Ethnobotany: Ethnopharmacology to Bioactive Compounds 9781032348148, 9781032348155, 9781003323969

Table of contents :
Cover
Title
Copyright
Preface
Contents
1. Taking Advantage of the Therapeutic/Nutritional Properties of Some Medicinal Plants for Use in Animal Feed
2. Resveratrol: Perspectives from Ethnobotanical uses to Health Applications
3. Coffee and Folk Medicine: Mechanisms and Activities
4. Use of Antidiabetic Medicinal Plants with Ethnomedicinal Information in Clinical Trials: Focus on Bioactive Compounds
5. Phytolaccaceae and Petiveriaceae Ethnobotany and Phytochemistry
6. Beyond Phytochemistry: Comparative Ethnobotany among Oneirogenic Alkaloid Containing Tabernaemontana species from Mexico and the Amazon and the African shrub Tabernanthe iboga (Apocynaceae)
7. Phytochemistry and Bioactivity from Huperzias, used by Healers from Saraguro Community, in the Southern Ecuadorian Andes
8. The Genus Alepidea: A Review of its Medicinal Uses, Phytochemistry and Pharmacological Activities
9. Genus Salvia: Its Secondary Metabolites and Roles in the Treatment of Common Cancer Types in Men and Women
10. Molecular Basis of Ethnobotany and the Quest for Flavonoids: An Analytical Journey
Index

Citation preview

Ethnobotany

Ethnopharmacology to Bioactive

Compounds

Editors

José L. Martinez

Vicerrectory of Research, Development and Innovation

Universidad de Santiago de Chile

Santiago, Chile

Alfred Maroyi

Department of Botany, University of Fort Hare

Alice, South Africa

Marcelo L. Wagner

Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires

Buenos Aires, Argentina

p, p,

A SCIENCE PUBLISHERS BOOK A SCIENCE PUBLISHERS BOOK

Cover credit:

Cover photograph reproduced by permission of Ignacio J. Agudelo, University of Buenos Aires,

Argentina.

First edition published 2023 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2023 José L. Martinez, Alfred Maroyi and Marcelo L. Wagner CRC Press is an imprint of Taylor & Francis Group, LLC Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors 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 of Congress Cataloging‑in‑Publication Data (applied for)

ISBN: 978-1-032-34814-8 (hbk) ISBN: 978-1-032-34815-5 (pbk) ISBN: 978-1-003-32396-9 (ebk) DOI: 10.1201/9781003323969 Typeset in Times New Roman by Radiant Productions

Preface

The development of natural products as pharmaceutical drugs and health products has been established on the basis of therapeutic properties of traditional medicines. Traditional medicines represent an important source of multi target therapeutics involving bioactive compounds contained in plant extracts. These bioactive compounds are responsible for biological activities associated with plant species used as traditional medicines. The multiple bioactive compounds usually have additive, antagonistic and synergistic effects. Currently, the screening of natural products such as medicinal plants has become an effective method for rapid selection of bioactive compounds with effective biological activities. Therefore, phytochemical research based on ethnopharmacology is considered an effective approach in the discovery of novel bioactive compounds with potential as drug leads and development process. Plant extracts used in indigenous pharmacopoeia of many cultures for treating several human and animal diseases represent a source of bioactive compounds required in the pharmaceutical drug discovery process. The therapeutic properties of bioactive compounds of medicinal plants still continue to be the subject of many researches throughout the world. Hence, in this book, an ethnobotanical review based on ethnopharmacology as an effective approach in the discovery of novel bioactive compounds is presented. The chapters are written by specialists from different countries with Chapter 1 focusing on therapeutic and nutritional properties of some medicinal plants for use as animal feed. Chapters 2 to 4 focus on ethnobotanical uses, health applications, mechanisms of action, biological activities and clinical trials of resveratrol, coffee and antidiabetic medicinal plants. Chapters 5 to 9 present the ethnobotany, phytochemistry and pharmacological activities of crude extracts or bioactive compounds isolated from members of the plant families Phytolaccaceae and Petiveriaceae, and species of the genera such as Tabernaemontana, Tabernanthe, Huperzia, Alepidea and Salvia. Chapter 10 deals with the molecular basis of the bioactive compound flavonoid from the perspective of modern phytochemistry. This book, therefore, is an important addition to the pharmaceutical literature as a single reference covering these essential aspects of ethnobotany focusing on the ethnopharmacological approach and the importance of bioactive compounds as potential pharmaceutical drug leads José L. Martinez, Chile Alfred Maroyi, South Africa Marcelo L. Wagner, Argentina

