phenolics using the Folin-ciocalteu method. The ethanolic extract of TP showed antioxidant activity 96.70% which was higher than that of gallic acid (92.92) and ascorbic acid (94.81) which were used as standards. The total phenolic content of TP 12 mg/g is GAE (Gallic acid equivalent) (Habila et al., 2010). 54.3.9 ANTICANCEROUS ACTIVITY Anticancer activity of leaf and flower aqueous and acetone extract was tested on prostate epithelial cancerous cells PC3 by measuring cell viability by MTT [3-(4, 5-dimethyl–thiazole-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. The results showed that flower crude extract has anticancer activity (Priya et al., 2011). Compounds of TP were tested for cytotoxicity against human lung cancer by MTT assay. The aqueous extract compound of Rf value 0.66 showed 90% reduced cell viability. Techniques (NMR, MS, and IR spectra) were used to reveal the compound as lupeol. The anticancer activity of the lupeol tested against human lung cancer evaluated the result by colonogenic survival determination, cell cycle control, cell-based assay for the inhibition of COX-2 activity and DNA fragmentation analysis. The compound lupeol exhibited potential anticancer property at 320 μg/mL concentration (Sanka­ ranarayanan et al., 2013). In vitro anticancer activity of TP leaf extracts of aqueous, acetone, ethanol was evaluated on cancerous cell lines by using the tryphan blue dye exclusion assay and the MTT assay. The result was observed in all cells. The acetone and ethanol leaf extracts showed notable anticancer activity on A549 (human lung cancer cell line), HepG2 (human liver carcinoma cell line) (Priya and Rao, 2015). The hydrodistilled essential oil of TP contains a total of 18 components that were identified by GC-MS analysis. Those dibutyl phthalate (19.29%),

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Trans-(α)-caryophyllene (9.55%), biformeme (3.95%), p-cymen-7-ol (2.52%), and 1,8-cineole (2.44%) are major phytoconstituents. Other minor compounds are trans-α-bergamotol (1.78%), 2-α-pinene (1.62%), α-selinine (1.49%), caryophyllene oxide (1.39%), α-humulene (0.95%). Crude-obtained essential oil was tested against human breast cancer cell line (MCF-7) to test its anticancer activity by using MTT assay with different concentrations (18.5–300 μg/mL). The IC50 value of MCF-7 cell line was 96.6 μg/mL. This activity is due to the presence of terpenes in the oil (Poonkodi et al., 2017). 54.3.10 ANTITUBERCULOSIS ACTIVITY Phytochemical study and antitubercular potential of methanol: water (MW); ethanol: water (EW); dichloromethane: methanol (DM) extracts of Tridax procumbens (TP) was tested against H37Rv Mycobacterium tuberculosis using microplate alamar blue assay (MABA) method. The ethanol: water (EW) extracts of TP exhibited significant antituberculosis activity with the MIC values of 0.8, 6.25 μg/mL compared to standard drug pyrazinamide, ciprofloxacin, and treptomycin with the MIC values of 3.125–6.25 μg/mL using MABA respectively against Mycobacterium tuberculosis (H37 RV strain) ATCC 27294. This antitubercular activity is due to the presence of flavonoids, tannins, phenolic group (Bhagat and Kondawar, 2019). 54.3.11 ANTIBACTERIAL ACTIVITY The leaf methanolic extracts of TP showed antibacterial activity by using the disc diffusion method. The highest inhibition zone was observed in Salmo­ nella typhi, S. flexneri and least or minimum activity in E. coli (Muthusamy et al., 2013). The whole plant extract of TP showed antibacterial activity against Pseudomonas aeruginosa. The same disk method was used to test other strains of bacterial species like two gram positive (Bacillus subtilis and Staphylococus aureus) and two gram negative (Escherichia coli and Pseu­ domonas aeruginosa) (Mahato and Chaudhary, 2005). Antibacterial activity of aqueous extracts of TP was observed against Aeromonas hydrophilla and Bacillus cereus by Perumal et al. (1999). The n-hexane extract showed activity against 5 of the 12 tested bacteria, 1 (Mycobacterium smegmatis) of the 5 is Gram-positive bacteria and 4 (E. coli, Klebsiella sp., Salmonella group C, S. paratyphi) are Gram-negative bacteria. Only two microorganisms (Bacillus cereus, Klebsiella sp.) were sensitive to the ethyl acetate extracts. On the other hand, the extracts of aerial

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parts of n-hexane showed activity against E. coli and only 2 Gram-positive bacteria (Mycobacterium smegmatis, Staphylococcus aureus) with ethyl acetate extract (Taddei and Rosas-Romero, 2000). The n-hexane extract of the TP flowers was tested against E. coli, and the ethyl acetate extract was tested against Bacillus cereus and Klebsiella sp. (Taddei and Rosas-Romero, 2000). The same extract of aerial parts was tested against E. coli, Salmonella group and Salmonella paratyphi, Mycobecterium smegmatis and S. aureus (Taddei and Rosas-Romero, 2000). Dhanabalan et al. (2008) also studied aqueous and methanol extracts of T. procumbens against Staphylococcus aureus strains that cause bovine mastitis. The plant extracts showed inhibitory activity against the tested organism. Kumar and Naidu (2011) demonstrated antibacterial activity with different polar solvent extractions of leaf and whole plant of TP against different bacterial strains E. coli, Klebsiella pneumoniae, Proteus vulgaris, Bacillus subtilis, Staphylococcus aureus. The ethanolic and methanolic extracts of Tridax procumbens successfully control the Bacillus subtilis and Staphylococcus aureus. The MIC value also revealed that almost all tested bacterial strains were sensitive to the ethanolic and methanolic extracts. From the earlier studies (Nair et al., 2005) it is also revealed that the organic solvent extract is better than aqueous extracts. Staphylococcus aureus was the most susceptible bacteria among all the bacterial strains (Kumar and Naidu, 2011). The MIC values of S. aureus are 1.96, 2.30 and 2.06, 2.86 with whole plant ethanolic, methanolic and leaf ethanolic, methanolic extractions, respectively. In the same way MIC values are for B. subtilis 2.30, 3.60, and 3.16, 3.90; for P. vulgaris 16.2, 17.8 and 18.6, 19.5; K. pneumoniae 13.6, 14.0 and 14.6, 15.2; and E. coli 15.2, 15.9 and 16.8, 17.6. 54.3.12 ANTIPROTOZOAL ACTIVITY Hexane extract of Tridax procumbens was found active against trypomasti­ gotes (the flagellated stage of trypanosomes) with an IC90 (complete inhibi­ tion) 260.3 μg/mL (Berger et al., 1998) 54.3.13 MALARIAL VECTOR REPELLENCY The essential oils were separated by the steam distillation method from Tridax procumbens leaves evaluated as mosquito repellent against malaria vector Anopheles stephensi in mosquito cages. Essential oils were tested at

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three gradient concentrations (2%, 4%, and 6%). TP exhibited a considerable repellent effect at 6% concentration (Rajkumar and Jebanesan, 2007). 54.3.14 LEISHMANICIDAL ACTIVITY The TP whole plant methanol extracts were evaluated in an in vitro bioassay for leishmanicidal activity against Leishmania mexicana promastigotes (IC50 < 50 μg/mL) (Peraza-Sánchez et al., 2007). The extract showed good leishmanicidal activity at 50 μg/mL. 54.3.15 ANTIFUNGAL ACTIVITY Antifungal activity of T. procumbens has been investigated by using different fungal strains like Microsporum gypseum, Microsporum fulvum, Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Trichosporon beigelii following agar well diffusion assay (Policegoudra et al., 2014). The result clearly showed that the inhibition of all dermatophytes with zones of inhibition ranged from 17 to 25 mm by the methanol extract. Trichophyton mentagrophytes was less susceptible, whereas Candida albi­ cans was highly susceptible. The MIC for the same ranged from 1.6 to12.8 mg for all the test organisms. Among the test organisms, Trichosporon beigelii and Candida albicans were clearly inhibited at a low MIC of 1.6 mg each. The DCM (Dichloromethane) fraction also was more effective against Candida albicans with an MIC of 0.2 mg. The DCM fraction MIC values in all dermatophytic fungi ranged from 0.4 to 3.2 mg. The DCM fraction antifungal activity was due to the presence of major bioactive compounds like 9-octadecenoicacid ethyl ester, cholestane, hexadecanoic acid ethyl ester, and 9,12-octadecadienoic acid ethyl ester. The cumulative antifungal effect with compounds of TP other than the above four may also play an important role in antifungal activity (Policegoudra et al., 2014). The oily, viscous dichloromethane (DCM) fraction showed more antifungal activity against all the test organisms like C. albicans with 32 mm of inhibition zone, and less effective against M. fulvum and T. rubrum. The antifungal activity of TP might be due to phenols, flavonoids, sterols, saponins, and fatty acids as reported earlier (Manjamalai et al., 2010). The bioactive compounds like 8,3′-dihydroxy-3,7,4′-trimethoxy-6-O-βd-glucopyranosylflavones, 6,8,3′-trihydroxy-3,7,4′-trimethoxyflavone, puerarin, esculetin, oleanolic acid, betulinic acid, centaurein, bergenin, and

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centaureidin also have antifungal activity (Xu et al., 2010; Jachak et al., 2011). Jindal and Kumar (2013) evaluated the antifungal potential of alkaloids and flavonoids of root, stem, leaf, and flower of T. procumbens against two pathogenic fungal strains (Aspergillus flavus and A. niger). MIC, MFC, and total activity were also evaluated for the determination of antifungal potential of each active extract. Remarkable activity against A. niger was observed by the flavonoid but not alkaloid in both the test fungi. Excellent antifungal potential was recorded for free flavonoid of TP stem (IZ 12 mm, AI 1.2, with same MIC and MFC 0.156 mg/mL), bound flavonoid of TP stem (IZ 10 mm, AI 1, MIC 0.312, and MFC 0.625 mg/mL) and flower of TP (IZ 10.2 mm, AI 1.02, with same MIC and MFC 0.312 mg/mL) against A. niger. 54.3.16 INSECTICIDAL ACTIVITY The essential oils isolated from Tridax procumbens (TP) exhibited insecti­ cidal activities against house flies, mosquito larvae, Dysdercus similes, and cockroaches. Essential oils of TP are highly potent, exhibit strong insect repellent activity, when tested against three varieties of ants. It was observed during the collection of TP that the plant is neither attacked by insects nor grazed by cattle, suggesting that the plants possess insect repellent or insec­ ticidal activity (Pathak and Dixit, 1988). KEYWORDS • • • • • •

Tridax procumbens Asteraceae medicinally important secondary metabolites tannins flavonoids

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Jhariya, S.; Rai, G.; Yadav, A. K.; Jain, A. P.; Lodhi, S. Protective Effects of Tridax procumbens Linn. Leaves on Experimentally Induced Gastric Ulcers in Rats. J. Herbs Spices Med. Plant. 2015, 21 (3), 308–320. DOI: https://doi.org/10.1080/10496475.2014.973083. Jindal, A.; Kumar, P. Antimicrobial Activity of Alkaloids of Tridax procumbens L. Against Human Pathogens. Int. J. Pharm. Sci. Res. 2012, 3 (9), 3481–3485. Jindal, A.; Kumar, P. In Vitro Antifungal Potential of Tridax procumbens L. Against

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Policegoudra, R. S.; Chattopadhyay, P.; Aradhya, S. M.; Shivaswamy, R.; Sing, L.; Veer, V. Inhibitory Effect of Tridax procumbens Against Human Skin Pathogens. J. Herb. Med. 2014, 4 (2), 83–88. DOI: https://doi.org/10.1016/j.hermed.2014.01.004. Poonkodi, K.; Jayapriya, V.; Sujitha, K.; et al. In-Vitro Anticancer Activity and Essential Oil Composition of Tridax procumbens L. Am. J. Pharm. Tech Res. 2017, 7 (2), 366–371. Priya, V. P.; Radhika, K.; Rao, S. A. In Vitro Anti-Cancer Activity of Aqueous and Acetone Extracts of Tridaxprocumbens Leaf on PC 3 Cell Lines. Int. J. Pharm. Pharm. Sci. 2011, 3 (4), 1–4. Priya, V. P.; Rao, S. A. Evaluation of Anticancer Activity of Tridax procumbens Leaf Extracts on A549 and HEP G2 Cell Lines. Asian J. Pharm. Clin. Res. 2015, 8 (3), 129–132. Rajkumar, S.; Jebanesan, A. Repellent Activity of Selected Plant Essential Oils Against the Malarial Fever Mosquito Anopheles stephensi. Trop. Biomed. 2007, 24 (2), 71–75. Raju, T. S.; Davidson, E. A. Structural Feature of Water Soluble Novel Polysaccharide Components from Leaves of Tridax procumbens Linn. Carbohydr. Res. 1994, 258, 243–254. Sailaja, B.; Gharathi, K.; Prasad, K. V. S. R. G. Role of Tridax procumbens Linn. In the Management of Experimentally Induced Urinary Calculi and Oxidative Stress in Rats. Indian J. Nat. Prod. Resour. 2012, 3 (4), 535–540. Salahdeen, H. M.; Yemitan, O. K.; Alada, A. R. A. Effect of Aqueous Leaf Extract of Tridax Procumbens on Blood Pressure and Heart Rate in Rats. Afr. J. Biomed. Res. 2004, 7 (1), 27–29. Samantha, B.; Heather, M.; Toma, T.; Esli-Armando, C. J.; Olga R. K. A Review of Medicinal Uses and Pharmacological Activities of Tridax procumbens (L.). J. Plant Stud. 2018, 7 (1), 19–35. Sanjay, M. J.; Raju, G.; Selvem, C.; Himanshu, M.; Amit, S.; Taj, K. Anti-Inflammatory, Cyclooxygenase Inhibitory and Antioxidant Activities of Standardized Extracts of Tridax procumbens. Fitoterapia 2011, 82 (2), 173–177. DOI: 10.1016/j.fitote.2010.08.016. Sankaranarayanan, S.; Bama, P.; Sathyabama, S.; Bhuvaneswari, N. Anticancer Compound Isolated from the Leaves of Tridax procumbens Against Human Lung Cancer Cell A-549. Asian J. Pharm. Clin. Res. 2013, 6 (2), 91–96. Saraf, S.; Dixit, V. K.; Hepatoprotective Activity of Tridax procumbens Part II. Fitoterapia 1991, 62, 534–536. Sawant, R.; Godghate, A. Preliminary Phytochemical Analysis of Leaves of Tridax procumbens Linn. Int. J. Sci. Environ. Technol. 2013, 2 (3), 388–394. Saxena, R. C.; Dixit, O. P.; Sukumaran, P. Laboratory Assessment of Indigenous Plant Extracts for Anti-Juvenile Hormone Activity in Culex quinquefasciatus. Indian J. Med. Res. 1992, 95, 204–206. Saxena, V. K.; Albert, S. β-Sitosterol-3-O-β-D-Xylopyranoside from the Flowers of Tridax procumbens Linn. J. Chem. Sci. 2005, 117 (3), 263–266. Singh, K.; Ahirwar, V. Acute and Chronic Toxicity Study of Tridax procumbens on Haemoglobin Percent and Blood Sugar Level of Sprague Dawley Rats. IJPIs J. Pharm. Toxicol. 2010, 1 (1), 1–6. Sreeramulu, N.; Sateesh, S.; Ragan, A.; Raju, V. S. Ethno-Botanico-Medicine for Common Human Ailments in Nalgonda and Warangal Districts of Telangana, Andhra Pradesh, India. Ann. Plant Sci. 2013, 02 (07), 220–229. Subramanian, S. S.; Ramakrishnan, S.; Nair, A. G. R. Isolation of Luteolin and Glucolutyeolin from the Flowers of Tridax procumbens. Curr. Sci. 1968, 37, 465–469.

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Taddei, A.; Rosas-Romero, A. J. Bioactivity Studies of Extracts from Tridax procumbens. Phytomedicine 2000, 7 (3), 235–238. Udupa, S. L.; Udupa, A. L.; Kulkarni, D. R. Influence of Tridax procumbens on Dead Space Wound Healing. Fitoterapia 1991, 62 (2), 146–150. Verma, R. K.; Gupta, M. Lipid Constituents of Tridax procumbens. Phytochemistry 1988, 27 (2), 459–463. DOI: https://doi.org/10.1016/0031-9422(88)83120-0. Verma, R. K.; Gupta, M. M. Lipid Constituents of Tridax procumbens. Indian Drugs 2004, 30 (2), 64–69. Viluvanthan, R.; Kanchi, S. S.; Thiruvengadam, D. Effect of Tridax procumbens on Liver Antioxidant Defence System During Lipopolysaccharide-Induced Hepatitis in D-Galactosomine Senitized Rats. Mol. Cell. Biochem. 2005, 269, 131–136. Vilwanthan, R.; Shivshangari, K. S.; Devak, T. Hepatoprotective Activity of Tridax procumbens Against D-galactosamine/Lipopolysaccharide-Induced Hepatitis in Rats. J. Ethnopharmacol. 2005, 101 (1–3), 55–60. Xu, R.; Zhang, J.; Yuan, K. Two Flavones from Tridax Procumbens Linn. Molecules 2010, 15, 6357–6364. DOI: 10.3390/molecules15096357. Yadava, R. N.; Saurabh, K. A New Flavone Glycoside: 5,7,4′-Trihydroxy-6, 3′-DimethoxyFlavone 5-O-Alpha-Lrhamnopyranoside from the Leaves Tridax procumbens Linn. J. Asian Nat. Prod. Res. 1998, 1 (2), 147–152. DOI: 10.1080/10286029808039857.

CHAPTER 55

Bioactives and Their Biological Potentialities of Wild Cinnamon [Cinnamomum malabatrum (Burm.f.) J.Presl (Lauraceae)] SARANYA SURENDRAN1, CHANDRA PRABHA AYYATHURAI2, and RAJU RAMASUBBU1* 1Department

of Biology, The Gandhigram Rural Institute (Deemed to be University), Gandhigram, Dindigul, Tamil Nadu, India

2Department

of Botany, G.T.N. College, Dindigul, Tamil Nadu, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Cinnamomum malabatrum, popularly known as wild cinnamon, belongs to one of the most medicinally active genera Cinnamomum of the family Laura­ ceae. Cinnamomum malabatrum leaves are used as aromatic and for medicinal and culinary purposes. Further, several medicinal properties such as treating wounds, intestinal worms, fevers, menstrual problems, and headaches were reported. This review aimed to illustrate the phytochemical and pharmaco­ logical aspects of C. malabatrum obtained from several scientific databases such as Scopus, Science Direct, Google Scholar, Elsevier, and Pubmed. Several studies have been attempted to isolate phytoconstituents such as (E)-caryo­ phyllene, α-humulene, spathulenol, benzyl benzoate, (E)-Cinnamyl acetate, globulol, linalool, β-Phellandrene, bicyclogermacrene, α-pinene, δ-cadinene, epiglobulol, alloaromadendrene, eugenol, germacrene, ocimene, benzyl acetate, 3,4′,5,7 tetra hydroxy flavones, quercetin 3-O-rutin, myristaldehyde, Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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geraniol, linalool, hexadecanoic acid methyl ester, 5-benzyloxy-4- butyl-2­ methyl-2-nonene. The pharmacological effects of various phytoconstituents were also reported to possess antioxidant, antibacterial, hyperlipidemic, antiinflammatory, and anticancer activity along with immunomodulatory effects. 55.1 INTRODUCTION Plants are the primary source of medicine used to treat numerous human diseases from thousands of years ago. Plants contain thousands of secondary metabolites that possess various biological potentialities and hence act as templates for developing novel drugs. Cinnamomum malabatrum is a tall evergreen tree, grows up to 15 m (Kumar et al., 2012). The leaves of C. malabatrum have been harvested from the wild for local use and sold as an adulterant in markets under the name of C. tamala due to their strong resemblance. Cinnamomum malabatrum was previously known as C. mala­ bathricum Lukman., C. ochraceum Blume, and C. rheedii Lukman. Cinna­ momum is reported with extensive usage to treat a wide array of diseases in various traditional systems of medicine, including the Indian and traditional Chinese systems of medicine. Of the 300 species of Cinnamomum reported detailed studies were carried out in only 40 species (Balijepalli et al., 2017). The bark of C. malabatrum was used as carminative, antispasmodic, hemo­ static, astringent, antiseptic, stomachic, germicidal, stimulant, carminative, hemostatic, astringent, diaphoretic, deobstruent, and galactagogue. The bark was also used to treat cough, diarrhea, dyspepsia, flatulence, vomiting, and dysentery. For rheumatism oil was extracted from the root bark and leaves were applied externally. Spicy leaves and bark are substituted/adulter­ ated for the commercial C. zeylanicum. The leaves of C. malabatrum are carminatives and used in colic and rheumatism. The leaves were reported as sweetish, heating, useful in Vata, scabies, disease of the anus and rectum, tridosha, piles, and heart troubles. Dried flower buds are used to cure cough and urinary infections (Agrawal et al., 2013). C. malabatrum is also useful for treating wounds, fevers, intestinal worms, headaches, and menstrual problems (Maridass, 2009.) 55.2 BIOACTIVES Leela et al. (2009) analyzed the chemical composition of essential oils isolated from aerial parts leaf, petiole, shoot, and terminal shoot of C. mala­ batrum using GC and GC–MS. Thirty-nine compounds, consisting of 54%

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sesquiterpenes, 27% esters, and 11% monoterpenes, were identified from the leaf essential oil. (E)-caryophyllene (28.6%) and bicyclogermacrene (14.4%), were the major sesquiterpenes and α-humulene, globulol, and spathulenol were the minor sesquiterpenes. The other constituents of the leaf oil were benzyl benzoate (8.5%), bicyclogermacrene (14.4%), (E)-cinnamyl acetate (15.1%), and (E)-caryophyllene (28.6%). (E)-Cinnamyl acetate (15.1%) and benzyl benzoate (8.5%) were the chief esters, whereas β-Phellandrene, α-pinene, and linalool were represented as prominent monoterpenes. Twenty-eight compounds were identified from the essential oil of petioles and shoots, whereas the terminal shoot oil comprises 34 compounds. The linalool dominates the essential oils obtained from petioles, shoots, and terminal shoots (77.8−79.4%). The sesquiterpene concentration increases from petiole to shoots; similarly, the ester content gradually decreased from leaf to shoot. Compared to the leaf oil, the petiole oil contained higher levels of monoterpenes and lower levels of esters and sesquiterpenes. Kumar et al. (2012) analyzed the chemical composition of the leaf essential oil of C. malabatrum sold as Tamalapatra which was recognized as a highly reputed commodity in the drug and spice trade. The compounds detected by GC-MS of C. malabatrum leaf volatile oil were spathulenol (13.88), epiglobulol (4.95%), δ-cadinene (4.33%), linalool (17.80%), alloaromadendrene (7.42%), α-humulene (2.96%), eugenol (3.70%), bicyclo­ germacrene (18.23%), germacrene (9.50%), trans-caryophyllene (14.38%). Cinnamomum malabatrum can be differentiated from C. tamala using physi­ cochemical and volatile oil composition as markers. Water-soluble ash was recorded as 1.31% for C. tamala , whereas in C. malabatrum, it was 0.45%. N-hexane-soluble matter of C. tamala was 1.91%, but it was 0.65% for C. malabatrum. Aravind et al. (2012) investigated the phenolic content of different solvent extracts of C. malabatrum leaves. Preliminary phytochemical screening of three extracts detected the presence of phenolics and flavonoids in large amounts. The total phenolic content was determined by the Folin-ciocalteu method for n-Hexane (μg/mL), alcoholic (56.00 μg/mL), and aqueous (29.2 μg/mL) extracts and flavonoid content was determined by the aluminum chloride colorimetric method for n-hexane (10.26 μg/mL), alcoholic (44.21 μg/mL), and aqueous (24.48 μg/mL) extracts. Aravind et al. (2013) isolated the phytocompounds from the fresh leaves of C. malabatrum by successive solvent extraction. A preliminary phyto­ chemical screening of the leaf and bark extract of the young tree showed the presence of phenolics, flavonoids, lignins, terpenes and terpenoids, plant

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acids, phytosterols, etc. The leaves were reported to contain various chemical constituents like β-caryophyllene, camphor, α-terpinol, γ-terpinene, eugenol, cadinene, cinnamic aldehyde, ocimene, limonene, geraniol, benzyl cinna­ mate, β-phellandrene, benzaldehyde, benzyl acetate, and eugenol acetate. Cinnamaldehyde (70–85%) was identified as an important constituent of bark oil along with 3,4′,5,7 tetra hydroxy flavones, 3,3′,4′,5,7-pentahydroxy flavones, kaempferol-3-O-sophoroside, and quercetin 3-O-rutin. Preliminary phytochemical studies on different extracts (petroleum ether, chloroform, acetone, alcohol (95%) and aqueous extracts showed the presence of certain phytochemicals like flavonoids, fixed oil, amino acids, tannins, and phytosterols. The phytochemical screening of C. malabatrum was reported by Natarajan et al. (2014), and the study indicated the presence of many phytocomponents that are responsible for its antioxidant and hypolipidemic activity. Aravind et al. (2014) accomplished the studies on GC-MS analysis of the bark essential oil of C. malabatrum. The bark, leaf, and berries were reported as aromatic due to the presence of volatile oils. GC-MS analysis of the bark oils resulted to identify about 61 phytocomponents (98.3% of total constituents). The major constituents were limonene (6.91%), linalool (68.21%), camphene (1.59%), geraniol (2.11%), eugenol (1.39%), myristaldehyde (2.69%), and linalool, an acyclic monoterpenoid. Therefore, the bark oil of C. malabatrum was a good source of linalool exhibiting several biological activities. Anil et al. (2018) carried out the GC-MS analysis of C. malabatrum essential oil and identified nine compounds. The major constituents of the oil were 5-benzyloxy-4-butyl-2methyl-2-nonene (17.26%), hexadecanoic acid methyl ester (16.48%), and 1-deoxy-D-ribitol. Structures of Bioactive compounds in Cinnamomum malabatrum

(Continued)

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55.3.1 ANTIOXIDANT ACTIVITY Kumar et al. (2010) reported the antioxidant potentiality of essential oil and aqueous extract by using DPPH. The IC50 value for the aqueous extract was 770 µg/mL and the essential oil was 1700 μg/mL. The free radical scavenging activity of the aqueous extract was much higher than the standard, whereas the scavenging activity of essential oil was comparatively very less. The total phenolic content in gallic acid equivalent was found to be 0.0324 mg/g in aqueous extract. The total flavonoids of aqueous extract in mg/g quercetin were found to be 0.0825 mg/g. Aravind et al. (2012) determined the presence of phenolic compounds in C. malabatrum leaf extracts (n-hexane, alcoholic, and aqueous extracts), which indicated the antioxidant activity. The antioxidant activity was analyzed by nitric oxide radical inhibition assay, hydrogen peroxide radical scavenging assay, and β-carotene linoleic acid emulsion method. The percentage of inhibition exhibited from the different concentrations of extracts was comparable with the percentage of inhibition obtained by the standard. The alcoholic extract has comparatively good nitric oxide scav­ enging ability when compared with other extracts. The alcoholic extract has exhibited comparatively higher nitric oxide, hydrogen peroxide, and lipid peroxide scavenging abilities. Natarajan et al. (2014) reported that C. malabatrum leaf extract resulted in a significant increase in the antioxidant enzyme activities and GSH contents in the liver and heart homogenate. Anil et al. (2018) reported the DPPH free radical scavenging activities at different concentrations of methanolic extract of C. malabatrum. As the concentration of extracts has increased from 25 to 400 μg/mL, the DPPH radical scavenging activity was also increased. Higher DPPH radical scavenging activity was observed at a concentration of 400 μg/mL, which was not highly different from that of the positive control. This finding was supported by a similar result reported by Kumar et al. (2010) where the DPPH radical scavenging activity was increased in a concentration-dependent manner. Anil et al. (2018) carried out molecular docking and in vitro studies on antioxidant activities of C. malabatrum with tyrosinase as an antioxidant receptor. DPPH antioxidant assay with methanol extract of cinnamon leaves showed higher activity at concentrations ranging from 100 to 400 µg/mL. Docking studies showed that 1-deoxy-D-ribitol was found to be a potent

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inhibitor of tyrosinase receptor since it has exhibited minimum free energy (−1.17 kcal/mol) and an inhibition constant (139.82 mM) and strongly docked using 8 hydrogen bond formations with 6 amino acid residues at the active site. 55.3.2 ANTIBACTERIAL ACTIVITY Kumar et al. (2010) reported that the essential oil of C. malabatrum has shown considerable bacterial activity against Staphylococcus aureus, Escherichia coli, Salmonella typhi, Pseudomonas aeruginosa, Bacillus cereus. Anil et al. (2018) have reported the antibacterial activity of C. malabatrum essen­ tial oil and crude extracts through various bacterial strains. The maximum inhibitory effect of essential oil and methanol extract was recorded against Streptococcus and Lactobacillus lactis with a zone of 2 cm. Acetone extract has exhibited little inhibitory effect against Mycobacterium tuberculosis and no activity was observed against Salmonella typhi, Lactobacillus plantarum, Escherichia coli, and Enterobacter aerogenes. Anil et al. (2018) carried out the docking and in vitro studies on antibacterial properties of C. malabatrum with tyrosinase, an antioxidant receptor. Comparative analysis revealed that the methanol extract and the essential oil of C. malabatrum exhibited the highest antibacterial activity against Streptococcus pyogenes with an inhibi­ tion zone of 2 cm. 55.3.3 HYPERLIPIDEMIC ACTIVITY Natarajan et al. (2014) have reported the reduction of elevated levels of lipids in the blood and thus reduce the risk factors responsible for developing ischemic heart disease cardiovascular or cerebrovascular diseases using ethanolic extract of C. malabatrum leaves on hyperlipidemic rats. The plant extract has shown a significant decrease in levels of TC, TG, LDL, VLDL and a significant increase in HDL cholesterol. They also reduced the athero­ genic index (A.I) and LDL/HDL ratio when compared to the hyperlipidemic control group. Atorvastatin and C. malabatrum leaf extract have resulted in a significant increase in the antioxidant enzyme activities and GSH contents in the liver and heart homogenate. Alcoholic extract of C. malabatrum has exhibited a significant increase in HMG Co-A/mevalonate ratio in the liver when compared to the normal group.

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55.3.4 ANTI-INFLAMMATORY ACTIVITY Aravind et al. (2013) investigated the anti-inflammatory activity of leaves of C. malabatrum alcoholic extract by the carrageenan-induced rat paw edema model using Plethysmometer and male Wistar albino rats. Signifi­ cant anti-inflammatory activity was observed by alcoholic extract, whereas ethanolic extract (250 mg/kg) has exhibited maximum dose-dependent antiinflammatory activity. 55.3.5 ANTICANCER ACTIVITY Agrawal et al. (2013) found out a new potent, nontoxic, minimal toxic anticancer drug from C. malabatrum and investigated its anticancer activity. The leaf powder of C. malabatrum was successively extracted with petro­ leum ether, chloroform, acetone, ethyl alcohol, and water. The preliminary phytochemical tests were carried out to determine the phytocompound and LD50 values for both alcohol and aqueous extract. The study demonstrated that the aqueous extract exhibited significant dose-dependent anticancer activity. The alcoholic and aqueous extract showed a significant decrease in solid tumor volume, an increase in peritoneal cell count and body weight compared to the tumor control group. Packiaraj et al. (2016) evaluated the cytotoxicity of Colletotrichum gloeosporioides CMS 3, using three cell lines (HeLa, MCF-7, and MG63), which showed reasonable activity against cell lines. MCF-7 has more sensi­ tivity to crude extract than HeLa and MG63 cell lines. Anil et al. (2018) analyzed the cytotoxicity of C. malabatrum essential oil against L929 cells that appeared to be active at the concentration from 50 to 400 μg/mL. The essential oil has shown the highest cytotoxic activity (77.33 + 0.629%) compared to other extracts. The current observations showed a dose-dependent cytotoxic activity in the extracts on L929 cells which exhibited 77.33 + 0.629% cytotoxic activity to L929 cell lines at the dose of 400 µg/mL. 55.3.6

IMMUNOMODULATORY EFFECTS

George and Veena (2018) evaluated the immunomodulatory effect of C. malabatrum ethanolic extract in cell-mediated immunity and analyzed the in vitro efficacy. The animals were treated with the ethanolic extract (2000 mg/

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kg/p.o.) exhibiting normal behavior without any sign of passivity, stereotypy, and vocalization. The in vitro effects of the extract were measured by the cell proliferation method followed by the MTT assay using murine macrophage cell line stimulated by lipopolysaccharide (LPS). The ethanolic extract (2000 mg/kg body weight) has not produced any behavioral abnormalities and mortality. Anil et al. (2018) carried out a molecular docking study on C. mala­ batrum leaf essential oil in which immunomodulatory effects 1-deoxy-D­ ribitol bind strongly to tyrosinase by forming 8 H-bond interaction with six amino acids (Asn-243, His-251, Ala-246, Val-38, Met-319, Arg-321) of tyrosinase. 1-deoxy-D-ribitol has shown good interaction with least binding energy and inhibition constant showing compound inhibits the protein well. These computational studies showed that the ligands 1-deoxy-D-ribitol and hexadecanoic acid could interfere with the target protein and further studies are needed to characterize and reveal its toxicity profile. KEYWORDS • • • •

Cinnamomum Lauraceae essential oil antioxidant

•

antimicrobial

REFERENCES Agarwal, S. K.; Chipa, R. C.; Samantha Suresh, K. C. Anticancer Activity of Cinnamomum malabatrum Burm. on Cholesterol Diet-Induced Rats. Int. J. Res. Pharmacol. Pharmacother. 2013, 2, 314–319. Anil, M. A.; Bency, J, B.; Helen, M. P. A.; Rani, S. D. Y. Docking and In Vitro Studies on Antioxidant, Antibacterial and Cytotoxic Properties of Cinnamon (Cinnamomum malabatrum). Int. J. Res. Anal. Rev. 2018, 4 (5), 66–72. Aravind, R.; Aneesh, T. P.; Bindu, A. R.; Bindu, K. Estimation of Phenolics and Evaluation of Antioxidant Activity of Cinnamomum malabatrum (Burm.f). Blume. Asian J. Res. Chem. 2012, 5 (5), 628–632. Aravind, R.; Bindu A. R.; Bindu K.; Alexeyena V. GC-MS Analysis of the Bark Essential Oil of Cinnamomum malabatrum (Burm. f.) Blume. Res. J. Pharm. Tech. 2014, 7 (7), 754–759.

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Aravind, R.; Bindu, A. R.; Bindu, K.; Kanthlal, S.; Anilkumar, B. Anti-Inflammatory Evaluation of the Cinnamomum malabatrum (Burm. f.) Blume Leaves Using Carrageenan Induced Rat Paw Oedema Method. Res. J. Pharm. Tech. 2013, 6 (7), 746–748. Balijepalli, M. K.; Buru, A. S.; Raghavendra, S.; Pichika, M. R. Cinnamomum Genus: A Review on Its Biological Activities. Int. J. Pharm. Pharm. Sci. 2017, 9 (2), 1–11. George, S.; Veena, R. In Vitro and In Vivo Studies of the Immunomodulatory Effect of Cinnamomum malabatrum on Female Wistar Rats. World J. Pharm. Res. 2018, 18 (7), 867–877. Kumar, H. B.; Basheer, S.; Haseena. Antioxidant Potential and Antimicrobial Activity of Cinnamomum malabatrum (Batka). Orient. J. Chem.2010, 26 (4), 1449–1453. Kumar, S. N. K.; Rajalekshmi, M.; Sangeetha, B.; Ravishankar, B.; Muralidhar, R. Chemical Examination of Leaves of Cinnamomum malabatrum (Burm. f.) Blume Sold as Tamalapatra. Phcog. J. 2012, 31 (4), 11–15. Leela, N. K.; Vipin, T. M.; Shafeekh, K. M.; Priyanka, V.; Rema, J. Chemical Composition of Essential Oils from Aerial Parts of Cinnamomum malabatrum (Burman f.) Bercht & Presl. Flavour Fragr. J. 2009, 24, 13–16. Maridass, M. Hepatoprotective Activity of Barks Extract of Six Cinnamomum Species on Carbon Tetrachloride-Induced in Albino Rats. Folia Med. Indones. 2009, 45(3), 204–207. Natarajan, P.; John, S.; Thangathirupathi, A.; Kala, R. Antihyperlipidemic Activity of Alcoholic Extract of Cinnamomum malabatrum Burm. on Cholesterol Diet Induced Rats. World J. Pharm. Res. 2014, 6 (3), 1599–1615. Packiaraj, R.; Jeyakumar, S.; Ayyappan, N.; Adhirajan, N.; Premkumar, G.; Rajarathinam, K.; Muthuramkumar, S. Antimicrobial and Cytotoxic Activities of Endophytic Fungus Colletotrichum gloeosporioides Isolated from Endemic Tree Cinnamomum malabatrum. Stud. Fungi. 2016, 1 (1), 104–113.

CHAPTER 56

Therapeutic Potential and Bioactives of Amaranthus spinosus L. VRUSHALI MANOJ HADKAR1, KALLIPUDI CHARISHMA REDDY2, and CHINNADURAI IMMANUEL SELVARAJ1* 1School

of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India

2School

of Agricultural Innovations and Advanced Learning, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Amaranthus spinosus L. is a medicinal plant that belongs to the family Amaranthaceae. The plant is commonly known as “Prickly Amaranthus”. A. spinosus extracts have been utilized in classical Nepalese, Indian, Thai, and Chinese practitioners to manage various ailments, including gynaeco­ logical conditions, urinary infections, pain, diarrhoea, diabetes, respiratory disorders, and diuretic. The leaves, stems and root of A. spinosus contains α-spinasterol, hentriacontane, and octacosanoate. The plant has bioactive compounds like 7-p-coumaroyl apigenin 4-O-beta-D-glucopyranoside, xylofuranosyl uracil, a coumaroyl flavone glycoside known as spinoside, beta-D-ribofuranosyl adenine, beta-sitosterol glucoside, quercetin, hydroxy­ cinnamates and kaempferol glycosides. The leaves of A. spinosus contain a large amount of oxalic acid. The seeds contain a very high concentration of squalene. A. spinosus oil has high tocotrienols in higher concentration, which is a rare form of vitamin E. The plant has some other phytoconstitu­ ents like lignan glycoside, amaranthoside, amaricin, coumaroyl adenosine, Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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and betaines trigonelline, stigmasterol glycoside, and glycine betaine. The plant has antiviral, antiproliferative, antimicrobial, neuroprotective, anti­ depressant, hepatoprotective, anti-hyperglycaemic, anti-hyperlipidaemic, cardioprotective, antinociceptive, anti-inflammatory, immunomodulatory, analgesic and antipyretic characteristics. 56.1

INTRODUCTION

Amaranthus spinosus L. is a medicinal plant that belongs to the family Amaranthaceae. The plant is commonly known as “dhuti ghans” or “ban lure” in Nepali, “prickly amaranthus” in English and Hindi-Tanduliyah (Khanal et al., 2015). A. spinosus is also widely distributed in Asia’s entire tropics and warm temperate regions from Japan, Indonesia, India, Bangla­ desh, and the Pacific Islands, and Australia (Mishra et al., 2012). A. spinosus is an annual and perennial herb that grows erect up to 100–130 cm tall. It is a much-branched monoecious herb having a purplish stem. Leaves of A. spinosus are alternate and stacked, simple without any stipules, and the petiole is as long as the leaf blade (Ganjare and Raut, 2019). Tamangs of Kathmandu valley consume the young leaves as a vegetable. Root and leaf decoction is taken to cure the intestinal ailment at Kathmandu valley. Root extract is taken in the morning to treat burning urination. It is consumed with warm water before leaving to bed to break and disintegrate kidney stones and pass it out during urination. In interior regions of Nepal, young leaves are cooked and eaten as a vegetable (Zheng and Wang, 2001; Khanal et al., 2015). Root paste is applied on boils to discharge pus, and root extract is prescribed for fever. Mashed plant and roots are applied to rheumatic areas, skin infections and wounds in the eastern parts of Nepal. The extract of roots with hot water is consumed orally by the Satars (an inherent people in the Terai region of Nepal) of Jhapa and Morang districts to arrest excessive bleeding during the first post-delivery stage (Govindarajan et al., 2005). A. spinosus extracts have been utilized in classical Nepalese, Indian, Thai, and Chinese practitioners to manage various ailments, including gyne­ cological conditions, urinary infections, pain, diarrhea, diabetes, respiratory disorders, and diuretic (Baral et al., 2011; Agra et al., 2008; Kirtikar and Basu, 2001). In India, Paharia and Santhali and tribes of eastern Bihar use the root extract of A. spinosus as a vermicide. At the same time, a hydroinfusion of the plant is used to treat persistent diarrhea in southern parts of

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Orissa (Zeashan et al., 2009b). Few tribes utilize A. spinosus to provoke abortion. Tribes of Kerala use the extract of A. spinosus to prevent swelling nearby stomach, whereas leaves are cooked without salt and eaten for 3–4 days to treat jaundice (Hema et al., 2006). However, antiviral, anticancer, neuroprotective, hepatoprotective, antidiabetic, cardioprotective character­ istics of Amaranthus with pertinence to the modern global health scenario are currently in the attention (Peter and Gandhi, 2017). The approximate composition of A. spinosus plant (leaf and stem) consists of carbohydrates, moisture content, ash, fat, protein, crude fiber and calorific value as 8.7, 84, 6.8, 1.4, 3.6, 0.6 and 62 percentages respectively. The nutritive value of A. spinosus plant is reported to possess 248, 4.5, 7.6, 13.1, 6.5, and 46.2 mg of Ca, Mg, K, Fe, Na, and carotene respectively (Ogwu and Chidozie, 2020). 56.2 BIOACTIVES A. spinosus contains numerous active phytoconstituents viz, alkaloids, amino acids, flavonoids, lipids, phenolic acids, saponins, terpenoids, glycosides, steroids, catechuic tannins, betalains, and carotenoids (Mathur et al., 2010). An exclusive study on A. spinosus reported major phytochemicals, such as alkaloids, terpenes, glycosides, and sugars found in the roots (Jhade et al., 2011). It has also shown other bioactive compounds like 7-p-coumaroyl apigenin 4-O-beta-D-glucopyranoside, xylofuranosyl uracil, a coumaroyl flavone glycoside known as spinoside, beta-D-ribofuranosyl adenine, beta­ sitosterol glucoside, quercetin, hydroxycinnamates and kaempferol glyco­ sides. Other phytoconstituents, such as betalains, betaxanthin, betacyanin, amaranthine, and isoamaranthine were reported. Bioactive compounds, such as gomphrenin, stigmasterol, betanin, linoleic acid, rutin, and beta-carotene were found to be present (Odhav et al., 2007). The leaves stems and root of A. spinosus contains α-spinasterol, hentriacontane, and octacosanoate (Chandrashekhar, 2018). The leaves of A. spinosus contain a large amount of oxalic acid. The seeds contain a very high concentration of squalene. A. spinosus oil has high tocotrienols in higher concentration, which is a rare form of vitamin E. The plant has some other phytoconstituents, such as lignan glycoside, amaranthoside, amaricin, coumaroyl adenosine, and betaines trigonelline, stigmasterol glycoside, and glycine betaine (Jamaluddin et al., 2011). The structures of some important compounds of A. spinosus are given in Figure 56.1.

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FIGURE 56.1 Structures of compounds present in Amaranthus spinosus. Gallic acid (1), vanillic acid (2), syringic acid (3), P-coumaric acid (4), ferulic acid (5), protocatechuic acid (6), caffeic acid (7), sinapic acid (8), salicylic acid (9), rutin (10), isoquercetin (11), quercetin (12), p-hydroxybenzoic acid (13), nicotiflorin (14), and vitexin (15); [Marvin 17.21.0, ChemAxon tool was used for drawing chemical structures].

56.3

PHARMACOLOGY

56.3.1 GENOTOXIC AND ANTIGENOTOXIC ACTIVITY In general, medicinal plants comprise many bioactive compounds that can reverse or act to block metastasis at early stages. Higher plants like angio­ sperms find their broader use in traditional medicines frequently analyzed for their prominent role in accentuating environmental genotoxicants’ action (Sreeranjini and Siril, 2011). A study of genotoxic and antigenotoxic activities of A. spinosus on A. cepa root tip cells reported that the root tips, when treated with higher concentrations (A1, A2, A3, and A4) of test solution showed acute toxicity in the genotoxic assay. Strong reduction in the mitotic index was noticed mainly at higher concentrations when compared with control (96.99 ± 1.37). Results show that the mitotic index after treatment for 3 h reached 23.37 ± 1.41 at the highest concentration (A4). After treatment for 1

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h, it reached 69.47 ± 5.83 at the lowest concentration (A1). Genotoxicity assay exhibited many mutagenic aberrations in the root tips of A. cepa when treated with the plant extract. The abnormality percentage observed is dependent on the concentration. At the highest concentration of plant extract, maximum abnormality was seen at [A4, 98.14 ± 0.70 (3 h) and 95.09 ± 2.66 (1 h)] as compared with control that was [0.00 ± 0.00 (½ h) and 0.79 ± 0.79 (2 h)]. The A. spinosus extract produced an active number of clastogenic aberrations. The results illustrated that the aqueous plant extract of A. spinosus could inhibit direct-acting mutagen (H2O2) specifically at an exact concentration (Prajitha and Thoppil, 2016). In modulatory treatment, the A. spinosus extract consider­ ably decreased the nuclear lesions induced by H2O2 (3%) at an acute concen­ tration (5 mg/L). The percentage of restraint of nuclear lesions at this critical concentration (5 mg/L) of plant extract was 67.51 ± 8.68. This impediment in the nuclear lesion was significant. Thus, the amount of antimutagenicity at this specific concentration was comparatively substantial, where the percentage of inhibition was more significant than 40% (Prajitha and Thoppil, 2016). 56.3.2 ANTIPROLIFERATIVE EFFECT A. spinosus has shown inhibition of the proliferative activity of HepG2 cells in a dosage-dependent manner. The half-maximal inhibitory concentration value (IC50) reported being 25.52 μmol/L. The phytoconstituent linoleic acid and standard doxorubicin showed IC50 values of 38.65 and 24.68 mol/L with inhibitory effects on HepG2 cells. Thus, A. spinosus has good anticancer activity against HCC comparable to the standard doxorubicin and better than linoleic acid (Mondal et al., 2016). The ethanolic extract of the leaves of A. spinosus at the doses of 100 and 200 mg/kg body weight was orally given to mice for 16 days. The study reported an antitumor activity of A. spinosus against Swiss albino mice bearing Ehrlich ascites carcinoma (EAC). A decreased tumor volume and viable cell count decreased, while increased mean survival time and nonvi­ able tumor cell count compared with the EAC control group’s mice. The study suggested that the ethanolic extract of leaves of A. spinosus showed significant antitumor effects in mice bearing EAC (Joshua et al., 2010). 56.3.3 ANTIOXIDANT ACTIVITY The extract of A. spinosus showed higher percentage inhibition of linoleic acid oxidation compared with the reference drug, BHT. The percentage of linoleic acid oxidation inhibition was (67.57%) for the A. spinosus. Hence, it

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has suggested more significant antioxidant activity with maximum reducing power of the aqueous extract of leaves of A. spinosus (Bulbul et al., 2011). 56.3.4 ANTIMICROBIAL ACTIVITY A. spinosus showed significant results when performed using disc diffusion assay with leaf extract of A. spinosus. Estimating the antimicrobial activity of A. spinosus leaf extracts against various food-borne and pathogenic microorganisms, two solvent systems of the leaf of A. spinosus showed a different result as 100% methanol leaf extract shows 25 mm of the inhibitory zone than 80% methanolic leaf extract, which revealed the inhibitory zone of 23 mm. The antifungal activity was the same as that of antibacterial activity except that the fungal strain’s effectiveness was not as effective as bacterial strains. The results for antifungal activity were 100% for methanolic leaf extract (Teklit, 2015). Antimicrobial activity studies of A. spinosus revealed that different parts of the plant were extracted in methanol, distilled water, and hexane and tested against various bacterial strains, such as Escherichia coli, Staphylococcus sp., Klebsiella sp., Pseudomonas sp., and Paracoccus sp. The three fungal strains were Alternaria sp., Fusarium sp., and Aspergillus sp. Among the plant parts of A. spinosus, the stem and flower exhibited more antibacterial activity. Zone of inhibition in E. coli was 14 mm and Pseudomonas was 13 mm, which was maximum from stem extract in methanol (3.8 mg/disc) and distilled water (4.7 mg/disc), respectively. Under investigation, flower extract prepared in distilled water inhibited all the strains. Maximum zones of inhibition for bacterial strains Staphylococcus (10 mm), Klebsiella sp. (15 mm), and Paracoccus sp. (9 mm) observed in flower extract prepared in different solvents. The methanolic extract of A. spinosus showed total inhibition of fungal growth. Hexane extract of root, leaves, and stem of A. spinosus shows partial inhibition of all fungal strains (Sheeba et al., 2012). 56.3.5 ANTIDEPRESSANT ACTIVITY A study involving the antidepressant activity of A. spinosus using methanolic extract (100 and 200 mg/kg), with standard reference escitalopram and imip­ ramine indicated that methanolic extract of A. spinosus showed significant antidepressant activity in tail suspension test (TST) and forced swim test (FST) models of depression (Kumar et al., 2014).

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56.3.6 ANTIPEPTIC ULCER ACTIVITY In a study, gastric and duodenal ulcers were produced in albino rats by administering ulcerogenic doses of ethanol and cysteamine, respectively. The effect of the powdered leaves of A. spinosus on the ulcer was studied. It was compared with the drug omeprazole. Results showed that the leaves of A. spinosus were known to have antipeptic ulcer activity against cyste­ amine and ethanol-induced peptic ulcers. Results also indicated that activity was less than that of the drug omeprazole (Ghosh et al., 2008). A. spinosus showed antigastric ulcer activity of root, stem, and leaves extract studied against ethanol, indomethacin, hydrochloric acid, pyloric ligation, and stressinduced gastric ulcers in albino rats. The standard used was omeprazole which is a known antigastric ulcer drug. Effective antigastric ulcer activity was observed by root, stem, and leaves extract of A. spinosus. The roots of the A. spinosus showed the highest activity than that of the drug omeprazole (Mitra, 2013). 56.3.7 ANALGESIC ACTIVITY AND ANTIPYRETIC ACTIVITY Analgesic activity of methanolic extract of A. spinosus was analyzed using radiant heat tail-flick models and writhing induced using acetic acid in mice. The methanol extract, when administered orally to mice (500 mg/kg of body weight), resulted in effective antinociceptive activity against thermal (radiant heat tail-flick test) and chemical (acetic acid-induced visceral pain) models of nociception (Taiab et al., 2011). A. spinosus methanolic leaf extract showed significant antipyretic activity using the pyrexia method induced by yeast at a 200 and 400 mg/kg concentration, compared with paracetamol as a standard drug (Kumar et al., 2010). 56.3.8 IMMUNOMODULATORY ACTIVITY AND ANTIFERTILITY ACTIVITY Aqueous extract of A. spinosus indicated a stimulatory effect of immu­ nomodulatory activity on spleen cells from female BALB/c mice. Direct activation of primary B-cell proliferation is due to a new protein having a molecular weight of 313 kDa and intense immunostimulating activity (Lin et al., 2005). The antifertility activity of alcoholic extracts of A. spinosus inter­ rupts pregnancy in rats. Alcoholic extract of A. spinosus with a dose of 150

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and 175 mg/kg body weight exhibited effective interception of pregnancy in the rat (Satyanarayana et al., 2008). 56.3.9 HEPATOPROTECTIVE ACTIVITY Active phytoconstituents in A. spinosus, such as flavonoids, triterpenes, phenolics, steroids, and saponins show hepatoprotective activity. Whole plant extract of A. spinosus prepared in alcohol at doses 100, 200, and 400 mg/kg body weight of rats in a dose-dependent manner normalized the elevated serum enzymes. Histopathological investigation of rat liver sections further confirmed the biochemical findings (Zeashan et al., 2008). Zeashan et al. (2010) evaluated hepatoprotective activity of ethanolic extracts of the whole plant of A. spinosus against liver injury in rats provoked by d-galactosamine/lipopolysaccharide (d-GalN/LPS). Phospholipids effec­ tively decreased while d-galactosamine/lipopolysaccharide (300 mg/kg body weight/30 μg/kg body weight) induced hepatic damage. Increased marker enzymes, such as lactate dehydrogenase, aspartate transaminase, alkaline phosphatase, alanine transaminase, and gamma-glutamyl transferase, and bilirubin levels in serum confirm the above result. Other parameters, such as cholesterol, triglycerides, and free fatty acids increased effectively in liver and serum compared with the control group. Rats pretreated with modi­ fied parameters, when administered with A. spinous extract (400 mg/kg), reversed to normal. The biochemical studies followed by histopathological examination of liver sections indicated that A. spinosus extract could provide significant protection against hepatocellular injury (Zeashan et al., 2010). 56.3.10 HEMATOLOGICAL ACTIVITY Several investigations have been done on hematological parameters, such as packed cell volume (PCV), hemoglobin (HB) and white blood cell (WBC), and red blood cell (RBC) counts in pigs (Olufemi et al., 2003) and rats (Srivastava et al., 2011) using the A. spinosus extract prepared in alcohol. The whole plant extract of A. spinosus effectively reduced the RBC, hemo­ globin, PCV, and mean corpuscular hemoglobin concentration (MCHC) and increased the WBC and mean corpuscular volume (MCV) (Bhande and Wasu, 2016).

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56.3.11 ANTIHYPERGLYCEMIC AND ANTIHYPERLIPIDEMIC ACTIVITY Methanolic extract of A. spinosus stem has significant antihyperglycemic and antihyperlipidemic effects in male Wister albino rats by administering a single dose of alloxan monohydrate (150 mg/kg) that induced diabetes in albino rats. A. spinosus extract prepared in methanol, administered daily to diabetes-induced rats for 15 days at single doses of 250 mg and 500 mg/kg. In streptozotocin-induced diabetic rats, A. spinosus methanolic extract when administered to find the effect of blood glucose levels in 250 and 500 mg/kg treated rats indicated that blood glucose levels at both doses decreased. It was 165 and 160 mg/100 mL on the 15th day, respectively. The serum, triglyc­ erides, total cholesterol, low-density lipid, and very low-density lipid levels were higher in untreated diabetic rats than those in normal rats. In contrast, the high-density lipid levels effectively decreased in the rats compared with those in normal rats (Balakrishnan and Pandhare, 2010). Diabetic rats when treated with methanolic extract of A. spinosus and a standard reference drug significantly decreased serum level of cholesterol, triglycerides, LDL levels, VLDL levels, and there is a significant rise in HLDL in diabetic rats. Thus, the extract of A. spinosus acted similarly to standard drug glibenclamide, and these results provided pharmacological evidence that A. spinosus act as an antidiabetic agent (Sangameswaran and Jayakar, 2008). 56.3.12 ANTI-INFLAMMATORY EFFECT Anti-inflammatory activity was studied using edema induced by carrageenan. It was described that rats pretreated with A. spinosus extract substantially decreased edema induced by carrageenan 30 min after administration to 7.95%, 3.19%, and 10.81% at concentrations of 100, 200, and 400 mg/kg of A. spinosus extract. The extract of A. spinosus at 100, 200, and 400 mg/ kg resulted in significant edema protection after 4 h (22.72%, 14.89%, and 12.16%). Further, it remained for 24 h only at a dose of higher concentration (6.82%, 9.57%, and 12.16%) beside, standard drug indomethacin showed 16.86% protection at 4 h and 14.45% at 24 h respectively (Zeashan et al., 2009b). The methanolic extract of A. spinosus leaves, when tested with different doses on various cell lines, possess substantial anticancer activity in cancers of the liver, breast, colorectal, and found to be nontoxic for healthier cell lines (Rajasekaran et al., 2014).

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56.3.13 ANTINOCICEPTIVE ACTIVITY The acetic acid writhing reflex of A. spinosus extract decreased stretching and writhing induced by 0.6% acetic acid at a dose of 10 mL/kg. Observed values that were 26.26%, 46.50%, and 56.05% at 100, 200, and 400 mg/kg showed significant and dose-dependent protective effects from A. spinosus extract, respectively. The study of formalin-induced pain evaluated that the first (0–5 min) and second phases (15–30 min) for A. spinosus both showed analgesic effects. The pain, including neurogenic substances, was observed to block only at 400 mg/kg (42.25%). Besides, all the doses of A. spinosus extract effectively blocked the inflammatory pains. Thus, A. spinosus extract was noticed to hinder the neurogenic-induced pain that was effective than the pain resulting from inflammatory pains (42.16%) (Zeashan et al., 2009a). KEYWORDS • • • • • •

Amaranthus spinosus squalene tocotrienols amaricin spinoside antiproliferative

REFERENCES Agra, M. D. F.; Silva, K. N.; Basilio, I. J. L. D.; De Freitas, P. F.; Filho, J. M. B. Survey of Medicinal Plants Used in the Region Northeast of Brazil. Braz. J. Pharmacog. 2008, 18, 472–508. Balakrishnan, S.; Pandhare, R. Antihyperglycemic and Antihyperlipidaemic Activities of Amaranthus spinosus Linn Extract on Alloxan Induced Diabetic Rats. Malays. J. Pharm. Sci. 2010, 8 (1), 13–22. Baral, M.; Datta, A.; Chakraborty, S.; Chakraborty, P. Pharmacognostic Studies on Stem and Leaves of Amaranthus spinosus Linn. Int. J. Appl. Biol. Pharm. 2011, 2, 41–7. Bhande, S. S.; Wasu, Y. H. Effect of Aqueous Extract of Amaranthus spinosus on Hematological Parameters of Wistar Albino Rats. J. Exp. Biol. Agric. Sci. 2016, 4 (1), 116–120. Bulbul, I. J.; Nahar, L.; Ripa, F. A.; Haque, O. Antibacterial, Cytotoxic and Antioxidant Activity of Chloroform, n-Hexane and Ethyl Acetate Extract of Plant Amaranthus spinosus. Int. J. Pharmtech. Res. 2011, 3 (3), 1675–1680.

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Chandrashekhar, K. A Review on Tanduliyaka (Amaranthus spinosus L.)—A Weed, a Vegetable and a Medicinal Plant. Int. J. Ayur. Med. 2018, 9 (4), 231–238. Ganjare, A.; Raut, N. Nutritional and Medicinal Potential of Amaranthus spinosus. J. Pharmacogn. Phytochem. 2019, 8 (3), 3149–3156. Ghosh, D.; Mitra, P.; Ghosh, T.; Mitra, P. K. Anti Peptic Ulcer Activity of the Leaves of Amaranthus spinosus L. in Rats. Pharmacol. 2008, 40, 126–131. Govindarajan, R.; Vijayakumar, M.; Pushpangadan, P. Antioxidant Approach to Disease Management and the Role of ‘Rasayana’ Herbs of Ayurveda. J. Ethnopharmacol. 2005, 99, 165–178. Hema, E. S.; Sivadasan, M.; Anil, K. N. Studies on Edible Species of Amaranthaceae and Araceae Used by Kuruma and Paniya Tribes in Wayanad District, Kerala, India. Ethnobotany 2006, 18, 122–126. Jamaluddin, A. T. M.; Qais, N.; Ali, M. A.; Howlader, M. A.; Shams-Ud-Doha, K. M.; Sarker, A. A. Analgesic Activity of Extracts of Whole Plants of Amaranthus spinosus Linn. Int. J. Drug. Dev. Res. 2011, 3 (4), 189–193. Jhade, D.; Ahirwar, D.; Jain, R.; Sharma, N. K.; Gupta, S. Pharmacognostic Standardization, Physico-and Phytochemical Evaluation of Amaranthus spinosus Linn. Root. J. Young. Pharm. 2011, 3 (3), 221–225. Joshua, L. S.; Pal, V. C.; Kumar, K. S.; Sahu, R. K.; Roy, A. Antitumor Activity of the Ethanol Extract of Amaranthus spinosus Leaves Against EAC Bearing Swiss Albino Mice. Pharm. Lett. 2010, 2 (2), 10–15. Khanal, D. P.; Raut, B.; Dangol, K. S. Phytochemical Screening, Pharmacognostic Evaluation and Biological Activity of Amaranthus spinosus L. J. Manmohan Mem. Inst. Health Sci. 2015, 1 (4), 29–34. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants; Vol. 1; Oriental Enterprises: Uttranchal, India, 2001. Kumar, B. A.; Lakshman, K.; Jayaveera, K. N.; Shekar, D. S.; Kumar, A. A.; Manoj, B. Antioxidant and Antipyretic Properties of Methanolic Extract of Amaranthus spinosus leaves. Asian Pac. J. Trop. Med. 2010, 3 (9), 702–706. Kumar, B. A.; Lakshman, K.; Velmurugan, C.; Sridhar, S. M.; Gopisetty, S. Antidepressant Activity of Methanolic Extract of Amaranthus spinosus. Basic. Clin. Neurosci. 2014, 5 (1), 11–17. Lin, B. F.; Chiang, B. L.; Lin, J. Y. Amaranthus spinosus Water Extract Directly Stimulates Proliferation of B Lymphocytes In Vitro. Int. Immunopharmacol. 2005, 5 (4), 711–722. Mathur, J.; Khatri, P.; Samanta, K. C.; Sharma, A.; Mandal, S. Pharmacognostic and Preliminary Phytochemical Investigations of Amaranthus spinosus (Linn.) Leaves. Int. J. Pharm. Pharm. Sci. 2010, 2 (4), 121–124. Mishra, S. B.; Verma, A.; Mukerjee, A.; Vijayakumar, M. Amaranthus spinosus L. (Amaranthaceae) Leaf Extract Attenuates Streptozotocin-Nicotinamide Induced Diabetes and Oxidative Stress in Albino Rats: A Histopathological Analysis. Asian Pac. J. Trop. Biomed. 2012, 2 (3), S1647–S1652. Mitra, P. K. Comparative Evaluation of Anti Gastric Ulcer Activity of Root, Stem and Leaves of Amaranthus spinosus Linn. in Rats. Int. J. Herb. Med. 2013, 1 (2), 1675–1680. Mondal, A.; Guria, T.; Maity, T. K.; Bishayee, A. A Novel Tetraenoic Fatty Acid Isolated from Amaranthus spinosus Inhibits Proliferation and Induces Apoptosis of Human Liver Cancer Cells. Int. J. Mol. Sci. 2016, 17 (10), 1604.

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Odhav, B.; Beekrum, S.; Akula, U. S.; Baijnath, H. Preliminary Assessment of Nutritional Value of Traditional Leafy Vegetables in KwaZulu-Natal, South Africa. J. Food Compost. Anal. 2007, 20(5), 430–435. Ogwu; Chidozie. M. Value of Amaranthus [L.] Species in Nigeria. In Nutritional Value of Amaranth; IntechOpen, 2020. Olufemi, B. E.; Assiak, I. E.; Ayoadi, G. O.; Onigemo, M. A. Studies on Effects of Amaranthus spinosus Leaf Extract on the Haematology of Growing Pigs. Afr. J. Biomed. Res. 2003, 6 (3), 149–150. Peter, K.; Gandhi, P. Rediscovering the Therapeutic Potential of Amaranthus Species: A Review. Egypt. J. Basic Appl. Sci. 2017, 4 (3), 196–205. Prajitha, V.; Thoppil, J. E. Genotoxic and Antigenotoxic Potential of the Aqueous Leaf Extracts of Amaranthus spinosus Linn. Using Allium cepa Assay. S. Afr. J. Bot. 2016, 102, 18–25. Rajasekaran, S.; Dinesh, M. G.; Kansrajh, C.; Baig, F. H. A. Amaranthus spinosus Leaf Extracts and Its Anti-Inflammatory Effects on Cancer. Indian J. Res. Pharm. Biotechnol. 2014, 2 (1), 1058. Sangameswaran, B.; Jayakar, B. Anti-Diabetic, Anti-Hyperlipidemic and Spermatogenic Effects of Amaranthus spinosus Linn. on Streptozotocin-Induced Diabetic Rats. J. Nat. Med. 2008, 62 (1), 79–82. Satyanarayana, T.; Chowdary, K. A.; Eswaraiah, M. C.; Ande, B. Anti-Fertility Screening of Selected Ethno Medicinal Plants. Pharmacogn. Mag. 2008, 4 (15), 51. Sheeba, A. M.; Deepthi, S. R.; Mini, I. Evaluation of Antimicrobial Potential of an Invasive Weed Amaranthus spinosus L. In Prospects in Bioscience: Addressing the Issues; Springer: India, 2012; pp 117–123. Sreeranjini, S.; Siril, E. A. Evaluation of Anti-Genotoxicity of the Leaf Extracts of Morinda citrifolia Linn. Plant Soil Environ. 2011, 57 (5), 222–227. Srivastava, A.; Singh, K.; Gul, T.; Ahirwar, V. Alterations in Hematocellular Components of Albino Rats Due to Methanolic Extract of Amaranthus spinosus. Pharmacie. Globale. 2011, 3 (6), 1–3. Taiab, M. J. A.; Nazmul, Q.; Asif, A. M.; Amran, H. M.; Shams-Ud-Doha, K. M.; Apurba, S. A. Analgesic Activity of Extracts of the Whole Plant of Amaranthus spinosus Linn. Int. J. Drug. Dev. Res. 2011, 3 (4), 189–193. Teklit, G A. Evaluation of Physiochemical, Phytochemical, Antioxidant and Antimicrobial Screening Parameters of Amaranthus spinosus Leaves. Nat. Prod. Chem. Res. 2015, 4, 199. Zeashan, H.; Amresh, G.; Singh, S.; Rao, C. V. Protective Effect of Amaranthus spinosus Against D-Galactosamine/Lipopolysaccharide-Induced Hepatic Failure. Pharm. Biol. 2010, 48 (10), 1157–1163. Zeashan, H.; Amresh, G.; Rao, C. V.; Singh, S. Antinociceptive Activity of Amaranthus spinosus in Experimental Animals. J. Ethnopharmacol. 2009a, 122 (3), 492–496. Zeashan, H.; Amresh, G.; Singh, S.; Rao, C. V. Antidiarrheal and Antiulcer Activity of Amaranthus spinosus in Experimental Animals. Pharm. Biol. 2009b, 47, 932–939. Zeashan, H.; Amresh, G.; Singh, S.; Rao, C. V. Hepatoprotective Activity of Amaranthus spinosus in Experimental Animals. Food. Chem. Toxicol. 2008, 46 (11), 3417–3421. Zheng, W.; Wang, S. Y. Antioxidant Activity and Phenolic Compounds in Selected Herbs. J. Agric. Food Chem. 2001, 49 (11), 5165–5170.

CHAPTER 57

Mussaenda macrophylla Wall.: Chemical Composition and Pharmacological Applications MARINA LALREMRUATI, MARY ZOSANGZUALI, C. LALMUANSANGI, F. NGHAKLIANA, and ZOTHANSIAMA* Department of Zoology, Mizoram University (A Central University), Aizawl, Mizoram 796004, India *Corresponding

author. E-mail: [email protected]

ABSTRACT Mussaenda macrophylla Wall. is a flowering shrub with an orange-colored inflorescence and belongs to the Rubiaceae family. It is reported to occur in south-east Asia, India, Myanmar and China. Different parts of M. macro­ phylla have been used as a traditional medicine to treat a variety of diseases, including cancer, sore throat, fever, chronic ulcer, diarrhea, dysentery, indi­ gestion and snakebites. The main phytochemicals found in various extracts of M. macrophylla are phenols, flavonoids, alkaloids, cardiac glycosides, saponins, terpenoids, steroids and tannins. A new iridoid glucoside, 6-epi­ barlerin, a novel sterol galactoside, and β-sitosterol were isolated from the stem bark of M. macrophylla. The root bark was used for isolation of four well-known triterpenoids and four brand-new triterpenoid glycosides. The therapeutic qualities of M. macrophylla have been reported by several studies which revealed its antioxidant, antimicrobial, antidiabetic, antihaemolytic and membrane stabilizing activities.

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INTRODUCTION

The genus Mussaenda has been reported to be a significant source of natural products in the field of pharmacology (Vidyalakshmi et al., 2008). Mussaenda macrophylla Wall., belonging to the Rubiaceae family, is a flowering shrub with an orange-colored inflorescence and is reported to occur in southeast Asia, India, China, and Myanmar in association with herbs and other shrubs (Arunachalam et al., 2015; Manandhar, 2002). Traditionally, different parts of M. macrophylla have been used to treat various health problems, such as cough, sore mouth, fever, chronic ulcer, diarrhea, dysentery, indigestion, cancer, and snake bites (Manandhar, 1994; Sharma et al., 2001; Rosangkima and Jagetia, 2015). Previous studies with M. macrophylla also revealed its antibacterial, anticoagulant, anti-inflammatory, and hepatoprotective activities (Dinda et al., 2008). This review intends to provide an overview of the bioactive components and pharmacological potential of M. macrophylla for an optimal assessment. 57.2

BIOACTIVES

Phytochemical screening of various extracts of M. macrophylla leaf revealed the presence of alkaloids, saponins, cardiac glycosides, terpenoids, tannins, and steroids. Different solvent extracts of M. macrophylla, however, contain different phytochemicals (Lalremruati et al., 2019). The total contents of phenol and flavonoid in M. macrophylla leaves were estimated on chloroform, methanol, and aqueous extracts. The highest total phenolic content (387.6 ± 14.1 mg GAE/g) was found in aqueous extract followed by methanolic (301.3 ± 21.7 mg GAE/g) and chloroform extract (226.9 ± 21.04 mg GAE/g). Flavonoid content followed the same pattern with aqueous extract possessing maximum flavonoid content (5,761.6 ± 38.5 mg quercetin equivalent/g) followed by methanolic (4864.7 ± 36.7 mg quercetin equivalent/g) and chloroform extract (4830.1 ± 32.8 mg quercetin equivalent/g) (Lalremruati et al., 2019). The total phenolic content of metha­ nolic fractions partitioned by modified Kupchan method was estimated by Islam et al. (2012) and the total phenolic content was observed in the range of 14.95 ± 0.56 to 38.50 ± 0.64 mg of GAE/g of sample with the highest phenolic compounds in the dichloromethane soluble fraction. The phytoconstituents of root bark of M. macrophylla include triterpe­ noid glycosides. Four known triterpenoids and four new triterpenoid glyco­ sides were isolated. The structures of the new triterpenoid glycosides were determined by several spectroscopic techniques including 2D NMR methods (Fig. 57.1) (Kim et al., 1999).

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FIGURE 57.1 Chemical structures of isolated compounds from M. macrophylla root bark: (1) 3-O-β-D-glucopyranosyl-28-O-α-L-rhamnopyranosyl-16α-hydroxy-23-deoxyprotobassicacid, (2) 28-O-β-D-glucopyranosyl-16 α-hydroxy-23-deoxyprotobassic acid, (3) 3-O-β-D-gluco-pyranosyl-28-O-α-L-rhamnopyranosyl-16α-hydroxyprotobassicacid, (4) 3-O-{[β-D-glucopyranosyl-(1→6)]-O-α-L-rhamnopyranosyl-(1→2)-O-β-D­ gl u cop y r a n os yl(1→2)}O-β-D-gl u cop y r a n os yl-(1→3)-O-β-D-glucopyranosyl­ cycloarta-22,24-dien-27-oic-acid(mussaendosideW), (5) 3-O-acetyloleanolic acid, (6) 3-O-acetyldaturadiol, (7) rotundicacid, (8)16α-hydroxyprotobassicacid.

From the stem bark of M. macrophylla, a new iridoid glucoside 6-epi­ barlerin and a new unique sterol galactoside as well as β-sitosterol were isolated (Fig. 57.2). 6-epi-Barlerin was isolated as an amorphous powder from the butanol fraction of methanolic extract of M. macrophylla stem bark by column chromatography through dianion HP-20 which was further recolumned using silica gel as stationary phase. A portion of the butanol fraction from M. macrophylla methanolic extract was packed in silica gel column chromatography (CC) to get a residue from CHCl3–MeOH (9:1) eluate. This residue on repeated CC over silica gel afforded aplysterol

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galactosidase amorphous powder. A sugar moiety identified as β-D-galactose and anaglycone identified as aplysterol were liberated on acid hydrolysis of the compound (Dinda et al., 2008).

FIGURE 57.2

57.3

Chemical structures of isolated compounds from M. macrophylla stem bark.

PHARMACOLOGY

57.3.1 ANTIOXIDANT ACTIVITY The antioxidant potential of M. macrophylla extract was evaluated by the phosphomolybdenum assay method in an experiment performed by Islam et al. (2012). They reported the total antioxidant activity (mg of ascorbic

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acid/100 g) of various extracts ranging from 0.211 ± 0.11 to 1.276 ± 0.45. Total phenolic content and total antioxidant activity of M. macrophylla showed a positive correlation having correlation coefficient (R2) values of 0.759. The dichloromethane soluble fraction of M. macrophylla leaves revealed DPPH radical scavenging activity with an IC50 = 42.95 ± 0.73 µg/mL. This notable free radical scavenging may be correlated with its high phenolic content or due to synergistic activity of different chemical substance present in the extracts (Islam et al., 2012). In a study conducted by Lalremruati et al. (2019), aqueous and methanolic extracts of M. macrophylla leaves were found to possess similar DPPH radical scavenging activity with IC50 of 26.43 ± 0.55 and 25.92 ± 0.33 μg/mL respectively. An antioxidant activity assay performed by Bhandari et al. (2020) revealed that M. macrophylla root extracts inhibited DPPH-free radical significantly which is almost similar to the standard ascorbic acid. In a study conducted by Lalremruati et al. (2019), the aqueous extract of M. macrophylla possessed the highest scavenging activity (IC50 = 4.12 ± 0.94 μg/mL) followed by methanolic extract (IC50; 7.83 ± 1.2 μg/mL) and chloroform extract (IC50; 40.24 ± 3.5 μg/mL) in the O2•− scavenging activity assay. The aqueous extract possessed higher O2•− scavenging activity than the standard ascorbic acid (IC50; 8.65 ± 1.6 μg/mL). The study showed that the methanolic and aqueous extracts of M. macro­ phylla were more effective in scavenging ABTS•+ radical (IC50; 17.20 ± 1.5 μg/mL and IC50; 25.95 ± 1.8 μg/mL, respectively) than the standard ascorbic acid (IC50; 39.70 ± 1.2 μg/mL). The phenol and flavonoid contents of M. macrophylla extracts showed a significant positive correlation with their free radicals (DPPH, O2•− and ABTS) scavenging activities. The reducing power of chloroform, methanol, and aqueous extracts of M. macrophylla was measured by determining the conversion of Fe3+ to Fe2+. The highest reducing activity was reported for methanolic extract (1.1 ± 0.0003) followed by aqueous (0.73 ± 0.002) and chloroform extracts (0.53 ± 0.0008). The reducing activity of methanolic extract was even higher than the standard ascorbic acid (0.87 ± 0.02). 57.3.2 ANTIMICROBIAL ACTIVITY The root bark of M. macrophylla was found to inhibit the growth of Porphy­ romonas gingivalis, a Gram-negative anaerobic oral bacteria, typically

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associated with human gum disease, in an antimicrobial screening against two oral pathogens, P. gingivalis and Streptococcus mutans. However, they were found to be inactive against S. mutans, a Gram-positive facultative anaerobic coccus that is the etiologic agent of human dental caries (Kim et al., 1999). The leaf extracts of M. macrophylla exhibited the zone of inhibi­ tion ranging from 6.0 to 11.0 mm against Gram-positive bacteria. The carbon tetrachloride soluble fraction showed 15, 13, and 11 mm zone of inhibition against Salmonella paratyphi, Aspergillus niger, and Staphylococcus aureus, respectively (Chowdhury et al., 2013). 57.3.3 ANTIDIABETIC ACTIVITY Ethanol and methanol extract of M. macrophylla root revealed potent antidia­ betic activity in an in vitro (Bhandari et al., 2020). The antidiabetic activity was measured according to established method by determining the extent of glucose diffusion inhibition by ethanol and methanol extract through a semipermeable membrane that can correlate their ability to slow down the diffusion and movement of glucose in the intestinal tract. 57.3.4 ANTIHAEMOLYTIC ACTIVITY The antihaemolytic activity was measured in an ex vivo study performed by Lalremruati et al. (2019) in various extracts of M. macrophylla leaf. The study showed a competent inhibitory effect against erythrocyte haemolysis with an inhibitory rate ranging from 69.17% to 80.53%. 57.3.5 LIPID PEROXIDATION INHIBITION The lipid peroxidation inhibitory potential of various M. macrophylla leaf extracts was estimated ex vivo in mice liver homogenate. Highest inhibition activity was reported for aqueous extract with an inhibition rate of 65.33% (Lalremruati et al., 2019). 57.3.6 MEMBRANE STABILIZING ACTIVITY Islam et al. (2013) demonstrated that the extracts of M. macrophylla leaves significantly protected the lysis of erythrocyte membrane mediated by hypo­ tonic solution and heat when compared with the standard acetyl salicylic acid. In hypotonic solution and heat-induced conditions, the petroleum

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ether and carbon tetrachloride soluble partitionates of methanolic extract of M. macrophylla exhibit 52.55% and 45.79% inhibition of RBC hemolysis induced by hypotonic solution, respectively. In addition, the petroleum ether soluble partitionate of methanol extract of M. macrophylla also protected 23.35% of heat-induced lysis of human erythrocyte membrane. KEYWORDS • • • • • • •

Mussaenda macrophylla traditional medicine pharmacological properties phytochemicals glycosides antioxidant anti-microbial

REFERENCES Arunachalam, S.; Gunasekaran, S.; Sundaramoorthy, S.; Sathiavelu, M. The Genus Mussaenda: A Phytopharmacological Review. J. Chem. Pharm. Res. 2015, 7 (7), 1037–1042. Bhandari, R.; Shrestha, D.; Pandey, J.; Gyawali, C.; Lamsal, M.; Sharma, S.; Rokaya, R. K.; Aryal, P.; Khadka, R. B. Study of In Vitro Anti-Oxidant and Anti-Diabetic Activity by Mussaenda macrophylla Root Extracts. Int. J. Curr. Pharm. Res. 2020, 12 (4), 70–74. Chowdhury, S. R.; Akter, S.; Sharmin, T.; Islam, F.; Quadery, T. M. Antimicrobial Activity of Five Medicinal Plants of Bangladesh. J. Pharmacogn. Phytochem. 2013, 2, 164–70. Dinda, B.; Majumder, S.; Arima, S.; Sato, N.; Harigaya, Y. Iridoid Glucoside and Sterol Galactoside from Mussaenda macrophylla. J. Nat. Med. 2008, 62, 447–451. Islam, F.; Chowdhury, S. R.; Sharmin, T.; Uddin, M. G.; Kaisar, M. A.; Rashid, M. A. In Vitro Membrane Stabilizing and Thrombolytic Activities of Ophirrhiza.mungos, Mussaenda macrophylla, Gmelina philippensis and Synedrella nodiflora growing in Bangladesh. J. Pharm. Nutr. Sci. 2013, 23, 71–75. Islam, F.; Quadery, T. M.; Chowdhury, S. R.; Kaisar, M. A.; Uddin, G.; Rashid, M. A. Antioxidant and Cytotoxic Activities of Mussaenda macrophylla. Bangladesh Pharm. J. 2012, 15, 69–71. Kim, N. C.; Desjardins, A. E.; Wu, C. D.; Kinghorn, A. D. Activity of Triterpenoid Glycosides from the Root Bark of Mussaenda macrophylla Against Two Oral Pathogens. J. Nat. Prod. 1999, 62, 1379–1384.

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Lalremruati, M.; Lalmuansangi, C.; ZothanSiama. Free Radical Scavenging Activity and Antioxidative Potential of Various Solvent Extracts of Mussaenda macrophylla Wall: An In Vitro and Ex Vivo Study. J. Appl. Pharm. Sci. 2019, 9 (12), 94–102. Manandhar, N. P. Biological Activity of Mussaenda macrophylla. Fitoterapia 1994, 65, 7–13. Manandhar, N. P. Plants and People of Nepal. J. Ethnobiol. 2002, 23 (2), 313–314. Rosangkima, G.; Jagetia, G. C. In Vitro Anticancer Screening of Medicinal Plants of Mizoram State, India, Against Dalton’s Lymphoma, MCF-7 and Hela Cells. Int. J. Recent Sci. Res. 2015, 6 (8), 5648–5653. Sharma, H. K.; Chhangte, L.; Dolui, A. K. Traditional Medicinal Plants of Mizoram, India. Fitoterapia 2001, 72,146–161. Vidyalakshmi, K. S.; Vasanthi, H. R.; Rajamanickam, G. V. Ethnobotany, Phytochemistry and Pharmacology of Mussaenda Species (Rubiaceae). Ethnobot. Leafl. 2008, 12, 469–475.

CHAPTER 58

Phytochemistry and Pharmacological Potentialities of Syzygium densiflorum Wall. ex Wight & Arn. and S. travancoricum Gamble (Myrtaceae) ATHIRA REGHUNATH1, ANJANA SURENDRAN2, and RAJU RAMASUBBU1* 1Department

of Biology, The Gandhigram Rural Institute (Deemed to be University) Gandhigram, Dindigul, Tamil Nadu, India

2Department

of Botany Arulmigu Palani Andavar Arts College for Women, Palani, Tamil Nadu, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Syzygium densiflorum Wall. ex Wight & Arn. and Syzygium travanco­ ricum Gamble are endemic trees of Southern Western Ghats. The fruits of S. densiflorum are used for edible and medicinal purposes by the tribes of the Nilgiri Hills of the Southern Western Ghats. Syzygium travanco­ ricum is traditionally used for curing diabetes and arthritis by local people and the essential oil isolated from the leaves are reported to be used in the perfume industry for skin waters and aftershaves. The leaves of S.densiflorum has shown higher quantities of tannins, phenols, quinines, coumarins and cardiac glycosides. The essential oils isolated from the leaves of S. travancoricum have been reported with trans-ocimene, caryo­ phyllene, copaene, trans β-ocimene, trans-β-caryophyllene, α-humulene,

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α-farnesene, n-hexadecanoic acid, nonane, dodecane, 2, 6, 10 trimethyl, mono (2-ethylhexyl) ester, 2-heptenal, (z), 1, 2-benzenediol acid 3-methyl. The various extracts of S. densiflorum possessed antimicrobial activity with maximum zone of inhibition. Also, several antimicrobial studies attempted on essential oil and crude extracts of S. travancoricum have shown higher inhibitory effects against various pathogens. Several investigations attempted on both S. densiflorum and S. travancoricum have revealed the efficiency of antidiabetic, antihyperlipidaemic, and antioxidant activities of extracts of various parts. 58.1

INTRODUCTION

Bioactive molecules are the main source of herbal medicines in recent days, and they have emerged as an effective therapeutic tool to satisfy a multiple-target strategy due to their inherent large-scale structural diver­ sity. Syzygium densiflorum Wall. ex Wight & Arn. is a large canopy tree growing above 15 m tall in riparian areas of higher altitudes (1500–2300 m) of evergreen forests of Southern Western Ghats (Ramasubbu et al., 2016). The fruits of S. densiflorum were used for edible and medicinal purposes by the tribes of the Nilgiri Hills of the Southern Western Ghats (Sasi and Rajendran, 2012). Also, Badagas, the tribes of Nilgiris, used S. densiflorum (=S. arnottianum) to treat toothache (Sathyavathi and Janardhanan, 2014). Syzygium travancoricum Gamble, a critically endangered tree endemic to Southern Western Ghats, India, was first discovered from the swampy lowlands of Travancore. This tree has been reported from evergreen and semi-evergreen forests and also reported in few sacred groves of Thiruvananthapuram, Thrissur Pathanamthitta, Alappuzha, and Kollam districts of Kerala (Sasidharan, 2006) and Nilgiry district of Tamil Nadu (Ramasubbu et al., 2016). S. travancoricum is a large-sized evergreen tree growing up to 25 m traditionally used for curing diabetes and arthritis by local people. The essential oil of S. travancoricum has been reported to possess herbal-spicy-woody notes and is used in the perfume industry for skin waters and aftershaves. The oil has also possessed a raw mango odor and used in flavoring. This tree possesses very important properties of cosmetic and medicinal importance. Hence, these properties help to add potential economic value to the plant for its conservation (Radha et al., 2002).

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58.2 BIOACTIVES 58.2.1 BIOACTIVES OF S. DENSIFLORUM Kiruthiga et al. (2011) investigated the chemical composition of crude extract of S. densiflorum by gas chromatography-mass spectrometry analysis. A total of 24 compounds were detected from the leaf of S. benthamianum (=S. densiflorum) with ethyl acetate as solvent. Of these, 4-(4-ethyl­ cyclohexyl)-1-pentyl-cyclohexene (24.07%), linoleic acid (15.16%), 2,6,10, -14,18-Penta-methyl-2,6,10,14,18-eicosapentaene (10.27%), 9,17-octadeca­ dienal, (z)-(9.96%), Z,E-3,13-octadecadien-1-ol (7.14%), and 7-pentadecyne (7.36%) were the prime constituents. The phytochemical constituents of leaf extracts of S. densiflorum were analyzed by Fathima and Pandian (2015) in which they identified the bioactive compounds by both qualitative and quantitative methods. Ethyl acetate extract of S. densiflorum has shown higher quantities of tannins, cardiac glycosides, phenols, and coumarins. Methanol extract of leaf showed a significant presence of tannins, quinines, phenols, and coumarins and the hexane extract indicated the presence of cardiac glycosides. Total phenol content of the methanolic extract was calculated as 389.0 mg/g, whereas, the flavonoid content was 152.8 mg/g. The total condensed tannin in methanol extract of S. densiflorum was found to be 589.3 mg/g. RameshKumar et al. (2015) have isolated essential oil from the leaves of S. arnottianum (=S. densiflorum) with 0.12% yield. The oil contained volatile compounds, such as caryophyllene oxide (15.4%) and selina-11-en-4 α-ol (13.0%). The oil was reported to contain sesquiterpene hydrocarbons (24.6%) and oxygenated sesquiterpenes (58.2%). Deepika et al. (2013) isolated essential oil from the leaves of S. benthamianum (=S. densiflorum). Among the 63 compounds detected from the oil, sitosteryl acetate (11.83%), stigmastan-3,5,22-trien (7.0%), 2,6-dimethyl-2-octene (6.99%), estra-1,3,5(10)-trien-17.beta.-ol (6.3%), ergosta-4,7,22-trien-3.beta-ol (5.19%), and 1-methylcholest-1,3,5(10)-trien­ 3-ol (5.06%) were recorded as major constituents. The bioactive compounds of methanolic leaf extract of S. arnottianum was analyzed by Krishna and Mohan (2017). About 11 bioactive compounds, such as 4-Amino­ pyrimidine, 5-methyl-1-Methyl-1H-1,2,4-triazole (14.32%), Oxazole, 4,5-dihydro-2-methyl-dichloroacetic acid, hexyl ester hydrazine (41.34%), [(1,2,3-.eta.)-2-butenyl].eta.8-1,3,5,7-cyclooctatetraene)-cyclopentane, 1,1-[3-(2-cyclopentylethyl)-1,5 pentanediyl]bis-propanedinitrile (20.16%), cyclohexane, 1,2,4,5-tetraethyl-2-thiopheneacetic acid, and oct-3-en-2-yl

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ester cyclopentanone (24.18%) were detected. Functional groups were analyzed by ATR-FTIR spectroscopy which revealed the presence of alkane, alkene, alcohol, alkyl halide, amine, alkyne, aromatic, ether, carbonyl, alde­ hyde, ester, and anhydride. Krishnasamy and Muthusamy (2015) carried out preliminary phyto­ chemical screening of ethyl acetate, n-hexane, and ethanol extracts of dried fruits of S. densiflorum. The presence of sterols, alkaloids, anthocyanins, flavonoids, terpenoids, phenols, fixed oils, carbohydrates, and fats were reported. Copious amounts of alkaloids were recorded from n-hexane and ethyl acetate extracts. The ethanolic fraction was recorded with a higher amount of sterols, anthocyanin, flavonoids, phenols, terpenoids, fats, carbo­ hydrates, and fixed oils. Rabeque and Padmavathy (2013) have investigated the quantitative phytochemicals of methanol, acetone, and aqueous leaf extracts. Acetone extract has recorded with 148.50 ± 0.98 mg/g of phenol, 0.83 ± 0.01 mg/g of flavonoids, 63.70 ± 1.96 mg/g of tannin, and 49.80 ± 0.33 mg/g of vitamin E. Methanol extract has reported to contain 145.50 ± 0.41 mg/g of phenol, 0.70 ± 0.02 mg/g of flavonoids, 14.10 ± 1.39 mg/g of tannin, and 54.30 ± 0.08 mg/g of vitamin E. Aqueous extract was also reported with 121.80 ± 6.61 mg/g of phenol, 0.46 ± 0.02 mg/g of flavonoids, 58.13 ± 0.82 mg/g of tannin, and 3.10 ± 1.88 mg/g of vitamin E (Padmavathy, 2013). Saranya et al. (2012) have isolated the essential oil from S. densiflorum with viscous and pale yellow and analyzed it through GC-MS. Among the 84 compounds detected, the major constituents β-maaliene (17.43%), isoledene (12.46%), α-gurjunene (10.44%), β-elemene (9.9%), and β-vatirenene (8.50%) were detected. Sesquiterpene has constituted 28.37% of essential oil along with monoterpenes (1.28%), triterpenes (0.18%) oxygenated monoter­ penes (0.02%), oxygenated diterpenes (0.05%), and aliphatic hydrocarbons (0.11%). Raja et al. (2013) reported the chemical constituents of leaf extracts of S. densiflorum. Saponins, phytosterols, tannins, phenolics, flavonoids, carbohydrates, proteins, and amino acids were reported from the ethanolic extract. Phytochemical analysis of ethyl acetate, hexane, and methanolic leaf extracts of S. densiflorum were performed by Subramanian et al. (2014). Analysis of ethyl acetate extract revealed the presence of a higher amount of phenolics, flavonoids, flavonol glycosides, and terpenoids. The methanolic extract was recorded with a higher concentration of phenolics, flavonoids and flavonol glycosides, which has indicated the presence of carbohydrates, terpenoids, and amino acids. The screening of hexane extract showed the presence of phenols, flavonoids, and terpenoids, whereas, flavonol glyco­ sides, carbohydrates, and amino acids were absent in hexane extract. The

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methanolic extract was recorded with higher total phenolic content (105.33 ± 2.52 µg/mL GAEs) followed by ethyl acetate extract (101.33 ± 1.53 µg/mL GAEs) and hexane extract (52.00 ± 2.00 µg/mL GAEs). The total flavonoid content of leaf extracts of S. densiflorum was recorded as higher (58.33 ± 1.53 µg/mL CEs) in ethyl acetate extract followed by methanol (38.33 ± 1.53 µg/mL CEs) and hexane extracts (34.00 ± 1.00 µg/mL CEs). Krishna (2018) studied the phytoconstituents of the leaf litter of S. densi­ florum (=S. arnottianum) in which, 24 compounds were recorded during the first stage of decomposition. But at the last stage of the experiment, only 20 compounds were observed. About 11 major functional groups were recorded at the beginning and some of them were degraded at the end of the study. Aldehydes, carbonyl, alkene, alkyl chlorides, ketones, olefins, triazoles, and alkane groups remained up to the end.

(Continued)

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58.2.2 BIOACTIVES OF S. TRAVANCORICUM Radha and Mohan (2000) analyzed the essential oils isolated from the fresh leaves of S. travancoricum, in which trans-ocimene, caryophyl­ lene, and copaene were identified as major constituents. Among the three components, trans-ocimene was recorded as the main component consti­ tuting 69.27% of the oil, followed by trans-caryophyllene and copaene. Shafi et al. (2002) has reported trans β-ocimene, trans-β-caryophyllene, α-humulene, α-farnesene as the major constituents of leaf essential oil of S. travancoricum. Jirovetz et al. (2001) studied the chemical composition and aromatic potentials of two samples of S. travancoricum leaf essential oil by Olfactometry, GC-MS, and GC-FID. More than 50 phytocompounds

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were identified using GC-MS from both samples, in which monoterpenes and sesquiterpenes were recorded as predominant compounds. Trans-βOcimene (44.7%) trans-β-caryophyllene (32.9%), α-humulene (6.7%), -farnesene (4.9%), and alloaromadendrene (3.6%) have reported from sample 1, whereas the sample 2 was reported with trans-β-ocimene (21.2%), trans-caryophyllene (20.7%), nerolidol (8.1%), α-humulene (5.4%), cis-βocimene (4.2%), aromadendrene (4.0%), β-selinene (3.5%), α-farnesene (2.8%), selinene (2.7%), globulol (2.0%), ledene (1.8%), β-eudesmol (1.2%), and spathulenol (1.1%). Rajalakshmi et al. (2016) have determined the biochemical compo­ nents of the leaves of S. travancoricum and Syzygium jambos using atomic absorption spectrophotometer and UV spectrophotometer. Among the two species, S. travancoricum has recorded higher mineral and vitamin content. Rajalakshmi et al. (2018) have reported HPTLC and GC-MS analysis of S. travancoricum leaf extracts. Different mobile phases were tried with HPTLC to separate various bioactive compounds, such as flavonoids, terpenoids, saponins, alkaloids, glycosides. A total of 29 compounds were detected from the hexane extract of S. travancoricum by GC-MS. Most common compounds detected were n-hexadecanoic acid (15.53%), nonane, odecane, 2,6,10-trimethyl (11%), mono (2-ethylhexyl) ester (10.76%), 2-heptenal, (z) (14.34%), and 1, 2-benzenediol acid, 3-methyl (8.9%). Pruthvi et al. (2020) has investigated the phytochemical constituents of chloroform, ethanol, and petroleum ether leaf extracts of S. travancoricum. The qualitative phytochemical analysis has shown the presence of flavo­ noids, sterols, phenols, alkaloids, tannins, carbohydrates, terpenoids, cardiac glycosides, oils, and fats in all extracts. Ethanol extract and petroleum ether extract have shown the presence of glycosides and anthraquinones. Suman­ gala et al. (2019) reported that stem and leaf extracts of S. travancoricum showed the presence of saponins and phenols from stem and tannins and terpenoids from leaf extracts.

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Phytochemicals reported from Syzygium travancoricum

58.3

PHARMACOLOGY

58.3.1 ANTIBACTERIAL ACTIVITY 58.3.1.1 ANTIBACTERIAL ACTIVITY OF S. DENSIFLORUM The leaf extracts of S. densiflorum possessed antibacterial activity against six gram-negative (Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris, Klebsiella pneumoniae, Vibrio cholerae and Escherichia coli) and two gram-positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains. 100 µg/mL of plant extract inhibited the growth of P. mirabilis and P. vulgaris and 500 µg/mL concentration inhibited the growth of S. aureus.

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P. aeruginosa, K. pneumoniae, V. cholerae, E. coli, and B. subtilis were inhibited at 250 µg/mL (Kiruthiga et al., 2011). The ethyl acetate extract of S. densiflorum exhibited a significant antibacterial effect against P. aeruginosa, K. pneumoniae, S. aureus, P. vulgaris, E. coli, and B. subtilis. Maximum zone of inhibition (13 mm) was observed against P. aeruginosa at 25 mg/ mL concentration. Minimum inhibitory concentration (MIC) and minimum lethal concentration (MLC) have indicated the significant activity of selected bacterial strains (Eganathan et al., 2012). Acetone, hexane, methanol, petroleum ether, and chloroform extracts of S. densiflorum leaves showed effective antibacterial activity against gram-negative bacteria, such as K. pneumoniae, E. coli, P. aeruginosa, and Klebsiella terrigena and gram-positive bacteria, such as S. aureus, Bacillus cereus, and Micrococcus mucilaginosus. Among that, methanolic extract was recorded with a maximum zone of inhibition followed by acetone, petroleum ether, hexane, and chloroform against tested bacterial strains at 200 µg/mL concentration. It has also shown the maximum zone of inhibition against B. cereus (26 ± 1.91 mm) followed by M. mucilaginosus (23 ± 3.76 mm), P. aeruginosa (22.5 ± 2.51 mm), K. terrigena (22 ± 1.98 mm), E. coli (21.5 ± 1.50 mm), K. pneumoniae (20 ± 1.73 mm), and S. aureus (17.5 ± 0.52 mm) (Manikandan et al., 2020). 58.3.1.2 ANTIBACTERIAL ACTIVITY OF S. TRAVANCORICUM Shafi et al. (2002) carried out antibacterial studies on essential oil of S. travan­ coricum in which, considerable antimicrobial activity was recorded against Bacillus sphaericus (11 mm), B. subtilis (10 mm), S. aureus (12 mm), E. coli (11 mm), Pseudomonas aeruginosa (11 mm), and Salmonella typhimurium (12 mm). Although, the essential oil of S. travancoricum has shown moderate activity when compared with S. cumini against S. typhimurium. Sumangala et al. (2019) carried out antimicrobial activity of stem and leaf extract of S. travancoricum against seven different pathogens, Streptococcus mutans, S. aureus, E. coli, K. pneumoniae, B. cereus, Salmonella typhi, and Pseudo­ monas aeruginosa. Stem and leaf extract of S. travancoricum has shown a higher inhibitory effect against S. typhi. Pruthvi et al. (2020) investigated crude extracts (petroleum ether, chloroform, and ethanol) of S. travancoricum leaves for antimicrobial assay. Antimicrobial studies were carried out against fungal pathogens (Aspergillus niger, Fusarium oxysporum, and Candida albicans) and bacterial pathogens (Listeria monocytogenes, Pseudomonas sp., Klebsiella spp., S. aureus, and E. coli).

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58.3.2 ANTIFUNGAL ACTIVITY 58.3.2.1 ANTIFUNGAL ACTIVITY OF S. DENSIFLORUM Leaf extract of S. densiflorum (S. benthamianum) was found to possess antifungal activity against Alternaria alternata, A. niger, and Penicillium chrys­ ogenum with minimum inhibitory concentration at 250 µg/mL (Kiruthiga et al., 2011). A niger, A. alternata, and Penicillium sp. were observed as resistant against fruit extract of S. densiflorum (Eganathan et al., 2012). Manikandan et al. (2020) evaluated the antifungal efficiencies of methanol, petroleum ether, acetone, chloroform, and hexane extracts from the leaves of S. densiflorum. The methanol extract was found to exhibit a maximum zone of inhibition against the tested fungal strains. It has shown that maximum zone of inhibition was observed against Candida albicans (24.5 ± 2.76 mm) followed by Candida sp. (22 ± 1.98 mm) and Candida glabrata (21.5 ± 1.31 mm) at 200 µg/mL. 58.3.3 ANTICANCER ACTIVITY 58.3.3.1 ANTICANCER ACTIVITY OF S. DENSIFLORUM 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay of leaves revealed the dose-dependent inhibition of Hep 2 cell growth. The ethyl acetate extract has shown maximum inhibition (84.76%) at a higher concentration (1000 µg/mL) (Kiruthiga et al., 2011). 58.3.4 ANTIDIABETIC AND ANTIHYPERLIPIDEMIC ACTIVITY 58.3.4.1 ANTIDIABETIC AND ANTIHYPERLIPIDEMIC ACTIVITY OF S. DENSIFLORUM The investigations have revealed that the antidiabetic property of fruit extracts of S. densiflorum. The ethanolic fruit extract showed comparatively higher α-amylase inhibitory activity than ethyl acetate and n-hexane extracts. The IC50 value of ethanolic extract for α-amylase inhibition assay was found to be 0.46 mg/mL at 0.5 mg/mL concentration (Krishnasamy and Muthusamy, 2015). The ethanolic extract of the leaf (200 mg/kg) has significantly reduced high blood glucose levels with a significant decrease of hyperlipidemia and

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reduction in cholesterol and triglycerides (Raja et al., 2013). The ethanolic extract of S. densiflorum fruits has also helped to improve insulin secre­ tion by β-cell restoration capacity. The increased concentration of ethanolic fruit extract of S. densiflorum has resulted in a significant reduction in BGL level of STZ-NA-induced rats. Triglycerides (TG) and total cholesterol (TC) content were found to be low and high-density lipoprotein cholesterol (HDL-C) was recorded as high in the treated rats (Krishnasamy et al., 2016). 58.3.5 ANTIOXIDANT ACTIVITY 58.3.5.1 ANTIOXIDANT ACTIVITY OF S. DENSIFLORUM The ethanolic extract of S. densiflorum fruits showed higher radical scav­ enging activity than ethyl acetate and n-hexane extracts. The IC50 values of ethanolic extracts by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, hydroxyl radical, superoxide radical, and lipid peroxidation assays were recorded as 0.01, 0.66, 0.16, and 0.46 mg/mL, respectively (Krishnasamy and Muthusamy, 2015). Jothiramshekar et al. (2013) reported that varia­ tions of plants growing at various altitudes have a significant impact on the various antioxidant activity of S. densiflorum. The leaf essential oil isolated from lower altitudes showed remarkably higher antioxidant activity than the higher altitude leaf oil. Leaf oil from a lower altitude has shown significantly higher activity against ferric ion, hydroxyl radical, and hydrogen peroxide. The ethyl acetate extract of S. densiflorum (S. benthamianum) leaves showed DPPH radical scavenging activity which possessed significant anti­ oxidant activity (94.7%) at a higher concentration (400 µg/mL) (Kiruthiga et al., 2011). The ethanolic extract of S. densiflorum leaves at 200 mg/kg concentration has significantly reduced the superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS). The IC50 value of ethanolic extract was found to be 79.00 ± 0.12 and 53.56 ± 0.20 µg/mL in nitric oxide method and DPPH method, respectively (Raja et al., 2013). Subramanian et al. (2014) evaluated the radical scavenging activities of methanol, hexane, and ethyl acetate extracts of S. densiflorum leaves. The maximum DPPH radical scavenging activity was recorded in ethyl acetate extract followed by methanol and hexane. Ethyl acetate and metha­ nolic extract have shown significantly high radical scavenging activity when compared with vitamin C. But hexane extract was recorded with

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very little activity. It has been reported that ethyl acetate extract has the highest ferric reducing power than methanol and hexane extracts (1.560, 1.037 and 0.604). In vivo experiments were carried out in STZ-NA induced rats with ethanolic fruit extract of S. densiflorum to analyze their antioxi­ dant property. The ethanolic extract-treated groups were observed with a reduced level of malondialdehyde (MDA), which indicated the reversal of lipid peroxidation (LPO) and antioxidant activity of fruit extract in STZ­ NA-induced rats. Also, a remarkable decrease was observed in superoxide dismutase (SOD) and catalase activity (CAT) in the disease control (Krish­ nasamy et al., 2016). 58.3.5.2 ANTIOXIDANT ACTIVITY OF S. TRAVANCORICUM Gopinath et al. (2017) worked on the green synthesis of dysprosium oxide nanosheets (Dy2O3 NS) using leaf extract of S. travancoricum. The synthe­ sized nanosheets were characterized by various spectral analyses, such as ATR-FT-IR, PL, UV–VIS–DRS, Raman spectroscopy, XRD, TEM with EDX, and XPS analysis. Rajalakshmi et al. (2018) carried out antioxidant studies on S. travan­ coricum and S. jambos leaf powders using in vitro methods. The ethanolic extract of S. travancoricum showed the highest rate of antioxidant activity when compared with S. jambos. S. travancoricum exhibited the highest level of polyphenol (4.72 g/100 g). However, further studies are required to understand the in vivo mechanisms of nutraceuticals effects and toxicity level. Pruthvi et al. (2020) investigated the antioxidant activity and total phenolic content of petroleum ether, chloroform, and ethanol crude extracts of Syzygium travancoricum leaves. The total phenolic content of petroleum ether was recorded as 5.70 µg of GAE and from chloroform and ethanol extracts, 23.34 and 27.76 µg of GAE were recorded respectively. The etha­ nolic extracts showed maximum absorbance at 1000 µg/mL concentration (1.60 and 2.31) followed by chloroform (1.13 and 2.05) and the petroleum ether (0.25 and 0.88). Ethanol extract has shown the highest percent of inhibition (96.11%) (DPPH), followed by 97.11% (nitric oxide), and 96.16% (ABTS scavenging assay). The study concluded that the scavenging activity of all three extracts was found to be increased with an increase in extract concentration.

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KEYWORDS • • • • •

antidiabetic antibacterial antihyperlipidaemic endemic trees southern Western Ghats

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CHAPTER 59

Bioactives and Ethnopharmacology of Pittosporum napaulense (DC.) Rehder & E.H. Wilson B. KAVITHA1* and N. YASODAMMA2 1Department

of Botany, Rayalaseema University, Kurnool, Andhra Pradesh 518007, India

2Department

of Botany, Sri Venkateswara University, Tirupati, Andhra Pradesh, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Pittosporum napaulense, of family Pittosporaceae, is a shrub or small tree. The present review gives an account on bioactives and pharmacological activitie of P. napaulense. Different extracts of P. napaulense showed a range of secondary metabolites including phenols, flavonoids, alkaloids, terpe­ noids, anthraquinones, tannins, steroids, lignins, saponins, glycosides and fixed oils. Acute toxicity studies revealed that aqueous extracts showed high toxic effects than the methanol and alcohol extracts of bark. The extracts of the different parts of P. napaulense were subjected to neuropharmacological and behavioral activities, analgesic, antiarthritic and anti-inflammatory activities and showed that the methanolic extract of bark is having prom­ ising activities than the other extracts. 59.1 INTRODUCTION Pittosporum napaulense (DC.) Rehder & E.H. Wilson belongs to the family Pittosporaceae. Synonyms of this species include Celastrus verticillatus Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Roxb., Pittosporum floribundum Wight & Arnott ex Royle, Pittosporum verticillatum Wall., Senacia napaulensis DC. (https://indiabiodiversity. org/species/show/263778). It is commonly called as golden fragrance cheesewood, ginger tree (English), rakamuki, chettu kasind (Telugu), raini, bagh muta, kisan, tumri (Hindi), chachin, debosunda, devson, devasundha, purshpashan (Odia), kattu sampangi, najundai, tammata (Tamil), kasumaram tumari, vikharl, vekhali, ekkadi, tammatha (Kannada), kasumaram (Malay­ alam), vehkali, vehyenti, vikhari, yekadia, yekkuddy (Marathi), dieng­ duma, dieng thyllong (Khasi), khorsane (Nepali), and shi-ing dieng-mulo (Assamese) in their native languages (https://www.catalogueoflife.org/data/ taxon/77LSF; Gunsai et al., 2020). This species is distributed in China, SE-Tibet, Bangladesh, Bhutan, Nepal, Pakistan, Myanmar, and India. It is found in wet pasture lands near water, up to 3,000 ft. in hilly country (https://www.flowersofindia.net/catalog/slides/ Golden%20Fragrance.html) These plants are small evergreen trees or erect shrubs, usually green. Bark very thin, surface rough with very prominent horizontal lenticels. Leaves clustered at branchlet apex, biennial; petiole stout, 1–2 cm, shiny green, leaf blade dark brown adaxially, oblong or oblong-lanceolate, thick leathery, glabrous abaxially. Flowers small greenish-white to cream, on terminal, paniculate or compound corymbose, usually brown pubescent. Capsule globose, 6–7 mm in diam, 1-celled, woody, 2- or 3-valved. The fruit capsule is typically split open. Seeds 2–3 mm in diam, 2–9 and orange, covered with oily resinous pulp. Flowering March–May, fruiting May–November (Singh and Diwakar, 2009). Root paste is externally applied to dropsical and rheumatic swellings. The roasted bark of young trees is used in the treatment of dysentery (Uphof, 1959). Bark powder in high dose internally acts as antidote to snake poison, general weakness, anemia, and stimulant and for preventing abortion in young women (Kirtikar and Basu, 1975). Bark decoctions or infusions are widely used to treat stomach complaints, abdominal pain, skin disease, chest infection, and fever (Burkill, 1985). The bark is used as a medicine against anemia and for preventing abortion in young women (Lovett et al., 2006). Bark powder is internally used for chronic bronchitis, leprous affections, and externally used for inflammatory, dropsical, rheumatic swellings, various forms of cutaneous diseases, secondary syphilis, chronic rheumatism, chronic bronchitis, and asthma (Pullaiah, 2006; Savithramma et al., 2007). Bark powder is externally used for ease pain and have a calming affect used in arthritis, inflammatory, spasmodic, sciatica, and sprains (Uphof, 1959). Bark

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paste is externally used for inflammatory, dropsical and rheumatic swelling, skin diseases and itches. It is mixed with root paste of Salacia brunoniana and applied externally on piles, and bark oil is externally used for rheuma­ tism, skin diseases, secondary syphilis (Pullaiah, 2006; Khare, 2007, 2008), itching, rheumatism, leprosy, sprain, bruises, sciatica, pulmonary affections, phthisis, and ophthalmia (www.Scribd.com/doc/pittosporum P. floribundum W.&A. for 6102281—Medicinal Plants, 2011). The dried root powder or bark is sometimes added to beer as an aphrodisiac (http://pza.sanbi.org/ pittosporumviridiflorum-plantzafrica.com). Mature fruit is internally eaten as a refrigerant and also for gastric discomfort (Manikandan, 2008). Ripen fruits are internally used for jaundice and piles (Ekka, 2016). Wood sticks are internally used for chewing sticks for oral care (Muhaseena et al., 2014). The narcotic action of the bark is due to the presence of yellow oleoresins, and also contains saponins and pittosporins (https://www.healthdictionary. org/pittosporum-floribundum). 59.2

BIOACTIVES

Stem bark, leaf, flower, fruit, and seed different extracts of P. napaulense (P. floribundum) were subjected to phytochemical screening represented alkaloids, phenols, flavonoids, lignins, anthraquinone, tannin, terpenoids, steroids, saponins, and glycosides. Fixed oils are present in all parts of all solvents. Methanol and alcohol extracts yielded highest number of phyto­ constituents in all parts (Nagamalleswari et al., 2013; Gandhi et al., 2019). The major chemical constituents présent in P. napaulense (P. floribundum) are phenolic compounds and flavonoids. The major phenolic compounds from stem bark are caffeic acid, gentisic acid, o-pyrocatechuic acid, transp-coumaric acid, o-coumaric acid, vanillic acid, and two unknown. Leaves possess salicylic acid, cinnamic acid, homoprotocatechuic acid, trans-sinapic acid, ferulic acid, phloretic acid, vanillic acid, melilotic acid, phloroglucinol, trans–chlorogenic acid and three unknown. The flowers contain neo–chlo­ rogenic acid, caffeic acid, scopoletin, m-hydroxybenzoic acid, o-coumaric acid, coumarin, salicylic acid, cis–sinapic acid, protocatechuic acid, o-pyrocatechuic acid, and three unknown. Fruit consists of neo–chlorogenic acid, caffeic acid, gentisic acid, m-hydroxybenzoic acid, homoprotocat­ echuic acid, cinnamic acid, coumarin and six unknown; seed with caffeic acid, protocatechuic acid, m-hydroxybenzoic acid, homoprotocatechuic acid, o-pyrocatechuic acid, cis–sinapic acid, trans-sinapic acid, and and six unknown compounds reported (Nagamalleswari, 2015).

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The major flavonoid compounds from stem bark are quercetin and one unknown. Leaves consist of quercetin, luteolin, and orientin. Flowers contain kaempferol and one unknown. Fruit consists of kaempferol, orientin, and quercetin. Seed has luteolin and quercetin (Nagamalleswari, 2015). Chemical Structures: Flavonoids

The major phytochemical constituents reported from P. napaulense (P. floribundum) are essential oils which include alpha-pinene, dipentene, linalool, cineol, methyl salicylate, decyl aldehyde, anisaldehyde, bergapten, eugenol, indole, salicylic, and benzoic acid (Sreelekha, 2012). The bark contains saponin, pittosporin (Khare, 2007). Stem bark oil with major constituents as n-tetradecanal, n-dodecanoic acid, butyl methyl ketone, and β-acoradiene (Sreelekha, 2012).

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59.3

PHARMACOLOGICAL STUDIES

59.3.1 ANTIMICROBIAL ACTIVITY The antimicrobial studies of P. floribundum aqueous, alcohol, methanol, hydroalcoholic, and ethyl acetate extracts of stem bark, leaf, fruit, and seed against Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa,

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Staphylococcus aureus, and on fungal strains Candida albicans and Asper­ gillus niger proved as the stem bark methanol extracts showed more effec­ tive inhibition zones against all selected microbial strains at 20–30 mg/mL with 16–25 mm inhibition zone. Further minimum inhibitory concentration ranges between 0.312 and 1.25 mg compared with Ampicillin and Nystatin (Nagamalleswari et al., 2013; Gandhi et al., 2019). 59.3.2 ACUTE AND SUB-ACUTE TOXICITY Acute toxicity studies of P. floribundum bark aqueous, methanol, and alcohol extracts were determined LD50 (Lethal Dose) values and behavioral studies on experimental rats. Aqueous extracts showed high toxic effects showing LD50 at 1337.5 mg/kg b.wt with effective lethal dose as the log dose 3.126 and the probit values 5.0. The bark methanol and ethanol extracts showed LD50 at 1834.6 mg/kg b.wt with log dose 3.265 and the probit value 5.0. Aqueous extract toxicity was observed until the death of all (100%) animals at 1800 mg/kg b.wt with methanol and ethanol at 2500 mg/kg b.wt. These doses are needed for the standardization of safe acute apply of the drug. Aqueous extracts showed high acute toxicity and sedative effective from 600 to 1800 mg/kg b.wt and 1300–2500 mg/kg b.wt with methanol and ethanol extracts. There is no sedative effect up to 2500 mg/kg b.wt. Hence, the usage of crude drugs may be recommended in sublethal doses after screening for subacute toxicity studies. All extracts up to 2500 mg/kg b.wt there is no change in the behavior of the experimental rats (Nagamalleswari et al., 2014). Sub-acute toxicity studies with all extracts between 10 and 150 mg/kg b.wt of daily doses up to 28th day behavioral observations, such as skin and fur, eyes, mucous membrane, salivation, diarrhea, anesthesia, sleep, coma morbidity, itching, tremors, lethargy, teeth condition, and in breathing abnormalities were recorded. Further no behavioral changes observed until the end of the experiment. Also observed the effect on water and food intake, body weight, organ weights, and hematological parameters with all extracts ranges from 10 mg to 150 mg kg b.wt of daily dose up to 28 days the effect on the growth and body mass of the rats was recorded from day one to 28th day. There is no much effect in hematological parameters, body mass, and difference in food and water intake up to dose level of 75 mg/kg b.wt. All extracts showed almost all same effect on the organ weight changes but at 150 mg/kg b.wt there is significant reduction in all organ weights. Effect

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of all extracts on biochemical parameters during sub-acute toxicity studies was observed significant decrease with concentration gradiance of drug. Total protein and albumin concentration were less affected with all extracts (Nagamalleswari et al., 2014). 59.3.3 ANTI-INFLAMMATORY ACTIVITY Carrageenan-Induced anti-inflammatory activity of P. floribundum stem bark, leaf, and seed aqueous, alcohol, and methanol extracts at 25 mg/kg. b.wt were proved more effective as anti-inflammatory, analgesic drug, and also sedatives may be applied as immediate analgesic and anti-inflammatory drug during emergency periods with a single dose. Diclofenac sodium was used as standard anti-inflammatory drug (Yasodamma et al., 2015a). 59.3.4 NEUROPHARMACOLOGICAL AND BEHAVIORAL ACTIVITIES P. floribundum stem bark aqueous, alcohol, and methanol extracts at 75 mg/ kg b.wt showed effective analgesic activity by reducing the writhings which indicates its action in the reduction of endogenous substances, such as pros­ taglandins, histamines, and serotonins, and thus reduces the pain. Increase in learning activity with the less number of head pokings into the hole, and further, animals started free floating on water showed as antianxiolytic drug, which may be due to the regulation of neurotransmitters. Sleeping duration of the drug (sedative/narcotic) also becomes less than that of the normal rats to that of phenobarbitone-treated rats, which showed its action as antidepres­ sant drug to that of Diazepam. Also proved bark aqueous extracts showed more sedative effect than the standard drug Diazepam. When compared with traditional antidepressant drug Diazepam, Significantly decreased number of locomotor movements than the normal rats were observed, which proved this antianxiolytic drug to be as sedative, analgesic, and also as narcotic drug (Yasodamma et al., 2015b). 59.3.5 ANTIARTHRITIC Antiarthritic activity of P. floribundum stem bark, leaf, and seed methanol, aqueous, and alcohol extracts at 75 mg showed the effect on paw volume, body weight on adjuvant-induced arthritic rats showed inhibition in the paw edema as 67.5%, 65%, and 62.5%, respectively. The treatments with bark

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extracts produced increased activity with increase of dose in the decrease of the rat paw edema as compared with the control after 21 days of drug treatment with individual daily doses. Decreased in body mass was observed at the dose level of 75 mg of all extracts on arthritic rats due to alteration in metabolic activities and also due to reduced absorption of leucine and glucose in rat intestine. Further studies have been conducted to test its effect on biochemical parameters and hematological parameters. Arthritic rats treated with drug extracts at 75 mg showed significant decrease in alkaline phosphatase 385.6, 400.7, and 450.2 aspartate amino transferase 148.8; 169.8, and 165.8 and alanine amino transferase 50.63; 53.42, and 56.73 IU/L respectively with all the three extracts. Arthritic rats treated with bark extracts showed significant decrease as that of diclofenac sodium-treated rats, the lymphocytes 52.46%; total WBC 5680 cells/cu.mm count, and ESR6.83 mm/h levels (Nagamalleswari, 2015). KEYWORDS • • • • •

Pittosporum napaulense pittosporaceae bioactives acute toxicity anti inflammatory

• • •

antiarthritic neuropharmacological behavioral activities

REFERENCES Burkill, H. M. The Useful Plants of West Tropical Africa; Families AD, Vol. 1; Royal Botanic Gardens, 1985. Ekka, A. Some Ethnomedicinally Important and Rare Plants of North-East Chhattisgarh India. Int. J. Adv. Res. Eng. 2016, 5 (10), 97–102. Gandhi, A. J.; Shukla, V. J.; Acharya, R. N. Qualitative, Quantitative Screening and Antifungal Study of Pittosporum floribundum Wight & Arn. J. Phytopharmacol. 2019, 8 (6), 299–302. Gunsai, K. K.; Gandhi, A. J.; Acharya, R.; Shukla, V. J. Ethnomedicinal Uses, Phytochemistry and Pharmacological Activities of Pittosporum floribundum Wight. & Arn.—A Review. Eur. J. Med. Plants 2020, 31 (3), 48–55.

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Khare, C. Pittosporum floribundum Wight & Arn. In Indian Medicinal Plants; Khare C., Eds.; Springer: New York, NY, 2007. Khare, C. P. Indian Medicinal Plants: An Illustrated Dictionary; Springer Science & Business Media, 2008; pp. 496–497. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants; International Book Distributors: Dehradun, India, Print., 1975; p 3:437. Lovett, J. C.; Ruffo, C. K.; Gereau, R. E.; Taplin, J. R. Field Guide to the Moist Forest Trees of Tanzania; Society for Environmental Exploration: London, UK, 2006; pp 1–303. Manikandan, P. A. Ethno-Medico-Botanical Studies of Badaga Population in the Nilgiri District of Tamilnadu, South India. Anc. Sci. Life. 2008, 27 (3), 50–59. Muhaseena, M. S.; Priyal, G.; Shakil, M.; Najim J.; Vidya, P.; Vishnudas, P. Medicinal Properties of Pittosporum and It’s Applicability in Oral Lesions. Univers. J. Pharm. 2014, 3 (3), 45–48. Nagamalleswari, K. Phytochemical and Biological Studies of Pittosporum floribundum Wt. & Arn. Ph.D. Thesis, Sri Venkateswara University, Tirupathi, 2015. Nagamalleswari, K.; Yasodamma, N.; Binny, A. J. R. Phytochemical Screening, Antibacterial and Antifungal Studies of Pittosporum floribundum Wight & Arn. Leaf, Bark, Fruit and Seed Extracts. Int. J. Pharm. Bio. Sci. 2013, 4 (2), 464–474. Nagamalleswari, K.; Yasodamma, N.; Chaitra, D. Acute Toxicity Studies of Pittosporum floribundum Wt. & Arn. A Herbal Drug from Tirumala Hills. Golden Res. Thoughts 2014, 4 (1), 1–8. Pullaiah, T. Biodiversity in India; Daya Books, 2002; p 4,481. Pullaiah, T. Encyclopedia of World Medicinal Plants; Vol. 2; Regency Publications: New Delhi, 2006; pp 1556–1557. Savithramma, N.; Sulochana, C.; Rao, K. N. Ethnobotanical Survey of Plants Used to Treat Asthma in Andhra Pradesh, India. J. Ethnopharmacol. 2007, 113 (1), 54–61. Singh, R. K.; Diwakar, P. G. Notes on the Identity and Taxonomic Status of Some Species and Infraspecific Taxa of Genus Pittosporum Banks ex Soland. J. Non-Timber For. Prod. 2009, 16 (3), 211–214. Sreelekha, M. Studies on Secondary Plant Metabolites and Their Biological Properties. Doctoral Dissertation, University of Calicut, Kerala, 2012. http://hdl.handle. net/10603/11195. Uphof, J. C. Dictionary of Economic Plants; 1959. www.Scribd.com/doc/pittosporum Pittosporum floribundum W.&A. for 6102281—Medicinal Plants, 2011. Yasodamma, N.; Malleswari, K. N.; Chaithra, D. Antiinflammatory Activity of Pittosporum floribundum Wt. & Arn. World J. Pharm. Pharm. Sci. 2015a, 4 (2), 351–362. Yasodamma, N.; Nagamalleswari, K.; Alekhya, C. Neuropharmacological and Behavioral Studies of Pittosporum floribundum Wt. & Arn. World J. Pharm. Pharm. Sci. 2015b, 4 (2), 363–381. https://indiabiodiversity.org/species/show/263778. https://www.flowersofindia.net/catalog/slides/Golden%20Fragrance.html. https://www.catalogueoflife.org/data/taxon/77LSF. http://pza.sanbi.org/pittosporumviridiflorum-plantzafrica.com. https://www.healthdictionary.org/pittosporum-floribundum

CHAPTER 60

Tree of Heaven: Ailanthus excelsa Roxb.— Chemistry and Pharmacology DIGAMBAR N. MOKAT* and TAI D. KHARAT Department of Botany, Savitribai Phule Pune University, Pune, Maharashtra 411007, India *Corresponding

author E-mail: [email protected]

ABSTRACT The tree Ailanthus excelsa Roxb. (Simaroubaceae) is commonly known as ‘Tree of Heaven’. Traditional uses, phytochemical and pharmacological investigation and Ayurvedic formulation have given the backbone to make this tree as a ‘Tree of Heaven’. It has antihypertensive, antispasmodic, anthelmintic, cardiac depressant properties and is used for treating extreme vaginal discharge, malaria, asthma, epilepsy, cough, cancer, colic pain, and polygenic disorder. It is used in the folk medicine for treating inflamma­ tion and rheumatoid arthritis. The stem bark and leaves are rich in bioactive compounds belonging to the classes lignin, glycosides, phenol, tannins, alkaloids, proteins, steroids, carbohydrates, flavonoids and saponins. 60.1 INTRODUCTION Ailanthus excelsa Roxb. (Simaroubaceae) is usually known as “Mahanimba” due to its similarity with Azadirachta indica (Neem tree) and Tree of Heaven in English. The word Ailanthus is from “ailanto,” that is, Tree of Heaven and in Latin word of “excelsa” means tall. It is a quick rising tree widely cultivated in several parts of India, in the locality of various villages. The Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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tree is indigenous to southern and central India and it is high of commercial and economic importance. The bark is smooth and light grayish in young trees with large leaf-scars, rough, granular, and grayish brown in older trees. Leaves are pinnately compound and up to 90 cm long with 8–14 leaflet pairs. Flowers are small with yellowish in panicles and fruits single-seeded samara (Shrimali et al., 2001). Ailanthus is the major constituent of the ayurvedic preparations, such as Brahat Gangadhara churna, Pusyanuga churna, and Aralu putpaka used in the management of atisara, arsa, krimi, brama, tvakroga, grahani, sannipatajwara, pravahika, prameha, gulma, swasa, and visaja roga (Khan et al., 1994; Lavhale and Mishra, 2007b). A. excelsa is used in the treatment of diarrhea and infectious diseases, especially in the case of blood in stool, the bark has been utilized in Austra­ lian medicine and Asian medicine to counteract worms, extreme vaginal discharge, malaria, asthma, antispasmodic, cardiac depressant properties, cure epilepsy, and heart problems (Chevellier, 1996). It has noticeable anti­ spasmodic and cardiac depressant possessions (Nadkarni, 1976). In Indian medicine system, A. excelsa is used in the treatment of respira­ tory disorders, cough, cancer, colic pain, polygenic disorder, and also used as antispasmodic, antifertility, bronchodilator, etc. Stem bark is reported for its potential against asthma (Ghumarea et al., 2014). The pollens are reported to be allergic in nature, hence, the leaves are collected at nonflowering stage. The bark is bitter, astringent, appetizer, anthelmintic, febrifuge used in dysen­ tery, earache, skin disease, rectum troubles, fever due to tridosha, dyspepsia, bronchitis, and asthma (Kirtikar and Basu, 1995; Polonsky, 1973). Fruits are used in the treatment of diarrhea, piles, polyurea, and fever. The root bark is used to cure epilepsy and heart diseases. In Africa, this plant is used in action to cure gonorrhea epilepsy, cramps, tape worm infestation, and high blood pressure (Sharma, 1996). Historically, the mattress prepared of leaves is used as bed for kids once affected by fever (Kirtikar and Basu, 1995). Due to the antihypertensive properties, the leaves of A. excelsa are utilized in Egyptian traditional medicine. 60.2

PHYTOCONSTITUENTS

The therapeutic importance of A. excelsa leaves is due to presence of lignin, glycosides, phenol, tannins, and saponins (Bhatt and Dhyani, 2012). The preliminary phytochemical compounds are glycoside, alkaloids, proteins, steroids, tannins, carbohydrates, phenolic compounds, flavonoids, and sapo­ nins (Kapoor et al., 1971). Three quassinoids, 1,2 and 3,4-dihydro excelsin

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(3) were sequestered from bark of stem, as well as five known quassinoids excelsin, glaucarubine, ailanthinone, glaucarubinone, and glaucarubolone. The glaucarubolone has been sequestered for the first time of this plant. The structural clarification is based on the analysis of spectroscopic data (Joshi et al., 2003b). Chromatographic separation of methanolic extract yielded six flavonoids for the first time from this species, namely, apigenin, luteolin, kaempferol-3-O-α arabinopyranoside, kaempferol-3-O-β-galactopyranoside, quercetin-3-O-α-arabinopyranoside, and luteolin-7-O-β-glucopyranoside (Loizzo et al., 2007). Quassinoids, namely, excelsin, glaucarubine, ailanthi­ none, glaucarubinone, and glaucarubolone are present in the bark of the stem. The leaves contain different flavonoids, such as kaempferol, luteolin, and apigenin and the fruits contain quercetin (Singh et al., 1983). A. excelsa has several biocompounds, such as quassinoids, alkaloids, terpenoids, and sterols, and it also has many bioactivities, such as hypo­ glycemic, gastroprotective, and antisecretory effects, bronchodilator, antifertility, anticancer, and antimicrobial activities (Khaled and Feitosa, 2019). Methanolic extract of leaves showed the presence of flavonoids, quassonoids, terpenoids, saponins, steroids, and alkaloids. The plant extract showed the presence of quercetin flavonoid which is noticed on the prepara­ tive TLC plate with the help of standard quercetin (Kumar et al., 2011). The phytoconstituents study of the leaves of A. excelsa discovered the presence of alkaloids, saponins, sterols, flavonoids, proteins, carbohydrates, and phenolic compounds (Siju et al., 2015). The phytochemical study and characterization of isolated alkaloidal fraction from the leaf showed the presence of triacetonamine, that is, 2,2,6,6-tetramethyl-4-piperidione (Tamboli and Kondawar, 2013). Quassinoid, 13,18-dehydroexcelsin and glaucarubol, excelsin, glaucarubin, all C20-quass­ inoids isolated from A. excelsa (Khan and Shamsuddin, 1978, 1980). The qualitative identification test discovered the presence of steroidal alkaloids, terpenoids, alkaloids, protein, fat, and oils in chloroform extract and glycoside, saponin, flavonoids, alkaloids, sugar in ethanol extract, and glycoside, protein, sugar in aqueous extract as well as fat and oils were present in the extract of petroleum ether. In all extracts tannin was absent (Bhatia and Sahai, 1985). 60.3 PHARMACOLOGY The leaf and bark extracts are astringent, anthelmintic, appetizer, febrifuge, bitter tonic, and taste bud stimulating (Mokat and Deokule, 2004; Bhalke and Giri, 2020). It is used as a folk medicine therapy for inflammation and

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rheumatoid, it has antipyretic, antifertility, antimalarial, antifungal and anti­ bacterial, antioxidant activity, diabetes, and anticancer properties (Bhandari and Gupta, 1972; Verma, 2016). 60.3.1 HEPATOPROTECTIVE ACTIVITY Ethanol extract of A. excelsa leaves revealed the protecting effects against CCl4-induced liver damage as shown by an important reduction in the CCl4 induced raised enzyme levels of serum glutamate oxaloacetate transaminase, alkaline phosphatase serum, and glutamate pyruvate transaminase. The phenolics might be responsible factor for the hepatoprotective activity (Lavhale et al., 2003a, 2003b). The hepatoprotective significance of etha­ nolic extract stem bark of A. excelsa was assessed in Wister albino rats by causing CCl4-induced liver damage.. The ethanolic extract at oral dose of 200 mg/kg showed hepatoprotective effect by lowering serum enzyme levels of glutamic pyruvic transaminase (SGPT), glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), and total bilirubin (TB) (Yoganandam et al., 2009a). The ethanolic extracts of the bark and leaves of A. excelsa were studied for hepatoprotective activity on investigational induced liver damage with CCl4. Both the extracts caused significant decrease in the raised enzyme levels of serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, and serum alkaline phosphatase. These results are suggestive of important hepatoprotective activity of the ethanolic extracts (Hukkeri et al., 2002). 60.3.2 HYPOTENSIVE ACTIVITY The in vitro hypotensive activities of the methanol extract and the isolated phytocompounds were clarified. All the flavonoids tested and displayed ACE inhibitory activity. In exact, the greatest active phytocompound was kaempferol-3-O-β-galactopyranoside with an IC50 value of 260 µM (Loizzo et al., 2007). The leaves showed that the screening program for antihyperten­ sive properties of plants exhibited a potent antihypertensive activity (Kundu and Laskar, 2010). 60.3.3 ANTIBACTERIAL ACTIVITY Silver nanoparticles were manufactured in a cost-effective and eco-friendly way by using aqueous leaf extract of A. excelsa. The leaf extract helped in the

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bioreduction of silver ions yielding silver nanoparticles. These biologically manufactured silver nanoparticles were found to show brilliant antibacterial effect against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and anticancer effect in contradiction of MCF-7 cell line (Vinmathi and Jacob, 2015). Ethyl acetate fraction bark of dried stem inhibited the growing of E. coli, S. aureus, and Bacillus subtilis (MIC: 6 mg disc G). Three active principles 1,12-deoxy-13-formylailanthinol, excelsin, and 13,18-dihydroexcelsin isolated from bark, which are responsible for antibacterial activity (Kumar et al., 2010a). 60.3.4 ANTICANCER ACTIVITY Four different compounds viz., glaucarubinone, ailanthione, combination of glaucarubol 15-isovalerate, and 13,18-dehydroglaucarubol 15-isovalerate were found. These different compounds are in control for tumor and cyto­ toxic activities of A. excelsa root bark extracts (Ogura et al., 1977). A. excelsa chloroform extract-1 (AECHL-1) treatment for 12–48 h. inhib­ ited cell proliferation and induced death in cell viz., B16F10, MDA-MB­ 231, MCF-7, PC3 with lowest growing inhibition in normal HEK 293. The antitumor conclusion of AECHL-1 was corresponding with conservative antitumor drugs paclitaxel and cisplatin. AECHL-1-induced growing inhibi­ tion was interrelated by S/G2-M detentions in MDA-MB-231, MCF-7, and PC3 cells and a G1 detention in B16F10 cells. Microtubule disruptions in MCF-7 cells treated with AECHL-1 in vitro were observed. Compared with control, hypodermal injection of AECHL-1 to the sites of tumor of mouse melanoma B16F10 fixed in C57BL/6 mice and human breast cancer MCF-7 cells in athymic nude mice showed in important diminution in tumor volume. In B16F10 tumors treated with AECHL-1 at 50 µg/mouse/day dose for 15 days the augmented expression of tumor suppressor proteins P53/p21 and diminution in the expression of the oncogene c-Myc, as well as depressed regulation of cyclin D1 and cdk4 were observed. Furthermore, AECHL-1 treatment established in the phosphorylation of p53 at serine 15 in B16F10 tumors, which look as if to show p53-dependent growth inhibitory responses (Lavhale and Mishra, 2007a). 60.3.5 ANTIFUNGAL ACTIVITY The presence of triterpenes type compounds confirmed by phytochemical analysis indicated that if detailed research is carried out on A. excelsa, some

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useful drugs may be developed for the treatment of fungal infection. The stem bark methanol extract of A. excelsa was separated by chloroform. The chloroform extract showed fungistatic and fungicidal activity in against Aspergillus niger, Aspergillus fumigatus, Penicillium requentence, Peni­ cillium notatum, and Botrytis cinerea (Joshi et al., 2003a). The antifungal activity of A. excelsa was evaluated using human pathogenic organism, such as A. niger, A. fumigatus, Aspergillus flavus, and P. notatum. The methanol extract of chloroform fraction revealed important wide spectrum of inhibi­ tion at 500 mg/mL concentration on fungi (Ratha et al., 2013). The various extracts of A. excelsa bark were also divided for antifungal activity against the fungal strains viz., A. terrus, A. niger, and A. flavus. The petroleum ether extract indicated little activity in contradiction of the Aspergillus terrus, A. niger, and A. flavus organisms when paralleled with standard drug of flucanazole. The methanol extract showed reasonable activity and the ethyl acetate extract displayed good activity in contradiction of A. terrus, A. niger, and A. flavus at 1 mg/mL paralleled to standard flucanazole (Patil et al., 2010). 60.3.6 ANTIASTHMATIC AND ANTIALLERGIC ACTIVITY In the treatment with methanol extract of leaves at 100 µg/mL in vitro and 100, 200, and 400 mg/kg p.o. in vivo models, different dose levels showed antiasthmatic activity. Inhibition of inflammatory intermediaries potentiates the antiasthmatic and antiallergic activity of methanol extract of leaves (Kumar et al., 2011). The antiallergic potential of leaves’ aqueous extract of A. excelsa at doses 100, 200, and 400 mg/kg, p.o. was assessed by using milk-induced leucocytosis and eosinophilia in mice, passive paw anaphylaxis in rat models though the anti-cataleptic assets were assessed by clonidine-induced catalepsy in mice mode. The extract pointedly condensed the leucocytosis and eosinophilia along with passive paw anaphylaxis in the investigational animals. The extract also importantly condensed clonidine­ induced catalepsy in mice. These results mention that leaves aqueous extract of A. excelsa may have the potential healing value in the cure of hypersensi­ tive diseases and to create adaptogenic properties (Kumar et al., 2010b). Stem bark methanolic extract of A. excelsa was assessed by using in vitro goat tracheal chain research model and in vivo milk-induced eosinophilia, milk-induced leucocytosis and clonidine-induced catalepsy in mice experi­ mental models. Treatment with methanolic extract of stem bark of A. excelsa

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at 30 μg mL−1, In vitro and 100, 200, and 400 mg kg−1 p.o. in vivo revealed significant decrease in marks and severity of symptoms. The consequences from many studies reveal that the antihistaminic activity of stem bark metha­ nolic extract of A. excelsa may be due to the decrease in histamine-induced reduction in goat tracheal chain research model and mast cell stabilizing potential. Inhibition of discharge of inflammatory intermediaries by reducing total leucocytes and eosinophiles count, potentiate the antiasthmatic activity (Kumar et al., 2010c). 60.3.7 HYPOGLYCEMIC ACTIVITY A single organization of leaves or stem bark extracts pull down the blood glucose of normal rats in a glucose tolerance test. Organization of each extract for 60 days produced important hypoglycemic effect on STZ-induced experimental diabetic rats, with enhanced renal parameters, which suggest its potential use in the cure of diabetes (Genta et al., 2005). 60.3.8 ANTIFERTILITY ACTIVITY The alcoholic extract of leaf and stem bark at a dose of 250 mg equal of plant material/kg body weight indicated strangely great anti-implantation and initial abortifacient activity in female albino rats. The results were in conformity with the traditional use of this plant by Irula women from the district of Nilgiri as an abortifacient (Dhanasekaran et al., 1993). The outcome of hydroalcoholic extract of stem bark (HEA) has been studied in rats to discover its antifertility activity. A strong anti-implantation (72%) and abortifacient activity (56%) was detected at the tested dose levels (200 and 400 mg/kg). The extract showed furthermore, significant rise in uterine weight in immature ovariectomized rats. Immediate management of extract with ethinylestradiol causes important antiestrogenic activity. All these explanations recommend that hydroalcoholic extract of A. excelsa has antifertility effect (Ravichandran et al., 2007). 60.3.9 GASTROPROTECTIVE AND ANTISECRETORY ACTIVITY Melanchauski et al. (2010) assessed the gastroprotective effect of four different extracts, that is, diethyl ether, petroleum ether, chloroform, and methanol extract of A. excelsa bark used by the ethanol-induced gastric lesion model. The pretreatment of experimental animals by using methanolic, petroleum

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ether, and chloroformic extracts (100 mg/kg, oral (p.o.)) of A. excelsa impor­ tantly reduced gastric lesion induced by ulcerogenic agent (56%, 47%, and 70%, respectively) as soon as equated with animals pretreated by vehicle. The diethyl ether pretreatment led to the least gastric lesion injury (83%), equivalent to the standard antiulcer drug, cimetidine, at the same dose (100 mg/kg, p.o.). The negligible in effect dose of diethyl ether extract, as well as cimetidine, given by intraduodenal route, expressively improved the pH values and condensed the acid production of gastric juice. Quassinoids, sterols and triterpenes are obtained in the diethyl ether stem bark extract of A. excelsa, which obtained the best gastroprotective action amongst the studied extracts. Therefore, A. excelsa tree showed the gastroprotective and antisecretory effects. 60.3.10 BRONCHODILATOR ACTIVITY The stem barks of A. excelsa used in traditional medicine. So, Kumar et al. (2010d) evaluated A. excelsa bark of nebulizer activity in eosinophilia and milk-induced leucocytosis, clonidine-induced mast cell degranulation, lung histopathology models, and bronchoalveolar lavage fluid (BALF). The stem bark aqueous extract of A. excelsa in doses of 100, 200, and 400 mg/kg indicated very significant activity (Kumar et al., 2010d). 60.3.11 ANTIDIARRHEAL ACTIVITY Methanolic extract of root bark of A. excelsa (MEA) was assessed by Munesh et al. (2011) by castor oil persuaded diarrhea and small intestinal transfer method at three doses, such as 100, 150, and 200 mg/kg/body wt. mice. The percentage (%) of inhibition of castor oil persuaded diarrhea in MEA-treated experimental mice was 55.27%, 66.33%, and 63.81% at 100, 150, and 200 mg/kg, respectively. Mean distance traveled by charcoal, as the percentage (%) of entire distance of small intestine (cm) is fewer at 150 mg/ kg of the dose of MEA and is comparable with the standard drug atropine sulfate which is used as a positive control and it is statistically significant. Therefore, it was recommended that A. excelsa can raise the absorption of water and electrolytes from the gastrointestinal tract while the extract condensed the small intestinal transfer. These results justify that come A. excelsa is useful in the treatment of diarrhea (Munesh et al., 2011).

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60.3.12 ANTI-INFLAMMATORY ACTIVITY Siju et al. (2015) assessed the in vitro anti-inflammatory activity of fractions of A. excelsa by human red blood cells (HRBCs) membrane stabilization. The reaction combination (2 mL) involved 1 mL test sample of concentra­ tions (1000 μg/mL) and 1 mL of 10% HRBCs suspension, instead of test sample, only saline was additional to the control test tube, and indomethacin was used as standard drug. The inhibition of heat induced HRBCs membrane lysis was taken as a portion of the anti-inflammatory activity. The methanol extract showed the greatest important membrane stabilizing action on HRBCs membrane. The extreme membrane stabilization of methanol extract of A. excelsa was found as 91.13% at dose 1000 μg/mL (Siju et al., 2015). The anti-inflammatory activity was deliberate by formalin-induced rat hind paw edema, which was measured by plethysmograph. Wistar strain rats of either sex weighing between 150 and 200 g were separated into five groups, each group consists of six animals. The first group was used as the control and established the vehicle, that is, Tween 80, the animals of second group were managed with standard drug diclofenac sodium, 200 mg/kg body weight. The animals of third, fourth, and fifth experimental groups were cured with crude extracts of A. excelsa bark at a dose of 200 mg/kg of body weight, orally. The volume of paw edema was measured in control and standard and treated groups consequently 1, 2, 3, and 4 h after formalin injection. The spectrum was used examine the anti-inflammatory activity of numerous parts used. At 1 h, diclofenac sodium revealed good anti-inflammatory activity equated to crude extracts. At 2 h, diclofenac sodium and ethyl acetate part designated good anti-inflammatory compared with the other groups. Similarly, at 3 h, diclofenac sodium and ethyl acetate part, methanol part indicated good antiinflammatory activity. At 4 h, anti-inflammatory activity was statistically dissimilar in all the test groups excluding petroleum ether part. It means, diclofenac sodium displayed maximum anti-inflammatory activity followed by crude extracts. Henceforth, the outcomes of the present examination determine that the ethyl acetate and methanol extract of A. excelsa bark is liable for the anti-inflammatory activity (Patil et al., 2010). 60.3.13 ANTIHYPOLIPIDEMIC ACTIVITY The stem bark of the A. excelsa was examined for hyperlipidemia-correlated disorder which is one of the main danger factors of coronary heart disease and atherosclerosis. The hypolipidemic activity of ethanolic extract and its

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parts of stem bark of A. excelsa was assessed on triton WR 1339-induced hyperlipidemic model, and significant results were obtained using the frac­ tionated part of ethanolic extract of A. excelsa (200 + 200 mg/kg) in reducing total cholesterol, triglycerides, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein. The observed result enables to assess the biological and molecular methods to confine the contrary effects of cardiovascular disorder mostly difficulties related to lipidemia (Srivastava et al., 2019). 60.3.14 ANTI-AMOEBIC ACTIVITY Qussainoids are active constituent in A. excelsa. The aqueous (AEAE), petroleum ether (PEAE), and defatted ethanolic (QEAE) extracts of stem bark of A. excelsa at the concentration of 100, 200, and 300 μg/mL were verified against Entamoeba histolytica for its anti-amoebic activity using standard drug of metronidazole and DMSO was used as control. The EC50 value for aqueous, petroleum ether, and defatted ethanolic extracts were 195, 185, and 150 μg/mL against E. histolytica, respectively. The reducing order of anti-amoebic activity was QEAE>AEAE> PEAE. The separation of active constituents responsible for the anti-amoebic activity may provide a strong, potent anti-amoebic drug molecule with minor side effects (Yoganandam et al., 2009b). 60.3.15 ANTIPLASMODIAL ACTIVITY The A. excelsa stem bark of methanolic extract inhibited in vitro growing of chloroquine-sensitive (D10) and unaffected strains (W2) of Plasmodium falciparum (IC50 4.6 and 2.8 μg/mL respectively). The result was reserved in the chloroform part (3.1 and 2.1 μg/mL respectively). The antiplasmodial activity could be credited to the harm of hemoglobin degradation through the inhibition of plasmepsin II activity (IC50 of 13.43 ± 1.74 μg/mL) and of the hem decontamination to hemozoin (Germama et al., 2008). 60.3.16 ANALGESIC ACTIVITY Analgesic activity was approved by experimental Tail flick method by using analgesiometer. Mice of 20–25 g of both sexes were weighed and taken basal

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reaction time to radiant heat by insertion of the previous 1–2 cm of the tail on the radiant heat source. The mouse was withdrawing its tail within 3–5 s. A cut off period of 10 s is rejected from the study. Novalgin at a dose of 50 mg/ kg body weight was inserted and the reminder reaction time was at 0, 30, 60, and 90 min after drug. As the reaction time reaches 10 s, it showed extreme analgesia and the tail is separated from the source of heat to elude tissue harm. In the same approach, the test sample petroleum ether, ethyl acetate, and methanol extracts at the dose of 200 mg/kg body weight and later the reaction time were at 0, 30, 60, and 90 min. The petroleum ether extract and ethyl acetate extract of A. excelsa bark discovered good activity after 60 min at a dose of 200 mg/kg body weight as paralleled to standard novalgin, and the methanol extract displayed less activity when as compared with standard (Patil et al., 2010). KEYWORDS • • • •

Ailanthus excelsa phytoconstituents ayurvedic preparations pharmacology

REFERENCES Bhalke, R. D.; Giri, M. A. Pharmacognostic and Phytochemical Investigation of Ailanthus excelsa Roxb. Bark. Asian J. Pharm. Clin. Res. 2020, 13 (3), 74–78. Bhandari, D. S.; Gupta, M. L. Studies on the Digestibility and Nutritive Value of Aralu (Ailanthus excelsa Roxb). Indian Vet. J. 1972, 49 (5), 512–516. Bhatia, N.; Sahai, M. Chemical Studies on Ailanthus excelsa. J. Indian Chem. Soc. 1985, 62, 75–75. Bhatt, S.; Dhyani, S. Preliminary Phytochemical Screening of Ailanthus excelsa Roxb. Int. J. Curr. Pharm. Res. 2012, 4 (1), 87–89. Chevellier, A. The Encyclopedia of Medicinal Plants, a Practical Reference Guide; Kindersley Dorling Ltd.: Great Britain, London, 1996; pp 74–80. Dhanasekaran, S.; Suresh, B.; Sethuraman, M.; Rajan, S.; Dubey, R. Antifertility Activity of Ailanthus excelsa Linn. in Female Albino Rats. Indian J. Exp. Biol. 1993, 31 (4), 384–385. Genta, S.; Cabrera, W.; Said, A.; Farag, A.; Rashed, K. Hypoglycemic Activity of Leaves and Stem Bark Extracts of Ailanthus excelsa in Normal and Diabetic Rats. Abstr. Biocell. 2005, 29 (1), 86.

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Germama, V.; Parapini, S.; Bascilico, N.; Taramaila, D. Anti-Plasmodial Activity of Stem Bark of Ailanthus excelsa. Fitoterapia 2008, 79 (2), 112–16. Ghumarea, P.; Jirekara, D. B.; Farooqui, M.; Naikwadec, S. D. Co-Chemical, Phytochemical Screening and Antimicrobial Activity of Ailanthus excelsa Leaves. Int. J. Chem. Sci. 2014, 12 (4), 1221–1230. Hukkeri, V. I.; Jaiprakash, B.; Lavhale, M. S.; Karadi, R. V.; Kuppast, I. J. Hepatoprotective Activity of Ailanthus excelsa Roxb. Leaf Extract on Experimental Liver Damage in Rats. Indian J. Pharm. Educ. 2002, 37, 105–106. Joshi, B. C.; Pandey, A.; Chaurasia; Pal, L. M.; Sharma, R. P.; Khare, A. Antifungal Activity of Stem Bark of Ailanthus excelsa. Fitoterapia 2003a, 74, 689–691. Joshi, B. C.; Pandey, A.; Sharma, R. P.; Khare A. Quassinoids from Ailanthus excelsa. Phytochemistry 2003b, 62 (4), 579–584. Kapoor, S. K.; Ahmad, P. I.; Zaman, A. Chemical Constituents of Ailanthus excelsa. Phytochemistry 1971, 10, 3333. Khaled, R.; Feitosa, C. M. Ailanthus excelsa (Roxb.): Phytochemical and Biological Review. Int. J. Innov. Pharm. Sci. Res. 2019, 7 (6), 46–52. Khan, M. S.; Kallm, Y. J.; Khan, I. U.; Khan, M. H. Chemical Investigation of Fruits and Leaves of Ailanthus excelsa Roxb. (Simaroubaceae). Indian Drugs. 1994, 31 (3), 125–126. Khan, S. A.; Shamsuddin, K. M. Isolation and Structure of 13, 18-Dehydroexcelsin, a Quassinoid and Glaucarubol from Ailanthus excelsa. Phytochemistry 1980, 19, 2484–2485. Khan, S. A.; Shamsuddin, K. M. Quassinoids from Ailanthus excelsa. Indian J. Chem. 1978, 16B, 1045–1046. Kirtikar, K. R.; Basu B. D. Indian Medicinal Plants; Vol. 1; International Books Distributors: Dehradun, 1995; pp 505–507. Kumar, D.; Bhat, Z. A.; Singh, P.; Khatanglakar, V.; Bhujbal, S. S. Antiasthmatic and Antiallergic Potential of Methanolic Extract of Leaves of Ailanthus excelsa. Rev. Bras. Farmacogn. Braz. J. Pharmacogn. 2011, 21 (1), 139–145. Kumar, D.; Bhat, Z. A.; Singh, P.; Shah, M. Y.; Bhujbal, S. S. Anti-Bacterial Activity of Dried Stem Bark Ailanthus excelsa Roxb. Int. J. Pharm. 2010a, 6 (5), 535–550. Kumar, D.; Bhat, Z. A.; Singh, P.; Shah, M. Y.; Bhujbal, S. S. Anti-Allergic and Anticataleptic Activity of Aqueous Extract of Leaves of Ailanthus excelsa. Int. J. Pharm. Sci. Res. 2010b, 1 (9), 45–51. Kumar, D.; Bhujbal, S. S.; Patil P. S.; Buge, P. V. In-Vitro and In-Vivo Activities of Stem Bark of Methanolic Extract of Ailanthus excelsa in the Management of Asthma. Int. J. Pharmacol. 2010c, 6, 284–89. Kumar, D.; Bhujbal, S. S.; Deoda, R. S.; Mudgade, S. C. Bronchodilator Activity of Aqueous Extract of Stem Bark of Ailanthus excelsa Roxb. Phcog. Res. 2010d, 2, 102–106. Kundu, P.; Laskar, S. A Brief Resume on the Genus Ailanthus: Chemical and Pharmacological Aspects. Phytochem. Rev. 2010, 9, 379–412. Lavhale, M. S.; Hukkeri, V. I.; Jaiprakash, B. Comparative Study of Leaves and Bark of Ailanthus excelsa Roxb. for Hepatoprotective Activity. Indian Drugs 2003a, 40 (6), 355–357. Lavhale, M. S.; Hukkeri, V. I.; Jaiprakash, B. Hepatoprotective Activity of Leaves of Ailanthus excelsa Roxb. on Experimental Liver Damage in Rats. Indian J. Pharm. Edu. 2003b, 37 (2), 105–106.

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Lavhale, M. S.; Mishra, S. H. A Novel Triterpenoid Isolated from the Root Bark of Ailanthus excelsa (Tree of Heaven), AECHL-1 as a Potential Anti-Cancer Agent. PLos one 2007a, 4, 5365–5365. Lavhale, M. S.; Mishra, S. H. Nutritional and Therapeutic Potential of Ailanthus excelsa—A Review. Phcog. Rev. 2007b, 1 (1), 105–113. Loizzo, M. R.; Said, A.; Tundis, R.; Khaled, R.; Statti, G. A.; Hufner, A; Menichini, F. Inhibition of Angioensin Converting Enzyme (ACE) by Flavonoids Isolated from Ailanthus excelsa (Roxb) (Simaroubaceae). Phytother. Res. 2007, 21, 32–36. Melanchauski, L. S.; Broto, A. P. G. S.; Moraes, T. M.; Nasser, A. L. M.; Said, A. Gastroprotective and Antisecretory Effects of Ailanthus excelsa (Roxb). J. Nat. Med. 2010, 64, 109–113. Mokat, D. N.; Deokule, S. S. Plants Used as Veterinary Medicine in Ratnagiri District of Maharashtra. Ethnobotany 2004, 16, 131–135. Munesh, M.; Sachan, N.; Phool, C.; Kamal, K. M.; Kumar, A. W. Antidiarrhoeal Potential of Methanolic Extract of Root Bark of Ailanthus excelsa. J. Pharm. Res. 2011, 4 (2), 422–423. Nadkarni, K. M. Indian Materia Medica; Popular Prakashan: Bombay, 1976; pp 56. Ogura, M.; Cordell, G. A.; Kinghorn, A. D.; Fransworth, N. R. Potential Anticancer Agents VI. Constituents of Ailanthus excelsa. Lloydia 1977, 40, 579–584. Patil, S. B.; Upender Reddy, C. H.; Goudgaon, N. M. Antifungal, Anti-Inflammatory and Analgesic Activity of Ailanthus excelsa Bark. Int. J. Pharm. Sci. Res. 2010, 1(12), 119–122. Polonsky, J. Quassinoid Bitter Principle. Fortschr. Chem. Org. Naturst. 1973, 30, 101. Ratha, R. R.; Shamkuwar, P. B.; Pawar, D. P. Antifungal Study of Ailanthus excelsa Leaves. J. Chem. Pharm. Res. 2013, 5 (6), 152–154. Ravichandran, V.; Suresh, B.; Sathishkumar, M. N.; Elango, K.; Srinivasan, R. Antifertility Activity of Hydroalcoholic Extract of Ailanthus excelsa (Roxb): An Ethnomedicine Used by Tribals of Nilgiris Region in Tamil Nadu. J. Ethnopharmacol. 2007, 112 (1), 189–191. Sharma, P. V. Dravya Guna-Vijnana Ayurvedic Series-III, Vegetable Drugs; Vol. 2, VIIth ed.; Chaukhambha Bharati Academy: Varanasi, 1996; pp 466–468. Shrimali, M.; Jain, D. C.; Darokar, M. P.; Sharma, R. P. Antibacterial Activity of Ailanthus excelsa (Roxb). Phytother. Res. 2001, 15, 165–166. Siju, P.; Ghetia, R.; Vadher, B.; Mital, N. M. In-Vitro Anti-Inflammatory Activity of Fractions of Ailanthus excelsa Roxb. by HRBC Membrane Stabilization. Asian J. Pharm. Tech. 2015, 5 (1), 29–31. Singh, U.; Wadhwani, A. M.; Johri, B. M. Dictionary of Economic Plants in India; Indian Council of Agricultural Research: New Delhi, 1983; p 9. Srivastava, V.; Dubey, S.; Singh, V. L. Hypolipidemic Activity of Stem Bark of Ailanthus excelsa Roxb. in Triton WR 1339 Induced Hyperlipidemic Rats. Res. J. Pharm. Tech. 2019, 12 (3), 1338–42. Tamboli, S. A.; Kondawar, M. S. Phytochemical Investigation and Characterization of Ethanolic Fraction of Ailanthus excelsa. Invent. Rapid plant. Act. 2013, 4, 1–6. Verma, S. Pharmacological Study on Ailanthus excelsa-Ardusa (Tree of Heaven) Simaroubaceae: A Multipurpose Tree. World J. Pharm. Res. 2016, 5 (12), 772–777. Vinmathi, V.; Jacob, S. J. P. A Green and Facile Approach for the Synthesis of Silver Nanoparticles Using Aqueous Extract of Ailanthus excelsa Leaves, Evaluation of Its Antibacterial and Anticancer Efficacy. Bull. Mater. Sci. 2015, 38 (3), 625–628.

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Yoganandam, G. P.; Periyanayagam, K.; Ilango, K. Protective Effect of Ethanolic Extract of Stem Bark of Ailanthus excelsa Roxb. Against CCl4 Induced Hepatotoxicity in Rats. Drug Invent. Today 2009a, 1, 28–31. Yoganandam, G. P.; Periyanayagam, K.; Ilango, K.; Biswas, D.; Gowri, R. In Vitro AntiAmoebic Activity of Stem Bark of Ailanthus excelsa Roxb. (Simaroubaceae). Newslett. Pharmacol. Online 2009b, 1, 27–34.

CHAPTER 61

Pharmacology and Therapeutic Potential of Cynodon dactylon (L.) Pers. JAISHREE VAIJANATHAPPA Faculty of Life Sciences, JSS Academy of Higher Education and Research, Mauritius, Avenue Droopnath Ramphul, Bonne Terre 73103, Vacaos, Mauritius E-mail: [email protected]

ABSTRACT The chapter provides a summary of the reported bioactives and pharmaco­ logical and therapeutic properties of Cynodon dactylon (L) Pers. It includes a collection of vernacular names in India, distribution of the plant and information, and synonyms. The chapter also explore about the extracts and phytoconstituents reported for different biological properties. 61.1 INTRODUCTION In India, Cynodon dactylon (L.) Pers. (Family: Poaceae) in most parts is distinguished as durva grass and utilized as a medication in the Ayurveda. Since Vedic times in Hindu customs, it is an important plant in the venerating of Lord Ganesha. It is additionally referred to in various nations as Bermuda grass, canine’s tooth grass, Bahama grass, Dhoob, Indian doab, arugampul, ethane grass, grama, wire grass, and scotch grass. The name was initiated from Africa in 1751 not Bermuda. It occurs all through the world in tropical to warm temperature up to 45°C in north and south scope and broadly spread throughout the southwest and southern United States. C. dactylon grows in Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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very much depleted soils, under water system and good cultivation. It prefers to grow in regions with 672–1751 mm rainfall, in bone-dry zones, in mild zones, in ocean coasts, and in tropics. The plant species is having several synonyms. The particular property of grass is profound root framework up to 2 m (6.6 ft) which assists with standing alive in dry spell conditions due to its penetrating nature in the soil. It is a creeper grass fosters the roots along the ground where a hub contacts the ground and structures a thick tangle. C. dactylon can be cultivated through rhizomes, seeds, and stolons. The seed heads are created in a bunch of spikes at the highest point of the stem, each spike 2–5 cm (0.79–1.97 in) long (Chopra et al., 1999; Kirtikar and Basu, 2001). 61.2 BIOACTIVES The chemical screening and literature review revealed that around 62–72 phytoconstituents in all extracts were confirmed qualitatively. The phyto­ constituents trans-ferulic acid (Singh et al., 2021), syringic and p-coumaric acid, orthohydroxy phenyl acetic acid, vanillic, and para hydroxyl benzoic acid were quantified (Surendra et al., 2008; The Ayurvedic Pharmacopoeia of India, 2001). From the aqueous extract of C. dactylon, few flavonoids, alkaloids, and glycosides were isolated and also other phytocompounds, such as β-carotene, palmitic acid, vitamin C, and fats were additionally reported (Garg and Paliwal, 2011a; Nagori and Solanki, 2011). The leaf extract was analyzed by GC-MS technique, and it was exposed that C. dactylon leaves have 12-octadecadienoyl chloride, glycerin, ethyl ester, hexadecanoic acid, linoleic acid, ethyl-d-glucopyranoside, and phytol (The Ayurvedic Phar­ macopoeia of India, 2001; Jatin and Priya, 2016). Few important isolated phytoconstituents structures are shown in Figure 61.1. 61.3 PHARMACOLOGY Traditionally, C. dactylon has been used in the treatment of hypertenstion, epilepsy, syphilis, snake bites, calcus, piles, wound infection, convulsions, and dropsy ailments. The antimicrobial, antiviral, antioxidant, hypolipidemic, antidiabetic, and hepatoprotective properties were reported for C. dactylon plant extracts. The pharmacological properties of the C. dactylon plant are due to a higher amount of polysaccharides, glycosides, terpenes, flavonoids,

Cynodon dactylon (L.) Pers.

FIGURE 61.1

Phytoconstituents isolated from Cynodon dactylon.

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phenolics, alkaloids, phytosterols, and amino acids concentrations (Rita et al., 2012; Singh et al., 2021). 61.3.1 ANTIOXIDANT ACTIVITY The successive extracts of aerial parts of C. dactylon were investigated for in vitro antioxidant activity and the degree of nonenzymatic hemoglobin glyco­ sylation by colorimetric method at 520 nm was estimated. The ethyl acetate extract showed higher antioxidant activity than the other successive extracts. The antioxidant activity of the extracts is comparable to that of standard antioxidant compounds (d-alpha-tocopherol and ascorbic acid) used (Pal et al., 2008) in this reported method. 61.3.2 ANTIFERTILITY ACTIVITY In vivo antifertility activity of ether, chloroform, and ethyl alcohol extracts of the entire plant of C. dactylon was evaluated in female Wistar albino rats. C. dactylon extract was subjected to acute oral toxicity and the extracts have not discovered any toxicity up to 2000 mg/kg b.w dose. The antifertility investigation of ethyl alcohol extract at the oral dose levels of 200 and 400 mg/kg was performed. The progestogenic and estrogenic consequences of ethyl alcohol extract were observed in immature rats. The examinations of uterus weight, hormonal level, biochemical parameters, vaginal cornifica­ tion, and deciduoma formation were accomplished and histopathology of the uterus additionally contemplated. Ethyl alcohol extract of C. dactylon-treated rats have shown maximum reduction in pregnancy and also observed that significant expansion in uterine weight and diminished deciduoma forma­ tion and proliferation in uterine histopathology were noticed. Biochemical and hormonal parameters findings proved antiprogestogenic and estrogenic potential of ethyl alcohol extract of C. dactylon. The results of the investiga­ tion affirmed that C. dactylon extracts have potent antifertility activity and is a herb for natural contraception (Malpani et al., 2020). 61.3.3 BRONCHODILATORY ACTIVITY The bronchodilatory study was assessed by chloroform extract of C. dactylon against acetylcholine-induced bronchospasm in guinea pig, and in vitro study was directed to determine the concentration response curve on isolated rat tracheal strip suspended in organ bath utilizing multichannel data

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acquisition system. The investigation results revealed that the chloroform extract has shown protection against acetylcholine-induced bronchospasm in guinea pigs, comparable with standard atropine. The chloroform extract of C. dactylon in the in vitro examines, relaxed high K+- instigated compression of rat tracheal strip and carbachol. The chloroform extract of C. dactylon was significantly inhibited high K+ and Ca+2-induced contraction response when compared with verapamil. The potent phosphodiestrase inhibitory action was confirmed by isoprenaline-actuated inhibitory response, similar to papaverine. The scopoletin as an active ingredient was identified by densitometry. The study results confirm that the bronchodilator activity of chloroform extract of C. dactylon is due to the occurrence of scopoletin and arbitrated all through calcium channel blocking and phosphodiestrase inhibi­ tion (Patel et al., 2013). The bronchodilatory study was assessed by chloroform concentrate of C. dactylon against acetylcholine-initiated bronchospasm in guinea pig and in vitro study was directed to decide the focus reaction bend on confined rodent tracheal strip suspended in organ shower utilizing multichannel informa­ tion procurement framework. The investigation results uncovered that the chloroform removal has shown assurance against acetylcholine-initiated bronchospasm in guinea pigs, practically identical with standard atropine. The chloroform concentrate of C. dactylon in the in vitro examines loosened up high K+-instigated compression of rodent tracheal strip and carbachol. The chloroform extricates essentially hindered high K+ and Ca+2 actuated contractile reaction when contrasted with verapamil. The strong phos­ phodiestrase inhibitory movement was affirmed by isoprenaline-actuated inhibitory reaction, like papaverine. The scopoletin as a functioning fixing was distinguished by densitometry. The examination results affirm that the bronchodilator action of chloroform concentrate of C. dactylon is because of quality of scopoletin and parleyed through calcium channel obstructing and phosphodiestrase restraint (Patel et al., 2013). 61.3.4 HEPATOPROTECTIVE ACTIVITY The ethanolic extract of C. dactylon was evaluated against carbon tetra chloride–induced hepatotoxicity in Wistar rats. The lower and higher doses of ethanolic extract (C. dactylon) at 100, 250, and 500 mg/kg were admin­ istered to animals. This study estimated the serum SGPT, SGOT, bilirubin, cholesterol, and ALP levels. The raised serum bilirubin and cholesterol levels were altogether diminished in the ethanol extract of C. dactylon-treated

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groups. It was observed that the hepatic damage in animals treated with ethanolic extract was negligible and making no harm to the hepatic cells and architectural frame of the liver. In conclusion, the extract activity was to preserving the structural integrity of cell membrane of hepatocytes and thereby maintaining the normal function of liver (Surendra et al., 2008). 61.3.5 ANTICONVULSANT PROPERTY The anticonvulsant action of ethanol extract of C. dactylon was evaluated against convulsions induced by pentylenetetrazole. Pentobarbitone sodium as reference drug and dopamine, epinephrine, nor epinephrine, GABA, 5-HT, and glutamic acid were used as standard catecholamine. The ethanolic extract imparted protective action against convulsions induced by pentylene­ tetrazole in mice. The significant increase of GABA was observed in mice brain after 6-week treatment, which is mostly involved in seizure activity. The study results showed that the significant anticonvulsive property of C. dactylon ethanol extract by altering the level of brain amino acids and catecholamine in mice (Garg and Paliwal, 2011a). 61.3.6 ANTICANCER ACTIVITY The in vivo chemopreventive property was investigated in albino rats by methanolic extract of C. dactylon against 1,2-dimethylhydrazine-induced colon carcinogenesis. At lower concentrations of the extract antiproliferative potential was confirmed and the extract has shown cytotoxicity on COLO 320 DM cells. The levels of antioxidant enzymes were increased in metha­ nolic extract-treated groups and diminished the concentration of dysplastic crypts in 1,2-dimethylhydrazine-instigated colon carcinogen. The evaluation proved that the C. dactylon methanol extract has anticancer property in COLO 320 DM cells and 1,2-dimethylhydrazine-instigated colon carcino­ genesis (Albert-baskar and Ignacimuthu, 2010). 61.3.7 HYPOGLYCEMIC ACTIVITY The ethanol extract of C. dactylon was assessed against streptozocin-initiated diabetes mellitus in rats for hypoglycemic activity. The extract was given orally at 250, 500, and 750 mg/kg b.w. to normal and streptozocin-induced

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diabetic rats. The study proved that the ethanol extract of C. dactylon had hypoglycemic property in conjunction with good hypolipidemic activity (Singh et al., 2008). 61.3.8 DIURETIC ACTIVITY The diuretic property of aqueous extract of C. dactylon was assessed by oral administration of various concentrations (125, 250, and 500 mg/kg of b.w.) and the standard drug furosemide at 15 mg/kg to hydrated male Wistar rats. After a single dose administration, their urine yield was estimated at various intervals. The outcomes showed that furosemide stimulated significant diuresis and electrolytes excretion during the first hour. The aqueous extract has found significant increase in urinary output and excretion of electrolytes at the dose of 500 mg/kg b.w. of C. dactylon. The pH of urine remained unchanged during the study (Gowda et al., 2009). The combination of C. dactylon rhizomes and Erica multiflora flowers extracts were tested for diuretic activity. The results were compared with the reference drug furosemide. The results found that significant increase in urinary output and electrolytes excretion. Aqueous herb extracts-treated group showed significant effect on urine yield and electrolytes excretion. The study affirmed their use in diuretic activity as natural remedy in traditional medicine (Sadki et al., 2010). 61.3.9 ANTINEPHROLITHIASIS PROPERTY The hydroalcoholic extract of C. dactylon was evaluated for antinephroli­ thiasis property in rats against experimentally induced nephrolithiasis. The effect of extract was examined by measuring urinary biochemical and other variables, such as crystalluria and renal histology. Calcium oxalate deposi­ tion levels were reduced and it confirmed the protective effect of C. dactylon extract. It is noticed that in medullary and papillary sections also calcium oxalate deposition levels were reduced (Khajavi Rad et al., 2011). 61.3.10 IMMUNOMODULATORY ACTIVITY Freshly prepared juice of C. dactylon was examined on BALB/c mice by the humoral antibody response (estimated by hemagglutination antibody titre

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and spleen cell assay). The juice was given by oral administration to BALB/c mice and observed that enhanced humoral antibody response upon antigen test (Mangathayaru et al., 2009). 61.3.11 PROTECTIVE EFFECT IN DIABETIC RETINOPATHY The hydroalcoholic extract of C. dactylon was standardized by GC-MS technique for secondary metabolites and 24 metabolites were identified. The secondary metabolites of C. dactylon were utilized to act as an antagonist to the receptor of angiotensin type 1 (AT1). These were considered as the ligands to function as an antagonist to the AT1. The Rasmol tool was used for visualizing AT1 structured PDB. Autodocking tool was used to investigate the ability of the ligands to bind with the AT1 receptors active site. The examination confirms that the metabolites of C. dactylon could be utilized to treat diabetic retinopathy (Jananie et al., 2012). 61.3.12 EFFECT ON FUNCTION OF ZEBRA FISH EMBRYO The extract of C. dactylon was used to measure the changes in cardiac function in Zebra fish embryo and to determine the cardiogenic effects by microvideography. In this study, during systole and diastole, blood circulation and the heart beat rate were measured in zebra fish embryos. The significant study results revealed that the heart beat rate in extract of C. dactylon-treated zebra fish embryos has increased than that of betamethosone caused heart beat rate (Kannan and Vincent, 2012). 61.3.13 INHIBITION OF ACETYLCHOLINESTERASE AND ANTIOXIDANT ACTIVITY The acetylcholinesterase inhibition in rat brain and antioxidant activity was carried out by using aqueous extract of C. dactylon. The extract significantly inhibited acetylcholinesterase in rat brain and carbofuran-induced oxida­ tive stress formation [single sub-acute oral dose (1.6 mg/kg) of carbofuran for 24 hr]. The concentration of acetylcholinesterases was measured in the rat brain and parameters of oxidative stress, such as antioxidant enzymes (Catalase, super oxide dismutase and glutathione-S-transferase) and lipid

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peroxidation were estimated. Results of the study revealed that the activi­ ties of glutathione-S-transferase and acetylcholinesterase were diminished. It was proved that this particular study was useful to develop new anticho­ linestesterase and antioxidants from C. dactylon against carbofuran (Rai et al., 2011). 61.3.14 ANTIVIRAL ACTIVITY ON WHITE SPOT SYNDROME VIRUS (WSSV) The C. dactylon extract was assessed in vivo antiviral activity on WSSV in black tiger shrimp Penaeus monodon. The C. dactylon extract was adminis­ tered orally with the concentration of 1% or 2% artificial pellet feed. Western blot analysis, PCR technique and bioassay were performed to confirm the WSSV infection. Results of the study concluded that C. dactylon has shown the inhibition of WSSV infection with no mortality (Balasubramanian et al., 2008). 61.3.15 ANALGESIC AND ANTIPYRETIC ACTIVITY The antipyretic and analgesic properties were investigated by C. dactylon aqueous extract at various doses by utilizing acetic acid induced, hot plate, writhing, and yeast-induced hyperthermia methods. The C. dactylon aqueous extract exhibited significant analgesic and antipyretic properties in all tested methods (Garg and Khosa, 2008). 61.3.16 ANTHELMINTIC ACTIVITY The petroleum ether, chloroform, ethanol, and aqueous extracts of aerial parts of C. dactylon were investigated for anthelmintic activity separately on adult earthworm (Pheritima posthuma). The results of the study found that the C. dactylon extracts of petroleum ether, chloroform, ethanol, aqueous at the concentration of 5 mg/mL showed characteristic anthel­ mintic activity. Whereas at 10 mg/mL concentration, the anthelmintic effect of all the tested extracts was comparable with that of the standard drugs albendazole (10 mg/mL) and piperazine citrate (10 mg/mL) and produced effects (Pal and Pandab, 2010; Abhishek and Thakur, 2012).

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61.3.17 ANTIDIARRHEAL ACTIVITY The C. dactylon whole plant material was extracted with hexane, dichlo­ romethane, ethyl acetate, and methanol successively and were assessed for antidiarrheal property against charcoal meal-induced gastro intestinal motility, enteropooling, and diarrhea models by castor oil induced in albino rats. Among all the tested extracts, methanol extract has shown significant reduction in diarrhea by castor oil. In charcoal meal-induced gastrointestinal motility, the methanol extract-treated group has shown decreased motility and in enteropooling model intestinal contents weight also found decreased. The outcomes proved that the plant has potent antidiarrheal activity (Babu et al., 2009). 61.3.18 ANTIMICROBIAL ACTIVITY The C. dactylon aqueous extract was assessed for antifungal and antibacte­ rial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, and Candida albi­ cans. The antimicrobial activity was conducted by well diffusion method in agar. The zone of inhibition of encompassing the well was estimated. The C. dactylon aqueous extract has shown better antimicrobial action against all the tested bacteria, on the other hand, on the fungus C. albicans, the activity was not found (Chaudhari et al., 2011; Rao et al., 2011). 61.3.19 EFFECT ON FUNCTIONS IN RIGHT-HEART FAILURE The C. dactylon hydroalcoholic extract was tested on cardiovascular contractility in normal hearts and monocrotaline (50 mg/kg b.w) induced (intraperitoneal injection) right-heart failed cardiovascular functions in rats. Different doses of extracts were treated orally after 2 weeks for 15 days. Cardiovascular capacities and markers of myocardial hypertrophy were assessed at the conclusion of the study. Consequences of the investiga­ tion showed that very few symptoms of dyspnea, fatigue, and peripheral cyanosis. In hydroalcoholic extract-treated groups, the endurance rate was found to be high and monocrotaline injected rats have also shown recovery in cardiac functions. The decreased heart and lung congestion was also found in extract-treated groups. In the secluded rat hearts, a remarkable positive inotropic effect has been shown by the extract which was associated with a left ventricular end diastolic pressure (Garjani et al., 2009).

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61.3.20 ANTI-INFLAMMATORY ACTIVITY The C. dactylon aqueous extract was investigated for anti-inflammatory activity by different inflammation methods, such as histamine, serotonin, carrageenan, dextran, and cotton pellet-induced rat paw edema. The aqueous extract was nontoxic up to 4 g/kg of extract dose when administered orally, no mortality was observed in acute toxicity study. The doses of extract were decided at three different levels (200, 400, and 600 mg/kg orally). The C. dactylon aqueous extract has shown good anti-inflammatory activity in all the tested models. It also has reduced the inflammation induced by histamine, serotonin, carrageenan, and dextran after 3 and 5 h. The edema formation was decreased at a dose of 600 mg/kg in dry weight cotton pellet, which was comparable with the standard drug indomethacin (10 mg/kg) (Garg and Paliwal, 2011b; Dhande, 2013). 61.3.21 ANTIHYPERLIPEDEMIC ACTIVITY The antihyperlipidemic activity of the entire plant of C. dactylon ethanol extract was evaluated for lowering lipid parameters in plasma in high choles­ terol diet fed rats. The effect of extract of C dactylon on the hyperlipidemia was determined by measuring the concentrations of triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, and very low-density lipoprotein cholesterol in plasma. C. dactylon extract has significantly decreased the concentrations of triglyceride, low-density lipoprotein cholesterol, total cholesterol, and very low-density lipoprotein cholesterol than cholesterol-fed control rats. The high-density lipoprotein cholesterol ratio was also declined significantly. The outcomes affirm that lipid-lowering effects of C dactylon may act as a new natural agent for inhibiting hyperlipidemia (Kaup et al., 2011). 61.3.22 CNS ACTIVITIES The aerial part of C. dactylon was extracted with ethanol and dried. The ethanol extract was evaluated by Pal (2008) for central nervous system activities in mice. The extract has shown significant depression in general behavioral profiles in mice. The ethanol extract of C. dactylon has signifi­ cantly increased the sleeping time in mice induced by standard hypnotics viz. meprobamate, diazepam, and pentobarbitone sodium in a dose-dependent manner. The extract also showed significant analgesic activities as confirmed by the significant decrease in the number of stretches and writhes observed in

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mice by 1.2% acetic acid solution. It also has shown potent analgesic activity induced by morphine and pethidine in mice. The extract in a dose-dependent manner inhibited the onset of convulsions induced by pentylenetetrazole. 61.3.23 GREEN SYNTHESIS OF C. DACTYLON CAPPED ZINC OXIDE NANOPARTICLES Zinc oxide and C. dactylon capped nanoparticles have been synthesized. Scanning electron microscopy analysis and X-ray diffraction data demon­ strated the crystallite size of nanoparticles with hexagonal nanorod structure. The developed nanoparticles were tested on K. pneumoniae. The zinc oxide and C. dactylon capped nanoparticles antibacterial activity against gramnegative bacteria was found to be high when compared with zinc oxide nanoparticles (Meenatchi et al., 2020). KEYWORDS • • • •

Cynodon dactylon phytoconstituents Poaceae Coumaric acid

•

bioactives

REFERENCES Abhishek, B.; Thakur, A. Anthelmintic activity of Cynodon dactylon. J. Pharmacogn. Phytochem. 2012, 1 (3), 1–3. Albert-Baskar, A.; Ignacimuthu, S. Chemopreventive Effect of Cynodon dactylon (L.) Pers. Extract Against DMH-Induced Colon Carcinogenesis in Experimental Animals. Exp. Toxicologic Pathol. 2010, 62 (4), 423–431. Babu, D. R.; Neeharika, V.; Pallavi, V.; Reddy, M. B. Antidiarrheal Activity of Cynodon dactylon Pers. Pharmacogn. Mag. 2009, 5 (19), 23–27. Balasubramanian, G.; Sarathi, M.; Venkatesan, C.; Thomas, J.; Hameed, A. S. Oral Administration of Antiviral Plant Extract of Cynodon dactylon on a Large Scale Production Against White Spot Syndrome Virus (WSSV) in Penaeus monodon. Aquaculture. 2008, 279 (1–4), 2–5.

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Chaudhari, Y.; Mody, H.R; Acharya, V. B. Antibacterial Activity of Cynodon dactylon on Different Bacterial Pathogens Isolated from Clinical Samples. Intern. J. Pharma. Stud. Res. 2011, 1, 16–20. Chopra, R. N.; Nayer, S. L.; Chopra, I. C. Glossary of Indian Medicinal Plants; Publication and Information Directorate, CSIR: New Delhi, 1999; p 88. Dhande, S. R. Anti-Inflammatory and Analgesic Properties of the 50% Ethanolic Extract of Cynodon dactylon Pers. Intern. Res. J. Invent. Pharma. Sci. 2013, 1 (2), 8–16. Garg, V. K.; Khosa, R. L. Analgesic and Anti-Pyretic Activity of Aqueous Extract of Cynodon dactylon. Pharmacol. Online 2008, 3, 12–18. Garg, V. K.; Paliwal, S. K. Anticonvulsant Activity of Ethanolic Extract of Cynodon dactylon. Der Pharmacia Sinica. 2011a, 2 (2), 86–90. Garg, V. K.; Paliwal, S. K. Anti-Inflammatory Activity of Aqueous Extract of Cynodon dactylon. Intern. J. Pharmacol. 2011b, 7 (3), 370–375. Garjani, A.; Afrooziyan, A.; Nazemiyeh, H.; Najafi, M.; Kharazmkia, A.; Maleki-Dizaji, N. Protective Effects of Hydroalcoholic Extract from Rhizomes of Cynodon dactylon (L.) Pers. on Compensated Right Heart Failure in Rats. BMC Complem. Altern. Med. 2009, 9 (1), 1–9. Gowda, K. P. S.; Satish, S.; Mahesh, C. M.; Vijaykumar. Study on the Diuretic Activity of Cynodon dactylon Root Stalk Extract in Albino Rats. Res. J. Pharm. Tech. 2009, 2 (2), 338–340. Jananie, R. K.; Priya, V.; Vijayalakshmi, K. Secondary Metabolites of Cynodon dactylon as an Antagonist to Angiotensin II Type1 Receptor: Novel in Silico Drug Targeting Approach for Diabetic Retinopathy. J. Pharmacol. Pharmacotherap. 2012, 3 (1), 20–25. Jatin, R. R.; Priya, R. S. Determination of Bioactive Components of Cynodon dactylon by GC-MS Analysis & It’s In Vitro Antimicrobial Activity. Intern. J. Pharm. Life Sci. 2016, 7 (1), 4880–4885. Kannan, R. R.; Vincent, S. G. Cynodon dactylon and Sida acuta Extracts Impact on the Function of the Cardiovascular System in Zebrafish Embryos. J. Biomed. Res. 2012, 26 (2), 90–97. Kaup, S. R.; Arunkumar, N.; Bernhardt, L. K.; Vasavi, R. G.; Shetty, S. S.; Pai, S. R.; Arunkumar, B. Antihyperlipedemic Activity of Cynodon dactylon Extract in High-Cholesterol Diet Fed Wistar Rats. Genomic Med. Biomarkers Health Sci. 2011, 3 (3–4), 98–102. Khajavi Rad, A.; Hajzadeh, M. A.; Rajaei, Z.; Sadeghian, M. H.; Hashemi, N.; Keshavarzi, Z. Preventive Effect of Cynodon dactylon Against Ethylene Glycol-Induced Nephrolithiasis in Male Rats. Avicenna J. Phytomed. 2011, 1 (1), 14–23. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants, Vol VIII, 3rd ed.; Sri Satguru Publications: Delhi, 2001; p 3692. Malpani, A.; Mahurkar, N.; Aswar, U. Phytochemical Analysis and Antifertility Potential of Cynodon dactylon in Female Wistar Rats: A Herbal Approach Towards Contraception. Chinese Herbal Med. 2020, 12 (3), 281–288. Mangathayaru, K.; Umadevi, M.; Reddy, C. U. Evaluation of the Immunomodulatory and DNA Protective Activities of the Shoots of Cynodon dactylon. J. Ethnopharmacol. 2009, 123 (1), 181–184. Meenatchi, T.; Palanimurugan, A.; Dhanalakshmi, A.; Maheshkumar, V.; Natarajan, B. Green Synthesis of Cynodon dactylon Capped Concentrations on ZnO Nanoparticles for Antibacterial Activity, ROS/ML-DNA Treatment and Compilation of Best Controlling Microbes by Mathematical Comparisons. Chem. Phys. Lett. 2020, 749, 137429.

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Nagori, B. P.; Solanki, R. Cynodon dactylon (L.) Pers: A Valuable Medicinal Plant. Res. J. Med. Plant 2011, 5, 508–514. Pal, D. Evaluation of CNS Activities of Aerial Parts of Cynodon dactylon Pers. in Mice. Acta Pol. Pharm. 2008, 65 (1), 37–43. Pal, D. K.; Kumar, M.; Chakraborty, P.; Kumar, S. Evaluation of the Antioxidant Activity of Aerial Parts of Cynodon dactylon. Asian J. Chem. 2008, 20 (3), 2479–2481. Pal, D.; Pandab, K. Evaluation of Anthelmintic Activities of Aerial Parts of Cynodon dactylon Pers. Ancient Sci. Life 2010, 30 (1), 12–13. Patel, M. R.; Bhalodia, Y. S.; Pathak, N. L.; Patel, M. S.; Suthar, K.; Patel, N.; Golwala, D. K.; Jivani, N. P. Study on the Mechanism of the Bronchodilatory Effects of Cynodon dactylon (Linn.) and Identification of the Active Ingredient. J. Ethnopharmacol. 2013, 150 (3), 946–952. Rai, D. K.; Sharma, R. K.; Rai, P. K.; Watal, G.; Sharma, B. Role of Aqueous Extract of Cynodon dactylon in Prevention of Carbofuran-Induced Oxidative Stress and Acetylcholinesterase Inhibition in Rat Brain. Cell. Mol. Biol. 2011, 57 (1), 135–142. Rao, A. S.; Nayanatara, A. K.; Kaup, R.; Sharma, A.; Kumar, A.; Vaghasiya, B. D.; Kishan, K.; Pai, S. R. Potential Antibacterial and Antifungal Activity of Aqueous Extract of Cynodon dactylon. Intern. J. Pharma. Res. Dev. 2011, 2 (11), 2889–2893. Rita, P.; Aninda, M.; Animesh, D. K. An Updated Overview on Cynodon dactylon (L.) Pers. Int. J. Res. Ayurveda Pharm. 2012, 3 (1), 11–14. Sadki, C.; Hacht, B.; Souliman, A.; Atmani, F. Acute Diuretic Activity of Aqueous Erica multiflora Flowers and Cynodon dactylon Rhizomes Extracts in Rats. J. Ethnopharmacol. 2010, 128 (2), 352–356. Singh, S. K.; Rai, P. K.; Jaiswal, D.; Watal, G. Evidence-Based Critical Evaluation of Glycemic Potential of Cynodon dactylon. Evidence-Based Complem. Altern. Med. 2008, 5 (4), 415–420. Singh, V.; Singh, A.; Singh, I. P.; Kumar, B. D. Phytomedicinal Properties of Cynodon dactylon (L.) Pers. (Durva) in Its Traditional Preparation and Extracts. Phytomed. Plus. 2021, 1 (1), 100020. Surendra, V.; Prakash, T.; Sharma, U. R.; Goli, D.; Fadadu, S. D.; Kotresha, D. Hepatoprotective Activity of Aerial Parts of Cynodon dactylon Against CCl4-Induced in Rats. Pharmacog Mag. 2008, 4, S195–S201. The Ayurvedic Pharmacopoeia of India, Ministry of Health and Family Welfare, Department of Ayush. Gov. of India, 2001, 4, 33–35.

CHAPTER 62

A Review on Phytochemistry and Pharmacological Activities of Aristolochia indica L. VISHAL P. DESHMUKH Department of Botany, Jagadamba Mahavidyalaya, Achalpur City, Dist. Amravati, Maharashtra, India E-mail: [email protected]

ABSTRACT Aristolochia indica is an important medicinal plant of Indian subcontinent belonging to family Aristolochiaceae. A. indica is globally recognized as an antidote against snake and scorpion bites. Various parts of A. indica are rich in important phytoconstituents. Compounds like Aristolochic acid and its derivatives were isolated from roots. A. indica reveals strong antibacterial, antifungal, antioxidant, anticancer, anti-venom, anti-diabetic, anti-isnflam­ matory, contraceptive potential and other important activities. This chapter reviews phytochemical and pharmacological activities of A. indica. 62.1

INTRODUCTION

Aristolochia indica L. (Indian Birthwort or snakeroot) is a rare endan­ gered medicinal plant belonging to the family Aristolochiaceae. It is widely scattered in subtropical, tropical, and Mediterranean regions (Dey and De, 2011). In the Indian context, the species was located in plains and low hills; it stretches from Nepal to lower Bengal to Bangladesh (Kanjilal

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et al., 2009). In Bengali, its trivial names are ‘‘‘Iswarmul,” “ghorth,” “tang gway,” “sobawai,” and “rudho jota” (Michl et al., 2013), ‘Hooka­ bel’ in Hindi, ‘Esvaraveru’ in Telugu and ‘Garudakkoti’ in Malayalam (Cynthia and Rajeshkumar, 2012; Joe et al., 2015), and ‘Cheriya arayan’ in Kerala (Rajashekharan et al., 1989). A. indica roots are widely used as an antidote against poisonous snake and scorpion bites throughout the world; it is also a well-known remedy to cure ulcer (Chopra et al., 1956). Constituents from roots also showed fertility-regulating activity (Che et al., 1984). 62.2 BIOACTIVES Chemical analysis of Aristolochia indica aqueous, chloroform, petroleum ether, and methanol extracts of fruits showed presence of alkaloids, anthocyanins, anthocyanidins, tannins, anthracene glycosides, steroids, flavonoids, triter­ penoids, polyuronides, coumarins, cardiac glycosides, emodins, carotenoids, anthraquinones, volatile oil, and saponoids (Bawankule and Chaturvedi, 2014). A. indica flower tested positive in carbohydrate, flavonoids, steroid, and saponins tests (Faisal et al., 2015). Flavonoids, tannins, steroids, and trit­ erpenoids were reported from leaves (Bhatnagar and Maharana, 2016). From methanolic extract of whole plant, alkaloids, cardiac glycosides, steroids, saponins, flavonoids, phenolics, and tannins along with primary metabolites like lipid, proteins, and carbohydrates were reported (Janani and Revathi, 2018a; Vaghasiya and Chanda, 2007). Ethanol extract of root tested posi­ tive in tests for flavonoids, alkaloids, carbohydrates, saponin, protein and amino acids, glycosides, phytosteriods, tannins, and phenolic compounds (Satheesh Kumar and Senthil Kumar, 2017). Alkaloids, phenols, xanthopro­ tein, glycosides, anthraquinones, tannins, saponins, sugar, terpenoids, and flavonoids were reported from the methanol extract of A. indica leaves and stem (Murugan and Mohan, 2012; Naz et al., 2017; Moazzem Hossen et al., 2014). Tannins, flavonoids, saponins, glycosides, phenol were reported in chloroform and aqueous extract of A. indica leaves and stem (Subramaniyan et al., 2015). Ethanol extract of A. indica leaves confirmed alkaloids, acidic compounds, carbohydrates, combined reducing sugars, flavonoids, glyco­ sides, reducing sugars, steroids, tannins, and terpenoids (Yasmin et al., 2016a, 2016b). Isolation of Aristolochic acid (I) was reported from roots (Coutts et al., 1959). A. indica roots ethanol extracts and its further fractions yielded aristolochic acid-I, l-methoxy-5,6-methylenedioxy-9-nitrophenanthrene and

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9-amino-1-methoxy-5,6-methylenedioxy-8-phenanthroic lactam (Kupchan and Doskotch, 1962). Ethanol extract of root yielded aristolochic acid derivatives such as aristololactam β-D-glucoside, aristololactam, aristolo­ chic acid-D methyl ether lactam, and aristolochic acid-D (Kupchan and Merianos, 1968). Chemical structure of Ishwarone was determined, which was extracted from A. indica (Fuhrer et al., 1970). Two novel sesquiterpene hydrocarbons such as aristolochene and ishwarane were derived from the roots of A. indica (Govindachari et al., 1970). Successive extrac­ tion of A. indica dry roots with petrol, benzene, chloroform, and alcohol yielded known compounds like aristolochic acid, aristolochic acid-D, aristololactam-β-D-glucoside, stigmast-4-en-3-one, sitosterol, p- coumaric acid, and five new phenanthrene derivatives viz., aristolochic acid A and B, aristolamide, aristolinic acid, and aristolochate (Pakrashi et al., 1977). Novel sesquiterpene (12S)-7,12-secoishwaran-12-ol and known (+)-ledol were isolated from petroleum ether extract of A. indica roots (Pakrashi et al., 1980). Aristololactam N-β-D-glucoside a phenanthrene derivative and 3β-hydroxy-stigmast-5-en-7-one and 6β-hydroxy-stigmast-4-en-3-one, identified as steroids, had been extracted from roots of A. indica (Achari et al., 1981). Novel 4,5-dioxoaporphine along with cepharadione A, aris­ tololactam AII and β-sitosterol-β-D-glucoside were successfully extracted from A. indica roots (Achari et al., 1982). Novel phenanthroid lactone, aris­ tololide, and other compounds like 5α-stigmastane-3,6-dione, (—)-cubebin and (—)-hinokinin were extracted from roots of A. indica (Achari et al., 1983). Aristolindiquinone, a new naphthoquinone compound, was derived from roots of A. indica (Che et al., 1983). Aristololactam-β-D-glucoside, an important DNA-binding alkaloid having intercalating potential, was isolated from the ethanol extract of A. indica (Chakraborty et al., 1989). Using the GC-FID method, fifty components were extracted from A. indica aerial parts essential oil with majority of β-caryophyllene, α-humulene, ishwarone, caryophyllene oxide I, ishwarol, linalool, α-terpinolene and rest of the compounds were in traces (Jirovetz et al., 2000). GC-MS investigation of A. indica stem essential oil identified fifteen compounds. Percentage wise trans-pinocarveol, α-pinene, and pinocarvone were the major constituents isolated; additionally, camphene, limonene, β-pinene, myrtenol, (E)-βionone, myrtenal, α-cadinol, α-terpinyl acetate, aromadendrene, carvone, terpinen-4-ol, and p-cymene were also found in certain amount (Kanjilal et al., 2009). ELISA analysis reported 0.46, 0.67, and 0.75 µg/mg concentra­ tion of aristolochic acid II from A. indica leaves, stem, and roots (Shang et al., 2011). Stigmast-5-en-3β-ol (β-sitosterol) was isolated from aerial parts of A. indica using TLC (Karan et al., 2012). Hydro-methanolic extract of A.