Contents

Preface 1. Taking Advantage of the Therapeutic/Nutritional Properties of Some Medicinal Plants for Use in Animal Feed Amner Muñoz‑Acevedo, Cindy P. Guzmán, Nubellys M. Peralta, María C. González and Martha Cervantes‑Díaz 2. Resveratrol: Perspectives from Ethnobotanical uses to Health Applications José L. Martinez, Onder Yumrutas, Maite Rodriguez, Miguel Rios, Rao Zahid Abbas, Luisauris Jaimes and Ali Parlar

iii 1

44

3. Coffee and Folk Medicine: Mechanisms and Activities 65 Filipe Kayodè Felisberto dos Santos, Ian Gardel Carvalho Barcellos Silva, Arquimedes Lopes Nunes Filho and Valdir Florêncio da Veiga Júnior 4. Use of Antidiabetic Medicinal Plants with Ethnomedicinal Information in Clinical Trials: Focus on Bioactive Compounds Anuar Salazar‑Gómez, Candy Carranza‑Álvarez, Fabiola Domínguez and Angel Josabad Alonso‑Castro

81

5. Phytolaccaceae and Petiveriaceae Ethnobotany and Phytochemistry Zilda Cristiani Gazim, Evellyn Claudia Wietzikoski Lovato,

Bárbara de Souza Arcanjo, Maria Graciela Iecher Faria Nunes,

Suelen Pereira Ruiz Herrig, Ana Daniela Lopes,

Carla Maria Mariano Fernandez, Giani Andrea Linde Colauto,

Nelson Barros Colauto and Juliana Silveira do Valle

101

6. Beyond Phytochemistry: Comparative Ethnobotany among Oneirogenic Alkaloid Containing Tabernaemontana species from Mexico and the Amazon and the African shrub Tabernanthe iboga (Apocynaceae) Felix Krengel, Ricardo Reyes‑Chilpa, Karla Paola García‑Cruz,

Olga Lucia Sanabria‑Diago, Willian Castillo‑Ordoñez and

Laura Cortés‑Zárraga

133

vi Ethnobotany: Ethnopharmacology to Bioactive Compounds 7. Phytochemistry and Bioactivity from Huperzias, used by Healers from Saraguro Community, in the Southern Ecuadorian Andes María‑Elena Cazar, Chabaco Armijos and Omar Malagón Avilés

159

8. The Genus Alepidea: A Review of its Medicinal Uses, Phytochemistry and Pharmacological Activities Alfred Maroyi, Ruvimbo Jessy Mapaya, Ahmad Cheikhyoussef and Natascha Cheikhyoussef

167

9. Genus Salvia: Its Secondary Metabolites and Roles in the Treatment of Common Cancer Types in Men and Women Onder Yumrutas, José L. Martinez, Ali Parlar, Bernardo Morales, Pınar Yumrutas and Luisauris Jaimes

191

10. Molecular Basis of Ethnobotany and the Quest for Flavonoids: An Analytical Journey Cecilia B. Dobrecky, Marcelo L. Wagner, Pablo A. Evelson and Silvia E. Lucangioli

216

Index

239

Chapter 1

Taking Advantage of the Therapeutic/Nutritional Properties of Some Medicinal Plants for Use in Animal Feed Amner Muñoz-Acevedo,1,* Cindy P. Guzmán,1 Nubellys M. Peralta,1 María C. González1 and Martha Cervantes-Díaz2

Introduction The Farm Management and Production Economics Service of the FAO Department of Agriculture is raising awareness of the role of wild/medicinal plants in many developing countries in which the population bases its economy on agroforestry practices/systems (combining agriculture and livestock, e.g., agrosilvipastoralism). In those cases where the rural population of these countries depends to some extent on livestock (it is considered as a source for social security and food) for their livelihood, ca. 30–35% of losses occur in the animal husbandry sectors due to lack of good sanitary/hygienic (diseases) and food/nutritional practices, as well as environmental conditions (food shortage and lack of water resources) (Castañeda Sifuentes et al. 2014, Maurer and Schueckler 1999, Quansah and Makkar 2012, Russo et al. 2009). Some of those wild plants from agropastoral farm households, in addition to being used as medicine and food for humans, are also used as forage/fodder (growth promoters) and medicine for animals (ethnoveterinary); and from the applications

Departamento de Química y Biología, Universidad del Norte, Barranquilla, Colombia. Grupo Investigaciones Ambientales para el Desarrollo Sostenible, Facultad de Química Ambiental, Universidad Santo Tomás, Bucaramanga, Colombia. * Corresponding author: [email protected]