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indica yielded twenty-one compounds including aristolochic acid I and its analogues on analyzed with LC-DAD-MS and 1H-NMR (Michl et al., 2013). A new reversed phase HPLC method was devised to isolate (-)hinokinin, aristolactam I, and aristolochic acids (I & II) from A. indica extracts; in addi­ tion to this, first time extraction of Astragalin was also reported (Desai et al., 2014). Methanol extract of A. indica leaves on GC-MS investigation scored 32 compounds (Pugazharasi et al., 2015). Aristolochic acid was isolated with a high percentage of recovery from stems of A. indica by developing a fast and precise HPLC method (Agrawal and Laddha, 2017). HPLC analysis of methanol extract of A. indica root bark showed high contents of flavonoids, phenolics, and tannins (Sivaraj et al., 2018). GC-MS analysis of methanol extract of A. indica leaves identified ten compounds viz. (3E, 13Z)-2-methyloctadeca-3,13-dien-1-ol; (2R, 3S)-2-decyl-3-(5- methylhexyl) oxirane; 3,3- dimethylcyclopentanecarboxylic acid; 3,5-dimethylhex-5-en3-ol; Hexyl (4-methylpentyl) oxalate; (8R, 9S, 13S, 14S, 17S)-13-methyl7,8,9,11,12,13,14,15,16,17-decahydro-6H cyclopenta[α]phenanthren-17-ol; 8-(2-octylcyclopropyl)octanal; bis(2-ethylhexyl) maleate; hentriacontan16-one and 1,1,3,3,5,5,7,7-octamethyltetrasiloxane (Gandhi et al., 2019). HPTLC detected higher concentration (6074.54 mg/g) of aristolochic acid in tissue culture raised A. indica as compared to its wild mother plants (5891.14 mg/g) (Dey et al., 2020). Among the twenty populations of A. indica collected from West Bengal, India, highest quantity of aristolochic acid (7643.67 μg/g of dry material) was reported from the Purulia district succeeded by Murshidabad, Jalpaiguri, and Birbhum districts chemotypes with 7398.34, 7345.09, and 6809.97 μg/g of dry material, respectively (Dey et al., 2021). 62.3 PHARMACOLOGY 62.3.1 ANTIVIRAL ACTIVITY A. indica extract failed to report any inhibitory action against white spot syndrome virus in shrimp (Balasubramanian et al., 2007). 62.3.2 ANTIBACTERIAL ACTIVITY Except Salmonella typhi and Staphylococcus simulans, methanol extract of A. indica root exhibited inhibitory potential against all tested bacterial strains with less than 125 µg/mL concentration (Anilkumar et al., 2014). Fifty

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FIGURE 62.1 Compounds extracted from A. indica. (Desai et al., 2014; Achari et al., 1981; Agrawal and Laddha, 2017; Chakraborty et al., 1989; Pakrashi et al., 1977; Che et al., 1983; Fuhrer et al., 1970; Govindachari et al., 1970; Karan et al., 2012; Kupchan and Merianos, 1968).

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FIGURE 62.2 Structures of (3E, 13Z)-2-methyloctadeca-3,13-dien-1-ol (1), (2R, 3S)-2-decyl-3-(5- methylhexyl)oxirane (2), 3,3-dimethylcyclopentanecarboxylic acid (3), 3,5-dimethylhex-5-en-3-ol (4), Hexyl (4-methylpentyl) oxalate (5), (8R, 9S, 13S, 14S, 17S)-13-methyl-7,8,9,11,12,13,14,15, 16, 17-decahydro-6H-cyclopenta[α]phenanthren-17-ol (6), 8-(2-octylcyclopropyl)octanal (7), Bis(2-ethylhexyl) maleate (8), Hentriacontan-16-one (9), 1,1,3,3,5,5,7,7-octamethyltetrasiloxane (10), reported in GC-MS investigation of A. indica leaf methanol extract (Gandhi et al., 2019).

percent and pure methanol extract of A. indica depicted antibacterial activity against all tested pathogens, except S. flexneri; also pure methanol extract showed maximum zone of inhibition against S. aureus (12.66 ± 0.03 mm) while least was recorded against P. aeruginosa (0.90 ± 0.05 mm) (Janani and Revathi, 2018a). Ethanol extract of A. indica showed highest inhibitory

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zones at 5000 µg concentration against P. aeruginosa, S. aureus, M. luteus, and M. roseus (Jeevan Ram et al., 2004). A. indica leaves and flower methanol extract possessed strong antibacterial activity; however, leaves extract revealed highest zone of inhibition against E. aerogenes and E. coli (25 and 20 mm respectively). The MIC values for methanol extract of leaves and flower against K. pneumoniae and E. coli were 22.6 and 24.2 µg/mL respectively (Kamaraj et al., 2012b). Dichloromethane and methanol extract of roots at 500 and 1000µg/mL concentrations revealed very strong inhibi­ tory action against eleven bacterial strains; however, it failed to do so against E. coli and P. aeruginosa (Kumar et al., 2006). Ethanol extract of A. indica leaves reported dose-dependent action and highest activity was recorded at 100 mg/mL concentrations against B. subtilis, S. aureus, and P. aeruginosa with 26, 25, and 24 mm zone of inhibition, respectively (Kumar et al., 2011). Methanol, acetone, and petroleum ether extract of A. indica leaves and stem revealed inhibitory action against all pathogens tested; however, methanol extract revealed potent action against S. aureus with 6 and 2 mm zone of inhibition (Murugan and Mohan, 2012). In the agar well diffusion method, ethanol extract of leaves and flower showed diverse inhibitory responses against Gram-positive and negative bacteria. Comparatively, efficacy of leaves is much better in hampering bacterial growth than flowers (Naik at al., 2015). Methanol extract of leaves revealed moderate inhibitory activity against A. baumannii, K. pneumoniae, P. aeruginosa, and S. aureus (Naz et al., 2017). A. indica aerial parts methanol extract at 500 µg/disc revealed inhibitory action only against B. cereus and failed to impede the growth of B. subtilis, P. aureus, and E. coli (Moazzem Hossen et al., 2014). Methanol extract of A. indica whole plant showed strong antibacterial activity against water-borne S. typhi compared to water extract (Pugazharasi et al., 2015). Aqueous and butanolic extract of A. indica revealed antibacterial potential; however, maximum inhibitory action was reported by butanolic extract against Listeria monocytogenes cattle pathogen (Ravikumar et al., 2005). A. indica essential oil reported reasonable activity against six bacterial strains (Shafi et al., 2002). Aqueous and chloroform extract of A. indica inhibited growth of B. pumilus and E. coli; however, hexane extract failed against E. coli (Sini and Malathy, 2005). Butanol extract of A. indica root showed activity similar to standard against B. subtilis (Umamaheshwari and Murthy, 2012). Methanol and acetone extract of A. indica found more potent against Gram-positive bacteria compared to Gram-negative (Vaghasiya and Chanda, 2007). Ethanol extract of A. indica exhibited its potency against multidrug-resistant bacteria with minimum inhibitory concentration range of

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50–100 μg/mL (Venkatadri et al., 2015). Ethanolic extract of leaves depicted highest antibacterial efficacy against both Gram-positive and Gram-negative bacteria (Yasmin et al., 2016a). P. aeruginosa was significantly inhibited by dichloromethane/methanol extract of root with 8.7 mg/mL MIC (Zameer et al., 2016). 62.3.3 ANTIFUNGAL ACTIVITY Methanol extract of A. indica root inhibited growth of Candida tropicalis, C. albicans, and Trichophyton rubrum with 16 ± 0, 18 ± 1.72, and 17 ± 0 mm zones of inhibition; however, it failed against Aspergillus flavus and Fusa­ rium oxysporum (Anilkumar et al., 2014). 50% and pure methanol extract of A. indica showed inhibitory action against all tested fungal strains, except T. mentagrophytes and Epidermophyton floccosum (Janani and Revathi, 2018a). Against C. albicans, ethanolic extract of A. indica showed 16, 13, and 12 mm zones of inhibition at 1500, 2500, and 5000 µg concentrations, respectively (Jeevan Ram et al., 2004). A. indica roots dichloromethane and methanol extract at 500 and 1000 µg/mL concentrations revealed complete inhibition of C. albicans and Saccharomyces cerevisiae, but partial inhibi­ tion was observed for A. niger (Kumar et al., 2006). A. indica leaves ethanol extract revealed dose-dependent activity and highest zone of inhibition was recorded against A. flavus, C. albicans, and A. fumigatus (28, 26, and 22 mm, respectively) (Kumar et al., 2011). Leaves and flowers ethanol extract revealed broad antifungal activity against B. sorokiniana, Curvularia sp., C. capsici, and F. oxysporum (Naik at al., 2015). Methanolic extract of A. indica leaves was efficiently inhibiting the mycelial growth of A. flavus, A. fumigatus, and Rhizopus oryzae with > 75% of average inhibition (Naz et al., 2017). Methanol and acetone extract revealed substantial inhibitory action against C. tropicalis and C. luteolus (Vaghasiya and Chanda, 2007). Mode­ rate inhibitory potential was revealed by 2% aqueous extract of A. indica against paddy pathogen Sclerotium oryzae (Venkateswarlu et al., 2013). 62.3.4 ANTIOXIDANT EFFICACY Methanol extract of A. indica roots revealed poor antioxidant potential in DPPH, reducing power and NBT superoxide radical scavenging assay as compared to other three Aristolochia species (Anilkumar et al., 2014). In TLC-assisted antioxidant assay, chloroform extract of A. indica leaves

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observed maximum 21 bands, while acetone and methanol extract depicted maximum inhibition in the DPPH method at 2.5 µg/mL concentration (Bhatnagar and Maharana, 2016). In Total Antioxidant activity, DPPH, H2O2, ABTS, superoxide, and lipid peroxidation assays, A. indica methanol extract depicted strong antioxidant activity with 68.24 ± 0.212, 66.45 ± 0.076, 49.82 ± 0.105, 70.95 ± 0.311, 52.97 ± 0.115, and 42.24 ± 0.080% of inhibition respectively (Janani and Revathi, 2018a). Chloroform extract of A. indica aerial parts showed sturdy antioxidant activity in DPPH and superoxide assays with IC50 = 7.325 and 8.498 µg/mL respectively (Karan et al., 2012). At 100µg/mL concentration, ethanol extract of leaves and flowers showed 48.68 and 10.52% radical scavenging activity in the DPPH method (Naik at al., 2015). Methanol extract of leaves revealed moderate DPPH and H2O2 scavenging activity with IC50 values of 179 ± 3 and 110 μg/ mL, respectively (Naz et al., 2017). A. indica aerial parts methanol extract showed poor action with an IC50 value of 223.63 µg/mL in DPPH assay (Moazzem Hossen et al., 2014). Methanol extract of root bark showed strong radical scavenging activity with an IC50 value of 35.92 μg/mL in DPPH assay; in phosphomolybdenum assay the extract revealed activity 76.36 ± 1.24 mg AAE/g extract and in lipid peroxidation assay extract showed 74.54 ± 0.28% of inhibition (Sivaraj et al., 2018). Chloroform extract of leaves had considerable antioxidant property than aqueous extract of A. indica roots when examined in DPPH, reducing power and H2O2 assay (Subramaniyan et al., 2015). In DPPH and reducing power assays, A. indica leaves revealed moderate antioxidant activity compared to other members of Aristolochia­ ceae species (Thirugnanasampandan et al., 2008). In TLC-based antioxidant assay, ethanolic extract of leaves revealed radical scavenging properties exhibited by yellow spot on TLC plate (Yasmin et al., 2016b). 62.3.5 HYPOGLYCEMIC EFFECT In the oral glucose tolerance test, ethanolic extract of A. indica leaves at 500 mg/kg body dose significantly retards the glucose level compared to control (Yasmin et al., 2016b). 62.3.6 ANTIMALARIAL ACTIVITY In the laboratory condition, ethanolic extracts of A. indica leaves revealed strong antimalarial activity against Anopheles stephensi larvae and pupa

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with LC50 = 262.66 ppm (larvae I instar) and 562.02 ppm (pupae); on the contrary, in field conditions extract showed 100% reduction in A. stephensi larvae after 72 h (Murugan et al., 2015). Aristolochic acid I and II extracted from A. indica leaves showed significant toxicity against first, second, third, and fourth instar larvae of A. stephensi. Against fourth instar larvae, both compounds observed LC50 values of 502.3 and 543.2 ppm respectively (Venkatraman et al., 2015). 62.3.7 ANTICANCER ACTIVITY In MTT assay, methanol extract of A. indica root revealed dose-dependent inhibition of subjected cell lines and most excellent activity was observed against MDAM B-231 (IC50 = 25 µg/mL) followed by HeLa cell line (Anilkumar et al., 2014). Methanolic extract of A. indica showed inhibitory activity against HepG2 and VERO cell lines with IC50 = 6.25 and 1.56 mg/ mL, respectively, in MTT assay (Janani and Revathi, 2018b). Methanolic extract of A. indica in the MTT assay proved nontoxic to HeLa cell lines till 100 μg/mL concentration (Kamaraj et al., 2012a). Ethanolic extract of root revealed dose-dependent antitumor activity against HT29 cell line in the MTT assay showing 69.21% of inhibitory action at100 μg/mL concentration of extract with IC50 = 28.56 (Kangralkar and Kulkarni, 2013). Methanol fraction of A. indica chloroform solution reported tumor inhibitory activity against adenocarcinoma 755 (Kupchan and Doskotch, 1962). Against MCF7 cell line chloroform extracts of A. indica showed distinct anticancer activity than ethanol extract (Subramaniyan et al., 2015). 62.3.8 ANTIVENOM PROPERTIES Hydro-ethanolic extract of A. indica at 1 g/kg dose was most effective against red scorpion venom with mean survival of 59 min with 50% survival of mice. 4 and 1 mg of extract is capable of inhibiting PLA2-dependent hemolysis of mice RBC’s and counteract coagulant activity induced by Mesobuthus tamulus venom, respectively (Attarde and Apte, 2013). 100 mg/kg of the A. indica root extract antagonize Russell’s viper venom and extended survival duration of rats (Bhattacharjee and Bhattacharyya, 2013). Aristolochic acid as well as its chloride and hydroxyl derivatives declined toxicity of Russell’s viper venom by hindering L-amino acid oxidase attachment to cell membrane and both derivatives showed inhibition of L-amino acid oxidase

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activity (Bhattacharjee et al., 2017). Against human PLA2, A. indica chemo­ type AI 1 with highest aristolochic acid content revealed utmost inhibition with an IC50 = 0.70 mg/mL (Dey et al., 2021). Methanol extract of A. indica whole plant fully nullifies fatal action of Russell’s viper venom with 2LD50 = 0.14 mg; the extract also reduces the venom-induced edema up to 30%. Low dose (0.11 mg) of the extract completely inhibits PLA2 generated hemolysis, whereas coagulant activity was wholly neutralized by 0.16 mg of extract. Fibrinolytic activity due to D. russelli venom was completely counterbal­ anced by 0.11 mg of plant extracts with ED50 = 0.5 mg (Meenatchisundaram et al., 2009). A. indica aqueous root extract revealed significant inhibitory action against human PLA2 enzyme with IC50 = 0.73 mg/mL (Modak et al., 2020). Crude extract of A. indica leaves and pure terpenoids isolated from it, reported rattlesnake venom neutralizing potential (Samy et al., 2008). A. indica root bark methanol extract showed 50.09 ± 0.05% inhibition to proteolytic activity of Scolopendra morsitans venom (Sivaraj et al., 2018). 62.3.9 CYTOTOXICITY ASSAYS In brine shrimp lethality assay, acetone extract of A. indica observed highest inhibition (55%) at 200 µg/mL dose (Bhatnagar and Maharana, 2016). Methanolic extract of A. indica leaves revealed dose-dependent mortality of brine shrimps with an LD50 value of 66 mg/L (Naz et al., 2017). Methanolic extracts of A. indica aerial part exhibited very strong cytotoxic activity with LC50 = 36.31 ± 0.43 µg/mL (Moazzem Hossen et al., 2014). Brine shrimp lethality bioassay used to determine cytotoxic potential of ethanolic extract of A. indica leaves and the LC50 of the extract was measured 26.2114 µg/mL (Yasmin et al., 2016b). Aqueous extract of roots depicted noteworthy brine shrimp mortality with an LC50 value of 13 µg/mL after 24 h (Krishnaraju et al., 2005). 62.3.10 ANTI-AMYLOIDOGENIC POTENTIAL An active peptide segment of fibrinolytic enzyme derived from A. indica roots revealed anti-amyloidogenic effects against Aβ fibrillation and toxicity through conformational changes and alteration of hydrophobicity of Aβ molecule (Bhattacharyya et al., 2020).

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62.3.11 ANTIFERTILITY ACTIVITY 95% ethanol extracts of A. indica roots reported significant retardation pregnancies number in rats and hamsters on postcoitally (1–10 and 1–6, days respectively) administration compared to standard; however, petroleum ether, chloroform, and aqueous fraction at various doses failed to show such effect and proved toxic (Che et al., 1984). 62.3.12 ANTIDIABETIC ACTIVITY In allaxon-induced diabetic rats, aqueous extracts of A. indica normalized glucose, cholesterol, and triglycerides levels in blood revealing potent hypo­ glycemic activity and it was found that extract protected animals from hepatic injuries linked with diabetes (Cynthia and Rajeshkumar, 2012). Alcoholic extract of A. indica at 400 mg/kg dose significantly lowered glucose level in blood of normal and alloxan-induced diabetic rats (113.51 ± 14.78 to 82.65 ± 12.09 mg/dl and 429.90 ± 10.4 to 305.34 ± 10.94 mg/dl respectively) after 6 h of oral treatment (Goverdhan et al., 2008). Methanol extract of A. indica demonstrated highest alpha-amylase and alpha-glucosidase inhibitory activity (60.12 ± 0.46 and 57.28 ± 0.80% respectively) at 300 and 400 µg/mL concentrations, respectively (Janani and Revathi, 2018b). Oral administra­ tion of A. indica aerial parts chloroform extract in alloxan-induced diabetic mice revealed declined levels of serum glucose at regular interval and highest reduction was observed at 500 mg/kg dose (414.2 ± 3.869 to 187.2 ± 2.312 mg/dl) after 4 h intervals. Subacute treatment of extract exhibits dose-dependent retardation in glucose serum level after 28 days (Karan et al., 2012). 62.3.13 ANTI-INFLAMMATORY ACTIVITY Rats poisoned with H. fossilis poison, on treatment with A. indica extract, showed fall in the inflammation volume (Das et al., 2010). Petroleum ether, dichloromethane, and ethyl acetate extract of A. indica revealed efficient inhibition of IL-6 by 78%, 68%, and 66%, respectively; (-)hinokinin and aris­ tolactam I isolated from A. indica revealed anti-inflammatory effects against IL-6 (IC50 = 20.5 ± 0.5 and 52 ± 8 mM) and TNFα (IC50 = 77.5 ± 27.5 and 116.8 ± 83.25 mM), respectively (Desai et al., 2014). Methanolic extract of A. indica revealed dose-dependent inhibition to albumin denaturation and

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heat-induced hemolysis. The higher percentage of inhibition of albumin denaturation and hemolysis (72.17 ± 0.46 and 77.06 ± 0.04) was observed at 500 µg/mL concentration (Janani and Revathi, 2018b). Compound 48/80 induced rat paw edema was significantly reduced (70%) when treated with 150 mg/kg dose of A. indica ethanol extract (Mathew et al., 2011). A. indica leaves methanol extract showed dose-dependent albumin denaturation inhi­ bition and heat-induced hemolysis of HRBCs with IC50 values of 129 ± 4.6 and 247 ± 5.4 μg/mL, respectively (Naz et al., 2017). 62.3.14 ANTI-MITOTIC ACTIVITY Root extract of A. indica (chemotype AI 1) showed significant anti-mitotic activity at 2.5, 5, and 10 mg/mL concentrations by lowering the mitotic index in the meristematic cells of A. cepa root. The A. indica root extracts also demonstrated clastogenic activity by inducing chromosomal breakages; besides this multipolarity, anaphase bridges, laggard chromosomes, and ghost cell appearance were also recorded (Dey et al., 2021). Aqueous extract of A. indica roots demonstrated strong antimitotic activity on meristematic cells of A. cepa roots at 10 mg/mL concentration with 1.77% of mitotic index (Modak et al., 2020). 62.3.15 GENOTOXIC EFFECT A. indica (chemotype AI 1) root extract at 2.5 mg/mL concentration revealed highest genotoxicity with maximum micronuclei formation (0.48%) in inter­ phase among all tested extracts (Dey et al., 2021). A. indica roots aqueous extract exhibited utmost genotoxic and cytotoxic action compared to ethyl methanesulfonate and maximum numbers of micronuclei were recorded in A. cepa root tips treated with extract (Modak et al., 2020). 62.3.16 ANTIDIARRHOEAL ACTIVITY In the castor oil-induced diarrhoeal model, 200 and 400 mg/kg doses of aqueous and ethanol extract of A. indica significantly declined defecation number and total weight of wet faecal matter compared to vehicle control; additionally, ethanol extract also retarded transit motility of charcoal meal (Dharmalingam et al., 2014). As compared to control, ethanolic extract of

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A. indica leaves at 250 and 500 mg/kg b.w. showed raise in the latent period and reduced total stool count in castor oil prompted diarrheal mice (Yasmin et al., 2016b). 62.3.17 TOXICITY ASSAYS No physical and behavioral changes were reported in rats with some minor exception on treatment with 2000 mg/kg dose of A. indica root extract after 4 h of day one (Faisal et al., 2015). 62.3.18 ANTIPLASMODIAL ACTIVITY A. indica leaves methanol extract revealed strong in vivo antiplasmodial activity against P. berghei-infected mice at 600 mg/kg dose depicting 72.0 ± 8.44% inhibition with ED50 values of 233.77 mg/kg (Gandhi et al., 2019). Among the thirteen screened plants, methanol extracts of A. indica were more active against P. falciparum than remaining plant extracts. Methanol extract of A. indica leaves showed very strong inhibitory action against CQ-sensitive 3D7 and resistant INDO strains of P. falciparum with IC50 = 10 and 17 μg/mL, respectively (Kamaraj et al., 2012a). 62.3.19 CONTRACEPTIVE POTENTIAL Aristolic acid extracted from A. indica showed disruption of pregnancy in mice by interrupting nidation after administered on day 1 of pregnancy (Ganguly et al., 1986). Oral administration of 100 mg/kg b.wt. of sesqui­ terpene derived from A. indica roots revealed strong interceptive and antiimplantation activity (100 and 91.7%) in female mice (Pakrashi and Shaha, 1977). In female mice, oral dose of 100 mg/kg body weight of A. indica roots petroleum ether, chloroform, and alcoholic extracts demonstrated complete interceptive activity (Pakrashi et al., 1976). Oral administration of A. indica derived aristolic acid at 60 mg/kg body weight showed fetal loss and inter­ ception (65 and 100%) in female mice (Pakrashi and Chakrabarty, 1978). Single dose of methyl ester of aristolic acid at 60 mg/kg body weight was responsible for 100% miscarriages in female mice on the sixth or seventh day of pregnancy (Pakrashi and Shaha, 1978). In day 6 pregnant mice,

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p-coumaric acid isolated from A. indica roots revealed 100% interceptive potential at a dose of 50 mg/kg body weight (Pakrashi and Pakrashi, 1979). 62.3.20 INSECTICIDAL AND LARVICIDAL ACTIVITY Against Culex gelidus and C. quinquefasciatus mosquitoes, methanol extract of A. indica leaves showed sturdy adulticidal activity with LD50 = 37.75 ± 2.58 and 80.06 ± 5.35 ppm respectively; also methanol extract demonstrated strong larvicidal activity against fourth instar larvae of both Culex species with LD50 = 12.47 ± 0.89 and 25.60 ± 1.71 ppm respectively (Kamaraj et al., 2010). 62.3.21 IMMUNOMODULATORY ACTIVITY Methanol extract of A. indica roots in carbon clearance test showed increased phagocytic index up to 0.0160 ± 0.00062 with 400 mg/kg body weight dose. In cell-mediated immune response, methanol extract at a dose of 400 mg/kg body weight revealed 17.280 ± 0.300% increase in paw volume. Significant increase in the % of agglutination and decrease in titer was recorded in sheep erythrocyte agglutination test by methanolic extract and its fractions (Mallaiah et al., 2015). 62.3.22 ANTIPRURITIC ACTIVITY In rats treated with compound 48/80, ethanol extract A. indica roots at 150 mg/kg dose significantly reduce scratching frequency from 76.66 ± 2.70 to 36.33 ± 1.15% and 500 mg/kg dose of ethanol extract reported zero mortality in compound 48/80-induced systemic anaphylaxis (Mathew et al., 2011). 62.3.23 MAST CELL STABILIZING ACTIVITY In the compound 48/80-induced allergy model, ethanol and petroleum ether extract of A. indica at 300 and 100 mg/kg dose revealed 69% of mast cell stabilizing activity comparable to ketotifen. In the sheep serum-induced allergy model, 150 and 300 mg/kg doses of ethanol extract and 100 mg/ kg dose of petroleum ether showed 66 and 67% protection against sheep serum-induced mast cell degranulation (Mathew et al., 2011).

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62.3.24 ANTI-PROTEINASE ACTIVITY Methanol extract of A. indica revealed dose-dependent proteinase inhibitory action with an IC50 value of 256 ± 5.4 μg/mL (Naz et al., 2017). 62.3.25 ANTHELMINTIC ACTIVITY Ethanolic A. indica leaves extract showed a dose-dependent effect on time required to paralyse and death of H. contortus, also 100 mg/mL dose of extract showed results similar to standard drug (Yasmin et al., 2016a). 62.3.26 ANALGESIC ACTIVITY 250 and 500 mg/kg b.w. dose of ethanolic extract of A. indica leaves significantly inhibited (23.85 and 66.92% respectively) acetic acid prompted writhing (Yasmin et al., 2016b). KEYWORDS • • • • • • •

Aristolochia indica aristolochic acid Aristololactam-β-D-glucoside anti-venom activity contraceptive endangered medicinal plant

REFERENCES Achari, B. A.; Bandyopadyay, S.; Saha, C. R.; Pakrashi, S. C. A Phenanthroid Lactone, Steroid and Lignans from Aristolochia indica. HeteroCycles 1983, 20, 771–774. Achari, B. A.; Chakrabarti, S.; Bandyopadhyay, S.; Pakrashi, S. C. A New 4,5-Dioxoaporphine and Other Constituents of Aristolochia indica. HeteroCycles 1982, 19, 1203–1206. Achari, B. A.; Chakrabarti, S.; Pakrashi, S. C. An n-Glycoside and Steroids from Aristolochia indica. Phytochemistry 1981, 20, 1444–1445.

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Agrawal, P.; Laddha, K. Development of Validated High-Performance Thin Layer Chromatography for Quantification of Aristolochic Acid in Different Species of the Aristolochiaceae Family. J. Food Drug Anal. 2017, 25, 425–429. Anilkumar, E. S.; Dan, M.; Nishanth Kumar, S.; Dileep Kumar, B. S.; Latha P. G. A Comparative Study on In-Vitro Antioxidant, Anticancer and Antimicrobial Activity of the Methanol Extracts of the Roots of Four Species of Aristolochia L. from Southern Western Ghats of India. Int. J. Adv. Res. 2014, 2, 153–164. Attarde, S. S.; Apte, K. G. Studies on Antivenom Activity of Aristolochia indica Plant Extract Against Red Scorpion Venom by In Vivo and In Vitro Methods. Int. J. Pharmacogn. Phytochem. Res. 2013, 5, 168–172. Balasubramanian, G.; Sarathi, M.; Rajesh Kumar, S.; Sahul Hameed, A. S. Screening the Antiviral Activity of Indian Medicinal Plants Against White Spot Syndrome Virus in Shrimp. Aquaculture 2007, 263, 15–19. Bawankule, D.; Chaturvedi, A. Phytochemical Investigation of Aristolochia indica L.- An Ethnomedicine on Snake Bite. Int. J. Life Sci. 2014, Special issue A2, 172–174. Bhatnagar, S.; Maharana, S. Phytochemical, Cytotoxic and Antioxidant Activities of Leaf Extracts of Aristolochia indica (Linn.). Adv. Biol. BioMed. 2016, 1, 1–5. Bhattacharjee, P.; Bera, I.; Chakraborty, S.; Ghoshal, N.; Bhattacharyya, D. Aristolochic Acid and Its Derivatives as Inhibitors of Snake Venom L- Amino Acid Oxidase. Toxicon 2017, 138, 1–17. Bhattacharjee, P.; Bhattacharyya, D. Characterization of the Aqueous Extract of the Root of Aristolochia indica: Evaluation of Its Traditional Use as an Antidote for Snake Bites. J. Ethnopharmacol 2013, 145, 220–226. Bhattacharyya, R.; Bhattacharjee, S.; Pathak, B. K.; Sengupta, J. Heptameric peptide interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers. ACS Omega 2020, 26, 16128–16138. Chakraborty, S.; Nandi, R.; Maiti, M.; Achari, B.; Saha, C. R.; Pakrashi, S. C. Aristololactamβ-D-Glucoside a New DNA Binding Monofunctional Intercalating Alkaloid. Biochem. Pharmacol 1989, 38, 3683–3687. Che, C-T.; Ahmed, M. S.; Kang, S. S.; Waller, D. P.; Bingel, W. A.; Martin, A.; Rajamahendran, P.; Bunyapraphatsar, N.; Lankin, D. C.; Cordell, G. A.; Soejarto, D. D.; Wijeseke, R. O. B.; Fong, H. H. S. Studies on Aristolochia III. Isolation and Biological Evaluation of Constituents of Aristolochia indica Roots for Fertility-Regulating Activity. J. Nat. Prod. 1984, 47, 331–341. Che, C-T.; Cordell, G. A.; Fong, H. H. S. Aristolindiquinone—A New Naphthoquinone from Aristolochia indica (Aristolochiaceae). Tetrahedron Lett. 1983, 24, 1333–1336. Chopra, R. N.; Nayar, S. L.; Chopra, I. C. Glossary of Indian Medicinal Plants. Council of Scientific and Industrial Research: ; New Delhi, 1956; p 104. Coutts, R. T.; Stenlake, J. B.; Williams, W. D. The Chemistry of the Aristolochia Species. Part V. A Comparative Study of Acidic and Basic Constituents of A. reticulata Linn., A. serpentaria Linn., A. longa Linn. and A. indica Linn. J. Pharm. Pharmacol. 1959, 11, 607–611. Cynthia, J. M.; Rajeshkumar, K. T. Effect of Aqueous Root Extract of Aristolochia indica (Linn) on Diabetes Induced Rats. Asian J. Plant Sci. Res. 2012, 2, 464–467. Das. R.; Kausik, A.; Pal, T. K. Anti-Inflammatory Activity Study of Antidote Aristolochia indica to the Venom of Heteropneustes fossilis in Rats. J. Chem. Pharm. Res. 2010, 2, 554–562.

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Desai, D. C.; Jacob, J.; Almeida, A.; Kshirsagar, R.; Manju, S. L. Isolation, Structural Elucidation and Anti-Inflammatory Activity of Astragalin, (−)Hinokinin, Aristolactam I and Aristolochic Acids (I & II) from Aristolochia indica. Nat. Prod. Res. 2014, 28, 1413–1417. Dey, A.; De, J. A. Aristolochia indica L.: A Review. Asian J. Plant Sci. 2011, 10, 108–116. Dey, A.; Dey, A.; Mukherjee, A.; Nandy, S.; Pandey, D. K. Chemotaxonomy of the Ethnic Antidote Aristolochia indica for Aristolochic Acid Content: Implications of AntiPhospholipase Activity and Genotoxicity Study. J. Ethnopharmacol. 2021, 266, 113416. Dey, A.; Nongdam, P.; Nandy, S.; Mukherjee, S.; Mukherjee, A.; Tikendra, L.; Hazra, A. K.; Pandey, D. K. Polyamine Elicited Aristolochic Acid Production in In Vitro Clonally Fidel Aristolochia indica L.: An ISSR and RAPD Markers and HPTLC Based Study. S. Afr. J. Bot. 2020. https://doi.org/10.1016/j.sajb.2020.06.018 Dharmalingam, S. R.; Madhappan, R.; Ramamurthy, S.; Chidambaram, K.; Srikanth, M. V.; Shanmugham, S.; Senthil Kumar, K. L. Investigation on Antidiarrhoeal Activity of Aristolochia indica Linn. Root Extracts in Mice. Afr. J. Tradit. Complement. Altern. Med. 2014, 11, 292–294. Faisal, M.; Sridhar, B.; Sunil Kumar, K. N.; Sudhakara,; Rav, M. Pharmacognostical, Phytochemical and Toxicity Profile of Flower of Ishwari—Aristolochia indica Linn. J. Phytopharmacol. 2015, 4, 133–138. Fuhrer, H.; Ganguly, A. K.; Gopinath, K. W.; Govindachari, T. R.; Nagarjan, K.; Pai, B. R.; Parthasarathy, P. C. Ishwarone. Tetrahedron 1970, 26, 2371–2390. Gandhi, P. R.; Kamaraj, C.; Vimalkumar, E.; Roopan, S. M. In Vivo Antiplasmodial Potential of Three Herbal Methanolic Extracts in Mice Infected with Plasmodium berghei NK65. Chin. Herb. Med. 2019, 11, 299–307. Ganguly, T.; Pakrashi, A.; Pal, A. K. Disruption of Pregnancy in Mouse by Aristolic Acid: I. Plausible Explanation in Relation to Early Pregnancy Events. Contraception 1986, 34, 625–637. Goverdhan, P.; Sandhya Rani, M.; Thirupathi, K.; Rani, S.; Sathesh, S.; Ravi Kumar, B.; Krishna Mohan, G. Hypoglycemic and Antihyperglycemic Effect of Aristolochia indica Normal and Alloxan Induced Diabetic Rats. Pharmacologyonline 2008, 1, 20–29. Govindachari, T. R.; Mohamed, P. A.; Parthasarathy, P. C. Ishwarane and Aristolochene, Two New Sesquiterpene Hydrocarbons from Aristolochia indica. Tetrahedron 1970, 26, 615–619. Janani, N.; Revathi, K. Antioxidant, Free Radical Scavenging and Antimicrobial Activities of Aristolochia indica L. World J. Pharm. Pharma. Sci. 2018a, 7, 980–991. Janani, N.; Revathi, K. In Vitro Evaluation of Aristolochia indica for Its Anti-Inflammatory, Antidiabetic and Anticancer Efficacy. Int. J. Curr. Res. Med. Sci. 2018b, 4, 23–30. Jeevan Ram, A.; Bhakshu, L. M.; Venkata Raju, R. R. In Vitro Antimicrobial Activity of Certain Medicinal Plants from Eastern Ghats, India, Used for Skin Diseases. J. Ethnopharmacol 2004, 90, 353–357. Jirovetz, L.; Buchbauer, G.; Puschmann, C.; Fleischhacker, W.; Shafi, P. M.; Rosamma, M. K. Analysis of the Essential Oil of the Aerial Parts of the Medicinal Plant Aristolochia indica Linn. (Aristolochiaceae) from South India. Sci. Pharm. 2000, 68, 309–316. Joe, M. M.; Benson, A.; Ayyanar, M.; Sa, T. Bioactive Compounds and Medical Significance of Some Endangered Medicinal Plants from the Western Ghats Region of India. In Biotechnology of Bioactive Compounds: Sources and Applications; Gupta, V. K., Tuohy, M. G., Lohani, M., O’Donovan, A., Eds.; John Wiley & Sons, Ltd., 2015.

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Kamaraj, C.; Kaushik, N. K.; Mohanakrishnan, D.; Elango, G.; Bagavan, A.; Zahir, A. A.; Rahuman, A. A.; Sahal, D. Antiplasmodial Potential of Medicinal Plant Extracts from Malaiyur and Javadhu Hills of South India. Parasitol. Res. 2012a, 111, 703–715. Kamaraj, C.; Rahuman, A. A.; Siva, C.; Iyappan, M.; Kirthi, A. V. Evaluation of Antibacterial Activity of Selected Medicinal Plant Extracts from South India Against Human Pathogens. Asian Pac. J. Trop. Med 2012b, 2, S296–S301. Kamaraj, C.; Rahuman, A. A.; Mahapatra, A.; Bagavan, A.; Elango, G. Insecticidal and Larvicidal Activities of Medicinal Plant Extracts Against Mosquitoes. Parasitol. Res. 2010, 107, 1337–1349. Kangralkar, V. A.; Kulkarni, A. R. In Vitro Cytotoxic Activity of Alcoholic Extract of Aristolochia indica. Res. J. Pharm. Tech. 2013, 6, 1240–1241. Kanjilal, P. B.; Kotoky, R.; Couladis, M. Chemical Composition of the Stem Oil of Aristolochia indica L. J. Essent. Oil Res. 2009, 21, 24–25. Karan, S. K.; Mishra, S. K.; Pal, D.; Mondal, A. Isolation of β-Sitosterol and Evaluation of Antidiabetic Activity of Aristolochia indica in Alloxan-Induced Diabetic Mice with a Reference to In-Vitro Antioxidant Activity. J. Med. Plants Res. 2012, 6, 1219–1223. Krishnaraju, A. V.; Rao, T. V. N.; Sundararaju, D.; Vanisree, M.; Tsay, H-S.; Subbaraju, G. V. Assessment of Bioactivity of Indian Medicinal Plants Using Brine Shrimp (Artemia salina) Lethality Assay. Int. J. Appl. Sci. Eng. 2005, 3, 125–134. Kumar, M. S.; Rajeswari; Astalakshmi, N. Evaluation of Antimicrobial Activities of Aristolochia indica (Linn). Int. J. Pharm. Pharm. Sci. 2011, 3, 271–272. Kumar, V. P.; Chauhan, N. S.; Padh, H.; Rajani, M. Search for Antibacterial and Antifungal Agents from Selected Indian Medicinal Plants. J. Ethnopharmacol. 2006, 107, 182–188. Kupchan, S. M.; Doskotch, R. W. Tumor inhibitors. I. Aristolochic Acid, the Active Principle of Aristolochia indica. J. Med. Chem. 1962, 5, 657–659. Kupchan, S. M.; Merianos, J. J. The Isolation and Structural Elucidation of Novel Derivatives of Aristolochic Acid from Aristolochia indica. J. Org. Chem. 1968, 33, 3735–3738. Mallaiah, G. K.; Thirupathi, K.; Krishna Mohan, G. Investigation on Aristolochia indica— Immunomodulator Activity. World J. Pharm. Pharm. Sci. 2015, 4, 1145–1159. Mathew, J. E.; Kaitheri, S. K.; Vachala, S. D.; Jose, M. Anti-Inflammatory, Antipruritic and Mast Cell Stabilizing Activity of Aristolochia indica. Iran J. Basic Med. Sci. 2011, 14, 422–427. Meenatchisundaram, S.; Parameswari, G.; Michael, A. Studies on Antivenom Activity of Andrographis paniculata and Aristolochia indica Plant Extracts Against Daboia russelli Venom by In Vivo and In Vitro Methods. Indian J. Sci. Technol. 2009, 2, 76–79. Michl, J.; Jennings, H. M.; Kite, G. C.; Ingrouille, M. J.; Simmonds, M. S. J.; Heinrich, M. Is Aristolochic Acid Nephropathy a Widespread Problem in Developing Countries? A Case Study of Aristolochia indica L. in Bangladesh Using an Ethnobotanical–Phytochemical Approach. J. Ethnopharmacol. 2013, 149, 235–244. Moazzem Hossen, S. M.; Hossain, M. S.; Islam, J.; Pinto, M. N.; Nur-E-Jannat; Ahmed, F. Comparative Preliminary Phytochemical and Biological Investigations on Andrographis paniculata (Nees) and Aristolochia indica (Linn). Der Pharma Chemica 2014, 6, 332–338. Modak, B. K.; Gorai, P.; Pandey, D. K.; Dey, A.; Malik, T. An Evidence Based Efficacy and Safety Assessment of the Ethnobiologicals Against Poisonous and Non-Poisonous Bites Used By the Tribals of Three Westernmost Districts of West Bengal, India: AntiPhospholipase A2 and Genotoxic Effects. PLoS One 2020, 15, e0242944.

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Murugan, K.; Labeeba, M. A.; Panneerselvam, C.; Dinesh, D.; Suresh, U.; Subramaniam, J.; Madhiyazhagan, P.; Hwang, J. S.; Wang, L.; Nicoletti, M.; Benelli, G. Aristolochia indica Green-Synthesized Silver Nanoparticles: A Sustainable Control Tool Against the Malaria Vector Anopheles stephensi? Res. Vet. Sci. 2015, 102, 127–135. Murugan, M.; Mohan, V. R. Efficacy of Different Solvent Extracts of Vitex trifolia L. and Aristolochia indica L. for Potential Antibacterial Activity. Sci. Res. Reporter 2012, 2, 110–114. Naik, A. S.; Siddiqua, S.; Shrunga, M. N.; Sunitha Kumari, L.; Prashith Kekuda, T. R.; Raghavendra, H. L. Antimicrobial and Radical Scavenging Efficacy of Leaf and Flower of Aristolochia indica Linn. Sci. Technol. Arts Res. J. 2015, 4, 103–108. Naz, R.; Ayub, H.; Nawaz, S.; Islam, Z. U.; Yasmin, T.; Bano, A.; Wakeel, A.; Zia, S.; Roberts, T. H. Antimicrobial Activity, Toxicity and Antiinflammatory Potential of Methanolic Extracts of Four Ethnomedicinal Plant Species from Punjab, Pakistan. BMC Complement. Altern. Med. 2017, 17, 302. Pakrashi, A.; Chakrabarty, B. Antifertility Effect of Aristolic Acid from Aristolochia indica (Linn) in Female Albino Rabbits. Experientia 1978, 34, 1377. Pakrashi, A.; Chakrabarty, B.; Dasgupta, A. Effect of the Extracts from Aristolochia indica Linn. on Interception in Female Mice. Experientia 1976, 32, 394–395. Pakrashi, A.; Pakrashi, P. Antifertility Efficacy of the Plant Aristolochia indica Linn. on Mouse. Contraception 1979, 20, 49–54. Pakrashi, A.; Shaha, C. Effect of a Sesquiterpene from Aristolochia indica Linn. on Fertility in Female Mice. Experientia 1977, 33, 1498–1499. Pakrashi, A.; Shaha, C. Effect of Methyl Ester of Aristolic Acid from Aristoiochia indica Linn. on Fertility of Female Mice. Experientia 1978, 34, 1192–1193. Pakrashi, S. C.; Dastidar, P. G.; Chakrabarty, S.; Achari, B. (12S)-7,12-Secoishwaran-12-ol a New Type of Sesquiterpene from Aristolochia indica Linn. J. Org. Chem. 1980, 45, 4765–4767. Pakrashi, S.C; Dastidar, P. G.; Basu, S.; Achari, B. New Phenanthrene Derivatives from Aristolochia indica. Phytochemistry 1977, 16, 1103–1104. Pugazharasi, G.; Christy, R.; Jaganathan, J.; Shree Devi, M. S.; Karthik, L. A Novel Approach on Herbal Water to Reduce Water Contaminant Salmonella typhi—An In Vitro Study. Malaya J. Biosci. 2015, 2, 166–176. Rajashekharan, S.; Pushpangadan, P.; Ratheesh kumar, P. K.; Jawahar, C. R.; Nair, C. P. R.; Sarada amma, L. Ethno-Medico-Botanical Studies of Cheriya Arayan-and Valiya Arayan(Aristolochia indica, Linn; Aristolochia tagala, Cham). Ancient Sci. Life 1989, 9, 99–106. Ravikumar, S.; Nazar, S.; Nuralshiefa, A.; Abideen, S. Antibacterial Activity of Traditional Therapeutic Coastal Medicinal Plants Against Some Pathogens. J. Environ. Biol. 2005, 26, 383–386. Samy, R. P.; Thwin, M. M.; Gopalakrishnakone, P.; Ignacimuthu, S. Ethnobotanical Survey of Folk Plants for the Treatment of Snakebites in Southern Part of Tamilnadu, India. J Ethnopharmacol. 2008, 115, 302–312. Satheesh Kumar, P.; Senthil Kumar, N. Physicochemical and Preliminary Phytochemical Studies on Aristolochia indica Linn Roots. I. J. Phytopharmacol. 2017, 8, 170–172. Shafi, P. M.; Rosamma, M. K.; Jamil, K.; Reddy, P. S. Antibacterial Activity of the Essential Oil from Aristolochia indica. Fitoterapia 2002, 73, 439–441.

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Shang, M-Y.; Tian, M.; Tanaka, H.; Li, X-W.; Cai, S-Q.; Shoyama, Y. Quality Control of Traditional Chinese Medicine by Monoclonal Antibody Method. Curr. Drug Discov. Technol. 2011, 8, 60–65. Sini, S.; Malathy, N. S. Antimicrobial Properties of Roots of Medicinal Plants. Anc. Sci. Life 2005, 25, 62–65. Sivaraj, D.; Shanmugam, S.; Rajan, M.; Sasidharan, S. P.; Sathyanarayanan, S.; Muniyandi, K.; Thangaraj, P.; de Souza Araújo, A. A. Evaluation of Aristolochia indica L. and Piper nigrum L. Methanol Extract Against Centipede Scolopendra morsitans L. Using Wistar Albino Rats and Screening of Bioactive Compounds by High Pressure Liquid Chromatography: A Polyherbal Formulation. Biomed. Pharmacother. 2018, 97, 1603–1612. Subramaniyan, V.; Saravanan, R.; Baskaran, D.; Ramalalingam, S. In Vitro Free Radical Scavenging and Anticancer Potential of Aristolochia indica L. Against MCF-7 cell line. Int. J. Pharm. Pharm. Sci. 2015, 7, 392–396. Thirugnanasampandan, R.; Mahendran, G.; Narmatha Bai, V. Antioxidant Properties of Some Medicinal Aristolochiaceae Species. Afr. J. Biotechnol. 2008, 7, 357–361. Umamaheshwari, S.; Murthy, S. M. Antibacterial Activity of Root of Aristolochia indica on Bacillus subtilis. RGUHS J. Pharm. Sci. 2012, 2, 82–85. Vaghasiya, Y.; Chanda, S. V. Screening of methanol and acetone extracts of fourteen Indian medicinal plants for antimicrobial activity. Turk. J. Biol. 2007, 31, 243–248. Venkatadri, B.; Arunagirinathan, N.; Rameshkumar, M. R.; Ramesh, L.; Dhanasezhian, A.; Agastian, P. In Vitro Antibacterial Activity of Aqueous and Ethanol Extracts of Aristolochia indica and Toddalia asiatica Against Multidrug Resistant Bacteria. Indian J. Pharm. Sci. 2015, 77, 788–791. Venkateswarlu, N., Vijaya, T.; Suresh Bhargav, D.; Chandra mouli, K.; Pragathi, D.; Anitha, D.; Reddy, V. N.; Sreeramulu, A. In Vitro Inhibitory Effects of Medicinal Plants Extracts on Sclerotium oryzae—A Fungi Causing Stem Rot Disease in Paddy. Int. J. Pharm. Biol. Sci. 2013, 3, 147–151. Venkatraman, P.; Subbiah, S. N.; Suyambulingam, A. K.; Annamalai, T.; Sengottayan, S. N. Toxicity of Aristolochic Acids Isolated from Aristolochia indica Linn (Aristolochiaceae) Against the Malarial Vector Anopheles stephensi Liston (Diptera: Culicidae). Exp. Parasitol. 2015, 153, 8–16. Yasmin, F.; Hossain, M.; Karim, R.; Sarder, M. M. Anti-Bacterial and Anthelmintic Effects of Ethanolic Leaf Extract of Aristolochia indica L. Biosci. Bioeng. Commun. 2016a, 2, 61–66. Yasmin, F.; Hossain, M.; Sarder, A.; Bokshi, B. Analgesic, Antidiarrheal, Antioxidant, Cytotoxic and Oral Glucose Tolerance Activities of Ethanolic Leaf Extract of Aristolochia indica L. Biosci. Bioeng. Commun. 2016b, 2, 137–143. Zameer, F.; Rukmangada, M. S.; Chauhan, J. B.; Khanum, S. A.; Kumar, P.; Devi, A. T.; Nagendra Prasad, M. N.; Dhananjaya, B. L. Evaluation of Adhesive and Anti-Adhesive Properties of Pseudomonas aeruginosa Biofilms and Their Inhibition By Herbal Plants. Iran. J. Microbiol. 2016, 8, 108–119.

CHAPTER 63

Pharmacological Activities of Diploclisia glaucescens (Blume) Diels RUTUJA J. TIRBHANE1, PRADIP V. DESHMUKH2, and UTKARSHA M. LEKHAK1* 1Department

of Biochemistry, The Institute of Science, Dr. Homi Bhabha State University, 15, Madame Cama Road, Mumbai 400032, India

2Angiosperm Taxonomy

Laboratory, Department of Botany, Shivaji University, Kolhapur 416004, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Diploclisia glaucescens is a member of the family Menispermaceae, well known for its phytoecdysteroids and triterpenoids saponins content from seeds, fruits, leaves, and stem of the plant. Some of the major phytochemicals of D. glaucescens include Diploclidine, Stigmasterol, Ecdysteroid, Stepha­ rine, Paristerone, Capitasterone, Triterpenoids and Phytolaccagenic acid. The plant is commonly used to cure human ailments such as skin diseases and to relieve sprain. It is reported to have antibacterial, anti-inflammatory, spermicidal activity against human spermatozoa, insectical and molluscidal activities. 63.1 INTRODUCTION Diploclisia glaucescens (Blume) Diels is a liana, with wrinkled bark, belonging to the family Menispermaceae. It occurs in moist and Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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semi-evergreen forests up to 1500 m and found in India, Sri Lanka, Southern China, and Southeast Asia (Jayasinghe et al., 2003a,2003b; Ranjith et al., 2018). Diploclisia glaucescens is commonly known as Vatoli, Vtan-vel (Marathi), Ramrakh (Konkani), Battavali, Natsjastam, Vattavalli, Vattoli (Malayalam), and Kottaiyachachi (Tamil). It is one of the medically impor­ tant plants that contain many pharmacologically active compounds. Leaves of this plant are round or kidney shaped, heart shaped, or abruptly ending at the base and about 6–8 cm long. Small yellow, unisexual flowers are borne in many flowered panicles. These flowers have large drooping panicles. Fruit is inverted egg shaped or oblong almost stalkless, an inch long (Jayasinghe et al., 2003a, 2003b; Deepa et al., 2017; Ranjith et al., 2018). Synonyms of the plant include Cebatha marcrocarpa (Wight & Arn.) Kuntze, Cocculus glaucescens BI., Diploclisia inclyta Miers, Cocculus macrocarpa Wight, Diploclisa pictinervis Miers, Menispermum glaucescens Spreng., Quinio cocculoides Schlecht. 63.2

BIOACTIVES

D. glaucescens is most commonly used to cure human aliments. Phyto­ chemical investigation revealed that phytoecdysteroids and triterpenoids saponins are major components of D. glaucescens. Distinct saponins, terpenoids, phycoecdysteroid, glycosides triterpenoids were reported from seeds, fruits, leaves, and stem of plant (Jayasinghe et al., 1992, 1993, 2002a, 2002b, 2003a, 2003b, 2007). Antimicrobial and phytochemical studies were carried out using ethanol, methanol, ethyl-acetate, chloroform, aqueous extract. Phenols, flavanoids, proteins, and amino acids were isolated from ethanol, aqueous, and chloroform extracts of leaves of D. glaucescens, while ethanol and chloroform, aqueous, ethanol, and aqueous extract showed pres­ ence of only glycoside, alkaloids and saponins, tannins, respectively, and chloroform showed absence of tannins (Sagyaraj et al., 2014). Stigmasterol and ecdysterone from stem were isolated from methanolic extract of stem. Separation of which led to the isolation of a novel pyrimidine ring containing ecdysterone, bidesmodic saponin named diploclidine whose structure was established by chemical and spectroscopic method as β-D-glucopyranosyl -3-β-(β-D-glucopyranosyl) -3-β-D- (β-D-glucopyranosyl)- 23-hydroxy30-carbomethyoyolean-12-en-28-oate) and thin-layer chromatography analysis showed presence of phytolaccagenic acid (Bandara et al., 1989a, 1989b; Jayasinghe et al., 2003a). While two new phenyl glycosides, namely,

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4-(2-nitroethyl) phenyl-β-D-xylopyranosyl (1→6)-β-glucopyranoside and 4-cyanophenyl- β-xylopyranosyl (1→6)-β-D-glucopyranoside were isolated from methanolic extract of fruits (Bandara et al., 1989a, 1989b). New ecdysteroid 2-deoxy-5-β-20-dihydroxyecdysterone together with 20-hydroxyecdysone, 3-deoxy-1-β,20-dihyroxyecdysterone, 2-deoxy20-hydroxyecdysterone, 24-ethyl- 20-hydroxyecdysone (makisterone C, lemmasterone, podoecdystrone) were isolated from the ethyl acetate extract of D. glaucescens (Jayasinghe et al., 2002a, 2002b, 2007). High Speed Counter Current Chromatography (HSCCC) from the ethyl acetate extract of the residue obtained after the evaporation of crude ethanolic extract of D. glaucescens showed presence of three ecdysteroids, namely, paristerone, ecdysterone, and capisterone. (Fang et al., 2017). Pentacyclic triterpenoids serjanic acid and phytolaccegenic as well as new glycoside 3-O-β-Dglucopyranosylphytolaccegenic acid have been isolated from the stem of D. glaucescens (Bandara et al., 1990). Seeds, stem, and roots of D. glaucescens showed presence of 20-hydroxyecdysone as a major constituent along with proporphine alkaloid stepharine, serajanic acid, phytolaccegenic acid, and their glycosides (Ranjith et al., 2018). 63.3

PHARMACOLOGY

63.3.1 ANTIBACTERIAL ACTIVITY Ethanolic extract of D. glaucescens showed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Salmonella paratyphi, Strep­ tococcus pneumoniae, Bacillus cereus, Proteus mirabilis, and Serratia marcescens. This may be because of various phytochemicals present in the extract. The highest antimicrobial activity was observed against S. paratyphi. However, chloroform extract showed antibacterial activity against Vibrio cholerae only. Octadecanoic acid-9-yne showed strong antibacterial activity (Sagayaraj et al., 2014). 63.3.2 ANTI-INFLAMMATORY ACTIVITY Three phytoecdysteroid such as paristerone, ecdysterone, and capisterone isolated from the stem of D. glauscescens showed significant anti-inflam­ matory activity by measuring the inhibitory ratios of β-glucoronidase release in rat polymorphornuclear leukocytes (PMN) induced by platelet-activating

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FIGURE 63.1 Structures of (1) Diploclidine, (2) Stigmasterol, (3) Ecdysteroid (Bandara et al., 1989b, Jayasinghe et al., 2003a, 2003b) (4) Stepharine (Ranjith et al., 2018) (5) Paristerone (6) Capitasterone (Fang et al., 2017) (7) Triterpenoids (8) Phytolaccagenic acid (Bandara et al., 1989a, 1989b; Ranjith et al., 2018).

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factor. But, 3-O-β-D-glucuronopyranosyl—28-O--D-glucopyranosyl serjanic acid showed mild inflammatory activity. These phytoecdysteroid interfere with membrane fluidity that leads to cell sensitization and modulate various signaling processes in immodulation and inflammation (Das et al., 2020). 63.3.3 INSECTICIDAL ACTIVITY A compound from D. glaucescens stem, ecdysterone (3%), showed an insec­ ticidal activity, whereas saponins and ethanol extract of seeds also showed insecticidal activity (Bandara et al., 1989a, 1989b). 63.3.4 MOLLUSCICIDAL ACTIVITY Methanol extract of D. glaucescens showed a molluscidal effect against Biomphalaria glabrata snails (Bandara et al., 1989b). However, the ecdys­ terone, bidesmodic saponin Diploclisin did not show any molluscicidal activity against Biompalalria glabrata (Bandara et al., 1989b). 63.3.5 SPERMICIDAL ACTIVITY Ecdysterone from the extract of stem showed significant spermicidal activity (Bandara et al., 1989b), although bidesmodic saponin diploclisin showed no activity against human spermatozoa (Bandara et al., 1989a). 63.3.6 TO CURE SKIN DISEASES Leaves of D. glaucescens with betel leaves (Piper leaves), tinder leaves, and coconut oil when boiled and applied over the skin, helped to get rid of scabies, a contagious itch (Gupta et al., 2017; Rani and Jeeva, 2018). 63.3.7 TO RELIEVE SPRAIN D. glaucescens leaves were heated with coconut oil (Cocos nucifera) and gingelly oil and applied externally to get relief from sprain (Sarwar, 2015).

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KEYWORDS • • • • •

Diploclisia glaucescens Menispermaceae phytoecdysteroids Diploclidine Stepharine

REFERENCES Bandara, B. M. R.; Jayasinghe, L.; Karunaratne, V.; Wannigama, G. P.; Kraus, W.; Bokel, M.; Subramaniam, S. Diploclisin, a Bidesmosidic Triterpenoid Saponins from Diploclisia glaucescens. Phytochemistry, 1989a, 28, 2783–2785. Bandara, B. M. R.; Jayasinghe, L.; Karunaratne, V.; Wannigama, G. P.; Bokel, M.; Kraus, W.; Sotheeswaran, S. Ecdysterone from Stem of Diploclisia glaucescens, Phytochemistry,1989b, 28, 1073–1075. Bandara, B. M. R.; Jayasinghe, L.; Karunaratne, V.; Wannigama, G. P.; Bokel, M. et al. Triterpenoidal Constituents of Diploclisia glaucescens, Planta medica, 1990, 56, 290–292. Das N.; Mishra S. K.; Bishayee A.; Ali E.S; Bishayee A.; The phytochemical, Biological, and Medicinal Attributes of Phytoecdysteroids: An Updated Review. Acta Pharmaceutica Sinica B, 2020. https://doi.org/10.1016/j.apsb.2020.10.012. Deepa, M. R.; Udayan, P. S.; Anilkumar, K. A. Taxonomical and Phytosociological Studies on Chithalikavu—A Sacred Grove, Thrissur District, Kerala. Trop. Plant Res. 2017, 4, 20–30. Fang, L.; Li, J.; Zhou, J.; Wang, X.; Guo, L. Isolation and Purification of Three Ecdysteroids from the Stems of Diploclisia glaucescens by Highspeed Countercurrent Chromatography and Their Anti-Inflammatory Activities In Vitro. Molecules 2017, 22, 1310. Gupta P.; Kumar A.; Sharma N, Patel M.; Maurya A.; Shrivastava S. A Review on Phytomedicines Used in Treatment of Most Common Skin Diseases. Ind. J. Drugs 2017, 5, 150–164. Jayasinghe, L.; Jayasoooriya, C. P.; Oyama, K.; Fujimoto, Y. 3-Deoxy -1β,20 Dihydroxyecdysone from Leaves of Diploclisia glaucescens. Steroids 2002a, 67, 555–558. Jayasinghe, L.; Jayasooriya, C. P.; Harab, N.; Fujimoto, Y. A Pyridine Ring-Containing Ecdysteroid from Diploclisia glaucescens. Tetrahedron Lett. 2003b, 44, 8769–8771. Jayasinghe, L.; Kumarihamy, B. M. M.; Arundathie B. G. S.; Dissanayake, L.; Hara, N.; Fujimoto, Y. A New Ecdysteroid 2-Deoxy-5β ,20-Dihydroxyecdysone from Fruits of Diploclisia glaucescens. Steroids 2003a, 68, 447–450. Jayasinghe, U. L. B.; Hara, N.; Fujimoto, Y. (2-Nitro-ethyl) Phenyl and Cyanopheyl Glycosides from the Fruits of Diploclisia glaucescens, Nat. Prod. Res. 2007, 260–264. Jayasinghe, U. L. B.; Jayasooriya, C. P.; Fujimoto, Y. Oleanan Glycosides from the Leaves of Diploclisia glaucescens. Fitotherapia 2002b, 73, 406–410.

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Jayasinghe, U. L. B.; Wannigama, G. P.; Balaasubbarmaniam, S.; Nasir H.; Rahman, A. U. Benzylisoquinone Alkaloids From Anamirta cocculus and Dipoclisia glaucescens. J. Natl. Sci Foundation Sri Lanka 1992, 20, 187–190. Jayasinghe, U. L. B.; Wannigama, G. P.; Macleod, J. K. Saponins of Diploclisia glaucescens. Nat. Prod. Lett. 1993, 2, 249–253. Rani, C. J. P.; Jeeva, S.; Medicinal Plants Used for the Treatment of Dermatological Ailments by the Kani Tribe of Kanyakumari Wildlife Sanctuary, Tamilnadu, India. Biosci. Discov. 2018, 9, 438–447. Ranjith, D.; Nisha, A. R.; Nair, S. N.; Litty, M.; Rahman, M.; Juliet, S. Evaluation of Analgesic and Anti-Inflammatory Activities of Herbal Formulation Used for Mastitis in Animals. Int. J. Appl. Sci. Eng. 2018, 6, 37–48. Sagayaraj, M. I.; Britto, S. J.; Arulappan, M. T.; Krishnakumar, J.; Thomas, S.; George, M. Antimicrobial Studies and Phtochemical Screning of Leaves in Tiliacora acuminata (Lam), Hook & Thomson and Diploclisia glaucescens (Blume) Diels Menispermaceae. Asian J. Pharm. Res. 2014, 4, 82–86. Sarwar, A. K. M. G. Medicinal Plant Genetic Resources of Bangladesh—Genera Represented by Single Species and Their Conservation Needs. J. Med. Plant Studies 2015, 3, 65–74.

CHAPTER 64

Phytochemical Composition and Pharmacological Properties of Red spinach (Amaranthus tricolor L.) VRUSHALI MANOJ HADKAR1, LANKAPOTHU VENKATA CHARISHMA2, and CHINNADURAI IMMANUEL SELVARAJ2* 1Department

of Biotechnology, School of Biosciences and Technology, VIT, Vellore 632014, Tamil Nadu, India

2VIT

Centre for Agricultural Innovations and Advanced Learning (VAIAL), School of Biosciences and Technology, VIT, Vellore- 632014 Tamil Nadu, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Amaranthus tricolor Linn. (Family - Amaranthaceae) is an ornate plant known commonly as Joseph’s coat. The entire plant is astringent; infusion of mature plants consumed internally improves eyesight and rejuvenate the liver. The leaves of A. tricolor are very nutritious and inexpensive; the leaves’ nutrients include carbohydrates, proteins, Vit A, C, B1, B2, B3, and rich in Fe and Ca; is an excellent source of fibre. A. tricolor is a more signifi­ cant therapeutic plant due to its large content of ascorbic acid, betacyanins, antioxidants and phenolic compounds of heterogeneous nature. The plant has antidiabetic, hepatoprotective, gastroprotective, antinociceptive, antiinflammatory, antitumor, sedative, anxiolytic, and antimicrobial properties. In Indian folkloric remedy, the plant is used to treat various sicknesses like Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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throat infections, coughs, eczema, toothache, diarrhoea, piles, leucorrhoea, gonorrhoea, and infertility issues. The plant extract can cure external sores, bladder discomfort, enhances kidney function and boosts digestion. Tannic acid, linolenic acid and palmitic acid were also found in the plant’s leaves. A. tricolor leaves have shown the presence of isoquercetin and rutin which was the most copious flavonoid; salicylic, gallic, syringic, vanilic, ferulic, p-coumaric, ellagic and sinapic acid were the most common phenolic acid that were known to be found. The flavonoids present in this plant, hydrobenzoic acids, and hydroxycinnamic acids enrich the cellular antioxidant defenses and may prolong healthy life when included in the daily diet. 64.1

INTRODUCTION

Amaranthus tricolor L. (Family - Amaranthaceae) is an ornate plant known commonly as Joseph’s coat (English and “laal shak” in the Bengali language (Rahmatullah et al., 2013). It also has common names, namely, Fountain Plant, Chinese Spinach, and Garden Amaranth. It was previously recognized as A. melancholicus Linn., A. gangeticus Linn., A. tristis Linn., or A. polygamus Linn. Hook. f. in part (Khare, 2008). The Ayurvedic name, Maarisha-rakta (red var.); Folkloric name is Laal Shaak, Laal Marashaa, while in Telugu it is known as Perugu thotakura and in Siddha or Tamil, Mulai Keerai or Thandu Keerai (Khare, 2008). The plant species is spread worldwide, including Bangladesh, the Indian States, namely, Kerala, Maha­ rashtra, Assam, Tamil Nadu, and Andhra Pradesh (Jahan et al., 2020). The species is grown in countries like Kenya, Benin, Tanzania, Nigeria, India, and Southern Africa (Aneja et al., 2011). A. tricolor is an annual herb with a height up to 60–125 cm; the plant can endure scorching summer (Shukla et al., 2006). The flowers are nonshowy, normally much-branched, stout stemmed, angularly branched, glabrous, or furnished in the uppermost sections with scanty, crisped bristles. Glabrous leaves or sparsely pilose on the ventral surface of the central venation, purplish or green-suffused, rather inconstant in size, up to 8 cm long and petiolate. The leaf lamina is rhomboid-ovate, broadly ovate, emarginate to round or sharp at the top; base shortly cuneate, decurrent near the petiole. Flowers, globose clusters with 4–25 mm in diameter, crimson or green colored, and frequently close to set a compact terminal spike of variable length, female and male flowers intermixed. Perianth segments, elliptic or oblong-elliptic, 3, 3–5 mm long, pale-membranous, narrowed above, pale-tipped awn, midrib excurrent into a long; ovoid-urceolate capsule with a tiny scruff below the style-base,

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membranous, circumscissile, dimly creased. Seed 1–1.5 mm, shining, black or brown, faintly reticulate and lenticular (Das, 2012). The entire plant is astringent; infusion of mature plants consumed inter­ nally improves eyesight and rejuvenates the liver. Amaranth has numerous health gains, primarily in the oil obtained from seeds (Jahan et al., 2020). The leaves of A. tricolor are very nutritious and inexpensive; the leaves’ nutrients include carbohydrates, proteins, Vit A, C, B1, B2, B3, and rich in Fe and Ca; is an excellent source of fiber. Its great nutritive importance is consumed more than other leafy vegetables (Bala et al., 2019). The plant is an astringent (in leucorrhoea, menorrhagia, hemorrhagic colitis, diarrhea); also used in cold, bronchitis, and emollient externally (Khare, 2008). This plant’s leaves and tender stalks can be used as salad and prepared as a leafy vegetable after cooking. The leaves of A. tricolor, are consumed in Africa, as a supplementary source of natural protein, which comprises equitable neces­ sary amino acids (Singh and Whitehead, 1996). Fresh plants and leaves of A. tricolor are cooked and consumed along with regular diet in China, Indonesia, South-East Asia, and India; they enrich foods with antioxidants, essential amino acids, and biologically vital elements (Gins et al., 2017; Rastogi and Shukla, 2013). In Russia, A. tricolor, known for its significant low-molecular antioxidants and gluten-free protein (e.g., phenolic compounds, vitamin C, squalene, betalain pigments), is appropriate and essential for the compensa­ tion of nutrient insufficiency (Gins et al., 2017). A. tricolor is a more significant therapeutic plant due to its large content of ascorbic acid, betacyanins, antioxidants, and phenolic compounds of hetero­ geneous nature (Peter and Gandhi, 2017). Antidiabetic (Peter and Gandhi, 2017; Rahmatullah et al., 2013; Clemente and Desai, 2011), hepatoprotective (Al-Dosari, 2010; Aneja et al., 2013), gastroprotective (Devaraj and Krishna, 2011), antitumor (Gins et al., 2017), and antimicrobial (Rao et al., 2012; Pulipati et al., 2014) properties of the extracts from the leaves of Amaran­ thus tricolor L. have been proved. The plant infusion, when taken regularly, improves vision and guards the liver (Larsen et al., 2003). In Indian folkloric remedy, the plant is used to treat various sicknesses like throat infections, coughs, eczema, toothache, diarrhoea, piles, leucorrhoea, gonorrhoea, and infertility issues (Aneja et al., 2011). The plant extract can cure external sores, bladder discomfort, enhances kidney function, and boosts digestion. The roots of A. tricolor are used as a medication for diarrhoea. It is prescribed for patients with raised blood cholesterol, colon cancer, and diabetes mellitus (Komor and Devi, 2006). Folk medicinal practitioners of Bangladesh use plants to treat anemia, pain, skin diseases, dysentery, as a blood purifier and

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to treat diabetes (Rahmatullah et al., 2013). One hundred grams of the A. tricolor leaves provides energy 23 kcal, 3.63 g of carbohydrate, 2.86 g of protein, 0.39 g of total fat, 2.20 g of dietary fiber, 28.10 mg vitamin C, 2.03 mg of vitamin E, 0.72 mg of niacin, 79 mg of sodium, 558 mg of potassium, 99 mg of calcium, 0.13 mg of copper, 79 mg of magnesium, 0.53 mg of zinc, and a modest quantity of beta-carotene (Komor and Devi, 2006). 64.2

BIOACTIVES

Phytochemical analysis revealed that A. tricolor has carbohydrates and flavonoids like quercetin, betacyanin A and betacyanin B, amaranthin, and isoamaranthin (Piattelli et al., 1964). A. tricolor is popularly known for its purple betalain pigments. Tannic acid, linolenic acid, and palmitic acid were also found in the plant’s leaves (Harborne, 1984). Various sterol compounds like spinasterol, cholesterol, campesterol, 24-methylene cholesterol, β-sitosterol, stigmasterol, fucosterol, and isofucosterol were also reported (Behari and Sharma, 1984). Phytochemical screening showed fatty acids like lignoceric and arachidic acid (Fernando and Bean, 1984). Proteins and amino acids like cysteine, proline, leucine, tryptophan, arginine, glutamic acid, histidine, lysine, phenylalanine, methionine, isoleucine, threonine, valine, and tyrosine were reported (Behari and Sharma, 1984). Preliminary results inferred that carbohydrates, phenolic compounds, glycosides, saponins and flavonoids, steroids were present in A. tricolor extracts. TLC was used to investigate the presence of carbohydrates, steroidal glycosides, flavonoids, and saponins in several solvent-based infusions of A. tricolor. Results indicate that carbohydrates, saponins, flavonoids, and steroidal glycosides were found in extracts (Rao et al., 2012). Preliminary results inferred that carbohydrates, phenolic compounds, glycosides, saponins and flavonoids, steroids were present in A. tricolor extracts. TLC was used to investigate carbohydrates, steroidal glycosides, flavonoids, and saponins in various solvent extracts of A. tricolor. Results indicate that carbohydrates, saponins, flavonoids, and steroidal glycosides were found in extracts (Rao et al., 2012). Preparative high-speed countercurrent chromatography was performed to isolate two chlorophyll breakdown products from lipophilic infusions of the aerial parts of A. tricolor, namely, chlorophyll-b methoxyl­ actone, and 132-hydroxy-(132-S)-phaeophytin-a. The major saturated fatty acid in leaves, seeds, and stems is palmitic acid to the extent of 18–25%; the primary unsaturated fatty acids are linolenic acid in leaves (42%) and linoleic

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acid in stems (46%) and seeds (49%) of the total fatty acids (Fernando and Bean, 1984). Older leaves of A. tricolor contain violet-red pigments such as amaranthin, betacyanins, and isoamaranthin (Piattelli et al., 1969). They are derivatives of betanidin, formed from 3,4-dihydroxyphenylalanine (Stobart et al., 1970). EC50 is a universally applied parameter to reveal and relate antioxidative potential in particular molecules. Few molecules in A. tricolor extracts possess EC50 value, namely, amaranthine (8.37 µM) and isoamaran­ thine (8.35 µM) (Santiago et al., 2014). A. tricolor contains isoamarantin, amarantin, amino acids, betaine, and sterols (Khare, 2008). A. tricolor leaves have shown the presence of isoquer­ cetin and rutin which was the most copious flavonoid; salicylic, gallic, syringic, vanilic, ferulic, p-coumaric, ellagic, and sinapic acid were the most common phenolic acids (Khanam and Oba, 2013). Betalain pigments produce yellow color; water soluble (betaxanthins) and betacyanins is characterized by red-violet color. The red-violet amaranthin is one of the novel betaxanthin, methyl derivatives of arginine betaxanthin and betalamic acid were shown to be present in leaves of A. tricolor. It is a rich source of B-carotene, zeaxanthin, lutein, and violaxanthin. It is also rich in minerals like vitamin C, calcium, iron, riboflavin, and foliate. Along with betaxanthin, amaranthin is also the chief pigment present in leaves of A. tricolor (Biswas et al., 2013). The most notable compounds present in A. tricolor are tannin, saponins, unsaturated fatty acids, tocopherols, lectins, phytosterols, tocotri­ enols, isoprenoid compounds, squalene, terpene alcohols, aliphatic alcohols, and polyphenols, which have characteristics associated with protection against cancer, improving the immunity system, control serum lipid levels, prevention against oxidation and minimizing pain (Velez-Jimenez et al., 2014). A sum of five carotenoid compounds was profiled in A. tricolor. Four compounds were xanthophylls (violaxanthin, lutein, zeaxanthin, and neoxanthin), and one of them was a precursor for vitamin A (beta-carotene). Among xanthophylls, lutein is the most abundant carotenoid, succeeded by violaxanthin and neoxanthin, while zeaxanthin’s content was less in A. tricolor. Percentage of zeaxanthin (4.98 to 6.15), lutein (27.85 to 29.27), violaxanthin (16.78 to 19. 79), neoxanthin (11.65 to 13.53), total xantho­ phylls (61.26 to 68.75), beta-carotene (31.25 to 38.74) to total carotenoids in mg 100 g-1 fresh weight (Sarker and Oba, 2020). A. tricolor also showed the presence of chlorogenic acid among hydroxycinnamic acids. The flavo­ noids present in this plant, hydrobenzoic acids, and hydroxycinnamic acids enrich the cellular antioxidant defenses and may prolong healthy life when

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included in the daily diet (Biswas et al., 2013). The phytocompounds present in Amaranthus tricolor are shown in Figures 64.1 and 64.2.

FIGURE 64.1 Phytocompounds present in Amaranthus tricolor: Amaranthin (1), Isoamaranthin (2), Quercetin (3), Spinasterol (4), Cholesterol (5), Campesterol (6), Methylene cholesterol (7), Stigmasterol (8), β-sitosterol (9), and Fucosterol (10) [Marvin 17.21.0, ChemAxon tool was used for drawing chemical structures].

64.3

PHARMACOLOGY

64.3.1 SEDATIVE AND ANXIOLYTIC ACTIVITY The study of the sedative activity of A. tricolor was experimented with using the open field test method, used to screen depressive action of the extract on the central nervous system in mice. Rotarod test and hole cross test were also used to study sedative activity. The study on locomotors activity, as carried out using hole cross tests and open field tests, recorded that the amplitude and frequency of action were reduced by both the doses of methanolic extract from the leaves of A. tricolor. An elevated plus-maze test was used to analyze the anxiolytic activity. In the trial, diazepam drug

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FIGURE 64.2 Phytocompounds present in Amaranthus tricolor Betaxanthin (11), Isoquercetin (12), Isoamaranthin (13), Rutin (14), Salicylic acid (15), Syringic acid (16), Gallic acid (17), Vanillic acid (18), Ferulic acid (19), P-coumaric acid (20), Ellagic acid (21), Sinapic acid (22), and Betalamic acid (23) [Marvin 17.21.0, ChemAxon tool was used for drawing chemical structures].

increased open arms exploration was believed to be anxiolytic. It was reported that there was a rise in open arm exploration (anxiolytic activity) that was due to A. tricolor extract, which enhanced the rate of listings within and period spent with the open arms. The A. tricolor methanolic extract has shown promising anxiolytic effects without causing any neuro­ muscular side effects. Thus A. tricolor act as GABAA agonists and the agonistic property could be ascribed to the CNS depressant effect of A. tricolor (Jahan et al., 2020). 64.3.2 ANTI-HYPERGLYCEMIC ACTIVITY A study was conducted to assess A. tricolor whole plant methanolic extracts’ possible glucose threshold efficiency using glucose-induced hyperglycemic mice models. The outcomes registered that the extract holds significantly

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reduced blood glucose levels on glucose-loaded mice at all the extracts’ dosages. The significant anti-hyperglycemic action was comparable to an approved drug, glibenclamide (10 mg/kg body weight), with the extract dosage at 400 mg /kg bw (Rahmatullah et al., 2013). Another study reported that the betalamic acid at 250 micrograms per milliliter concentration restrained the porcine pancreatic α-amylase activity by 22%, besides amaran­ thin and betaxanthin did not show any inhibition. The reference standard used was acarbose which at 250 μg/mL concentration inhibited the porcine pancreatic α-amylase activity by 40.9%. Therefore, betalamic acid is known to possess alpha-amylase inhibitory potential, whereas both amaranthin and betaxanthin did not show alpha-amylase inhibitory potential (Biswas et al., 2013; Tundis et al., 2010). 64.3.3 ANTINOCICEPTIVE ACTIVITY In antinociceptive property tests, A. tricolor extract confirmed there is a direct correlation between the dosage of the extract and the reduction in the writh­ ings’ number produced in mice by administering acetic acid (intraperitoneal). At a 400 mg extract per kg body weight dosage, the highest antinociceptive action was observed, which correlated positively a regular antinociceptive medication, aspirin, given at a dosage of two hundred miligrams per kg BW (Rahmatullah et al., 2013). 64.3.4 ANTIOXIDANT ACTIVITY A. tricolor leaves have high total polyphenol content and hence correlated with their antioxidant activity. The high quantity of betacyanin in A. tricolor offers the leaves a deep red chroma, heightens antioxidant capability due to the presence of phenolic compounds (Khandaker et al. 2008). Antioxidant capacity of A. tricolor (DPPH) differed from 12.27 to 29.38 µg g−1; anti­ oxidant capacity (ABTS+) extended from 26.69 µg g−1 to 63.79 µg−1. The antioxidant capacity of total betacyanins, betaxanthins, and betalains had profoundly notable positive comparisons between themselves and between whole carotenoids, antioxidant capability (ABTS+ and DPPH). The antioxi­ dant activities of different betalains isolated from A. tricolor extract possess moderate antioxidant activity; the EC50 value of amaranthine (8.37 µM) and isoamaranthine (8.35 µM) when compared to ascorbic acid (13.93 µM), an approved antioxidant. The results conclude that more significant inhibition

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(%) represented more ROS scavenging action of radicals and more potent antioxidants (Cai et al., 2003). The aqueous extract of A. tricolor leaves is as potent as ascorbic acid with maximum inhibition of 62.96% at 100 µg/mL, similar to 67.64% vitamin C at the equivalent concentration. The reducing power of A. tricolor leaves extracts is very strong, and the extract’s power increases with the quantity of sample. The aqueous extract of A. tricolor resembled to be as effective as ascorbic acid with absorbance maxima of 0.383 at 100 µg/ mL when compared with 1.501 at 100 µg/ mL Vit. C. The aqueous extracts revealed more absorbance value relevant to vitamin C in hydrogen peroxide scavenging activity (Rao et al., 2012). The antioxidant activity of different extracts of A. tricolor was evaluated based on DPPH (2, 2-Diphenyl-1-picrylhydrazyl) radical scavenging effect. Various concentra­ tions of the methanolic crude extracts of Amaranthus tricolor 100–500 μg/ mL were prepared. One milliliter of each prepared concentration combined with three milliliters of DPPH (0.1 mM) solution in methanol. Further, after the incubation period, absorbance was checked at 517 nm in UV-Visible Spectrophotometer (Kumar et al., 2013; Morrison and Twumasi, 2010). The p-Nitroso dimethyl aniline radical scavenging method (p-NDA) was used to estimate the scavenging activity of A. tricolor by the amount of inhibi­ tion of bleaching in the presence and absence of the plant extract solutions. A. tricolor showed better antioxidant potential than the standard ascorbic acid. The methanolic leaf extracts were believed to show strong antioxidant activity in a dose-dependent manner. The IC50 values of plant methanolic extract, chloroform extract, aqueous, and ascorbic acid were 290, 657, 830, and 130 μg/mL. In the p-NDA hydroxyl radical scavenging method, the methanolic plant extract showed higher activity, chloroform plant extract showed moderate activity, and aqueous plant extract showed the lowest activity (Pulipati et al., 2017). The antioxidant enzyme system gets changed during postmenopause due to oestrogen insufficiency, which has got antioxidant characteristics. Therefore, the study investigated the impact of supplementation of amaranth leaves powder (ALP) on antioxidant and indicators for oxidative stress levels in the blood. Aged gentlewomen around 45–60 years were given every day with nine grams of A. tricolor leaf powder (ALP) for 90 days along with their regular diet. The control group was not supplemented with ALP. Serum ascorbic acid, serum retinol, malondialdehyde, superoxide dismutase, and glutathione peroxidase were examined after and before supplementation. The hemoglobin and blood glucose level of the participants were investigated.

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The data exhibited that daily intake of ALP primarily increased serum ascorbic acid (5.9%), serum retinol (5.0%), superoxide dismutase (10.8%), and glutathione peroxidase (11.9%). In contradiction, malondialdehyde decreased to the tune of 9.6%, a marker for oxidative stress in the postmenopausal women group. There was an increase in hemoglobin (5.3%) and a drop in fasting blood glucose level (10.4%). The results indicated that A. tricolor possesses antioxidant property and has the therapeutic potential to limit complexities during postmenopause (Kushwaha et al., 2014). The antioxidant potential has been ascribed due to the presence of high levels of phenolics and flavonoids. Leaves and flowers of A. tricolor and their extract were shown to have the maximum antioxidant action related to different plant parts. The principal radical scavenger was rutin present in A. tricolor that showed the total antioxidant activity assay of its dry leaf powder was 1 g equivalent to 0.035 g/mL of ascorbic acid (Clemente and Desai, 2011). The leaves of every Amaranthus spp. are rich in iron and calcium; however, the presence of more oxalic acid decreases their bioavailability. Betacyanins (coloring pigments) in A. tricolor possess antioxidant activity (Cai et al., 1998). 64.3.5 ANTI-INFLAMMATORY PROPERTIES Oxidative stress produced by inflammation damages macromolecules is a critical physiological feature of all chronic diseases. The aqueousalcoholic leaf extract of A. tricolor reports to show an anti-inflammatory activity against carrageenan-induced rat paw edema and pelleted-cotton provoked granuloma in rats, and also antinociceptive activity was shown against writhing model induced with acetic acid (Bihani et al., 2013). In a study, a concentration-dependent usage of A. tricolor methanolic plant extract reduced the fraction of writhings produced in mice by intraperito­ neal administration of acetic acid. The highest antinociceptive activity was witnessed at a dosage of four hundred milligrams of extract per kilograms body weight, compared to aspirin (200 mg/kg body weight) (Rahmatullah et al., 2013). 64.3.6 HEPATOPROTECTIVE ACTIVITY Amaranthus tricolor ethanolic leaf extract (ATE), examined for its effective­ ness upon CCl4, provoked toxicity to liver in rats. The hepatoprotective action

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of ATE was assessed by estimating different parameters of liver toxicity, lipid characterization, and histopathology. The outcomes revealed that ATE administration for 21 days primarily decreased the raised levels of serum aspartate aminotransferase (AST/GOT), alanine aminotransferase (ALT/ GPT), alkaline phosphatase, Gamma-glutamyl transferase (GGT), choles­ terol, bilirubin, VLDL, LDL, Malondialdehyde (MDA), and triglycerides provoked by CCl4. Furthermore, treatment with ATE increases nonprotein sulfhydryl (NP-SH) activity and increases total protein (TP) significantly in liver tissues. Examination of the liver histopathology in rat tissue sections supports the biochemical findings (Al-Dosari, 2010). A paracetamol-induced hepatotoxic model was used to study the hepatoprotective activity of aqueous extracts of A. tricolor roots. Aqueous extract of A. tricolor reported the hepatoprotective activity against hepa­ totoxicity induced with paracetamol. The study was carried out using two doses, and higher hepatoprotection was found at 400 mg/kg body weight. The results were comparatively more elevated than the standard paracetamol and control group. Thus, paracetamol has significantly improved SGOT, SGPT, TB, and ALP levels in the experiment. Therefore, the trial with silymarin, two hundred milligrams per kg body weight and four hundred milligrams per kg body weight of water-based root extracts of Amaranthus tricolor, lowered the elevated levels of serum glutamic pyruvate transaminase, serum glutamic oxaloacetic transaminase, total bilirubin, and alkaline phosphatase. These declines were higher as compared to the control and the hepatotoxin paracetamol used. The treat­ ment has also improved hepatic architecture or reduced hepatic damage (Aneja et al., 2013). 64.3.7 GASTROPROTECTIVE ACTIVITY It has been known that the plant-originated “gastroprotectors” with various compositions have been used in folk and clinical medicine due to their beneficial effects on the mucosa of the gastrointestinal tract. Leaf extracts of the A. tricolor hold an excellent antigastric ulcer activity in laboratory animals. The efficiency of leaves extract of A. tricolor on gastric discharge, and the influence of gastric cytoprotection were assessed using five distinct patterns of gastric ulcers: pylorus ligation-induced, acetic acid-induced, ischemia-reperfusion-induced, indomethacin-induced, and ethanol-induced gastric ulcers. Various extracts of A. tricolor leaves, namely, petroleum ether

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extract (PEAT), ethanolic extract (EAT), ethyl acetate extract (EAAT), and chloroform extract (CAT) served at a dosage of two hundred milligrams per kilogram per oral (p.o). The investigation on acute oral toxicity with a dosage of up to 2000 mg/kg, p.o. revealed that all the extracts were harmless; therefore, one-tenth of the dosage was chosen to assess antiulcer activity. The acetic acid-induced chronic gastric ulcers with a treatment of EAAT and EAT (200 mg/kg, p.o.) revealed a gastric ulcer-healing effect. Ethanolic extract (EAT) and ethyl acetate extract (EAAT) restrained gastric discharge in pylorus-ligated rats showed a gastric cytoprotective influence in indomethacin-induced and ethanol-induced gastric ulcers. At the same time, CAT and PEAT conferred no notable antiulcer effect (Devaraj and Krishna, 2011). 64.3.8 ANTIDIABETIC ACTIVITY It was observed that A. tricolor plant extracts effectively reduced serum glucose, total cholesterol, LDL, serum TG, and VLDL, but as compared to diabetic control, it showed elevated HDL in diabetic rats induced with alloxan. The plant extract has shown to reduce the body weight of treated diabetic rats and improve hemoglobin levels (Clemente and Desai, 2011). 64.3.9 ANTIMICROBIAL ACTIVITY Due to ingredients like polyphenolics and others, A. tricolor is reported to have significant antimicrobial activity. Extracts of A. tricolor were prepared using various solvents based on the polarity and analyzed for antimicrobial activity using a cup plate method. Microorganisms used in the study were gram +ve bacteria (Staphylococcus aureus and Bacillus subtilis) and gram −ve bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, and Escherichia coli). Standard strepto­ mycin and control (DMSO) were referred to as a control in this study. The agar well diffusion method was used to study preliminary in vitro screening of the plant extracts’ antibacterial activity from Amaranthus tricolor. The methanolic fraction showed the maximum activity compared with chloroform, ethyl acetate, and petroleum ether extracts. The metha­ nolic extract has shown higher activity against E. coli accompanied by S. aureus and P. aeruginosa. Ethyl acetate extract exhibited higher activity against E. coli and S. aureus, modest action upon P. aeruginosa, and least

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action upon K. pneumoniae. The chloroform distillation of A. tricolor displayed notable action against E. coli and S. aureus accompanied by K. pneumoniae and restrained S. mutans. Besides, petroleum ether infusion manifested maximum action upon E. coli and S. aureus, accompanied by K. pneumoniae and E. faecalis. Thus, it was revealed that all the four extracts of A. tricolor examined for antibacterial action efficiently repressed the microbes (Rao et al., 2012). Pulipati et al. (2014) assessed the antibacterial activity of A. tricolor methanolic leaf fraction against clinical isolates of UTI-causing bacteria. Pathogenic clinical isolates causing UTI, namely, Enterococcus faecalis, Staphylococcus sapro­ phyticus, Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, and Klebsiella pneumoniae were used for investigation. The antibacterial attribute was ascertained by the agar well diffusion method. The resazurin microtiter plate assay method ascertained the minimal inhibitory concen­ tration (MIC) for crude A. tricolor leaf extract. The outcomes show A. tricolor (methanolic leaf extract) has significant antibacterial action upon examined microorganisms. Minimum activity upon E. faecalis, medium activity was witnessed against P. vulgaris, and the maximum antimicrobial activity was witnessed upon E. coli concerning the zone width displayed by the organisms. The MIC range from 0.36 to 5.0 mg/mL. Liu et al. (2016) concluded that the effective antibacterial ingredient of A. tricolor infusions is palmitic acid (C16H32O2). 64.3.10 ANTITUMOR ACTIVITY The study aims to isolate, characterize, and evaluate a lead phytochemical molecule for anticancer action of A. tricolor. The methanolic leaf extract of A. tricolor (ATME) was fractionated with an equivalent quantity of water and chloroform. The chloroform extract was fractionated further with (6:4 v/v) of n-hexane: ethyl acetate as mobile phase as recommended (HPTLC). The third portion was chosen for additional in-silico investigation and anti­ cancer activity. The structural elucidation of the separated compound was determined as a flavonol glycoside 24- methylene cycloartenol (SOWIS­ III). The combination was anchored with a receptor of human oestrogen and validated as a lead molecule. In the DPPH method, 24-methylene cyclo­ artenol displayed a robust radical scavenging attribute in a dose-dependent manner. The IC50 values of 24-methylene cycloartenol and ascorbic acid were 31.03 and 14.29 µg/mL, respectively. The compound restrained the

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growth of MCF-7 (human breast cancer cell lines; IC50 value 16.93 μg/mL); cisplatin (IC50 value 4.586 μg/mL) ascertained by MTT assay (Pulipati et al., 2021). A. tricolor (Synon. Amaranthus gangeticus) has numerous pigmented compounds, such as carotenoids and betacyanin than green color amaranth. A. tricolor leave extracts repressed the increase of liver (HepG2), colon (Caco­ 2), and breast (MCF-7) cancer cell lines and manifested anticancer potential (Sani et al., 2004). The transformation of arachidonic acid to prostaglandins is a rate-limiting step catalyzed by cyclooxygenases 2 (COX-2) and -1 (COX-1). Prostaglandins are accountable for arbitrating inflammation in the body. COX-2 is provoked by numerous carcinogens, cytokines, and growth factors, whereas COX-1 is constitutively manifested in cells associated with routine physiological roles (Smith et al., 2000). The lipoxygenases and cyclooxygenases metabolize arachidonic acids and linoleic to eicosanoids, which induce mutagenesis (Ding et al., 2001). Various types of cancers, including breast, colon, pancreas, lung, and oesophagus and squamous cell carcinoma of the neck and head, result in overexpression of COX-2 enzyme (Smith et al., 2000; Dempke et al., 2001). The prostaglandins represent a significant part in the extension of tumor blood vessels. Hence, the course of carcinogenesis may be repressed by COX enzyme inhibitors (Williams et al., 1999). The bioassay-guided separation of stem and leaves extracts of Amaranthus tricolor generated three galactosyl diacylglycerols (galactosyl diacylglyc­ erol, 1-linolenoyl-2-palmitoyl-3- galactosylglycerol, and 1-linolenoyl-2-ste­ royl3-galactosylglycerol) with strong cyclooxygenase and human tumor cell outgrowth inhibitory activities. The three pure compounds inhibited cyclo­ oxygenase-2 (COX-2) enzyme over 87, 74, and 95% and cyclooxygenase-1 (COX-1) enzyme over 78, 63, and 93 per cent, individually. These pure compounds were experimented with antiproliferative activity using human CNS (central nervous system; SF-268), AGS (gastric), NCI-H460 (lung), HCT-116 (colon), and breast cancer cell lines (MCF-7). Galactosyl diacyl­ glycerol (Compound 1) inhibited the growth of SF-268, AGS, NCI-H460, HCT-116 plus MCF-7 tumor cell lines with the IC50 values of 71.8, 49.1, 62.5, 42.8, and 39.2 μg/mL, sequentially. For HCT-116, MCF-7, and AGS cancer cell lines, the IC50 values of 1-linolenoyl-2-palmitoyl-3- galacto­ sylglycerol (compound 2) and 1-linolenoyl-2-steroyl3-galactosylglycerol (compound 3) were 71.3, 58.7, and 74.3 μg/mL and 73.1, 85.4, and 83.4, sequentially (Jayaprakasam et al., 2004).

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KEYWORDS

• • • • • •

Amaranthus tricolor amaranthine hepatoprotective purple betalain isoquercetin rutin

REFERENCES Al-Dosari, M. S. The Effectiveness of Ethanolic Extract of Amaranthus tricolor L.: A Natural Hepatoprotective Agent. Am. J. Chin. Med. 2010, 38 (06), 1051–1064. Aneja, S.; Vats, M.; Aggarwal, S.; Sardana, S. Phytochemistry and Hepatoprotective Activity of Aqueous Extract of Amaranthus tricolor Linn. Roots. J. Ayurveda. Integr. Med. 2013, 4 (4), 211. Aneja, S.; Vats, M.; Sardana, S; Aggarwal, S. Pharmacognostic Evaluation and Phytochemical Studies on the Roots of Amaranthus tricolor (Linn.). Int. J. Pharm. Sci. Res. 2011, 2 (9), 2332. Bala, V. C.; Avid, M.; Kumar, P.; Sangam. A Review on Amaranthus tricolor as a Traditional Medicinal Plant. World. J. Pharm. Res. 2019, 8 (11), 226–237. Behari, M.; Sharma, R. K. Isolation and Characterization of Hydrocarbons, Alcohols and Sterols from Amaranthus tricolor. Acta Ciencia Indica, [Series] Chemistry 1984, 10, 42–45. Bihani, G. V.; Bodhankar, S. L.; Kadam, P. P.; Zambare, G. N. Anti-Nociceptive and AntiInflammatory Activity of Hydroalcoholic Extract of Leaves of Amaranthus tricolor L. Pharm. Lett. 2013, 5 (3), 48–55. Biswas, M.; Dey, S.; Sen, R. Betalains from Amaranthus tricolor L. J. Pharmacogn. Phytochem. 2013, 1 (5), 87–95. Cai, Y.; Sun, M.; Corke, H. Antioxidant Activity of Betalains from Plants of the Amaranthaceae. J. Agric. Food Chem. 2003, 51 (8), 2288–2294. Cai, Y.; Sun, M.; Wu, H.; Huang, R.; Corke, H. Characterization and Quantification of Betacyanin Pigments from Diverse Amaranthus Species. J. Agric. Food Chem. 1998, 46, 2063–2070. Clemente, A.; Desai, P. V. Evaluation of the Hematological, Hypoglycemic, Hypolipidemic and Antioxidant Properties of Amaranthus tricolor Leaf Extract in Rat. Trop. J. Pharm. Res. 2011, 10 (5), 595–602. Das, S. Systematics and Taxonomic Delimitation of Vegetable, Grain and Weed Amaranths: A Morphological and Biochemical Approach. Genet. Resour. Crop Evol. 2012, 59 (2), 289–303.

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Dempke, W.; Rie, C.; Grothey, A.; Schmoll, H. J. Cyclooxygenase-2: A Novel Target for Cancer Chemotherapy? J. Can. Res. Clin. Oncol. 2001, 127, 411–417. Devaraj, V. C.; Krishna, B. G. Gastric Antisecretory and Cytoprotective Effects of Leaf Extracts of Amaranthus tricolor Linn. in Rats. Zhong xi yi jie he xue bao= Chin. J. Integr. Med. 2011, 9 (9), 1031–1038. Ding, X.; Tong, W.; Adrian, T. E. Cyclooxygenases and Lipoxygenases as Potential Targets for Treatment of Pancreatic Cancer. Pancreatology 2001, 1, 291–299. Fernando, T.; Bean, G. Fatty Acids and Sterols of Amaranthus tricolor L. Food Chem. 1984, 15 (3), 233–237. Gins, M. S.; Gins, V. K.; Motyleva, S. M.; Kulikov, I. M.; Medvedev, S. M.; Pivovarov, V. F.; Mertvishcheva, M. E. Metabolites with Antioxidant and Protective Functions from Leaves of Vegetable Amaranth (Amaranthus tricolor L.). Sel’skokhozyaistvennaya biologiya [Agricultural Biology], 2017, 52 (5), 1030–1040. Harborne, J. B. Methods of Plant Analysis. In Phytochemical Methods; Springer: Dordrecht, 1984; pp 1–36. Jahan, N.; Hossain, M. R.; Hossain, M. K.; Alam, M. R.; Das, S. New Insight in the Sedative and Anxiolytic Activities of Amaranthus tricolor L. Leaves Extract in Mice. Asian. J. Agric. Food. Sci. 2020, 16–24. Jayaprakasam, B.; Zhang, Y.; Nair, M. G. Tumor Cell Proliferation and Cyclooxygenase Enzyme Inhibitory Compounds in Amaranthus tricolor. J. Agric. Food. Chem. 2004, 52 (23), 6939–6943. Khanam, U. K. S.; Oba, S. Bioactive Substances in Leaves of Two Amaranth Species, Amaranthus tricolor and A. hypochondriacus. Can. J. Plant. Sci. 2013, 93 (1), 47–58. Khandaker, L.; Ali, M. B.; Oba, S. Total Polyphenol and Antioxidant Activity of Red Amaranth (Amaranthus tricolor L.) as Affected by Different Sunlight Level. J. Jpn. Soc. Hortic. Sci. 2008, 77 (4), 395–401. Khare, C. P. Indian Medicinal Plants: An Illustrated Dictionary; Springer-Verlag: Berlin/ Heidelberg, 2008. Komor, P.; Devi, OS. Edible Bio-Resources & Livelihoods; Assam State Biodiversity Board: Guwahati, India, 2006. Kumar, S.; Raghavendra, M.; Reddy, A. M.; Yadav, P. R.; Raju, A. S. Comparative Studies on the In Vitro Antioxidant Properties of Methanolic Leafy Extracts from Six Edible Leafy Vegetables of India L. Asian. J. Pharm. Clin. Res. 2013, 6 (3), 96–99. Kushwaha, S.; Chawla, P.; Kochhar, A. Effect of Supplementation of Drumstick (Moringa oleifera) and Amaranth (Amaranthus tricolor) Leaves Powder on Antioxidant Profile and Oxidative Status Among Postmenopausal Women. J. Food Sci. Tech. 2014, 51 (11), 3464–3469. Larsen, T.; Thilsted, S. H.; Biswas, S. K.; Tetens, I. The Leafy Vegetable Amaranth (Amaranthus gangeticus) Is a Potent Inhibitor of Calcium Availability and Retention In Rice-Based Diets. Br. J. Nutr. 2003, 90 (3), 521–527. Liu, S. Q.; Zhang, Y.; Wang, C.; Su, P.; Liao, X. L.; Bai, L. Y. Preliminary Study on Component Analysis of Amaranthus tricolor Leaf Extracts Against Plant Pathogenic Bacteria. Egypt. J. Biol. Pest Control, 2016, 26 (3), 643–650. Morrison, J. F.; Twumasi, S. K. Comparative Studies on the In Vitro Antioxidant Properties of Methanolic and Hydro-Ethanolic Leafy Extracts from Eight Edible Leafy Vegetables of Ghana. Afr. J. Biotechnol. 2010, 9 (32), 5177–5184.

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Peter, K.; Gandhi, P. Rediscovering the Therapeutic Potential of Amaranthus Species: A Review. Egypt. J. Basic Appl. Sci. 2017, 4 (3), 196–205. Piattelli, M.; De Nicola, M. G.; Castrogiovanni, V. Photocontrol of Amaranthin Synthesis in Amaranthus tricolor. Phytochemistry 1969, 8 (4), 731–736. Piattelli, M.; Minale, L.; Prota, G. Isolation and Structure of Amaranthine and Isoamaranthine. Ann. Chim. 1964, 54 (10), 963–968. Pulipati, S.; Babu, P. S. Dommati, H. Phytochemical, In-Silico Analysis and Anticancer Activity of a Bioactive Principle Isolated from Amaranthus tricolor (L). Res. J Biotech. 2021, 16 (3), 122–133. Pulipati, S.; Babu, P. S.; Narasu, M. L. Quantitative Determination of Tannin Content and Evaluation of Antibacterial Activity of Amaranthus tricolor (L). Int. J. Biol. Pharm. Res. 2014, 5, 623–626. Pulipati, S.; Babu, P. S.; Naveena, U.; Parveen, S. R.; Nausheen, S. S.; Sai, M. T. N. Determination of Total Phenolic, Tannin, Flavonoid Contents and Evaluation of Antioxidant Property of Amaranthus tricolor (L). Int. J. Pharmacogn. Phytochem. Res. 2017, 9 (6), 814–819. Rahmatullah, M.; Hosain, M.; Rahman, S.; Akter, M.; Rahman, F.; Rehana, F.; Munmun, M.; Kalpana, M. A. Antihyperglycemic and Antinociceptive Activity Evaluation of Methanolic Extract of Whole Plant of Amaranthus tricolor L. (Amaranthaceae). Afr. J. Tradit. Complement. Altern. Med. 2013, 10 (5), 408–411. Rao, K. N.; Padhy, S. K.; Dinakaran, S. K.; Banji, D.; Avasarala, H.; Ghosh, S.; Prasad, M. S. Pharmacognostic, Phytochemical, Antimicrobial and Antioxidant Activity Evaluation of Amaranthus tricolor Linn. Leaf. Asian. J. Chem. 2012, 24 (1), 455–460. Rastogi, A.; Shukla, S. Amaranth: A New Millennium Crop of Nutraceutical Values. Crit. Rev. Food. Sci. Nutr. 2013, 53 (2), 109–125. Sani, H. A.; Rahmat, A.; Ismail, M.; Rosli, R.; Endrini, S. Potential Anticancer Effect of Red Spinach (Amaranthus tricolor) Extract. Asia Pacific J. Clin. Nutri. 2004, 13, 396–400. Santiago, P. D.; Tenbergen, K.; Vélez-Jiménez, E.; Cardador-Martínez, M. A. Functional Attributes of Amaranth. Austin. J. Nutr. Food Sci. 2014, 2 (1), 1–6. Sarker, U.; Oba, S. Leaf Pigmentation, Its Profiles and Radical Scavenging Activity in Selected Amaranthus tricolor Leafy Vegetables. Sci. Rep. 2020, 10 (1), 1–10. Shukla, S.; Bhargava, A.; Chatterjee, A.; Srivastava, J.; Singh, N.; Singh, S. P. Mineral Profile and Variability in Vegetable Amaranth (Amaranthus tricolor). Plant Foods Hum. Nutr. 2006, 61 (1), 23–28. Singh, B. P.; Whitehead, W. F. Management Methods for Producing Vegetable Amaranth. In Progress in New Crops; Janick. J., $d.; ASHS Press: Arlington, VA, 1996; pp 511–515. Smith, W. L.; DeWitt, D. L.; Garavito, R. M. Cyclooxygenases: Structural, Cellular, and Molecular Biology. Annu. Rev. Biochem. 2000, 69, 145–182. Stobart, A. K.; Pinfield, N. J.; Kinsman, L. T. The Effects of Hormones and Inhibitors on Amaranthin Synthesis in Seedlings of Amaranthus tricolor. Planta 1970, 94 (2), 152–155. Tundis, R.; Loizzo, M. R.; Menichini, F. Natural Products as α-Amylase and α-Glucosidase Inhibitors and Their Hypoglycaemic Potential in the Treatment of Diabetes: An Update. Mini. Rev. Med. Chem. 2010, 10 (4), 315–331. Velez-Jimenez, E.; Tenbergen, K.; Santiago, P.; Cardador-Martínez, M. A. 2014. Functional Attributes of Amaranth. Austin J. Nutr. Food Sci. 2014, 2 (1), 1–6. Williams, C. S.; Mann, M.; DuBois, R. N. The Role of Cyclooxygenases in Inflammation, Cancer, and Development. Oncogene 1999, 18, 7908–7916.

CHAPTER 65

Bioactive Molecules and Pharmacology Studies of Ecbolium viride (Forssk.) Alston SIBBALA SUBRAMANYAM1,*, V. L. ASHOK BABU2, V. SALEEM BASHA3, and K. N. JAYAVEERA4 1Department

of Pharmaceutical Sciences, Vignan’s Foundation for Science, Technology & Research (VFSTR) - (Deemed to be University), Vadlamudi, Guntur, India

2Department

of Pharmacognosy, M.S. Ramaiah University of Applied Sciences, Bengaluru 560054, India

3Department

of Chemistry, Government Degree College (Autonomous), Anantapur 515001, India

4Department

of Chemistry, Jawaharlal Nehru Technological University, Anantapur 515002, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Ecbolium viride (Forssk.) Alston belongs to the family Acanthaceae. Several scientific studies have revealed that E. viride consists of bioactive ingredi­ ents such as luteolin, orientin, vitexin, alkaloids, carbohydrates, glycosides, tannins, saponins, sterol mixtures (sitosterol, stigmasterol, and campestrol) and lignans like ecbolin B, ecbolin A. Pharmacological investigations based on in vitro and in vivo studies of E. viride revealed that it possessed antiinflammatory, analgesic, antioxidant, cytotoxic, hepatoprotective, and antiplasmodial activities. Traditionally, different parts of this plant, like Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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roots, leaves, and stems, as well as the whole plant, are used in folklore medicine for various ailments like tumors, jaundice, menorrhea, rheuma­ tism, inflammation. 65.1 INTRODUCTION Ecbolium viride (Forssk.) Alston, a perennial woody under shrub, belongs to family Acanthaceae. It has three synonyms as Justicia viridis Forssk., Ecbolium linneanum Kurz, and Justicia rotundifolia Nees. It is also known by the common names such as Green Shrimp Plant, Blue fox tail, Nilambari (Tamil), Udajat (Hindi), Karimkurunni (Malayalam), Nakka toka (Telugu), Kappubobbali, Kappukarni (Kannada), Sahacharah (Sanskrit), Neel Kantha (Bengali). Ecbolium viride is commonly used in Indian traditional medicinal systems like Siddha, Ayurveda, Unani, and Folk (Khare, 2007; Nair et al., 1985). Juice from macerated leaves is orally administered for fever and snake bite (Khare, 2004; Nabila et al., 2011). The roots and leaves of this plant are useful to treat tumor (Yusuf et al., 2009). The aqueous extract from roots of E. viride is used against jaundice in folk medicine (Nair et al., 2007), rheumatism (Shanmugam et al., 2009), and menorrhagia (Kirtikar and Basu, 1987). All parts of the E. viride are used for treating gout and dysuria (Vollesen, 1989). E. viride is used to treat ailments related to cardiovascular (Asolkar et al., 1992). Leaf poultice is used for leprosy. Decoction from the leaves and flowers of this is administered internally as diuretic and gonor­ rhea. Root juice is used as anti-helmenthic as well as for the treatment of premenstrual colic (Sharma and Sharma, 2010). Ecbolium viride, an erect glabrous herb, is found to grow in the plains of India, Arabia, Malaysia, Sri Lanka, and Tropical Africa (Cecilia et al. 2014; Rastogi and Mehrotra, 1979). The plant is up to 1.3 m tall with large, oblongovate, or lanceolate leaves (11.5–15 cm), tapering to the base. The plant is with sessile flowers, spikes are 5–24 am long, present in opposite pairs. Fruits are ovoid and capsule with two seeds. 65.2 BIOACTIVES The plant E. viride yielded five main bioactive components. These are a sterol mixture, namely, β-sitosterol, stigmasterol and campestrol, and four different furofuran lignans, namely, ecbolin A6-(3,4-methylenedioxyphenyl)­ 2-(2,5,6-trimethoxy-3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]

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octane, ecbolin B 2-(2-methoxy-3,4-methylenedioxyphenyl)-6-(2-me­ thoxy-3,4-methylenedioxyphenyl)-3,7,7-dioxabicyclo[ 3.3.0] octane,4βhydroxy-2′,2″-dimethoxysesamin, and (+)-2′,2″-dihydroxysesamin (2,6-bis (2- hydroxy-3,4-methylenedioxy)-3,7-dioxabicyclo (3,3,0) octane (Nair et al., 1975). The furofuran lignans were found to exhibit different biological activities (Hu et al., 2005; Sonar et al., 2006) which may be attributed to methylenedioxy moiety. In addition, four glycoflavones luteolin, orientin, vitexin, and isoorientin were isolated from the ethanolic extract from the root, flower, and leaves of the plant (Nair et al.,1975). The ethyl acetate extract from the root of E. viride yielded a novel heterofuranoid compound methoxy-5-[4-(4-methoxy-1,3-benzodioxol-5-yl)perhydro-1H,3H-furo[3,4c]furan-1-yl]-1,3-benzodioxole (Ezhilmuthu et al., 2008). A novel flavone glycoside luteolin-7-O-(2”sinapoyl) glucoside was isolated from the ethyl acetate extract of the roots (Lalitha and Sethuraman, 2011). The GC-MS analysis of ethanolic extracts of leaf of E. viride revealed the presence of (R)-4-(1′,1′-Dimethylethyl)-1,3,2-dioxathiolane-2-one, Neophytadiene,3,5­ Dioxohexanoic acid, 3-chloromethyl furan, 9,12,15-octadecatrienoic acid (Dipankar et al., 2011). Ecbolin A, a furofuran type of unsymmetrical lignan, was isolated from the chloroform extract of Ecbolium linneanum Kurz., root (Venkataraman and Gopalakrishnan, 2002). Important structural aspects of the bioactives from Ecbolium viride are given below.

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PHARMACOLOGY

65.3.1 ANTIBACTERIAL ACTIVITY Siraj et al. (2013) evaluated the antibacterial activity of E. viride by using the disc diffusion method. The antibacterial effect of ethanolic extract E. viride was tested against 10 pathogenic bacterial strains at the concentrations of 250 µg/disc and 500 µg/disc. The results were compared with standard drug Mecillinam (25 µg/disc) by measuring zone of inhibition. At 250 μg/disc the extract showed activity against Salmonella typhi (8 mm), Escherichia coli (7 mm), Shigella sonnei (9 mm), Shigella boydii (7 mm), Enterococcus faecalis (8 mm), Streptococcus agalactiae (10 mm), and Staphylococcus saprophyticus (6 mm). At 500 μg/disc, it showed activity against Salmonella typhi (10 mm), Escherichia coli (10 mm), Shigella flexneri (8 mm), Shigella sonnei (14 mm), Shigella boydii (9 mm), Enterococcus faecalis (10 mm),

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Streptococcus agalactiae (13 mm), Streptococcus pyogenes (7 mm), and Staphylococcus saprophyticus (7 mm). 65.3.2 ANTIFUNGAL ACTIVITY The antifungal action of aqueous and methanolic leaves extract of E. viride was tested by Elamathi et al. (2012) against four different fungi and reported high activity of methanolic extract as compared with aqueous extract. Antifungal capacity of chloroform, ethyl acetate, and methanol extracts of E. viride leaf was studied by Subhashini and Poonguzhali (2012) against three different fungi using the agar well diffusion method and evaluated by measuring diameter of zone inhibition. Significant antifungal activity was observed in the methanol extract of E. viride leaves. Cecilia et al. (2012b) evaluated Minimum Inhibitory Concentration (MIC) of active compound Ecbolin A from the ethyl acetate extract of E. viride root against twelve fungi using micro-broth dilution technique. The results showed that the MIC values of the leaf extract against the tested fungi were Malassezia pachydermatis (62.5 µg/mL), Candida albicans (125 µg/ mL), and Scopulariopsis species (250 µg/mL). 65.3.3 ANTIMICROBIAL ACTIVITY Abdel-Sattar et al. (2008) investigated the antimicrobial activity of twenty wild plants from the western regions of the Kingdom of Saudi Arabia. The methanolic extracts of the aerial parts were evaluated against eight microorganisms such as Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus, Sarcina lutea, Bacillus subtilis, Myco­ bacterium phlei, and Candida albicans were used. The findings showed that the extracts displayed a significant strong antibacterial activity against both Gram-positive and Gram-negative bacteria. Cecilia et al. (2012a) tested antimicrobial action of root extract of E. viride in methanol, ethyl acetate, and hexane against 19 bacterial and 12 fungal species by disc diffusion method and also by determination of minimum inhibitory concentration method. The outcomes of the study revealed that ethyl acetate extract possessed higher grade of antimicrobial activity compared to other extracts. The highest antibacterial activity (MIC-0.039 mg/mL) was displayed against Staphylococcus aureus (ATCC 25923). The

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highest antifungal activity (MIC-0.25 mg/mL) was shown against Malas­ sezia pachydermatis. Dipankar et al. (2012) evaluated antimicrobial activity of ethanol, acetone, dichloromethane, and petroleum ether extracts of E. linneanum leaf and stem using the agar well diffusion method at different concentrations (50–250 mg/mL) and kanamycin (30 μg), norfloxacin (10 μg), and ciprofloxacin (5 μg) were used as standards. The pathogens were strongly inhibited by leaf extracts whereas acetone extract of stem could not inhibit the growth even at higher concentrations. Thus, the findings showed that leaf extracts were more effective than those of extracts from the stem. 65.3.4 FREE RADICAL SCAVENGING ACTIVITY Ashok Babu et al. (2011) reported the free radical quenching capacity of methanolic root extract of E. viride by employing three different established methods, such as DPPH radical quenching activity, nitric oxide quenching capacity, and reductive capacity assay. The extract at 100 μg concentration exhibited significant antioxidant activity with 78.25, 69.79%, and 0.2756 (absorbance) in DPPH radical scavenging activity, nitric oxide quenching capacity, and reductive capacity assay respectively and the activity was comparable to standard. The results of the study revealed that methanolic extract of E. viride possessed antioxidant activity. Dipankar et al. (2012) assessed antioxidative property of leaf and stem extracts of E. linneanum. The DPPH radical quenching activity of dichloro­ methane and ethanolic extracts of leaf and stem exhibited more than 50%, whereas ethanol and acetone extracts of exhibited potential effect of 72.7% and 73.1% at 500 μg/mL respectively when compared with standard ascorbic acid. Results of reducing power assay of extracts showed that acetone extract of stem, ethanol, and acetone extracts of leaves exhibited higher activity that was comparable with standard ascorbic acid. The total antioxidant potential was higher in acetone extracts of leaf and stem. Ashok Babu et al. (2018) investigated the antioxidant activity of the methanolic extract of E. viride roots in vivo. The levels of superoxide dismutase, catalase, thiobarbituric acid reactive substances, and glutathione were estimated in hepatotoxicity induced by carbon tetra chloride in rats. The methanol extract (400 mg/kg) significantly enlarged the levels of catalase, superoxide dismutase, and glutathione and significantly decreased the level of lipid peroxides. The findings of the study revealed that the methanolic extract of the tested plant had potent antioxidant activity.

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65.3.5 ANTI-INFLAMMATORY ACTIVITY Lalitha and Sethuraman (2010) examined the anti-inflammatory activity of root extract of E. viride in both cotton pellet granuloma and carrageenaninduced paw edema models. Oral administration of E. viride root extract condensed inflammation significantly in both the carrageenan paw edema and the cotton pellet granuloma models. The results of the study validated the traditional use of E. viride in the treatment of inflammatory disease. 65.3.6 CYTOTOXIC ACTIVITY Lalitha and Sethuraman (2011) evaluated cytotoxic activity of methanolic extracts of aerial parts against the MRC5 human cell line. Cytotoxicity was investigated by the colorimetric MTT assay in 96-well microplates. The 50% inhibitory concentration (IC50) value was assessed based on a concentrationresponse curve. The IC50 value for the extract was found to be 60.1 μg/mL. Dipankar et al. (2012) reported in vitro anticancer activity of ethanolic extracts of stem and leaf extracts of E. viride (Syn.: E. linneanum). Cytotox­ icity was examined in HeLa cervical cancer cell line by trypan blue assay and the ethanolic extract of leaf exhibited cytotoxic activity against the tested cell line with 80% cell death. 65.3.7 HEPATOPROTECTIVE ACTIVITY Narayanan et al. (2012) reported hepatoprotective activity of ethanolic leaf extract of E. viride in CCl4 induced rats. Rats were treated orally for seven days with suspension of extract (100 mg/kg) and (200 mg/kg) and refer­ ence drug silymarin (25 mg/kg), respectively. Biochemical parameters were estimated. The results indicated that hepatoprotective activity was confirmed by biomedical parameters and histopathological studies. Malarvizhi et al. (2012) reported ethanol and water extracts from leaves of E. viride to evaluate protective effect on acetaminophen provoked toxic hepatitis. Treatment with extracts at the dose of (200 and 400 mg/kg) significantly ameliorated the toxic manifestations to normalcy. Treatment with extracts significantly counteracted the lipid peroxidation, restored level of glutathione G, antioxidant enzymes, and levels of membrane bound phosphatases. Cheedella et al. (2013) showed that the ethanol extract of E. viride root presented a notable hepatoprotective activity toward paracetamol

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encouraged hepatotoxicity as reported from the marker enzymes of serum in rats. Treatment of rats with different quantities of plant extracts (100 mg/ kg, 200 mg/kg, and 400 mg/kg) significantly altered serum marker enzymes levels against paracetamol treated rats when compared with standard drug silymarin (25 mg/kg). Priyadharshni et al. (2011) investigated methanolic extract of whole plant of E. viride against carbon tetrachloride and paracetamol-induced hepato­ toxicity in rats. E. viride (10 mg/kg and 200 mg/kg) exhibited significant hepatoprotective capacity by dropping carbon tetrachloride and paracetamol­ generated modifications in biochemical parameters such as Serum glutamic oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), Alkaline Phosphatase (ALP), total bilirubin, direct bilirubin and liver glutathione were evident by enzymatic examination. Ashoka Babu et al. (2012) evaluated the hepatoprotective effect of the methanolic root extract of E. viride against CCl4 induced hepatic damage in rats. Methanolic extract of E. viride (200 and 400 mg/kg) diminished CCl4 (1 mL/kg) induced levels of toxicity on biochemical markers, that is, SGPT, SGOT, ALP, triglycerides, liver weight, and reduced total proteins significantly. Malarvizhi et al. (2013) investigated hepatoprotective effect of ethanol and aqueous extracts of E. viride leaf against paracetamol-generated hepatotoxicity in rat models. The plants extracts and silymarin were admin­ istered at the dose of (200 and 400 mg/kg p.o), for 14 days. The hepa­ totoxicity caused in significant upsurge in the serum hepatic markers like aspartate transaminase, alanine transaminase, alkaline phosphatase, acid phosphatase, γ-glutamyl transpeptidase, lactate dehydrogenase and total bilirubin. Further, acetaminophen altered the hematological profiles such as total leukocyte count, total erythrocyte count, and hemoglobin content and lipid parameters. Plant extracts tested had significantly ameliorated the toxic events of acetaminophen and maintained the structural integrity of the hepatocytes. Hepatoprotective action of aqueous extract of E. viride was evaluated in thioacetamide-induced liver cirrhosis in albino rats (Salunkhe and Patil., 2017). The thioacetamide-generated toxicity in albino rats was represented by the significant upsurge in total bilirubin, direct bilirubin, SGOT, and SGPT while significant reduction in liver protein level. The treatment of E. viride resulted in remarkable decrease in total bilirubin, direct bilirubin, SGOT, and SGPT while significant growth in liver proteins when compared to the thioacetamide-induced group indicating its hepatoprotective activity.

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65.3.8 ANTI-TRYPANOSOMAL ACTIVITY Abdel-Sattar et al. (2009) estimated the anti-trypanosomal activity of metha­ nolic extracts of aerial parts of E. viride against Trypanosoma brucei using concentration-response curve using the Alamar Blue sensitivity assay model. The standard positive controls used were Melarsoprol and pentamidine. The IC50 value estimated from a dose-response curve was found to be 9.37 μg/ mL. 65.3.9 ANTI-PLASMODIAL ACTIVITY Abdel-Sattar et al. (2009) investigated the antiplasmodial activity of metha­ nolic extracts of aerial parts of E. viride toward chloroquine-resistant strain (K1) and sensitive strain (FCR3). Samples were screened by the antimalarial assay system by testing parasite lactate dehydrogenase (pLDH) activity using Malstat reagent toward strains of Plasmodium falciparum. The posi­ tive controls were chloroquine and artemisinin. The 50% inhibitory concen­ tration (IC50) value estimated from a dose-response curve was found to be >12.50 μg/mL. 65.3.10 ANTIDIARRHOEAL ACTIVITY Siraj et al. (2013) tested antidiarrhoeal activity of the ethanol extract of E. viride leaf by castor oil-induced diarrhea in the mice model. The extract caused a significant increase in latent period [1.18 and 2.04 h], that is, slowed the commencement of diarrhoeal incident at the doses of 250 and 500 mg/kg of body weight respectively when compared to the standard loperamide where the mean latent period was 2.49 h. The leaf extract also significantly decreased the occurrence of defecation at the doses of 250 and 500 mg/kg of body weight, while the average mean numbers of stool at the first, second, third, fourth hour of study were 9.8 h. Khan et al. (2013) screened ethanolic extracts of E. viride leaf for antidiarrhoeal activity by the castor-induced diarrhea method which showed an antidiar­ rhoeal effect of 6.8 and 5.8 mean inhibition at the doses of 250 and 500 mg/kg of leaf extract. It raised the latent period and reduced the number of stools.

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65.3.11 LARVICIDAL AND PUPICIDAL ACTIVITIES Cecilia et al. (2014) have reported the mosquitocidal activity of various frac­ tions and isolated constituents from the ethyl acetate root extract of E. viride on larvae and pupae of Culex quinquefasciatus Say (Diptera: Culicidae). The larvae and pupae were subjected to doses of 6.125 ppm, 12.5 ppm, 25 ppm, and 50 ppm for fractions and 1, 2.5, 5, and 10 ppm for the isolated compound. Among the 12 fractions tested, fraction 6 from the ethyl acetate extract of E. viride was shown to possess the highest larvicidal and pupicidal activities against C. quinquefasciatus. The lethal concentration (LC50 and LC90) values of fraction 6 were 4.26 and 9.0 ppm against C. quinquefasciatus larvae and 6.55 and 12.19 ppm against C. quinquefasciatus pupae, respectively, in 24 h. Fraction 7 was reported to show moderate activity with the LC50 and LC90 values of 11.25 and 25.02 ppm against C. quinquefasciatus larvae and 13.33 and 31.15 ppm against C. quinquefasciatus pupae, respectively, in 24 h. The compounds Ecbolin A and ecbolin B were isolated from fractions 7 and 6, respectively. 65.3.12 ANALGESIC ACTIVITY Analgesic activity of the ethanolic leaf extract of E. linneanum was tested by acetic acid-induced writhing model in mice (Siraj et al., 2013). The extract produced 63.80% writhing at a dose of 250 mg/kg body weight and 45.51% writhing at a dose of 500 mg/kg body weight. At the same time the leaf extract showed 36.20% and 54.48% writhing inhibition at the concentra­ tions of 250 and 500 mg/kg respectively and the activity is equivalent to the standard drug Diclofenac-Na 75.51% at the dose of 25 mg/kg. KEYWORDS • • • • •

Ecbolium viride Sitosterol Ecbolin B Ecbolin A anti-inflammatory

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REFERENCES Abdel-Sattar, E.; Harraz, F. M.; Al-Ansari, S. M. A.; EIMekkawy, S.; Ichino. C.; Kiyohara. H.; Otoguro. K.; Omura, S; Yamada, H. Antiplasmodial and Antitrypanosomal Activity of Plants from the Kingdom of Saudi Arabia. J. Nat. Med. 2009, 63, 232–239. Abdel-Sattar, E.; Harraz, F. M.; El Gayed, S. H. Antimicrobial Activity of Extracts of Some Plants Collected from the Kingdom of Saudi Arabia. J. King Abdulaziz Univ. Mar. Sci. 2008, 15 (1), 25–33. Ashok Babu, V. L.; Arunachalam, G.; Jayaveera, K. N.; Madhavan, V.; Shanaz, B. Free Radical Scavenging Activity of Methanolic Extract of Ecbolium viride (Forssk). Alston Roots. Der Pharm. Lett. 2011, 3 (4), 285–288. Ashoka Babu, V. L.; Arunachalam, G.; Madhavan, V. Evaluation of In Vivo Antioxidant Potential of Ecbolium viride (Forssk.) Alston Roots on Carbon Tetra Chloride Induced Oxidative Stress in Wister Rats. J. Dental Oro-facial Res. 2018, 14 (1), 35–40. Ashoka Babu, V. L.; Arunchalam, G.; Jayaveera, K. N.; Madhvan, V.; Banu, S. Hepatoprotective Activity of Methanolic Extract of Ecbolium viride Alston Root Against Carbon Tetrachloride Induced Hepatotoxicity. Int. Res. J. Pharm. 2012, 3 (8), 251–253. Asolkar, L. V.; Kakkar, K. K.; Chakre, O. J. Second Supplement to Glossary of Indian Medicinal Plants with Active Principles; Part-1 (A-K), CSIR: New Delhi, 1992. Cecilia, K. F.; Ravindhran, R.; Duraipandiyan, V. Ecbolin A: A Bioactive Compound from the Roots of Ecbolium viride (Forssk.) Alston. Asian J. Pharm. Clin. Res. 2012b, 5 (4), 99–101. Cecilia, K. F.; Ravindhran, R.; Duraipandiyan, V. Evaluation of Antimicrobial Efficacy of Ecbolium viride (Forssk.) Alston Root Extracts. Asian J. Pharm. Clin. Res. 2012a, 5 (3), 239–241. Cecilia, K. F.; Ravindhran, R.; Gandhi, M. R.; Reegan, A. D.; Balakrishna, K.; Ignacimuthu, S. Larvicidal and Pupicidal Activities of Ecbolin A and Ecbolin B Isolated from Ecbolium viride (Forssk.) Alston Against Culex quinquefasciatus Say (Diptera: Culicidae). J. Parasitol. Res.2014, 113 (9), 3477–3484. Cheedella, H. K.; Alluri, R; Ghanta, K. M. Hepatoprotective and Antioxidant Effect of Ecbolium viride Alston Roots Against Paracetamol-Induced Hepatotoxicity in Albino Wistar Rats. J. Pharm. Res. 2013, 7, 496–501. Dipankar, C.; Arun, K.; Pathak, A; Murugan, S. Phytochemical Screening and Antimicrobial Activity of Extracts from Leaves and Stem of Ecbolium linneanum. Bangladesh J. Pharmacol. 2011, 6, 84–91. Dipankar, C.; Murugan, S. In Vitro Antioxidant and Cytotoxic Activity of Leaves and Stem Extracts of Ecbolium linneanum. Int. J. Pharm. Bio. Sci. 2012, 3 (3), 112–120. Elamathi, R.; Kavitha, R.; Kamalakannan, P.; Deepa, T.; Sridhar, S. Preliminary Phytochemical and Antimicrobial Studies on the Leaf of Ecbolium viride. World. J. Pharm. Med. 2012, 2, 5–10. Ezhilmuthu, R. P.; Vembu, N.; Sulochana, N. 4-Methoxy-5-[4- (4-methoxy-1,3-benzodioxol5-yl)perhydro-1H,3H-furo[3,4-c]furan-1-yl]-1,3-benzodioxole Acta Cryst. 2008, E64, 1306. Hu, S. L; She, N. F; Wu, A. X. (2RS, 3SR)-Diethyl 2,3-bis (1,3-benzodioxole-5-Carbonyl) Succinate. Acta Cryst. E. 2005, 61, 3317–3318. Khan, M. S. S.; Islam, R.; Chowdhury, M. K. H. The Study of Analgesic, Antidiarrhoeal and Anti-Oxidant Effect of Ethanolic Extracts of Ecbolium viride in Albino Mice. Int. J. Phytoph. 2013, 3 (1), 30–36.

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Khare, C. P. Indian Herbal Remedies: Rational Western Therapy, Ayurvedic and Other Traditional Usage, Botany; Springer: New York, 2004. Khare, C. P. Indian Medicinal Plants: An Illustrated Dictionary; Springer: New Delhi, 2007. Kirtikar, K. R.; Basu, B. D. Indian Medicinal Plants, Vol. 3; International Book Publishers: Dehradun, India, 1987; p 1904. Lalitha, K. G.; Sethuraman, M. G. Anti-Inflammatory Activity of Roots of Ecbolium viride (Forsk) Merrill. J. Ethnopharmacol. 2010, 128, 248–250. Lalitha, K. G.; Sethuraman, M. G. Cytotoxic Activity of Flavones Glycoside from the Root of Ecbolium viride (Forsk) Merill. Indian Drugs. 2011, 48 (7), 27–31. Malarvizhi, P.; Selvaraj, B.; Krishnakumar, E.; Shanmugapandiyan, P. Anti-Toxic Potential of Ecbolium viride (Forsk.) Alston in Acetaminophen Provoked Hepatopathy. Asian J. Pharm. Clin. Res. 2013, 6 (2), 61–65. Malarvizhi, P.; Selvaraj, B.; Ulaganathan, I.; Shanmugapandiyan, P. Membrane Stabilizing Potential of Ecbolium viride on Acetaminophen Provoked Hepatotoxicity. Int. J. Bio. Pharma. Res. 2012, 3 (7), 883–889. Nabila, I.; Rezwana, A.; Nazmus, S. A. F. M; Syeda, S.; Farhana, I. J.; Farhana, I.; Anita, R. C.; Shah, A. M. D.; Kakoli, R. B.; Rownak, J.; Mohammed, R. A Survey of Medicinal Plants Used By Folk Medicinal Practitioners in Three Villages of Jessore District, Bangladesh. Am. Eurasian J. Sustain. Agric. 2011, 5 (2), 219–225. Nair, A. G. R.; Ramesh, P.; Sankarasubramanian, S. Occurence of Glycoflavones in Acanthaceae. Phytochemistry 1975, 14, 1644. Nair, R.; Kalariya, T.; Chandra, S. Antibacterial Activity of Some Plant Extracts Used in Folk Medicine. J. Herb. Pharmacother. 2007, 7, 191–201. Nair, V. K.; Yoganarasimhan, S. N.; Keshavamurthy, K. R.; Holla, B. V. A Concept to Improve the Stagnant Ayurvedic Materia Medica. Anc. Sci. Life1985, 5, 49–53. Narayanan, J. J.; Janorious Winka, J.; Rajkumar, M.; SenthilKumar, K. L. Study of Hepatoprotective Activity of Ecbolium viride (Forssk.) Alston. IOSR J. Pharmacy 2012, 2 (2), 157–161. Priyadharshni, S. P. P.; Satyanarayana, T; Ganga Rao, B; Rajesh, K. Hepatoprotective Activity of Ecbolium viride (Forsk.) Alst. (Acanthaceae) on Experimental Liver Damage in Rats. Int. Res. J. Pharm. App. Sci. 2011, 1 (1), 27–33. Rastogi, R. P.; Mehrotra, B. N. Compendium of Indian Medicinal Plants; CDRI: Lucknow and NISC: New Delhi, 1970–1979; p 288. Salunkhe, A. J.; Patil, R. N. Effect of Aqueous Extract of Ecbolium viride on Thioacetamide Induced Liver Cirrhosis in Albino Rat. Biosci. Discov. 2017, 8 (4), 664–670. Shanmugam, S.; Gayathri, N.; Sakthivel, B.; Ramar, S.; Rajendran, K. Plants Used as Medicine By Paliyar Tribes of Shenbagathope in Virudhunagar District of Tamil Nadu, India. Ethnobot. Leafl. 2009, 13, 370–378. Sharma, H. K.; Sharma, R. Ethnomedicine of Sonarpur, Kamrup District, Assam. Indian J. Trad. Knowl. 2010, 9 (1), 163–165. Siraj, M. A.; Emrul, H.; Das, K. K.; Sanjana, S.; Farjana, Y. Assessment of Antidiarrhoeal, Analgesic and Antibacterial Activity of Ethanolic Extract of Ecbolium linneanum. (Acanthaceae) Leaves. Int. J. Pharm. Sci. Invent. 2013, 2 (2), 41–46. Sonar, N.; Venkatraj, M.; Parkin, S.; Crooks, P. A. (Z)-2- (1,3-Benzodioxol-5-ylmethylene)-1­ Azabicyclo[2.2.2]Octan-3-One. Acta Cryst. E. 2006, 62, 05742–05744. Subhashini, S.; Poonguzhali, T. V. In Vitro Antibacterial and Antifungal Property of Ecbolium viride (Forsk) Merrill. Int. J. Curr. Sci.2012, 43, 251–255.

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Vollesen, K. A Revision of Megalochlamys and Ecbolium (Acanthaceae: Justicieae). Kew Bull. 1989, 44 (4), 610–680. Yusuf, A. M.; Olfedehan, O. A.; Obun, C. O.; Inuwa, M.; Garba, M. H.; Shagwa, S. M. Nutritional Evaluation of Shea Butter Fat in Fattening of Yankasa Sheep. Pak. J. Nutr. 2009, 8 (7), 1062–1067.

CHAPTER 66

Phytoconstituents and Pharmacological Activities of Star Fruit [Averrhoa carambola L. (Family: Oxalidaceae)] SAVALIRAM G. GHANE1, SAMADHAN R. WAGHMODE2, and RAHUL L. ZANAN3* 1Department

of Botany, Shivaji University, Vidyanagar, Kolhapur,

Maharashtra 416004, India

2Department

of Microbiology, Elphinstone College,

Dr. Homi Bhabha State University, Madam Cama Road, Mumbai,

Maharashtra 400032, India

3Department

of Botany, Elphinstone College, Dr. Homi Bhabha State

University, Madam Cama Road, Mumbai, Maharashtra 400032, India

*Corresponding

author.

E-mail: [email protected]; [email protected]

ABSTRACT Averrhoa carambola (Family: Oxalidaceae) commonly known as Star fruit or Chinese gooseberry. Fruit is the excellent source of minerals, vitamins, β carotene, and other essential organic acids. Traditionally, fruits, leaves, flowers, roots and seeds are used to treat several diseases. Various researchers analyzed nutritional composition and other active metabolites from the fruit. Fruit is important source of different flavonoids, terpenes and phenolics. It is having various biological activities like antibacterial, antidiarrheal, hepatoprotective, antidotal, antidiabetic, anthelmintic, antioxidant, antiulcer, convulsant, antiulcerogenic, antineoplastic, analgesic, anti-Inflammatory, Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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DNA cleavage, cytotoxic and anticancer activity. This chapter provided updated information on the plant morphology, traditional use, bioactive compounds and biological activities of A. carambola. 66.1

INTRODUCTION

Averrhoa carambola L. (Syn.: Averrhoa acutangula Stokes, Averrhoa pentandra Blanco, Connaropsis philippica Fern.-Vill., Sarcotheca philip­ pica (Fern.-Vill.) Hallier f.) is believed to have originated in Ceylon and the Moluccas (POWO, 2019). It is also grown in Malaysia, Taiwan, Thai­ land, Israel, Florida, Brazil, Philippines, China, Australia, Indonesia, India, Bangladesh, and South pacific islands like Tahiti, New Caledonia, Nether­ lands, New Guinea, Guam, and Hawalii (Ghani, 2003; Morton, 1987; Ray, 2002; Khoo et al., 2016). It is commonly called as Star fruit or Chinese gooseberry. It is known by various names, Belimbing (Indonesian, Malay), Balimbing and Saranate (Filipino), Carambolier (French), Arkin (Florida), Ma fueang (Thai), Caramboleiro (Portuguese), Carambolera (Spanish), Khe ta (Vietnamese), and Kamaranga (Sinhala). In India, it is known in various regional languages, Karmaranga (Sanskrit), Kamrakh and Karmal (Hindi), Kamranga (Bengali), Kordoi or Rohdoi (Assamese), Kamrakh (Gujarati), Karambal (Marathi), Ambanamkaya (Telugu), Thambaratham or Tamarattai (Tamil), and Caturappuli (Malayalam) (Orwa et al., 2009; Nandkarni, 1976). It is a small, attractive, multistemmed, slow growing, evergreen woody tree. It can grow up to 10 m with short trunk, bushy with many branches, spreading 20–25 feet in diameter with rounded crown. Trunk at the base reach up to 15 cm in diameter. Bark is light brown, smooth, and finely fissured. Leaves deciduous, alternate, spirally arranged, imparipinnate, ovate to ovate-oblong in shape, 15–25 cm long, shortly petiolate with 5–11 green pedant leaflets of 2–9 cm long and 1–4.5 cm wide. Leaves are compound, soft, pubescent, medium-green, smooth on the upper surface, and whitish on the underside. Leaflets are sensitive to light and tend to fold together at night, also sensitive to abrupt shock. Flowers are bright purple or pink colored, produced on twigs in axils of leaves, and arranged in small clusters attached with red stalks. Flowers are small, 6 mm wide, and pedicellate with 5 petals and sepals. Fruits are green when small and unripe, yellow or orange after maturity and ripe; fleshy, oblong, ovate or ellipsoid, lobed, 5–6 angled, 5–15 cm long, and up to 9 cm wide. Fruits star shaped, fragile, susceptible to wind, crunchy, slightly tart, acidic, sour to mildly sweetish or sweetish in taste, odor resembles oxalic acid. Skin is thin, light to dark yellow, and

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smooth with waxy cuticle. Flesh light yellow to yellow, translucent, and juicy without fiber. Each fruit have five seeds or up to 12 or none at all, 0.6–1 cm long, edible, thin, light brown, enclosed by a gelatinous aril, and lose viability in a few days after removal from the fruit. Propagated from fully developed seeds, germinate in 1 week in summer, 14–18 days needed in winter (Tidbury, 1976; Morton, 1987; Kapoor, 1990; Warrier and Nair 2002; Anonymous, 2002; Kapoor, 2000; Thomas et al., 2008). Fruits are good source of minerals (sodium, potassium, calcium, phos­ phorous, magnesium, iron, copper, zinc, and manganese), vitamins (vitamin B1, B2, and C), β-carotene, and organic acids (tartaric acid, oxalic acid, ketoglutaric acid, and citric acid) (Carolino et al., 2005; Singh et al., 2014; Moresco et al., 2012). Traditionally, fruits are used to treat mouth ulcer, throat inflammation, toothache, cough, asthma, hiccups, indigestion, food poisoning, colic, diarrhea, jaundice, malarial splenomegaly, haemorrhoids, skin rashes, pruritis, sunstroke, eye related problems, high blood pressure, diabetes, diuretic in kidney, and bladder related problems. It is also used as digestive, tonic, antipyretic, laxative, appetite stimulant, sialogogue, astringent, antiscorbutic, and to increase the secretion of saliva, aphrodisiac for both men and women. Leaves are useful against chicken pox, ringworm, tinea, cold, headache, stomach ulcers, improves digestion, aphthous stoma­ titis, angina, vermifuge, fever, coughs, malaria, oliguria, boils, pyodermas, postpartum edema, gastroenteritis, and traumatic injury. Flowers are used in vermifuge, fever, malaria, dermatitis, antihelmintic, and subcalorism. Roots are used to treat arthralgia, chronic headache, epitaxis, spermatorrhea, and antidote for poison. Seeds are used as emmenagogue, galactagogue, abor­ tifacient, mildly intoxicating, asthma, jaundice, and colic (Barwick, 2004; Sheth and Ashok, 2005; Anonymous, 2002; Manandhar and Manandhar, 2002; Chung et al., 1998; Kakati et al., 2020). 66.2 BIOACTIVES Phytochemical investigation confirmed the presence of alkaloids, amino acids, carbohydrates, starch, reducing sugars, glycosides, phenolics, sapo­ nins, tannins, and flavonoids from the fruits (Aye et al., 2019). Gross et al. (1983) recorded 22 µg/g FW total carotenoid content from fruit. Among that, phytofluene (17%), γ-carotene (25%), β-cryptoflavin (34%), and mutatoxan­ thin (14%) were recorded as a major carotenoid, whereas β-carotene, neuro­ sporene, β-apo-8′-carotenal, β-cryptoxanthin, β-cryptochrome and lutein were observed in small amounts. Recently, Islam et al. (2020) identified

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glucose, sucrose, raffinose, L-proline, betaine, L-carnitine, choline, succinic acid, malic acid, nonanedioic acid, caprylic acid, 2-hydroxyheptanoic acid, nonanoic acid, capric acid, 3-hydroxysuberic acid, lauric acid, tridecanoic acid, myristic acid, palmitoleic acid, palmitic acid, 16-hydroxypalmitic acid, linoleic acid, octadecanoic acid, coriolic acid, 2-hydroxybehenic acid, cerebronic acid, salicylic acid, protocatechuic acid, vanillic acid, gallic acid, syringic acid, epicatechin, aromadendrin, epigallocatechin, procyanidin B2, gentisein, norathyriol, sugiol, cinnamic acid, methyl salicylate, ethyl proto­ catechuate, sorbitol, quinic acid, and gingerol from the ethanol extracts of bark by using positive paper spray ionization mass spectrometry. Lutz and Winterhalter (1994) identified (l’S,4E)-2,3 dihydroabscisic alcohol from ether extract of fruit by using multilayer coil countercurrent chromatography, HPLC, and NMR spectroscopy. Leivas et al. (2015) characterized polysaccharides from the fruit and identified as rhamnogalac­ turonan I. Further, they also recorded pectic type II arabinogalactans from the fruit (Leivas et al., 2016a). Leivas et al. (2016b) identified substituted galacturonan, which composed of (1→4)-linked α-d-Galp A units branched at O-2 by (1→5)-linked α-l-Araf and terminal α-l-Araf and α-d-Galp A units. Gunawardena et al. (2015) isolated nine phytotoxic compounds viz. cis­ abscisic acid, trans-abscisic acid, trans-abscisic alcohol, (6S,9R)-vomifoliol (blumenol A), cis-abscisic acid β-D-glucopyranosyl ester, trans-abscisic alcohol β-D-glucopyranoside, (6S,9R)-roseoside, cis-abscisic alcohol β-D-glucopyranoside, and (–)-epicatechin from the fruit. Yang et al. (2014) isolated two tetrahydroisoquinoline alkaloids, (1R*,3S*)-1-(5-hydroxymethylfuran-2-yl)-3-carboxy-6-hydroxy­ 8-methoxyl-1,2,3,4-tetrahydroisoquinoline and (1S*,3S*)-1-methyl-3­ carboxy-6-hydroxy-8-methyoxyl-1,2,3,4-tetrahydroisoquinoline along with vanillic acid, ferulic acid, 8,9,10-trihydroxythymol, and arjunolic acid from the fruit. Yang et al. (2015) identified four dihydrochalcone C-glycosides (carambolaside A-D) along with hovertichoside C, isovitexin 2″-O-α-L-rhamnopyranoside, and carambolaflavone from the fruit. Two alkyl glycosides (heptyl vicianoside and methyl 2-O-β-dfucopyranosyl-α-larabinofuranoside) along with octyl vicianoside, cis-3-hexenyl rutinoside, and methyl α-d-fructofuranoside were reported from the fruit (Yang et al., 2019). Jia et al. (2017) isolated eleven nonflavonoid phenolic compounds namely two alkyl phenol diglucosides (carambolaside K and carambola­ side L), four phenylpropanoids ((+)-isolariciresinol 9-O-b-D-glucoside, (+)-lyoniresinol 9-O-b-D-glucoside, (-)-lyoniresinol 9-O-β-D-glucoside and 1-O-feruloyl-β-D-glucose), three benzoic acids (protocatechuic

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acid, 1-O-vanilloyl-β-D-glucose and tecomin), phenol (koaburaside), and naphthoquinone ((+)-cryptosporin) from fresh fruit. Further, Jia et al. (2018) identified total 13 flavonoids namely 8-carboxymethyl-(+)epicatechin methyl ester, pinobanksin 3-O-β-D-glucoside, carambolasides M–Q, (+)-epicatechin, aromadendrin 3-O-β-D-glucoside, helicioside A, taxifolin 3′-O-β-D-glucoside, galangin 3-O-rutinoside, and isorhamnetin 3-O-rutinoside from fresh fruit. Jia et al. (2019) isolated 16 carotenoid derivatives namely C13-norisoprenoid glucoside, (5R,6S,7E,9R)-5,6,9-tri­ hydroxy-7-megastigmene 9-O-β-D-glucoside; C15-norisoprenoid, (6S,7E,10S)-D9,15-10-hydroxyabscisic alcohol; dehydrovomifoliol; 3-oxo-α-ionol 9-O-β-D-glucoside; roseoside; 3-oxo-9-O-β-D-glucosyloxy4,6E-megastigmadien; 4-oxo-β-ionol 9-O-β-D-glucoside; cannabiside D; dendranthemoside B; icariside B2; officinoside A; abscisic acid; abscisyl β-D-glucoside; 9E-abscisic acid; 9E-abscisyl β-D-glucoside; and 9E-abscisic alcohol β-D-glucoside from the fresh fruit. Flavone C-glycosides such as carambolaflavone and isovitexin were isolated from the leaves (Daisuke et al., 2005). Moresco et al. (2012) observed β-sitosterol, apigenin-6-C-β-L-fucopyranoside, apigenin-6-C-(2″O-α-L-rhamnopyranosyl)-β-L-fucopyranoside, and apigenin-6-C-(2″-O-αL-rhamnopyranosyl)-β-D-glucopyranoside from hydroalcoholic extract of leaves. Poongodi and Nazeema (2016) identified propoxur-M, benzofuran, caryophyllene, 2-norpinene, cycloheptasiloxane, 4-hexen-1-ol, octadecyl trimethyls, benzene propanoic acid, 9-octadecenoic acid, and 2-bromopropi­ onic acid from the leaves using GC-MS. Yang et al. (2020a) isolated five flavan3-ols (epicatechin-(5,6-bc)-4β-(p-hydroxyphenyl)-dihydro-2(3H)-pyranone, epicatechin-(7,8-bc)-4α-(p-hydroxyphenyl)-dihydro-2(3H)-pyranone, epicatechin-(7,8-bc)-4β-(p-hydroxyphenyl)-dihydro-2(3H)-pyranone, 6-(S-2-pyrrolidinone-5-yl)epicatechin and 6-(R-2-pyrrolidinone-5-yl)epicat­ echin) and two 2-diglycosyloxybenzoates (benzyl 2-β-D-apiofuranosyl(1→6)-β-D-glucopyranosyloxybenzoate, methyl 2-β-D-apiofuranosyl(1→6)-β-D-glucopyranosyloxybenzoate) from the leaves. Further, they isolated ten dihydrochalcone C-glycosides (carambolaside R1‒R3, S1, S2, T1‒T3, 3-hydroxycarambolaside T1, and 3-hydroxycarambolaside P) along with carambolaside I and -P from the leaves (Yang et al., 2020b). Siddika et al. (2020) identified 5-(4-nitrobenzylidene)-1,3-thiazol-4(5H)-one; ethyl benzene; o-xylene; 2-(2-butoxyethoxy)-ethanol; 2,4,4,6-tetramethyl-6-phen­ ylheptane; 1,3-bis (hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione and estra-1,2,5(10)-trien-17-ol from the leaves.

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Mia et al. (2007) isolated p-anisaldehyde and β-sitosterol from carbon tetrachloride and chloroform soluble portion of the methanolic extract of stem bark. Chakthong et al. (2010) isolated two alkyl phenols (2,5-dimethoxy­ 3-undecylphenol and 5-methoxy-3-undecylphenol) and two benzoquinones (5-O-methylembelin and 2-dehydroxy-5-O-methylembelin) from the wood. Six chiral lignans and nine phenolic glycosides such as 3,4,5-trimethoxyphenol-1-O-β-D-glucopyranoside, benzyl-1-O-β-Dglucopyranoside, (+)-5′-methoxyisolariciresinol 3α-O-β-D-glucopyranoside, (+)-isolariciresinol 3α-O-β-D-glucopyranoside, koaburaside, (+)-lyoni­ resinol 3α-O-β-D-glucopyranoside, (−)-lyoniresinol 3α-O-β-Dglucopyranoside, (−)-5′-methoxyisolariciresinol 3α-O-β-D-glucopyranoside, (−)-isolariciresinol 3α-O-β-D-glucopyranoside, 3,5-dimethoxy4-hydroxyphenyl 1-O-β-apiofuranosyl (1″→6′)-O-β-D-glucopyranoside, 3,4,5-trimethoxyphenyl 1-O-β-apiofuranosyl (1″→6′)-β-glucopyranoside, methoxyhydroquinone-4-β-D-glucopyranoside, (2S)-2-O-β-Dglucopyranosyl-2-hydroxyphenylacetic acid, 3-hydroxy-4-methoxyphenol 1-O-β-D-apiofuranosyl-(1″→6′)-O-β-D-glucopyranoside and 4-hydroxy3-methoxyphenol 1-O-β-dapiofuranosyl-(1″→6′)-O-β-D-glucopyranoside were identified from the butanol fraction of root (Wen et al., 2012). Wilson et al. (1985) identified total 41 volatiles from fruit by using a capillary gas chromatography-mass spectroscopy. Among them acetal­ dehyde, ethyl acetate, 2-methyl-1-propanol, 1-pentanol, 1-penten-3-ol, 3-methyl-2-butanone, 3-methyl-1-butanol, ethyl butyrate plus hexanal, cis-3-hexen-1-ol, trans-3-hexen-1-ol, hexanol, α-pinene, benzaldehyde, 6-methyl-5- hepten-2-one, 6-methyl-5-hepten-2-ol, β-binene, ethyl hexanoate, 1,8-cineole, 1imonene, benzyl alcohol, octanol plus acetophe­ none, methyl benzoate, ethyl sorbate, phenylethyl alcohol, veratrole, borneol, diethyl succinate, o-methylacetophenone, 4-terpineol, ethyl benzoate, methyl salicylate, ethyl nicotinate, benzothiazole, methyl anthranilate, carvone, phenylethyl acetate, diethyl glutarate, cinnamyl aldehyde, quino­ line, cinnamyl acetate, and β-ionone were detected. Recently, Ramadan et al. (2020) studied 24 volatiles from the fruit using HS-SPME-GC-MS and GC-MS-post silylation and compounds were identified as 2-heptanone; 2-hydroxy-2-methylhept-6-en-3-one; 2-nonanone; 4-ketoisophorone; 3-hexanone, 2,4-dimethyl-; nerylacetone; methyl caproate; ethyl caproate; 3-hexen-1-ol, propanoate, (Z)-; methyl caprylate; linalyl acetate; oxalic acid, butyl propyl ester; oxalic acid, heptyl propyl ester; nonanal; decanal; 2-cyclocitral; myristicin; myrcene; limonene; hexanoic acid; 2,5-dimethyl cyclohexanol; and (E)-anethole; safrole and tridecane, 4-methyl-.

Averrhoa carambola L.

FIGURE 66.1

Bioactive compounds from Averrhoa carambola.

FIGURE 66.2

Bioactive compounds from Averrhoa carambola.

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PHARMACOLOGY

66.3.1 ANTIBACTERIAL ACTIVITY Petroleum ether soluble fraction of the methanolic extract of stem bark (400 μg/disc) showed superior antibacterial potential against Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Staphylococcus aureus, Sarcina lutea, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Shigella paratyphi, Shigella dysenteriae, Vibrio mimicus, and Vibrio parahe­ molyticus (9.20 ± 1.10, 10.11 ± 2.10, 10.10 ± 2.42, 10.33 ± 0.86, 10.36 ± 1.25, 12.25 ± 1.29, 8.00 ± 1.11, 10.11 ± 1.87, 10.41 ± 1.34, 12.27 ± 1.36, 10.16 ± 0.89, and 10.19 ± 0.47 mm zone of inhibition, respectively) (Mia et al., 2007). Ethanolic bark extract showed antibacterial activity against S. typhi, P. aeruginosa, E. coli and B. megaterium with 3, 1.5, 2.5, and 1.5 mm of zone of inhibition, respectively using disc diffusion method (Das et al., 2013). Das (2012) observed that the ethanolic extract of green fruits (10 mg dry weight/disc) showed higher antimicrobial potential as compared to ripen fruit extract. Among the different microorganisms, the highest zone of inhibition (10.67 ± 1.527, 10.67 ± 0.577) was observed against E. coli and S. aureus. Silver nanoparticles synthesized from fruit (100 ppm) showed 26 and 8 mm zone of inhibition against E. coli and P. aeruginosa, respectively (Mane-Gavade et al., 2015). Ethanolic extract of shade dried leaves (400 mg/ mL) evaluated against S. aureus, E. coli, Klebsiella spp., P. aeruginosa, and Candida albicans. Study showed 16.04 ± 0.2856, 15.4 ± 0.2645, 17.9 ± 0.158, 18 ± 0.2549, and 17.9 ± 0.1516 mm zone of inhibition, respectively, against the tested microorganisms (Phukan and Ahmed, 2016). Ethanolic leaf extract (500 μg/disc) also found active against Streptococcus agalactiae, Strepto­ coccus pyogenes, S. dysenteriae, Pseudomonas spp., and Staphylococcus saprophyticus with 8–12 mm zone of inhibition (Hossain et al., 2017). 66.3.2 ANTIFUNGAL ACTIVITY Petroleum ether soluble fraction of the methanolic extract of stem bark (400 μg/disc) showed notable antifungal activity against C. albicans, Aspergillus niger, and Sacharomyces cerevaceae with 10.18 ± 1.15, 08.42 ± 1.37, and 10.24 ± 1.67 mm zone of inhibition, respectively (Mia et al., 2007). Simi­ larly, methanolic leaf extract (25 mg/mL) showed 12.17 ± 0.02, 11.07 ± 0.06, 19.03 ± 0.06, 18.12 ± 0.02, and 11.11 ± 0.01 mm zone of inhibition against C. albicans, Candida tropicalis, Candida krusei, Fusarium oxysporum, and Trichophyton mentagrophytes (Majhi et al., 2019).

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66.3.3 ANTIDOTAL ACTIVITY Fluoride-induced (100 ppm) male albino rats were supplemented with fruit powder (10 g/100 g) for 30 days showed enhancement in lipid content, antioxidant potential, and atherogenic index of plasma (347.77 ± 0.81 mg/ dl, 246.46 ± 0.38 μmole/L, and 1.65 ± 0.01 mg/dl, respectively) than the fluoride exposed rats (470.17 ± 0.63 mg/dl, 246.46 ± 0.38 μmole/L, and 3.33 ± 0.03 mg/dl, respectively) (Vasant and Narasimhacharya, 2014). 66.3.4 ANTIDIABETIC ACTIVITY Oral administration of methanolic extract of leaves (400 mg/kg b.w.) to the glucose-loaded mice, reduced 34.1% serum glucose level (Shahreen et al., 2012). Similarly, ethanolic root extracts (150—1200 mg/kg body weight/d for 21 days) were administered to streptozotocin diabetic mice (120 mg/kg b.w. injected through the tail vein) and showed decrease in blood glucose level, total cholesterol, triglycerides, and free fatty acids and increase in insulin content (Xu et al., 2014). Pham et al. (2017) injected aqueous fruit juice in streptozotocin induced diabetic mice exhibited decrease in fasting blood glucose, free fatty acids, total cholesterol, triglycerides, and blood urea nitrogen after 21 days of treatment. At the same time, increase in sorbitol dehy­ drogenase, cyclic adenosine monophosphate, malondialdehyde, superoxide dismutase, and insulin were also reported. Oral administration of apigenin­ 6-C-β-fucopyranoside and apigenin-6-C-(2″-O-α-rhamnopyranosyl)-βfucopyranoside isolated from leaves showed potent hypoglycemic activity and could be a potent antihyperglycemic agent (Cazarolli et al., 2012). Recently, Islam et al. (2020) noted that the ethanolic bark extract and nora­ thyriol isolated from bark showed significant α-glucosidase activity (IC50 7.15 ± 0.06 and 0.81 ± 0.01 µg/mL, respectively). 2-Dodecyl-6-methoxycycyclohexa-2,5-1,4-dione was isolated from roots and examined on obesity and insulin resistance induced by a high-fat diet in C57BL/6J mice (Li et al., 2016). Decrease in glucose, total choles­ terol, triglycerides, free fatty acids, insulin, interleukin-6 and tumor necrosis factor-α was observed. In addition, improvement in insulin secretion, hepatic steatosis, and adipocyte hypertrophy were also recorded. Several researchers confirmed the protective role of 2-dodecyl-6-methoxycycyclohexa-2,5-1,4dione in kidney damage, inflammation through inhibition of the TLR4/ MyD88/NF-κB signaling pathway, diabetic kidney disease by inhibiting the TLR4-BAMBISmad2/3 and TLR4/TGFβ signaling pathway in diabetic mice (Lu et al., 2019; Zhang et al. 2019; Zhang et al., 2020).

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66.3.5 DNA CLEAVAGE ACTIVITY Aqueous and ethanolic extracts of fruit evaluated against supercoiled plasmid DNA of E. coli using gel electrophoresis. Aqueous extract (0.500 and 0.600 µg/µL) and ethanolic extract (0.375, 0.500, and 0.600 µg/µL) showed DNA cleaving properties (Khanam et al., 2015). 66.3.6 ANTIOXIDANT ACTIVITY Most promising antioxidant potential in terms of DPPH radical scavenging and reducing power of iron was observed from ethyl acetate and n-butanol fractions of hydroalcoholic extract (5–200 μg/mL) of leaves (IC50 90.92 and 124.48 μg/mL, respectively) (Moresco et al., 2012). Gallic acid, epicatechin, protocatechuic acid, norathyriol, and gingerol isolated from bark showed significant DPPH radical scavenging activity (IC50 3.85 ± 0.47, 8.37 ± 0.96, 9.83 ± 0.27, 4.90 ± 0.09, and 6.12 ± 0.67 µg/mL, respectively). Similarly, gallic acid and norathyriol showed significant ABTS radical scavenging activity (IC50 8.67 ± 1.21 and 9.63 ± 0.47 µg/mL, respectively) (Islam et al., 2020). Oral administration of ethanolic extract (800 mg/kg p.o. per day) and paracetamol (250 mg/kg p.o. per day) for 10 days showed 4.46 ± 0.1904 U/mg protein superoxide dismutase, 26.41 ± 0.1869 µM/min/mL catalase and 43.3 ± 0.1183 µM/mg protein reduced glutathione activities (Phukan and Ahmed, 2016). Fresh dehydrated, oven dried, and sun-dried methanolic fruit extracts (70%) of Honey sweet (IC50 178.89 ± 5.43, 196.62 ± 4.80, 312.27 ± 3.88 and 483.93 ± 9.43 ppm, respectively) and Arkin (IC50 164.87 ± 8.37, 179.27 ± 4.58, 210.77 ± 5.87 and 395.26 ± 17.25 ppm, respec­ tively) varieties showed promising DPPH radical scavenging activity (Ruvini et al., 2017). Antioxidant potential of ethanolic extracts from fruit pulp, green fruit bagasse, ripe fruit bagasse, stem bark and leaf showed 429.55 ± 151.08, 198.44 ± 65.43, 225.11 ± 18.35, 1971.77 ± 10.71, and 1040.66 ± 23.09 μmol ET/g DPPH and 7106.72 ± 649.12, 4738.12 ± 1019.33, 5284.43 ± 1141.30, 79932.29 ± 269.06, and 11162.20 ± 2395.23 μmol ET/g FRAP activity (Silva et al., 2021). Several authors reported appreciable antioxidant activities from the different extracts (Das et al., 2013; Dhanira et al., 2020; Shui and Leong, 2006; Hasan et al., 2015; Adiyaman et al., 2016; Pang et al., 2016). 66.3.7 ANTINEOPLASTIC ACTIVITY Antineoplastic effect of methanolic leaf extract (50 mg/kg) against Ehrlich ascites carcinoma in mice noted with decreased viable cells count

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(1.02 ± 0.23 × 107 cells/mL/mouse), increase in body weight (4.18 ± 0.98 g), survival time (35.4 ± 6.02 days), and restoration of altered haematological parameters (Hgb, 14.61 ± 2.30 g/dL, RBC, 4.95 ± 0.56 × 109 cells/mL and WBC, 21.0 ± 3.70 × 107 cells/mL) in the treated cancer cells (Siddika et al., 2020). 66.3.8 CYTOTOXIC ACTIVITY The treatment of methanolic fruit extract (500 μg/mL) was subjected to cytotoxic study using brine shrimp lethality bioassay and showed LC50 value of 243.571 μg/mL indicating cytotoxic activity (Hasan et al., 2015). Similarly, Das et al. (2013) noted LC50 value of 19.95 from ethanolic bark extract using the brine shrimp lethality bioassay. Different concentrations of aqueous extract of leaves (10–1000 μg/mL) showed fluctuating LC50 values (1056.99–9908.32 μg/mL) with increasing extraction time (30–90 min) when tested in brine shrimp lethality assay (Tristantini and Rahmi, 2016). Ethanolic leaf extract noted with 100 and 160 μg/mL LC50 and LC90 values, respectively, in lethality assay (Hossain et al., 2017). 66.3.9 ANTICANCER ACTIVITY Oral administration of ethyl alcohol extract of fruit (25 mg/kg b.w./day) for five consecutive days in diethylnitrosamine induced (15 mg/kg b.w.) and CCl4-promoted Swiss albino mice (1.6 g/kg b.w.) was studied. It showed reduction in tumor incidence (80%), tumor yield (10.12), and tumor burden (8.1) of liver cancer. Authors observed significant reduction in lipid peroxidation and elevation of superoxide dismutase and catalase activities suggested prophylactic role against hepatocellular carcinoma in mice (Singh et al., 2014). Methanolic extract (1000 μg) against breast cancer cell line (MCF-7) showed 52.325 ± 0.622% cytotoxicity and 47.675 ± 0.622% cell viability. They also recorded IC50 value of 170.326 μg/mL (Poongodi and Nazeema, 2016). Antidiabetic cyclohexanedione compound, 2-dodecyl­ 6-methoxycyclohexa-2,5-diene-1,4-dione isolated from the roots and molecular mechanism against human breast cancer cells was investigated. They observed suppressed growth of breast carcinoma cells and increased in intracellular reactive oxygen species. The apoptosis involved intrinsic mito­ chondrial and extrinsic receptor pathway indicating the safe use for treating breast cancer (Gao et al., 2015).

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66.3.10 ANTHELMINTIC ACTIVITY Aqueous leaves extract (100 mg/mL) showed 10.83 ± 1.72 and 16.16 ± 1.85 min time of paralysis and death in Pheretima posthuma, which confirmed the anthelmintic activity (Shah et al., 2011). 66.3.11 ANTIDIARRHOEAL ACTIVITY Ethanolic leaf extract (250 and 500 mg/kg) significantly reduced number of stools (25% and 31.25%, respectively) in castor oil-induced diarrhoeal mice (Hossain et al., 2017). Ethanolic and aqueous extract were found to safe of up to a dose of 2000 mg/kg body weight of mice. Ethanolic extract (200 mg/ kg) showed 189.83 ± 23.796 min onset time of diarrhea with 5.167 ± 0.872 number of feces, 3.667 ± 0.494 number of wet feces, and 0.15 ± 0.023 g of wet feces on castor oil-induced diarrhea in mice. Similarly, prostaglandininduced diarrhea in mice showed 182.5 ± 11.494 min onset time of diarrhea with 4.667 ± 0.667 number of feces, 3.333 ± 0.615 number of wet feces and 0.187 ± 0.035 g of wet feces confirmed the role in the prevention and treatment of diarrhea (Pal et al., 2019a). 66.3.12 HEPATOPROTECTIVE ACTIVITY Oral administration of stem ethanolic extract (500 mg) for 10 days in CCl4­ induced hepatic damaged rats showed significant decrease in aspartate trans­ aminase (85.00 ± 1.065 IU/L), alanine transaminase (95.00 ± 1.065 IU/L), and alkaline phosphotase (85.00 ± 1.461 IU/L) enzymes, which revealed hepatoprotective potential (Chinna et al., 2013). 66.3.13 ANTI-INFLAMMATORY ACTIVITY Inflammation effect of leaf ethanolic extracts (hexane, ethyl acetate, and n-butanol fractions) on mice using oil-induced ear edema model noted with 73 ± 7, 75 ± 5, and 63 ± 14% inhibition respectively which confirmed the anti-inflammatory potential (Cabrini et al., 2011). 66.3.14 ANALGESIC ACTIVITY Analgesic activity of fruit extracts (400 mg/kg) in Swiss albino mice was performed using acetic acid-induced writhing method and radiant heat tail-flick test. Researchers noted 42.76% inhibition of writhing in acetic

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acid-induced writhing method. In radiant heat tail-flick method, 40.88% elongation of tail flicking was observed after 60 minutes (Das and Ahmed, 2012). Analgesic activity of ethanolic extract (400 mg/kg) in acetic acid-induced writhing method showed 57% inhibition in Swiss albino mice. Similarly, eddy’s hot plate mediated pain reaction method showed 10.2 ± 0.1633, 10.06 ± 0.1706, and 10.35 ± 0.1477 sec reaction time for pain threshold after 30, 60, and 120 min, respectively (Phukan and Ahmed, 2016). Leaf ethanolic extract (500 mg/kg body weight) showed 40.28% writhing reflex inhibition in acetic acid-induced Swiss-albino mice. Stan­ dard diclofenac sodium (25 mg/kg body weight) showed 69.45% inhibition (Hossain et al., 2017). 66.3.15 ANTIULCER ACTIVITY Ethanolic and aqueous extract of dried leaves (200 mg/kg) showed 54.34% and 65.22% ulcer protection in Wistar albino rats using ethanol-induced ulcer model. Pylorus ligation method showed 51.06% and 61.71% ulcer protection, respectively. They also confirmed that the doses of 2000 mg/ kg ethanolic and aqueous extract were found absolutely safe (Pal et al., 2019b). 66.3.16 CONVULSANT ACTIVITY Neurotoxic fraction (26.7 mM) from the fruits significantly inhibited GABA binding (65% relative to the control) with IC50 value of 0.89 mM (Carolino et al., 2005). 66.3.17 ANTIULCEROGENIC ACTIVITY Oral administration of water–alcoholic extract (800 and 1200 mg/kg) of leaves were examined for gastric lesions induced by acidified ethanol and indomethacin in male Wistar rats. Acidified ethanol-induced ulcer model in rats showed significant antiulcer activity with 20.73 ± 3.42 and 8.90 ± 1.58 ulcer index, respectively. Whereas, indomethacin and acute stress-induced ulcer models did not showed significant antiulcer activity (Gonçalves et al., 2006).

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KEYWORDS • • • • •

carotene anticancer activity antiulcer activity antidiabetic activity hepatoprotective activity

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Das, B. N.; Ahmed, M. Analgesic Activity of the Fruit Extract of Averrhoa carambola. Int. J. Life Sci. Bt. Pharm. Res. 2012, 1 (3), 22–26. Das, J.; Datta, Z.; Saha, A.; Nur, S. M.; Barua, P.; Rahman, M. M.; Chowdhury, K. A. A.; Chowdhury, M. M.; Chowdhury, R. H.; Mannan, A. A Comprehensive Study on Antioxidant, Antibacterial, Cytotoxic and Phytochemical Properties of Averrhoa carambola. Int. J. Bioassays. 2013, 02 (05), 803–807. Das, S. Antimicrobial and Antioxidant Activities of Green and Ripe Fruits of Averrhoa carambola Linn. and Zizyphus mauritiana Lam. Asian J. Pharm. Clin. Res. 2012, l5 (3), 102–105. Dhanira, A.; Elya, B.; Basah, K. Antioxidant Activity Test of Fractions from Star Fruit Leaves (Averrhoa carambola L.) from Three Regions in West Java. Int. J. App. Pharm. 2020, 12 (1), 97–100. Gao, Y.; Huang, R.; Gong, Y.; Park, H. S.; Wen, Q.; Almosnid, N. M.; Chippada-Venkata, U. D.; Hosain, N. A.; Vick, E.; Farone, A.; Altman, E. The Antidiabetic Compound 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, Isolated from Averrhoa carambola L., Demonstrates Significant Antitumor Potential Against Human Breast Cancer Cells. Oncotarget 2015, 6 (27), 24304–243019. Ghani, A. Medicinal Plants of Bangladesh with Chemical Constituents and Uses, 2nd ed.; Asiatic Society of Bangladesh: Dhaka, 2003; p 10. Gonçalves, S. T.; Baroni, S.; Bersani-Amado, F. A.; Melo, G. A. N.; Cortez, D. A. G.; BersaniAmado, C. A.; Cuman, R. K. N. Preliminary Studies on Gastric Anti-Ulcerogenic Effects of Averrhoa carambola in Rats. Acta Farm. Bonaerense. 2006, 25 (2), 245–247. Gross, J.; Ikan, R.; Eckhardt, G. Carotenoids of the Fruit of Averrhoa carambola. Phytochemistry 1983, 22 (6), 1479–1481. Gunawardena, D. C.; Jayasinghe, L.; Fujimoto, Y. Phytotoxic Constituents of the Fruits of Averrhoa carambola. Chem. Nat. Compd. 2015, 51 (3), 532–533. Hasan, M. R.; Islam, T.; Roy, A.; Islam, M. S.; Islam, M. A.; Rafiquzzaman, M. Evaluation of In-Vitro Antioxidant and Brine Shrimp Lethality Activities of Fruit Extract of Averrhoa carambola L. Int. J. Pharm. Sci. Res. 2015, 6 (9), 3821–3828. Hossain, T.; Barman, A. K.; Karmakar, U. K.; Bokshi, B.; Dev, S.; Biswas, N. N. Phytochemical and Pharmacological Evaluation of Leaves of Averrhoa carambola Linn. (Family: Oxalidaceae). Biosci. Bioeng. Commun. 2017, 3 (1), 144–151. Islam, S.; Alam, B. M.; Ahmed, A.; Lee, S.; Lee, S-H.; Kim, S. Identification of Secondary Metabolites in Averrhoa carambola L. Bark By High-Resolution Mass Spectrometry and Evaluation for α-Glucosidase, Tyrosinase, Elastase, and Antioxidant Potential. Food Chem. 2020, 332, 127377. Jia, X.; Xie, H.; Jiang, Y.; Wei, X. Flavonoids Isolated from the Fresh Sweet Fruit of Averrhoa carambola, Commonly Known as Star Fruit. Phytochemistry 2018, 153, 156–162. Jia, X.; Yang, D.; Xie, H.; Jiang, Y.; Wei, X. Non-Flavonoid Phenolics from Averrhoa carambola Fresh Fruit. J. Funct. Foods. 2017, 32, 419–425. Jia, X.; Yang, D.; Yang, Y.; Xie, H. Carotenoid-Derived Flavor Precursors from Averrhoa carambola Fresh Fruit. Molecules 2019, 24, 256. Kakati, M. K.; Sharma, R.; Bharadwaj, B.; Sarma, N. K.; Das, B.; Dutta, R. A Systematic Overview on Some of the Traditionally Used Plants of Assam. J. Drug Deliv. Ther. 2020, 10, 358–366. Kapoor, L. D. CRC Handbook of Ayurvedic Medicinal Plants; CRC Press: Boca Raton, 1990; p 58.

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Kapoor, L. D. Handbook of Ayurvedic Medicinal Plants: Herbal Reference Library; CRC Press: Boca Raton, 2000. Khanam, Z.; Sam, K. H.; Zakaria, N. H. B. M.; Ching, C. H.; Bhat, I. U. H. Determination of Polyphenolic Content, HPLC Analyses and DNA Cleavage Activity of Malaysian Averrhoa carambola L. Fruit Extracts. J. King Saud Univ. Sci. 2015, 27, 331–337. Khoo, H. E.; Azlan, A.; Kong, K. W.; Ismail, A. Phytochemicals and Medicinal Properties of Indigenous Tropical Fruits with Potential for Commercial Development. Evid. Based Complement. Altern. Med. 2016, 7591951. Leivas, C. L.; Iacomini, M.; Cordeiro, L. M. C. Pectic Type II Arabinogalactans from Starfruit (Averrhoa carambola L.) Food Chem. 2016a, 199, 252–257. Leivas, C. L.; Nascimento, L. F.; Barros, W. M.; Santos, A. R. S.; Iacomini, M.; Cordeiro, L. M. C. Substituted Galacturonan from Starfruit: Chemical Structure Andantinociceptive and Anti-Inflammatory Effects. Int. J. Biol. Macromol. 2016b, 84, 295–300. Leivas, C. L.; Iacomini, M.; Cordeiro, L. M. C. Structural Characterization of a Rhamnogalacturonan I-Arabinan-Type I Arabinogalactan Macromolecule from Starfruit (Averrhoa carambola L.). Carbohydr. Polym. 2015, 121, 224–230. Li, J.; Wei, X.; Xie, Q.; Thai, T.; Pham, H.; Wei, J.; He, P.; Jiao, Y.; Xu, X.; Huong, T.; Nguyen, G.; Wen, Q.; Huang, R. Protective effects of 2-dodecyl-6-Methoxycyclohexa-2,5diene-1,4-Dione Isolated from Averrhoa carambola L. (Oxalidaceae) Roots on High-Fat Diet-Induced Obesity and Insulin Resistance in Mice. Cell Physiol. Biochem. 2016, 40, 993–1004. Lu, S.; Zhang, H.; Wei, X.; Huang, X.; Chen, L.; Jiang, L.; Wu, X.; Zhou, X.; Qin, L.; Li, Y.; Lin, X.; Huang, R. 2-dodecyl-6-Methoxycyclohexa-2,5-diene-1,4-Dione Isolated from Averrhoa carambola L. Root Ameliorates Diabetic Nephropathy by Inhibiting the TLR4/ MyD88/NF-κB Pathway. Diab. Metab. Syndr. Obes. 2019, 12, 1355–1363. Lutz, A.; Winterhalter, P. Dihydroabscisic Alcohol from Averrhoa carambola Fruit. Phytochemistry 1994, 36 (3), 811–812. Majhi, B.; Satapathy, K. B.; Mishra, S. K. Antimicrobial Activity of Averrhoa carambola L. Leaf Extract and Its Phytochemical Analysis. Res.J. Pharm. Tech. 2019, 12 (3), 1219–1224. Manandhar, N. P.; Manandhar, S. Plants and People of Nepal; Timber Press: Portland, 2002. Mane-Gavade, S. J.; Nikam, G. H.; Dhabbe, R. S.; Sabale, S. R.; Tamhankar, B. V.; Mulik, G. N. Green Synthesis of Silver Nanoparticles by Using Carambola Fruit Extract and Their Antibacterial Activity. Adv. Nat. Sci. Nanosci. Nanotechnol. 2015, 6, 045015. Mia, M. M.; Rahman, M. S.; Begum, K.; Begum, B.; Rashid, M. A. Phytochemical and Biological Studies of Averrhoa carambola. Dhaka Univ. J. Pharm. Sci. 2007, 6 (2), 125–128. Moresco, H. H.; Queiroz, G. S.; Pizzolatti, M. G.; Brighente, I. M. C. Chemical Constituents and Evaluation of the Toxic and Antioxidant Activities of Averrhoa carambola leaves. Rev. Bras. Farmacogn. 2012, 22 (2), 319–324. Morton, J. F. Fruits of Warm Climates; Flair Books: Miami, FL, 1987; pp 125–128. Nandkarni, K. M. Indian Materia Medica, Vol. 1; Bombay Popular Prakashan: Mumbai, 1976; pp 165–166. Orwa, C.; Mutua, A.; Kindt, R.; Simons, A.; Jamnadass, R. H. Agroforestree Database: A Tree Reference and Selection Guide Version 4.0; World Agroforestry Centre (ICRAF): Nairobi, Kenya, 2009. Pal, A.; Chinnaiyan, S. K.; Gandhare, B.; Bhattacharjee, C. Anti-Diarrhoeal Activity of Leaves of Averrhoa carambola Linn. Int. J. Phytopharm. 2019a, 9 (2), e5208.

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Pal, A.; Chinnaiyan, S. K.; Mallik, A.; Bhattacharjee, C. Anti-Ulcer Activity of Leaves of Averrhoa carambola Linn. Int. J. Pharmc. Res. 2019b, 09 (05), e5209. Pang, D.; You, L.; Li, T.; Zhou, L.; Sun-Waterhouse, D.; Liu, R. H. Phenolic Profiles and Chemical- or Cell-Based Antioxidant Activities of Four Star Fruit (Averrhoa carambola) cultivars. RSC Adv. 2016, 6, 90646. Pham, H. T. T.; Huang, W.; Han, C.; Li, J.; Xie, Q.; Wei, J.; Xu, X.; Lai, Z.; Huang, X.; Huang, R.; Wen, Q. Effects of Averrhoa carambola L. (Oxalidaceae) Juice Mediated on Hyperglycemia, Hyperlipidemia, and Its Influence on Regulatory Protein Expression in the Injured Kidneys of Streptozotocin-Induced Diabetic Mice. Am. J. Transl. Res. 2017, 9 (1), 36–49. Phukan, S.; Ahmed, A. Evaluation of the Antimicrobial, Analgesic and Antioxidant Activity of Ethanolic Extract of the Leaves of Averrhoa Carambola. Int. J. Pharm. Sci. Res. 2016, 7 (4), 1716–1723. Poongodi, T.; Nazeema, T. H. In Vitro Cytotoxicity, Phytochemistry and GC-MS Analysis of Averrhoa carambola (Leaf) Against MCF-7 Breast Cancer Cell Line. Int. J. Curr. Res. 2016, 8 (04), 29044–29048. Qin, L.; Zhang, X.; Zhou, X.; Wu, X.; Huang, X.; Chen, M.; Wu, Y.; Lu, S.; Zhang, H.; Xu, X.; Wei, X.; Zhang, S.; Huang, R. Protective Effect of Benzoquinone Isolated from the Roots of Averrhoa carambola L. on Streptozotocin-Induced Diabetic Mice by Inhibiting the TLR4/NF-κB Signaling Pathway. Diab. Metab. Syndr. Obes. 2020, 13, 2129–2138. Ramadan, N. S.; Wessjohann, L. A.; Mocan, A.; Vodnar, D. C.; El-Sayed, N. H.; El-Toumy, S. A.; Mohamed, D. A.; Aziz, Z. A.; Ehrlich, A.; Farag, M. A. Nutrient and Sensory Metabolites Profiling of Averrhoa carambola L. (Star Fruit) in the Context of Its Origin and Ripening Stage by GC/MS and Chemometric Analysis. Molecules 2020, 25, 2423. Ray, P. K. Breeding Tropical and Sub-Tropical Fruits; Narosa Pub. House: New Delhi, 2002; pp 307–309. Ruvini, L.; Dissanayaka, W. M. M. M. K.; Chathuni, J.; Rizliya, V.; Swarna, W.; Barana, C. J. Effect of Different Drying Methods on Antioxidant Activity of Star Fruits (Averrhoa carambola L.). J. Nutr. Diet. Suppl. 2017, 1 (1), 101. Shah, A.; Raut, A. B.; Baheti, A.; Kuchekar, B. S. In Vitro Anthelmintic Activity of Leaf Extract of Averrhoa carambola Against Pheretima posthuma. Pharmacol. Online. 2011, 1, 524–527. Shahreen, S.; Banik, J.; Hafiz, A.; Rahman, S.; Zaman, A. T.; Shoyeb, M. A.; Chowdhury, M. H.; Rahmatullah, M. Antihyperglycemic Activities of Leaves of Three Edible Fruit Plants (Averrhoa carambola, Ficus hispida and Syzygium samarangense) of Bangladesh. Afr. J. Tradit. Complement. Altern. Med. 2012, 9 (2), 287–291. Sheth, A.; Ashok, K. The Herbs of Ayurveda, Vol. 1; Sheth Publisher, 2005; p 140. Shui, G.; Leong, L. P. Residue from Star Fruit as Valuable Source for Functional Food Ingredients and Antioxidant Nutraceuticals. Food Chem. 2006, 97, 277–284. Siddika, A.; Zahan, T.; Khatun, L.; Habib, M. R.; Aziz, M. A.; Tareq, A. R. M., Rahman, M. H.; Karim, M. R. In Vivo the Antioxidative Extract of Averrhoa carambola Linn. Leaves Induced Apoptosis in Ehrilch Ascites Carcinoma by Modulating p53 Expression. Food Sci. Biotechnol. 2020, 29 (9), 1251–1260. Silva, K. B.; Pinheiro, C. T. S.; Soares, C. R. M.; Souza, M. A.; Matos-Rocha, T. J.; Fonseca, S. A.; Pavão, J. M. S. J.; Costa, J. G.; Pires, L. L. S.; Santos, A. F. Phytochemical Characterization, Antioxidant Potential and Antimicrobial Activity of Averrhoa carambola L. (Oxalidaceae) Against Multiresistant Pathogens. Braz. J. Biol. 2021, 81 (3), 509–515.

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Singh, R.; Sharma, J.; Goyal, P. K. Prophylactic role of Averrhoa carambola (Star Fruit) Extract Against Chemically Induced Hepatocellular Carcinoma in Swiss Albino Mice. Adv. Pharmacol. Sci. 2014, 2014, 158936. Thomas, S.; Patil, D. A.; Patil, A. G.; Chandra, N. Pharmacognostic Evalution & Physiochemical Analysis of A.C L. Fruit. J. Herbal Med. Toxicol. 2008, 2 (2), 51–54. Tidbury, G. E. Averrhoa spp. -Carambola and Bilimbi. In The Propagation of Tropical Fruit Trees; Garner, R. J., Chaudhary, S. A., Eds.; FAO, CAB: London, 1976; pp 291–310. Tristantini, D.; Rahmi, A. Brine Shrimp Lethality Test of the Water Extract of Averrhoa carambola L. Leaves. Sriwijaya International Conference on Engineering, Science and Technology, Indonesia. 2016, 128–130. Vasant, R. A.; Narasimhacharya, A. V. R. L. Antidotal Activity of Averrhoa carambola (Star Fruit) on Fluoride Induced Toxicity in Rats. Interdiscip. Toxicol. 2014, 7 (2), 103–110. Warrier, P. K.; Nair, R. V. Indian Medicinal Plants: A Compendium of 500 Species; Orient Longman: Madras, 2002; p 224. Wen, Q.; Lin, X.; Liu, Y.; Xu, X.; Liang, T.; Zheng, N.; Kintoko, K.; Huang, R. Phenolic and Lignan Glycosides from the Butanol Extract of Averrhoa carambola L. Root. Molecules 2012, 17, 12330–12340. Wilson, C. W.; Shaw, P. E.; Knight, R. J.; Nagy, S.Jr.; Klim, M. Volatile Constituents of Carambola (Averrhoa carambola L.). J. Agric. Food Chem. 1985, 33, 199–201. Xu, X.; Liang, T.; Wen, W.; Lin, X.; Tang, J.; Zuo, Q.; Tao, L.; Xuan, F.; Huang, R. Protective Effects of Total Extracts of Averrhoa carambola L. (Oxalidaceae) Roots on StreptozotocinInduced Diabetic Mice. Cell Physiol. Biochem. 2014, 33, 1272–1282. Yang, D.; Jia, X.; Xie, H. Heptyl Vicianoside and Methyl Caramboside from Sour Star Fruit. Nat. Prod. Res. 2019, 33 (21), 1–4. Yang, D.; Xie, H.; Jia, X.; Wei, X. Flavonoid C-Glycosides from Star Fruit and Their Antioxidant Activity. J. Funct. Foods. 2015, 16, 204–210. Yang, D.; Xie, H.; Yang, B.; Wei, X. Two Tetrahydroisoquinoline Alkaloids from the Fruit of Averrhoa carambola. Phytochem. Lett. 2014, 7, 217–220. Yang, Y.; Xie, H.; Jiang, Y.; Wei, X. Flavan-3-ols and 2-Diglycosyloxybenzoates from the Leaves of Averrhoa carambola. Fitoterapia 2020a, 140, 104442. Yang, Y.; Jia, X.; Xie, H.; Wei, X. Dihydrochalcone C-Glycosides from Averrhoa carambola leaves. Phytochemistry 2020b, 174, 112364. Zhang, H.; Lu, S.; Chen, L.; Huang, X.; Jiang, L.; Li, Y.; Liao, P.; Wu, X.; Zhou, X.; Qin, L.; Wei, J.; Huang, R. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-Dione, Isolated from the Root of Averrhoa carambola L., Protects Against Diabetic Kidney Disease by Inhibiting TLR4/TGFβ Signaling Pathway. Int. Immunopharmacol. 2020, 80, 106–120. Zhang, H.; Wei, X.; Lu, S.; Lin, X.; Huang, J.; Chen, L.; Huang, X.; Jiang, L.; Li, Y.; Qin, L.; Wei, J.; Huang, R. Protective Effect of DMDD, Isolated from the Root of Averrhoa carambola L., on High Glucose Induced EMT in HK-2 Cells by Inhibiting the TLR4­ BAMBISmad2/3 Signaling Pathway. Biomed. Pharmacother. 2019, 113, 108705. Zheng, N.; Lin, X.; Wen, Q.; Kintoko; Zhang, S.; Huang, J.; Xu, X.; Huang, R. Effect of 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione, Isolated from Averrhoa carambola L. (Oxalidaceae) Roots, on Advanced Glycation End-Product-Mediated Renal Injury in Type 2 Diabetic KKAy Mice. Toxicol. Lett. 2021, 339, 88–96.

CHAPTER 67

Pharmacological and Phytochemical Review of a Vulnerable Medicinal Plant Embelia ribes Burm. f. VIDYA V. KAMBLE1, VISHWAS A. BAPAT2, and NIKHIL B. GAIKWAD1,* 1Department

of Botany, Shivaji University, Kolhapur, Maharashtra 416004, India

2Department

of Biotechnology, Shivaji University, Kolhapur, Maharashtra 416004, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Embelia ribes Burm. f., known as Vidanga or Vavding by Ayurvedic experts, is reported under Red listed species. E. ribes has been used from the ancient times as an important ingredient in number of Ayurvedic formulations. Around 75 traditional Ayurvedic drugs formulations are reported by using E. ribes. Embelin is the principal chemical compound present in berries of E. ribes and it is been included in the Indian Pharmacopoeia as an official drug in 1966. Along with embelin, embelinol, embeliaribyl ester, embeliol, and vilangin compounds were reported from the dry seeds of E. ribes. Embelin drug is obtained from matured berries of E. ribes. Th present chapter reviews the traditional uses, phytochemistry and pharmacology of E. ribes. 67.1 INTRODUCTION Embelia ribes Burm. f. known as Vidanga or Vavding by Ayurvedic experts and it is reported under Red listed species. It is a dioecious woody liana Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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belongs to family Primulaceae. It is mainly distributed in warmer regions of northern and southern hemisphere. E. ribes is Indo Malayan species. It is reported in India, Sri Lanka, Singapore, Malaysia, and South China. Nowa­ days it is confined to sacred groves, limited to a few leftover forest patches, and medicinal plant conservation areas established by Forest Department. National Medicinal Plant Board and the Maharashtra State Horticulture and Medicinal Plant Board reporting E. ribes under “Priority Species List” for cultivation (Mhaskar et al., 2011). From Tamil Nadu and Karnataka states from India, species are also reported to be vulnerable and at lower risk in Kerala state. It is Near Threatened-NT in Arunachal Pradesh and Data Deficient-DD in Assam, Meghalaya, Sikkim, and Maharashtra. At northern parts of Western Ghats, E. ribes is found on edges of fragmented evergreen and semievergreen forests (Ravikumar and Ved, 2000; Mhaskar et al., 2011). E. ribes Burm. f., has been used from the ancient times as an important ingredient in number of Ayurvedic formulations (Warrier et al., 2001). It is found to be used in Ayurvedic texts such as Sushurta Samhita, Ashtangahri­ dayam, and Charakh Samhita along with Unani, Siddha, homopathic system of medicine. Embelin is the principal chemical compound present in berries of E. ribes and it is been included in the Indian Pharmacopoeia as an official drug in 1966. Embelin drug is obtained from matured berries of E. ribes (Ved and Archana, 2006). E. ribes possess six different ayurvedic properties such as rasa (taste), guna (qualities), virya (torrid potency), vipaka, prabhava (special effect), and tridosha (Syed et al., 2011). Around 75 traditional Ayurvedic drugs formulations are reported by using E. ribes. Maturity and harvesting at proper time are also main features for the effectiveness of this herb. 67.2

PHYTOCHEMISTRY

The dry seeds of E. ribes are the industrially required main part of the plant. Since embelin, an active principle compound is present only in the berries of E. ribes (Hao et al., 2005). Along with embelin, embelinol, embeliaribyl ester, embeliol, and vilangin compounds were reported from the dry seeds of E. ribes (Biradar, 2010). From E. ribes, Johri et al. (1990) reported presence of potassium embelate. Presence of alkaloid, quercitol, christembine, fatty ingredients, tannins, aresinoid, and little quantity of volatile oil was reported by Ibrahim et al. (2010). There is presence of K, Cr, Cu, Ca, Mn, and Zn along with high carbohydrates (Indrayan et al., 2005). From ethanolic extract of E. ribes roots, number of compounds were isolated such as nitrogen-containing

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3-alkyl-1, 4-benzoquinone derivative, 4-benzoquinone, a gomphilactone derivative 5,6-dihydroxy-7-tridecyl-3-[4-tridecyl-3-hydroxy-5-oxo2(5H)furylidene]-2-oxo3(2H) –benzofuran and N-(3-carboxylpropyl)-5-amino2-hydroxy-3tridecyl-1 (Lin et al., 2006). Another nitrogen containing 3-alkyl-1, 4-benzoquinone, N-(3-carboxylpropyl)-5-amino-2-hydroxy3­ tridecyl-1,4-benzoquinone were reported from E. ribes using microwaveassisted extraction (McErlean and Moody, 2007). Extraction of embelin using microwave-assisted extraction was also carried out by Latha (2007) with 95% recovery of, here aromatic hydrotropes such as sodium cumene­ sulfonate (NaCS) and sodium n butyl benzene sulfonate (NaNBBS) were helpful for extraction from aqueous solution of hydrotropes elevated purity (Latha, 2006). It was found that nonpolar solvents such as dichloromethane and hexane were not effective for embelin extraction (Latha, 2007). Morphological, microscopic, physicochemical, and phytochemical screening of E. ribes fruits and powder has been studied (Sudani et al., 2011). FTIR analysis of different solvent extract of leaves, stem, and seeds of E. ribes have been investigated (Kamble and Gaikwad, 2016) and reported presence of different functional groups and its importance. Fluorescence study from leaves and stem powder of E. ribes was carried out where powder is treated with various chemical reagents was examined under visible and ultraviolet light have shown different fluorescence effect (Kamble and Gaikwad, 2019). 67.2.1 ACTIVE PRINCIPAL COMPOUND OF E. RIBES—EMBELIN The major active compound embelin (2,5-dihydroxy-3-undecyl-1,4-benzo­ quinone) found in the members of family Primulaceae especially in genus Embelia and Ardisia species. Similarly embelin was recorded from members of Primulaceae and Oxalidaceae (Lysimachia species and Oxalis erythrorhiz) (Podolak et al., 2005; Podolak and Strzałka, 2008; Feresin et al., 2003).

FIGURE 67.1

Structure of embelin.

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PHARMACOLOGY OF EMBELIN AND EMBELIN DERIVATIVES

E. ribes has been used in number of folk and traditional system of medicine. Its conventional use as medicine has lead to the scientific investigation for its potential to cure diseases (Harish et al., 2012). 67.3.1 ANALGESIC ACTIVITY Potassium embelate shown price binding in the synaptosomes of rat brain and reported no effect of naloxone and morphine (Johri et al., 1990). Potent analgesic activity was shown by embelin compared with pentazocine (Mahendran et al., 2011a, 2011b, 2014). 67.3.2 ANTIDIABETIC ACTIVITY Embelin derivative 6-bromoembelin and vilangin have importance in diabetes treatment (Durg et al., 2017). Embelin is reported to reduce plasma glucose and body mass in diabetic rats (Stalin et al., 2016). Embelin has shown normal lipid profiles in diabetic rats with significant increase in advent of PPAR in epididymal body fat. Embelin possess antidiabetic factor as it is clinically effective for the management of diabetes mellitus type 2 (Naik et al., 2013). Diabetic rats treated with embelin have shown regeneration of islet cells (Gupta et al., 2012). Embelin is helpful in adipose tissue responsive­ ness, improve glycemic control, protect beta-cell, and maintain glucose balance in adipose tissue (Gandhi et al., 2013). Wound healing property of embelin was observed in diabetic rats induced by STZ also effective in deletion, cutting and dead space models. Embelin cream and embelin oral administration reported enhanced outcome and increase of rate in wound curative with amplification of total protein, DNA, hydroxypoline, and hexosamine contents of the diabetic mouse (Deshmukh and Gupta, 2013). Embelin is report to hold significant antidiabetic effect by re-establishment of biochemical parameters changed by alloxan with regard to the normal (Mahendran et al., 2011a, 2011b). Sahu et al. (2013) reported the activity of embelin on lithium-induced nephrogenic diabetes insipidus in rats. From the above reports, embelin is proven to possess strong antidiabetic activity and act as a pontial molecule in the diabetes mellitus therapeutic approach and its worries.

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67.3.3 CARDIOPROTECTIVE ACTIVITY Substantial research work is done on cardioprotective effect of embelin. Heart injury was persuaded using isoproterenol (ISO) in male Albino rats, afterward the rats were medicated with embelin and reported to decrease the myocardial injury (Kocak et al., 2016). Pretreatment of embelin before inducing myocardial infarction has reduced mycocardial mitochondrial respiratory enzyme activity. Hence embelin is suggested to prevent ischemic heart diseases like myocardial infarction. It also increases antioxidant level and lipid peroxidase activity (Sahu et al., 2014). Embelin is effective in ISO-activated cardiac arrest in rats which resulted in decline in heart rate, hypertension, and improvement of concentration of serum lactate dehydrogenase, serum creatinine kinase, and cardiac lipid peroxides. There was also increase in myocardial endogenous antioxidant (Rajakumar and Shivanna, 2009; Chen et al., 2015). Embelin is found to be protective on myocardial ischemia injury in a rabbit (Zhao et al., 2015). From all the above results it is clear that embelin is protective against myocardial necrosis in rats, inhibits free radical production, and also increases activity of detoxifying enzymes like glutathione (GSH)-S-transferase in vivo. 67.3.4 ANTIHYPERGLYCEMIC ACTIVITY E. ribes aqueous extract produces significant decrease in heart rate, blood glucose, systolic blood pressure, serum lactate dehydrogenase, blood glyco­ sylated hemoglobin, creatine kinase, and enhancement in bloodGSH levels. Aqueous and ethanolic extract of E. ribes proved to be potent in lowering blood glucose and blood pressure with increase in endogenous antioxidant activity against free radicals produced under hyperglycemic conditions (Bhandari et al., 2007; Bhandari and Ansari, 2008a, 2008b). 67.3.5 NEUROPROTECTIVE ACTIVITY Water extract of E. ribes is reported to improve cerebral ischemia/reperfu­ sion damage and enhancement in the antioxidant activity against middle cerebral artery occlusion persuaded cerebral infarction in rats, thus appre­ ciably escalating poststroke grip strength activity. It also reverses the level of thiobarbituric acid reactive substances (TBARSs) and enhances GSH, glutathione reductase, GSH peroxidase, and GSH-S-transferase (Bhandari and Ansari, 2008b).

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Ethanolic extract of E. ribes is reported to decrease the amount of LDH, homocysteine, triglycerides, total cholesterol, in serum, and lipid peroxides (LPO) quantity in brain homogenates of significant increase in serum HDL-C intensity and GSH volume in brain homogenates methionine lead to hyperhomocysteinemic rats. There was also significant increase in serum HDL-C levels and GSH content with respect to pathogenic control rats. Histopathological examination of nerve cells in methionine-medicated rats shown degenerative change and these changes were reduced to usual morphology by E. ribes ethanolic extracts (Ansari and Bhandari, 2008b). Middle cerebral artery blockage induced focal ischemia stroke in rats was improved treating with E. ribes ethanolic extract with enhanced antioxidant function (Ansari et al., 2008a, 2008b). 67.3.6 HEPATOPROTECTIVE ACTIVITY E. ribes is also reported to be useful in treatment of jaundice. Number of Ayurvedic formulations have E. ribes as a basic constituent. Ethanolic extract effect of E. ribes was studied on paracetamol-induced liver cell damage in mice. Dose-dependent fall in the serum glutamate pyruvate transaminase levels was observed. The histopathology of liver has shown normal liver of mice treated with alcoholic extract of E. ribes with dose-dependant manner. Therefore, the ethyl alcohol extract of E. ribes has liver damage protecting activity against paracetamol-induced severe hepatocellular damage in mice (Tabassum and Agrawal, 2003). 67.3.7 ANTITUMOR ACTIVITY A chemopreventive effect of embelin was studied against N-nitrosodiethyl­ amine/Phenobarbital-generate liver cancer in Wistar rats. It was reported that embelin was able to avert induction of liver hyperplastic nodules, increase in the amount of hepatic diagnostic markers, weight loss, and low level of proteins in blood (Sreepriya and Bali, 2005). In an experimental trial, reduc­ tion in the values of total hexose and hexosamine to near normal in plasma, liver, and kidney of tumor-bearing rats deal with embelin on carbohydrate moieties of glycoprotein, thus indicating the antitumor activity of embelin (Sukumar et al., 2004). In an experimental trial, reduction in the values of total hexose and hexosamine to near normal in plasma, liver, and kidney of tumor-bearing rats treated with embelin on carbohydrate moieties of glycoprotein, thus

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indicating the antitumor activity of embelin (Sukumar et al., 2004). Total breakup of the microtubule association, increase in number of cells occluded in mitotic phase and apoptosis was observed in HL-60 cells when treated with 1, 4-benzoquinone derivatives 5-O-ethylembelin and 5-O-methylembelin. Thus 1, 4-benzoquinone derivatives 5-O-ethylembelin and 5-O-methylem­ belin proven to be the mitotic inhibitor and cancer-preventing molecules targeting microtubular proteins (Xu et al., 2005). Embelin is reported to be an inhibitor of XIAP through computational structure-based database screening (Chen et al., 2006). Effect of embelin demonstrates anticancer, anti-inflammatory, and apop­ totic actions (Dharmapatni et al., 2015). It was reported that embelin is able to inhibit tumor necrosis factor, alpha-induced NF-kappaB activation, the TNF - originate enabling of the repression of subunit of NF-kappaB kinase, IkappaB phosphorylation, IkappaB degradation, p65 phosphorylation, nuclear translocation. It also shows suppression of NF-kappa B-dependent reporter gene transcription, TNF receptor-1, TNFR1-correlated death domain protein, TNFR-related factor-2, NF-kappa B inducing kinase, and Ikappa B kinase. Embelin downregulate gene products that were responsible in cell continuation, multiplication, invasion, and spread of the tumor along with increase in programmed cell death by cytokine and chemotherapeutic compounds. Also there was suppression of NF-kappaB activated by diverse stimuli (Ahn et al., 2007). Chemical carcinogen-persuded colon carcinogenesis is partly reliant on the existence of efficient PPARgamma, which has been inhibited by embelin. It has been reported that embelin inhibit spreading and persuaded apoptosis in HCT116 cells with distinct upregulation of PPARgamma. It significantly inhibited expressions of survivin, cyclin D1, and c-Myc, which were moder­ ately depending on PPARgamma. There was reduction in incidence of colon cancer, noticed in PPARgamma ( + / + ) mice; however, not in PPARgamma ( + /−) mice and also responsible for inhibition of NF-kappaB action in PPARgamma ( + / + ) mice but slightly in PPARgamma ( + /−) mice (Dai et al., 2009) Prostate cancer cells were tested against bicalutamide and embelin under in vitro and in vivo and it was found that embelin found to be more lethal than bicalutamide in the prostate tumor cells. It was observed that amalgamation of bicalutamide and embelin was synergic for C4-2. But it was found to be slightly antagonistic for LNCaP cells (Danquah et al., 2009). Against glioblastoma cells and human astrocytes tumor necrosis factor-related apoptosis-promoting ligand (TRAIL) was tested with embelin.

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Embelin largely changed malignant glioma cells to TRAIL-bring about programmed cell death. In combination, there was activation of initiator caspases-8/-9 and effector caspases-3/-7. Embelin alone downregulated expression of long- and short-isoform of c-FLIP and enforced appearance of short isoform of c-FLIP attenuated apoptosis (Siegelin et al., 2009). Dai et al. (2011) reported the role of IAP inhibitor embelin in improve­ ment of restorative efficiency of ionizing radiation in prostate cancer. Embelin is reported to stop osteoclastogenesis stimulated by receptor activator of NF-B ligand and tumor cells in vitro during slowdown of the NF-B cell signaling pathway (Reuter et al., 2010). Embelin is reported to be antidepressant in chronic unpredictable stress-induced mice (Wang et al., 2018). Embelin is also known for its anti-tumor activity in gastric cancer cells (Wang et al., 2014). Embelin is reported to decrease systemic swelling and improve organ damage in rats (Zhou et al., 2015). 67.3.8 ANTIOXIDANT ACTIVITY Embelin obtained from the E. ribes is known to trap DPPH radical and reduce hydroxyl radical stimulated deoxyribose degeneration. Embelin is studied using nanosecond pulse radiolysis method with reference to its kinetics and method of the reactions with hydroxyl, one-electron oxidizing, organohaloperoxyl, and thiyl radicals (Joshi et al., 2007). Ethanolic extract of berries showed 69.07 ± 0.71% inhibition by DPPH activity along with 398 ± 2.16 mMFe + 2/g FRAP activity (Shadma and Naheed, 2014). Similarly, DPPH inhibition with 71.67 ± 0.81% and FRAP activity showing 422 ± 2.15 mMFe + 2/g is reported (Neelam et al., 2011). Naraporn and Varipat (2009) have revealed 60.75 ± 0.16 Acs AE/g dry basis FRAP activity from E. ribes leaves. Kamble and Gaikwad (2019) from E. ribes ethanolic extract of stem reported highest antioxidant activity toward DPPH (84.86 ± 0.11%) while in stem highest FRAP activity (72.22 ± 0.31 mg Fe + 2E/g DW) was observed in methanolic extract. Maximum DPPH (67.48 ± 0.17%) radical scavenging activity and FRAP activity (66.73 ± 0.60 mg Fe(II)/g DW) were reported in berries from ethanolic and methanolic extracts (Kamble et al., 2020). 67.3.9 WOUND HEALING ACTIVITY Injury recovery action by cutting, removal, and dead space wound models Swiss Albino Rats was studied by using ethyl alcohol extracts of leaves and

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berries of E. ribes. There was considerable injury recovery activity reported in both ethanol extract of the leaves and berries. The recovery of injury rate was increased due to rapid epithelialization of the incision injury in embelin dealt groups. In absence of monocytes, granulation tissue of embelin deliv­ ered group has revealed increased cross-linking of collagen fiber through histological studies (Kumara et al., 2012). 67.3.10 ACETYLCHOLINESTERASE ACTIVITY Alzheimer’s disorder resulted due to defective of cholinergic neurotrans­ mission in the brain. For application of cholinesterase inhibitors is general practice in Alzheimer’s disorder therapy, since loss of cholinergic cells result in the loss of neurotransmitter acetylcholine especially in the basal part of the brain. The clinical potency of cholinesterase inhibitors is the product of extended half-life of acetylcholine during inhibition of AChE. The half-life of acetylcholine inhibition of methanolic extract of E. ribes root proves the authenticated conventional use of E. ribes for improvement of cognition (Vinutha et al., 2007). 67.3.11 ANTIFERTILITY ACTIVITY Histological observations of in vivo and in vitro therapy of embelin in male albino rats have shown morphological changes in spermatozoa, displaying the antispermatogenic effect (Gupta et al., 1989; Gupta and Sharma 2006). Embelin is reported to suppress ovarian productivity of sex steroid hormones by interfering with progenitive role in female rats (Wango, 2005). Embelin is one of the components of pippaliyadi yoga or pippaliyadivati an ayurvedic birth control medicine used in India since ancient times. Decrease in body mass of pups was observed with increase in dose, while with low dose adverse effects were not reported. In utero exposure to pippaliyadi do not show any unfavorable outcome on the postnatal growth and generative performance of the F1 progeny (Balasinor et al., 2007). 67.3.12 ANTIBACTERIAL ACTIVITY Embelin obtained from the berries of E. ribes reported considerable inhibition of Gram positive (Staphylococcus aureus and Staphylococcus

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pyogenes) and Gram negative (Shigella flexneri, Shigella sonnei, and Pseudomonas aeruginosa) bacteria and average activity against Gramnegative bacteria (Salmonella typhi, Shigella boydii, and Proteus mirabilis) by Chitra et al., (2003). E. ribes methanolic and water extracts possess average antibacterial activity against multi-drug resistant S. typhi (Rani and Khullar, 2004). 67.3.13 ANTHELMINTIC ACTIVITY Berries of E. ribes is known for its anthelmintic activity. E. ribes seed oil of was used in the treatment against Pheritima posthuma. Compared with Mucuna pruriensi, Celastrus paniculata, Impatiens balsamina, and Gynan­ dropsis gynandra. Embelia oil has shown moderate to significant anthel­ mintic activity (Jalalpure et al., 2007). Ethanolic extract of E. ribes berries has shown 93% of anthelmintic efficacy against gastrointestinal nematodal larvae Haemonchus contortus (Hordegen et al., 2006). 67.3.14 TOXICITY STUDIES Low birth weights of fetuses and smaller length were observed during utili­ zation of an ayurvedic birth control pippaliyadivati which shows toxicity of embryo and teratogenicity in fetus and deformaties of soft tissues and skel­ etons were investigated. Herniation was observed in intestines into umbilical cord in fetuses of mothers (Chaudhury et al., 2001). 67.3.15 LIPID PEROXIDATION Embelin was tested for hepatic antioxidant capacity in CCl4-treated rats. There was minimal damage observed in both liver and serum. Therefore embelin acts as normal antioxidant beside liver damage induced in rats (Singh et al., 2009). The water extract of E. ribes berries augments anti­ oxidant protection against methionine persuaded hyperhomocysteinemia, hyperlipidaemia, and oxidative stress in brain. It also reduced LPO levels by increasing GSH content in hyperhomocysteinimic rats (Bhandari et al., 2008). Alcoholic extract of E. ribes berries have revealed antihyperhomocyste­ inemic and lipid-lowering ability in hyperhomocysteinemic rats (Ansari and

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Bhandari, 2008a). In rats, when diabetes was induced by streptozotocin, etha­ nolic extract of E. ribes berries have shown lipid-lowering and antioxidant potential to overcome this and reported to reduce the hepatic and pancreas TBARSs thus proves the diabetic elevated cholesterol of E. ribes (Bhandari et al., 2002). Water extract of E. ribes was equated with Tinospora cordifolia and Cyperus rotundus on hyperlipidaemic rats (Pande et al., 2006). Embelin decreases adipogenesis and lipogenesis and inhibits high-fat-diet-induced obesity (Gao et al., 2017). 67.3.16 HPLC ANALYSIS Embelin estimation from E. tsjeramcottam and E. ribes was carried out with 3.96% and 4.33% of embelin content (Sudhakar et al., 2005; Raja et al., 2005). Variation in phenolic content was analyzed between diverse samples of E. ribes (Sharadha et al., 2009). On the basis of solvent used for embelin extraction, variability in embelin quantity was reported and recovery was maximum in polar solvents contrast to nonpolar (Latha, 2007). Nagamani et al., (2013) estimated embelin content by HPLC from different accessions from Western Ghats of India and reported highest content from Kerala accession. Quantification of embelin using several extraction techniques was studied by HPLC analysis and highest embelin content of 5.08% was reported in microwave-assisted extraction (Kamble et al., 2020). Speedy and precise HPTLC method was recognized for quantitative detection of embelin from five different Embelia species (Vijayan and Raghu, 2021). KEYWORDS • • • • •

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Dai, Y.; Desano, J.; Qu, Y.; Tang, W.; Meng, Y.; Lawrence, T. S.; Xu, L. Natural IAP Inhibitor Embelin Enhances Therapeutic Efficacy of Ionizing Radiation in Prostate Cancer. Am. J. Cancer Res. 2011, 1 (2), 128–143. Dai, Y.; Qiao, L.; Chan, K. W.; Yang, M.; Ye, J.; Ma, J.; Zou, B.; Gu, Q.; Wang, J.; Pang, R.; Lan, Y.; Wong, B. Peroxisome Proliferator Activated Receptor-Gamma Contributes to the Inhibitory Effects of Embelin on Colon Carcinogenesis. Cancer Res. 2009, 69 (11), 4776–4783. Danquah, M.; Li, F.; Duke, C.B 3rd.; Miller, D. D.; Mahato, R. I. Micellar Delivery of Bicalutamide and Embelin for Treating Prostate Cancer. Pharm. Res. 2009, 26 (9), 2081–2092. Deshmukh, P. T.; Gupta, V. B. Embelin Accelerates Cutaneous Wound Healing in Diabetic Rats. J. Asian Nat. Prod. Res. 2013, 15 (2), 158–165. Dharmapatni, A. A.; Cantley, M. D.; Marino, V.; Perilli, E.; Crotti, T. N.; Smith, M. D.; Haynes, D. The X-Linked Inhibitor of Apoptosis Protein Inhibitor Embelin Suppresses Inflammation and Bone Erosion in Collagen Antibody Induced Arthritis Mice. Mediators Inflamm. 2015, 640 (42), 1–10. Durg, S.; B, N. K.; Vandal, R.; Dhadde, S. B.; Thippesamy, B. S.; Veerapur, V. P.; Shrishailappa, B. Antipsychotic Activity of Embelin Isolated from Embelia ribes: A Preliminary Study. Biomed. Pharmacother. 2017, 90, 328–331. Feresin, G. E.; Tapia, A.; Sortino, M.; Zacchino, S.; Rojas, de.A. A.; Inchausti, A.; Yaluff, G.; Rodriguez, J.; Theoduloz, C.; Schmeda-Hirschmann, G. Bioactive alkyl Phenols and Embelin from Oxalis erythrorhiza. J. Ethnopharmacol. 2003, 88, 241–247. Gandhi, G. R.; Stalin, A.; Balakrishna, K.; Ignacimuthu, S.; Paulraj, M. G.; Vishal, R. Insulin Sensitization Via Partial Agonism of PPAR-γ and Glucose Uptake Through Translocation and Activation of GLUT4 in P13K/p-Akt Signaling Pathway by Embelin in Type 2 Diabetic Rats. Biochim. Biophys. Acta 2013, 1830 (1), 2243–2255. Gao, Y.; Li, J.; Xu, X.; Wang, S.; Yang, Y.; Zhou, J.; Zhang, L.; Zheng, F.; Li, X.; Wang, B. Embelin Attenuates Adipogenesis and Lipogenesis Through Activating Canonical Wnt Signaling and Inhibits High-Fat-Diet-Induced Obesity. Int. J. Obes. 2017, 41 (5), 729–738. Gupta, R. S.; Sharma, R. A Review on Medicinal Plants Exhibiting Antifertility Activity in Males. Nat. Prod. Radiance 2006, 5 (5), 389–410. Gupta, R.; Sharma, A. K.; Sharma, M. C.; Gupta, R. S. Antioxidant Activity and Protection of Pancreatic β-Cells by Embelin in Streptozocin-Induced Diabetes. J. Diab. 2012, 4 (3), 248–256 Gupta, S.; Sanyal, S. N.; Kanwar, U. Antispermatogenic Effect of Embelin, a Plant Benzoquinone, on Male Albino Rats In Vivo and In Vitro. Contraception 1989, 39 (3), 307–320. Hao, K.; Ali, M.; Siddiqui, A. W. New Compounds from the Seeds of Embelia ribes Burm. Pharmazie.2005, 60, 69–71. Harish, G. U.; Vijay, D.; Renuka, J.; Villoo, M. P. Endangered medicinal plant Embelia ribes Burm.f.—A Review. Pharmacogn. J. 2012, 4 (27), 6–19. Hordegen, P.; Cabaret, J.; Hertzberg, H.; Langhans, W.; Maurer,V. In vitro screening of six anthelmintic plant products against larval Haemonchus contortus with a modified methyl­ thiazolyl-tetrazolium reduction assay. J. Ethnopharmacol. 2006, 108(1), 85–89. Ibrahim, K. M.; Afzal, A.; Akram, M.; Mohiuddin, E.; Khan, U.; Sultan, A.; Ali, S.S M.; Asif, M.; Ghazala, S.; Khalil, A.; Riaz, U. R. Monograph of Embelia ribes. Afr. J. Plant Sci. 2010, 4 (12), 503–505.

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CHAPTER 68

Bioactives and Pharmacology of Tamarix aphylla (L.) Karst. CHAUDHARY HIRAL, NAINESH R. MODI*, AND DESAI KRISHNA Department of Botany, Bioinformatics and Climate Change Impacts Management, Gujarat University, Ahmedabad, Gujarat 380009, India. *Corresponding

author. E-mail: [email protected]

ABSTRACT Tamarix aphylla is a halophytic, perennial plant belonging to Tamaricaceae family. It is used as folk medicine to treat various diseases including hepa­ titis, small pox and other skin ailments by local tribes. Biological active substances of the plant such as alkaloids, flavonoids, terpenoids, polyphenols and tannins have received great attention due to its remarkable medicinal properties. Thus, the current chapter mainly focuses on phytochemistry and bioactive profiling of T. aphylla with its potent pharmacological activities. Moreover, the structure diversity of various compounds found in whole plant is described below with its antimicrobial, anticancer, anti-diabetic, anti-inflammatory activities. 68.1 INTRODUCTION Tamarix aphylla (L.) Karst. is a halophytic, evergreen plant of Tamaricaceae family. It can withstand a wide range of environmental condition and salt induced oxidative stress due to development of antioxidant molecule such as phenolic acids and flavonoids (Mahfoudhi et al., 2014). Synonyms of the plant include Thuja aphylla L., Tamarix articulata Vahl., and T. orientalis Forsk. It is also known as Ghaz, Tarfa, Abal (Ali et al., 2019), Athel tamarisk and saltcedar (Orabi et al., 2011). It is a perennial tree or shrub, up to 18 m Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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in height with 3 mm long leaves (Ullah et al., 2017). Flowers are bisexual, pinkish in colour with white pedicel, sepals are free, broad, ovate to elliptic and obtuse, petals are also free and trigonous capsule with raceme inflores­ cence (Ali et al., 2019). Tamarix aphylla has remarkable medicinal properties and grows in temperate and subtropical regions (Ali et al., 2019). Tamarix aphylla is also used as folk medicine such as anti-inflammatory, carmina­ tive, analgesic, antipyretic, antimicrobial, antifungal, diuretic, antioxidant, antihemorrhoid, aphrodisiac, anthelmintic, gingivitis and other skin disease (Ullah et al., 2017; Ali et al., 2019). It is also used for handling internal haematomas, tuberculosis, leprosy, smallpox, aphrodisiac, hepatitis, ezema and other skin ailment (Azaizeh et al., 2006; Ullah et al., 2017). It plays important role in cardio-protective effect in doxorubicin induced cardiotox­ icity (Ullah et al., 2017). This review focuses on the bioactive compounds of T. aphylla and its pharmacological activity. 68.2

BIOACTIVES

Phytochemical analysis revealed the presence of various chemical compounds. Tamarix aphylla showed the presence of flavonoid, terpenoids, glycoside, steroid, carboxylic acid, and cardiac glycoside (Ullah et al., 2017). In previous studies alkaloids, anthraquinones and saponins were absent in all extracts of T. aphylla (Mohammedi and Atik, 2011). The presence of alka­ loids and saponins was conformed in the subsequent studies on T. aphylla (Ali et al., 2019). Previous researches were focused on gallic acid, ellagic acid, ellagitannins and flavonoids from galls, floral parts and barks (Bolous, 1999). Polyphenol compounds are major phytoconstituents found as a gallic acid, isoferulic acid, ellegic acid, juglanin and dehydrodigallic acids in the different parts including bark (Ali et al., 2019). In this plant, 14 phenolic compounds were identified for the first time using HPLC-UV/DAD, MS2, and HPLC-ESI-MS with an ion trap mass analyzer and (Mahfoudhi et al., 2014). The total amount of phenolic in the leaves was 993.1 ± 22.5 g/g, while in the stem phenolic amount was 113.1 ± 25.8 g/g (Mahfoudhi et al., 2014). Gallic acid (120.6 ± 1.2 g/g), quercetin (125.7 ± 4.7 g/g) and ellagic acid (211.4 ± 10.8 g/g), were the most abundant constituents in the leaves, while the kaempferol (16.3 ± 1.6 g/g), gallic acid (24.3 ± 3.3) and ellagic acid (44.4 ± 3.9 g/g) were present in the stem (Mahfoudhi et al., 2014). The tamarixetin 3, 3’-disodium sulfate and glycosylated isoferulic acid were isolated from flowers of T. aphylla (Nawwar et al., 2009). Flavo­ noids of galls are present as a quercetin and its glycoside, isoquercitrin, and

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methyl derivatives tamarixin and tamarixetin (Ali et al., 2019). Galls are astringent in nature because the presence of tannins and major proportion of hydrolysable tannins used as aphrodisiac (Ali et al., 2019)). Alrumman (2016) reported ten different chemical compounds from hexane extracts of fresh and dry leaf by GC-MS analysis where propenoic acid (28.99%) and β-D-mannofuranose (23.04) were in significant amount. The GC-MS analysis of the hexane extracts of Tamarix aphylla leaves revealed the pres­ ence of ten different chemical compounds (Pejin et al., 2015). The results showed various biological activities such as anticancer activity found in Asarone derivatives for example β-asarone, and phytols were found to have antiradical activity. The antiradical activity using electron paramagnetic resonance toward hydroxyl radical (OH), superoxide anion radical, carbon dioxide anion radical, methoxy radical, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide radical (NO) (Pejin et al., 2015).

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Tamarix aphylla (L.) Karst.

FIGURE 68.1

68.3

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Structure of bioactive compounds found in Tamarix aphylla.

PHARMACOLOGICAL ACTIVITIES

68.3.1 ANTIBACTERIAL ACTIVITY Tamarix aphylla has antibacterial properties against various bacterial strains. Alrumman (2016) examined the great antimicrobial potential of Tamarix aphylla fresh and dry leaves using polar and non-polar solvent extraction method against eight clinical isolates of bacteria. The results suggested that hot water extract showed 75% activities against the microbes, while the cold water extract has no effect (Alrumman, 2016). The dry and fresh leaves extracts of T. aphylla in various solvents such as methanol, acetone, chloro­ form, petroleum ether and diethyl ether showed 100% lethal effects against all the pathogenic microbes tested (Alrumman, 2016). The methanolic extract against Proteus mirabilis, petroleum ether extract against Candida species and diethyl ether a standard antibiotic drug against Klebsiella oxytoca has significant results (Alrumman, 2016). The alkaloids and flavonoids of T. aphylla leaves showed antimicrobial activities on four different bacterial strains (Adnan et al., 2015). The alkaloid has highest inhibition against S. aureus (14 ± 0.6 mm) followed by P. aeruginosa (13 ± 0.7 mm) and S. typhi

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(12 ± 2 mm) whereas, lowest inhibition in E. coli (7 ± 2 mm) (Adnan et al., 2015). In the case of flavonoids, highest inhibition against S. typhi (17 ± 0.7 mm) followed by S. aureus bacterial strain (14 ± 0.7 mm) (Adnan et al., 2015). The P. aeruginosa also showed significant inhibition zone (13 ± 0.33 mm) against flavonoids (Adnan et al., 2015). Like alkaloids, the flavonoid has less activity against E. coli bacterium (Adnan et al., 2015). 68.3.2 ANTIFUNGAL ACTIVITY Antifungal activities of stem-bark extract were performed in five solvent, methanol, ethanol, chloroform, distilled water and acetone (Bibi et al., 2015). Tamarix aphylla crude ethanolic extracts tested against six pathogenic fungi, namely Aspergillus flavus, A. fumigatus, A. niger, Penicillium notatum, Fusarium oxysporum, and Saccharomyces cerevisiae in different organic solvents according to polarity order constituent’s affinities (Ali et al., 2019). Fungal growth inhibition was reported when compared to Terbinafine, which is standard antifungal synthetic drug (Bibi et al., 2015). Terbinafine was used in various concentrations and mixed with distilled water against different fungi (Ali et al., 2015). Among all the solvents, chloroform was proved to be most significant solvent which inhibits 9.37 ± 0.33% growth in A. niger, 87.95 ± 1.15% in P. notatum, 88.48 ± 0.88% in A. flavus, 97.68 ± 0.58% in F. oxysporum, 91.46 ± 2.08% in A. fumigatus, and 92.68 ± 3.33% in S. cerevisiae (Bibi et al., 2015). The chloroform extract had the highest inhibi­ tion percentage followed by ethanol, acetone, methanol and distilled water extracts (Bibi et al., 2015). 68.3.3 ANTIOXIDANT ACTIVITY Preliminary screening of T. aphylla leaves extract in ethyl acetate showed the presence of alkaloids, saponins, flavonoids and tannins whereas steroids and triterpenoids were absent (Al-Othman et al., 2015). Total phenolic content of the ethyl acetate extract was measured using a spectrophotometric method (Ali et al., 2015). The result suggested that maximum phenol content was 39.3 mg gallic acid/g dry extract (Al-Othman et al., 2015). The antioxidant activity is determined by effect of phenolic compound on radical DPPH (Al-Othman et al., 2015). The DPPH antioxidant assay evaluated at 1, 5, 10, 15, 20 and 25 mg/mL concentration of T. aphylla extracts corresponded to 22.1%, 31.4%, 39.2%, 53.5%, 60.0% and 63.3% scavenging activities

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respectively (Al-Othman et al., 2015). However, at the same concentrations of ascorbic acid, scavenging activities 33.1%, 46.2%, 51.6%, 67.3%, and 72.2% were observed (Al-Othman et al., 2015). IC50 value of T. aphylla was found to be 14.0 mg/mL whereas 9.0 mg/mL for ascorbic acid which is the sample quantity required reducing DPPH free radicle absorption by 50% (AL-Othman et al., 2015). Thus relative ascorbic acid, plant extract has the highest IC50 quality (Al-Othman, et al., 2015). 68.3.4 ANTI-DIABETIC AND HYPOLIPEDEMIC ACTIVITY The anti-diabetic potential was evaluated from the methanolic extracts of T. aphylla leaves. In one group of rat model streptozotocin (STZ) admin­ istrations induce the hyperglycaemic state and later on to compare with the normal control (Ali et al., 2019). The antihyperglycemic effect of the extract was probably due to the presence of tannins, flavonoids and phenolic components in the leaves of T. aphylla (Ali et al., 2019). The presence of flavonoids, terpenoids and coumarins along with other metabolic is known to be probable causes of a plant to be an antidiabitic (Ali et al., 2019). Hebi and Eddouks (2017) suggested that antihyperglycemic activity along with the antioxidant potential showed significant results when compared with the standard antidiabetic drug glibenclamide. The hypolipedemic effect was studied using the aqueous extract of aerial parts of Tamarix aphylla (Hebi and Eddouks, 2017). Male Wistar rats were orally administered the extract dose as per (5 mg/mL) body weight (Hebi and Eddouks, 2017). The results indicated that the lowering in serum total cholesterol level and triglycerides level, while high-density lipoprotein cholesterol (HDL-c) was raised (Hebi and Eddouks, 2017). These results were obtained from normal and STZinduced diabetic rat groups (Hebi and Eddouks, 2017). 68.3.5 ANTICANCER ACTIVITY Apoptosis is mediated by up-regulation of Caspases, a class of cysteine proteins that cleaves hundreds of proteins (El-Aarag et al., 2019). The anti­ apoptotic Bcl-2 protein inhibits apoptosis through the proapoptotic protein Bax inhibition (El-Aarag et al., 2019). El-Aarag et al., (2019) studied the significant effect of 3, 5-dihydroxy-4, 7-dimethoxyflavone which is isolated from the T. aphylla and tested against liver injury in mice (El-Aarag et al., 2019). The administration of carbon tetrachloride (CCl4) induced liver injury

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in mice by causing the histopathological changes in liver tissue (El-Aarag et al., 2019). The liver damages were reduced after pre-treatment along with flavone at dose 10 and 25 mg/kg (El-Aarag et al., 2019). It also decrease the hepatic malondialdehyde (MDA) level in liver and increased catalase activities (CAT), liver superoxide dismutase (SOD) and glutathione peroxi­ dase (Gpx) compared with their CCl4 model group (El-Aarag et al., 2019). The flavone treatment enhanced the level of B-cell lymphoma-2 (Bcl-2) protein level, while it supressed the level of cysteine-aspartic acid protease-3 (Caspase-3), transforming growth factor-β1 (TGF-β1), Bcl-2 associated x protein (Bax), and CD31 the immunohistochemical screening (El-Aarag et al., 2019). The findings revealed that flavone can prevent liver injury in mice by affecting apoptotic, angiogenesis and oxidation mechanisms (El-Aarag et al., 2019). Alhourani et al. (2018) studied the aqueous and ethanol extract against human MCF-7(breast adenocarcinoma), Caco-2 (Colorectal adenocarci­ noma), and Panc-1 (pancreatic carcinoma) cancer cell line as well as fibro­ blasts of normal human for in vitro screening of anti-proliferative properties of T. aphylla. The result indicated that significant effects were observed against MCF-7 cells with IC50 value 2.17 ± 0.10 and 26.65 ± 3.09 µg/mL for aqueous and ethanol extract respectively (Alhourani et al., 2018). Moreover, aqueous extract of T. aphylla had a comparable cytotoxic effect to cisplatin drug (IC50 value of 1.17 ± 0.13 µg/mL); despite having higher safety against fibroblast cells (Alhourani et al., 2018). The results suggested that Tamarix aphylla could be a significant source for cytotoxic agent with higher safety profile (Alhourani et al., 2018). 68.3.6 ANTI-INFLAMMATORY, ANTIPYRETIC AND WOUND HEALING EFFECT Inflammation is a universal defence mechanism in host which is regulated by large number of inflammatory mediators (Abo-Dola et al., 2015). The anti-inflammatory assay of T. aphylla ethanolic extract was evaluated using rat by carrageenan- induced paw formalin edema method (Abo-Dola et al., 2015). Wound healing efficiency also studied by the tissue excision method (Abo-Dola et al., 2015). The study was proving the plant extracts and its gel formulation having anti-inflammatory and wound healing properties (AboDola et al., 2015). The ethanolic extract of T. aphylla at a dose of 200 mg/ kg showed highest EI% after 4 h of oral dosing of the extract suspended

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in distilled water (Abo-Dola et al., 2015). Abo-Dola et al. (2015) observed that plant extract at a dose of 200 and 100 mg/kg inhibited granuloma tissue formation by 71.86% and 67.05% respectively. It also reduced the rat’s body temperature and increase the response time in rat compared to acetylsalicylic acid (Abo-Dola et al., 2015). The anti-inflammatory and analgesic effects of T. aphylla because the presence of saponins, steroids and triterpenoids and antipyretic activity and membrane stabilizing ability due to saponins (AboDola et al., 2015). It also showed that heat or hypotonic solution inhibited RBCs haemolysis compared to acetylsalicylic acid and also indicates the ability of membrane stabilization (Abo-Dola et al., 2015). KEYWORDS • • • • • •

Tamarix aphylla bioactive compound phytochemistry antimicrobial anticancer antidiabetic

REFERENCES Abo-Dola, M. A.; Lutfi, M. F.; Bakhiet, A. O.; Mohamed, A. H. Anti-Inflammatory, Analgesic, Antipyretic and the Membrane-Stabilizing Effects of Tamarix aphylla Ethanolic Extract. Eur. J. Med. Plants 2015, 5 (4), 341–348. Adnan, M.; Tariq, A.; Bibi, R.; Abd-Elsalam, N. M.; Rehman, H.; Murad, W.; Aziz, M. A. Antimicrobial Potential of Alkaloids and Flavonoids Extracted from Tamatrix aphylla Leaves Against Common Human Pathogenic Bacteria. Afr. J. Tradit. Complem. Altern. Med. 2015, 12 (2), 27–31. Alhourani, N.; Kasabri, V.; Bustanji, Y.; Abbassi, R.; Hudaib, M. Potential Antiproliferative Activity and Evaluation of Essential Oil Composition of the Aerial Parts of Tamarix aphylla (L.) H. Karst.: A Wild Grown Medicinal Plant in Jordan. Evidence-Based Complem. Altern. Medicine, 2018, 2018, 1–7. Ali, M.; Alhazmi, H. A.; Ansari, S. H.; Hussain, A.; Ahmad, S.; Alam, M. S., et al. Tamarix aphylla (L.) Karst. Phytochemical and Bioactive Profile Compilations of Less Discussed But Effective Naturally Growing Saudi Plant. Plant and Human Health, 2019, 3, 343–352.

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Al-Othman, M. R.; Alkhattaf, F. S.; Abd-El-Aziz, A. R. Antioxident and Chemical Constituents of Ethyl Acetate Extract of Tamarix aphylla Leaves in Saudi Arabia. Pak. J. Bot. 2015, 52, 6. Alrumman, S. A. Phytochemical and Antimicrobial Properties of Tamarix aphylla L. Leaves Growing Naturally in the Abha Region, Saudi Arabia. Arabian J. Sci. Eng. 2016, 41 (6), 2123–2129. Azaizeh, H.; Saad, B.; Khalil, K.; Said, O. The State of the Art of Traditional Arab Herbal Medicine in the Eastern Region of the Mediterranean: A Review. Evidence-Based Complem. Altern. Med. 2006, 3 (2), 229–235. Bibi, S.; Afzal, M.; Aziz, N.; Din, B. U.; Khan, M. Y.; Khan, A.; Komal, H. Antifungal Activity of Tamarix aphylla (L) Karst. Stem-Bark Extract Against Some Pathogenic Fungi. Am-Eurasian J. Agric. Environ. Sci. 2015, 15, 541–545. Bolous, L. Flora of Egypt, Vol. 2; Al Hadara Publishing: Cairo, 1999; p 124. El-Aarag, B.; Khairy, A.; Khalifa, S. A.; El-Seedi, H. R. Protective Effects of Flavone from Tamarix aphylla Against CC14-Induced Liver Injury in Mice Mediate By Suppression of Oxidative Stress, Apoptosis and Angiogenesis. Intern. J. Mol. Sci. 2019, 20 (20), 5215. Hebi, M.; Eddouks, M. Hypolipedemic Activity of Tamarix articulata Vahl in Diabetic Rats. J. Integr. Med. 2017, 15 (6), 476–482. Mahfoudhi, A.; Prencipe, F. P.; Mighri, Z.; Pellati, F. Metabolite Profiling of Polyphenols in the Tunisian plant Tamarix aphylla (L.) Karst. J. Pharm. Biomed. Analys. 2014, 99, 97–105. Mohammedi, Z.; Atik, F. Impact of Solvent Extraction Type on Total Polyphenols Content and Biological Activity from Tamarix aphylla (L.) Karst. Int. J. Pharm. Bio. Sci. 2011, 2 (1), 609–615. Nawwar, M. A. M.; Hussein, S. A. M.; Ayoub, N. A.; Hofmann, K.; Linscheid, M.; Harms, M.; Lindequist, U. Aphyllin, the First Isoferulic Acid Glycoside and Other Phenolics from Tamarix aphylla Flowers. Die Pharmazie 2009, 64 (5), 342–347. Orabi, M. A.; Taniguchi, S.; Terabayashi, S.; Hatano, T. Hydrolyzable Tannins of Tamaricaceous Plants. IV. Micropropogation and Ellagitannins Production in Shoot Culture of Tamarix tetrandra. Phytochemistry 2011, 72 (16), 1978–1989. Pejin, B.; Ciric, A.; Glamoclija, J.; Nikolic, M.; Sokovic, M. In Vitro Antiquorum Sensing Activity of Phytol. Nat. Prod. Res. 2015, 29 (4), 374–377. Ullah, R.; Tariq, S. A.; Khan, N.; Sharif, N.; Din, Z. U.; Mansoor, K. Antihyperglycemic Effect of Methanol Extract of Tamarix aphylla L. Karst (Saltcedar) in Streptozocin–Nicotinamide Induced Diabetic Rats. Asian Pacific J. Trop. Biomed. 2017, 7 (7), 619–623.

CHAPTER 69

Bioactives and Pharmacology Avicennia marina (Forssk.) Vierh. JITENDRA R. PATIL1, SAVALIRAM G. GHANE2, and GANESH C. NIKALJE1* 1Department

of Botany, Seva Sadan’s R. K. Talreja College of Arts, Science and Commerce, Affiliated to University of Mumbai, Ulhasnagar 421 003, Maharashtra, India

2Department

of Botany, Shivaji University, Kolhapur 416 004, Maharashtra, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT The bark, stem, leaves, fruits, and seeds of Avicennia marina are used in folk medicines, mainly in the treatment of skin diseases, ulcers, smallpox, and rheumatism. The phytochemical analysis of different plant parts such as stem, leaves, seeds, pneumatophores, etc. of A. marina revealed the presence of bioactive compounds such as alkaloids, coumarin, cardiac glycosides, flavonoids, phenols, steroids, saponins, tannins, and triterpenoids along with carbohydrates and fatty acids. The triterpenoid compounds such as betulinic acid, taraxerol, and taraxerone along with a minute amount of a hydrocarbon-triacontane have been isolated from the ether extract of bark of A. marina. Many flavone compounds have been isolated from the aerial plant parts from time to time. The first alkaloid isolated from the plant was indolyl-3-carboxylic acid. The extracts of various plant parts and isolated bioactive compounds showed pharmacological activities like antimicrobial, anti- inflammatory, antioxidant, anticancer etc. In addition, it shows contra­ ceptive, antifertility, aphrodisiac, analgesic, and antiulcer activity. Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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INTRODUCTION

The bark, stem, leaves, fruits, and seeds of Avicennia marina are used in folk medicines, mainly in the treatment of skin diseases, ulcers, small pox, and rheumatism. The bark/stem of Avicennia alba Blume (a variant to A. marina) is also ethnomedicinally used in the treatment of asthma, boils, paralysis, rheumatism, scabies, sexual disorders, skin diseases, and snake-bites. In addition, it shows contraceptive, antifertility, aphrodisiac, analgesic, and antiulcer activity (Thatoi et al., 2016; Bibi et al., 2019). 69.2

BIOACTIVES

The phytochemical analysis of different plant parts such as stem, leaves, seeds, pneumatophores, etc. of A. marina revealed the presence of bioac­ tive compounds such asalkaloids, coumarin, cardiac glycosides, flavo­ noids, phenols, steroids, saponins, tannins, and triterpenoids along with carbohydrates and fatty acids (Khafagi et al., 2003; Khattab et al., 2012; Shanmugapriya et al., 2012; Tukiran, 2013; Mouafi et al., 2014; Poompozhil and Kumarasamy, 2014; Thatoi et al., 2016; Vasanthakumar et al., 2019). Avicennia marina is used as a source of tannins in many countries and its timber in boat building. The bark of A. marina also contains many acidic and neutral constituents (Bell and Duewell, 1961). The bark, leaves, and fruits are used as traditional medicines especially in curing skin diseases. 69.2.1 TERPENOIDS AND STEROIDS The triterpenoid compounds such as betulinic acid (0.3 %), taraxerol (0.06 %), and taraxerone (0.05 %) along with a minute amount of a hydro­ carbon—triacontane have been isolated from the ether extract of bark of A. marina (Bell and Duewell, 1961). Three new abietane diterpenoids were isolated from twig, a pair of inseparable epimers 6Hα-11,12,16-trihydroxy­ 6,7-secoabieta-8,11,13-triene-6,7-dial 11,6-hemiacetal, and 6Hβ-11,12,16trihydroxy-6,7-secoabieta-8,11,13-triene-6,7-dial 11,6-hemiacetal, as well as 6,11,12,16-tetrahydroxy-5,8,11,13-abitetetraen-7-one. These three compounds have moderate cytotoxic and antimicrobial potential (Han et al., 2008). Terpenoids and steroids like lupeol, betulin, β-sitosterol, and ergost-6, 22-diene-5,8-epidioxy-3β-ol (Jia et al., 2004) and betulinic acid (Feng et

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al., 2007) were reported from leaf extracts. In addition, the pneumatophores extracts also showed presence of two sterols; Stigmasterol-3-O-β-d galacto­ pyranoside and stigmasterol and three triterpenoids, lupeol, taraxerol, and betulinic acid (Mahera et al., 2011). 69.2.2 NAPHTHALENE DERIVATIVES The naphthofuranone phytoalexins like naphtha[1,2-b]furan-4,5-dione; 3-hydroxy-naphtha[1,2-b]furan- 4,5-dione, and2-[2′-(2′-hydroxy)propyl]naphtha[1,2-b]furan-4,5-dione were isolated from the wounded tissues infected with the fungal pathogen Phytophora (Sutton et al., 1985). The two naphthoquinone derivatives—avicequinone B and avicequinone C have been isolated from the leaves (Jia et al., 2004). The phytochemical screening of extract of twigs showed the presence of seven new naphthoquinone deriva­ tives avicennone A-G, along with the known compounds avicequinone A, stenocarpoquinone B, avicenol A, and avicenol C (Han et al., 2007). In addi­ tion, the new lignan (7′S,8′R)-4,4′,9′-trihydroxy-3,3′,5,5′-tetramethoxy-7,8dehydro-9-al-2,7′-cycloligan, have been isolated together with the known compound, lyoniresinol from twig (Han et al., 2008). 69.2.3 FLAVONES Many flavone compounds that have been isolated from the aerial parts of plant from time to time are as follows: Lluteolin 7-O-methylether (Sharaf et al., 2000); 5-hydroxy-4′, 7-dimethoxyflavone, quercetin and kaempferol (Jia et al., 2004); 4′,5-dihydroxy-3′,7-dimethoxyflavone, 4′,5-dihydroxy-3′,5′,7trimethoxyflavone, 4′,5,7- trihydroxyflavone, and 5,7-dihydroxy-3′,4′,5′trimethoxyflavone (Feng et al., 2006a, 2007). Kar et al. (2014) isolated new flavone from methanol extract of aerial parts of Avicennia alba—2[3′-(3″-(hydroxymethyl)oxiran-2″-yl)-2′-methoxy-4′-(methoxymethyl) phenyl]-4H-chromen-4-one. 69.2.4 GLUCOSIDES 69.2.4.1 IRIDOID GLUCOSIDES The number of studies reported the isolation of iridoid glucosides from this plant. The iridoid glucosides isolated from A. marina are as follows: Geni­ posidic acid, 2′-cinnamoyl-mussaenosidic acid, geniposide, mussaenoside,

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2′-cinnamoyl-mussaenoside, 10-O-(5-phenyl-2,4-pentadienoyl)-geniposide, 7-O-(5-phenyl-2,4-pentadienoyl)-8-epiloganin (König et al., 1985); 10-O-[(E)-cinnamoyl]-geniposidic acid, 10-O-[(E)-p-coumaroyl]geniposidic acid, 10-O-[(E)-caffeoyl]-geniposidic acid (Shaker et al., 2001); 2′-O-[(2E,4E)-5-phenylpenta-2,4-dienoyl]-mussaenosidic acid, and 2′-O-(4-mehtoxycinnamoyl)-mussaenosidic acid,2′-O­ coumaroylmussaenosidic acid (Feng et al., 2006b); marinoids A–E (Sun et al., 2008). The iridoid glucosides may play a role for chemical defense against ecological invasion. 69.2.4.2 PHENYLPROPANOID GLYCOSIDES The HPLC analysis of methanol extract of leaves showed the presence of three phenylpropanoid glycosides as follows: Verbascoside, isoverbascoside, and derhamnosyl verbascoside. Verbascoside is known for its antiviral and antibacterial activities (Fauvel et al., 1993). Also, another phenylpropanoid glycoside, namely, diacetylmartynoside have been isolated from the twig extract (Han et al., 2008). 69.2.4.3 ABIETANE DITERPENOID GLUCOSIDES The following two abietane diterpenoid glucosides have been isolated from the twigs of the plant: 11-hydroxy-8,11,13-abietatriene 12-O-β-xylopyranoside and lyoniresinol 9′-O- β-d-glucopyranoside (Han et al., 2008). 69.2.5 FLAVONOIDS Few flavonoids from the methanol extract of the aerial parts have been isolated, namely, chrysoeriol 7-O-glucoside, isorhamnetin 3-O-rutinoside, luteolin 7-O-methylether 3′-O-β-D-glucoside, and luteolin 7-O-methy­ lether 3′-O-β-D-galactoside (Sharaf et al., 2000), while few flavonoid compounds have been isolated from the ethanol extract of leaves, namely, quercetin-3-O­ dihydroquercetin, quercetin-3-O-β-d-xylopyranoside, β-d-galactopyranoside, isohametin-7-O-pentoside, and rutin. All these compounds show antibacterial properties (Zamani et al., 2019)

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69.2.6 ALKALOIDS The first alkaloid isolated from the plant was indolyl-3-carboxylic acid (Feng et al., 2007). Later, two alkaloids were isolated from ethanol extract of leaves, namely, berberine, and papaverine. These alkaloid derivatives have antibacterial properties (Zamani et al., 2019). 69.2.7 FATTY ACIDS AND OTHERS There are many fatty acids, carbohydrates, and other bioactive compounds such as p-methoxy cinnamic acid (Jia et al., 2004); syringaresinol (Feng et al., 2007); 3(R)-hydroxy-5-phenyl-4(E)-pentanoic acid (Sun et al., 2008) were isolated from various parts of plants. The GC-MS analysis of ethyl acetate extracts of various parts exhibits the presence of 2- propenoic acid, 3-phenyl ester; and 3-acetyl methoxyphenyl; phenol; benzaldehyde,3hydroxyl-4- methoxy; 1,2-benzenediol; phosphonic acid, p-hydroxyphenyl; 4H- pyran-4-one, and 2,3-dihydro-3,5-dihydroxy-6-methyl (Khattab et al., 2012). While the GC-MS analysis of ethanol extract of leaves revealed the presence of bioactive compounds such as n-hexadecanoic acid, 2-cyclo­ hexen-1-one, and 4-hydroxy-3,5,5-trimethyl-4-(3-oxo-1-butenyl); squalene and 2R,3S-butane-1,2,3,4-tetraol; palmitic acid; hexadecanoic acid and ethyl ester; 3,7,11,15-tetramethyl-2-hexadecen-1ol; phytol; (E)-9-octadecenoic acid ethyl ester; dodecanoic acid; octadecanoic acid, 2-methyl-,methyl ester; 3-cyclohexen-1 carboxaldehyde, 3-methyl; cis-9-hexadecenal; and 3,7-dimethyl-2,6-octadienyl ester. Most of these constituents have antimi­ crobial, anticancer, antiinflammatory, and antioxidant potential (Kumar and Rajakumar, 2016; Dhayanithi et al., 2012).

FIGURE 69.1

Structures of few Terpenoids and steroids isolated from A. marina.

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FIGURE 69.2

Naphthalene derivatives isolated from A. marina (Han et al., 2007).

FIGURE 69.3

Structures of few Glucosides isolated from A. marina.

Avicennia marina (Forssk.) Vierh.

69.3

381

PHARMACOLOGY

With reference to pharmacology, A. marina is one of the most studied species of Avicennia. 69.3.1 ANTIMICROBIAL ACTIVITY Many researchers have reported the antimicrobial potential of leaf and other plant parts of A. marina (Shanmugapriya et al., 2012; Vasanthakumar et al., 2019). The ethyl acetate, methanol, and chloroform extracts of A. marina leaves showed antibacterial activity against the multidrug resistant strains of Staphylococcus aureus. The methanolic leaf extract showed the highest activity (Dhayanithi et al., 2012). Even the antimicrobial activity against few antibiotic resistant and pathogenic bacteria, and fungi has also been reported (Mouafi et al., 2014). The antibacterial activity of leaf and stem extracts has been reported against Agrobacterium tumefaciens, Bacillus cereus, Bacillus subtilis, Escherichia coli, Escherichia faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Salmonella typhi, S. paratyphi, S. aureus, Streptococcus pneumoniae, Streptococcus mutans, and Shigella flexneri, etc. The antifungal activity was also reported against Pencillium digitatum (Mohammed et al., 2014; Thatoi et al., 2016; Anantha­ valli and Karpagam, 2017; Karthi et al., 2020; Ibrahim et al., 2020). Even the compounds 6,11,12,16-tetrahydroxy-5,8,11 and 13-abitetetraen-7-one isolated from twig shows broad antimicrobial activity against Gram-positive and Gram-negative bacteria; mycobacteria; and yeast (Han et al., 2008). 69.3.2 ANTICANDIDAL ACTIVITY The aqueous and ethanol extract of various parts of plant shows anticandidal activity against the Candida albicans and Candida tropicals. 69.3.3 ANTI-INFLAMMATORY ACTIVITY The polyphenolic compounds present in plant reveal significant reduction in inflammation caused by rheumatoid arthritis in rat. Betulinic acid also exhibits anti-inflammatory activity (Thatoi et al., 2016).

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69.3.4 ANTIOXIDANT ACTIVITY In the α,α-diphenyl-β-picrylhydrazyl (DPPH) radical-scavenging assay, the extract of plant showed high antioxidant activity (89.85% scavenging). The flavone compounds such as 4′,5,7-trihydroxyflavone and luteolin 7-O-methylether isolated from aerial part also showed moderate antioxidant activity (Shanmugapriya et al., 2012). The fruit and leaf extracts exhibited the antioxidant activity against the molecules such as2,2′-azino-bis(3­ ethylbenzothiazoline-6-sulphonic acid (ABTS), CrO5 (chromium peroxide) and ferric reducing ability of plasma (FRAP) molecules (Thatoi et al., 2016; Mohammed et al., 2014) 69.3.5 ANTIVIRAL ACTIVITY The aqueous extract of root and shoots of seedlings revealed antibacterio­ phage activity using coliphage against E. coli NRRL B-3704. The shoot extract showed more activity than roots. The ethanol extract of leaf exhibit antiviral activity against encephalomyocarditis virus and hepatitis B virus (Thatoi et al., 2016). The leaf and seed extract showed bioactivity against the Herpes simplex virus (HSV) and enzyme reverse transcriptase of HIV1 (Namazi et al., 2013; Hajjar, 2016). 69.3.6 ANTIPLASMODIAL/ANTIMALARIAL ACTIVITY The aqueous extracts of plant showed cytotoxicity against the larvae of the brine shrimp Artemia salina. 69.3.7 MOSQUITOCIDAL ACTIVITY The acetone extract of plant exhibit mosquitocidal activity against larvae of three major mosquito vectors Culex quinquefasciatus (LC50 = 0.197 mg/ mL; LC90 =1.5011 mg/mL), Anopheles stephensi (LC50 = 0.176 mg/Ml; LC90 = 3.6290 mg/ml), and Aedes aegypti (LC50=0.164 mg/mL; LC90 = 4.3554 mg/mL) (Karthi et al., 2020). 69.3.8 ANTICANCER ACTIVITY The flavanoid isolated from aerial part of plant luteolin 7-O-methylether 3′-O-β-d-glucoside and its aglycone, luteolin 7-O-methylether showed

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moderate cytotoxity against BT-20 human carcinoma cells; which are responsible for breast cancer, with ED50 of 16 μg/mL and 18 μg/mL, respec­ tively (Sharaf et al., 2000). The three abietane diterpenoids and compound 6,11,12,16-tetrahydroxy-5,8,11,13-abitetetraen-7-one isolated from twig show moderate antiproliferative and cytotoxic activity against L-929, K562, and HeLa cell lines (Han et al., 2008). The extracts of leaf also showed cytotoxicity against HL60, MDA-MB231, and NCI-H23 cell lines (Sukh­ ramani and Patel, 2013; Thatoi et al., 2016). The hexane extract of leaves shows high cell inhibitory effect on HCT-116, HepG2, and MCF-7 cell lines (Albinhassan et al., 2020). 69.3.9 ANTIGLYCATION/ANTIDIABETIC ACTIVITY Avicennia marina is the only species of Avicennia which is reported for its antidiabetic activity. The sterol- stigmasterol-3-O-β-D galactopyranoside, isolated from the pneumatophores has potential of advanced glycated ends products (AGE) inhibition. The leaf extract revealed antihyperglycemic activity (Mahera et al., 2011; Thatoi et al., 2016). 69.3.10 ANTIANDROGENIC ACTIVITY Jain et al. (2014) demonstrated the antiandrogenic activity of avicequinone C isolated from heartwood extract of A. marina. It inhibits the activity of andro­ genic alopecia (AGA) causing enzyme 5α-reductase (5α-R) [E.C.1.3.99.5], which is responsible for the over-production of 5α-dihydrotestosterone (5α-DHT). 69.3.11 IN VITRO PHOTOTOXICITY The shoot and root extracts treated with long-wavelength ultraviolet (UV) radiation induces phototoxic activity against few microbes, which may reflect immediate production of phytoalexin defense compounds (Khafagi et al., 2003). 69.3.12 NO TOXICITY The aqueous and methanolic extract of plant shows insignificant toxicity effect against normal cell line, HEK-293T (Sukhramani and Patel, 2013).

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KEYWORDS • • • • • •

Avicennia marina Terpenoids steroids glucosides antimicrobial activity anticancer activity

REFERENCES Albinhassan, T. H.; Saleh, K. A.;Barhoumi, Z.;Alshehri, M. A.; Al-Ghazzawi, A. M. Anticancer, anti-proliferative activity of Avicennia marina plant extracts. J. Can. Res. Ther. 2020 (In press). Ananthavalli, M.; Karpagam, S. Antibacterial Activity and Phytochemical Content of Avicennia marina Collected from Polluted and Unpolluted Site. J. Med. Plants Studies 2017, 5 (3), 47–49. Bell, K. H.; Duewell, H. Triterpenoids from the Bark of Avicennia marina. Australian J. Chem. 1961, 14 (4), 662–663. Bibi, S. N.; Fawzi, M. M.; Gokhan, Z.; Rajesh, J., Nadeem, N.; Kannan, R. R. R. et al. Ethnopharmacology, Phytochemistry, and Global Distribution of Mangroves―A Comprehensive Review. Marine Drugs 2019, 17 (4), 231. Dhayanithi, N. B.; Kumar, T. A.; Murthy, R. G.; Kathiresan, K. Isolation of Antibacterials from the Mangrove, Avicennia marina and Their Activity Against Multi Drug Resistant Staphylococcus aureus. Asian Pacific J. Trop. Biomed. 2012, 2 (3), S1892–S1895. Fauvel, M. T.; Taoubi, K.; Gleye, J.; Fouraste, I. Phenylpropanoid Glycosides from Avicennia marina. Planta Medica 1993, 59 (04), 387–387. Feng, Y.; Li, X. M.; Duan, X. J.; Wang, B. G. A New Acylated Iridoid Glucoside from Avicennia marina. Chinese Chem. Lett. 2006a, 17 (9), 1201–1204. Feng, Y.; Li, X. M.; Duan, X. J.; Wang, B. G. Iridoid Glucosides and Flavones from the Aerial Parts of Avicennia marina. Chem. Biodiversity 2006b, 3 (7), 799–806. Feng, Y.; Li, X. M.; Wang, B. G. Chemical Constituents in Aerial Parts of Mangrove Plant Avicennia marina. Chin. Trad. Herb.Drugs, 2007, 38 (9), 1301–1303. Hajjar DA. Bio-Prospecting of Plants and Marine Organisms in Saudi Arabia for New Potential Bioactivity. Doctoral dissertation, 2016. Han, L.; Huang, X.; Dahse, H. M., Moellmann, U., Fu, H., Grabley, S. et al. Unusual Naphthoquinone Derivatives from the Twigs of Avicennia marina. J. Nat. Prod. 2007, 70 (6), 923–927.

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Han, L.; Huang, X.; Dahse, H. M.; Moellmann, U.; Grabley, S.; Lin, W.; Sattler, I. New Abietane Diterpenoids from the Mangrove Avicennia marina. Planta Medica 2008, 74 (04), 432–437. Ibrahim, H. A.; Shaaban, M. T.; Hanafi, A. A.; Abdelsalam, K. M. Inhibition of Bacteria Isolated from Human Specimens by Selected Marine-Origin Extracts. Egypt. J. Exp. Biol. (Bot.) 2020, 16 (1), 91–103. Jain, R.; Monthakantirat, O.; Tengamnuay, P.; De-Eknamkul, W. Avicequinone C Isolated from Avicennia marina Exhibits 5α-Reductase-Type 1 Inhibitory Activity Using an Androgenic Alopecia Relevant Cell-Based Assay System. Molecules 2014, 19 (5), 6809–6821. Jia, R.; Guo, Y. W.; Hou, H. X. Studies on the Chemical Constituents from Leaves of Avicenniamarina. Chin. J. Nat. Med. 2004, 2, 16–19. Kar, D. R.; Kumar, P. S.; Ghosh, G.; Sahu, P. K. Isolation and Characterization of Flavone from the Aerial Parts of Avicennia alba Blume. Orient. J. Chem. 2014, 30 (2), 705–711. Karthi, S.; Vinothkumar, M.; Karthic, U.; Manigandan, V.; Saravanan, R.; Vasantha-Srinivasan, P.; Krutmuang, P. Biological Effects of Avicennia marina (Forssk.) Vierh. Extracts on Physiological, Biochemical, and Antimicrobial Activities Against Three Challenging Mosquito Vectors and Microbial Pathogens. Environ. Sci. Pollution Res. 2020, 27, 1–14. Khafagi, I.; Gab-Alla, A.; Salama, W.; Fouda, M. Biological Activities and Phytochemical Constituents of the Gray Mangrove Avicennia marina (Forssk.) Vierh. Egyptian J. Biol. 2003, 5 (1), 62–69. Khattab, R.; Gaballa, A.; Zakaria, S.; Ali, A. A.; Sallam, I.;Temraz, T. Phytochemical Analysis of Avicennia marina and Rhizophora mucronata by GC-MS. Catrina: Intern. J. Environ. Sci. 2012, 7 (1), 115–120. König, G.; Rimpler, H. Iridoid Glucosides in Avicennia marina. Phytochemistry 1985, 24 (6), 1245–1248. Kumar, D.; Rajakumar, R. Gas Chromatography-Mass Spectrometry Analysis of Bioactive Components from the Ethanol Extract of Avicennia marina Leaves. Innovare J. Sci. 2016, 4 (4),9–12. Mahera, S. A.; Ahmad, V. U.; Saifullah, S. M.; Mohammad, F. V.; Ambreen, K. Steroids and Triterpenoids from Grey Mangrove Avicennia marina. Pakistan J. Bot. 2011, 43 (2), 1417–1422. Mohammed, N. S.;Srinivasulu, A.; Chittibabu, B.; Rao, V. Isolation and Purification of Antibacterial Principle from Avicennia marina L in Methanol. Int. J. Pharm. Pharma. Sci. 2014, 7 (1), 38–41. Mouafi, F. E.; Abdel-Aziz, S. M.; Bashir, A. A.; Fyiad, A. A. Phytochemical Analysis and Antimicrobial Activity of Mangrove Leaves (Avicenna marina and Rhizophora stylosa) Against Some Pathogens. World Appl. Sci. J. 2014, 29 (4), 547–554. Namazi, R.; Zabihollahi, R.; Behbahani, M.; Rezaei, A. Inhibitory Activity of Avicennia marina, a Medicinal Plant in Persian Folk Medicine, Against HIV and HSV. Iran. J. Pharma. Res. 2013, 12 (2), 435–443. Poompozhil, S.; Kumarasamy, D. Studies on Phytochemical Constituents of Some Selected Mangroves. J. Acad. Ind. Res. 2014, 2, 590–592. Shanmugapriya, R.; Ramanathan, T.; Renugadevi, G. Phytochemical Characterization and Antimicrobial Efficiency of Mangrove Plants Avicennia marina and Avicennia officinalis. Int. J. Pharma. Biol. Arch. 2012, 3 (2), 348–351. Shaker, K. H.; Elgamal, M. H. A.; Seifert, K. Iridoids from Avicennia marina. Zeitschriftfür Naturforschung C. 2001, 56 (11–12), 965–968.

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Sharaf, M.; El-Ansari, M. A.; Saleh, N. A. M. New Flavonoids from Avicennia marina. Fitoterapia, 2000, 71 (3), 274–277. Sukhramani, P. S.; Patel, P. M. Biological Screening of Avicennia marina for Anticancer Activity. Der Pharm Sin 2013, 4 (2), 125–130. Sun, Y.; Ouyang, J.; Deng, Z.; Li, Q.; Lin, W. Structure Elucidation of Five New Iridoid Glucosides from the Leaves of Avicennia marina. Magn. Reson. Chem. 2008, 46 (7), 638–642. Sutton, D. C.; Gillan, F. T.; Susic, M. Naphthofuranone Phytoalexins from the Grey Mangrove, Avicennia marina. Phytochemistry 1985, 24 (12), 2877–2879. Thatoi, H.; Samantaray, D.; Das, S. K. The Genus Avicennia, a Pioneer Group of Dominant Mangrove Plant Species with Potential Medicinal Values: A Review. Front. Life Sci 2016, 9 (4), 267–291. Tukiran, B. Phytochemical Analysis of Some Plants in Indonesia. J. Biol. Agric. Healthc. 2013, 3, 6–10. Vasanthakumar, K.; Dineshkumar, G.; Jayaseelan, K. Phytochemical Screening, GC-MS Analysis and Antibacterial Evaluation of Ethanolic Leaves Extract of Avicennia marina. J. Drug Deliv. Therap. 2019, 9 (4-A), 145–150. Zamani, M. Z.; Prajitno, A.; Fadjar, M. Morphological Characteristics of Bioactive Compounds on Api-Apimangrove Leaves Extract (Avicennia marina) Based on Leaves Age. Res. J. Life Sci. 2019, 6 (3), 35–43.

CHAPTER 70

Phytochemical and Pharmacological Properties of Himalayan Silver Birch (Betula utilis D. Don): A Dominant Treeline Forming Species KHASHTI DASILA and MITHILESH SINGH* G. B. Pant National Institute of Himalayan Environment, Kosi- Katarmal, Almora, 263643, Uttarakhand, India *Corresponding

author.

E-mail: [email protected]; [email protected]

ABSTRACT Betula utilis D. Don (Family: Betulaceae), commonly known as Himalayan silver birch and Bhojpatra, is the only dominant broadleaved angiosperm tree species that grows up to 20 m in height in subalpine zone of Himalayan Region. The epithet utilis indicates multiple uses of its different plant parts ranging from paper, textile, building construction to medicinal value. The species is used in various Indian indigenous systems of medicine to treat and cure tridosa—‘vata’ (air), ‘pitta’ (phlegm) and ‘kaph’ (cough). The bark is a rich source of medicinally valuable phytochemical compounds like triterpe­ noids, phenolics, flavonoids, and essential oils. These compounds exhibited various pharmaceutical potential such as antimicrobial, anti-hyperglycemic, anticancer, antioxidant, anti-HIV, hepatoprotective, anti-obesity, antima­ larial, antiurolithiatic and anti-inflammatory activities. Betulin forms the highest composition, i.e., up to 20- 45% among identified triterpenes of dry outer bark weight. The amount of betulin varies from species to species and Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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its regional locations. It can also be found in a lesser amount in the root and leaves of the birch species. However, the beulin amount in B. utilis found up to 12% of its weight. 70.1

INTRODUCTION

Betula utilis D. Don (Family: Betulaceae), commonly known as Hima­ layan silver birch and Bhojpatra (Hindi), is the only dominant broadleaved angiosperm tree species that grows up to 20 m in height in subalpine zone of Himalayan Region (Zobel and Singh, 1997). The epithet utilis indicates multiple uses of its different plant parts ranging from paper, textile, and building construction to medicinal value. The species is distributed in the sub-alpine zone between 2700 and 4500 m elevation in the Himalayan Region of Afghanistan, Bhutan, China, Nepal, and Pakistan (Shaw et al., 2014). The high freezing tolerance potential make the species capable to form treeline (uppermost limit of tree species) in the Himalayan Region (Zobel and Singh, 1997). The reddish white, shinning, and smooth bark of the species is the striking feature which contains numerous papers like layer with broad horizontal roll. The papery bark of the plant was used as paper substitute in ancient time for the inscription of religious texts. The local people used the bark as packaging material for pipes, bandage, cigarette paper, umbrella cover, and in textile (Anonymous, 1988). 70.2

BIOACTIVES

The species is used in various Indian indigenous systems of medicine to treat and cure tridosa- “vata” (air), “pitta” (phlegm), and “kaph” (cough). The bark is significantly used in Ayurveda and Unani medicine systems in various forms including powder, paste, infusion, and decoction forms for the treatment of various diseases such as skin disinfectant, wound healing, leprosy, convul­ sions, bronchitis, and in ear- and blood-related diseases (Chauhan, 1999; Gorsi and Miraj, 2002; Selvam, 2008; Bisht et al., 2011). The bark is also used as a tonic to treat jaundice, constipation, and cough (Shukla et al., 2017). Various pharmaceutical potentials such as antimicrobial (Kumaraswamy et al., 2008), antihyperglycemic (Ahmad et al., 2008), anticancer, antioxidant, and anti-HIV (Ju et al., 2004; Sakarkar and Deshmukh, 2011; Rastogi et al., 2015; Shukla et al., 2017) activities have been reported. The bark has been the subject of scientific research due to presence of many bioactive compounds such as triterpenoids, phenolics, flavonoids, and essential oils.

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70.2.1 TRITERPENOIDS The birch species is rich sources of pentacyclic triterpene compound such as sitosterol, betulin, betulinic acid, lupeol, oleanolic acid, acety­ loleanolic acid, lupenone, methyl betulonate, methyl betulate, ursolic acid (UA), β-amyrin, and karachic acid (Nadakarni, 1976; Khan and Atta-Ur-Rahman, 1975; Krasutsky, 2006; Selvam, 2008; Mishra et al., 2016). These triterpenes are well known for various biological activities including antivirus, anti-inflammatory, anticancer, and other properties (Laszczyk, 2009). Betulin forms the highest composition of triterpenes up to 20–45% (Kuznetsova et al., 2010) of dry outer bark weight. The amount of betulin depends on the birch spices and its regional locations (O’Connell et al., 1988; Holonec et al., 2012; Hu et al., 2013). It can also be found in lesser amount in the root and leaves of the birch species (Yin et al., 2013). It exhibits significant therapeutic activity as antitumor, antiviral, and antiseptic (Krasutsky, 2006), and involved as highly active derivatives in chemical modulation that can comparable to clinically used drugs (Cichewicz and Kouzi, 2004; Alakurtti et al., 2006). The outer bark of common European birch species contains 10–20% of lupeol and betulinic acid (Orsini et al., 2015) and shows similar efficiency in their biological activities (Krasutsky, 2006; Saleem, 2009; Gallo and Sarachine, 2009; Ghaffar et al., 2012). The chemical structure of major triterpenoids of B. utilis are shown in Figure 70.1.

FIGURE 70.1 Triterpenoids compounds from B. utilis bark.

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70.2.2 ESSENTIAL OILS Methyl salicylate and terpenes are the major constituents of the essential oils in genus Betula (Nath et al., 1991; Dung et al., 1995; Baser and Demirci, 2007). The essential oils, namely, geranic acid, β-seleneol, β-linalool, terragon, β-sesquiphellendrene, champacol, 1,8-cineol, 2,4-decadienal, cadinene, and palmitic acid have been identified with the help of chro­ matographic techniques, that is, gas chromatography–mass spectrometry (GC–MS) analysis (Fig. 70.2). The essential oil of B. utilis bark also exhibits a potent antimicrobial activity (Pal et al., 2015a).

FIGURE 70.2

Essential oil compound in B. utilis bark.

70.2.3 PHENOLICS AND FLAVONOIDS Mishra et al. (2020) developed and validated ultra-high-performance liquid chromatographywith hybrid linear ion trap triple quadrupole mass spec­ trometry (UHPLC-ESI-MS/MS) method for investigation of geographical variations in triterpenoids, phenolics, and flavonoids from stem bark of B. utilis. The UHPLC-ESI-MS/MS analysis confirmed the presence of phenolic acid, namely, caffeic acid, ferulic acid, and chlorogenic acid and flavonoids, namely, quercetin, kaempferol, apigenin, catechin, and luteolin in the methanolic bark extracts (Mishra et al., 2020). The bark of B. utilis is also the source of various fatty acid constituents including linoleic, myristic, oleic, and palmitic (Pal et al., 2015b). Figure 70.3 represents the chemical structures of phenolics and flavonoids reported in bark sample of B. utilis.

Betula utilis D. Don

FIGURE 70.3

70.3

391

Phenolic and flavonoid compounds in B. utilis bark.

PHARMACOLOGY

70.3.1 ANTIVIRAL ACTIVITY Although less comprehensive pharmacological studies have been done on antiviral activity of B. utilis, betulinic acid, a derivative of betulin was exten­ sively studied for anti-HIV activity and antiviral activities (Dzubak et al. 2006). Betulinic acid derivatives inhibits the HIV-1 replication (Fujoka et al., 1994) and act as inhibitors for HIV-1 entry, protease, reverse transcriptase, and integrase and also on gp120/cd4 binding (Mayaux et al., 1994; Xu et al., 1996). The betulinic acid derivatives able to inhibit HIV-1 in the very initial stage of the viral life cycle. Therefore, these compounds have potential as a useful addition in anti-HIV therapy mainly relies on the protease and reverse transcriptase inhibitors (Mayaux et al., 1994). 70.3.2 ANTIBACTERIAL ACTIVITY Kumaraswamy et al. (2008) evaluated the aqueous and organic solvents (petroleum ether, chloroform, methanol, and ethanol) extracts of B. utilis bark for antibacterial activity by agar-well diffusion method. The extracts were tested against total of fourteen important human pathogens, namely, Citrobacter sp., Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, Salmonella typhi, Salmonella paratyphi A, S. paratyphi B, Salmonella typhimurium, Higella boydii, Shigella flexneri, S.

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sonnei, Staphylococcus aureus, and S. faecalis. Among the studied extracts, only methanol and ethanol extracts exhibited antibacterial activity against all the tested pathogens. The inhibitory potential of methanolic extracts was found to be significantly higher than the antibiotics, that is, gentamicin. Pal et al. (2015a) evaluated the antibacterial activity of essential oil of stem bark of B. utilis that exhibited significant inhibition against S. aureus (120 µg/ mL), Bacillus subtilis (240 µg/mL), E. coli (120 µg/mL), and P. aeruginosa (120 µg/mL). 70.3.3 ANTIFUNGAL ACTIVITY Antifungal activity of the essential oil of B. utilis bark extracts has also been reported against Candida albicans with the minimum inhibitory concentra­ tion (MIC) value of 60.5 µg/mL (Pal et al., 2015a). 70.3.4 ANTIOXIDANT EFFICACY Betula utilis has free radical scavenging potential and reduces free radicals to stop the free radical chain reaction. Kumaraswamy and Satish (2008) evalu­ ated the antioxidant activity of B. utilis leaves extracts. The methanolic leaves extracts have the highest DPPH scavenging property (8.4 ± 0.42 µg/mL IC50) followed by chloroform extracts (25.37 ± 1.16 µg/mL IC50), aqueous extracts (35.08 ± 2.05 µg/mL IC50), and petroleum ether extracts (25.32 ± 1.82% inhibition at 100 µg/mL). However, the methanol and aqueous leaves extracts of B. utilis exhibited a better ABTS scavenging activity (83.18 and 37.14 µg/mL IC50), while petroleum ether and chloroform extracts have 9.58 and 9.22% scavenging activity at 100 and 50 µg/mL, respectively. Wani et al. (2018) compared the antioxidant activity of the different parts, that is leaves, root, and bark extracted in different solvents such as chloroform, dichloromethane, ethanol, hexane, methanol, and petroleum ether including water. The results indicated that ethanolic bark extracts (84.8 ± 2.5 µg/ mL), methanolic root (43.9 ± 2.8 µg/mL IC50), and leaves (85.2 ± 3.1 µg/ mL) extracts exhibited maximum DPPH scavenging potential. Kumar et al. (2020) also evaluated the ethanolic bark and leaves extracts of B. utilis for their antioxidant activity and the result indicated that leaves extracts have high DPPH (47.91 ± 0.040%) percent inhibition than bark (66.92 ± 0.034%) extracts (Kumar et al. 2020).

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70.3.5 HEPATOPROTECTIVE ACTIVITY Duraiswamy et al. (2012) reported the in vitro and in vivo hepatoprotective activity of ethanolic and aqueous bark extracts of B. utilis against galactos­ amine (D-galN) induced hepatic damage. The extract doses 100 and 200 mg/ kg body weight were carried out against D-galN. However, dose 400 mg/kg body weight induces liver injury in rats. The biochemical parameters were restored significantly to normal and the minimum restoration was recorded at 62.5 µg/mL in both extracts. In vivo treatment with both ethanolic and aqueous extracts showed significant decreases in serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and TB and a significant elevation in serum levels of the total protein (TP), triglycerides (TGL), and albumin in dose-dependent manner. However, the normal liver morphology was completely lost and marked with centrilobular necrosis, focal necrosis, and bile duct proliferation in D-galN-treated mice liver. Such findings, therefore, suggested that B. utilis extracts may serve as a useful adjuvant in several clinical conditions associated with liver damage. 70.3.6 ANTIHYPERGLYCEMIC EFFECT The hydro–ethanolic extract of the stem wood of B. utilis was also found to possess significant antihyperglycemic activity on streptozotocin-induced diabetic rats. The administration of B. utilis bark extract was found to decline the blood glucose level from 1 to 3 h in diabetic rats than control. The maximum decline in blood glucose was noted in ethanolic extract at 3 h of treatment (Ahmad et al., 2008). 70.3.7 ANTIOBESITY POTENTIAL Kumar et al. (2020) carried out the screening of high-altitude Himalayan herbs including B. utilis for their antiobesity potential using lipase and amylase inhibition assay. The result indicated that B. utilis bark extracts have significantly higher lipase and amylase percent inhibition property than leaves extracts. The recorded lipase and amylase inhibition percent of bark extracts was 74.91 ± 0.02% and 64.89 ± 0.03% with respective IC50 values 59.71 and 36.96 (Kumar et al., 2020).

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70.3.8 ANTIMALARIAL ACTIVITY The scientific information is available on the antimalarial activity of B. utilis. However, the aqueous stem extract of Betula species (B. alnoides) has been reported for possessing antimalarial potential against chloroquine-sensitive Plasmodium berghei. A significant dose levels of 200, 400, and 600 mg/ kg body weight suppressed the parasitemia by 46.90, 58.39, and 71.26%, respectively. However, a single oral dose of 5000 mg/kg body weight had no significant variation in the biochemical parameters and toxic effects on the morphology and function of the liver and kidneys (Chaniad et al., 2019). 70.3.9 ANTIUROLITHIATIC ACTIVITY The hydroethanolic leaves extract of B. utilis has been reported for anti­ urolithiatic activity using ethylene glycol model in rat (Shah et al., 2017). The ethylene glycol (0.75%) with different ethanolic extract concentration or dose (250 and 500 mg/kg) along with standard (cystone 750 mg/kg) was administered to induce the urolithiasis in healthy male Wistar rats. The results showed a significant reduction in all the elevated biochemical parameters (blood urea nitrogen, calcium, creatinine, phosphate, oxalate, and uric acid), restored the urine pH to normal and increased urine volume as compared to the control. The study supports the urolithiasis potential of B. utilis alcoholic extracts (Shah et al., 2017). 70.3.10 ANTICANCER ACTIVITY The excessive reactive oxygen species (ROS) generate oxidative stress which causes significant cellular organelles and genes damage and subsequently leads to cell death. The oxidative stress plays an important role in the cancer progression as well as in cancer treatment (Manda et al., 2009). Mishra et al. (2016) evaluated B. utilis bark for in vitro anticancer activity. The bark extracted in methanol and fractionated with hexane, ethyl acetate, chloro­ form, n-butanol, and water and evaluated for in-vitro anticancer activity in different cancer cell lines [brain (A-172), breast (MCF-7, MDA-MB-468), cervical (HeLa), colon (DLD-1), head and neck (FaDu), liver (PLC/PRF/5), lung (A549), ovary (SK-OV-3), pancreas (MIAPaCa-2), prostate (DU145), and renal (786–0, Caki-1)]. Ethyl acetate fraction was found the most potent for inducing the cytotoxic activity against tested cancer cell lines. Column

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chromatography and spectroscopic analyses of ethyl acetate extract fraction leads to isolation and identification of six triterpenes including betulin, betu­ linic acid, lupeol, UA, oleanolic acid and β-amyrin. The in vitro cytotoxic analysis of isolated triterpenes against different cancer cell lines showed that UA have potent tumor cell-specific cytotoxic property against breast cancer. Ursolic acid exhibited selective apoptotic action for cancer cells because it attributed in activation of apoptosis pathway via upregulation of DR4, DR5, and PARP cleavage in cancer cell lines over non-tumorigenic cells. Ursolic acid also mediated intracellular ROS generation, mitochondrial membrane potential disruption and inhibited breast cancer migration which contributed to its anticancer effect (Mishra et al., 2016). Betulin is the major bioactive compound that can be easily converted to betulinic acid. According to the Wealth of India data (1985), betulinic acid is identified as a highly selective growth inhibitor of human melanoma, neuroectodermal, and malignant tumor cells and induces their apoptosis. Betulinic acid alone and in combination with ionizing radiation have strongly and consistently able to suppress the growth and colony forming ability of all human melanoma cell lines (Setzer et al., 2000). Zuco et al. (2002) studied the in vitro cytotoxicity of betulinic acid against a series of neoplastic cell lines, including melanomas, cell lung carcinomas, ovarian and cervical carcinomas. They found that a very narrow dose range (1.5–4.5 mg/mL) can exert antiproliferative activity on all the tested lines. Betulinic acid was also reported as a new cytotoxic agent against neuroectodermal tumor cells including glioblastoma, medulloblastoma, neuroblastoma, and Ewing’s sarcoma cells, which represented as common solid tumors of childhood (Fulda et al., 1999). The in vitro cytotoxic effect of betulinic acid against different cancer cell line have been investigated by various authors. The reported effective dose (ED 50) of betulinic acid was ranged for melanoma 1.1–4.8 μg/mL (Pisha et al., 1995); neuroblastoma, 2–10 μg/mL (Fulda et al., 1997); medulloblastoma, 3–15 μg/mL; glioblastoma, 5–16 μg/mL (Fulda et al., 1999); head and neck cancer, 8 μg/mL (Thurnher et al., 2003); ovarian carcinoma,1.8–4.5 μg/mL; cervix carcinoma, 1.8 μg/mL; lung carcinoma, 1.5–4.2 μg/mL (Zuco et al., 2002); and leukemia, 2–15 μg/mL (Ehrhardt et al., 2004). 70.3.11 ANTIINFLAMMATORY ACTIVITY Vary mild lipoxygenase (LOX) inhibition activity was recorded in metha­ nolic (18.74%) and aqueous extracts (28.78%) at 1 mg/mL leaves extracts. Lipoxygenases belongs to non-heme iron-containing dioxygenases family

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and play a vital role in the biosynthesis of leukotrienes. These leukotrienes have been hypothesized the significant role in the pathophysiology of many inflammatory and allergic diseases such as rheumatoid arthritis, psoriasis, asthmatic responses, and glomerular nephritis (Sircar et al., 1983; Bhat­ tacharjee, 2007; Kumaraswamy and Satish, 2008). KEYWORDS • • • • •

Himalayan silver birch Tridosa bioactive compounds pharmaceutical potential betulin

REFERENCES Ahmad, R.; Srivastava, S. P.; Maurya, R.; Rajendran, S. M.; Arya, K. R.; Srivastava, A. K. Mild Antihyperglycaemic Activity in Eclipta alba, Berberis aristata, Betula utilis, Cedrus deodara, Myristica fragrans and Terminalia chebula. Indian J. Sci. Technol. 2008, 1 (5), 1–6. Alakurtti, S.; Mäkelä, T.; Koskimies, S.; Yli-Kauhaluoma, J. Pharmacological Properties of the Ubiquitous Natural Product Betulin. Eur. J. Pharm. Sci. 2006, 29, 1–13. Anonymous. Betula. The Wealth of India: Raw Material, Vol. 2, 1st ed.; Publication Information Directorate, CSIR: New Delhi, 1988; p 148. Baser, K. H. C.; Demirci, B. Studies on Betula Essential oil. Arkivoc. 2007, 7, 335–348. Bhattacharjee, S. Reactive Oxygen Species and Oxidative Burst: Roles in Stress, Senescence and Signal Transduction in Plants. Curr. Sci. 2007, 89 (7), 1113–1121. Bisht, V. K.; Negi, J. S.; Bhandari, A. K.; Sundriyal, R. C. Anti-Cancerous Plants of Uttarakhand Himalaya: A Review. Int. J. Cancer Res. 2011, 7 (8), 192–208. Chaniad, P.; Techarang, T., Phuwajaroanpong, A.; Punsawad, C. Antimalarial Activity and Toxicological Assessment of Betula alnoides Extract Against Plasmodium berghei Infections in Mice. Evid. Based Complement. Altern. Med. 2019, 1–8. Chauhan, N. S. Medicinal and Aromatic Plants of Himachal Pradesh; Indus Publishing, 1999. Cichewicz, R. H.; Kouzi, S. A.; Chemistry, Biological Activity, and Chemotherapeutic Potential of Betulinic Acid for the Prevention and Treatment of Cancer and HIV Infection. Med. Res. Rev. 2004, 24, 90–114. Dung, N. X.; Moi, L. D.; Leclercq, P. A. Constituents of the Bark Oil of Betula alnoides Ham ex. D. Don from Vietnam. J. Essent. Oil Res. 1995, 7, 565–566.

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Duraiswamy, B.; Satishkumar, M. N.; Gupta, S.; Rawat, M.; Porwal, O.; Murugan, R. Hepatoprotective Activity of Betula utilis Bark on D-Galactosamine Induced Hepatic Insult. World J. Pharm. Pharma. Sci. 2012, 1, 456–471. Dzubak, P.; Hajduch, M.; Vydra, D.; Hustova, A.; Kvasnica, M.; Biedermann, D.; Markova, L.; Urban, M.; Sarek, J. Pharmacological, Activities of Natural, Triterpenoids, and Their Therapeutic Implications. Nat. Prod. Rep. 2006, 23, 394. Ehrhardt, H.; Fulda, S.; Fuhrer, M.; Debatin, K. M.; Jeremias, I. Betulinic Acid-Induced Apoptosis in Leukemia Cells. Leukemia 2004, 18 (8), 1406–1412. Fujoka, T.; Kashiwada, Y.; Kilkushi, R. E.; Consentino, L. M.; Ballas, L. M.; Jiang, J. B.; Janzen, W. P.; Chen, I. S.; Lee, K. H. Current Developments in the Discovery and Design of New Drug Candidates from Plant Natural Product Leads. J. Nat. Prod. 1994, 57, 243–249. Fulda, S.; Friesen, C.; Los, M.; Scaffidi, C.; Mier, W.; Benedict, M. et al. Betulinic Acid Triggers CD95 (APO-1/Fas)-and p53-Independent Apoptosis via Activation of Caspases in Neuroectodermal Tumors. Cancer Res. 1997, 57 (21), 4956–4964. Fulda, S.; Jeremias, I.; Steiner, H. H.; Pietsch, T.; Debatin, K. M. Betulinic Acid a New Cytotoxic Agent Against Malignant Brain-Tumor Cells. Int. J. Cancer. 1999, 82 (3), 435–441. Gallo, M. B.; Sarachine, M. J. Biological Activities of Lupeol. Int. J. Biomed. Pharm. Sci. 2009, 3 (1), 46–66. Ghaffari, M.; Ahmad, F.; Bin, H.; Samzadeh-Kermani, A. Biological Activity of Betulinic Acid: A Review. Pharm. Pharmacol. 2012, 3, 119–123. Gorsi, M. S.; Miraj, S. Ethenomedicinal Survey of Plants of Khanabad Village and Its Allied Areas, District Gilgit. Asian J. Plant Sci. 2002, 1 (5), 604–615. Holonec, L.; Ranga, F.; Cranic, D.; Truta, A.; Socaciu, C. Evaluation of Betulin and Betulinic Acid Content in Birch Bark from Different Forestry Areas of Western Carpathians. Not. Bot. Horti. Agrobo. 2012, 40, 99–105. Hu, Z.; Guo, N.; Wang, Z.; Liu, Y.; Wang, Y.; Ding, W. et al. Development and Validation of an LC-ESI/MS/MS Method with Precolumn Derivatization for the Determination of Betulin in Rat Plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2013, 939, 38–44. Ju, E. M.; Lee, S. E.; Hwang, H. J.; Kim, J. H. Antioxidant and Anticancer Activity of Extract from Betula platyphylla var. japonica. Life Sci. 2004, 74, 1013–1026. Khan, M. A.; Atta-ur-Rahman. Karachic Acid: A New Triterpenoid from Betula utilis. Phytochemistry 1975, 14, 789–791. Krasutsky, P. A. Birch Bark Research and Development. Nat. Prod. Rep. 2006, 23, 919–942. Kumar, M.; Guleria, S.; Chawla, P.; Khan, A.; Modi, V. K.; Kumar, N.; Kaushik, R. AntiObesity Efficacy of the Selected High Altitude Himalayan Herbs: In Vitro Studies. J. Food Sci. Technol. 2020, 57, 3081–3090. Kumaraswamy, M. V.; Kavitha, H. U.; Satish, S. Antibacterial Evaluation and Phytochemical Analysis of Betula utilis D. Don Against Some Human Pathogenic Bacteria. Adv. Biol. Res. 2008, 2, 21–25. Kumaraswamy, M. V.; Satish, S. Free Radical Scavenging Activity and Lipoxygenase Inhibition of Woodfordia fructicosa Kurz and Betula utilis Wall. Afr. J. Biotechnol. 2008, 7 (12), 2013–2016. Kuznetsova, S. A.; Kuznetsov, B. N.; Skvortsova, G. P.; Vasileva, N. Y.; Skurydina, E. S.; Kalacheva, G. S. Development of the Method of Obtaining Betulin Diacetate and Dipropionate from Birch Bark. Chem. Sustain. Dev 2010, 18, 265–272.

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Laszczyk, M. N. Pentacyclic, Triterpenes of the Lupane, Oleanane and Ursane Group as Tools in Cancer Therapy. Planta Med. 2009, 75, 1549–1560. Manda, G.; Nechifor, M. T.; Neagu, T. Reactive Oxygen Species, Cancer and Anti-Cancer Therapies. Curr. Chem. Biol. 2009, 3, 342–366. Mayaux, J. F.; Bousseau, A.; Pauwels, R.; Huet, T.; Henin, Y.; Dereu, N.; Evers, M.; Soler, F.; Poujado, C.; De Clercq, E.; Le Pecq, J. B. Activation and Inhibition of Proteasomes by Betulinic Acid and Its Derivatives. Natl. Acad. Sci. 1994, 91 (9), 3564–3568. Mishra, T.; Arya, R. K.; Meena, S.; Joshi, P.; Pal, M.; Meena, B.; Upreti, D. K.; Rana, T. S.; Datta, D. Isolation, Characterization and Anticancer Potential of Cytotoxic Triterpenes from Betula utilis bark. PloS One 2016, 11 (7), 1:14. Mishra, T.; Chandra, P.; Kumar, B.; Baleshwar, M.; Joshi, P.; Rana, T. S.; Upreti, D. K.; Pal, M. Phytochemical Profiling of the Stem Bark of Betula utilis from Different Geographical Regions of India Using UHPLC-ESI-MS/MS. Anal. Sci. Adv. 2020, 1–8. Nadakarni, K. M. Betula utilis D. Don. Indian Mater. Med., 1976, 1, 198–1296. Nath, S. C.; Bardoloi, D. N.; SarmaBoruah, A. K. Methyl Salicylate- The Major Component of the Stembark Oil of Betula alnoides Buch-Ham, J. Essent. Oil Res. 1991, 3, 463–454. O’Connell, M. M.; Bentleya, M. D.; Campbell, C. S.; Cole, B. J. W. Betulin and Lupeol in Bark from Four White-Barked Birches. Phytochemistry 1988, 27, 2175–2176. Orsini, S.; Ribechini, E.; Modugno, F.; Klügl, J.; Di Pietro, G.; Colombini, M. Micromorphological and Chemical Elucidation of the Degradation Mechanisms of Birch Bark Archaeological Artefacts. Herit. Sci. 2015, 3 (1), 1–11. Pal, M.; Mishra, T.; Kumar, A.; Baleshwar, Upreti, D.; Rana, T. Chemical Constituents and Antimicrobial, Potential, of Essential Oil from Betula utilis Growing in High Altitude of Himalaya, (India). J. Essent. Oil Bear. Plants. 2015a, 18 (5), 1078–1082. Pal, M.; Mishra, T.; Kumar, A.; Upreti, D.; Rana, T. Characterization of Fatty Acids in the Bark of Growing in High Altitudes of Himalaya. Chem. Nat. Compd. 2015b, 2 (51): 326–327. Pisha, E.; Chai, H.; Lee, I. S.; Chagwedera, T. E.; Farnsworth, N. R.; Cordell, G. A.; et al. Discovery of Betulinic Acid as a Selective Inhibitor of Human Melanoma That Functions By Induction of Apoptosis. Nat. Med. 1995, 1 (10), 1046–1051. Rastogi, S.; Pandey, M. M.; Rawat, A. K. S. Medicinal Plants of the Genus Betula—Traditional Uses and a Phytochemical–Pharmacological Review. J. Ethnopharmacol. 2015, 159, 62–83. Sakarkar, D. M.; Deshmukh, V. N. Ethnopharmacological Review of Traditional Medicinal Plants for Anticancer Activity. Int. J. Pharm Tech. Res. 2011, 3, 298–308. Saleem, M. Lupeol a Novel Anti-Inflammatory and Anti-Cancer Dietary Triterpene. Cancer Lett. 2009, 285, 109–115. Selvam, A. B. D. Inventory of Vegetable Crude Drug Samples Housed in Botanical Survey of India, Howrah. Pharmacogn. Rev. 2008, 2 (3), 61–94. Setzer, E.; Pimental, E.; Wacheck, V.; Schlegal, W.; Pehamberger, H.; Jansen, B.; Kodym R.; Effects of Betulinic Acid Alone and in Combination with Irradiation in Human Melanoma Cells. J. Investig. Dermatol. 2000, 114 (5), 935–940. Shah, S. K.; Patel, K. M.; Vaviya, P. M. Evaluation of Antiurolithiatic Activity of Betula utilis in Rats Using Ethylene Glycol Model. Asian J. Pharm. Res. 2017, 7 (2), 81–87. Shaw, K.; Roy, S.; Wilson, B. Betula utilis. The IUCN Red List of Threatened Species. IUCN. 2014, 1–9. Shukla, S.; Mishra, T.; Pal, M.; Meena, B.; Rana, T. S.; Upreti, D. K. Comparative Analysis, of Fatty, Acids and Antioxidant Activity of Betula utilis Bark Collected from Different Geographical Region of India. Free Radicals Antioxidants 2017, 7 (1), 80–85.

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Sircar, J. C.; Schwender, C. F.; Johnson, E. A. Soybean Lipoxygenase Inhibition by Nonsteroidal Anti-Inflammatory Drugs. Prostagalndins 1983, 25 (3), 393–396. The Wealth of India. A Dictionary of Indian Raw Material and Industrial Product. Cancer Res. 1985, 1, p.185. Thurnher, D.; Turhani, D.; Pelzmann, M.; Wannemacher, B.; Knerer, B.; Formanek, M.; Wacheck, V.; Selzer, E. Betulinic Acid a New Cytotoxic Compound Against Malignant Head and Neck Cancer Cells. Head Neck 2003, 25 (9), 732–740. Wani, M. S.; Gupta, R. C.; Munshi, A. H.; Pradhan, S. K. Phytochemical Screening, Total Phenolics, Flavonoid Content and Antioxidant Potential of Different Parts of Betula utilis D. Don from Kashmir Himalaya. Int. J. Pharm. Sci. Res. 2018, 9 (6), 2411–2417. Xu, H. X.; Zeng, F. Q.; Wan, M.; Sim, K. Y. Anti-HIV Triterpene Acids from Geum japonicum. J. Nat. Prod. 1996, 59, 643–645. Yin, J.; Ma, H.; Gong, Y.; Xiao, J.; Jiang, L.; Zhan, Y. et al. Effect of MeJA and Light on the Accumulation, of Betulin, and Oleanolic Acid in the Saplings of White Birch (Betula platyphylla Suk.). Am. J. Plant Sci. 2013, 4, 7–15. Zobel, D.; Singh, S. P. Himalayan Forests and Ecological Generalizations. BioSci. 1997, 47, 735–745. Zuco, V.; Supino. R.; Righetti, C.; Cleris, L.; Marchesi, E.; Gambacorti C.; Formelli, F. Selective Cytotoxicity of Betulinic Acid on Tumor Cell Lines, But Not on Normal Cells. Cancer Lett. 2002, 175 (1), 17–25.

CHAPTER 71

A Comprehensive Review on Phytochemistry and Pharmacological Potential of Musanga cecropioides R.Br. ex Tedlie VISHAL P. DESHMUKH Department of Botany, Jagadamba Mahavidyalaya, Achalpur City, Dist-Amravati, Maharashtra, India E-mail: [email protected]

ABSTRACT Musanga cecropioides R.Br. ex Tedlie is an important tree with medicinal importance scattered in tropic rain forest of West Africa. It is also known as the umbrella tree or corkwood. Root sap of this tree is a rich source of many vital phytoconstituents. Cecropiacic acid, musangic acid and cecropic acids are important compounds reported from M. cecropioides. Locally it is mostly used to cure rheumatism, leprosy, cough chest infection, trypanoso­ miasis, hypertension, toothache, malaria, jaundice, wound, etc. M. cecropi­ oides reveals strong antibacterial, antifungal, antioxidant, hepatoprotective, hypotensive, antidiabetic and other important activities. This chapter gives phytochemical diversity and pharmacological activities of M. cecropioides. 71.1

INTRODUCTION

Musanga cecropioides R.Br. ex Tedlie belongs to the family Cecropiaceae is a fast-growing tree distributed all over mixed deciduous tropical rain forest of West Africa stretching from Guinea to Congo (Ayinde et al., 2006). Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Taxonomically this genus is quite critical and is placed in families like

Urticaceae (Corner, 1962), Moraceae (Keay, 1989), and most recently in

Cecropiaceae (Takhtajan, 2009; Nyananyo and Offiong, 2012). It can grow up to 20 m and forms an umbrella-shaped crown on a straight trunk, interest­ ingly there are stilt roots up to 3 m from ground. Due to its shape, it is known as the umbrella tree or corkwood; parasolier in French and “Oghohen” in Nigeria. Yoruba, Igbo, and Efik ethnic groups of Nigeria called it by “Aga” or “Agbawo,” “Onru,” and “Uno,” respectively (Etuk, 2006; Idu et al., 2008). Traditionally in West Tropical African and Cameroon folk medicine leaves, stem bark and sap of M. cecropioides are used regularly to cure rheumatism, leprosy, cough chest infection, trypanosomiasis, hypertension, toothache, malaria, jaundice, wound, etc. (Burkill, 1985; Betti and Lejoly, 2009). 71.2

BIOACTIVES

Chemical screening revealed the occurrence of alkaloids, anthraquinones, cardiac glycosides, flavonoids, phlobatannins, reducing sugars, saponins, and tannins from aqueous and hydromethanolic extract of M. cecropioides stem bark (Adeneye et al., 2006a; Ayinde et al., 2003; Ayinde et al., 2006, Omoruyi et al., 2015; Legbosi and Ellis, 2018). Liquid extract of M. cecro­ pioides contain alkaloids, anthraquinones, anthocyanosides, cardiac glyco­ sides, cyanogenic glycosides, flavonoids, phlobatannins, saponins, tannins, and reducing sugar (Peter et al., 2015). Hydro-ethanolic extracts of M. cecropioides leaves and bark revealed the presence of alkaloids, flavonoids, tannins, anthraquinone free and bound, saponins, and cardiac glycosides (Kadiri and Ajayi, 2009). Phytochemical examination of the M. cecropioides adventitious root sap cited the presence of tannins, saponins, soluble, and total oxalate (Uwah et al., 2013). In another analysis of M. cecropioides root sap only polyphenols and saponosides were detected (Azame et al., 2020). Alkaloids, phenols, coumarins, gallic tannins, sterols, and triterpenes were derived from hydro-ethanolic extract of M. cecropioides stem bark, however, in foliage extract, flavonoids were reported in addition to abovecited phytoconstituents (Tchouya and Nantia, 2015). Hydro-methanolic extracts of M. cecropioides leaves confirmed alkaloids, saponins, tannins, flavonoids, and cardiac glycosides (Nwidu et al., 2018). Aqueous extract of M. cecropioides leaves identified coumarins, flavonoids, phenols, tannins, and triterpenes (Meva et al., 2017). Hydro-ethanolic extracts of M. cecro­ pioides recorded the presence of alkaloids, catechic tannins, triterpenes,

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phenolic compounds, and saponins (Nyunaï et al., 2016). Methanol extract of M. cecropioides trunk bark tested positive for alkaloids, saponins, sterols, reducing sugars, flavonoids, terpenes, phenols, coumarins, glycosides, triterpenes, and tannins (Mabeku et al., 2011; Didier et al., 2018; Legbosi and Ibor, 2019; Elisée et al., 2020). Qualitative analysis of hydro-alcoholic extracts of M. cecropioides stem bark and leaves identified occurrence of alkaloids, terpenoids, sterols, flavonoids, saponins, phenols, and tannins (Ibitoye et al., 2020). Aqueous, ethanolic, and hydro-ethanolic extracts of M. cecropioides stem revealed presence of secondary metabolites like alkaloids, polyphenols, flavonoids, tannins, steroids, terpenes, and saponins, however, aqueous extract is deficient in saponins (Joseph et al., 2020). Two phenolic compounds namely 3,4-dihydroxybenzoic acid and 3,4-dihydroxybenzalde­ hyde were isolated from ethyl acetate fraction of M. cecropioides stem bark aqueous extract (Ayinde et al., 2007). Cecropiacic acid and its methyl ester, a novel pentacyclic A-ring seco triterpenoids along with methyl tormentate, 2α-hydroxy oleanolic acid, and ursolic acid were reported from ethyl acetate fraction of M. cecropioides stem bark (Lontsi et al., 1987). Ethyl acetate fraction of M. cecropioides stem bark yielded another A-ring seco triterpene, musangic acid, additionally benthamic acid, 3-rhamnosyl benthamic acid, tormentic acid and oleanolic acid, ursolic acids and their 2α-hydroxy forms were also extracted (Lontsi et al., 1989). From ethyl acetate fraction of M. cecropioides trunk wood, six methyl esters of pentacyclic triterpenic acids were isolated with cecropic acid as first record to this plant (Lontsi et al., 1990). n-butanol fraction of methanol extract of M. cecropioides rootwood reported novel musancropic acids A and B, an A-ring contracted triterpenes (Lontsi et al., 1991a). Cecropiacic acid and two new seco-derivatives, namely musangic acids A and B were successfully isolated from methanol extract of M. cecropioides rootwood (Lontsi et al., 1991b). Novel methyl musangicate (musangicic acid) and methyl euscaphate were the two penta­ cyclic triterpenes successfully derived from methanol extract of M. cecro­ pioides rootwood (Lontsi et al., 1992). Along with methyl ursolate, methyl oleanolate, methyl 2α-hydroxyursolate, methyl 2α-hydroxyoleanolate, and methyl pomolate, a novel ursane-type saponin methyl kalaate (kalaic acid) was extracted from ethyl acetate fraction of M. cecropioides stem bark (Lontsi et al., 1998a). Methyl tormentate, methyl 2-acetyltormentate, methyl 28-glucosyltormentate, methyl pomolate, methyl euscaphate along with new pentacyclic triterpene, and methyl cecropioate (Cecropioic acid) were extracted from methanol extract of M. cecropioides rootwood (Lontsi et al., 1998b). Triterpene acids such as tormentic acid, 2-acetyl tormentic acid,

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3-acetyl tormentic acid, and euscaphic acid were reported first time from ethanol extract of M. cecropioides root wood (Ojinnaka and Okogun, 1985). Gas chromatography analysis of M. cecropioides dried leaves confirmed the presence of nine essential amino acids with highest representation (20.39 ± 0.39 mg/100 g DW) of Serine (Shemishere et al., 2018).

FIGURE 71.1 Triterpenoid acids, saponins, and phenolic compounds isolated from M. cecropioides (Lontsi et al., 1987, 1989, 1990, 1991a, 1991b, 1992, 1998a, 1998b; Ayinde et al., 2007).

71.3

PHARMACOLOGY

71.3.1 ANTIBACTERIAL ACTIVITY Methanol and dichloromethane (1:1) extract of M. cecropioides leaves showed most potent antibacterial activity against Mycobacterium

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smegmatis (ATCC 23246) with MIC of 65 µg/mL, whereas moderate activity with MIC of 130 µg/mL was observed against both Moraxella catarrhalis (ATCC 14468) and Mycobacterium aurum (NCTC 10437) and poor inhibition recorded against Klebsiella pneumoniae (ATCC 13883) and Staphylococcus aureus (ATCC 25923) with 1000 and 4000 µg/mL MIC, respectively (Fomogne-Fodjo et al., 2014). Alkaloid extract and fractions of the M. cecropioides leaves and stem revealed significant inhibitory activity against all four bacterial strains; however, against B. subtilis alkaloid extract of the leaves proved better with highest zone of inhibition (18.6 ± 1.1 mm) than stem bark alkaloid fraction (16.3 ± 1.5 mm ZI) (Ibitoye et al., 2020). Amongst the tannic, ethanolic, and hydroethanolic extract of M. cecropioides bark, tannic extract revealed broad spectrum activity against all examined bacterial strains except P. aeruginosa HM 601and S. enteritidis NR4311 with MIC range of 6.25 and 12.5 mg/mL. Based on MBC/MIC ratio, tannic and ethanol extract revealed strongest bactericidal activity against E. coli ATCC 25922 and S. enteritidis NR 4311 and the ratio is equal to 1 (Joseph et al., 2020). Methanol and hydroethanolic extract of M. cecropioides stem bark revealed low activity against K. pneumoniae (Mabeku et al., 2011). Adventitious root sap of M. cecropioides depicts significant antimicrobial activity against E. coli, Streptococcus sp and Staphylococcus sp, however, the sap proved most active against E. coli with 20 mm zone of inhibition (Uwah et al., 2013). 71.3.2 ANTIFUNGAL ACTIVITY Alkaloid extract and fraction of the M. cecropioides leaves and stem signif­ icantly inhibited growth of Candida albicans at 500 mg/mL concentration and both extracts recorded 20 and 18 mm zone of inhibition, respectively (Ibitoye et al., 2020). Methanol and hydroethanolic extract of M. cecropi­ oides stem bark demonstrated very low (9 and 10 mm) activity against C. albicans and Candida glabrata, respectively (Mabeku et al., 2011). Hot water and ethanol extract of M. cecropioides leaves showed preservative potential and can apply for blocking fungal attack (Okon-Akan et al., 2020). C. albicans is tested against adventitious root sap of M. cecropioides, the sap found to inhibit fungal growth with 14 mm zone of inhibition (Uwah et al., 2013).

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71.3.3 ANTIOXIDANT EFFICACY A study performed in Cameroon showed that in DPPH assay, tannic extract M. cecropioides bark depicted strongest antioxidant potential with IC50, EC50 and PA values of 19.673 ± 0.555, 1.967 ± 0.055 µg/mL and 50.859 ± 1.432 mL/µg, respectively, however, aqueous extract demonstrated weakest action with 237.89 ± 0.435, 23.789 ± 0.044 µg/mL and 4.449 ± 1.316 mL/ µg, respectively (Joseph et al., 2020). Hydro-ethanolic extract of stem bark of M. cecropioides revealed highest inhibitory activity at 40 mg/mL in DPPH assay and the measured IC50 value is 6.23; also 40 mg/mL concentration of extract showed maximum (387.00 ± 15.40) ferric reducing antioxidant power (Nyunaï et al., 2016). In DPPH radical scavenging assay, hydro-ethanolic extract of M. cecropioides stem bark showed significantly higher antioxidant potential with IC50 = 0.29±0.02 µg/mL as compared with leaves with IC50 = 6.36 ± 0.89 µg/mL (Tchouya and Nantia, 2015). 71.3.4

HEPATOPROTECTIVE ACTIVITY

A total of 125, 250, and 500 mg/kg body weight of M. cecropioides stem bark aqueous extract significantly retard elevated serum alanine, aspartate aminotransferase, and ornithine carbamoyl transferase in rats with hepa­ tocellular injuries induced by carbon tetrachloride and acetaminophen. Pretreated rats with aqueous extract revealed protection of liver tissues from toxic actions of carbon tetrachloride and acetaminophen (Adeneye, 2009). M. cecropioides aqueous stem bark extract significantly reduced alkaline phosphatase, alanine amino-transferases, aspartate amino-transferases levels in serum, and lipid peroxidation marker; also application of extract notably decreases the severity of hepatic damage (Omoruyi et al., 2015). Rats orally treated with carbon tetrachloride show raised serum biochemical param­ eters and fat deposits, inflammatory infiltrates in the liver histology, on contrary declined total protein, catalase, and superoxide dismutase were also recorded. Pretreatment of rats with stem bark aqueous extract bring all above parameters to normal stage (Omoruyi and Enogieru, 2018). Raised levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, conjugated bilirubin, and total bilirubin due to carbon tetrachloride were brought down significantly with administration of hydro-methanolic leaves extract of M. cecropioides. Histopathological occurrence of mitotic bodies and fibrin deposition areas in the rats treated with 141.4 mg/kg extract was correlated with ongoing tissue repair processes (Nwidu et al., 2018).

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71.3.5 HYPOTENSIVE ACTIVITY In a study performed in Nigeria, dose-dependent drop down in the systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate is observed in rats after intravenous injection of M. cecropioides stem bark aqueous extract (Adeneye et al., 2006b). Aqueous extract of M. cecro­ pioides stem bark showed dose-dependent decrease in mean arterial pressure (mean arterial pressure fall at 10 and 40 mg/kg dose is 4.51 ± 0.5 mmHg and 65.23 ± 6.28 mmHg, respectively); also in isolated rabbit heart, the ampli­ tude and force of contraction are astonishingly diminished at 1.0 mg/mL aqueous extract (Ayinde et al., 2003). 3,4-dihydroxybenzaldehyde isolated from ethyl acetate fraction of M. cecropioides stem bark revealed 12.61 ± 2.45 and 17.88 ± 0.73 mmHg fall of arterial blood pressure in rabbits at 2.5 and 10 mg/kg of compound respectively; also pretreatment of atropine or promethazine does not affect the potency of compound (Ayinde et al., 2010). Intravenous 15–30 mg/kg dose of M. cecropioides leaves aqueous extract showed blood pressure fall in hypertensive (35–57%) and normotensive rats (27%) in comparison to saponins derived from aqueous extract showing 55% and 30% of blood pressure fall in hypertensive and normotensive rats, respectively (Dongmo et al., 1996). M. cecropioides leaves aqueous extract and saponin derived from extract revealed dose-dependent fall of blood pres­ sure in hypertensive and normotensive rats and potencies of these extracts was increased (more than 62%) by intravenous treatment of phentolamine. On the contrary, salbutamol generates a 30% reduction in hypotensive effect of aqueous extract (Dongmo et al., 2002). The aqueous extract of M. cecro­ pioides leaves showed significant lowering of blood pressure of the cats only and failed to depict it in rats; on the contrary n-butanol extract observed significant hypotensive effect in both cats and rats (Kamanyi et al., 1996). 71.3.6 TOXICITY EFFECTS Oral administration of M. cecropioides stem bark extract (LD50 = 3000 mg/ kg body weight p.o.) showed no mortality in rats, it also revealed significant reduction in weight gain, differential eosinophil count, and rise in serum creatinine. Interestingly, in tested rats, the extract hardly affected organ weights, other serum electrolytes, liver enzymes, and other hematological indices (Adeneye et al., 2006a). In acute toxicity study, 50–50% combined dose of M. cecropioides bark trunk and C. micranthum fruit at the end of 14 days reported no physiological changes with first 5 days aggressiveness

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in rats as an exception and LD50 > 5000 mg/kg; Subacute toxicity of this combined extract revealed salivary secretions, nasal excretions and sneezes (rats 1, 2, 3) during the 3rd and 4th week of treatment. Combined extract hardly causes any changes in urea and creatinine (Didier et al., 2018). M. cecropiodes leaves methanol extract up to 3.0 g/kg showed no mortality and behavioural changes in acute toxicity test (Eboji and Sowemimo, 2014). The 50–50% combined dose of M. cecropioides bark trunk and fruits of Picralima nitida revealed no abnormalities in acute toxicity except aggressiveness in rats on the first day and as no mortality recorded the LD50 > 5000 mg/kg. In subacute toxicity assays overall increase in body weight of rats was recorded and many blood parameters were significantly lowered than control (Elisée et al., 2020). In an acute toxicity test, a single oral dose of M. cecropioides hydromethanolic stem-bark extract revealed no behavioral toxicity and deaths in rats. Although subchronic tests showed significant elevation in male and female rats’ average body weight, but with no effect on organ weight, hematology, lipid peroxidation, lipid profile, and antioxidant activities. Oral administration of 125 mg/kg extract is found safe and nontoxic (Legbosi and Ellis, 2018). Various toxicities, modified electrolytes profiles, and histomorphological changes in liver, kidney, and lungs of rats induced by valproic acid were significantly turned round by subacute oral administra­ tion of M. cecropiodes stem bark methanol extract (Legbosi and Ibor, 2019). Hydro-methanolic extracts of M. cecropioides leaves revealed toxicity above 2000 mg/kg dose and LD50 = 1414.2 mg/kg (Nwidu et al., 2018). Aqueous extract of M. cecropioides stem bark showed acute toxicity LD50 = 2000 mg/kg with no mortality proving its less toxic nature. In determination of subacute toxicity oral dose of 200, 300, and 600 mg/kg for 28 days revealed that extract hardly affects relative organ weight, also no significant changes were observed in biochemical markers, hematological analysis, and serum lipid profile. Micro-observation failed to reveal any histological changes in organs like liver and kidney (Medou et al., 2019). 71.3.7 HYPOGLYCEMIC EFFECTS Of 70% ethanol extract of stem bark of M. cecropioides has hypoglycaemic potential. Of 200, 300, and 400 mg/kg body weight of the extract showed dose-dependent glucose reduction with minor fluctuation (Nyunaï et al., 2016). Oral administration of aqueous and ethanol extract of M. cecropioides stem bark at 250, 500, and 1000 mg/kg for 14 days revealed dose-dependent

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hypoglycemic effects in normal rats by declining fasting plasma glucose levels (Adeneye et al., 2007). 71.3.8 ANTIDIABETIC EFFECTS Oral treatment of aqueous and ethanol extract of M. cecropioides stem bark at 250, 500, and 1000 mg/kg dose for 14 days to alloxan-induced diabetic rats showed dose-related antidiabetic effects. At equal dose of treatment, ethanol extract proved better in showing significant antidiabetic activity than aqueous extract (Adeneye et al., 2007). In the alloxan-induced diabetic rats, ethyl acetate, butanol, dichloromethane, and n-hexane fractions of M. cecropioides at 200 mg/kg dose revealed significant reduction in increased blood glucose level. Amongst these fractions, dichloromethane fraction proved most potent in lowering blood sugar (Ajayi and Igboekwe, 2013). 71.3.9 OXYTOCIC EFFECTS Aqueous extract of M. cecropioides stem bark showed dose dependant enhancement in the force of uterine contraction in rat-isolated uterus. Least uterine contraction force of 1.10 ± 0.15 g was generated by 12.5 mg dose of extract while, greatest uterine contraction force of 2.53 ± 0.6 g was produced by 1600 mg dose of extract. Oral co-administration of oxytocin and aqueous extract generated significantly superior force of uterine contraction than alone any of these two (Ayinde et al., 2006). M. cecropioides aqueous and n-butanol leaf extract generate well-sustained contractile effect on the uterine strips of rats, while chloroform extract unable to show any effect. Above contractile effects can be antagonized with treatment of ethanol (Kamanyi et al., 1992). Ethanol extract of Ghanaian M. cecropioides folium induce force of uterine muscle contraction similar to 70% of acetylcholine generated utmost response (Larsen et al., 2016). 71.3.10 EFFECT ON GASTROINTESTINAL MOTILITY M. cecropiodes leaves aqueous extract revealed dose-related inhibition of pendular movement of the rabbit ileum and highest inhibition (77.1%) was recorded for 20 mg/mL of extract (Aziba and Gbile, 2000).

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71.3.11 ANALGESIC ACTIVITY Intraperitoneal injection of aqueous extract of M. cecropioides showed doserelated reduction of acetic acid induced writhing in mice and the effect of 20 mg/kg extract is equivalent to 10 mg/kg of paracetamol (Aziba and Gbile, 2000). In acetic acid induced squirming method treatment with M. cecropi­ oides leaves aqueous extract didn’t show any symptoms of pain (Balla and Ahmed, 2017). In the formalin-induced pain test, 50, 100, 200, and 400 mg/ kg extract revealed nondose dependent significant drop down of the paw licking time, it is reported more distinctly in the second phase. In the tail immersion and hot plate tests, extract showed nondose dependent significant increase in mean reaction time of mice as compared to control (Owolabi and Olokpa, 2011). Rats treated with aqueous extract of M. cecropioides did not show symptoms of pain like abdominal pain, forelimb torsion and trunk stretching showing inhibitory potential of extract (Senjobi et al., 2012). 71.3.12 INHIBITORY EFFECTS ON AORTA CONTRACTION Contractile responses of noradrenaline and high Ca2+ 55 mM in rats are inhibited by M. cecropiodes extract (Aziba, 2005). 71.3.13 ANTIHYPERTENSIVE EFFECT Aqueous extract of M. cecropioides leaves showed dose dependant antihy­ pertensive effects in rats (Balla and Ahmed, 2017). In smooth and skeletal muscles in rodents, M. cecropioides aqueous extract demonstrated anti­ hypertensive potential (Senjobi et al., 2012). 71.3.14 VASODILATING PROPERTIES M. cecropiodes leaves aqueous extract induces 21.8 ± 2.4% of endothelium­ dependent relaxation of aortic ring segments, while the acetylcholine generates utmost 85.3 ± 4.7% relaxation. In angiotensin converting enzyme inhibition test, at low concentration M. cecropioides methanol extract depict complete inhibition of angiotensin converting enzyme (Dongmo et al., 2002). In baseline aortic rings, aqueous extract of M. cecropioides leaves showed dose dependent contraction. In the absence and presence of endothelium,

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extract reported maximal contractile response of 1095 ± 70 and 890 ± 55 mg, respectively, with EC50 values of 9.37 (± 1.51) × 10−4 and 2.63 (± 0.14) × 10−3 g/mL, respectively (Kamanyi et al., 1991). 71.3.15 ANTI-INFLAMMATORY ACTIVITY M. cecropiodes leaves methanol extract showed dose-related inhibition in carrageenan-induced paw edema in rats and highest inhibition was recorded at 150 mg/kg dose (71.47%, 90 min). In case of histamine and serotonininduced paw edema assay, extract showed 83.33% and 45% inhibition at 120 min, respectively. The extract at 200 mg/kg dose revealed 59.20% of inhibi­ tion in xylene induced ear edema in mice (Eboji and Sowemimo, 2014). In Carrageenan-induced rat paw edema test, out of 50, 100, 150, and 200 mg/ kg doses of methanol extract of M. cecropioides leaves, highest inhibition (71.43%) of edema was achieved with 150 mg/kg dose of the extract at 90 min. In the serotonin-induced rat paw edema 150 mg/kg dose of extract revealed gentle (45.0%) inhibitory effect at 120 min compared to standard. In the histamine model, the dose of 150 mg/kg extract, proved much better than standard and exhibited 83.33% inhibitory effect at 120 min. Xylene-induced ear edema revealed dose-dependent inhibition of edema with highest 59.25% inhibition at 200 mg/kg dose of extract (Sowemimo et al., 2015). 71.3.16 CYTOTOXIC ACTIVITY In cytotoxic assay using Vero cells, tannic extract of M. cecropioides stem showed very poor cytotoxic activity with cytotoxic median moncentration (CC50) value > 1000 μg/mL (Joseph et al., 2020). Aqueous extract of M. cecropioides stem bark showed weaker activity with CC50 values of >64, >6.6, and >1.5 against MRC-5, MR-C5/Tbb, and MRC-5/T.cruzi cells respectively (Musuyu Muganza et al., 2012). 71.3.17 ANGIOTENSIN CONVERTING ENZYME—INHIBITION ACTIVITY Methanolic extract of M. cecropioides leaves having highest (13%) procyani­ dins showed 100% inhibition of angiotensin-converting enzyme at 0.33 mg/ mL concentration compared to other plants (Lacaille-Dubois et al., 2001).

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71.3.18 WOUND HEALING ACTIVITY Wounded rats after receiving M. cecropioides root sap reported less inflamed wounds and on 21st day significant increase in wound healing activity were observed (Azame et al., 2020). 71.3.19 ANTIPROTOZOAL ACTIVITY Study performed in Democratic Republic of Congo revealed that aqueous extract of M. cecropioides stem bark possesses strong activity against Trypanosomam brucei and Leishmania infantum with IC50 values of 9.62 and 6.35 µg/mL (Musuyu Muganza et al., 2012). 71.3.20 EFFECTS ON SERUM LIPIDS Aqueous, ethanolic, and acetylated ethanolic extracts of the M. cecropioides budsheath after 27-day oral treatment, female Sprague Dawley rats showed significant elevation in fasting serum triglycerides. Nondose dependent decrease in serum cholesterol levels was observed in rats treated with these three extracts (Odesanmi et al., 2000). 71.3.21 ANTIDIARRHEAL ACTIVITY In case of castor oil-induced diarrhea in rats, 100, 200, and 400 mg/kg doses of M. cecropioides stem bark alcoholic extract revealed dose-dependent antidiarrheal activity confirmed through lessening in the number and fecal material mass generated (Owolabi et al., 2010). 71.3.22 ADAPTOGENIC EFFECT Oral feeding of the M. cecropioides aqueous extract of 100, 200, and 300 mg/kg doses significantly escalating swimming survival time (3.01± 0.92, 3.34±0.18, 3.73±0.98 min respectively) compared to the 2.25 ± 0.08 mins for control group. Additionally in chronic cold stress, dose-dependent decrease in blood glucose, blood cells and the urinary ascorbic acid were recorded compared with control (Owolabi et al., 2019).

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71.3.23 DIURETIC EFFECTS Aqueous extract of M. cecropioides at 1.33 mg/100 mL concentration significantly enhances urinary output and sodium flux compared to control (Peter et al., 2015). 71.3.24 ANTINOCICEPTIVE ACTIVITY In mouse writhing test, ethanol extract of M. cecropioides leaves at 50, 100, and 200 mg/kg doses revealed significant decrease in number of writhes as the dose concentration increases and 200 mg/kg dose showed highest 55.12% of inhibition. Ethanol extract in formalin test dose-dependently inhibited nociceptive reaction and highest inhibition of 66.81% was recorded against 200 mg/kg of extract dose. In the tail clip test, ethanol extract at 200 mg/kg dose revealed enhanced reaction latency time with 17.02% inhibition at 90 min (Sowemimo et al., 2015). 71.3.25 α-GLUCOSIDASE AND α-AMYLASE INHIBITORY ACTIVITIES During demonstration of α-glucosidase inhibition activity, A, B, and C frac­ tions obtained from aqueous extract of M. cecropioides stem bark showed 14.84, 83.10, and 69.86 µg/mL inhibitory concentrations, respectively, however, fraction D of extract perform better with IC50 value of 0.70 µg/ mL. In the case of α-amylase inhibitory activity, fractions A-D showed IC50 values of 63.51, 221.5, 691.1, and 604.4 µg/mL, respectively. Amongst all tested fractions, fraction A revealed inhibiting action against α-amylase and α-glucosidase, whereas potent α-glucosidase inhibition activity was demon­ strated by fraction D (Tchamgoué et al., 2020). KEYWORDS • • • • •

cecropiacic acid medicinal plant Musanga cecropioides musangic acid root sap

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REFERENCES Adeneye, A. A. Protective Activity of the Stem Bark Aqueous Extract of Musanga cecropioides in Carbon Tetrachloride- and Acetaminophen Induced Acute Hepatotoxicity in Rats. Afr. J. Trad. Complement. Altern. Med. 2009, 6, 131–138. Adeneye, A. A.; Ajagbonna, O. P.; Adeleke, T. I.; Bello, S. O. Preliminary Toxicity and Phytochemical Studies of the Stem Bark Aqueous Extract of Musanga cecropioides in Rats. J. Ethnopharmacol. 2006a, 105, 374–379. Adeneye, A. A.; Ajagbonna, O. P.; Ayodele, O. W. Hypoglycemic and Antidiabetic Activities on the Stem Bark Aqueous and Ethanol Extracts of Musanga cecropioides in Normal and Alloxan-Induced Diabetic Rats. Fitoterapia 2007, 78, 502–505. Adeneye, A. A.; Ajagbonna, O. P.; Mojiminiyi, F. B. O.; Odigie, I. P.; Ojobor, P. D.; Etarrh, R. R.; Adeneye, A. K. The Hypotensive Mechanisms for the Aqueous Stem Bark Extract of Musanga cecropioides in Sprague-Dawley Rats. J. Ethnopharmacol. 2006b, 106, 203–207. Ajayi, G. O.; Igboekwe, N. A. Evaluation of Anti-Diabetic Potential of the Leaves of Musanga cecropioides R. Brown. Planta Med. 2013, 79, PE7. Ayinde, B. A.; Omogbai, E. K. I.; Onwukaeme, D. N. Hypotensive Effects of 3, 4-Dihydroxybenzyaldehyde Isolated from the Stem Bark of Musanga cecropioides. J. Pharmacogn. Phytother. 2010, 1, 004–009. Ayinde, B. A.; Omogbai, E. K. I.; Onwukaeme, D. N. Pharmacognostic Characteristics and Hypotensive Effect of the Stem Bark of Musanga cecropioides R. Br. (Moraceae). West Afr. J. Pharmacol. Drug Res. 2003, 19, 37–41. Ayinde, B. A.; Onwukaeme, D. N.; Nworgu, Z. A. M. Oxytocic Effects of the Water Extract of Musanga cecropioides R. Brown (Moraceae) Stem Bark. Afr. J. Biotechnol. 2006, 5, 1350–1354. Ayinde, B. A.; Onwukaeme, D. N.; Omogbai, E. K. Isolation and Characterization of Two Phenolic Compounds from the Stem Bark of Musanga cecropioides R. Brown (Moraceae). Acta Pol. Pharm. 2007, 64, 183–185. Azame, T. L.; Estella, T. F.; Borgia, N. N.; Joseph, N.; Ntungwen, F. C. Phytochemical Screening, Healing Activity and Acute Toxicity of the Sap of the Roots of Musanga cecropioides and the Aqueous Extract of the Whole Plant Acmella caulirhiza in Wistar Rats. Health Sci. Dis. 2020, 21, 1–10. Aziba, P. I. Inhibitory Effects of Musanga cecropioides on Noradrenaline and PotassiumInduced Contractions in Rat Thoracic Aorta. Afr. J. Biomed. Res. 2005, 8, 59–61. Aziba, P. I.; Gbile, Z. O. Pharmacological Screening of the Aqueous Extract of Musanga cecropioides. Fitoterapia 2000, 71, 143–146. Balla, S.; Ahmed, M. Evaluation of Anti-Hypertensive and Analgesic Activities of Musanga cecropioides in Rodents. Adv. Agron. Plant Breed. Hortic. 2017, 5, 1–7. Betti, J. L.; Lejoly, J. Contribution to the Knowledge of Medicinal Plants of the Dja Biosphere Reserve, Cameroon: Plants Used for Treating Jaundice. J. Med. Plant Res. 2009, 3, 1056–1065. Burkill, H. M. The Useful Plants of West Tropical Africa; 2nd ed., Vol. 1; Families A–D. Royal Botanic Gardens, Kew: Richmond, United Kingdom, 1985. Corner, E. J. H. The Classification of Moraceae. Gardens Bull. Singap. 1962, 19, 187–252. Didier, D. S.; Gisèle, E. L.; Elisée, T. S.; Cécile, O. E.; Jacques, Y.; Vanessa, B.; Jean Pierre, N. M.; Téclaire, N. F.; Pierre, N. J.; Christian, N. C. Acute and Subacute Toxicity Study of the Combination of Aqueous Extracts of the Trunk Bark of Musanga cecropioides R. Br.

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(Cecropiaceae) and the Fruits of Combretum micranthum G. Don (Combretaceae). Saudi J. Med. Pharm. Sci. 2018, 4, 108–1026. Dongmo, A. B.; Kamanyi, A.; Bopelet, M. Saponins from the Leaves of Musanga cecropioides (Cecropiaceae) Constitute a Possible Source of Potent Hypotensive Principles. Phytother. Res. 1996, 10, 23–27. Dongmo, A. B.; Kamanyi, A.; Franck, U.; Wagner, H. Vasodilating Properties of Extracts from the Leaves of Musanga cecropioides (R. Brown). Phytother. Res. 2002, 16, S6–S9. Eboji, O.; Sowemimo, A. Anti-Inflammatory Activity of Musanga cecropioides R. Br ex. Tedlie. Plant. Med. 2014, 80, PD52. Elisée. T. S.; Jacques, Y.; Denis, B. H.; Brice, M. O. P.; Moïse, N. H. J.; Teclaire, N. F.; Christian, N. C.; Pierre, N. J.; Cathérine, K. P.; Marguerite, E. L. G.; Didier, D. S.; Jacob, C. Acute and Subacute Toxicity Studies of the Combination of the Aqueous Extracts of Trunk Bark of Musanga cecropioides R. Br. (Cecropiaceae) and Fruits of Picralima nitida (Stapf) T. Durand & H. Durand (Apocynaceae). Saudi J. Med. Pharm. Sci. 2020, 6, 334–348. Etuk, E. U. A Review of Medicinal Plants with Hypotensive or Antihypertensive Effects. J. Med. Sci. 2006, 6, 894–900. Fomogne-Fodjo, M. C. Y.; Van Vuuren, S.; Ndinteh, D. T.; Krause, R. W. M.; Olivier, D. K. Antibacterial Activities of Plants from Central Africa Used Traditionally by the Bakola Pygmies for Treating Respiratory and Tuberculosis-Related Symptoms. J. Ethnopharmacol. 2014, 155, 123–131. Ibitoye, S. F.; Ukpo, G.; Rabiu, A. S. Qualitative Phytochemical Screening and Antimicrobial Evaluation of the Total Alkaloids of the Hydroalcoholic Extracts of the Leaves and Stem Bark of Musanga cecropioides (Urticaceae). Ann. Health Res. 2020, 6, 74–84. Idu, M.; Obaruyi, G. O.; Erhabor, J. O. Ethnobotanical Uses of Plants Among the Binis in the Treatment of Ophthalmic and ENT (Ear, Nose and Throat) Ailments. Ethnobot. Leaflets. 2008, 13, 480–496. Joseph, N.; Laure, S. M. S.; Matchawe, C.; Joseph, N. Comparative Study of the Antibacterial and Antioxidant Properties of Raw and Tannic Extract of the Bark of Musanga cecropioides R.Br. & Tedlie (Urticaceae). Pharm. Chem. J. 2020, 7, 1–11. Kadiri, A. B.; Ajayi, G. O. Phyto-anatomical Characteristics of the West African (Umbrella Tree) Musanga cecropioides M. Smithii R. Br. (Moraceae). Indian J. Sci. Technol. 2009, 2, 1–5. Kamanyi, A.; Bopelet, M.; Aloamaka, C. P.; Obiefuna, P. C. M.; Ebeigbe, A. B. EndotheliumDependent Rat Aortic Relaxation to the Aqueous Leaf Extract of Musanga cecropioides. J. Ethnopharmacol. 1991, 34, 283–286. Kamanyi, A.; Bopelet, M.; Lontsi, D.; Noamesi, B. K. Hypotensive Effects of some Extracts of the Leaves of Musanga cecropioides (Cecropiaceae) Studies in the Cat and the Rat. Phytomedicine 1996, 2, 209–212. Kamanyi, A.; Bopelet, M.; Tatchum, T. R. Contractile Effect of some Extracts from the Leaves of Musanga cecropioides (Cecropiaceae) on Uterine Smooth Muscle of the Rat. Phytother. Res. 1992, 6, 165–167. Keay, R. W. J. Trees of Nigeria; Oxford University Press: New York, 1989. Lacaille-Dubois, M. A.; Franck, U.; Wagner, H. Search for Potential Angiotensin Converting Enzyme (ACE)-Inhibitors from Plants. Phytomedicine 2001, 8, 47–52. Larsen, B. H. V.; Soelberg. J.; Kristiansen, U.; Jäger, A. K. Uterine Contraction Induced by Ghanaian Plants Used to Induce Abortion. S. Afr. J. Bot. 2016, 106, 137–139.

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Legbosi, N. L.; Ellis, T. R. Sub-Chronic Toxicity of Hydromethanolic Stem Bark Extract of Musanga cecropioides (Urticaceae) in Rat. EC Pharmacol. Toxicol. 2018, 6, 76–95. Legbosi, N. L.; Ibor, O. Y. Musanga cecropioides (Urticaceae) Stem-Bark Mitigates Sodium Valproate–Induced Pantoxicity Derangement in Albino Rats. GSC Biol. Pharm. Sci. 2019, 7, 6–27. Lontsi, D.; Sondengam, L.; Ayafor, J. F. Cecropiacic Acid, a New Pentacyclic A-Ring Seco Triterpenoid from Musanga cecropioides. Tetrahedron Lett. 1987, 28, 6683–6686. Lontsi, D.; Sondengam, L.; Ayafor, J. F. Chemical Studies on the Cecropiaceae: A Novel A-Ring Seco Triterpene from Musanga cecropioides. J. Nat. Prod. 1989, 52, 52–56. Lontsi, D.; Sondengam, L.; Ayafor, J. F.; Tsoupras, M. G.; Tabacchi, R. Further Triterpenoids of Musanga cecropioides: The Structure of Cecropic Acid. Plant. Med. 1990, 56, 287–289. Lontsi, D.; Sondengam, L.; BoDo, B.; Martin, M. T. Kalaic Acid, a New Ursane-Type Saponin from Musanga cecropioides. Plant. Med. 1998a, 64, 189–191. Lontsi, D.; Sondengam, L.; Martin, M. T.; BoDo, B. Musancropic Acids a and b: A-Ring Contracted Triterpenes from Musanga cecropioides. Phytochemistry 1991a, 30, 2361–2364. Lontsi, D.; Sondengam, L.; Martin, M. T.; BoDo, B. Seco-Ring-a-Triterpenoids from the Rootwood of Musanga cecropioides. Phytochemistry 1991b, 30, 1621–1624. Lontsi, D.; Sondengam, L.; Martin, M. T.; BoDo, B. Musangicic Acid, a Triterpenoid Constituent of Musanga cecropioides. Phytochemistry 1992, 31, 4285–4288. Lontsi, D.; Sondengam, L.; Martin, M. T.; BoDo, B. Cecropioic Acid, a Pentacyclic Triterpene from Musanga cecropioides. Phytochemistry 1998b, 48, 171–174. Mabeku, L. B. K.; Roger, K. J.; Louis, O. E. J. Screening of some Plants Used in the Cameroonian Folk Medicine for the Treatment of Infectious Diseases. Int. J. Biol. 2011, 3, 13–21. Medou, F. M.; Nyunaï, N.; Bika Lele, E. C.; Oumarou, G. H.; Metsadjio, A. N. Acute and 28 Days Toxicity Assessment of Aqueous Extract of Stem Bark of Musanga cecropioides (Urticaceae). Adv. Complement. Altern. Med. 2019, 4, 337–345. Meva, F. E.; Ndom, J. C.; Yonga, A. W.; Ntoumba, A. A.; Kedi, P. B. E.; Loudang, R. N.; Segnou, M. L.; Mang, R. E.; Mbeng, J. O. A.; Mpondo, E. A. M.; Mbaze, L. M. Synthesis of Copper Nanoparticles Mediated Musanga cecropioides Leaf Extract and Their Application in the Degradation of Organic Dyes. Int. J. Green Herb. Chem. 2017, 6, 280–290. Musuyu Muganza, D.; Fruth, B. I.; Nzunzu Lami, J.; Mesia, G. K.; Kambu, O. K.; Tona, G. L.; Cimanga Kanyanga, R.; Cos, P.; Maes, L.; Apers, S.; Pieters, L. In Vitro Antiprotozoal and Cytotoxic Activity of 33 Ethonopharmacologically Selected Medicinal Plants from Democratic Republic of Congo. J. Ethnopharmacol. 2012, 141, 301–308. Nwidu, L. L.; Oboma, Y. I.; Elmorsy, E.; Carter, W. G. Hepatoprotective Effect of Hydromethanolic Leaf Extract of Musanga cecropioides (Urticaceae) on Carbon Tetrachloride-Induced Liver Injury and Oxidative Stress. J. Taibah Univ. Med. Sci. 2018, 13, 344–354. Nyananyo, B. L.; Offiong, I. An Evaluation of the Taxonomic Status of Musanga cecropioides and Myrianthus arboreus. Niger. J. Bot. 2012, 25, 1–22. Nyunaï, N.; Yaya, A. J. G.; Tabi, T. G. N.; Tchamgoue, A. D.; Ngondé, M. C.; Minka, C. S. M. Anti-Hyperglycemic and Antioxidant Potential of Water-Ethanol Extract of Musanga cecropioides Stem Bark. Int. J. Pharm. Sci. Drug Res. 2016, 8, 43–49. Odesanmi, O. S.; Magbagbeola, O. A.; Akinwande, A. I. A Comparison of the Effects of Extracts of Musanga cecropioides on Serum Lipids to that of Combined Oral Contraceptive­ Neogynon-ed fe in Female Rats. Nig. J. Nat. Prod. Med. 2000, 4, 52–56.

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Ojinnaka, C. M.; Okogun, J. I. The Chemical Constituents of Musanga cecropioides. J. Nat. Prod. 1985, 48, 337. Okon-Akan, O. A.; Abiola, J. K.; Olaoye, K. O.; Okanlawon, F. B. Efficacy of Preservative Potentials of Cola nitida and Musanga cecropioides Leaf Extracts Against Brown Rot Fungus on Gmelina arborea and Pinus carribaae Wood Samples. J. Res. For. Wildl. Environ. 2020, 12, 86–91. Omoruyi, S. I.; Enogieru, A. B. Musanga cecropioides (Cecropiaceae) Attenuates Carbon Tetrachloride-Induced Nonalcoholic Fatty Liver Disease in Wistar Rats. Trop. J. Nat. Prod. Res. 2018, 2, 482–488. Omoruyi, S. I.; Enogieru, A. B.; Momodu, O. I.; Ayinde, B. A.; Grillo, B. D. ParacetamolInduced Liver Damage: Ameliorative Effects of the Crude Aqueous Extract of Musanga cecropioides. Niger J. Health Sci. 2015, 15, 2–7. Owolabi, O. J.; Olokpa E. E. Antinociceptive effect of the ethanol extract of the stem bark of Musanga cecropioides in mice. J. Pharma & Bioresour. 2011, 8, 41–48. Owolabi, O. J.; Ayinde, B. A.; Nworgu, Z. A. M.; Ogbonna. O. O. Antidiarrheal evaluation of the ethanol extract of Musanga cecropioides stem bark. Methods Find. Exp. Clin. Pharmacol. 2010, 32, 407–411. Owolabi, T. A.; Ezenwa, K. C.; Olayioye, E. Y.; Iyorhibe, O. C.; Amodu, E.; Aferuan, O. F.; Okubor, P. C.; Ayinde. B. A.; Okogun, J. I. Adaptogenic (Anti-Stress) Effect of Aqueous Musanga cecropioides (Urticaceae). Int. J. Curr. Microbiol. App. Sci. 2019, 8, 2558–2565. Peter, A. O.; Ariyo, A. L.; Olawunmi, I. O. Diuretic Effects of Aqueous Crude Extract of Musanga cecropioides in Normotensive Sprague Dawley Rat. J. Biol. Agric. Healthcare 2015, 5, 47–53. Senjobi, C. T.; Ettu, A. O.; Gbile, Z. O. Pharmacological Screening of Nigerian Species of Musanga cecropioides R. Br ex Teddlie (Moraceae) in Rodents as Anti-Hypertensive. Afr. J. Plant Sci. 2012, 6, 232–238. Shemishere, U. B.; Taiwo, J. E.; Erhunse, N.; Omoregie, E. S. Comparative Study on the Proximate Analysis and Nutritional Composition of Musanga cecropioides and Maesobotrya barteri Leaves. J. Appl. Sci. Environ. Manag. 2018, 22, 287–291. Sowemimo, A.; Okwuchuku. E.; Samuel, F. M.; Ayoola, O.; Mutiat, I. Musanga cecropioides Leaf Extract Exhibits Anti-Inflammatory and Anti-Nociceptive Activities in Animal Models. Rev. Bras. Farmacogn. 2015, 25, 506–512. Takhtajan, A. Flowering Plants; 2nd ed.; Springer, 2009. Tchamgoué, D. A.; Kopa, K. T.; Nyunaï, N.; Diboué Betote, P. H.; Nguimmo, M. A.; Medou, M. F. Carbohydrates Test and In Vitro Inhibitory Activities of Alpha-Glucosidase and Alpha-Amylase of Stem Bark Extracts of Musanga cecropioides. Pharm. Res. 2020, 4, 1–9. Tchouya, G. R. F.; Nantia, E. A. Phytochemical Analysis, Antioxidant Evaluation and Total Phenolic Content of the Leaves and Stem Bark of Musanga cecropioides R.Br. ex Tedlie (Cecropiaceae), growing in Gabon. J. Pharmacogn. Phytochem. 2015, 3, 192–195. Uwah, A. F.; Otitoju, O.; Ndem, J. I.; Peter, A. I. Chemical Composition and Antimicrobial Activities of Adventitious Root Sap of Musanga cecropioides. Der Pharm. Lett. 2013, 5, 13–16.

CHAPTER 72

Angelica glauca Edgew.—An Ethnopharmacological, Phytochemical, and Pharmacological Review SWATI1* and H. K. PANDEY2 1Faculty

of Pharmacy, DIT University, Dehra Dun, Uttarakhand, 248009, India

2Defence

Institute of Bio-Energy Research, DRDO, Haldwani, Uttarakhand 263139, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Angelica glauca belonging to the family Apiaceae is locally known as Chora or Gandrayan. It is an aromatic and medicinal herb endemic to the Himalayas. The root is considered as cardioactive and stimulant, carmi­ native, expectorant, diaphoretic and useful in stomach ailments and also used in rheumatism and urinary disorders. It is also used for flavouring confectionery and liquors. Several studies have scientifically evaluated the plant’s pharmacological potential, including anti-oxidant, anti-inflam­ matory, antifungal, antibacterial, anticancer and nervous system disorders. The biological activities of A. glauca are mostly due to its essential oils and coumarins content. The plant contains major constituents such as (Z)-ligustilide, (Z)-butylidene phthalide, and (E)-butylidene phthalide. Due to its high essential oil content, the plant has high market demand in the cosmetics, perfume and drug industries.

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72.1 INTRODUCTION Angelica glauca Edgew. (family Apiaceae) is an aromatic, large, smooth, glabrous, perennial, or biennial herb of 3–6 ft height. Roots are tuberous and aromatic. The stem is erect, finely grooved, stout, and fistular. Leaves are large, 1–3 ternately-pinnate; leaflets 2.5–8 cm long, often in threes or sometimes reduced to one, oval to lanceolate, mucronulate-serrate, upper surface waxy, greenish-blue beneath, and long stalked. Its flower is white or purple, many in compound long stalked umbels; peduncle stout, 15–20 cm long; pedicels 5–6 cm long. Fruits are flattened, glabrous, elliptic to oblong, dorsal and intermediate ridges thick, corky, obtuse, not winged, lateral ridge broadly membranous, free, winged; commissure 2–4 vittae. Its seeds are 1.2 mm thick and grooved on the inner face. Flowering and fruiting during July–October. During September and October roots are harvested when seeds become partially mature due to their important role as a folk medicine (Seth and Devi, 2014). A. glauca is found in moist and shady alpine scrub and forest fringes between 2700 and 4000 m elevations in the Indian Himalayas. It is found in India, Pakistan, and Afghanistan. In India, it occurs from north temperate to alpine regions of different Himalayan states such as Uttarakhand, Himachal Pradesh (Chamba, Kinnaur, Kullu, Shimla), Jammu & Kashmir, and Sikkim (Seth and Devi, 2014). It is known as Chorak, Kshemak, Taskar in Sanskrit, Chora, Choru, Gandrayan in Hindi and Angelica in English, while the trade name is Gandrayan. The root is used as stimulant and cardioactive, expectorant, carminative, and useful in stomach ailments (Anonymous, 1985) and also used in urinary disorders and rheumatism. The powdered root along with milk is used to treat bronchitis (Sarker and Nahar, 2004). It is also used for liquors and flavoring confectionery 72.2 TRADITIONAL USES AND ETHNOPHARMACOLOGY Traditionally, A. glauca is used in aromatic spices, condiments, and medi­ cines. Large quantities of Dongcha, which is prepared with the powder of A. glauca and Pleurospermum angelicoides rhizomes mixed with Allium leaves and salt are consumed by local inhabitants of Tibet and Nanda Devi Biosphere Reserve. The decantant of A. glauca and P. angelicoides root stocks boiled in water are used to treat headaches and stomach pains (Kandari et al., 2007).

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During the 19th century, American physician used Angelica for heart­ burn, indigestion, bronchitis, and fevers. A Chinese researcher reported that Angelica is used against anaemia as it increases the red blood cells in blood. In Ayurveda, Charaka rishi prescribed Angelica roots for headache, epilepsy, hiccough, and bronchial asthma whereas Sushruta prescribed its leaves against skin eruptions, swelling, and fracture of bones (Butola et al., 2016). In the Uttarakhand regions, the roots are used in dal flavoring to enhance taste (Collet, 1921). For increasing vitality and strength, the herb is given to women after the delivery. In traditional medicine, it is used in the treatment of dysentery, constipation, dyspepsia, loss of appetite, and menorrhagia (Jain and Tarafder, 1970). The roots are stomachic, carminative, and stimulant; are also useful in treatments for anorexia, spasms, flatulent colic, and bronchitis. It provides remedy from colds and improves lactation in cattle. It is used as an ingredient of incense (Dhoop) and as a snake or insect repellent. The aromatic root is used for flavoring confectionery items and wines. Fruit oil contains many furocoumarins, and is used in obstinate constipation, dyspepsia, and biliousness. The powdered root is administered with warm water in stomach ailments of children (Seth and Devi, 2014). In the Tibetan health system, it is considered to be beneficial in restoring kidney disease and treating anemia, debility, fluid retention in the joints, stomach disorders, and lung diseases. The roots are boiled with water to use as a cough syrup as an expectorant. It is also used as herbal tea by boiling with water, sugar, and tea leaf. Especially local people from the Niti and Mana Valleys of Uttarakhand sell A. glauca in trade of medicinal plants (Reddy, 2020). 72.3

PHYTOCHEMISTRY

Coumarins are the phenolic substances made of fused a-pyrone rings and benzene. From the roots of A. glauca, six irritant and cytotoxic coumarins have been isolated such as 6-methoxy-7,8 methylenedioxycoumarin, 5,6,7-trimethoxycoumarin, decursinol angelate, bergapten, nodakenetin, and decursin (Saeed and Sabir, 2008). Z-lingustilide and Z-butylidinephthalide have been recorded as the active principles responsible for their antiasthmatic and spasmolytic properties. Z-lingustilide, caryophyllene oxide, Z-butylidi­ nephthalide, caryophyllene, and methyl octadecadinoate have been isolated from the n-hexane extracts of root of A. glauca collected from Uttarakhand and their identification was done by different chemical and spectral methods (GC-MS, TLC, NMR, HPLC) (Khetwal et al., 2004). A symmetric dimer

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of the butylidenephthalide 1 (E-ligustilide) has been found as angelicolide (Banerjee et al., 1984). Kaul et al. (1996) had isolated 68 compounds from essential oil of its roots which are as below. The essential oil yield of roots varies from 0.50% to 1.50% (Kaul et al., 1996; Vashistha et al., 2006). 1. Ethanol 2. 3-methyloct-2-ene 3. 3-methyloct-2-ene (isomer) 4. α-pinene 5. camphene 6. sabinene* 7. β-pinene 8. myrcene* 9. α-pheIlandrene 10. p-cymene 11. β-phellandrene 12. τ-terpinene 13. camphor* 14. pentylbenzene 15. borneol* 16. terpinene-4-oI* 17. α terpineoI* 18. Methylchavicol 19. Trans-carveol 20. Cis-carveol 21. Citronellol 22. Nerol* 23. Carvone

24. cis-anethol 25. geraniol* 26. trans-anethol 27. terpinen-4-yl acetate 28. a-terpineyl acetate* 29. citronellyl acetate 30. eugenol 31. α-cubebene 32. geranyl acetate* 33. α-ylangene 34. α-copaene 35. methyleugenol 36. β-bourbonene 37. β-elemene 38. α-gurjunene 39. β-caryophyllene 40. α-guaiaene 41. α-humulene 42. germacrene D 43. ar-curcumene 44. τ-gurjunene 45. τ-muurolene 46. α-muurolene

47. β-bisabolene 48. τ-cadinene 49. δ-cadinene 50. elemol 51. spathulenol 52. β-caryophyllene oxide 53. globulol 54. τ-eudesmol 55. T-cadinol 56. β-eudesmol 57. α-cadinol 58. β-bisaboIoI* 59. α-bisaboIoI 60. (Z)-butylidenephthalide 61. (E)-butylidenephthalide 62. (Z)-Iigustilide 63. 3-valerylphthalide 64. (E)-Iigustilide 65. 3-hexyl-4,5-dihydrophthalide 66. methyl pentadecanoate 67. 6, 7-dihydroxy-6,7-dihydroligustilide (an isomer) 68. 6,7-dihydroxy-6, 7-dihydro-

In the study, the roots collected from two high alpine locations (Ghesh and Kedarnath) and essential oil were obtained by hydro-distillation method, further estimated by gas chromatography–mass spectrometry (GC–MS) and GC (Purohit et al., 2015). The roots yielded 0.3% and 1.8% (v/w) volatile oils in Kedarnath and Ghesh, respectively. The essential oil content in Kedarnath sample was found to be maximum as compared with other Hima­ layan locations. The results revealed an identification of 26 components, accounting 98.2% and 97.7% in the oils from Kedarnath and Ghesh popula­ tions, respectively. The major parts in the oils were constituted by phthalides and ligustilides: (Z)-ligustilide (53.0% and 40.6% in Kedarnath and Ghesh,

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respectively), (Z)-butylidene phthalide (32.8% in Kedarnath and 20.7% in Ghesh, (E)-butylidene phthalide (2.5% in Kedarnath and 5.9% in Ghesh and (E)-ligustilide (2.3% in Kedarnath and 2.1% in Ghesh. Monoterpene hydrocarbons were also found in noticeable amounts in Ghesh population (19.5%), having major compounds such as myrcene (8.3%), α-phellandrene (6.9%), sabinene (2.3%), and p-cymene (0.7%), whereas in the essential oil from Kedarnath population, monoterpene hydrocarbons constituted only 3.8% of the oil having comparatively lesser portions of myrcene, α phellan­ drene, sabinene, p-cymene, and α-pinene. β-Phellandrene was found 1.3% in Kedarnath population whereas 0.2% in Ghesh population. Ligustilide improves cognitive function and alleviates brain damage (Feng et al., 2012). (Z)-ligustilide and phthalide possessed antiproliferative (Kan et al., 2008) and anti-inflammatory effects (Chung et al., 2012). Agnihotri et al. (2004) reported that fresh aerial parts of A. glauca collected from several locations of Jammu and Kashmir, on hydro-distillation provided a light pale colored essential oil. The 34 compounds were reported from the essential oil by the help of capillary GC, GC-MS, and NMR. Major compounds of the oil were characterized as α-phellandrene (13.5%), trans-carveol (12.0%), β-pinene (11.7%), thujene (7.5%), β-caryophyllene oxide (7.2%), β-caryophyllene (7.0%), nerolidol (6.5%), α-terpinene (6.7%), germacrene D (4.5%), and β-bisabolene (5.2%). A. glauca collected from Panwali Kantha (Uttarakhand) and Sissu (Himachal Pradesh). Essential oil was extracted from A. glauca using Clevenger apparatus (Rajendra et al., 2017). Twenty-two compounds constituted 94.10% of the total volatile oil in the samples collected from Sissu and 21 compounds constituted 90.70% of the total volatile oil in the samples collected from Panwali Kantha, was identified using GC-FID and GC-MS analysis. The major component of the essential oil was Z ligustilide 39.72% in Sissu and 74.11% in Panwali Kantha. The oil from Sissu showed appreciable amount of limonene (10.21%), methyl chavicol (6.29%), methyl eugenol (10.65%), kessane (2.33%), spathulenol (2.81%), etc. On the other hand, the oil from Panwali Kantha showed highest (74.11%) percentage of Z-ligustilide. Percentage of monoterpene hydrocarbons was almost similar, whereas other class of compounds revealed much variation between the studied populations. The study revealed that percentage of most of the constituents varied in this study as well as in previous studies, for example, limonene, β-ocimene, γ-terpinene, methyl chavicol, methyl eugenol, δ-cadinene, spathulenol, Z-3-butilidene phthalide, E-3-butilidene phthalide, Z-ligustilide, and E-ligustilide. The study revealed that quantitative as well

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as qualitative composition of the essential oil varied as compared with the previous studies (Kaul et al., 1996; Agnihotri et al., 2004; Joshi et al., 2005; Thappa et al., 2005). Variations in the essential oil composition attributed to various factors such as ecotype, phenophases, and the environment including temperature, relative humidity, irradiance, and photoperiod. A study was conducted by Tewari et al. (2018) to estimate the essential oil composition of A. glauca roots from Uttarakhand region. The hydrodistillation method was used to extract the essential oil from dried roots of A. glauca and subjected to gas chromatography-mass spectrometry. The chief compounds found were trans-ligustilide, (Z)-3-butylidenephthalide, β-phellandrene, α-phellandrene, p-cymene and (-)-spathulenol. Swati et al. (2020) investigated the chemical composition of A. glauca roots. The essential oil was isolated from A. glauca roots collected from high altitude region of Himachal Pradesh by the hydro-distillation method and identified by GC/MS. GC/MS analysis of essential oil identified 24 different chemical constituents, including limonene (27.95%), Z-ligustilide (23.31%), and ß-ocimene (6.95%) as major compounds. The essential oil composition of A. glauca from the selected area of Himachal Pradesh was not reported so far. 72.4

IMPORTANCE OF A. GLAUCA

Roots contain angelic acid, angelisine resin, and valeric acid (Blake, 2004) and have carminative, expectorant, cardioactive, stimulant, digestive, and stomachic properties (Chopra et al., 1956). Phellandrene has the nervous system stimulating action. The bitterness of furocoumarins accounts for digestive stimulation effects. Coumarin is the parent molecule of Warfarin which acts as a Vitamin K antagonist (Hoult and Paya, 1996). Coumarin compounds play important role in anti-inflammatory and antimicrobial prop­ erties. The constituent bergapten showed antipsoriatic, whereas linalool and borneol have antibacterial and antifungal activity. Due to strong odor, the oil is necessary for industrial uses, that is, fixative of perfume and root parts for the preparation of gin and the liquours known as bitters (Mehra et al., 1969). 72.5

PHARMACOLOGY

72.5.1 ANTIOXIDANT ACTIVITY The hydroalcoholic and aqueous extract of A. glauca collected from Hima­ layan region were evaluated for their antioxidant constituents and antioxidant activity. The hydroalcoholic extract exhibited the highest amount of total

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phenol, total flavonoids, and total tannin content compared with aqueous extract. The IC50 values of scavenging DPPH radicals for the hydroalcoholic and aqueous extract were found 68.1 ± 0.34 and 188.3 ± 0.001 μg/mL. The hydroalcoholic extract of A. glauca exhibited better DPPH radical scav­ enging activity than aqueous extract (Swati et al., 2021). The antioxidant activity of the A. glauca oil was estimated by DPPH method and inhibition of linoleic acid oxidation. IC50 value of A. glauca oil was found at 32.32 μg/mL. The oil DPPH inhibition percentage was showed lower (93.9%) as compared with synthetic BHT (98.4%). The peroxidation inhibition percentage of A. glauca oil exhibited 44.03%, that was found lower than BHT (93.04%) (Irshad et al., 2011). Rawat and Gupta (2017) reported the total phenol, flavonoid, and anti­ oxidant potential of seeds of A. glauca collected from 17 different locations of Uttarakhand. The total polyphenol content, total flavonoid, and antioxi­ dant potential of the methanolic and acetonic extracts of seed were found significantly in high amounts with increasing the altitude. The methanolic seed extract of Bageshwar (3353 m) exhibited the maximum total phenolic content 1521 μg gallic acid equivalent/50 mg of dry weight and antioxidant activity in β-carotene (77.7%) and DPPH activity (37.4%). The methanol, petroleum ether, aqueous extract, and chloroform extract of A. glauca, Alysicarpus vaginalis (L.) DC. and Peristrophe bicalyculata (Retz.) Nees were evaluated for their free radical scavenging properties. This study revealed that the plants exhibited antioxidant activity (Arya and Mehta, 2017). 72.5.2 ANTIMICROBIAL ACTIVITY The antimicrobial activity of A. glauca oil were screened against two Gramnegative bacteria: Escherichia coli ATCC 25922 and Pasteurella multocida (local isolate), Gram-positive bacteria: Staphylococcus aureus, API Staph TAC 6736152 and Bacillus subtilis JS 2004, and four pathogenic fungi, Candida albicans, Microsporum canis, Aspergillus flavus, and Fusarium solani. The results obtained from disc diffusion method, followed by measurement of minimum inhibitory concentration (MIC), revealed the following order Escherichia coli > Staphylococcus aureus > Pasturella multocida > Bacillus subtilis. The E. coli and S. aureus showed 24.6 and 22.8 mm zone of inhibition and the lowest MIC values (141.3 and 159.3 μg/mL), respectively. Bacillus subtilis showed lowest inhibition zones (20.3 mm) and highest MIC value (182.6 μg/mL). A. glauca oil has antibacterial activity

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comparable with the standard drug, amoxycillin. The oil from A. glauca has antifungal activities comparable with the standard drug (flumequinene). The order was found Microsporum canis > Fusarium solani > Candida albicans > Aspergillus flavus. It can be concluded that the essential oil of A. glauca has strong and broad spectrum of antimicrobial activity (Irshad et al., 2011). 72.5.3

IRRITANT AND CYTOTOXIC ACTIVITY

The irritant and cytotoxic capabilities of coumarin isolated from chloroform and methanolic extracts of A. glauca roots were evaluated. The irritant effects were evaluated on albino mice and cytotoxic effects on mature brine shrimp (Artemia salina) larvae (nauplii), followed by fractionation to isolate and characterize its active compounds, whose effectiveness were evaluated by ID50 and LC50. The most effective and persistent irritant compounds were found decursinol angelate and decursin with least ID50. 6-Methoxy­ 7,8-methylenedioxycoumarin and bergaten showed an intermediate irritant reaction, while 5,6,7-trimethoxycoumarin and nodakenetin have the least irritant and least persistent reaction on mouse ears. Both decursin and decursinol angelate revealed stronger cytotoxic agents than other coumarins. 5,6,7-trimethoxycoumarin showed an intermediate cytotoxic behavior, while other three coumarins, that is, bergapten, 6-methoxy-7,8-methylenedioxy­ coumarin and nodakenetin, exhibited the least cytotoxic capacity against brine shrimp larvae (Saeed and Sabir, 2008). 72.5.4 ANTI-ANXIETY ACTIVITY Antianxiety potential of the A. glauca was evaluated by experimental model of anxiety (Chandra et al., 2016). The methanolic extract of A. glauca was studied at graded doses to evaluate its anxiolytic effect. The anxiolytic activity was measured by behavioral observations conducted through elevated plus maze, open field, and hole board test and compared with control and standard control. Pretreatment with methanolic extract of A. glauca roots increased the time spent in open arms and decreased time spent in closed arms signifi­ cantly at 100 and 200 mg/kg doses. Number of head dips, time spent in head dipping, and number of assisted rearing were increased markedly at all three doses of A. glauca as compared with control animals. The Open field test showed prominent effect at the doses of 100 and 200 mg/kg of A. glauca but 400 mg/kg dose showed mild decreases as compared with control animals.

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The gross behavior activity such as gait, ptosis, piloerrection, tremors, lacri­ mation, urination, writhing reflexes, pineal reflexes, corneal reflexes, and straub tail were found normal after treatment with crude extract of A. glauca. The result indicates that A. glauca possesses anxiolytic property. The effect of A. glauca may affect certain endogenous mediators to reduce anxiety. 72.5.5 BRONCHORELAXANT ACTIVITY The bronchorelaxant activity of A. glauca essential oil in histamine and oval­ bumin (OVA)-induced bronchoconstriction in guinea pigs and albino mice. The essential oil of A. glauca has broncho-relaxation in both histamine and OVA-induced bronchoconstriction in guinea pigs and albino mice (Sharma et al., 2017). 72.5.6 COGNITIVE EFFECT The root extract of A. glauca has a promising memory enhancing impact against scopolamine induced cognitive dysfunction in rats (Puri et al., 2014). 72.5.7 HEPATOPROTECTIVE ACTIVITY The aqueous extracts of A. glauca are hepatoprotective and showed anti­ oxidant activity against carbontetrachloride-induced hepatotoxicity in rats (Joshi et al., 2008). KEYWORDS • • • • •

Angelica glauca ethnopharmacology traditional phytochemistry pharmacology

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REFERENCES Agnihotri, V. K.; Thappa, R. K.; Baleshwar, M.; Kapachi, B. K.; Saxena, R. K.; Qazi G. N.; Agarwal S. G. Essential Oil Composition of Aerial Parts of Angelica glauca Growing Wild in North-West Himalaya (India). Phytochemistry 2004, 65, 2411–2413. Anonymous. Wealth of India; Revised ed.; Publication and Information Directorate, CSIR: New Delhi, 1985; p 429. Arya, P.; Mehta, J. P. Antioxidant Potential of Himalayan Medicinal Plants Angelica glauca, Alysicarpus vaginalis and Peristrophe bicalyculata. Int. J. Curr. Microbiol. Appl. Sci. 2017, 6 (7), 1892–1901. Banerjee, S. K.; Gupta, B. D.; Sheldrick, W. S.; Hofle, G. Lactonic Constituents of Angelica glauca. Liebigs Ann. Chem. 1984, 888–893. Blake, S. Medicinal Plant Constituents: Medicinal Plant from A to B; Lifelong Press: New

York, 2004; p 542. Butola, J. S.; Vashistha, R. K.; Malik, A. R.; Rawat, M. S. Ethnomedicinal Importance of Gandrayan (A. glauca) in the North-Western Part of Indian Himalayan Region. Med. Plant. 2016, 8 (4), 313–318.

Chandra, J.; Joshi, H.; Bahuguna, P.; Kedia, V. K.; Kumar, R.; Kumar, R. Behavioral Effects of High Altitude Medicinal Plant in Rats. Sch. Acad. J. Pharm. 2016, 5 (9), 377–382. Chopra, R. N.; Nayar, S. L.; Chopra, I. C. Glossary of Indian Medicinal Plants; CSIR: New Delhi, 1956. Chung, J. W.; Choi, R. J.; Seo, E. K.; Nam, J. W.; Dong, M. S.; Shin, E. M.; Guo, L. Y.; Kim, Y. S. Anti-Inflammatory Effects of (Z)-Ligustilide Through Suppression of MitogenActivated Protein Kinases and Nuclear Factor-kB Activation Pathways. Arch. Pharm. Res. 2012, 35, 723–732. Collet, H. Flora Simlensis: A Handbook of the Following Plants of Simla and Neighbourhood; Reprint; Bishen Singh Mahendra Pal Singh: Dehra Dun, 1921. Feng, Z.; Lu, Y.; Wu, X.; Zhao, P.; Li, J.; Peng, B.; Qian, Z.; Zhu, L. Ligustilide Alleviates Brain Damage and Improves Cognitive Function in Rats of Chronic Cerebral Hypoperfusion. J. Ethnopharmacol. 2012, 144, 313–321. Hoult, J. R. S.; Paya M. Pharmacological and Biochemical Activities of Simple Coumarins: Natural Products with Therapeutical Potential. Gen. Pharmacol. 1996, 27, 713–722. Irshad, M.; Rehman, Shahid, M.; Aziz S.; Ghous, T. Antioxidant, Antimicrobial and Phytotoxic Activities of Essential Oil of Angelica glauca. Asian J. Chem. 2011, 23 (5), 1947–1951. Jain, S. K.; Tarafder, C. R. Medicinal Plant Lore of the Santals. A Revival of P. O. Boddings, work. Econ. Bot. 1970, 24, 241–278. Joshi, S.; Prakash, O.; Agarwal, G.; Pant, A. K. Variations in Composition of Essential Oil of Angelica glauca Edgew. Root from Different Regions. Indian Perfum. 2005, 49 (3), 339–343. Joshi, S.; Prakash, O.; Hore, S. K.; Zafar, A.; Pant A. Hepatoprotective and Antioxidant Activity of the Aqueous Extract of Angelica glauca Edgew. Root. Asian J. Trad. Med. 2008, 3 (2), 58–66. Kan, W. L.; Cho, C. H.; Rudd, J. A.; Lin, G. Study of the Antiproliferative Effects and Synergy of Phthalides from Angelica sinensis on Colon Cancer Cells. J. Ethnopharmacol. 2008, 120, 36–43. Kandari, L. S., Rao, K. S., Chauhan, K., Maikhuri, R. K., Purohit, V. K., Phondani, P. C., Saxena, K. G. Effect of Presowing Treatments on the Seed Germination of Two Endangered

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Medicinal Herbs of the Himalaya (Angelica glauca Edgew. and Pleurospermum angelicoides (Wall. ex DC.) Benth. ex C. B. Clarke). Proc. Indian Natl. Sci. Acad. 2007, 73, 11–16. Kaul, P. N.; Mallavarapu, G. R.; Chamoli, R. P. The Essential Oil Composition of Angelica glauca roots. Plant. Med. 1996, 62, 80–81. Khetwal, K. S.; Pathak, S. K.; Sajwan, K.; Pandey, B.; Adhikari, A. Constituents of HighAltitude Himalayan Herb Angelica glauca. Indian J. Chem. 2004, 43, 2452–2455. Mehra P. N.; Bhatnagar J. K.; Handa S. S. Researches in Pharmaconosy in India. Res. Bull. (N. S.) Punjab Univ. Chandigarh 1969, 20, 261–337. Puri, A.; Srivastava, P.; Pandey, P.; Yadav, R. S.; Bhatt, P. C. Scopolamine Induced Behavioral and Biochemical Modifications and Protective Effect of Celastrus paniculatous and Angelica glauca in Rats. Int. J. Nutr. Pharmacol. Neurol. Dis. 2014, 4, 158–169. Purohit, V. K.; Andola, H. C.; Haider, S. Z.; Tiwari, D.; Bahuguna, Y. M.; Gairola, K. C.; Arunachalam, K. Essential Oil Constituents of Angelica glauca Edgew. Roots: An Endangered Species from Uttarakhand Himalaya (India). Natl. Acad. Sci. Lett. 2015, 38 (5), 445–447. Rajendra, S.; Chauhan, M. C.; Nautiyal, Y. M.; Bahuguna.; Aldo, T. Volatile Composition of Underground Parts of Angelica glauca Edgew. from Two Distant Populations of India. J. Essent. Oil Bear. Plant. 2017, 20 (3), 851–854. Rawat, T.; Gupta, S. Antioxidant Potential of Angelica glauca of Uttarakhand Region. J. Adv. Microbiol. 2017, 3 (2), 100–109. Reddy. 2020. https://vikaspedia.in/agriculture/crop-production/package-of practices/ medicinal-and-aromatic-plants/angelica-glauca. Saeed, M. A.; Sabir A. W. Irritant and Cytotoxic Coumarins from Angelica glauca Edgew Roots. J. Asian Nat. Prod. Res. 2008, 10, 49–58. Sarker, S. D.; Nahar L. Natural Medicine: The Genus Angelica. Curr. Med. Chem. 2004, 11, 1479–1500. Seth, M. K.; Devi, U. Medicinal Plants of Tehsil Spiti of Himachal Pradesh and their Therapeutic Utility. Curr. Trends Med. Bot. 2014, 15–58. Sharma, S.; Rasal, V. P.; Patil, P. A.; Joshi, R. K. Effect of Angelica glauca Essential Oil on Allergic Airway Changes Induced by Histamine and Ovalbumin in Experimental Animals. Indian J. Pharmacol. 2017, 49, 55–59. Swati; Pandey, H. K.; Singh, A.; Meena, H. S.; Bala, M. Chemical Composition and In-Vitro Antioxidant Activity of Angelica glauca Collected from Western Himalayan Region. Int. J. Pharm. Res. 2020, 1, 2720–2725. Swati; Pandey, H.; Singh, A.; Meena, H.; Bala, M. Evaluation of Phytochemical Biochemical and In Vitro Antioxidant Potential of Angelica glauca Grown at High Altitude Areas of Western Himalayas. Def. Life Sci. J. 2021, 6 (2), 117–121. Tewari, D.; Sah, A. N.; Tripathi, Y. C. Chemical Composition of Angelica glauca Roots Volatile Oil from Indian Himalayan Region by GC-MS. J. Essent. Oil Bear. Plant. 2018, 21 (6), 1636–1641. Thappa, R. K.; Kaul, P.; Chisti, A. M.; Kapahi, B. K.; Suri, O. P.; Agarwal, S. G. Variability in the Essential Oil of Angelica glauca Edgew. of Different Geographical Regions. J. Essent. Oil Res. 2005, 17 (4), 361–363. Vashistha R.; Nautiyal B. P.; Nautiyal M. C. Conservation Status and Morphological Variations Between Populations of Angelica glauca Edgew. and Angelica archangelica Linn. on Garhwal Himalaya. Curr. Sci. 2006, 91 (11), 1537–1542.

CHAPTER 73

Clusia nemorosa G. Mey: A Plant with Pharmacological Potential JAMYLLE NUNES DE SOUZA FERRO*,

MARIA DANIELMA DOS SANTOS REIS, FELIPE LIMA PORTO,

RAFAEL VRIJDAGS CALADO, TAYHANA PRISCILA MEDEIROS SOUZA,

and EMILIANO BARRETO

Laboratory of Cell Biology, Federal University of Alagoas, Alagoas, Brazil *Corresponding

author. E-mail: [email protected]

ABSTRACT Clusia nemorosa G. Mey is distributed in South America countries, from tropical to subtropical regions. It is known for the beauty of its flowers, being used as an ornamental plant. In addition, the use of its root, leaves and tree bark has been described for the treatment of wounds and pain. About 10 papers point to the presence of 20 different compounds, mainly terpenes such as betulinic acid and friedelin; flavonoids and steroids such as quercertin and stigmasterol, respectively, being present in different parts of the medicinal plant, such as fruits, flowers, leaves, roots and tree bark. Most of the studies present the phytochemical characterization, being only 3 that investigated the extracts from this plant. The works indicate that extracts obtained from the leaves have antimicrobial and antinociceptive effects, and extracts obtained from the bark of the tree have an anti-inflammatory effect in vivo and in vitro. There are a few studies evaluating the pharmacological potential of this species. However, due to the already confirmed presence of different substances with pharmacological potential, it is believed that this species can be used and better characterized in view of its biological effects. Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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73.1

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

INTRODUCTION

Clusia nemorosa G. Mey (family Clusiaceae) is a species of shrub tree typi­ cally found in tropical, neotropical, and subtropical regions, extending from North to South America (Oliveira et al., 1999; Gomes et al., 2020). It is well distributed in the coastal region from North to Southeast of Brazil, being present mainly in restinga and mangrove areas (Oliveira et al, 2008). This distribution reflects the ability of this plant to adapt to climate changes as also as to both drier and flooded regions. Depending on the location, it is popularly named as “orelha-de-burro,” “clusia-capelinha,” “camaçari” ou “pororoca” (De Andrade et al., 1998; Gomes et al., 2020). C. nemorosa is also known for its ornamental beautiful white flowers and the presence of green fruits (Lopes and Machado, 1998; Oliveira et al., 2008; Montade et al., 2016; Alencar and Marinho, 2017). In folk medicine, the latex obtained from the roots and bark of this plant is used to treat body aches, cracked heels, dermatoses, and persistent sores. It could also be mixed with water to be used as an antiseptic. The macerate of the inner bark serves as antiseptic and wound healing (DeFilipps et al., 2004). 73.2

BIOACTIVES

In the different parts of the plant, flowers, fruits, leaves, and stem bark, there are the predominance of polyisoprenylated compounds, terpenoids, polyisoprenylated benzophenones, xanthones, flavonoids, sesquiterpenes hydrocarbons, phloroglucinol derivatives, condensed tannins, and steroids (Monache et al., 1988; De Andrade et al., 1998; Oliveira et al., 1999; Melo et al., 2009; Camara et al., 2018; Ferreira et al., 2015; Gomes et al., 2020) The fruits produce latex and resins that provide metabolites that can help to protect the plant against attacks by herbivores, contributing to the preser­ vation of the fruits conditions so that birds can have access to the seeds, and help in their dispersion (Camara et al., 2018). In the volatile oils obtained by hydrodistillation of the fruits of C. nemorosa, the presence of isoprenoids and sesquiterpenoids compounds as β-caryophyllene and α-humulene, and a smaller amount (percentage >1%) of the fatty acids hexadecanol, octa­ decene, and hexadecane was observed in all samples collected (Oliveira et al., 2008). Interestingly, the profile of the molecules varies according to the type of soil where the plant is cultivated. In clay soils, a greater presence of oxygenated sesquiterpenes, with a caryophyllene core, was identified,

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with β-caryophyllene, caryophylline oxide, and α-humulene, the latter being in greater proportion in these samples, while in iron-rich rocky soils, there was the presence of ɣ-muurolene, Δ-cadidene, and the β-caryophyllene. The β-caryophyllene (37.3–48.6%) was the major compound in the iron-rich rocky samples (Oliveira et al., 2008). The chloroform extract obtained from the fruits of C. nemorosa showed the presence of nemorosinic acids A and B, which were observed in a 1:1 ratio, which were identified by 1H and 13C NMR by the presence of the signals of chromene ring, a benzoyl moiety, a chelated hydroxy group, and isopentenyl chain (Monache et al., 1991). The dichloromethane extract of the fruit showed the presence of friedelin (pentacyclic triterpene), stigmasterol (steroid), β-sitosterol glycoside (saponin steroid), kaempferol and quercetin (flavonoids), and dimethyl citrate (citric acid derivative), all described for the first time in the fruits of this species (Ferreira et al., 2015). In the same study, a phloroglucinol derivative named nemorosic acid was identified. The presence of polyisoprenylated alkyl-arylketones named nemorosonol and nemorosonol B in the fruits of C. nemorosa was also reported (Monache, 1990; Cerrini et al., 1993). A high quantity of isoprenoids (90%) was identi­ fied in the methanolic extract of the fruit, with the trans-β-farnesene being the major component (24.3%) (Camara et al., 2018). The phytochemical composition of the flowers of C. nemorosa showed the polyisoprenylated benzophenones as the main components of floral resins and the presence of fatty acids. The oils obtained from the stamens contained the presence of fatty acids, oleic acid, and stearic acid. In the same work was identified a benzophenone O-methyl derivate (7-epi-nemorosone), present in the floral resin of C. nemorosa male (Oliveira et al., 1999). Chromatographic analyses performed on the roots of C. nemorosa showed the presence of betulinic acid, a pentacyclic triterpene, isolated from the hexane extract (Melo et al., 2009). This triterpene has anti-inflammatory and antinociceptive effects, representing a promising molecule with biological activity (Melo et al., 2009). The methanol extract obtained from the stem bark besides presenting betulinic acid showed also the presence of a mixture of friedelin and friedelin-3β-ol (De Andrade et al., 1998). A phytochemical prospection carried out on the ethanolic extract obtained from the leaves of C. nemorosa showed the presence of phenolic compounds: phenols, flavonoids, and xanthones (Oliveira et al., 2016). In earlier studies, the methanol: water fraction of the ethanolic extract obtained from the leaves showed the presence of betulinic acid, kaempferol, and β-sitosterol glucoside (De Andrade et al., 1998).

Class Pentacyclic triterpene

Part of the plant Fraction Leaves; roots Ethanol

β-sitosterol β-sitosterol glu-coside Dimethyl citrate Friedelin,

Steroid alkyl chro-mone Citric acid derivative Pentacyclic triterpene

Fruits Leaves Fruits Bark; Fruits

Dichloromethane & methanol Ethanol Dichloromethane & methanol Ethanol

Friedelin-3β-ol. Isomeric clusianone

Pentacyclic triterpene

Bark Fruits

Ethanol

Kaempferol

Flavonoid

Leaves; Fruits

Ethanol

Kolanone Nemorosinic acid

Polyisoprenylated benzophenones phloroglucinol derivative

Fruits Fruits

Dichloromethane & methanol

Nemorosonol

modified polyisoprenylated benzophenones Nemorosonol B Polyisoprenylated alkyl-arylketones Octa-cosanoyl ferulate Saturated fatty alcohols Polyisoprenylated benzophenones Polyisoprenylated compound Quercetin Flavonoid Stigmasterol Steroid Trans-β-farnesene Sesquiterpene hydrocarbons Xanthone Xanthone 5,7-dihydroxy-2alkylchromone 7-epi-nemorosone

Alkyl chro-mone Benzophenone

Fruits Fruits Bark

Benzene extract Ethanol

Fruits Fruits Fruits (latex) Flowers (resin)

Dichloromethane & methanol Dichloromethane & methanol apolar fraction Hexane fractions from diazomethane extraction in ethanol Ethanol diazomethane extraction in ethanol

Leaves Flower

Reference De Andrade et al. (1998) and Melo et al. (2009) Ferreira et al. (2015) De Andrade et al. (1998) Ferreira et al. (2015) De Andrade et al. (1998) and Ferreira et al. (2015) De Andrade et al. (1998) Monache et al. (1988) and McMadlish (1976) De Andrade et al. (1998) and Ferreira et al. (2015) Monache et al. (1988) Monache et al. (1991) and Ferreira et al. (2015) Monache et al. (1988) and Cerrini et al. (1993) Monache (1990) De Andrade et al. (1998) Ferreira et al. (2015) Ferreira et al. (2015) Camara et al. (2018) Oliveira et al. (1999) De Andrade et al. (1998) Oliveira et al. (1999)

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

Compound Betulinic acid

434

TABLE 73.1 List of the compounds identified in Clusia nemorosa G. Mey.

Clusia nemorosa G. Mey

73.3

435

PHARMACOLOGY

73.3.1 ANTIMICROBIAL EFFECT Ethanolic extract from the leaves of C. nemorosa was tested against known pathogens, such as Escherichia coli, Staphylococcus aureus, and Pseudo­ monas aeruginosa. When the extract was used alone, it did not show any significant antimicrobial effect, with MIC ≥ 1.024 mg/mL, however, it was able to optimize the effect of standard drugs, such as amikacin, neomycin, and gentamicin, in a synergic action (Oliveira et al., 2016). 73.3.2 ANTI-INFLAMMATORY ACTIVITY The intraperitoneal administration of the hexane extract of leaves from C. nemorosa (HECn) showed an anti-inflammatory effect in mice, by decreasing total protein extravasation and leukocyte number, especially, polymorphonuclear leukocyte, as well as promoting a significant reduction in tumor necrosis factor levels in pleurisy induced by carrageenan. The HECn had also direct effects on human neutrophils in vitro, reducing chemotaxis induced by CXCL1, formyl-methionyl-leucyl-phenylalanine, leukotriene B4, and platelet-activating factor, without affecting the cell viability (Farias et al., 2011). 73.3.3 ANTINOCICEPTIVE ACTIVITY The hexane extract of leaves from C. nemorosa showed an antinocicep­ tive effect in acetic acid-induced abdominal constriction test and the second phase of formalin test in mice. The authors suggested that this effect is due to the action of the fraction in α2-adrenergic receptors (Ferro et al., 2013). Despite having few studies on the pharmacological activity of this plant, different compounds present in C. nemorosa have been widely evaluated in preclinical studies using experimental models in vitro and in vivo. For example, friedelin, quercetin, and betulinic acid have been demonstrated as antinociceptive (Antonisamy et al., 2011), anti-inflammatory (Li et al., 2016; Ou et al., 2019), and antiproliferative (Subashu-Babu et al., 2017) compounds, which highlight the pharmacological potential of this plant.

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KEYWORDS • • • • •

Clusiaceae Clusia nemorosa pharmacological effects medicinal pants terpenoids

REFERENCES Alencar, A. C.; Marinho, L. C. Flora das cangas da Serra dos Carajás, Pará, Brazil: Clusiaceae. Rodriguésia 2017, 68 (3), 935–944. Antonisamy, P.; Duraipandiyan, V.; Ignacimuthu, S. Anti-Inflammatory, Analgesic and Antipyretic Effects of Friedelin Isolated from Azima tetracantha Lam. in Mood and Rat Models. J. Pharm. Pharmacol. 2011, 63 (8), 1070–1077. Camara, C. A. G.; Marsaioli, A. J.; Beittrich, V. Chemical Constituents of Apolar Fractions from Fruit Latex of Twelve Clusia Species (Clusiaceae). Anais da Academia Brasileira de Ciências 2018, 90 (2), 1919–1927. Cerrini, S.; Lamba, D.; Monache, D. F.; Pinheiros, R. M. Nemorosonol, a Derivative of Tricyclo-[4.3.1.3,7]-Decane-7-Hydroxy-2,9-Dione from Clusia nemorosa. Phytochemistry 1993, 32 (4), 1023–1028. De Andrade, M. R.; Almeida, E. X.; Conserva, L. M. Alkyl Chrome and Other Compounds from Clusia nemorosa. Phytochemistry 1998, 47 (7), 1431–1433. DeFilipps, R. A.; Maina, S. L.; Crepin, J. Medicinal Plants of the Guianas (Guyana, Surinam, French Guiana); Department of Botany, National Museum of Natural History, Smithsonian Institution: Washington, DC, 2004. Farias, J. A. C.; Ferro, J. N. S.; Silva, J. P.; Agra, I. K. R.; Oliveira, F. M.; Candea, A. L. P.; Conte, F. P.; Ferraris, F. K.; Henriques, M. G. M. O.; Conserva, L. M.; Barreto, E. Modulation of Inflammatory Processes by Leaves Extract from Clusia nemorosa Both In Vitro and In Vivo Animal Models. Inflammation 2011, 35 (2), 764–771. Ferreira, R. O.; Silva, T. M. S.; Carvalho, M. G. New Polyprenylated Phloroglucinol and Other Compounds Isolated from the Fruits of Clusia nemorosa (Clusiaceae). Molecules 2015, 20, 14326–14333. Ferro, J. N. S.; Silva, J. P.; Conserva, L. M.; Barreto, E. Leaf Extracts from Clusia nemorosa Induces an Antinociceptive Effect in Mice via a Mechanism that Is Adrenergic Systems Dependent. Chin. J. Nat. Med. 2013, 11 (4), 385–390. Gomes, A. N. P.; Ferreira, J. O.; Souza, K. M. S.; Ferreira, L. C. A.; Silva, M. P.; Camara, C. A.; Silva, T. M. S. Composição química das flores e frutos de Clusia nemorosa G. Mey. (Clusiaceae) utilizando UPLC-DAD-qTOF-MS. Revista Virtual de Química, 2020, 12 (5), 1161–1175.

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Li, Y.; Yao, J.; Han, C.; Yang, J.; Chaudry, M. T.; Wang, S.; Liu, H.; Yin, Y. Quercetin, Inflammation and Immunity. Nutrients 2016, 8, 167. Lopes, A. V.; Machado, I. C. Floral Biology and Reproductive Ecology of Clusia nemorosa (Clusiaceae) in Northeastern Brazil. Plant Syst. Evolut. 1998, 213, 71–90. McMadlish, L. E.; Hanson, J. C.; Stout, G. H. The Structures of Two Derivatives of Bicyclo[3,3,1]Nonane-2,4,9-Trione. A Natural Product: Clusioanone, C33H42)4, and Trimethylated Catechinic Acid, C18H20O6. Acta. Cryst. 1976, B32, 1793–1801. Melo, C. L.; Queiroz, M. G. R.; Arruda-Filho, A. C. V.; Rodrigues, A. M.; Souza, D. F.; Almeida, J. G. L.; Pessoa, O. D. L.; Silveira, E. R.; Menezes, D. B.; Melo, T. S.; Santos, F. A.; Rao, V. S. Betulinic Acid, a Natural Pentacyclic Triterpenoid, Prevents Abdominal Fat Accumulation in Mice Fed a High-Fat Diet. J. Agric. Food Chem. 2009, 57, 8776–8781. Monache, F. D. Nemorosonol B, a Polyisoprenylated Alkyl-Aryl Ketone from Clusia nemorosa. Bull. Chem. Soc. Ethiop. 1990, 4 (1), 67–69. Monache, F. D.; Monache, G. D.; Gács-Baitz, E. Two Polyisoprenylated Ketones from Clusia nemorosa. Phytochemistry 1991, 30 (2), 703–705. Monache, F. D., Monache, G. D., Pinheiro, M. R., Radics, L. Nemorosonol, a Derivative of Tricyclo-[4.3.1.3,7]-Decane-7-Hydroxy-2,9-Dione from Clusia nemorosa. Phytochemistry 1988, 27 (7), 2305–2308. Montade, V.; Diogo, I. J. S.; Bremond, L.; Favier, C.; Costa, I. R.; Ledru, M-P.; Paradis, L.; Martins, E. S. P. R.; Burte, J.; Magalhães e Silva, F. H.; Verola, C. F. Pollen-Based Characterisation of Montane Forest Types in North-Eastern Brazil. Rev. Paleobot. Palynol. 2016. Oliveira, C. M. A.; Porto, A. L. M.; Bittrich, V.; Marsaioli, A. J. Two Polisoprenylated Benzophenones from the Floral Resins of Three Clusia Species. Phytochemistry 1999, 50, 1073–1079. Oliveira, J. C. S.; Neves, I. A.; Camara, C. A. G.; Schwartz, M. O. E. Volatile Constituents of the Fruits of Clusia nemorosa G. Mey. from Different Region of Atlantic Coast Restingas of Pernambuco (Northeast of Brazil). J. Essent. Oil Res. 2008, 20 (3), 219–222. Oliveira, A. H.; Andrade, A. O.; Vandesmet, L. C. S.; Silva, M. A. P.; Coutinho, H. D. M.; Santos, M. A. F. Atividade moduladora de extratos etanólicos das folhas de Clusia nemorosa G. Mey. (Clusiaceae) sobre drogas antimicrobianas. Revista Cubana de Plantas Medicinales 2016, 21 (1), 1–8. Ou, Z.; Zhao, J.; Zhu, L.; Huang, L.; Ma, Y.; Ma, C.; Luo, C.; Zhu, Z.; Yuan, Z.; Wu, J.; Li, R.; Yi, J. Anti-Inflammatory Effect and Potential Mechanism of Betulinic Acid on LambdaCarrageenan-Induced Paw Edema in Mice. Biomed. Pharmacother. 2019, 118, 109347. Subashu-Babu, P.; Li, D. K.; Alshatwi, A. A. MCF-7 Breast Cancer Cell: Regulate Early Expression of Cdkn2a and pRb1, Neutralize mdm2-p53 Amalgamation and Functional Stabilisation of p53. Exp. Toxicol. Pathol. 2017, 69 (8), 630–636.

CHAPTER 74

Phytochemical Constituents and Pharmacology of Eclipta prostrata (L.) L. THADIYAN PARAMBIL IJINU1,2*,

SREEJITH PONGILLYATHUNDIYIL SASIDHARAN3,

VASANTHA KAVUNKAL HRIDYA4, SULOCHANA PRIJI5,

SHARAD SRIVASTAVA6, and PALPU PUSHPANGADAN1

1Amity

Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India 2Naturæ Scientific, Kerala University Business Innovation and Incubation

Centre, Karyavattom. Thiruvananthapuram 695581, Kerala, India 3Multidisciplinary

Research Unit, Government Medical College, Thiruvananthapuram 695011, Kerala, India

4Chemical

Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India

5Department

of Botany, University of Kerala, Thiruvananthapuram 695581, Kerala, India

6Pharmacognosy

Division, CSIR-National Botanical Research Institute, Lucknow 226001, Uttar Pradesh, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Eclipta prostrata (L.) L. is an herbaceous annual that grows 30–50 cm tall and belongs to the family Asteraceae. E. prostrata is a native of Asia and Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

is now extensively distributed in tropical, subtropical, and warm temperate regions around the world. In India, it is popularly known as bhringaraj, and is a well-known ingredient in most of the herbal hair oil preparations. In Ayurveda, it is used to expel intestinal worms and as a medication for coughs, asthma, night blindness, eye disorders, headaches, and illnesses of the hair and its growth. The main bioactive marker compound is wedelolactone, a coumestan derivative. The other coumestans are dimethyl wedelolactone, iso-dimethyl wedelolactone, coumestan, and dimethyl wedelolactone gluco­ side. The oleanane triterpene glycosides reported are eclalbasaponins I-VI; and the taraxastane triterpene glycosides are eclalbasaponins VII-X. Extracts and isolated compounds present in the various parts of E. prostrata showed antioxidant, hepatoprotective, anti-inflammatory, analgesic, antihyperlipid­ emic, osteoprotective, antidiabetic, neuroprotective, anticancer, antivenom, antimicrobial, antifibrotic, wound healing, nephroprotective, and hair growth promoting activities. 74.1

INTRODUCTION

Eclipta prostrata (L.) L. (Syn.: Acmella lanceolata Link ex Spreng., Amellus carolinianus Walter, Anthemis abyssinica J.Gay ex A.Rich., A. cotula-foetida Crantz, A. cotuloides Raf. ex DC., A. galilaea Eig, Bellis racemosa Steud., Buphthalmum diffusum Vahl ex DC., Chamaemelum foetidum Garsault, C. foetidum Baumg., Cotula alba (L.) L., Eclipta alba (L.) Hassk., Eleuther­ anthera prostrata (L.) Sch.Bip., Eupatoriophalacron album (L.) Hitchc., Galinsoga oblonga DC., G. oblongifolia (Hook.) DC., Polygyne inconspicua Phil., Spilanthes pseudo-acmella (L.) Murray, Verbesina alba L., Verbesina conyzoides Trew, Verbesina pseudoacmella L., Wedelia psammophila Poepp. and Wilborgia oblongifolia Hook.) belongs to Asteraceae family. It is a herbaceous annual that grows 30–50 cm tall, erect or prostrate, lot of branches, strigosely hirsute, and roots at nodes. Leaves opposite, sessile, oblong-lanceolate. Flowers small, white, in solitary, axillary peduncled rayed heads. Achenes black; pappus scales dentate (Sasidharan, 2004, 2011). Vernac­ ular names of this plant include bhargaram, bhringaraj, kesharaj, superna, tekarajah, ajagara, bhekaraja, bhrin, bhringa, brngaja, ekaraja, gasodara, kesa­ ranjana, keshya, kuntalavardhana, mahabhringa, markava, nagamara, nilab­ hringaraja, patanga, pitripriya, rangaka, shyamala (Sanskrit), babri, bhangra, bharangraj, mocakand, jalmagra, mochkand (Hindi), Kayyonni, Kannunni, Kaythonni (Malayalam), akulatikacceti, amaritavikam, ankarakam, arupakam, arupatacceti, carutaricceti, cavunayakam, civalotani, garuga, irukankiyan,

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kaikeci, kaiviciyilai, kancan, kannanmuli, kariccai, karikkantu, karisalankanni, karisillan kanni, karishalanganni, kecarancanam, kokanakam, kotikkaiyan, makacacceti, mancikaicceti, markkaci, mitukayam, naraitiraiyillan, nauvuku, nilamarkkam, pirinkaracam, pirunkaracakam, pukaracceti, tekaracikacceti, tiripurattaittiyitton, vatanapputu, vellaikkaricalankanni, viricikai (Tamil), ajagara, bara-garagada-gida, bhringaraja, garagada-sappu, garagalu, kaadige, kaadige garike, kadigga-garaga, kaeshavardhana, ranjana (Kannada), galagara chettu, garugalu, gunta-galijeru, guntagalijeru, guntakalaagara, galagarach­ ettu, gunta-galijaeru (Telugu), bhringu raaja, bhangra, maakaa, mako, markava (Marathi), bhra nga ra dza, bhri-ga, brin ga ra dza (Tibetan), ab bhangra, babri, bhangra, bhangra sabz (Urdu), kadim-el-bint, suweyd (Arabic), and eclipta, trailing eclipta (English). E. prostrata is a native of Asia and is now exten­ sively distributed in tropical, subtropical, and warm temperate regions around the world (Liu et al., 2012). It is a cosmopolitan weed, commonly found throughout India, up to 2000 m on the hills. E. prostrata is used in Ayurveda to expel intestinal worms and as a medication for cough, asthma, night blindness, eye disorders, headaches, and illnesses of the hair and its growth. The plant is also used as a liver protector. Application of E. prostrata leaves along with sesame oil is useful to treat elephantiasis. The plant juice is mixed with honey and considered as a popular remedy for catarrh in infants. Leaf paste is used to cure allergy (Khan and Khan, 2008; Rahmatullah et al., 2009; Pushpangadan et al., 2016). In China and Korea, it is used to cure hepatic, renal, and hemorrhagic diseases (Chinese Pharmacopoeia Commission, 2015; Park et al., 2018). In Thailand, E. prostrata is used for various purposes, leaves for hair dying and skin diseases; stems as a blood tonic or to treat tuberculosis, amoebiasis, and asthma; roots as an antibacterial and liver protective agent (Tewtrakul et al., 2007). In Brazil, it is widely used to treat snakebites, syphilis, filariasis, and leprosy (Morel et al., 2017). 74.2 PHYTOCHEMICAL CONSTITUENTS E. prostrata contains steroids, flavonoids (Sarg et al., 1981), alkaloids, steroidal alkaloids (Abdel-Kader et al., 1998), saponins, thiophenes (Singh, 1988; Xi et al., 2014a; Yu et al., 2020), triterpenes (Yahara et al., 1994, 1997), polypeptides, polyacetylenes (Singh and Bhargava, 1922), cardiac glycosides, lipids, and coumestans (Wagner et al., 1986; Sun et al., 2010). The main bioactive marker compound wedelolactone is a coumestan deriva­ tive, firstly reported by Wagner et al. (1986). The other coumestans of E.

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prostrata includes dimethyl wedelolactone, iso-dimethyl wedelolactone, coumestan, dimethyl wedelolactone glucoside (Yuan et al., 2009, 2011; Zhang and Guo, 2001; Sun et al., 2010). Yahara et al. (1994, 1997) isolated oleanane triterpene glycosides—eclalbasaponins I-VI; and taraxastane triterpene glycosides—eclalbasaponins VII-X. Other terpenoids such as α-amyrin, β-amyrin, oleanolic acid, echinocysticacid, ursolic acid, and their derivatives have also been reported (Zhang and Chen, 1996a, b; Zhang et al., 1997; Zhao et al., 2001, 2002; Upadhyay et al., 2001; Yuan et al., 2011; Sun et al., 2010; Xi et al., 2014a, b; Han et al., 2013; Kim et al., 2015). Flavonoid compounds isolated from E. prostrata includes quercetin, apigenin, luteolin, diosmetin, pratensein and orobol. Merulinic acid C and β-amyrone were firstly reported by Sun et al. (2010). Abdel-Kader et al. (1998) isolated eight steroidal alkaloids (e.g., verazine). Other steroids such as daucosterol, stigmasterol, ecliptalbine, and β-sitosterol are also been isolated (Zhang and Chen, 1996b; Yuan et al., 2011; Zhang and Guo, 2001). Thiophenes components were also found in E. prostrata, includes mono-, di-, and trithiophene derivatives (Xi et al., 2014b), ecliprostins A-C (Yu et al., 2020). Lin et al. (2010) reported a total of 55 compounds from aerial part of the plant by hydro-distillation and gas chromatography–mass spectrometry. The major compounds include heptadecane (14.78%), 6,10,14-trimethyl-2-pentadecanone (12.80%), n-hexadecanoic acid (8.98%), pentadecane (8.68%), eudesma-4(14),11-diene (5.86%), phytol (3.77%), octadec-9-enoic acid (3.35%), 1,2-benzenedicarboxylic acid diisooctyl ester (2.74%), (Z,Z)-9,12-octadecadienoic acid (2.36%), (Z)-7,11-dimethyl­ 3-methylene-1,6,10-dodecatriene (2.08%), and (Z,Z,Z)-1,5,9,9-tetramethyl­ 1,4,7-cycloundecatriene (2.07%).

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PHARMACOLOGICAL STUDIES

74.3.1 ANTIOXIDANT ACTIVITY Methanolic extract of E. prostrata showed potent free radical scavenging activity both in 2,2-diphenyl-1-picrylhydrazyl (IC50 58.63 µg/mL) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (IC50 73.22 µg/mL) assays (Singh et al., 2019). Nahid et al. (2017) have proved the antioxidant activity of methanol extract of E. prostrata leaves (IC50 42.1 µg/mL) in 2,2-diphenyl-1-picrylhydrazyl assay. The ferric reducing power of 200 µg/ mL of the extract was found to be equivalent to 12.18 µg/mL of gallic acid. Gani and Devi (2015) reported that the methanol extract at a concentration of 100 µg/mL showed potent 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity (80.13%). Chan et al. (2014) demonstrated that E. prostrata water extract showed 2,2-diphenyl-1-picrylhydrazyl and superoxide radicals scav­ enging, and ferrous ion chelating activities with IC50 0.23, 0.48 and 1.25 mg/ mL, respectively. Hossain et al. (2011) found that the ethyl acetate fraction of methanolic extract of E. prostrata showed nitric oxide, 2,2-diphenyl­ 1-picrylhydrazyl and peroxynitrite radicals scavenging activities with IC50 45.98, 12.98, and 14.45 μg/mL, respectively. Rao et al. (2009) revealed dose-dependent antioxidant potential of aqueous extract of E. prostrata (25–100 mg/mL) in different methods. Karthikumar et al. (2007) found that the ethanol extract of aerial part of E. prostrata (500 µg/mL) showed good antioxidant (77.62%) activity. 74.3.2 HEPATOPROTECTIVE ACTIVITY Ethanolic extract of E. prostrata (200 mg/kg) showed hepatoprotective activity by reducing the serum biochemical parameters (aspartate trans­ aminase, alanine transaminase, alkaline phosphatise and acid phosphatase) in carbon tetrachloride-induced liver toxicity in Wistar rats (Dheeba et al., 2012). Water extract of E. prostrata (0, 1–0.3 mg/mL) on ethanol-treated (96 µl/mL) primary rat hepatocytes showed significant reduction in the release of alanine transaminase and aspartate transaminase. The water extract (30 mg/kg) also showed hepatoprotective activity in ethanol (5 g/kg) induced hepatotoxicity in male Wistar rats by reducing the level of alanine trans­ aminase and aspartate transaminase after 4 h (Pramyothin et al., 2007). E. prostrata extract significantly inhibited the elevation of serum transaminases

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induced by carbon tetrachloride (31.25 μl/kg) in mice, and β-D-galactosamine (188 mg/kg) in rats (Lin et al., 1996). 74.3.3 ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES Water extract (500 mg/kg) of E. prostrata is found to improve colitis symptoms and decrease disease activity index scores in dextran sulfate sodium-induced mouse model by inhibiting the expressions of cyclo­ oxygenase-2 and hypoxia-inducible factor-1α (Kim et al., 2017). Ryu et al. (2013) found that, echinocystic acid isolated from the ethyl acetate fraction of ethanol extract of E. prostrata showed dose-dependent antiinflammatory property by inhibiting nitric oxide and cytokines (tumor necrosis factor-α and interleukin-6) synthesis, and nuclear translocation of p65 in lipopolysaccharide-induced RAW 264.7 macrophages. In vivo studies on acute (carrageenan induced) and subacute (formalin induced) inflammatory rat models revealed the dose-dependent anti-inflammatory activities of ethanolic extract (200 and 400 mg/kg) (Sharma et al., 2011). Orobol isolated from E. prostrata dose dependently (IC50 4.6 μM) downregulated the inducible nitric oxide synthase and cyclooxygenase-2 gene expressions in lipopolysaccharide-induced RAW 264.7 cells (Tewtrakul et al., 2011). Arunachalam et al. (2009) found that methanolic extract of leaves of E. prostrata (100 and 200 mg/kg) showed anti-inflammatory activity in carrageenan and egg white induced paw edema in albino Wistar rats, dose dependently. Hossain et al. (2011) reported the dose-dependent (200 and 400 mg/kg) analgesic and anti-inflammatory activities of ethyl acetate fraction of the methanol extract of E. prostrata in rats. The fraction showed 86.80% reduction in carrageenan-induced paw edema. Dithala et al. (2012) reported that the ethyl acetate extract of E. prostrata (50 and 100 mg/kg) showed good analgesic activity, dose dependently. The water extract of E. prostrata showed ameliorative effects on induced periodontitis in rat models by inhibiting alveolar bone loss and modulating the inflam­ matory mediators (Park et al., 2018). Morel et al. (2017) revealed that treatment with standardized methanol extract (250 mg/kg) significantly reduced respiratory resistance and elastance in allergen-induced murine asthma Balb/c mice model. Further, the extract significantly reduced the total number of inflammatory cells, eosinophils, and concentrations of interleukin-4, IL-5, and IL-13 in lung homogenate.

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74.3.4 ANTIHYPERLIPIDEMIC ACTIVITY Zhao et al. (2015) found that the ethanol fraction of E. prostrata (75, 150, and 250 mg/kg) ameliorates hyperlipidemia in male hamster by reducing oxidative stress and the transcription of genes involved in lipid metabolism. In another study, the freeze-dried butanol fraction of E. prostrata (50 and 100 mg/kg) reduced the serum triacylglycerol (9.8–19.0% ), total choles­ terol (10.7–13.4% ), low-density lipoprotein cholesterol (10–13.0%) and increased high-density lipoprotein cholesterol (13–19%) n Charles River Sprague–Dawley CD rats (Kim et al., 2008). The aqueous leaf extract of the E. prostrata (200 mg/kg) significantly reduced the total cholesterol, triglycerides, total protein, and increased high-density lipoprotein in the atherogenic diet induced hyperlipidemic rats (Dhandapani, 2007). Kumari et al. (2006) found that the alcohol extract of E. prostrata (150 mg/kg) signifi­ cantly reduced the lipid and cholesterol level in male Wistar albino rats. 74.3.5 OSTEOPROTECTIVE ACTIVITY Zhao et al. (2019) found that the ethanol extract (0.48 g/kg) of E. prostrata promoted growth of Lactobacillus and Lactococcus in gut and regulated the dynamic balance of bone absorption and formation. Treatment of 3-month old female ovariectomy-induced Sprague–Dawley rats with echinocystic acid (5 and 15 mg/kg/day) improved the biomechanical property of the femur and prevented changes on level of different metabolic biomarkers including alkaline phosphatase, deoxypyridinoline, urinary calcium, osteo­ calcin, phosphorus, and reduced the level of serum interleukin-1β and tumor necrosis factor-α (Deng et al., 2015). Zhang et al. (2013) reported the antios­ teoporotic effect of E. prostrata (1.4 g/kg/day) on ovariectomy-induced rats by inhibiting bone loss and downregulating nuclear factor κ-B ligand gene expression in tibiae and interleukin-6 level in serum and also by upregulating calcitonin in serum. Ethyl acetate extract of E. prostrata (20 μg/mL) and its constituent wedelolactone (5 μg/mL) were found to reduce the prolifera­ tion of preosteoclastic RAW264.7 by 75 and 15.1%, respectively (Liu et al., 2014). Liu and Ma (2017) found that the extract of E. prostrata aerial parts inhibited osteoclastic bone resorption by controlling nuclear factor-kappa B expression. The ethanol extract and volatile components of E. prostrata (1–100 μg/mL) induce differentiation, proliferation and increased the alka­ line phosphatase activity in primary osteoblasts of Sprague-Dawley rats (Lin et al., 2010). Lee et al. (2009) reported that diosmetin, 3′-hydroxybiochanin

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A and 3′-O-methylorobol isolated from methanol extract of E. prostrata showed osteoblast differentiation of primary culture of mouse osteoblasts at concentrations ranging from 1 to 25 µM without enhancing the osteoblast proliferation. 74.3.6 ANTIDIABETIC ACTIVITY Raoul et al. (2018) showed that aqueous extract of E. prostrata leaves (200, 400, and 800 mg/kg) lowered the glycemic peak in hyper glycemic rat model 30 min after the overdose of glucose and the effect continued until the fifth hour. The E. prostrata extract (300 mg/kg) and its constituent eclalbasaponin II (10 mg/kg) treatment reduced the blood sugar level without any hepato­ toxicity in alloxan-induced diabetic rats (Rahman et al., 2011). 74.3.7 NEUROPROTECTIVE ACTIVITY The ethanol extract of E. prostrata (100 μg/mL) significantly ameliorated the memory activity in the scopolamine-induced cognitive impairment and facilitates long-term potentiation in the hippocampus through activation of Akt/GSK-3β signalling pathway (Jung et al., 2016). Treatment with butanol fraction of methanol extract of E. prostrata (50 or 100 mg/kg) increased the formation of neurotransmitter acetylcholine (13.1% and 19.7%, respectively) in the brain of Charles River cesarean-derived male rats. It also inhibited oxidative stress in the brain and enhanced superoxide dismutase activity by 9.6% and 11.6%, respectively (Kim et al., 2010). 74.3.8 ANTICANCER ACTIVITY E. prostrata extract (0.05 and 1.0 mg/mL) dose-dependently inhibited migra­ tion and proliferation of periodontal ligament cells. The IC50 value of extract on PDLCs was found to be approximately 0.23 mg/mL after 48 h of treat­ ment (Nguyen et al., 2016). Lee et al. (2015) found that the hexane fraction of E. prostrata induced apoptosis in human endometrial cancer cells (Hec1A and Ishikawa) (IC50 < 1 μM). It has been revealed that 30% ethanol fraction and isolated eclalbasaponin I dose-dependently decreased the proliferation of smmc-7721 with IC50 74.23 and 111.17 μg/mL, respectively (Liu et al., 2012). Khanna and Kannabiran (2009) found that dasyscyphin C isolated

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from E. prostrata leaves have significant cytoxicity effect in Human cervical carcinoma cells with IC50 50 μg/mL. The nontoxic dose of aqueous alcoholic E. prostrata extract (100 μg/mL) attenuated SCC-9, HSC-3, and TW2.6 cell migration and invasion through the inhibition of matrix metalloproteinase-2 expression via ERK 1/2 pathway (Liao et al., 2018). The methanol and aqueous extracts of E. prostrata (IC50 between 31 and 70 μg/mL) inhibited invasion and migration on a variety of cancer cells without affecting cell adhesion (Lirdprapamongkol et al., 2008). The ethanol extract of E. prostrata is found to be effective in decreasing the hydroxyproline level and lung histological changes in bleomycin (5 mg/kg) induced pulmonary fibrosis in mice. The extract reduced the expressions of cyclooxygenase-2, trans­ forming growth factor-β1, matrix metalloproteinase-2 and α-smooth muscle actin, increased the ratio of MMP9/tissue inhibitors of metalloproteinase 1 and reduced oxidative stress. Moreover, its component ecliptasaponin A (80 mg/kg) reduced the pathological changes of lung and levels of TGF-β1 and α-SMA (You et al., 2015). 74.3.9 ANTIVENOM ACTIVITY Butanol extract of E. prostrata aerial parts (2.5 mg) cause 100% neutral­ ization of Malayan pit viper (Calloselasma rhodostoma) venom and puri­ fied butanolic extract (1.5–4.5 mg) neutralized the venom by 50–58% in Swiss albino mice. Both extracts partially inhibited the hemorrhagic effect and displayed very low antiphospholipase A2 activity and did not inhibit proteolytic activity of venom (Pithayanukul et al., 2004). Melo et al. (1994) reported the antimyotoxic and antihemorrhagic activities of both aqueous extract and wedelolactone against crotalid venoms (Bothrops jararaca, Bothrops Jararacussu, and Lachesis muta) and purified myotoxins (bothrop­ stoxin, bothropasin, and crotoxin) in in vitro and in vivo models. The extract and wedelolactone neutralized the myotoxicity of the crotalid venoms and mycotoxins, inhibited the hemorrhagic effect of B. jararaca venom, phos­ pholipase A2 activity of crotoxin and the proteolytic activity of B. jararaca venom (Melo et al., 1994; Melo and Ownby, 1999). Mors et al. (1989) discovered that the ethanol extract of E. prostrata aerial parts (1.8 mg; LD50 0.08 µg venom/g animal) neutralized up to four fatal doses of rattlesnake venom (Crotalus durissus terrificus). The three compounds isolated from the plant, wedelolactone (0.54 mg/animal), sitosterol (2.3 mg/animal), and stigmasterol (2.3 mg/animal) also showed venom neutralization potential.

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74.3.10 ANTIMICROBIAL ACTIVITY Nahid et al. (2017) found that the methanol extract (100 mg/mL) of E. prostrata showed highest activity against Streptococcus pyogenes. Nagab­ hushan et al. (2013) revealed the antifungal activity of petroleum ether extract of E. prostrata on infectious fungus Microsporum and Trichophyton with minimum inhibitory concentration of 0.15 mg/mL. Saponin fraction isolated from the leaves of E. prostrata exhibited antibacterial and antifungal activities with MIC of 1000–1200 mg/L for bacteria (Pseudomonas aerugi­ nosa, Escherichia coli, Salmonella typhi, Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus aureus) and 1400 mg/L for fungus (Aspergillus fumigatus, A. niger and A. flavus) (Khanna and Kannabiran, 2008). Karthikumar et al. (2007) found that the ethanol extract of E. prostrata (50 µg) showed maximum growth inhibition against Salmonella typhi. The methanolic extract (1 mg) of E. prostrata showed highest activity against Staphylococcus aureus (Wiart et al., 2004). The carbon tetrachloride and chloroform soluble fractions of the E. prostrata extract were found to be potent in microbial growth inhibition (Rahman and Rashid, 2008). Wede­ lolactone isolated from E. prostrata showed highest activity against HIV-1 integrase (IC50 4.0 µM), followed by orobol (IC50 8.1 µM). In HIV-1 protease inhibiting activity, 5-hydroxymethyl-(2,2′:5′,2″) terthienyl tiglate exhibited highest effect with an IC50 58.3 µM followed by ecliptal with IC50 83.3 µM (Tewtrakul et al., 2007). 74.3.11 ANTIFIBROTIC ACTIVITY Lee et al. (2008) found that the methanolic extract of aerial parts of E. prostrata showed 51% cell growth inhibition at 100 mg/mL in rat hepatic stellate cell line, HSC-T6. The isolated compounds, echinocystic acid, and eclalbasaponin II also exhibits significant inhibition in the proliferation of HSC-T6 in dose and time-dependent manners. 74.3.12 WOUND HEALING ACTIVITY It was observed that the incisions on rats were completely healed after 14 days of treatment with the aqueous and hydro-ethanolic extract of E. prostrata compared with 18 days in the control group (Raoul et al., 2018).

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74.3.13 NEPHROPROTECTIVE ACTIVITY Xu et al. (2014) showed the effects of E. prostrata (70% aqueous ethanol extract) on the activity and expression of 11β-Hydroxysteroid dehydroge­ nase in rat liver and kidney. Oral administration of extract (14 or 28 g/kg) significantly increased the activity of 11β-HSD I in the liver and 11β-HSD II in the kidney. The administration of extract improved the efficacy and reduced adverse drug reactions of glucocorticoid in patients undergoing combinational therapy. 74.3.14 HAIR GROWTH PROMOTING ACTIVITY Lee et al. (2020) found that the E. prostrata extract enhances scalp condi­ tion and prevent hair loss in patients. E. prostrata improved the induction of anagen in the dorsal skin of mice, characterized by the development of the inner root sheath together with the hair shaft, and the emergence of the hair shaft through the epidermis (Lee et al., 2019). Begum et al. (2015) found that the petroleum ether extract of E. prostrata promotes follicular keratinocyte proliferation and delays terminal differentiation by down regulating TGF-1 expression. Datta et al. (2009) found that the methanol extract of E. prostrata showed hair growth promoting activity. 74.3.15 TOXICITY STUDY Acute oral toxicity study revealed that methanol extract of E. prostrata and its different organic fractions in water up to 1500 mg/kg did not cause mortality in Swiss albino mice and albino Wistar rats during 48 h treatment. However some changes in behavior, locomotor ataxia, diarrhea, and weight loss were observed when compared with control (Hossain et al., 2011). Singh et al. (2013) found that the LD50 value of aqueous extract of E. prostrata in female Swiss albino mice is 2316.626 mg/kg. ACKNOWLEDGMENTS The authors express their sincere thanks to Dr. Ashok K. Chauhan, Founder President, Ritnand Balved Education Foundation (RBEF) and Amity Group of Institutions, and Dr. Atul Chauhan, Chancellor, Amity University Uttar

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Pradesh (AUUP) for facilitating this work. Thadiyan Parambil Ijinu is receiving Young Scientist Fellowship from the Department of Science and Technology, Government of India (SP/YO/413/2018). KEYWORDS • • • • • • • •

traditional medicine Bhringaraj Coumestan Wedelolactone Eclalbasaponins antioxidant hepatoprotective hair growth promoting

REFERENCES Abdel-Kader, M. S.; Bahler, B. D.; Malone, S.; Werkhoven, M. C.; van Troon, F.; David, X.; Wisse, J. H.; Bursuker, I.; Neddermann, K. M.; Mamber, S. W.; Kingston, D. G. DNA-Damaging Steroidal Alkaloids from Eclipta alba from the Suriname Rainforest. J. Nat. Prod. 1998, 61, 1202–1208. Arunachalam, G.; Subramanian, N.; Pazhani, G. P.; Ravichandran, V. Anti-Inflammatory Activity of Methanolic Extract of Eclipta prostrata L. (Asteraceae). Afr. J. Pharm. Pharmacol. 2009, 3, 97–100. Begum, S.; Lee, M. R.; Gu, L. J.; Hossain, J.; Sung, C. K. Exogenous Stimulation with Eclipta alba Promotes Hair Matrix Keratinocyte Proliferation and Downregulates TGF-β1 Expression in Nude Mice. Int. J. Mol. Med. 2015, 35, 496–502. Chan, C. F.; Huang, W.-Y.; Guo, H.-Y.; Wang, B. R. Potent Antioxidative and UVB Protective Effect of Water Extract of Eclipta prostrata L. Sci. World J. 2014, 759039. Chinese Pharmacopoeia Commission. Pharmacopoeia of the People’s Republic of China; Vol 1; China Medical Science Publisher: Beijing, 2015; pp 374–375. Datta, K.; Singh, A. T.; Mukherjee, A.; Bhat, B.; Ramesh, B.; Burman, A. C. Eclipta alba Extract with Potential for Hair Growth Promoting Activity. J. Ethnopharmacol. 2009, 124, 450–456 Deng, Y. T.; Kang, W. B.; Zhao, J. N.; Liu, G.; Zhao, M. G. Osteoprotective Effect of Echinocystic Acid, a Triterpone Component from Eclipta prostrata, in OvariectomyInduced Osteoporotic Rats. PLoS One 2015, 10, e0136572.

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Dhandapani, R. Hypolipidemic Activity of Eclipta prostrata (L.) L. Leaf Extract in Atherogenic Diet Induced Hyperlipidemic Rats. Indian J. Exp. Biol. 2007, 45, 617–619. Dheeba, B.; Vaishnavi, E.; Sampathkumar, P.; Kannan, M. Hepatoprotective and Curative Effect of Eclipta prostrata on CCl4 Induced Hepatotoxicity in Albino Rats. Biosci. Biotechnol. Res. Asia 2012, 9, 309–314. Dithala, S.; Kiranmai, M.; Dorababu, N.; Mohammed, I. Pharmacognostical, Phytochemical and Analgesic Activity of Eclipta prostrata. L (Asteraceae). J. Glob. Trends Pharm. Sci. 2012, 3, 740–746. Gani, A. M. S.; Devi, N. D. Antioxidant Activity of Methanolic Extract of Eclipta prostrata L. Int. J. Phytopharm. 2015, 21–24. Han, L. F.; Zhao, J.; Zhang, Y.; Agyemang, K.; Liu, E. W.; Wang, T. Chemical Constituents from Dried Aerial Parts of Eclipta prostrata. Chin. Herb. Med. 2013, 5, 313–316. Hossain, M. S.; Alam, M. B.; Chowdhury, N. S.; Asadujjama, M.; Zahan, R.; Islam, M. M.; Mazumder, M. E. H.; Haque, M. E.; Islam, A. Antioxidant, Analgesic and Anti-Inflammatory Activities of the Herb Eclipta prostrata. J. Pharmacol. Toxicol. 2011, 6, 468–480. Jung, W. Y.; Kim, H.; Park, H. J.; Jeon, S. J.; Park, H. J.; Choi, H. J.; Kim, N. J.; Jang, D. S.; Kim, D. H.; Ryu, J. H. The Ethanolic Extract of the Eclipta prostrata L. Ameliorates the Cognitive Impairment in Mice Induced by Scopolamine. J. Ethnopharmacol. 2016, 190, 165–173. Karthikumar, S.; Vigneswari, K.; Jegatheesan, K. Screening of Antibacterial and Antioxidant Activities of Leaves of Eclipta prostrata. Sci. Res. Essays 2007, 2, 101–04. Khan, A. V.; Khan, A. A. Ethnomedicinal Uses of Eclipta prostrata Linn. Indian J. Tradit. Knowl. 2008, 7, 316–320. Khanna, V. G.; Kannabiran, K. Antimicrobial Activity of Saponin Fractions of the Leaves of Gymnema sylvestre and Eclipta prostrata. World J. Microbiol. Biotechnol. 2008, 24, 2737–2740. Khanna, V.G; Kannabiran, K. Anticancer-Cytotoxic Activity of Saponins Isolated from the Leaves of Gymnema sylvestre and Eclipta prostrata on HeLa Cells. Int. J. Green Pharm. 2009, 3, 227–229. Kim, D. I.; Lee, S. H.; Choi, J. H.; Lillehoj, H. S.; Yu, M. H.; Lee, G. S. The Butanol Fraction of Eclipta prostrata (Linn) Effectively Reduces Serum Lipid Levels and Improves Antioxidant Activities in CD Rats. Nutr. Res. 2008, 28, 550–554 Kim, D. I.; Lee, S. H.; Hong, J. H.; Lillehoj, H. S.; Park, H. J.; Rhie, S. G.; Lee, G. S. The Butanol Fraction of Eclipta prostrata (Linn) Increases the Formation of Brain Acetylcholine and Decreases Oxidative Stress in the Brain and Serum of Cesarean-Derived Rats. Nutr. Res. 2010, 30, 579–584. Kim, D. S.; Kim, S. H.; Kee, J. Y.; Han, Y. H.; Park, J.; Mun, J. G.; Joo, M. J.; Jeon, Y. D.; Kim, S. J.; Park, S. H.; Park, S. J.; Um, J. Y.; Hong, S. H. Eclipta prostrata Improves DSS-Induced Colitis Through Regulation of Inflammatory Response in Intestinal Epithelial Cells. Am. J. Chin. Med. 2017, 45, 1047–1060. Kim, H. Y.; Kim, H. M.; Ryu, B.; Lee, J. S.; Choi, J. H.; Jang, D. S. Constituents of the Aerial Parts of Eclipta prostrata and Their Cytotoxicity on Human Ovarian Cancer Cells In Vitro. Arch. Pharm. Res. (Seoul) 2015, 38, 1963–1969. Kumari, C. S.; Govindasamy, S.; Sukumar, E. Lipid Lowering Activity of Eclipta prostrata in Experimental Hyperlipidemia. J. Ethnopharmacol. 2006, 105, 332–335.

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Production of Th2 Cytokines in a Murine Model of Asthma. J. Ethnopharmacol. 2017, 198, 226–234. Mors, W. B.; do Nascimento, M. C.; Parente, J. P.; da Silva, M. H.; Melo, P. A.; Suarez-Kurtz, G. Neutralization of Lethal and Myotoxic Activities of South American Rattlesnake Venom by Extracts and Constituents of the Plant Eclipta prostrata (Asteraceae). Toxicon 1989, 27, 1003–1009. Nagabhushan; Raveesha, K. A.; Shrisha, D. L. Antidermatophytic Activity of Eclipta prostrata L. Against Human Infective Trichophyton and Microsporum spp. Int. J. Chem. Anal. Sci. 2013, 4, 136–138. Nahid, A.; Neelabh, C.; Navneet, K. Evaluation of Antioxidant and Antimicrobial Potentials of Eclipta prostrata Collected from the Nepal Region. J. Pharm. Innov. 2017, 6, 4–7. Nguyen, T. T.; Choonate, S.; Puengsurin, D.; Srichan, R.; Mala, S.; Surarit, R. Effects of Eclipta prostrata and Eclipta alba on Survival, Proliferation, Migration of Periodontal Ligament Cell. Mahidol Dent. J. 2016, 36, 165–173. Park, J. H.; Lee, H.; Yang, W. M. The Effects of Eclipta prostrata L. (Ecliptae herba) on Periodontitis Rats. J. Korean Med. 2018, 39, 63–74. Pithayanukul, P.; Laovachirasuwan, S.; Bavovada, R.; Pakmanee, N.; Suttisri, R. Anti-venom potential of butanolic extract of Eclipta prostrata against Malayan pit viper venom. J. Ethnopharmacol. 2004, 90, 347–352. Pramyothin, P.; Tungkasen, H.; Poungshompoo, S. Hepatoprotective activity of Eclipta prostrata Linn. Extract in Ethanol Induced Rat Hepatic Injury. J. Trad. Med. 2007, 24, 164–167. Pushpangadan, P.; George, V., Sreedevi, P.; Ijinu, T. P.; Anzar, S.; Bincy, A. J. 46. Eclipta alba (L.) Hassk. In Plants for Health and Nutritional Security; Amity Institute for Herbal and Biotech Products Development: Thiruvananthapuram, 695005, India, 2016; pp 226–229. Rahman, M. S.; Rashid, M. A. Antimicrobial Activity and Cytotoxicity of Eclipta prostrata. Orient. Pharm. Exp. Med. 2008, 8, 47–52. Rahman, M. S.; Rahman, M. Z.; Begum, B.; Chowdhury, R.; Islam, S. N.; Rashid, M. Antidiabetic Principle from Eclipta prostrata. Latin Am. J. Pharm. 2011, 30, 1656–1660. Rahmatullah, M.; Mollik, A. H.; Ali Azam, A. T. M.; Islam, R.; Chowdhury, A. M.; Jahan, R.; Chowdhury, M. H.; Rahman, T. Ethnobotanical Survey of the Santal Tribe Residing in Takurgaon District, Bangladesh. Am. Eurasian J. Sustain. Agric. 2009, 3, 889–898. Rao, D. B.; Kiran, C. R.; Madhavi, Y.; Rao, P. K.; Rao, T. R. Evaluation of Antioxidant Potential of a Clitoria ternatea L. and Eclipta prostrata L. Indian J. Biochem. Biophys. 2009, 46, 247–252. Raoul, A.; Jonas, M. C.; Rommelle, S. M. C.; Romaric, E. I. D. G.; Martin, D.; Antoine, A. A. Antidiabetic and Wounds Healing Activities of Eclipta prostrata (Asteraceae) Leaves. Int. J. Adv. Res. 2018, 6, 393–398. Ryu, S.; Shin, J. S.; Jung, J. Y.; Cho, Y.-W.; Kim, S. J.; Jang, D. S.; Lee, K.-T. Echinocystic Acid Isolated from Eclipta prostrata Suppresses Lipopolysaccharide-Induced INOS, TNF-α, and IL-6 Expressions via NF-ΚB Inactivation in RAW 264.7 Macrophages. Plant. Med. 2013, 79, 1031–1037. Sarg, T. M.; Salam, N. A. A.; El-Domiaty, M.; Khafagy, S. M. The Steroid, Triterpenoid and Flavonoid Constituents of Eclipta alba (L.) Hassk (Compositae) Grown in Egypt. Sci. Pharm. 1981, 49, 262–264. Sasidharan, N. Biodiversity Documentation for Kerala, Part 6: Flowering Plants; Kerala Forest Research Institute: Kerala, India, 2004.

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CHAPTER 75

Phytochemical Potential and Pharmacology of Ephedra alata Decne. SAVALIRAM G. GHANE1, SANTOSHKUMAR JAYAGOUDAR2, PRADEEP BHAT3, and RAHUL L. ZANAN4* 1Laboratory

of Plant Physiology, Department of Botany, Shivaji University, Vidyanagar, Kolhapur, Maharashtra 416004, India 2Department

of Botany, G. S. S. College & Rani Channamma University P. G. Centre, Belagavi, Karnataka 590006, India 3ICMR-

National Institute of Traditional Medicine, Nehru Nagar, Belagavi,

Karnataka 590010, India

4Department

of Botany, Elphinstone College, Dr. Homi Bhabha State

University, Madam Cama Road, Mumbai, Maharashtra 400032, India

*Corresponding

author.

E-mail: [email protected]; [email protected]

ABSTRACT Ephedra alata (Family: Ephedraceae) is evergreen xerophytic shruby gymno­ sperm, distributed from arid and semiarid regions of the world. Traditionally it is used for treating asthma, cold, fever, flu, headache and nasal congestion. Various alkaloids, polyphenols, phenolic, flavonoids, fatty acids, essential oil and volatiles were recorded from this plant. The stem is source of impor­ tant alkaloid, ephedrine. Various biological activities were reported from this plant like, antidiabetic, anticancer, antioxidant, antipesticidal, diuretic, anti­ hypertensive, analgesic, anti-Inflammatory, antimicrobial, hypolipidaemic, cytostatic, aflatoxin inhibitory, nephrotoxic and hepatotoxic, wound and Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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burn healing activity. This chapter provided complete information on the plant morphology, traditional use, bioactive compounds and pharmaceutical activities of E. alata. 75.1

INTRODUCTION

Ephedra alata Decne. belongs to family Ephedraceae. It is distributed in arid and semiarid regions of the world from Algeria, Egypt, Libyan, Morocco, Tunisia, Mauritania, Chad, Mali, Saudi Arabia, Iraq, Iran, Palestine, Lebanon, Sinai, Jordan, Syria, and Western Sahara (Al-Snafi, 2017; Anony­ mous, 2021a,b). It is commonly called as Ephedra (English), Alanda, Alanda Mujanaa, Theel maiz, Anab bahar, Ather, and Jashia (Arabic) (Al-Snafi, 2017). It is small, evergreen shrub, almost leafless, and 60–90 cm high. Stem slender, erect, branched at base, small ribbed and channeled, terminating in a sharp point, green in color, and 1.5 mm in diameter. Nodes reddish brown in color, 4–6 cm apart, small triangular leaves present at stem base. Flowers and fruits minute, yellow-green, pine-like odor, and astringent taste (Blumenthal and King, 1995; Fukushima, 2004, Al-Snafi, 2017). In the traditional medicine, it is used to treat asthma, cold, flu, chills, fever, headache, nasal congestion, and cough. It is toxic, diaphoretic, astringent, depurative, bronchodilator, antitussive, convulsant, rhinitis, expectorant, analeptic, cardiotonic, antiviral against herpes simplex-1 virus (HSV), and used to treat cancer, respiratory diseases, cephalagia, edema, central nervous system, rheumatism, dropsy, coryza, and athralgia (Rawi and Chakravarty, 1964; Boulos, 1983, Hussein, 1985; Soltan and Zaki, 2009; Hadjadj et al., 2020; Rashed, 2021). 75.2

BIOACTIVES

The preliminary phytochemical analyses by Jaradat et al. (2015) confirmed the presence of cardiac glycosides, alkaloids, reducing sugars, phenolic, and flavonoid compounds from aqueous, methanolic, acetone, and ethanolic extracts of aerial plant part. Further, Kittana et al. (2017) observed phytochem­ ical compounds (flavonoids, alkaloids, phytosteroids, phenolic compounds, volatile oils, and tannins) from the aqueous extract. Hegazi and El-Lamey (2011) in vitro produced five medicinally important phenolic compounds (chlorogenic acid, rutin, catechin, quercetin, coumaric acid) from the callus supplemented with 1 mg/L of each 2,4-D and kinetin. Danciu et al. (2019) identified polyphenols namely, caffeic acid, epicatechin, p-coumaric acid,

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rosmarinic acid, resveratrol, quercitin, and kaempferol from hydroalcoholic extract of the aerial plant part using LC-MS. Ziani et al. (2019) identified total 10 phenolic compounds, namely, myricetin-C-hexoside isomer 1 and 2, biochanin A 7-O-glucoside (sissotrin), 5,5′-dihydroxi-methoxy-isoflavoneO-glucoside, quercetin-3-O-rutinoside, isorhamnetin-3-O-glucoside, kaempferol-O-di-deoxyhexoside, and hydroxydaidzein-8-C-glucoside isomer (hydroxypuerarin isomer) 1, 2, and 3 by LC-DAD-ESI/MSn from infusion (1:100 m/v with distillated boiling water), decoctions (1:100 m/v distillated water), and hydroethanolic extracts of aerial plant part. Benabder­ rahim et al. (2019) recorded six phenolic compounds (quinic acid, gallic acid, 4-O-caffeoylquinic acid, syringic acid, p-coumaric acid, and trans­ ferulic acid) and eight flavonoids (catechin (+), epicatechin, rutin, quercetrin (quercetin-3-o-rhamonoside), naringenin, luteolin, cirsilineol, and acacetin) from hydroethanolic extract of aerial parts. Mighri et al. (2019) developed a sensitive and validated method (LC-ESI/MS) for determination of phenolic compounds from hydromethanolic extract and its fractions (dichloromethane, ethyl acetate, butanol and water). They recorded 24 phenolic compounds, namely, quinic acid, gallic acid, protocatchuic acid, (+)-catechin, chlorogenic acid, 4-O-caffeoylquinic acid, caffeic acid, syringic acid, (−)-epicatechin, p-coumaric acid, trans-ferulic acid, rutin, quercetrin, naringin, apigetrin, trans-cinnamic acid, quercetin, kaempferol, naringenin, apigenin, luteolin, cirsiliol, cirsilineol, and acacetin. Recently, Soumaya et al. (2020) noted phenolic compounds like, gallic acid, epigallocatechin, catechin, chlorogenic acid, epicatechin- 3-O-gallate, caffeic acid, syringic acid, p-coumaric acid, sinapic acid, hydroxycinnamic acid, myricitrin, luteolin-7-O-glucoside, isoquercitrin, rutin, kaempferol 3-O-rutinoside, trans-cinnamic acid, quer­ cetin, and kaempferol from ethyl acetate and ethanol extracts of aerial plant part. Chromatographic separation of methanolic extract of female cone was carried out by HPLC and confirmed the presence of phenolic compounds such as, gallic acid, chlorogenic acid, vanillic acid, vanillin, p-coumaric acid, rutin, naringenin, and quercetin (Chouikh, 2020). Nawwar et al. (1984) identified two new flavonoids [herbacetin 8-methyl ether 3-0-glucoside-7-0-rutinoside and herbacetin 7-O-(6″-quinylglucoside)] and five previously known flavonoids (vicenin II, lucenin III, kaempferol3rhamnoside, quercetin 3-rhamnoside and herbacetin 7-glucoside) from the whole plant. Further, Nawwar et al. (1985) identified furanofuran lignansyringaresinol from chloroform extract for the first time in Ephedraceae. New alkaloid, ephedralone identified from the aqueous extract. Also, they recorded p-coumaric acid and nilocitin from chloroform and ethanolic extracts,

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respectively. Caveney et al. (2001) identified 6-hydroxykynurenic acid, ephed­ rine, pseudo-ephedrine and tannin from the stem of E. alata. Mighri et al. (2017) identified four new alkaloids like azetidine, 1,2-dimethyl-3-phenylaziridine, N-ethyl benzamide, and N-methyl-mandelamide along with previously known six alkaloids; pseudoephedrine, norephedrine, ethylephedrine, deoxyephed­ rine, methylephedrine, ephedroxane, and four unknown alkaloids. For the first time, Mighri et al. (2017) identified 14 fatty acid composition, namely, lauric acid, tetradecanoic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, oleic acid, linolelaidic acid, linoleic acid, docosanoic acid, eicosanoic acid, 7,10,13-Eicosatrienoic acid, cis-11,14,17-eicosatrie­ noic acid, heneicosanoic acid, and tetracosanoic acid from hexane extracts using GC-MS. Further, Soua et al. (2020) characterized polysaccharides extracted from dried stem powder and noted ash, carbohydrates, proteins, lipids, uronic acid and moisture content. They also recorded calcium, sodium, potassium, zinc, magnesium, manganese, iron and copper. Among the different monosaccharide, glucose was the most abundant sugar, followed by galactose, mannose, arabinose, and gluconic acid. Chouitah (2019) characterized hydrodistillated essential oil from aerial part using GC-MS and identified 18 volatiles in which β-pinene, α-terpinyl acetate, β-selinene, borneol and β-cadinene were found as major compounds. Mighri et al. (2017) identified 85 compounds from the fresh, dry, powdered, and without powdered hexane extracts. Among all, identified compounds were from hydrocarbons, alcohols, terpenes, esters, aldehydes, and other with unknown functional groups. Jerbi et al. (2016) identified 19 volatiles (α-pinene; 1,8-cineole; 4-methyldecane; 2-methyl­ decane; 1-nonen-3-ol; (Z)-3-undecene; linalool; (E)-2-undecene; camphor; α-terpineol; linalyl acetate; (Z)-3-tridecene; (E)-anethole; 1-tridecene; n-tridecane; (E)-2-tridecene; (Z)-2-tridecene; 2,3,5,8-tetramethyldecane and n-pentadecane) from the essential oil obtained by hydro-distillation of stem. Chebouat et al. (2016) investigated dichloromethane extract of the leaves and flowers for its chemical composition using GC-MS. From leaves extract, they identified 52 compounds, namely, ethanol, 2-butoxy; benzaldehyde; hexanoic acid; (methylthio) ethane; cyclopentasiloxane, decamethyl; thiourea; benzoic acid; 1-amino-pyrrolidine; thiophene, 2,5-dihydro; 1H-pyrrole-2,5-dione-3-ethyl-4-methyl; nonanoic acid; 2H-pyrrol-2-one, 1,5-dihydro-1-methyl; tetrasiloxane, decamethyl; benzen­ emethanol; benzenepropanoic acid; benzaldehyde, 4-hydroxy; 2-propenoic acid, 3-phenyl, methyl; benzaldehyde, 4-hydroxy-3-methoxy; 2-propenoic acid, 3-phenyl; benzene, (2-methoxyethyl); ethanedioic acid, (trimethyl);

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anhydro-beta-D-glucopyranose1,6; heptanoic acid; benzoic acid, 4-hydroxy, ethyl ester; -dideuterio-4-phenylbutylamine3,3; trimethyl4,4,5-dioxo­ lane,1,3-; benzenepropanol, 4-hydroxy; 3-methyl-5-nitropyrazole; benzoni­ trile, 4-formyl; 1-hydroxy-5-methylbenzotriazole; cyclohexene-l-methanol, 5-hydrox; benzeneacetic acid, alpha-hydrox; benzaldehyde, 4-hydroxy3,5-dimethyl; ethyl vanillylether; 3H-pyrazol-3-one, 1,2-dihydro; phenol, 4-(3-hydroxy-1- propenyl); N,N-diethyl-2-pyridylethylamine; (-)-loliolide; N-methyl-2-(2-propinyl) oxybenzamid; benzenemethanol, 3,4-dimethoxy; hexadecanoic acid; -benzenedicarboxylic acid, mono1,2; 4a-methyl4,4a-dihydrophenanthren; eicosenoic acid, methyl ester; octadecanoic acid; tricyclo(3,3,1,1(3,7))decane-2-car; benzaldehyde, 4-hydroxy-3-methoxy; benzenedicarboxylic acid; 1H-indole-3-acetonitrile, (trimethyl); 2-allyl1-methylnaphthalene; propenoic acid, dimethyl and benzoxathiole1,3-. Similarly from the flower extract, they identified 65 compounds viz., N1,N3diethylpropane-1,3-diamine; 2,2,3,3-tetramethyl-1-D1-aziridine; ethane,1,1, 2,2-tetrachloro-; furan, tetrahydro-3-methyl; benzaldehyde; hexanoic acid; pentanoic acid, ethyl esther; benzenemethanol; gamma-D2-tetrahydropyran; ethanone,1- (1H-pyrrol-2-yl); butanoic acid, 3-methyl, 2-methyl; octane; benzeneethanol; pentaerythritol, tetranitrate; benzoic acid; 1-aminopyrrolidine; thiophene,2,5-dihydro; 1,2-ethanediol, 1-phenyl; benzeneacetic acid, ethyl ester; benzeneacetic acid; 2-butene, 1,1-dimethoxy; benzoic acid, phenyl ester; 2H-pyrrol-2-one,1,5-dihydro-1-methyl; phenol, 5-methyl2-(1-methylethyl); benzenemethanol; benzenepropanoic acid; ethyl, 3-phenylpropionate; benzaldehyde, 4-hydroxy; (Z)-3-phenyl-2- propenoic acid; benzaldehyde, 4-hydroxy- 3-methoxy; 2-propenoic acid, 3-phenyl; guanidine, cyano; 4-methylcyclohexa-2-EN-1-OL; benzoic acid, 4-hydroxy, ethyl ester; 2(4H)-benzofuranone; -dimethyl-3-(methoxymethyl)-pbenzoquinone2,6; benzoic acid, 4-hydroxy- 3-methoxy; hexanoic acid, ethyl ester; benzene acetic acid, 4-hydroxy-3-methoxy; benzaldehyde, 4-hydroxy3,5-dimethyl; undecanenitrile; phenol,4-(3-hydroxy-1-propenyl)-2; ethanol, 2-(diethylamino)-, hydroc; nonylphenol; phenol, 4-methoxy; cyclopentane,1,1,3,3-tetramethyl; phosphine oxide, dimethyl (trifluor); 2-propenoic acid, 3-(4- hydroxy-3-methyl); 5-methyl-8-nitro-imidazo(1,2A)pyrane; 1,4-cyclohexanedione,2,2,6-trimethyl; N-(gamma-L-glutamyl)­ L-proline; hexadecanoic acid; 4a-methyl-4,4a-dihydrophenanthren; 9- hexadecenoic acid; 1-hexadecanol; oxacyclotetradecane-2,11-dione; 6-formyl-5,7-dimethylphthalide; 9-octadecenamide; heneicosane; 2-nitro-2(3-oxobutyl)cyclooctanon; thiosulfuric acid; 1,2-benzenedicarboxylic acid, diis 3; heneicosane; pyrimido[1,2-a]azepine; benzaldehyde, 2,4-dihydroxy.

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FIGURE 75.1

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

Phenolics and flavonoids from Ephedra alata.

Ephedra alata Decne.

FIGURE 75.2

Lignan and alkaloids from Ephedra alata.

FIGURE 75.3

Fatty acids from Ephedra alata.

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FIGURE 75.4

75.3

Major essential oil composition in Ephedra alata.

PHARMACOLOGY

75.3.1 ANTIOXIDANT ACTIVITY Jaradat et al. (2015) evaluated antioxidant activity of methanolic extract of aerial plant part using DPPH assay. Among the different concentrations (1–100 μg/mL), 40 μg/mL concentration showed the most promising activity with 71.36 ± 1.21% inhibition, whereas maximum antioxidant activity (75.02 ± 1.67% inhibition) recorded at 100 μg/mL concentration. The extract showed IC50 value of 16.03 μg/mL compared with trolox standard (3.6 μg/

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mL). Further, Jerbi et al. (2016) investigated DPPH free radical-scavenging activity of stem extracts and essential oil. Only stem methanolic extracts showed strong radical-scavenging activity with IC50 value of 0.027 mg/mL followed by ethyl acetate (0.107 mg/mL). Shawarb et al. (2017) recorded antioxidant potential using DPPH assay with IC50 value of 15.85 μg/mL from leaves methanolic extract. Kmail et al. (2017) investigated antioxidant activity using the DPPH scavenging assay, ABTS assay and reducing power of hydroethanolic extracts of aerial plant part and recorded 100 ± 4, 154 ± 1, and 530 ± 1 µg/mL IC50 values, respectively. Mighri et al. (2017) also exam­ ined antioxidant potential for hexane extracts and alkaloids of the aerial part using phosphomolybdenum, DPPH and FRAP assay. Among the different methods, alkaloid fractions obtained from fresh and dry powder showed significant FRAP reducing power (1433 ± 17 and 1200 ± 6 μM, respectively) followed by alkaloids from fresh and dry non powdered plant material (1112 ± 9 and 926 ± 7 μM, respectively). Rimawi et al. (2017) evaluated antioxi­ dant potential of dried plant material with 95% and 80% ethanol and water extracts using different assay. Ethanolic extract (95%) showed 11.1 ± 0.2 mmol/g, 3272 ± 30 μmol/g, 351.7 ± 1.2 μmol/g, 47.5 ± 1.0 μmol/g, 91.5 ± 0.6 and 87.0 ± 0.3% inhibition in FRAP, CUPRAC, DPPH, ABTS, DPPH and ABTS, respectively. Similarly, 80% ethanolic extract revealed 21.3 ± 0.4 mmol/g, 6442 ± 52 μmol/g, 482.5 ± 1.7 μmol/g, 66.0 ± 1.5 μmol/g, 95.3 ± 0.6 and 91.0 ± 0.6% inhibition using FRAP, CUPRAC, DPPH, ABTS, DPPH, and ABTS, respectively. The least antioxidant recorded in water extract. Recently, Ziani et al. (2019) estimated antioxidant activity of infusion (1:100 m/v with distillated boiling water), decoctions (1:100 m/v distillated water) and hydroethanolic extracts of aerial plant part using DPPH radicalscavenging, reducing power, β-carotene bleaching and TBARS assay and EC50 value was calculated. Infusion showed 450 ± 7, 108 ± 1, 131 ± 1, and 128 ± 2 μg/mL of EC50 values, respectively. Likewise, decoction noted with 455 ± 6, 109 ± 3, 173 ± 3, and 118 ± 2 μg/mL of EC50 values. Further, hydro­ ethanolic extracts also showed 540 ± 3, 377 ± 4, 502 ± 8, and 118 ± 4 μg/ mL of EC50 values respectively for all tested methods. Danciu et al. (2019) noted 7453.18 ± 2.5 µmol trolox/g extract of antioxidant potential from hydroalcoholic extract of aerial plant part. Benabderrahim et al. (2019) noted 33.51 ± 0.05 and 37.86 ± 0.03 mg TEAC/100 g extract of DPPH and ABTS antioxidant potential from methanolic extract of aerial plant part. Mighri et al. (2019) recorded antioxidant capacity from hydromethanolic extract and its fractions (dichloromethane, ethyl acetate, butanol, and water) using total antioxidant capacity, DPPH and FRAP assays. Among the different extracts

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studied, dichloromethane showed the highest total antioxidant capacity (221.71 ± 8.90 mg AAEq/g DE). Similarly, butanol and ethyl acetate also showed higher DPPH scavenging activity with IC50 values of 0.176 ± 0.002 and 0.180 ± 0.002, respectively. In addition, dichloromethane and ethyl acetate extracts exhibited strong ferric reducing antioxidant power (18.32 ± 0.07 and 21.36 ± 0.04 mM TEq/g DE, respectively). Soua et al. (2020) examined antioxidant potential of stem powder polysaccharide extract with various methods. They recorded total antioxidant capacity using phospho­ molybdate method with IC50 values of 3.2 mg/mL. Concentration-dependent DPPH free radical and ABTS scavenging capacity and reducing power capacity was observed wherein effective DPPH and ABTS activity (47.32 ± 0.32 and 84.17 ± 2.16%) were observed at 0.3 and 2 mg/mL concentra­ tions, respectively. β-carotene bleaching assay confirmed the IC50 value of 4.2 mg/mL, which were more efficient. Ferrous ion-chelating activity was highest 96.23% at 10 mg/mg extract. Different extracts from aerial plant part (hexane, ethyl acetate, and ethanol) showed ˃1000, 83.07 ± 0.2 and 3.37 ± 0.1 mg/mL of IC50 for DPPH; ˃1000, ˃1000 and 262.22 ± 5.1 mg/ mL of EC50 for reducing power; 2.30 ± 2.1, 93.67 ± 2.1 and 280.50 ± 3.9 mg GAE/g DW total antioxidant capacity, respectively (Soumaya et al., 2020). Chouikh (2020) tested methanolic extract of dried female cones for antioxidant activity using DPPH free radical scavenging assay and noted strong antioxidant potential with IC50 value of 31.08 μg/mL. These findings confirmed the antioxidant potential of the plant. 75.3.2 ANTIPESTICIDAL ACTIVITY Medila et al. (2020) evaluated protective effect of aqueous extract against pesticide (metribuzin) induced Albino rats. After 50 days of metribuzin induction, they recorded increased glucose level, plasma urea, and creati­ nine, which causes induction of oxidative damage. The supplementation of 200 mg/kg b.w. plant extract significantly reduced the adverse effects of metribuzin. 75.3.3 ANTIHYPERTENSIVE ACTIVITY Soua et al. (2020) recorded 82.49 ± 0.66% angiotensin-converting enzyme inhibitory activity from at 1 mg/mL stem powder polysaccharide extract with 0.21 mg/mL of IC50 value. These findings prove that the plant could be a promising natural source of antihypertensive agents.

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75.3.4 ANTIBACTERIAL ACTIVITY Antibacterial potential of hydrodistillated essential oil from aerial plant was estimated. Escherichia coli showed the highest inhibition followed by Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus with 17.3 ± 0.10, 12 ± 0.02, 11.50 ± 0.03 and 10 ± 0.1 mm diameter zone of inhibition, respectively (Chouitah, 2019). Further, Chebouat et al. (2014) screened leaves and flower extracts for their antibacterial potential against Gram-positive and -negative bacteria. Among the different extracts, ethyl acetate extract of flowers (1000 μg/mL) showed high antibacterial potential against Serratia marcescens ATCC 13880, Pseudomonas aeruginosa ATCC 10145, Bacillus subtilis ATCC 6051, E. coli ATCC 25922, Enterococcus faecalis ATCC 29212, S. aureus ATCC 25923, and B. cereus ATCC 11778 with 1, 0.9, 1.5, 1, 1.5, 1.5, and 1.4 cm zone of inhibition, respectively. Same concentration of ethyl acetate extract of leaves showed high antibacterial potential against B. subtilis ATCC 6051, S. aureus ATCC 25923, and B. cereus ATCC 11778 with 1.7, 1.2, and 1.2 cm zone of inhibition, respectively. Palici et al. (2015) noted considerable antibacterial activity from aerial plant part extract against B. subtilis, M. catarrhalis, and methicillin-resistant and nonresistant S. aureus using disc diffusion method. They recorded 9.5, 7.5, 14.5, and 9.5 mm zone of inhibition, respectively. They also recorded >5 mg/ mL MIC value in methicillin-resistant S. aureus. Jerbi et al. (2016) screened various stem extracts and essential oil from stem for antimicrobial potential using Gram-positive and -negative bacteria. Methanolic extract showed strong antimicrobial potential against Enterococcus facealis, Baccilus cereus, Baccillus subtilus, Listeria monocytogenèse, Salmonella enterica, and Salmonella sp. with 13 ± 0.353, 11 ± 0.707, 13 ± 0.707, 12 ± 0, 12 ± 1.414, and 11 ± 0.176 mm zone of inhibition, respectively. Similarly, essential oil showed antibacterial activity against E. facealis, B. cereus, S. enterica, and Salmonella sp. with 9 ± 0.707, 8 ± 1.414, 8 ± 0.707 and 8 ± 0 mm zone of inhibition, respectively. Ziani et al. (2019) evaluated antimicrobial activity from infusion (1:100 m/v with distillated boiling water), decoctions (1:100 m/v distillated water) and hydroethanolic extracts of aerial plant part using microdilution plate method and MIC values were calculated. Among the different extracts, hydroethanolic extracts showed strong antimicrobial activity against E. coli ESBL, E. coli, methicillin-susceptible S. aureus and methicillin resistant S. aureus with 5 mg/mL of MIC values each. The hydroalcoholic extract of the aerial plant part (30 µg/mL) showed 7 mm zone of inhibition against

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Klebsiella pneumoniae, Shigella flexneri, S. enterica, E. coli, P. aeruginosa and E. faecalis with 200, 200, 200, 200, 200, and 100 µg/mL MIC; 10 mm inhibition zone against Candida albicans and C. parapsilosis with 50 µg/mL MIC of each and 9 mm inhibition zone against S. aureus with 50 µg/mL MIC (Danciu et al., 2019). 75.3.5 ANTIFUNGAL ACTIVITY Belaidi et al. (2020) evaluated antifungal potential of the methanolic and ethanolic plant extract against Bayoud disease causal agent, Fusarium oxys­ porum f. sp. albedinis on date palm. They observed inhibited fungal mycelial growth using methanolic (25.4 and 70.6%) and ethanolic (28.3 and 70.9%) extracts at 10.1 and 10.2 g/mL concentration. 75.3.6 ANTIVIRAL ACTIVITY Hydro-alcoholic extract at 500–1000 µg/mL (12.5%) concentration showed appreciable antiviral activity against HSV (Soltan and Zaki, 2009). 75.3.7 WOUND AND BURN HEALING ACTIVITY Kittana et al. (2017) developed polyethylene glycol-based ointment containing aqueous extract of E. alata and examined in vivo wound healing activity. For the study, they used adult Syrian hamsters and evaluated for deep wound. After wound induction, ointment was applied for 15 days and recorded higher degree of fibrosis and faster healing than the control (placebo ointment) indicating better heal repair activity. After induction of burn ulcers, ointment was applied for 15 days and recorded better fibrosis and collagen fibers deposition and faster burn healing than the control (placebo ointment) indicating better burn healing repair activity. 75.3.8 ANTICANCER ACTIVITY Ethnobotanical survey confirmed that the oral administration of leaves and stem decoction used for cancer treatment (Bourhia et al., 2019). Hydroalco­ holic extract of the aerial plant part (10 and 30 µg/mL) against the MCF-7 human breast cancer cell line showed 19.68 ± 4.2 and 56.45 ± 3.9% inhibition,

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respectively. Cytotoxicity using MTT colorimetric assay recorded more than 13% at 30 µg/mL hydroalcoholic extract. At the same concentration, MCF-7 cells were treated for 72 h and analyzed by DAPI staining. They recorded morphological changes such as chromatin condensation, early apoptosis, late apoptosis and necrosis indicating strong inhibitory potential on MCF-7 cells (Danciu et al., 2019). Sioud et al. (2020a) tested effects of E. alata toward a 4T1 breast cancer model in vitro and in vivo. They observed induced apoptosis in a caspase-dependent manner with 6 μg/mL of extract and 10 μM cisplatin (an anticancer drugs), which leads to decreased breast tumor growth (more than 80%). They also noted that plant extract inhibited 4T1 breast cancer cell viability. Elshibani et al. (2020) evaluated methanolic extract for cytotoxic activity using HEPG2 human liver cancer cell line and PC3 human prostate cancer cell line. Methanolic extract against HEPG2 and PC3 cell lines showed significant cytotoxicity with IC50 values of 32.9 and 30.4 μg/mL, respec­ tively, as compared with standard drug (doxorubicin) (21.6 and 23.8 μg/ mL, respectively). Soumaya et al. (2020) also assessed antiproliferative effects of hexane, ethyl acetate and ethanol extracts from aerial plant part against hormone-dependent human MCF-7 breast cancer cell, normal cells Vero and H9c2 cardiomyoblasts cell line using MTT and resazurin assays. Among these extracts, ethyl acetate extract showed high cytotoxicity using MTT (IC50 26 and 22 mg/mL) and resazurin assays (IC50 16 and 12 mg/mL) against MCF-7 and H9C2 myoblast cell lines, respectively. 75.3.9 DIURETIC ACTIVITY Rahhal et al. (2018) investigated oral administration of aqueous plants extracts of E. alata (500 mg/kg) for diuretic activity using adult male CD-1 mice. The study revealed significant increase in urine output volume up to 207 mL) within 4 h and 500 ± 135 mL on 4 h as compared to positive control (furosemide) (760 ± 117 mL urine output on 4 h) indicating potential diuretic property. They also stated that the dose of 5 g/kg for 2 weeks was found to be safe. 75.3.10 HYPOLIPIDAEMIC ACTIVITY Chouikh (2020) recorded hypolipidaemic activity of methanolic extract of female cone on male rats. The combination of 50 mg/kg bw of extract and 100 mg/kg bw of triton X-100 significantly increase the activity of aspartate

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aminotransferase and alanine aminotransferase enzymes. Triton X-100 significantly increase the lipid parameters; however plant extract did not show any significant difference in lipid parameters. 75.3.11 ANALGESIC ACTIVITY Chouikh (2020) investigated the effect of methanolic extract of female cone for abdominal writhings induced by acetic acid in rats. Extract (50 mg/kg) showed 18 ± 0.52 abdominal cramps with 30.7% inhibition revealed strong analgesic activity. They also confirmed that the administration of 100 mg/kg extract found to be safe. 75.3.12 ANTI-INFLAMMATORY ACTIVITY Kmail et al. (2017) examined anti-inflammatory activity using in vitro mono and co-culture systems. Hydroethanolic extracts of aerial plant part (62.5 and 125μg/mL) modulated the production of pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokine (IL-10) in the LPS-activated THP1-derived macrophages in monoculture and co-culture system. They also recorded that 125 mg/mL extract showed more than 90% cell viability in the monoculture and coculture systems and about 80% in THP-1 mono culture system. Further, Soumaya et al. (2020) also noted anti-inflammatory activity of hexane, ethyl acetate and ethanol extracts from aerial plant part using nitrite production inhibition in LPS-stimulated RAW 264.7 macrophages. Highest inhibition (62%) was recorded from ethyl acetate extract (10 µg/ mL). IC50 values were 5 and 59 µg/mL for ethyl acetate and ethanol extract, respectively. It suggested the use of E. alata for the treatment or prevention of inflammatory diseases. 75.3.13 CYTOSTATIC ACTIVITY Kmail et al. (2015) treated hydroethanolic extract of E. alata for cytostatic effects on human THP-1 derived macrophages, HepG2 cells and their co-cultures for 72 h with different concentrations (0–1000 μg/mL). They recorded significant cytostatic activity in monocultures and co-cultures (IC50 380 μg/mL each). They also recorded no significant cytotoxicity up to 500 μg/mL extract for 24h.

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75.3.14 AFLATOXIN INHIBITORY ACTIVITY Al-Qarawi et al. (2011) investigated effect of aqueous extract of E. alata for inhibition of growth characters and aflatoxin production in Aspergillus flavus. They observed inhibited radial growth rate (0.152 cm/day) and conidial production (0.584 conidia mm-2 × 104) of A. flavus when treated with 2% of plant extract after incubation of 96 h in the dark at 28°C temperature. They also noted reduction in mycelial dry weight (0.1015 g/50 mL culture medium) and complete inhibition of production of aflatoxin in culture medium (0.0 µg/50 mL culture medium). Similar concentration of plant extract showed complete inhibition of production of aflatoxin B1 in stored maize and soybean seeds. They also recommended that the use of E. alata as biological control to preserve fodder. 75.3.15 ANTIDIABETIC ACTIVITY Lamine et al. (2019) analyzed decoction from aerial plant part for α-amylase and α-glucosidase inhibitory activities (IC50 1.60 and 3.88 mg/mL, respec­ tively) indicating strong antidiabetic activity. Oral administration of decoc­ tion (300 mg/kg of body weight) for 28 days to diabetic Wistar male rats showed lowering in glucose (7.62 ± 0.32 mmol/L), LDL-C (0.51 ± 0.01 mmol/L), HDL-C (0.38 ± 0.01 mmol/L), CHOL-T, (1.4 ± 0.01 mmol/L), TG (1.1 ± 0.01 mmol/L), amylase and lipase level (2055.83 ± 41.64 and 19.16 ± 0.98 U/L, respectively) than the nontreated rats. Whereas, SOD (202.22 ± 10.33 UI/mg of PT), CAT (0.01 ± 0.001 UI/mg of PT), GPx (4.72 ± 0.56 nmol of oxidized GSH/mg of PT), malondialdehyde (MDA) (0.7 ± 0.13 nmol/mg PT) and protein carbonyls (0.2 ± 0.04 nmol/mg PT) showed elevated level. 75.3.16 NEPHROTOXICITY AND HEPATOTOXICITY Sioud et al. (2020b) investigated protective effect of methanolic extract and ephedrine isolated from E. alata against cisplatin (a powerful anticancer agent) induced damaged in pathogen-free BALB/c mice. They recorded reduction of glutathione, superoxide dismutase, catalase, glutathione-S­ transferase; increased malondialdehyde content, and interferon gamma level in serum; DNA damage at renal, hepatic, and blood cells in cisplatin induced rat kidney and liver whereas methanolic extract restored all the parameters, indicating use of methanolic extract for reducing oxidative stress and

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genotoxicity. They also noted, intraperitoneal administration of methanolic extract did not show toxicity (LD50 1000 mg/kg). KEYWORDS • • • • •

Ephedra alata ephedrine anticancer and antidiabetic activity nephrotoxic hepatotoxic activity

REFERENCES Al-Qarawi, A. A.; Abd-Allah, E. F.; Hashem, A. Ephedra alata as Biologically-Based Strategy Inhibit Aflatoxigenic Seedborne Mold. Afr. J. Microbiol. Res. 2011, 5 (16), 2297–2303. Al-Snafi, A. E. Therapeutic Importance of Ephedra alata and Ephedra foliata—A Review. IndoAm. J. Pharm. Sci. 2017, 4 (2), 399–406. Anonymous. U. S. National Plant Germplasm System; Taxon: Ephedra alata Decne, 2021a. https://npgsweb.ars-grin.gov/gringlobal/taxon/taxonomydetail?id=15213 (cited on June 23, 2021). Anonymous. Plants of the World Online, Royal Botanical Garden, Kew, 2021b. http://www. plantsoftheworldonline.org/taxon/urn:lsid:ipni.org:names:383343–1 (cited on June 23, 2021). Belaidi, H.; Toumi-Benali, F.; Benzohra, I. E.; Boumaaza, B. Antifungal Activity of Plant Extract of Ephedra alata subsp. alenda (Stapf) Trab., on Mycelial Growth of Fusarium oxysporum f. sp. albedinis, the Causal Agent of Bayoud Disease on Date Palm (Phoenix dactylifera L.). South Asian J. Exp. Biol. 2020, 10 (4), 192–197. Benabderrahim, M. A.; Yahia, Y.; Bettaieb, I.; Elfalleh, W.; Nagaz, K. Antioxidant Activity and Phenolic Profile of a Collection of Medicinal Plants from Tunisian Arid and Saharan Regions. Ind. Crops Prod. 2019, 138, 111427. Blumenthal, M.; King, P. Ma Huang: Ancient Herb, Modern Medicine, Regulatory Dilemma. A Review of the Botany, Chemistry, Medicinal Uses, Safety Concerns, and Legal Status of Ephedra and Its Alkaloids. Herb. Gram. 1995, 34, 22–57. Boulos, L. Medicinal Plants of North Africa; Reference Publications Inc.: Michigan, 1983. Bourhia, M.; Shahat, A. A.; Almarfadi, O. M.; Naser, F. A.; Abdelmageed, W. M.; Said, A. A. H.; El-Gueddari, F.; Naamane, A.; Benbacer, L.; Khlil, N. Ethnopharmacological Survey of Herbal Remedies Used for the Treatment of Cancer in the Greater Casablanca-Morocco. Evid. Based Complement. Altern. Med. 2019, 1613457, 1–9.

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Caveney, S.; Charlet, D. A.; Freitag, H.; Maier-Stolte, M.; Starratt, A. N. New Observations on the Secondary Chemistry of World Ephedra (Ephedraceae). Am. J. Bot. 2001, 88 (7), 1199–1208. Chebouat, E.; Dadamoussa, B.; Gharabli, S.; Gherraf, N.; Allaoui, M.; Cheriti, A.; Lahham, A.; Zellagui, A. Assessment of Antimicrobial Activity of Flavonoids Extract from Ephedra alata. Der Pharm. Lett. 2014, 6 (3), 27–30. Chebouat, E.; Gherraf, N.; Dadamoussa, B.; Allaoui, M.; Chirite, A.; Zellagui, A. Chemical Composition of the Dichloromethane Extract of Ephedra alata Leaves and Flowers. Der Pharm. Lett. 2016, 8 (6), 10–13. Chouikh, A. Phytochemical Profile, Antioxidant, Analgesic and Hypolipidaemic Effects of Ephedra alata Decne. Female Cones Extract. Farmacia 2020, 68 (6), 1011–1020. Chouitah, O. The Essential Oil of Algerian Ephedra alata subsp. alenda and Its Antimicrobial Properties. J. New. Biol. Rep. 2019, 8 (3), 190–193. Danciu, C.; Muntean, D.; Alexa, E.; Farcas, C.; Oprean, C.; Zupko, I.; Bor, A.; Minda, D.; Proks, M.; Buda, V.; Hancianu, M.; Cioanca, O.; Soica, C.; Popescu, S.; Dehelean, C. A. Phytochemical Characterization and Evaluation of the Antimicrobial, Antiproliferative and Pro-Apoptotic Potential of Ephedra alata Decne. Hydroalcoholic Extract Against the MCF-7 Breast Cancer Cell Line. Molecules 2019, 24, 13. Elshibani, F.; Gehawe, H. A.; Fallah, G.; Alamami, A. Screening of In Vitro Cytotoxic Activity of Ephedra alata Used Traditionally to Treat Cancer in Libya. Int. J. Herb. 2020, 8 (5), 23–25. Fukushima K. Bioactivity of Ephedra: Integrating Cytotoxicity Assessment with Real-Time Biosensing. M.Sc. Thesis. University of Maryland, College Park, 2004. Hadjadj, K.; Daoudi, B. B.; Guerine, L. Importance thérapeutique de la plante Ephedra alata subsp. alenda dans la médecine traditionnelle pour la population de la région de Guettara (Djelfa, Algérie). Lejeunia Revue De Botanique. 2020, 201, 1–18. Hegazi, G. A. E. M.; El-Lamey, T. M. In Vitro Production of Some Phenolic Compounds from Ephedra alata Decne. J. Appl. Environ. Biol. Sci. 2011, 1 (8), 158–163. Hussein, F. Medicinal Plants in Libya; Arab Encyclopedia House: Lebanon, 1985; p 426. Jaradat, N.; Hussen, F.; Ali, A. A. Preliminary Phytochemical Screening, Quantitative Estimation of Total Flavonoids, Total Phenols and Antioxidant Activity of Ephedra alata Decne. J. Mater. Environ. Sci. 2015, 6 (6), 1771–1778. Jerbi, A.; Zehri, S.; Abdnnabi, R.; Gharsallah, N.; Kammoun, M. Essential Oil Composition, Free-Radical-Scavenging and Antibacterial Effect from Stems of Ephedra alata alenda in Tunisia. J. Essent. Oil-Bear. Plants. 2016, 19, 1503–1509. Kittana, N.; Abu-Rass, H.; Sabra, R.; Manasra, L.; Hanany, H.; Jaradat, N.; Hussein, F.; Zaid, A. N. Topical Aqueous Extract of Ephedra alata Can Improve Wound Healing in an Animal Model. Chin. J. Traumatol. 2017, 20, 108–113. Kmail, A.; Lyoussi, B.; Zaid, H.; Imtara, H.; Saad, B. In Vitro Evaluation of AntiInflammatory and Antioxidant Effects of Asparagus aphyllus L., Crataegus azarolus L., and Ephedra alata Decne. in Monocultures and Co-Cultures of HepG2 and THP-1-Derived Macrophages. Pharmacogn. Commun. 2017, 7 (1), 24–33. Kmail, A.; Lyoussi, B.; Zaid, H.; Saad, B. In Vitro Assessments of Cytotoxic and Cytostatic Effects of Asparagus aphyllus, Crataegus aronia, and Ephedra alata in Monocultures and Co-Cultures of Hepg2 and THP-1-Derived Macrophages. Pharmacogn. Commun. 2015, 5 (3), 165–172.

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Lamine, J. B.; Boujbiha, M. A.; Dahane, S.; Cherifa, A. B.; Khlifi, A.; Chahdoura, H.; Yakoubi, M. T.; Ferchichi, S.; Ayeb, N. E.; Achour, L. α-Amylase and α-Glucosidase Inhibitor Effects and Pancreatic Response to Diabetes Mellitus on Wistar Rats of Ephedra alata Areal Part Decoction with Immunohistochemical Analyses. Environ. Sci. Pollut. Res. 2019, 26 (10), 9739–9754. Medila, I.; Toumi, I.; Adaika, A. The Protective Effect of Ephedra alata Aqueous Extract Against Metribuzin Intoxication on Albino Wistar Rat. Nat. Prod. J. 2020, 10. DOI: 10.21 74/2210315510999200529145153. Mighri, H.; Akrout, A.; Bennour, N.; Eljeni, H.; Zammouri, T.; Neffati, M. LC/MS Method Development for the Determination of the Phenolic Compounds of Tunisian Ephedra alata Hydro-Methanolic Extract and Its Fractions and Evaluation of Their Antioxidant Activities. S. Afr. J. Bot. 2019, 124, 102–110. Mighri, H.; Bennour, N.; Eljeni, H.; Neffati, M.; Akrout, A. Chromatography Analysis of Fatty Acids, Volatile Compounds and Alkaloids of Ephedra alata Growing Wild in Southern Tunisia and Evaluation of Their Antioxidant Activity. Int. J. Pharmacogn. Phytochem. Res. 2017, 9 (9), 1249–1259. Nawwar, M. A. M.; Barakat, H. H.; Buddrus, J.; Linscheid, M. Alkaloidal, Lignan and Phenolic Constituents of Ephedra alata. Phytochemistry 1985, 24 (4), 818–819. Nawwar, M. A. M.; El-Sissi, H. I.; Barakat, H. H. Flavonoid Constituents of Ephedra alata. Phytochemistry 1984, 23 (12), 2937–2939. Palici, I. F.; Liktor-Busa, E.; Zupkó, I.; Touzard, B.; Chaieb, M.; Urbán, E.; Hohmann, J. Study of In Vitro Antimicrobial and Antiproliferative Activities of Selected Saharan Plants. Acta Biol. Hung. 2015, 66 (4), 385–394. Rahhal, B.; Jaradat, N.; Basha, W.; Shraim, M.; Zyoud, A.; Hattab, S. The Diuretic Activity of Ephedra alata and Plumbago europaea in Mice Using an Aqueous Extract. Mor. J. Chem. 2018, 6 (4), 569–576. Rashed, K. Phytochemical and Biological Activities of Ephedra alata: A Review. Int. J. Sci. Invent. Today 2021, 10 (3), 175–178. Rawi, A. L.; Chakravarty, H. Medicinal Plants of Iraq; Government Press: Baghdad, 1964; pp 39–40. Rimawi, F. A.; Lafi, S. A.; Abbadi, J.; Alamarneh, A. A. A.; Sawahreh, R. A.; Odeh, I. Analysis of Phenolic and Flavonoids of Wild Ephedra alata Plant Extracts by LC/PDA and LC/MS and Their Antioxidant Activity. Afr. J. Tradit. Complement. Altern. Med. 2017, 14 (2), 130–141. Shawarb, N.; Jaradat, N.; Qauod, H. A.; Alkowni, R.; Hussein, F. Investigation of Antibacterial & Antioxidant Activity for Methanolic Extract from Different Edible Plant Species in Palestine. Mor. J. Chem. 2017, 5 (4), 573–579. Sioud, F.; Amor, S.; Toumia, I.; Lahmar, A.; Aires, V.; Chekir-Ghedira, L.; Delmas, D. A New Highlight of Ephedra alata Decne Properties as Potential Adjuvant in Combination with Cisplatin to Induce Cell Death of 4T1 Breast Cancer Cells In Vitro and In Vivo. Cells 2020a, 9, 362. Sioud, F.; Toumia, I. B.; Lahmer, A.; Khlifi, R.; Dhaouefi, Z.; Maatouk, M.; Ghedira, K.; Chekir-Ghedira, L. Methanolic Extract of Ephedra alata Ameliorates Cisplatin-Induced Nephrotoxicity and Hepatotoxicity Through Reducing Oxidative Stress and Genotoxicity. Environ. Sci. Pollut. Res. Int. 2020b, 27 (11), 12792–12801. Soltan, M. M.; Zaki, A. K. Antiviral Screening of Forty-Two Egyptian Medicinal Plants. J. Ethnopharmacol. 2009, 126, 102–107.

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Soua, L.; Koubaa, M.; Barba, F. J.; Fakhfakh, J.; Ghamgui, H. K.; Chaabouni, S. E. WaterSoluble Polysaccharides from Ephedra alata Stems: Structural Characterization, Functional Properties, and Antioxidant Activity. Molecules 2020, 25, 2210. Soumaya, B.; Yosra, E.; Rim, B. M.; Sarra, D.; Sawsen, S.; Sarra, B.; Kamel, M.; Wissem, A. W.; Isoda, H.; Wided, M. K. Preliminary Phytochemical Analysis, Antioxidant, AntiInflammatory and Anticancer Activities of Two Tunisian Ephedra Species: Ephedra alata and Ephedra fragilis. S. Afr. J. Bot. 2020, 135, 1–8. Ziani, B. E. C.; Heleno, S. A.; Bachari, K.; Dias, M. I.; Alves, M. J.; Barros, L.; Ferreira, I. C. F. R. Phenolic Compounds Characterization by LC-DAD- ESI/MSn and Bioactive Properties of Thymus algeriensis Boiss. & Reut. and Ephedra alata Decne. Food Res. Int. 2019, 116, 312–319.

CHAPTER 76

Ephedra sinica Stapf—An Exemplary Source of Ephedrine-Type Alkaloids SURAJ B. PATEL1, PRADEEP BHAT2,

SANTOSHKUMAR JAYAGOUDAR3, RAHUL L. ZANAN4, and

SAVALIRAM G. GHANE1*

1Plant

Physiology Laboratory, Department of Botany, Shivaji University,

Kolhapur, 416004, Maharashtra, India

2ICMR—National

Institute of Traditional Medicine, Nehru Nagar,

Belagavi, Karnataka 590010, India

3Department

of Botany, G. S. S. College & Rani Channamma

University P. G. Centre, Belagavi, Karnataka 590006, India

4Department

of Botany, Elphinstone College, Dr. Homi Bhabha State

University, Madam Cama Road, Mumbai 400032 Maharashtra, India

*Corresponding

author.

E-mail: [email protected]; [email protected]

ABSTRACT Ephedra sinica Stapf is commonly called as Chinese Ephedra. It is cultivated in Mangolia, Russia, and China. Traditional practitioners used this plant in the treatment of fever, sweetening, cough, bronchial asthma, flue, edema, cold, cough, headache, and many allergies. Plant also has a great potential in lowering liver heat, removing abdominal mass, reducing swelling and healing different types of injuries. Many bioactives like alkaloids, phenols, flavanols, lignans, naphthalenes, quinones, terpenoids reported from fruits, seeds and roots of E. sinica. Chinese Ephedra is a pharmacologically very Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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active plant and possesses several bioactivities like antioxidant, antilipase, neuroprotective, antiangiogenic, anti-invasive, anticancer, antiviral, anti­ microbial, anticomplement, antineuroinflamantory and analgesic. 76.1

INTRODUCTION

Ephedra sinica Stapf (Family: Ephedraceae) is well known in Chinese medi­ cine by the name Ma Huang and commonly called as Chinese Ephedra. E. flava F. P. Sm. and E. ma-huang Tang S. Liu are the synonyms of E. sinica. This is cultivated in Mangolia, Russia, and China since last 5000 years (Elhadef et al., 2020). This is small subshrub, near about 40 cm high, sparsely branched plant found in sandy places, plains and mountain slopes. Stem woody, short and prostrate having straight or curved branches. Leaves are opposite and look like scale. Pollen cones are solitary or found in cluster; sessile or pedunculate. Bracts are found in four pairs; membranous having obtuse or subacute apex. Seed cones are solitary, found in four pairs at terminal or some time at axil­ lary position. Generally, two seeds are found with black-red or greyish brown color. Pollination in May to June and seed mature in August to September (Khasbagan and Soyolt, 2007). The first evidence of pharmaceutical potential was recorded in Chinese traditional book “Pen Ts’ao” written by “Shen Nung” in 2800 BC who is legendary Chinese herbalist (Khasbagan and Soyolt, 2007). Literature review revealed that bodyguard of Genghis Khan, who was founder and first Khagan-Emperor of the Mongol Empire, consumed Ephedra tea to stay alert during his duty (Chevallier, 1996). Many traditional healers used this plant in treatment of fever, sweetening, cough, bronchial asthma, flue, edema, cold, coughs, headache, and many allergies (Elhadef et al., 2020; Zhang et al., 2020). In several western countries, it was used as dietary supplement but later on banned due to side effects. In Mongolian medicine, stem is used for lowering liver heat, removing abdominal mass, reducing swelling and healing different types of injuries. Several traditional prescriptions famous in Chinese medicine are “Gurgum” (powder of seven medicinal plants) and “Zhegergen” (four medicinal decoction) showed presence of E. sinica (Khasbagan and Soyolt, 2007). These therapeutic and versatile effects are attributed due to the potent metabolites found in E. sinica. 76.2

BIOACTIVES

This is known for the presence of several alkaloids including macrocyclic spermine-, imidazole-, and amphetamine-types. These alkaloids have been mainly reported from root and stem extracts. Kurosawa et al. (2003) and Zhu and

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Hesse (1988) differentiated macrocyclic spermine alkaloids such as ephedradine A, ephedradine B, ephedradine C and ephedradine D from the root extract. From the fresh young stem extract, Krizevski et al. (2010) isolated amphetamine-type alkaloids like D(–)-ephedrine, L(+)-pseudoephedrine, D(–)norephedrine, L(+)­ noreseudoephedrine, D(–)methylephedrine, L(+)-methylpseudoephedrine, ephedroxane, 3,4-dimethyl-5-pheyloxazolidine, 2,3,4-trimethyl-5-phenylox­ azolidin, Obenzoyl-L(+)-pseudoephedrin, O-benzoyl-D(–)-ephedrine, (S)-N­ ((1R, 2S)-1-hydroxy-1-phenylpropan-2-yl)-5- oxopyrrolidine-2-carboxamide. Several other metabolically active alkaloids like (±)-1-phenyl-2-imido-1­ propanol, N-methybenzlamine maokonine and tetramethylpyrazine were separated from stem (Zhao et al., 2009). Aqueous alcoholic extract showed presence of bioactive groups like flavonols, dihydroflavanol and flavonone (Amakura et al., 2013). From the flavonols category, number of compounds such as kaempferol, herbacetin, pollenitin B, herbacetin 7-methyl ether, quer­ cetin, trans-cinnamic acid, syringin, herbacetin-8-methyl ether 3-O-glucoside, herbacetin 7-O-glucoside, kaempferol 3-O-rhamnoside 7-O-glucoside, kaempferol-3-O-glucoside-7-O-rhamnoside and herbacetin 7-O-neohesper­ idoside were recorded. Similarly, dihydroquercetin, 3-hydroxynaringenin are dihydroflavanol and 3′,4′,5,7-tetrahydroxy flavanone, naringenin, hesperidin, and flavonone have been reported (Zhang et al., 2018). In addition, flavanols like, (–)-epicatechin, (–)-epiafzelechin, catechin, afzelechin, leucocyanidin and symplocoside; flavones such as tricin, luteolin, apigenin, 3-methoxyherbaceti, apigenin-5-rhamnoside, 6-C-glycosyl-chrys­ oeriol, swertisin, isovitexin-2″-O-rhamnoside, and vitexin were identified by several researchers (Amakura et al., 2013; Zhang et al., 2018). Phenolic acids such as trans-cinnamic acid, syringin, 2-hydroxyl-5-methoxybenzoic acid, iso-ferulic acid, caffeic acid, chlorogenic acid, (3R)-3-O-β-D-glucopyranosyl3-phenylpropanoic acid were also recorded (Amakura et al., 2013; Zhang et al., 2018). Literature reviewed by Zhang et al. (2018) reported presence of anthocyan (leucopelargonin and leucodelphinidin), lignans (sesquipinsapol B), naphthalenes (methyl-2,3-methylenedioxy-6-naphthalenecarboxylic acid methyl ester), esters (ethyl caprylate), and quinones (physcion, rhein) from different parts. Terpenoids like (–)-α-terpineol-8-O-β-D-glucopyranoside, (+)-α, terpineol-8-O-β-D-glucopyranoside, geranyl-β-D-glucopyranoside, daucosterol, sitosterol, and stigmasterol-3-O-β-D-glucopyranoside were also reported from the root (Zhang et al., 2018). Tao et al. (2008), Zang et al. (2013), and Amakura et al. (2013) inves­ tigated A-type proanthocyanidins, wherein dimer, trimer, and tetramer proanthocyanidins were also reported. Dimer such as ephedrannin A, -B,

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muhuannin A, -D, -B, and -E investigated by Tao et al. (2008). Similarly, dimers-ephedrannin D1 to D14 and trimer proanthocyanidins such as ephe­ drannin Tr1 to Tr13 were identified by Zang et al. (2013). Amakura et al. (2013) separated tetramer proanthocyanidins like ephedrannin Te1 to Te5.

FIGURE 76.1 Potent metabolites reported from E. sinica; 1. Ephedradine, A 2. Ephedradine B, 3. Ephedradine C, 4. Ephedradine D, 5. Feruloylhistamine, 6. D(–)-Ephedrine, 7. Ephedroxane, 8. Maokonine, 9. Tetramethylpyrazine, 10. Herbacetin, 11. Kaempferol, 12. Quercetin, 13. Herbacetin 7-O glucoside, 14. Herbacetin 7-O-neohesperidoside, 15. Dihydroquercetin, 16. Naringenin.

Ephedra sinica Stapf

FIGURE 76.2

Bioactive compounds from E. sinica.

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76.3

Phytochemistry and Pharmacology of Medicinal Plants, Volume 2

PHARMACOLOGY

76.3.1 CYTOTOXIC ACTIVITY Aqueous and methanolic extracts were tested against two human hepatocel­ lular carcinoma cell lines (Hep3B and HepG2). Cell growth and viability of cell lines were assessed by using SRB (Sulforhodamine B) assay. Extract concentration kept in each well was 13 µg/mL. Further, cells were treated with extract for 2–3 days, where 5% CO2 and 100% relative humidity were maintained and absorption measured at 564 nm wavelength. Aqueous and methanolic extracts denoted significant IC50 values (≥100 µg/mL) against HepG2 cell line. Similarly, in case of Hep3B cell line methanolic extract performed better (IC50 value 81 ± 7 µg/mL). Water extract also denoted significant activity with IC50 value ≥100 µg/mL (Park et al., 2002). Similarly, water fraction of methanol extract of E. sinica evaluated to determine cyto­ toxicity against B16F10 cells (murine melanoma cells) and HUVEC (human umbilical venous endothelial cells). Extract treated at the doses of 100, 30, 10, 3, and 1 µg/mL showed cytotoxic activity in dose dependent manner. The highest activity was recorded at 100 µg/mL concentration (64.30 ± 1.21 and 57.19 ± 1.11%, respectively), while 30 µg/mL denoted negligible response against the both the cell lines (92.50 ± 1.95 and 89.99 ± 1.87%, respectively) (Nam et al., 2003). 76.3.2 ANTIOXIDANT ACTIVITY Song et al. (2010) evaluated antioxidant activity of dried plant powder in aqueous methanol extract using trolox equivalent antioxidant capacity (TEAP) and ferric reducing antioxidant power assay (FRAP). They found that, 100 µL diluted extract exhibited significant TEAP (197.69 ± 3.36 μmol Trolox/g) and FRAP (388.68 ± 9.58 μmol Fe2+/g) activities. Li et al. (2013) determined antioxidant activity of aqueous extract of using same assays and found promising TEAP (125.72 ± 1.86 mol trolox/g) and FRAP (148.21 ± 29.37 mol Fe(II)/g) activities. 76.3.3 ANTILIPASE ACTIVITY Antilipase activity of the air-dried plant powder was assessed. Plant mate­ rial (50 g) was extracted in 500 mL methanol using an ultrasound bath.

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2,4-Dinitrophenyl butyrate (DNPB) was used as artificial substrate in this reaction. Activity was checked against porcine pancreatic lipase (PPL) by spectrophotometric method. Result showed that extract of E. sinica at 0.2 mg/mL showed 25.9 ± 4.3% inhibition that suggested presence of reliable antilipase activity (Zheng et al., 2010). 76.3.4 NEUROPROTECTIVE EFFECT Alzheimer’s disease considered as very common dementia among the elderly. Presence of Aβ toxicity in plant, believed as important therapeutic approach to control Alzheimer’s disease. Park et al. (2009) determined significant activity in E. sinica against Aβ-induced toxicity. They treated PC12 rat pheo­ chromocytoma cells with different concentrations of extract (100, 20 and 4 µg/mL). Rosmarinic acid was used as positive control. Results showed that 100 µg/mL extract protected PC12 cells against Aβ insult with ED50 value of 3.5 µg/mL, indicating strong neuroprotective property. 76.3.5 ANTINEUROINFLAMANTORY PROPERTY Gold nanoparticle synthesized from stem of E. sinica possesses remarkable antineuroinflammatory properties. This activity assessed on production of pro-inflammatory mediators like prostaglandin E2, nitric oxide (NO), and reactive oxygen species as well as cytokines like tumor necrosis factor-α, IL-1β, and IL-6 in lipopolysaccharide (LPS)-stimulated microglia. Results showed that nanoparticles significantly suppress the LPS induced production of pro-inflammatory mediators and cytokines. RT-PCR and western blotting analysis supported that the suppression in transcription and translation of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated microglia (Park et al., 2019). 76.3.6 ANTIANGIOGENIC ACTIVITY Nam et al. (2003) evaluated antiangiogenic activity of water fraction of methanol extract (30, 10, and 3 µg/mL) using HUVEC model. Phase contrast microscopy was used to measure total length of tube structure. The tube like network formed by HUVEC was inhibited in dose dependent manner. They reported highest noncytotoxicity (91.24 ± 1.59%) at 30 µg/mL dose,

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followed by 10 and 3 µg/mL (71.25 ± 1.56, 15.48 ± 1.24%, respectively). In the study Nam et al. (2003) proved the antiangiogenic potential of the plant with IC50 value of 7.68 µg/mL. 76.3.7 ANTI-INVASIVE ACTIVITY Nam et al. (2003) determine anti-invasive activity of aqueous fraction obtained from methanol extract of E. sinica. Plant extract (30, 10, and 3 µg/ mL) were used to treat B16F10 (a melanoma murine tumor) cell line. Saline treated cells were used as control. Highest invasion inhibition of cells was recorded at 30 µg/mL (95.21 ± 2.15%), while lowest at 3 µg/mL (9.58 ± 0.95%). They also found that 8.9 µg/mL extract significantly inhibited the invasion of the B16F10 cells through the matrix membrane by 50% relative to a vehicle-treated control. 76.3.8 ANTICANCER ACTIVITY Hyuga et al. (2016) obtained ephedrine free Ephedra extract by ion exchange chromatography and activity was evaluated against human breast cancer cell line (MDAMB-231). Plant extract at 40 µg/mL concentration suppress the hepatocyte growth factor-induced cancer cell motility. On the basis of the results, authors suggested the use of ephedrine free extract as an anticancer drug. 76.3.9 ANTIVIRAL ACTIVITY Murakami et al. (2008) reported antiviral activity of Ephedra herb extract against human immunodeficiency virus type 1 (HIV-1). Treatment of extract induces replication of latent HIV-1 by activating NF-κB and U1 cell line. NF-κB is cellular transcription factor which regulate cellular and viral gene expression. Similarly, polysaccharides from E. sinica were actively used for treating against H1N1 virus. In experiment, mice were infected with FM1 virus and further treated with polysaccharides. Metagene sequencing was performed for sequencing intestinal content of mouse. Results showed that treatment showed significant therapeutic effect on lung injury caused by H1N1. Richness of Lactobacillales and Bifidobacteriaceae was observed in the intestinal flora and the metabolome increased significantly in the KEGG pathway (Xiaoting et al., 2020).

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76.3.10 ANTIMICROBIAL ACTIVITY Butanol soluble extract of ethanolic extract of the stem showed presence of several bioactive compounds, which was evaluated against bacteria (Gram­ positive bacteria, Bacillus subtilis, Staphylococcus aureus, and Gram-negative bacteria, Escherichia coli, Pseudomonas aeruginosa), and fungi (Candida albicans). The highest activity found in Ephedrannin Te4 (MIC= 0.0835 mM) for P. aeruginosa. In S. aureus, highest inhibition reported by compound namely gallocatechin and Ephedrannin Te3 (MIC= 0.0817 and 0.0835 mM, respectively). Compound Ephedrannin Te1 represented the highest inhibition against C. albicans (MIC = 0.00515 mM) (Zang et al., 2013). 76.3.11 ANTICOMPLEMENT ACTIVITY Xia et al. (2011) performed anticomplement activity of dry stem of E. sinica. Normal human serum along with gelatin veronal buffer mixed with plant extract. After respective incubation period optical density was determined at 450 nm. Results showed that isolated polysaccharide exhibited compa­ rable inhibitory effect when compared with positive control (rosmaric acid). Extract represent 50 µg/mL IC50 value against positive control (IC50 64 µg/ mL). Acidic polysaccharides isolated from the plant exhibited comparable inhibitory effects on the complement system. 76.3.12 MELANOGENESIS Ephedrannins A and -B denoted effect on mushroom tyrosinase and mela­ nogesis in several cell lines. Kim et al. (2015) studied effect of bioactive compounds from root of E. sinica on melanin and tyrosinase production in melanoma cells (B16F10). These cells were treated with melanin stimulating hormone- α-MSH and observed that the melanin production in B16F10 cells was inhibited by ephedrannin A (10, 20, 30, or 40 μg/mL) and ephedrannin B (1, 2, 3, or 4 μg/mL) in concentration dependent manner. Both compounds showed suppression in transcription of tyrosinase in cell resulting in inhibi­ tion of melanin production. 76.3.13 ANALGESIC ACTIVITY Analgesic activity was evaluated by formalin test and rotarod test on experi­ mental mice. In formalin test, mice was orally administered by extract at concentration of 700 mg/kg for successive 3 days. On third day mice were

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injected with 2.5% formalin and paw licking was recorded after 30 min. Rotard test was done by orally administrating extract (700 mg/kg) and then endurance time was measure at 30 min and 6 h time interval. Results explained that paw licking time in mice was declined in dose dependent manner. Similarly, experimental mice showed no significant difference in endurance time at different time intervals. These results revealed that plant extract possessed the analgesic action (Hyuga et al., 2016; Nakamori et al., 2019). KEYWORDS • • • • •

Ephedra sinica Chinese Ephedra alkaloids antilipase phenols

REFERENCES Amakura, Y.; Yoshimura, M.; Yamakami, S.; Yoshida, T.; Wakana, D.; Hyuga, M.; Hyuga, S.; Hanawa, T.; Goda, Y. Characterization of Phenolic Constituents from Ephedra Herb Extract. Mol. 2013, 18 (5), 5326–5334. Chevallier, A. The Encyclopedia of Medicinal Plants; DK Publishing Inc.: New York, 1996. Elhadef, K.; Smaoui, S.; Fourati, M.; Hlima, H. B.; Mtibaa, A. C.; Sellem, I.; Ennouri, K.; Mellouli, L. A Review on Worldwide Ephedra History and Story: From Fossils to Natural Products Mass Spectroscopy Characterization and Biopharmacotherapy Potential. Evid. Based Complement Altern. Med. 2020, 1540638. Hyuga, S.; Hyuga, M.; Oshima, N.; Maruyama, T.; Kamakura, H.; Yamashita, T.; Yoshimura, M.; Amakura, Y.; Hakamatsuka, T.; Odaguchi, H.; Goda, Y.; Hanawa, T. Ephedrine Alkaloids-Free Ephedra Herb Extract: A Safer Alternative to Ephedra with Comparable Analgesic, Anticancer, and Anti-Influenza Activities. J. Nat. Med. 2016, 70 (3), 571–583.

Khasbagan; Soyolt. Ephedra sinica Stapf (Ephedraceae): The Fleshy Bracts of Seed Cones

Used in Mongolian Food and Its Nutritional Components. Econ. Bot. 2007, 61, 192–197.

Kim, I. S.; Yoon, S. J.; Park, Y. J.; Lee, H. B. Inhibitory Effect of ephedrannins A and B from Roots of Ephedra sinica Stapf on Melanogenesis. Biochim. Biophys. Acta. 2015, 1850, 1389–1396.

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Krizevski, R.; Bar, E.; Shalit, O.; Sitrit, Y.; Ben-Shabat, S.; Lewinsohn, E. Composition and Stereochemistry of Ephedrine Alkaloids Accumulation in Ephedra sinica Stapf. Phytochemestry 2010, 71, 895–903. Kurosawa, W.; Kan, T.; Fukuyama, T. Stereocontrolled Total Synthesis of (–)-ephedradine A (orantine). J. Am. Chem. Soc. 2003, 125 (27), 8112–8113. Li, S.; Li, S. K.; Gan, R. Y.; Song, F. L.; Kuang, L.; Li, H. B. Antioxidant Capacities and Total Phenolic Contents of Infusions from 223 Medicinal Plants. Ind. Crops Prod. 2013, 21, 289–298. Murakami, T.; Harada, H.; Suico, M. A.; Shuto, T.; Suzu, S.; Kai, H.; Okada, S. Ephedrae Herba, a Component of Japanese Herbal Medicine Mao-to, Efficiently Activates the Replication of Latent Human Immunodeficiency Virus Type 1 (HIV-1) in a Monocytic Cell Line. Biol. Pharm. Bull. 2008, 31 (12), 2334–2337. Nakamori, S.; Takahashi, J.; Hyuga, S.; Yang, J.; Takemoto, H.; Maruyama, T.; Oshima, N.; Uchiyama, N.; Amakura, Y.; Hyuga, M.; Hakamatsuka, T.; Goda, Y.; Odaguchi, H.; Hanawa, T.; Kobayashi, Y. Analgesic Effects of Ephedra Herb Extract, Ephedrine Alkaloids-Free Ephedra Herb Extract, Ephedrine, and Pseudoephedrine on Formalin-Induced Pain. Biol. Pharm. Bull. 2019, 42 (9), 1538–1544. Nam, N. H.; Lee, C. W.; Hong, D. H.; Kim, H. M.; Bae, K. H.; Ahn, B. Z. Antiinvasive, Antiangiogenic and Antitumour Activity of Ephedra sinica Extract. Phytother. Res. 2003, 17 (1), 70–76. Park, K. J.; Yang, S.; Ah Eun, Y.; Kim, S. Y.; Lee, H. H.; Kang, H. Cytotoxic Effects of Korean Medicinal Herbs Determined with Hepatocellular Carcinoma Cell Lines. Pharm. Biol. 2002, 40 (03), 189–195. Park, S. Y.; Kim, H. S.; Hong, S. S.; Sul, D.; Hwang, K. W.; Lee, D. The Neuroprotective Effects of Traditional Oriental Herbal Medicines Against β-Amyloid-Induced Toxicity. Pharm. Biol. 2009, 47 (10), 976–981. Park, S. Y.; Yi, E. H.; Kim, Y.; Park, G. Anti-Neuroinflammatory Effects of Ephedra sinica Stapf Extract-Capped Gold Nanoparticles in Microglia. Int. J. Nanomed. 2019, 14, 2861–2877. Song, F. L.; Gan, R. Y.; Zhang, Y.; Xiao, Q.; Kuang, L.; Li, H. B. Total Phenolic Contents and Antioxidant Capacities of Selected Chinese Medicinal Plants. Int. J. Mol. Sci. 2010, 11 (6), 2362–2372. Tao, H.; Wang, L.; Cui, Z.; Zhao, D.; Liu, Y. Dimeric Proanthocyanidins from the Roots of Ephedra sinica. Planta Med. 2008, 74 (15), 1823–1825. Xia, Y.; Kuang, H.; Yang, B.; Wang, Q.; Liang, J.; Sun, Y.; Wang, Y. Optimum Extraction of Acidic Polysaccharides from the Stems of Ephedra sinica Stapf by Box–Behnken Statistical Design and Its Anti-Complement Activity. Carbohydr. Polym. 2011, 84, 282–291. Xiaoting, L.; Shanshan, L.; Qiuhong, W.; Weichen, D.; Haixue, K. Metagenomics Approach the Intestinal Microbiome Structure and Function in the Anti-H1N1 of a Traditional Chinese Medicine Acid Polysaccharide. Microb. Pathog. 2020, 147, 104351. Zang, X.; Shang, M.; Xu, F.; Liang, J.; Wang, X.; Mikage, M.; Cai, S. A-Type Proanthocyanidins from the Stems of Ephedra sinica (Ephedraceae) and Their Antimicrobial Activities. Molecules 2013, 18 (5), 5172–5189. Zhang, B. M.; Wang, Z. B.; Xin, P.; Wang, Q. H.; Bu, H.; Kuang, H. X. Phytochemistry and Pharmacology of Genus Ephedra. Chin. J. Nat. Med. 2018, 16 (11), 811–828.

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Zhang, Q.; Xue, X. Z.; Miao, S. M.; Cui, J. L.; Qin, X. M. Differential Relationship of Fungal Endophytic Communities and Metabolic Profiling in the Stems and Roots of Ephedra sinica Based on Metagenomics and Metabolomics. Symbiosis 2020, 81, 115–125. Zhao, W.; Deng, A. J.; Du, G. H.; Zhang, J. L.; Li, Z. H.; Qin, H. L. Chemical Constituents of the Stems of Ephedra sinica. J. Asian Nat. Prod. Res. 2009, 11 (2), 168–171. Zheng, C. D.; Duan, Y. Q.; Gao, J. M.; Ruan, Z. G. Screening for Anti-Lipase Properties of 37 Traditional Chinese Medicinal Herbs. J. Chin. Med. Assoc. 2010, 73 (6), 319–324. Zhu, J.; Hesse, M. The Spermine Alkaloids of Chaenorhinum minus. Planta. Med. 1988, 54 (5), 430–433.

CHAPTER 77

Pharmacological Review of Potential Underutilized Plant Rhus mysorensis G. Don NILESH VITTHALRAO PAWAR and ASHOK DATTATRAY CHOUGALE The New College, Kolhapur, Maharashtra, India *Corresponding

author.

E-mail: [email protected], [email protected]

ABSTRACT

Rhus mysorensis is a gregarious aromatic shrub with spiny branches and brown bark. It is widely distributed in scrub jungles and in dry deciduous forests of Indian subcontinent. In recent years, this plant is used against various diseases due to its most valued therapeutic nature. Fruits are edible and widely used in pharmacological applica­ tions along with other plant parts also. The roots are used to reduce inflammation and antidiarrheal. The fruits ripened fruits are used as an antioxidant. The present review reveals with an information on phytochemistry and pharmacology of the Rhus mysorensis. 77.1

INTRODUCTION

The genus Rhus of the family Anacardiaceae comprises of more than 250 species, distributed all over the world, particularly in the tropical and subtropical regions. Rhus mysorensis G. Don is a small aromatic shrub with a brown bark. Leaves are separated into 3 leaflets, which are stalkless and lobed. Flowers are white or greenish, small, and present in panicles in leaf Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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axils. 4-5-parted small sepals, 5 ovate petals. Ovary 1-celled and fruit is compressed drupe. It is common in foothills scrub jungle, dry slopes, and exposed rocks in hot and dry regions of India, Pakistan, and Sri Lanka. Common names for this plant include English: Mysore Sumac, Hindi: Dansara, Dasni; Kannada: Hulmari, Sabale; Malayalam: Chippamaram; Tamil: Neyyikiluvai, Chippa Maram, Neyyi kiluvai; Telugu: Sitha, Sundari, Sappli; Marathi: Amboni. All the plant parts of R. mysorensis are used as traditional medicines. Leaf decoction is used in itching, diarrhea, and stomatitis and leaf paste is against rash. The leaf, stem and root used in treatment of diabetes, HSV2 infection, and Psoriasis. 77.2

BIOACTIVES

Renuka Rani et al. (2016) isolated three flavonoids from R. myso­ rensis, namely, 2-(3,4- dihydroxyphenyl)-hydroxy-4H-chromen-4-one 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, and 2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-4Hchromen-4-one. Leaves of R. mysorensis showed the presence of cardiac glycosides, saponins, flavonoids, tannins and phenols (Aman et al., 2010). Srivastava et al. (2006) identified 55 compounds in the leaf and/or flower (inflorescence) essential oils of R. mysorensis by using GC and GC–MS. Monoterpenes α-pinene and limonene were found to be the major molecules in both kinds of oils. Sabinene and α- and β-eudesmol, the other major components of the two oils were also recorded. 77.3

PHARMACOLOGY

77.3.1 ANTIBACTERIAL ACTIVITY The root extract of R. mysorensis found efficient against human patho­ genic organisms like bacterial agents’ namely, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis Proteus vulgaris, Bacillus cereus, Klebsiella pneumoniae, Salmonella typhi, etc. (Renuka rani et al., 2016). Methanolic extracts of fruits and leaves of R. mysorensis were assessed against more than 10 bacterial species by paper disc diffusion assay and showed momentous antimicrobial activity against S. aureus, Xanthomonas axonopodis pv. malvacearum, S. typhi, and Xanthomonas oryzae pv. oryzae (Aman et al., 2010).

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77.3.2 ANTIFUNGAL ACTIVITY The fungus like Aspergillus niger, Candida albicans were used to study antifungal activity by Renuka rani et al. (2016) and recorded prominent results. 77.3.3 ANTIOXIDANT EFFICACY Methanolic extract and its active chloroform fraction of whole plant of R. mysorensis showed high antioxidant activities against H2O2-induced oxidative stress. Strong activities of DPPH and ABTS assays can be related with the presence of antioxidant compounds like phenolics and flavonoids (Penumala et al., 2018). 77.3.4 HEPATOPROTECTIVE ACTIVITY Whole plant extract of R. mysorensis in ethanol was used by Dudekula et al. (2014) for hepatoprotective activities against liver damage in rats. Deepak Reddy et al. (2010) carried out hepatoprotective activities of R. mysorensis against albino rats. 77.3.5 ANTI UROLITHIATIC ACTIVITY Sudheshna et al. (2015) demonstrated the result of the ethanol extract of R. mysorensis, which showed significant antiurolithiatic activity when compared with the standard drug cystone. Shade dried powder of R. myso­ rensis whole plant extracted in 80%v/v ethanol prevented the urinary stone formation (Mounika et al., 2015). 77.3.6 NEUROPROTECTIVE ACTIVITY The active chloroform fractions of the R. mysorensis extract showed significant nueroprotective activity against H2O2-induced oxidative stress in neuronal cells, due to phenolics and flavonoids present in it (Penumala et al., 2018).

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77.3.7 ANTI-INFLAMMATORY ACTIVITY Flavonoid compounds isolated form R. mysorensis showed concentrated dependent protein denaturation. Isolated flavonoid compounds exhibited significant in vivo anti-inflammatory activity by significant inhibition of edema (Renuka Rani et al., 2017). 77.3.8 ANTIALZHEIMER ACTIVITY Methanolic extract of R. mysorensis and its derived chloroform fraction showed significant inhibitory activity against AChE, BuChE, α- and β-Glc enzymes. It reveals that, in future R. mysorensis will work as multifunctional therapeutic remedy for Alzheimer (Penumala et al., 2018). 77.3.9 ANTHELMINTHIC ACTIVITY Leaves extract of R. mysorensis showed potent anthelminthic activity due to active compounds present in the leaves (Swathi and Shekshavali, 2016). 77.3.10 ANTIDIABETIC ACTIVITY Lamba et al. in 2014 studied root extracts of R. mysorensis using hydroetha­ nolic and showed significant antidiabetic activity in Wistar rats, and results forwarded for development of phytomedicine against diabetes mellitus. Methanolic extract along with derived chloroform fraction of R. mysorensis exhibited high inhibitory activity β-Glc enzymes, due to this R. mysorensis can work as multifunctional therapeutic remedy for the treatment of Type 2 Diabetes Mellitus (Penumala et al. 2018). 77.3.11 XANTHINE OXIDASE INHIBITORY ACTIVITY Vivenkanandan et al. (2018) reported xanthine oxidase inhibitory activity of methanolic leaf extract of R. mysorensis. Methanolic extract can be used to treat hyperuricemia and gout.

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77.4

CONCLUSION

On the basis of literature available, it was confirmed that, there was no toxicity of compounds reported from R. mysorensis, furthermore there is need to be toxicity study of isolated chemical compounds. Composed information in this review shows that the R. mysorensis have not been fully explored for phytochemicals. Some pharmacological applications are mentioned in this review but further, there is need to investigate phytochemicals and pharma­ cological applications. KEYWORDS • • • • •

Rhus mysorensis antimicrobial antioxidant active compounds pharmacology

REFERENCES Aman, M.; Rai, V. R.; Samaga, P. V. Antimicrobial and Phytochemical Screening of Boswellia serrata Roxb., Rhus mysorensis Heyne, Strychnos potatorum Linn. f. and Schefflera stellata Gaertn. Med. Arom. Plant Sci. Biotechnol. 2010, 4 (1), 69–72. Deepak Reddy, G.; Sree Kumar Reddy, G.; Surya Narayana Reddy, A.; Vamsi Rajasekhar Reddy, P. Hepatoprotective Activity of Rhus mysorensis Against Carbon Tetrachloride Induced Hepatotoxicity in Albino Rats. Int. J. Pharm. Sci. Rev. Res.2010, 4, 46–48. Dudekula, N. K.; Duza, M. B.; Janardhan, N.; Duraivel, S. Evaluation of the Hepatoprotective Activity of Rhus mysorensis in Albino Rats. Indian J. Res. Pharm. Biotechnol. 2014, 2 (1), 1010–1014. Lamba, S. M.; Sulakhiya, K.; Kumar, P.; Lahkar, M.; Barua, C. C.; Bezbarua, B. AntiDiabetic, Hypolipidemic and Anti-Oxidant Activities of Hydroethanolic Root Extract of Rhus mysurensis Heyne in Streptozotocin Induced Diabetes in Wistar Male Rats. Phcog. J. 2014, 6 (3), 62–71. Mounika, M.; Rodda, R.; Sushma, M.; Uma Maheswara Rao,V. Evaluation of Antiurolithiatic Activity of Rhus mysorensis Against Ethylene Glycol Induced Urolithiasis in Wistar Rats. World J. Pharm. Res., 2015, 4 (11), 966–980. Penumala, M.; Raveendra Babu, Z.; Shaik, J. B.; Suresh Kumar Reddy, M.; Ramakrishna, V.; Amooru, D. G. Phytochemical Profiling and In Vitro Screening for Anticholinesterase,

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Antioxidant, Antiglucosidase and Neuroprotective Effect of Three Traditional Medicinal Plants for Alzheimer’s Disease and Diabetes Mellitus Dual Therapy. BMC Complem. Altern. Med. 2018, 18, 77. https://doi.org/10.1186/s12906-018-2140-x. Renuka rani, G.; Singara Charya, M. A.; Viswanadham, M.; Murali Krishna, T. Antiinflammatory Activity of Flavonoids Isolated from Rhus mysorensis. IOSR J. Pharm. Biol. Sci. 2017, 12 (3), 37–40. Renuka Rani, G.; Singara Charya, M. A.; Viswanadham, M.; Murali Krishna, T.; Srinivas, G.; Rajashekar, K. Phytochemical Analysis and Antimicrobial Activities of Rhus mysorensis. Intern. J. Adv. Res. 2016, 4 (1), 503–515. Srivastava, S.; Gopal Rao, M.; Sanjay Kumar, R.; Singh, D.; Mishra, R.; Pandey-Rai, S.; Kumar, S. Composition of the Essential Oils of the Leaves and Flowers of Rhus mysurensis Heyne ex Wight & Arn. Growing in the Aravalli Mountain Range at New Delhi. Flavour Fragr. J. 2006, 21, 228–229. Sudheshna, L.; Loka, S. K.C.; Srinivasa Rao, A. Anti Urolithiatic Activity of Rhus mysorensis Against Experimentally Induced Urolithiasis in Male Albino Rats. J. Med. Sci. Clin. Res. 2015, 3 (9) 7546–7551. Swathi, H.; Shekshavali, T. In Vitro Evaluation of Anthelmintic Activity of Rhus mysorensis Leaves. Res. J. Pharmacol. Pharmacodyn. 2016, 8 (3), 115–117. DOI: 10.5958/2321-5836.2016.00021.5 Swathi, H.; Shekshavali, T.; Kuppast, I. J.; Ravi, M. C.; Priyanka R. A Review on Rhus mysorensis. Pharma Innov. J. 2015, 4, 94–96. Vivekanandan, K.; Bhavya, E.; Stalin, C.; Lakshmi Prasanna, T. Xanthine Oxidase Inhibitory Activity of Rhus mysorensis Leaves. Asian J. Pharm. Clin. Res. 2018, 11 (4), 198–199.

CHAPTER 78

Devil’s Cherry (Atropa belladonna L.): A Systematic Review on Its Phytoactives and Pharmacological Properties PRADEEP BHAT1, HARSHA V. HEGDE1, SAVALIRAM G. GHANE2, and SANTOSHKUMAR JAYAGOUDAR3* 1ICMR—National

Institute of Traditional Medicine, Nehru Nagar, Belagavi, Karnataka 590010, India

2Department

of Botany, Shivaji University, Vidyanagar, Kolhapur, Maharashtra 416004, India

3Department

of Botany, G. S. S. College & Rani Channamma University P. G. Centre, Belagavi, Karnataka 590006, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Atropa belladonna L. (Family: Solanaceae) is commonly known as Devil’s cherry, and belladonna. The plant is famous for its alkaloid compound ‘atropine’. Earlier, it was used to dilate the pupils and applied to the cheeks for attractive look. It possesses a diverse set of characteristics and hence, traditionally used to treat many diseases and also used as poison during the middle ages in Europe. The plant is known to be antispasmodic, seda­ tive, diuretic and used to get rid of various eye diseases using homeopathic medicines. The purpose of this review is to summarize and to collect the supporting evidences for traditional uses of the plant with its toxicology, phytochemistry, ethnopharmacology and pharmacological activities. Reports revealed that the plant mainly contained coumarins, flavonoids Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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and phenolics. Several tropane alkaloids such as atropine, norhyoscyamine, belladonnine, hyoscyamine, apoatropine, 6β-hydroxy-hyoscyamine, and scopolamine have been identified using CE-ESI-TOF-MS. Previous find­ ings disclosed the presence of quercetin 3-O-rhamnoside, rutin, kaempferol rhamnoside and kaempferol flavonoids, bergapten, xanthotoxin and umbel­ liferone coumarin constituents. Many pharmacological effects such as anti-inflammatory, wound healing, acaricidal, anti-cholinergic, analgesic, neurological, antigastric and immunological activities have been discussed sequentially, along with the phytochemicals responsible for the observed pharmacological effects. 78.1

INTRODUCTION

Atropa belladonna L. belongs to the family Solanaceae. A. digitaloides Pascher, A. borealis Kreyer ex Pascher, A. lethalis Salisb., A. cordata Pascher, A. mediterranea Kreyer ex Pascher, Belladonna trichotoma Scop., B. baccifera Lam., and Boberella belladonna (L.) E.H.L.Krause are some of the synonyms of this species (POWO, 2019; www.theplantlist.org). The vernacular names of this plant are Devil’s cherry, Naughty man’s cherry, Black cherry, Deadly nightshade, Belladonna, Bellatona, Dwayberry, Great morel, Angur sheaf, Seeme belladonna, and Sagangur Suchi (Godara et al., 2014; www.theplantlist.org). Devil’s cherry is a perennial herb growing up to 5 feet height. Leaves alternate, dull, darkish green in color with unequal sides, leaf length 3–10 inches; the upper leaves in pairs and the lower solitary, oval in shape; petioles short with acute apex. Flowers originate in the leaf axils, 2.5–3 cm size, slightly reflexed, pendent, bell-shaped, furrowed with five large teeth (lobes) with dark green and gray-purple color tinge. Fruit a smooth berry, nearly 0.5 inch, shining black or purple in color after maturity. It is native to Germany, Czechoslovakia, France, Albania, Austria, Algeria, Bulgaria, Belgium, Corse, Great Britain, Greece, Iran, Krym, Italy, Hungary, Morocco, Lebanon-Syria, Netherlands, Poland, Spain, Portugal, Switzerland, Sardegna, North Caucasus, Sicilia, Transcaucasus, Yugoslavia, Turkey, Romania, and Ukraine. The plant is introduced to Southeast China, Denmark, Baltic States, Missouri, Illinois, New Zealand South, Sweden, Ireland, and South Australia (POWO, 2019).

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The name “Atropa” is derived from “Atropos” in Greek mythology, refers to one among the three fates, the cutter of the thread of destiny and “bella­ donna” means “beautiful women” in Italian. During ancient Roman times the plant was one of the classic poisons known. The alkaloid compound atropine derived from this plant was used by the Roman traditional women to dilate the pupils and applied to the cheeks for attractive look (Rajput, 2013). The compound is reported to treat hay fever, Parkinson’s disease, whooping cough, asthma, to regulate heartbeats and as an anesthetic drug (Owais et al., 2014). The compound atropine along with other alkaloid scopolamine from this plant is reported for treating one of the major cardiovascular ailments like bradycardia. During the Middle Ages in Europe, the plant was traditionally used to treat many diseases and also used as poison. The fumes of burnt belladonna plants were used in the treatment of various airborne human disorders and to get rid of bronchoconstriction problems (Rajput, 2013). The plant is known to be antispasmodic, sedative, diuretic, and used to get rid of various eye diseases in homeopathic medicine (Godara et al., 2014). The plant has long been used for treating headache, menstrual disorders, peptic ulcer, inflammation, muscle spasm in bile duct, stomach, and intestine. It is also used as antidote for some mushroom poisons, insect bites, paralysis, traumas, and to treat the patients suffering from debilitating diseases (Owais et al., 2014). 78.2 BIOACTIVES A. belladonna contains the tropane alkaloids such as atropine, hyoscya­ mine, and scopolamine, which are used as key ingredients in several herbal and homeopathic remedies (Malik et al. 2021). Coumarins, flavonoids, and phenolics have been reported from the plant. HPLC analyses revealed the presence of bergapten, xanthotoxin, and umbelliferone coumarins. The analyses also disclosed the presence of quercetin 3-O-rhamnoside, rutin, kaempferol rhamnoside, and kaempferol flavonoids (Al-Ashaal et al., 2018).

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FIGURE 78.1 Structures of Atropine (1), Belladonnine (2), Hyoscyamine (3), Kaempferol (4), Kaempferol rhamnoside (5), Littorine (6), Norhyoscyamine (7), Pseudotropine (8), Quercetin 3-O-rhamnoside (9), Rutin (10), Scopolamine (11).

Arraez-Roman et al. (2008) characterized seven tropane alkaloid compounds from the leaves using ESI-TOF-MS. Optimum electrophoretic

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separation was also obtained using 60 mM ammonium acetate alkaline solution containing 5% isopropanol (pH 8.5). Several tropane alkaloids such as atropine, norhyoscyamine, belladonnine, hyoscyamine, apoatro­ pine, 6β-hydroxy-hyoscyamine, and scopolamine were identified using the optimum CE-ESI-TOF-MS conditions such as true isotopic patterns, sensi­ tivity, and mass accuracy. However, CE-ESI-IT-MS was used to separate the compound littorine. 78.3

PHARMACOLOGY

78.3.1 ANTI-INFLAMMATORY ACTIVITY Sultana (2014) evaluated the in vivo anti-inflammatory potential of the crude ethanolic extract obtained from the parts of A. belladonna (excluding roots and berries). Anti-inflammatory activity was examined by formalin-induced paw edema in mice model. Indomethacin and tween 80 were used as positive and negative controls. The edema was induced by injecting 20-mL of 1% formalin saline solution intradermally into the hind paw of mouse and then placed for observation in the Plexiglas chamber. The increase in paw volume was recorded subsequently. An hour prior to the formalin injection, the specified animals were intragastrically treated with different doses of plant extracts (50, 250, and 400 mg/kg), standard indomethacin (10 mg/kg), and equal volume of vehicle (Tween 80). The efficacy of treated drugs at various concentrations and time intervals were compared with the control group. The considerable anti-inflammatory effect (38.1%) was found at 400 mg/kg dose and the effect of crude ethanol extract and indomethacin on paw edema was 3.0 ± 0.41 mm (1 mL/kg dose) and 3.1 ± 0.32 mm (10 mg/kg dose). The percentage of decrease in edema is represented by 55.7%, 70.3%, and 75.2% after 1, 2, and 3 h of treatment. At the dose of 50 mg/kg, the extract showed decrease in paw edema by 10.8% (1 h), 12.1% (3 h), and 12.8% (5 h). Similarly, the extract at 250 mg/kg dose showed decreased paw edema percentage (19.5%, 25.7%, and 26.1%) after 1, 2, and 3 h, respectively. Owais et al. (2014) carried out in vivo anti-inflammatory assay of whole plant methanolic extract in formalin-induced inflammation in mice model. The formalin was injected to dorsal surface of the hind paw of mice and the specific duration spent by the animal in licking the paw was recorded. It was found that the extract at 100 mg recorded 1.23 ± 0.25 and 1.23 ± 0.09 min (licking period in minutes at 15 and 30 min duration), followed by 300

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mg dose of the extract (1.21 ± 0.22 and 1.54 ± 0.14 min at 15 and 30 min duration, respectively). Whereas, the standard diclofenac sodium expressed 1.09 ± 0.01 and 0.04 ± 0.01 min at 15 and 30 min durations, respectively. 78.3.2 WOUND HEALING PROPERTY The wound healing assay of A. belladonna aqueous extract in skin wounds was studied in male Sprague–Dawley rats through two parallel, full-thick­ ness, and skin incision wound model (Gal et al., 2009). The histopathological studies of the skin tissues of experimental animals showed significantly lesser number of inflammatory cells, increased angiogenesis, progress in the healing and epidermal regeneration in extract treated wounds, compared with the control animals. The lowest wound tensile strength was observed in the control group (B5-C) (8.5 ± 1.6 g/mm2), after 5 days. The elevated wound tensile strength was noted in the rats treated for 2 days in the treat­ ment group (B5-T2) (10.3 ± 2.0 g/mm2), while the highest wound stiffness was measured in the animals from B5-T5 group treated for 5 days (10.7 ± 2.5 g/mm2). The difference between control and both the experimental groups were found statistically significant (B5-C v/s. B5-T2, p < 0.05; B5-C v/s. B5-T5, p < 0.01) (Gal et al., 2009). 78.3.3 ACARICIDAL ACTIVITY Acaricidal activity of A. belladonna and its constituents (scopolamine and atropine) were studied by Godara et al. (2014) through in vitro model against the tick parasite Rhipicephalus microplus. The methanol extract derived from aerial part of the plant at 1.25–20% concentrations along with scopol­ amine and atropine compounds (0.1% concentration each) were used for the activity. The LC50 and LC95 of the extract were found to be 6.875% and 17.306%, respectively. However, the extract at 10% concentration caused a significant reduction in the production of eggs and the extract found lethal to ticks at 20% concentration. In larval packet test, the extract found lethal to larvae at 10% and 20% concentrations with LC50 and LC95 of 1.321 and 4.935%, after 24 h, respectively. Whereas the compounds scopolamine and atropine completely blocked the hatching of eggs as well as 100% mortality of larvae, followed by 93.3 and 60.0% mortality of adult ticks, respectively (Godara et al., 2014).

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78.3.4 ANTICHOLINERGIC ACTIVITY Rajput (2013) discussed the anticholinergic activity of A. belladonna alka­ loids such as atropine, scopolamine, and hyoscyamine on human body. The consumption of A. belladonna plant cause anticholinergic toxidrome affects due to the presence of these alkaloids and they affect both peripheral and central and nervous system, causing tachycardia, acute delirium, dry mouth, hallucination, vomiting, flushed skin and blurry vision, loss of memory, disorientation, confusion, agitated delirium, and in-coordinated movements with acute psychosis. 78.3.5 ANALGESIC ACTIVITY Owais et al. (2014) investigated in vivo analgesic activity of A. belladonna methanol extract using acetic acid-induced writhing inhibition in mice model. Before administering the methanol extract to the animals, writhes were induced by injecting 0.6% acetic acid intraperitoneally. The extract was administered orally and immediately after inducing the acetic acid, the number of writhes was counted for 30 min. It was found from the results that the extract at 300 mg concentration showed 57.1% inhibition of writhes, followed by diclofenac sodium and 100 mg extract concentrations with 42 and 28.5% inhibitions respectively. 78.3.6 NEUROPHARMACOLOGICAL ACTIVITY In vivo neuropharmacological activity of A. belladonna methanol extract was studied by using cage cross, head dip, rearing, open field, light and dark, trac­ tion and swimming test models (Owais et al., 2014). The experimental mice showed high locomotive activity at 300 mg dose of A. belladonna extract in open field activity test. Further in cage crossing test, the mice showed significant activities at 100 and 300 mg concentrations (15.17 ± 1.70 and 6.50 ± 0.76, respectively). In case of head dip test to check the learning ability of mice, in both the concentrations of 100 and 300 mg the test drug showed significant learning activities (6.00 ± 0.73 and 6.17 ± 0.60, respectively). 78.3.7 GASTRIC EFFECTS Bousta et al. (2001) evaluated the efficacy of A. belladonna extract in low doses on stress-induced gastric alterations through microscopic technique after inducing experimental stress in mice. The results demonstrated that low

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doses of A. belladonna caused a significant gastric alteration. Severity of gastric erosions in stressed mice was represented by mean severity score through the different test groups such as unstressed saline group (2.677 ± 0.211), stressed saline group (8.111 ± 0.511) and stressed/treated A. bella­ donna extract groups (4.023 ± 1.022). 78.3.8 IMMUNOLOGICAL EFFECTS The study evaluated the effects of low doses of A. belladonna extract on stress induced, immunological alterations in treated mice (Bousta et al., 2001). Immunological studies were performed to count the white blood cell components such as lymphocytes, basophils, monocytes and neutrophils by coulter counter method. In the experimentally stress-induced group treated with A. belladonna at 9 CH, a significant increase in the lympho­ cyte number was observed, whereas A. belladonna at 15 CH significantly decreased the number of lymphocytes. However, the basophil and neutro­ phil numbers were greatly increased in 5 and 9 CH of A. belladonna treated mice. Whereas, the number of monocytes were significantly increased in stressed and treated mice with 5 CH and 15 CH of A. belladonna. In the unstressed mice treated with 5 and 15 CH, the number of basophils was increased significantly. On the contrary, the decrease in the number of basophils was observed in the unstressed-saline mice treated with 9 CH of this product. KEYWORDS • • • • • • •

Atropa belladonna Solanaceae poisonous plants phytochemistry atropine ethnomedicine pharmacology

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REFERENCES Al-Ashaal, H. A. A. H.; Abuelnaga, A.; El–Beih, A. A.; Din, S. S. E. Anti Food Poisoning Pathogenic Bacteria in Correlation to Coumarins and Flavonoids of Atropa belladonna Field Plant and In Vitro Cultures. J. Pharm. Sci. Res. 2018, 10 (2), 235–239. Arraez-Roman, D.; Zurek, G.; Bäßmann, C.; Segura-Carretero, A.; Fernandez-Gutierrez, A. Characterization of Atropa belladonna L. Compounds by Capillary ElectrophoresisElectrospray Ionization-Time of Flight-Mass Spectrometry and Capillary ElectrophoresisElectrospray Ionization-Ion Trap-Mass Spectrometry. Electrophoresis 2008, 29, 2112–2116. Bousta, D.; Soulimani, R.; Jarmouni, I.; Belon, P.; Falla, J.; Froment, N.; Younos, C. Neurotropic, Immunological and Gastric Effects of Low Doses of Atropa belladonna L., Gelsemium sempervirens L. and Poumon histamine in Stressed Mice. J. Ethnopharmacol. 2001, 74, 205–215. Gal, P.; Toporcer, T.; Grendel, T.; Vidova, Z.; Smetana Jr, K.; Dvorankova, B.; Gal, T.; Mozes, S.; Lenhardt, L.; Longauer, F.; Sabol, M.; Sabo, J.; Backor, M. Effect of Atropa belladonna L. on Skin Wound Healing: Biomechanical and Histological Study in Rats and In Vitro Study in Keratinocytes, 3T3 Fibroblasts, and Human Umbilical Vein Endothelial Cells. Wound Rep. Reg. 2009, 17, 378–386. Godara, R.; Katoch, M.; Katoch, R.; Yadav, A.; Parveen, S.; Vij, B.; Khajuria, V.; Singh, G.; Singh, N. K. In Vitro Acaricidal Activity of Atropa belladonna and Its Components, Scopolamine and Atropine, Against Rhipicephalus (Boophilus) microplus. Sci. World J. 2014, Article ID 713170, 1–6 pages. http://dx.doi.org/10.1155/2014/713170. Malik, M.; Hussain, S.; Sajjad, N.; Nazir, S.; Gondal, M. U.; Malik, J. A. Physicochemical Analysis, Qualitative and Quantitative Investigation of Atropine in Medicinal Plant Atropa belladonna. Eur. J. Pharma. Med. Res. 2021, 8 (5), 149–157. Owais, F.; Anwar, S.; Saeed, F.; Muhammad, S.; Ishtiaque, S.; Mohiuddin, O. Analgesic, Anti-Inflammatory and Neuropharmacological Effects of Atropa belladonna. Pak. J. Pharm. Sci., Conference Issue, 2014, 27 (6), 2183–2187. POWO. Plants of the World Online. Facilitated by the Royal Botanic Gardens, Kew. 2019. Published on the Internet. http://www.plantsoftheworldonline.org/ (accessed on Feb 2, 2021). Rajput, H. Effects of Atropa belladonna as an Anti-Cholinergic. Nat. Prod. Chem. Res. 2013, 1 (1), 1–2. DOI: 10.4172/2329–6836.1000104. Sultana, T. In Vivo Evaluation of the Anti-Inflammatory Activity of Ethanolic Extract of Atropa belladonna. Int. J. Res. Pharm. Biosci. 2014, 1 (1), 5–7.

CHAPTER 79

Traditional Use, Chemical Constituents, and Pharmacology of Cocos nucifera L. THADIYAN PARAMBIL IJINU1,2*, MANIKANTAN AMBIKA CHITHRA1,

MAHESWARI PRIYA RANI3, THOMAS ASWANY2,4,

VARUGHESE GEORGE1, and PALPU PUSHPANGADAN1

1Amity

Institute for Herbal and Biotech Products Development, Thiruvananthapuram 695005, Kerala, India 2Naturæ

Scientific, Kerala University Business Innovation and Incubation Centre, Karyavattom Campus, Thiruvananthapuram 695581, Kerala, India

3Phytochemistry

and Pharmacology Division, Jawaharlal Nehru Tropical Botanic Garden and Research Institute, Thiruvananthapuram 695562, Kerala, India

4Department

of Biotechnology, Malankara Catholic College, Kanyakumari 629153, Tamil Nadu, India

*Corresponding

author. E-mail: [email protected]

ABSTRACT Cocos nucifera L. is popularly known as the “coconut tree”, belongs to the family Arecaceae. Different parts of C. nucifera are used in traditional medi­ cine around the world to treat a wide range of ailments, including typhoid, influenza, ear infections, tuberculosis, constipation, gum disease, jaundice, tumours, venereal maladies, etc. The fresh juice of the C. nucifera inflorescence is used in Indian traditional medicine to cure dyspepsia, diarrhoea, dysentery, diabetes, haemoptysis, and strangury. Lauric acid accounts for about 50% of the total fatty acids present in coconut oil. Other medium-chain saturated fatty Phytochemistry and Pharmacology of Medicinal Plants, Volume 2: T. Pullaiah (Ed.) © 2023 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)

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acids present in C. nucifera oil are myristic acid, caprylic acid, capric acid, and caproic acid. C. nucifera endocarp ethanolic extract contains myristic acid, syringaldehyde, eugenol, vanillin, 2,4-di-tert-butylphenol, lauric acid, palmitic acid methyl ester, and γ-sitosterol. Extracts, isolated compounds, oil, and fatty acids present in the various parts of C. nucifera showed antioxidant, hepatoprotective, anti-inflammatory, analgesic, cardioprotective, antihyper­ lipidemic, antidiabetic, anticancer, immunomodulatory, nephroprotective, neuroprotective, wound healing, and antimicrobial properties. 79.1

INTRODUCTION

Cocos nucifera L. (Syn.: Calappa nucifera (L.) Kuntze, Cocos indica Royle, Cocos nana Griff., Palma cocos Mill.) is the only species of the genus Cocos, which belongs to the Arecaceae family. Vernacular names of this plant include kalpavriksha, karakatoyah, dirghapatrah, uchchataru, trnamvruk­ shah, trinetraphalah, kikih, karakambhas, narikera, trnamdrumah, durhah, kaushikaphalah, trnamrajah, khanamudakah, dirgapadapah (Sanskrit), nariyal (Hindi), thengu (Malayalam), tengku (Tamil), tengu (Kannada), narikel (Telugu), narlu (Konkani), shriphal, naral (Marathi), nariyel (Guja­ rati), narikol (Assamese), narakela, narokel (Bengali), noril (Kashmiri), yubi (Manipuri), nariyel (Urdu), and coconut tree, palm tree (English). The C. nucifera is a long-lived plant, which may survive for up to 100 years. It has a single trunk that is 20–30 m tall, usually erect, but may be slightly curved, the bark is smooth and grey, thickened at the base, and marked by ringed scars left by fallen leaf bases. The leaves are found on the top of the trunk, 3.5–6 m in length, pinnate, linear-lanceolate, more or less recurved, rigid, with bright green leaflets. A coconut tree typically produces 12–20 inflorescences per year. Spathes shield the immature inflorescence (spadix), each inflorescence branch (rachilla) bears both male and female flowers. Normally there are only a few female flowers per inflorescence but there are thousands of male flowers. Pollination occurs in newly opened male flowers, with the help of nectar attracted insects. The fruits are large, dry, ovoid drupes, up to 40 cm long and 30 cm wide. As the fruit is monosperm, it contains a single seed. A brown testa covers the seed, which encloses about 1–2 cm thick white layer of meat. This section yields copra oil and opalescent liquid coconut water, filling the middle cavity three-quarters full. The embryo is lodged beneath one of the nut’s three germinating pores in the meat. The root system of C. nucifera is fasciculate, with thousands of roots that grow throughout life span. Just a tiny percentage of the roots penetrate

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deep into the soil for stability. Coconut palm is an important multifunctional tropical tree in the humid tropics that sustained the communities living on the shore and on islands for their livelihood (Jerard et al., 2008). The plant is reputed to have its origin in Southeast Asia (Lima et al., 2015). People scattered across the world with different cultures, languages, beliefs and races have considered coconut to be a reliable fount of nourishment and medication. It is used in traditional medicine all throughout the world to treat a wide range of ailments. Antihelmintic, antitoxin, antiseptic astringent, bacte­ ricidal, diuretic, laxative, vermifugal, stomachic, and supportive effects have been recorded (Ross, 2000). It is also utilized as a solution for typhoid, influ­ enza, ear infection, tuberculosis, constipation, gum disease, jaundice, tumors, and venereal maladies (Obidoa et al., 2010). The fresh juice of the C. nucifera inflorescence is used in Indian traditional medicine to cure dyspepsia, diar­ rhoea, dysentery, diabetes, haemoptysis, and strangury (Renjith et al., 2013). Native people of tropical countries use tender coconut water to treat problems associated with digestion. The saturated fatty acid, lauric acid is liable for antimicrobial effect of coconut. Henceforth it is helpful in curing gastrointestinal tract disorders. Coconut water diminishes the manifestations related with inflammatory bowel diseases and stomach ulcers. Coconut water is currently considered as a viable nourishing source that can boost energy and endurance, improving physical, and athletic execution. Tender coconut water is utilized as a substitute for sterile glucose. It is additionally utilized as a remedy for poison. Coconut water is employed to kill worms, which may be liable for stomach cramps (Elumalai et al., 2014). Coconut water is utilized in the treatment of urinary tract, gall bladder and kidney problems. Lehyam prepared from blossoms helps to improve the health of the uterus and regulates bleeding after delivery (Anosike and Obidoa, 2010). In tropical countries, coconut oil is commonly applied to moisturize the skin, alleviate dryness, flaking, and to avoid stretch marks in skin. It is also used for burns, eczema, wounds, bruises, rashes, and dermatitis. Coconut oil helps the skin to maintain natural chemical equilibrium and offers protection from the damaging effects of ultraviolet radiation from the sun (Fife, 2000). It is antifungal and is used for the treatment of several fungal infections of the skin such as foot thrush, ringworm, and candidiasis (Bergsson, 2001). Ayurveda explains “coconut fruit is sweet to taste and acts as a bodily coolant. It is unctuous and difficult to digest.” In Ayurveda, coconut is used for hyperacidity, burning micturition, retention of urine, provide physical strength, burning sensation of body during measles and herpes, diarrhea, thirst, and gynaecological disorders (Rajith et al., 2009). Coconut pulp is a

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nutrient-dense food that can help you gain weight. Coconut pulp takes longer to digest, strengthens muscles, and helps to cleanse the bladder. Tender coconut is used for the treatment of fever and skin diseases caused by pitta imbalance, and acts as a digestive stimulant, diuretic, and aphrodisiac. The coconut oil is used as a hair oil to enhance hair growth and prevents dandruff. Ayurveda recommends coconut oil in conditions such as dry skin and skin diseases. The use of coconut oil has been found to be beneficial in psoriasis, eczema, and dermatitis. Flowers are used to prevent frequent bowel movements in diar­ rhoea and dysentery. Flowers can aid in the reduction of frequent urination. Coconut inflorescence is used in gynaecological disorders such as dysmenor­ rhoea, leucorrhoea, etc. Coconut water, fruit and oil help to reduce excess heat from the eyes and improve vision. Coconut not only enhances vision but also benefits eye diseases, particularly in conjunctivitis and eye flu. Gentle massage with coconut oil helps to reduce dark circles under the eyes (Singh, 2014). Coconut milk has immense significance in traditional Ayurvedic medicine. It is commonly used to keep the electrolyte balance and to rule out dehydration losses. Also, it is used for the treatment of ulcer in mouth (Ganguly, 2013). 79.2

PHYTOCHEMICAL CONSTITUENTS

Lauric acid and α-tocopherol are found in the oil recovered from the solid albumen of C. nucifera. The flavonoids and saponins were identified as root phenolic compounds. The phytochemicals lupeol methyl ether, skimmiwallin, and isoskimmiwallin were reported in leaf epicuticular wax (Lima et al. 2015). The most common flavan-3-ol units are (+)-catechin, (−)-epicatechin, (+)-gallocatechin and (−) epigallocatechin, while (+)-afzelechin and (−)-epiaf­ zelechin have been reported to a lesser extent (Padumadasa et al., 2016). The triglycerides in coconut oil comprise a mixture of short- and mediumchain saturated (92%) and unsaturated (8%) fatty acids, lauric acid accounting for about 50% of the total fatty acids. Lauric acid is transformed into mono­ laurin, the active metabolite of lauric acid in the human body. Other medium chain saturated fatty acids are myristic acid (20%), caprylic acid (9%), capric acid (8%) and caproic acid (5%). Palmitic acid and stearic acid are two longchain fatty acids found in coconut oil. There is a small percentage of unsatu­ rated fatty acids in coconut oil namely linoleic acid and linolenic acid (1–3%), arachidonic acid (0.2%), and eicosinoic acid (0.2%) (Obidoa et al., 2010). Electrospray ionization-mass spectrometry fingerprinting of lipid compounds in coconut oil of fifteen different varieties and one coconut oil processed on an industrial scale showed predominance of diacylglycerols and triacylglycerols (Ferreira et al., 2019). C. nucifera endocarp ethanolic extract contains myristic

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acid, syringaldehyde, eugenol, vanillin, 2,4-di-tert-butylphenol, lauric acid, palmitic acid methyl ester, and γ-sitosterol (Singla and Dubey, 2019). Tender coconut water is a transparent, sweet, and sterile liquid that contains carbohydrates, vitamins, minerals, electrolytes, enzymes, amino acids, cytokines, and phytohormones. Vitamin B, nicotinic acid, pantothenic acid, biotin, riboflavin, folic acid, trace quantities of vitamins B1, B6 and C, pyridoxine, thiamine, folic acid, amino acids, plant hormones, enzymes, and growth-promoting factors were identified in the liquid albumen (Lima et al., 2015). Asghar et al. (2019) found that coconut sap is rich in vitamin C (116.19 µg/mL) and ash (0.27%) contents, especially potassium (960.87 mg/L) and sodium (183.21 mg/L).

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PHARMACOLOGICAL STUDIES

Extracts and isolated compounds from various parts of the C. nucifera, and coconut water showed wide range of pharmacological properties. 79.3.1 ANTIOXIDANT ACTIVITY Chithra et al. (2020a) found that the phenolic-rich inflorescence extract of C. nucifera demonstrated significant free radical scavenging activity on 2,2′-diphenyl-1-picryl hydrazyl assay, 2,2′-azinobis (3-ethylbenzthiazoline6-sulphonic acid) assays, and ferric reducing activity with IC50 values 65.72, 66.94, and 89.84 μg/mL, respectively. Tender coconut was found to have an antioxidant effect on isoproterenol-induced myocardial infarction in rats (Anurag and Rajamohan, 2003; Prathapan and Rajamohan, 2010). Asghar et al. (2019) found that the coconut sap possesses potent 2,2-diphenyl­ 1-picrylhydrzyl and 2,2′-azino-bis-3-ethylbenzthiazoline-6-6-sulfonic acid radical scavenging, and ferric reducing antioxidant power. 79.3.2 HEPATOPROTECTIVE ACTIVITY Chithra et al. (2020a) found that phenolic rich C. nucifera inflorescence extract (100, 200 and 400 mg/kg) significantly protected from acetamino­ phen-induced liver toxicity, dose dependently. It increased the antioxidant status of the cells by the production of glutathione, glutathione S-transferase, and glutathione peroxidise, and prevented rise in serum alanine amino transferase, aspartate amino transferase, and alkaline phosphatase. It also reduced the amount of malondialdehyde in the serum. Studies revealed that tender coconut water has significant hepatoprotective property on carbon tetrachloride-induced hepatic injury in rats. No significant changes were observed in liver antioxidant status and histopathology of coconut water treated group (Loki and Rajamohan, 2003). Pre-treatment of the rats with 10 mL/kg of virgin coconut oil significantly reduced the liver damage induced by paracetamol, 3 g/kg body weight (Zakaria et al., 2011a). 79.3.3 ANTI-INFLAMMATORY ACTIVITY Phenolic-rich C. nucifera inflorescence extract (100 µg/mL) significantly reduced the total cyclooxygenase (68.67%), 5-lipoxygenase (63.67%)­ induced nitric oxide synthase, nitric oxide, and prostaglandin in lipopoly­ saccharide-induced RAW264.7 cells. It further decreased the interleukin-1β,

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interleukin-6, tumor necrosis factor-α, and nuclear factor kappa B (Chithra et al., 2020b). In addition, Chithra et al. (2020b) also discovered that inflorescence extract of C. nucifera (400 mg/kg) substantially reduced carrageenan-induced acute paw edema (59.81%) and formalin-induced chronic paw edema (52.90%) in mice. Coconut oil is reported to possess antiinflammatory activity (Rinaldi et al., 2009; Intahphuak et al., 2010; Naskar et al., 2013). Zakaria et al. (2011b) demonstrated the anti-inflammatory proper­ ties of virgin coconut oil on various in vivo models. C. nucifera husk fiber aqueous crude extract (10, 50 and 100 mg/kg) significantly inhibited the inflammation induced by carrageenan and formalin treatment by reducing cell migration, protein extravasation, and tumor necrosis factor-α production (Silva et al., 2013). 79.3.4 ANALGESIC ACTIVITY Phenolic-rich C. nucifera inflorescence extract (400 mg/kg) exhibited a substantial antinociceptive effect on acetic acid-induced writhing (48.21%) and Eddy’s hot plate methods (Chithra et al., 2020b). Alviano et al. (2004) found that coconut husk fiber aqueous extract possess analgesic property. Naskar et al. (2013) reported that aqueous methanolic extract of C. nucifera spadix showed analgesic activity in in vivo models. C. nucifera aqueous extract and virgin coconut oil were also shown to have a moderate analgesic effect on acetic acid-mediated writhing responses in mice (Alviano et al., 2004; Intahphuak et al., 2010). C. nucifera root ethanol extract (40, 60, and 80 mg/kg) considerably reduced the number of writhes and stretches caused by acetic acid injection in mice. It also potentiated analgesia induced by morphine and pethidine in mice (Pal et al., 2011). 79.3.5 CARDIOPROTECTIVE ACTIVITY Studies carried out using virgin coconut oil extracted from fresh coconut kernel by wet processing under mild temperature exhibit significant hypo­ lipidemic, antioxidant, and antithrombotic effects compared with copra oil and sunflower oil in normal and cholesterol-fed rats (Nevin and Rajamohan, 2004, 2006; Arunima and Rajamohan, 2013). This therapeutic and nutri­ tional potential of virgin coconut oil is due to the presence of unsaponifiable components. Coconut kernel protein has been shown to have cardioprotective property in rats against isoproterenol-induced myocardial infarction (Mini

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and Rajamohan, 2002). The antioxidant, antithrombotic, and cardioprotec­ tive effects of tender coconut were also reported in rats-induced myocardial infarction (Anurag and Rajamohan, 2003; Prathapan and Rajamohan, 2010). Tender coconut water also exhibited significant blood pressure lowering effect (Bhagya et al. 2012). Tender coconut water could also decrease serum levels of total cholesterol, very low lipoprotein density, medium lipoprotein content, and triglyceride (Lima et al., 2015). 79.3.6 ANTIHYPERLIPIDEMIC ACTIVITY Mini and Rajamohan (2004) studied the hypolipidemic effect of L-arginine­ rich coconut protein in ethanol-induced hyperlipidemia in male albino rats. Result showed that there is considerable decrease in total cholesterol, low-density lipoproteins, very low-density lipoproteins, triglycerides, and atherogenic index. The coconut protein also decreased activity of β-hydroxy β-methylglutaryl-CoA reductase in the liver and increased activity of lipopro­ tein lipase in the heart. Müller et al. (2003) found that the coconut oil-based diet lowers postprandial tissue plasminogen activator antigen concentration. Lipoprotein (a) levels appear to be influenced by the quantities of dietary saturated fatty acids rather than the percentage of saturated fat energy. Dietary administration of virgin coconut oil (10% w/w) showed significant antithrombotic effect in comparison with copra oil (10% w/w) and sunflower oil (10% w/w) in cholesterol (1%) fed along with the normal laboratory diet (10 g/rat) for 45 days. Virgin coconut oil also reduced the cholesterol and triglyceride levels and maintained the levels of blood coagulation factors (Nevin and Rajamohan, 2007). 79.3.7 ANTIDIABETIC ACTIVITY Dietary supplementation of coconut fiber had a substantial hypoglycemic effect in normal rats (Sindhurani and Rajamohan, 2000). In alloxan-induced diabetic mice, mature coconut water dramatically reduced the hyperglycemia, and oxidative stress (Preetha et al., 2012). C. nucifera flower extract substan­ tially lowered the elevated blood sugar, uric acid, creatinine and glycosyl­ ated hemoglobin levels (Saranya et al., 2014). Renjith and Rajamohan (2012) demonstrated that C. nucifera inflorescence extract significantly ameliorated the adverse influence of alloxan in rats. Salil et al. (2011) found that arginine-rich coconut kernel protein restored the glycogen and

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carbohydrate metabolizing enzyme levels in alloxan (150 mg/kg) induced diabetic Sprague-Dawley rats. Ethanolic extract of C. nucifera endocarp showed significant α-amylase inhibition (IC50 63–126 µg/ml) in dinitrosali­ cylic acid-based α-amylase assay (Singla and Dubey, 2019). Intraperitoneal administration of ethyl acetate fraction (50 mg/kg) of C. nucifera husk fiber methanol extract exhibited significant inhibition on α-amylase activity, lipid peroxidation, and blood glucose within 5 days in alloxan-induced hypergly­ caemic rats (Muritala et al., 2018). 79.3.8 ANTICANCER ACTIVITY Aqueous extracts (0, 5, 50, and 500 μg/mL) of the husk fiber of two different varieties of C. nucifera showed almost equal cytotoxicity against leukemia cell line K562 (60.1% and 47.5%, respectively) evaluated by 3-[4,5-dimeth­ ylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay for 48 h (Koschek et al., 2007). 79.3.9 IMMUNOMODULATORY ACTIVITY Oral administration of coconut protein increased the blood parameters like red blood cells, white blood cells, and platelet counts in cyclophosphamide treated immune suppressed Swiss albino mice (Vigila and Baskaran, 2008). Winarsi et al. (2008) found that Zn rich virgin coconut oil one tablespoon per day maintained the neutrophil count and nature killer cells, increased the level of cytotoxic T-lymphocytes, T-helper cells, and interleukin-2 in vaginal candidiasis patient. 79.3.10 NEPHROPROTECTIVE ACTIVITY Coconut water prevented crystal deposition in renal tissue and decreased the amount of crystals in urine. It also helped to protect the kidneys from oxidative stress and impaired renal function (Gandhi et al., 2013). 79.3.11 NEUROPROTECTIVE ACTIVITY Ethanol extract of C. nucifera root (40, 60, and 80 mg/kg) dose-dependently enhanced the sleeping time of mice induced by standard hypnotics (pento­ barbital sodium, diazepam, and meprobamate. Pretreatment with ethanol extract of C. nucifera root (25–80 mg/kg) showed significant protection against pentylenetetrazole-induced convulsions (Pal et al., 2011).

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79.3.12 WOUND HEALING ACTIVITY Radenahmad et al. (2006) found that phytoestrogen-rich young coconut juice (100 mL/kg/day) significantly accelerated wound healing in ovariectomized rats. 79.3.13 ANTIMICROBIAL ACTIVITY Alcoholic extract of C. nucifera (100 mg/mL) showed good inhibition against Streptococcus salivarius (16.3 mm) followed by Streptococcus mutans (15.3 mm), Streptococcus mitis (13.3 mm), and Lactobacillus acidophilus (13.3 mm) (Jose et al., 2014). Akinpelu et al. (2015) found that n-butanol frac­ tion of aqueous methanolic extract of C. nucifera husk showed minimum inhibitory concentration of 0.16 mg/mL against Enterococcus faecalis. Crude water extract and catechin rich fraction demonstrated potent inhibi­ tion against acyclovir-resistant herpes simplex virus type 1 (Esquenazi et al., 2002). Methanolic extract of C. nucifera mesocarp exhibited potent activity against Staphylococcus aureus ATCC 25923 (Chakraborty and Mitra, 2008). The shell extract of C. nucifera showed effective against Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus, Trichophyton rubrum, Tricho­ phyton mentagrophytes, Trichophyton verrucosum, Microsporum canis, and Microsporum gypseum (Thebo et al., 2016). 79.3.14 ANTIPARASITIC ACTIVITY Ethyl acetate extract fraction of C. nucifera West African Tall husk fiber showed good antimalarial activity against Plasmodium falciparum W2 strain (IC50 10.94 μg/mL) in vitro and against Plasmodium berghei NK65 strain in vivo caused 50% and more decrease in parasitaemia on fifth and sitxh days after inoculation at various doses (31.25–500 mg/kg) (Adebayo et al., 2013). White flesh methanol extract of C. nucifera (200 and 400 mg/kg) signifi­ cantly reduced the parasitaemia, investigated against P. berghei (NK65) infections in mice (Al-Adhroey et al., 2011). The polyphenolic-rich extract of C. nucifera husk fiber showed leishmanicidal activity, with minimal inhibitory concentration of 10 μg/mL (Mendonca-Filho et al., 2004). The decoction made from C. nucifera leaves inhibited the growth of P. berghei by up to 54% at subtoxic doses (intramuscular) in P. berghei-infected mice. The C. nucifera leaf decoction demonstrated toxicity at 2000 mg/kg/day in

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an acute toxicity trial, as evidenced by necropsy examination (Tayler et al., 2020). The aqueous decoction of leaves of C. nucifera showed antiplasmodial activity against P. falciparum at 10% v/v concentration (Tayler et al., 2019). 79.3.15 TOXICITY STUDIES C. nucifera inflorescence acetone extract showed no toxicity in acute toxicity study conducted in mice by Chithra et al. (2020a), and the LD50 value was found to be greater than 5000 mg/kg. In rats, administration of fermented virgin coconut oil showed no toxicity in acute (5000 mg/kg), subchronic (175, 550, and 2000 mg/kg) and chronic (175, 550, and 2000 mg/ kg) models (Ibrahim et al., 2016). Ekanayake et al. (2019) investigated the acute (2000 mg/kg) and subacute (1.75, 3.5, 7, and 14 mg/kg) toxicity studies of ethyl acetate soluble proanthocyanidins from C. nucifera inflorescence and found that no rat in either the acute or subacute toxicity study exhibited mortality or clinical signs of toxicity. Also, there is no significant change in their mean body weight, food, and water intake, haematology, serum biochemistry, and histopathology as compared with control group. Toxicity studies conducted in Swiss albino mice demonstrated safety profile of the C. nucifera leaf extracts (Paul et al., 2012). Jawad and Ali (2010) found that C. nucifera fruit alcoholic extract is not toxic to laboratory mice and that a low dose (125 mg/kg) causes enhancement in male fertility of mice, while a higher dose (200 mg/kg) causes a reduction in sperm concentra­ tion. Olaniyan et al. (2021) investigated the effect of C. nucifera oil on lead acetate-induced reproductive toxicity in male Wistar rats. C. nucifera oil treated group significantly increased the testosterone, luteinizing hormone and sperm parameters compared with positive control. Also the oil-treated group showed significant decrease in the malondialdehyde levels. ACKNOWLEDGMENTS The authors express their sincere thanks to Dr. Ashok K. Chauhan, Founder President, Ritnand Balved Education Foundation (RBEF) and Amity Group of Institutions, and Dr. Atul Chauhan, Chancellor, Amity University Uttar Pradesh (AUUP) for facilitating this work. Thadiyan Parambil Ijinu is receiving Young Scientist Fellowship from the Department of Science and Technology, Government of India (SP/YO/413/2018).

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KEYWORDS • • • • • •

traditional medicine coconut tree coconut oil lauric acid antioxidant hepatoprotective

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Paul, N.; Roy, R.; Sanjib, B. S.; Biswas, M. Acute and Sub-Chronic Toxicity Study of Cocos nucifera Leaf Extracts in Mice. J. Adv. Pharm. Edu. Res. 2012, 2, 74–81. Prathapan, A.; Rajamohan, T. Antioxidant and Antithrombotic Activity of Tender Coconut Water in Experimental Myocardial Infarction. J. Food Biochem. 2010, 35, 1501–1507. Preetha, P. P.; Girija Devi, V.; Rajamohan, T. Hypoglycemic and Antioxidant Potential of Coconut Water in Experimental Diabetes. Food Funct. 2012, 3, 753–757. Radenahmad, N.; Vongvatcharanon, U.; Withyachumnarnkul, B.; Connor, J. R. Serum Levels of 17β-Estradiol in Ovariectomized Rats Fed Young-Coconut-Juice and Its Effect on Wound Healing. Songklanakarin J. Sci. Technol. 2006, 28, 897–910. Rajith, N. P.; Navas, M.; Asha, NL.; Thaha, MA.; Vimal Kumar, CS.; Anish, N.; Rajsekharan, S.; George, V.; Pushpangadan, P. Ethnobotanical Studies on Coconut Palm (Cocos nucifera L.) with Special Reference to South Kerala. Ethnobotany 2009, 21, 32–40. Renjith, R. S.; Chikku, A. M.; Rajamohan, T. Cytoprotective, Antihyperglycemic and Phytochemical Properties of Cocos nucifera (L.) Inflorescence. Asian Pac. J. Trop. Med. 2013, 6, 804–810. Renjith, R. S.; Rajamohan, T. Young Inflorescence of Cocos nucifera Contributes to Improvement of Glucose Homeostasis and Antioxidant Status in Diabetic Rats. Int. J. Diab. Dev. Countries 2012, 32, 193–198. Rinaldi, S.; Silva, D. O.; Bello, F.; Alviano, C. S.; Alviano, D. S.; Matheus, M. E.; Fernandes, P. D. Characterization of the Antinociceptive and Anti-Inflammatory Activities from Cocos nucifera Linn. J. Ethnopharmacol. 2009, 122, 541–546. Ross, J. M. A. The Diet Cure; Penguin Book: New York, 2000; pp 23–34. Salil, G.; Nevin, K. G.; Rajamohan, T. Arginine Rich Coconut Kernel Protein Modulates Diabetes in Alloxan Treated Rats. Chemico-Biol Interact. 2011, 189, 107–111. Saranya, S.; Pradeepa, S.; Subramanian, S. S. Biochemical Evaluation of Antidiabetic Activity of Cocos nucifera Flowers in STZ Induced Diabetic Rats. Int. J. Pharm.Sci. Rev. Res. 2014, 26, 67–75. Silva, R. R.; e Silva D. O.; Fontes, H. R.; Alviano, C. S.; Fernandes, P. D.; Alviano, D. S. Anti-Inflammatory, Antioxidant, and Antimicrobial Activities of Cocos nucifera var. typica. BMC Complement. Altern. Med. 2013, 13, 107. Sindhurani, J. A.; Rajamohan, T. Effects of Different Levels of Coconut Fiber on Blood Glucose, Serum Insulin and Minerals in Rats. Indian J. Physiol. Pharmacol. 2000, 44, 97–100. Singh, J. Coconut (Nariyal) Health Benefits and Medicinal Uses. 2014. https://www. ayurtimes.com/coconut-health-benefits-medicinal-uses/ (accessed on Feb 05, 2021). Singla, R. K.; Dubey, A. K. Phytochemical Profiling, GC-MS Analysis and α-Amylase Inhibitory Potential of Ethanolic Extract of Cocos nucifera Linn. Endocarp. Endocr. Metab. Immune. Disord. Drug. Targets. 2019, 19, 419–442. Tayler, N. M.; Boya, C. A.; Herrera, L.; Moy, J.; Ng, M.; Pineda, L.; Almanza, A.; Rosero, S.; Coronado, L. M.; Correa, R.; Santamaría, R.; Caballero, Z.; Durant-Archibold, A. A.; Tidgewell, K. J.; Balunas, M. J.; Gerwick, W. H.; Spadafora, A.; Gutiérrez, M.; Spadafora, C. Analysis of the Antiparasitic and Anticancer Activity of the Coconut Palm (Cocos nucifera L. Arecaceae) from the Natural Reserve of Punta Patiño, Darién. PLoS One 2019, 14, e0214193. Tayler, N. M.; De Jesús, R.; Spadafora, R.; Coronado, L. M.; Spadafora, C. Antiplasmodial Activity of Cocos nucifera Leaves in Plasmodium berghei-Infected Mice. J. Parasit. Dis. 2020, 44, 305–313.

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Index

A Achyranthes asper, 125–126

bioactives, 126–129

pharmacological activities, 129–130

antiallergic activity, 131

antibacterial activity, 130

anti-carcinogenic activity, 133

antidiabetic activity, 132

antifertility activity, 131

anti-hyperlipidemic activity, 132

anti-inflammatory activity, 130

antiparasitic activity, 133

bronchial asthma, 133

bronchoprotective effect, 133–134

cardiovascular activity, 131

hepatotoxicity, 132

immunomodulatory activity, 133

leprosy, 132

nephroprotective activity, 134

phosphorlase activity, 134

Ailanthus excelsa Roxb, 239

pharmacology, 241–242

analgesicl activity, 248–249

anti-amoebic activity, 248

antiasthmatic and antiallergic activity,

244–245

antibacterial activity, 242–243

anticancer activity, 243

antidiarrheal activity, 246

antifertility activity, 245

antifungal activity, 243–244

antihypolipidemic activity, 247–248

anti-inflammatory activity, 246

antiplasmodial activity, 248

antisecretory activity, 245–246

gastroprotective activity, 245–246

hepatoprotective activity, 242

hypoglycemic activity, 245

hypotensive activity, 242

phytoconstituents, 240–241

Amaranthus tricolor L, 297

bioactives, 300–302 pharmacology

antidiabetic activity, 308

anti-hyperglycemic activity, 303–304

anti-inflammatory properties, 306

antimicrobial activity, 308–309

antinociceptive activity, 304

antioxidant activity, 304–306

antitumor activity, 309–310

gastroprotective activity, 307–308

hepatoprotective activity, 306–307

sedative and anxiolytic activity, 302–303

Angelica glauca

ethnopharmacology, 420–421

importance of, 424

pharmacology

anti-anxiety activity, 426–427

antimicrobial activity, 425–426

antioxidant activity, 424–425

bronchorelaxant activity, 427

cognitive effect, 427

and cytotoxic activity, 426

hepatoprotective activity, 427

irritant, 426

phytochemistry

essential oil content, 422

fresh aerial parts, 423

studies, 423–424

Z-butylidinephthalide, 421

Z-lingustilide, 421

traditional uses, 420–421

Aristolochia indica L, 267

bioactives, 268–270

pharmacology

analgesic activity, 282

anthelmintic activity, 282

anti-amyloidogenic potential, 277

antibacterial activity, 270–274

anticancer activity, 276

antidiabetic activity, 278

antidiarrhoeal activity, 279–280

524 antifertility activity, 278

antifungal activity, 274

anti-inflammatory activity, 278–279

antimalarial activity, 275–276

anti-mitotic activity, 279

antioxidant activity, 274–275

antiplasmodial activity, 280

antipruritic activity, 281

antivenom properties, 276–277

antiviral activity, 270

contraceptive potential, 280–281

cytotoxicity assays, 277

genotoxic effect, 279

hypoglycemic effect, 275

immunomodulatory activity, 281

insecticidal activity, 281

larvicidal activity, 281

mast cell stabilizing activity, 282

toxicity assays, 280

Atropa belladonna L., 497

bioactives, 499

optimum electrophoretic, 500–501

pharmacology

acaricidal activity of, 502

analgesic activity, 503

anticholinergic activity, 503

anti-inflammatory activity, 501–502

gastric alterations, 503–504

immunological effects, 504

neuropharmacological activity, 503

wound healing assay, 502

Averrhoa carambola L, 329

bioactives, 331–335

pharmacology

analgesic activity, 340–341

anthelmintic activity, 340

antibacterial activity, 336

anticancer activity, 339

antidiabetic activity, 337

antidiarrhoeal activity, 340

antidotal activity, 337

antifungal activity, 336

anti-inflammatory activity, 340

antineoplastic activity, 338–339

antioxidant activity, 338

antiulcer activity, 341

antiulcerogenic activity, 341

convulsant activity, 341

Index cytotoxic activity, 339

DNA cleavage activity, 338

hepatoprotective activity, 340

Avicennia marina (Forssk.), 375

bioactives, 376

alkaloids, 379

fatty acids, 379–380

flavones, 377

flavonoids, 378

naphthalene derivatives, 377

terpenoids and steroids, 376–377

glucosides

abietane diterpenoid, 378

iridoid, 377–378

phenylpropanoid, 378

pharmacology

antiandrogenic activity, 383

anticancer activity, 382–383

anticandidal activity, 381

antiglycation/antidiabetic activity, 383

anti-inflammatory activity, 381

antimicrobial activity, 381

antiplasmodial/antimalarial activity,

382

antiviral activity, 382

mosquitocidal activity, 382

toxicity, 383

in vitro phototoxicity, 383

B Betula utilis bioactives, 388

essential oils, 390

phenolics and flavonoids, 390–391

triterpenoids, 389

pharmacology

antibacterial activity, 391–392

anticancer activity, 394–395

antifungal activity, 392

antihyperglycemic effect, 393

antiinflammatory activity, 395–396

antimalarial activity, 394

antiobesity potential, 393

antioxidant efficacy, 392

antiurolithiatic activity, 394

antiviral activity, 391

hepatoprotective activity, 393

Index

525

C Chandramulika. See Kaempferia galanga L

Clusia nemorosa G.

bioactives, 432

chromatographic analyses, 433

phytochemical prospection, 433

pharmacology

anti-inflammatory activity, 435

antimicrobial effect, 435

antinociceptive activity, 435

Cocos nucifera L.

coconut pulp, 510

coconut water, 509

flowers, 510

Lehyam, 509

pharmacological studies

analgesic activity, 513

anticancer activity, 515

antidiabetic activity, 514–515

antihyperlipidemic activity, 514

anti-inflammatory activity, 512–513

antimicrobial activity, 516

antioxidant activity, 512

antiparasitic activity, 516–517

cardioprotective activity, 513–514

hepatoprotective activity, 512

immunomodulatory activity, 515

nephroprotective activity, 515

neuroprotective activity, 515

toxicity studies, 517

wound healing activity, 516

phytochemical constituents

coconut oil, 510

palmitic acid, 510

stearic acid, 510

tender coconut water, 511

tropical countries, 509

Cycas beddomei dyer, 155–156

bioactives, 157–159

pharmacological uses

acute toxicity, 161

analgesic activity, 161

anthelmintic activity, 162

antibacterial activity, 159–160

anti-inflammatory activity, 162–163

antioxidant activity, 160–161

antiulcer activity, 162

hepatoprotective effects, 160

Cynodon dactylon (L.)

bioactives, 254

pharmacology, 254–256

acetylcholinesterase activity, 260–261

analgesic activity, 261

anthelmintic activity, 261

anticancer activity, 258

anticonvulsant property, 258

antidiarrheal activity, 262

antifertility activity, 256

antihyperlipedemic activity, 263

anti-inflammatory activity, 263

antimicrobial activity, 262

antinephrolithiasis property, 259

antioxidant activity, 256, 260–261

antipyretic activity, 261

bronchodilatory activity, 256–257

CNS activity, 263–264

diabetic retinopathy, protective effect,

260

diuretic activity, 259

hepatoprotective activity, 257–258

hypoglycemic activity, 258–259

mmunomodulatory activity, 259–260

right-heart failure, effect, 262

white spot syndrome virus (WSSV), 261

zebra fish embryo, effect, 260

zinc oxide nanoparticles, green

synthesis, 264

D 2,4-Dinitrophenyl butyrate (DNPB), 483

Diploclisia glaucescens (Blume), 289

bioactives, 290–291

pharmacology

antibacterial activity, 291

anti-inflammatory activity, 291–293

cure skin diseases, 293

insecticidal activity, 293

molluscicidal activity, 293

relieve sprain, 293

spermicidal activity, 293

E Ecbolium viride (Forssk.), 315

bioactives, 316–318

pharmacology

analgesic activity, 324

526 antibacterial activity, 318–319

antidiarrhoeal activity, 323

antifungal activity, 319

anti-inflammatory activity, 321

antimicrobial activity, 319–320

anti-plasmodial activity, 323

anti-trypanosomal activity, 323

cytotoxic activity, 321

free radical scavenging activity, 320

hepatoprotective activity, 321–322

larvicidal and pupicidal activities, 324

Eclipta prostrata (L.), 440

pharmacological studies

analgesic activities, 445

anticancer activity, 447–448

antidiabetic activity, 447

antifibrotic activity, 449

antihyperlipidemic activity, 446

anti-inflammatory, 445

antimicrobial activity, 449

antioxidant activity, 444

antivenom activity, 448

hair growth promoting activity, 450

hepatoprotective activity, 444–445

nephroprotective activity, 450

neuroprotective activity, 447

osteoprotective activity, 446–447

toxicity study, 450

wound healing activity, 449

phytochemical constituents, 441–442

Embelia ribes, 347

active principal compound, 349

embelin and derivatives, pharmacology

acetylcholinesterase activity, 355

analgesic activity, 350

anthelmintic activity, 356

antibacterial activity, 355–356

antidiabetic activity, 350

antifertility activity, 355

antihyperglycemic activity, 351

antioxidant activity, 354

antitumor activity, 352–354

cardioprotective activity, 351

hepatoprotective activity, 352

HPLC analysis, 357

lipid peroxidation, 356–357

neuroprotective activity, 351–352

toxicity studies, 356

wound healing activity, 354–355

Index phytochemistry, 348–349 Ephedra alata bioactives

flavonoids, 459

hydrodistillated essential oil, 460

methanolic extract, 459

phytochemical analyses, 458

essential oil composition, 464

fatty acids, 463

lignan and alkaloids, 463

pharmacology

aflatoxin inhibitory activity, 471

analgesic activity, 470

antibacterial activity, 467–468

anticancer activity, 468–469

antidiabetic activity, 471

antifungal activity, 468

antihypertensive activity, 466

anti-inflammatory activity, 470

antioxidant activity, 464–466

antipesticidal activity, 466

antiviral activity, 468

cytostatic activity, 470

diuretic activity, 469

and hepatotoxicity, 471–472

hypolipidaemic activity, 469–470

nephrotoxicity, 471–472

wound and burn healing activity, 468

phenolics and flavonoids, 462

Ephedra sinica Stapf

bioactive compounds, 481

bioactives, 478–480

pharmacology

analgesic activity, 485–486

antiangiogenic activity, 483–484

anticancer activity, 484

anticomplement activity, 485

anti-invasive activity, 484

antilipase activity, 482–483

antimicrobial activity, 485

antineuroinflamantory property, 483

antioxidant activity, 482

antiviral activity, 484

cytotoxic activity, 482

2,4-Dinitrophenyl butyrate (DNPB), 483

melanogenesis, 485

neuroprotective effect, 483

potent metabolites, 480

Index

527

G Garcinia mangostana, 139–140

bioactive compounds, 140–141

chemical structures of xanthones, 141

pharmacology

anticancer effects, 145–146

antiinflammatory properties, 144

antimicrobial effects, 147–148

antioxidant properties, 141–144

effects against diabetes, 146–147

mitochondrial effect, 145

cytotoxicity, 50

larvicidal activity, 48

wound healing properties, 44

K

Kaempferia galanga L., 77–78 pharmacology

amoebicidal activity, 80

analgesic activity, 80

and anticancer activity, 81

antidengue effect, 80

anti-inflammatory activity, 80

antimicrobial activity, 79

H antinociceptive efficacy, 81

Hedychium spicatum, 53–54

antioxidant activity, 80

bioactives, 54–57

antithrombotic effect, 81

pharmacology

antituberculosis activity, 81

analgesic activity, 68

chemo-preventive, 81

anthelmintic properties, 71

hypolipidemic activity, 81

antiasthmatic and antiallergic activities,

hypopigmentary effect, 82

66–67

larvicidal activity, 82

antibacterial and antifungal activities, 66

nematocidal activity, 82

anticancer and cytotoxic activities, 57–62

osteolysis inhibitory effect, 82

antihyperglycemic activity, 68

sedative effects, 82–83

anti-inflammatory effect, 69

vasorelaxant efficiency, 83

antimalarial potential, 70

wound healing activity, 83

antioxidant and radical scavenging

potential, 62

blood pressure lowering activity, 67

hair growth promoting activity, 70

hepatoprotective activity, 67–68

and memory restorative activity, 69

nootropic effects, 69

pediculicidal activity, 70–71

properties, 63–65

toxicity, 69

tranquillizing activity, 69–70

ulcer protective activity, 70

phytochemical constituents, 56

traditional uses, 55

Hydnocarpus, 41–43

bioactives, 41–43

pharmacology

antihyperlipidemic efficacy, 48

anti-inflammatory activity, 49–50

antimicrobial effects, 46

antioxidant activity, 49

chaulmoogric acid structure, 45

M Memcylon lushingtonii pharmacology

antimicrobial activity, 34

antioxidant activity, 34

postcoital contraceptive efficacy, 34

Memecylon jadhavii, 27

nomenclature status, 24

pharmacology, hepatoprotective activity,

36

sessile benth, 26

uses, 24

wightii, 26

Memecylon lawsonii pharmacology

antimicrobial activity, 34

antioxidant activity, 34

Memecylon lushingtonii bioactives, 29

gamble, 25–26

528 Memecylon sessile bioactives, 29

pharmacology

antimicrobial activity, 35

antioxidant activity, 35

Memecylon sisparense gamble, 24–25

bioactives, 27–28

pharmacology

antimicrobial activity, 31

antioxidant and cardioprotective

activity, 30

nephroprotective activity, 30

Memecylon subramanii bioactives, 30

pharmacology

antimicrobial activity, 36

antioxidant activity, 36

Memecylon Subramanii, 27

Memecylon talbotianum, 25

bioactives, 28–29

pharmacology

antidiabetic activity, 31

antifungal activity, 33

anti-inflammatory properties, 31–32

antimicrobial activity, 33

antioxidant properties, 32

Memecylon wightii bioactives, 29

pharmacology

antimicrobial activity, 35

antioxidant activity, 35

Musanga cecropioides bioactives, 402–404 pharmacology

adaptogenic effect, 412

α-amylase inhibitory activities, 413

analgesic activity, 410

angiotensin converting enzyme, 411

antibacterial activity, 404–405

antidiabetic effects, 409

antidiarrheal activity, 412

antifungal activity, 405

antihypertensive effect, 410

anti-inflammatory activity, 411

antinociceptive activity, 413

antioxidant efficacy, 406

antiprotozoal activity, 412

Index aorta contraction, 410

cytotoxic activity, 411

diuretic effects, 413

gastrointestinal motility, 409

α-glucosidase, 413

hepatoprotective activity, 406

hypoglycemic effects, 408–409

hypotensive activity, 407

oxytocic effects, 409

serum lipids, 412

toxicity effects, 407–408

vasodilating properties, 410–411

wound healing activity, 412

Musk Willow. See Salix aegyptiaca L. Mussaenda macrophylla Wall, 205

bioactives, 206–208

pharmacology

antidiabetic activity, 210

antihaemolytic activity, 210

antimicrobial activity, 209–210

antioxidant activity, 208–209

lipid peroxidation inhibition, 210

membrane stabilizing activity, 210–211

N Nymphaea pubescens, 99–100 bioactivities antibacterial and antifungal activity, 102–103

anticancer activity, 104

antihyperglycaemic, 104–105

antihyperlipidemic effect, 104–105

antioxidant activity, 103

cardioprotective activity, 105

hepatoprotective activity, 103

neuroprotective activity, 105

phytochemistry, 100–102

P Phyla nodiflora (L.), 109–110 bioactives, 110–112

quantitative analysis, 111

structures with functional groups, 113

pharmacology

antidandruff activity, 119

antidiabetic effect, 117–118

antidiarrhoeal activity, 120

Index

529

antidiuretic activity, 116

and antihyperuricemic effect, 116

anti-inflammatory potential, 116–117

antimelanogenesis properties, 120

antimicrobial activity, 113–114

antitumor activity, 115–116

antiurolithiatic activity, 117

blood clotting, effect on, 118

hair growth, effect on, 119

hepatoprotective activity, 118–119

hepatoprotective and antioxidant

properties, 115

hypoxaemia effect, 119

neuropharmacological profile, 118,

119–120 Pittosporum napaulense (DC.), 229

bioactives, 231–234

pharmacological studies

acute and sub-acute toxicity, 235–236

antiarthritic, 236–237

anti-inflammatory activity, 236

antimicrobial activity, 234–235

neuropharmacological and behavioral

activity, 236

R Rhus mysorensis bioactives, 490

pharmacology

anthelminthic activity, 493

anthine oxidase inhibitory activity, 493

anti urolithiatic activity, 492

antialzheimer activity, 493

antibacterial activity, 490

antidiabetic activity, 493

antifungal activity, 492

anti-inflammatory activity, 493

antioxidant efficacy, 492

hepatoprotective activity, 492

neuroprotective activity, 492

S S. travancoricum, 213

bioactives, 218–220

pharmacology

antibacterial activity, 221

antioxidant activity, 224

Salix aegyptiaca L.

bioactives, 3–4

chemical structures of eugenol, 4

pharmacology

anticarcinogenic effect, 7–8

antifibrillation therapeutic drug effect,

8

and anti-inflammatory characteristics,

4–5

antinociceptive, 4–5

antinociceptive effect, 7

antioxidant property, 5–6

anxiolytic property, 6–7

flavoring agent, 8

hypercholesterolemia effect, 7

Salvadora persica, 11–12 bioactives, 12–14 pharmacology analgesic and anti-inflammatory activity, 16

anthelmintic activity, 17

anticonvulsant activity, 17

antidiabetic activity, 17–18

antifertility activity, 17

antimicrobial activity, 14–15

antioxidant activity, 16

antiplasmodial activity, 18

antiulcer activity, 17

cytotoxic activity, 18

dental plaque inhibiting activity, 15

diuretic activity, 16

oral health, 15

wound healing activity, 16

Syzygium densiflorum, 213

bioactives, 215–218

pharmacology

antibacterial activity, 220

anticancer activity, 222

antidiabetic activity, 222–223

antifungal activity, 222

antihyperlipidemic activity, 222–223

antioxidant activity, 223–224

T Tamarix aphylla (L.), 365

bioactives, 366–369

pharmacological

antibacterial activity, 369–370

530 anticancer activity, 371–372 anti-diabetic and hypolipedemic activity, 371

antifungal activity, 370

anti-inflammatory activity, 372–373

antioxidant activity, 370–371

antipyretic activity, 372–373

wound healing effect, 372–373

Terminalia pallida, 87–88

bioactive compounds, 88–89

pharmacological activities

analgesic activity, 93

antiadipogenic activity, 94

antibacterial activity, 90

antidiabetic activity, 94–95

antifungal activity, 90–91

antihyperlipidemic activity, 93

Index antipyretic effect, 92

antiulcer activity, 93

atherosclerosis activity, 94

cardioprotective effect, 91–92

hepatoprotective effect, 92

thrombolytic activity, 94

W White spot syndrome virus (WSSV), 261

Z Zebra fish embryo

effect, 260

Zinc oxide

nanoparticles, green synthesis, 264