1 2

2

Ethnobotany: Ethnopharmacology to Bioactive Compounds

mentioned above, these have helped partly to solve the problem, reaching an importance during the last decade, due to the discovery of some effective products that are a cheaper, easier, and more sustainable alternative to synthetic drugs (Khan et al. 2021, Konsala et al. 2013, Maurer and Schueckler 1999, Russo et al. 2009, Tipu et al. 2006). Consequently, the use of the resources and the biodiversity of the countries has made it possible to find some plants that, based on their chemical compositions, could be used as available/suitable sources of food (for man/animals) providing the basic nutritional requirements, as well as being useful to alleviate/protect/prevent ailments/ diseases; these plants could act as growth and health promoters (de Medeiros et al. 2021, Hashemi and Davoodi 2011, Lachat et al. 2018). Further than that, a variety of these herbs/spices/medicinal plants are generally recognized as safe (GRAS) and could be suitable substitutes (natural origin) for chemical additives (synthetic origin) in food due to the broad biological properties (e.g., bactericidal/antifungal, antiviral, anti-inflammatory, antiparasitic, immunostimulant, and preservative/antioxidant for food), which is advantageous for those plants that can be used as food for both humans and animals because they would act as nutraceuticals (Duke 2001, FDA 2020, Nieto 2020, Tipu et al. 2006, Shikov et al. 2017). On the other hand, medicinal food plants are defined as those food plants whose consumed parts have therapeutic properties based on traditional medicine. In this concept, it should be clarified that such foods not only serve to satisfy hunger and provide essential macro-/micro-nutrients to the body, but also supply bioactive ingredients that help reduce nutrition-related diseases and other ailments that ensure physical well-being; the medicinal foods are consumed as part of the normal eating pattern. Therefore, this type of food would cover both nutritional and health care aspects, if they were used as animal feed (Awuchi 2019, Ramalingum and Fawzi Mahomoodally 2014, Rivera et al. 2005, Xu et al. 2020). If the review by Mayer et al. (2014) on the treatment of European organic livestock (e.g., cattle, equine, pigs, poultry, rabbits) with medicinal plants as ethno­ veterinary medicine is taken into account, the species belonging to the Asteraceae, Fabaceae, and Lamiaceae families were the most important; some of these species (e.g., Malva sylvestris, Urtica dioica, Olea europeae, Sambucus nigra) could be used as antiparasitic and against gastrointestinal and dermatological disorders, as well as immunostimulatory agents, and less consistent as treatments for illness of the genital and respiratory tracts. Finally, some examples of types of plants are Artocarpus altilis (fruits/leaves/ seeds), Azadirachta indica (whole plant), Manihot esculenta (leaves/roots), Prosopis juliflora (fruits/leaves), which contained carbohydrates, proteins, fibers, and fat, along with terpenoid, phenolic, flavonoid, and glycoside compounds; these chemical components confer certain therapeutic properties or antinutritional factors to those plants that would help or not to maintain the animal health.

Nutritional Benefits of Medicinal Plants Used for Animal Feed 3

Mining Text In order to analyze and understand the scientific dynamic related to the nutritional and therapeutic properties of some medicinal plants used for animal feed, the following search equation was structured: (TITLE-ABS-KEY (“medicinal plant*” OR “Prosopis juliflora” OR “Azadirachta indica” OR “Manihot esculenta” OR “Artocarpus altilis”) AND TITLE-ABS-KEY (“Therapeutic propert*” OR “nutritional propert*” OR “animal feed”)) AND DOCTYPE (ar) AND PUBYEAR > 2000). According to this search 695 articles indexed in the Scopus database (Elsevier, BV, 2021) were obtained. Then, the data were processed using VantagePoint text mining software (academic version 12, Search Technology). Figure 1 Displays the distribution of the number of scientific articles per year (2000–2020 timeline) related to the subject under study. As a result, an exponential growing trend could be seen during this period of time, where 2020 was the year with the highest scientific activity (79 records); nonetheless, there was a drastic decrease in the number of articles published in 2017. Lastly, so far in 2021, 45 articles have already been listed in the Scopus database. In addition, the data analysis by De Solla Price´s Law (De Solla Price 1963) showed that the growth rate (percentage value per year) of publications associated to this topic was 19.17%/year. Additionally, the main areas of knowledge, in which the published articles on the nutritional/therapeutic properties of medicinal plants used as animal feed fit, were agricultural and biological sciences (339 registers), pharmacology, toxicology and pharmaceutics (193 registers), biochemistry, genetics and molecular biology (154 registers), medicine (132 registers) and veterinary (99 registers), among others. If the major scientific journals of dissemination on the theme of interest are considered, they were: Tropical Animal Health and Production (46 records), Journal 90 80

1000 800

y = 24.165e0.1764x R² = 0.9676

600

Number of records

70 60 50

400 200 0

0

5

10

15

20

40 30 20 10 0

Series1

2000 12

2001 15

2002 7

2003 6

2004 13

2005 14

2006 13

2007 10

2008 18

2009 24

2010 29

2011 40

2012 40

2013 44

2014 47

2015 48

2016 67

2017 32

2018 42

2019 58

2020 82

Figure 1. Source: Bibliometry Unit-CRAI Library, Universidad Santo Tomás (Bucaramanga).

Calculations according to the Scopus information (Elsevier, B.V., 2021) processed with VantagePoint software (version 12.0, Search Technology).

4

Ethnobotany: Ethnopharmacology to Bioactive Compounds

of Animal Physiology and Animal Nutrition/Journal of Ethnopharmacology (each with 20 records), Fish and Shellfish Immunology (19 records), Journal of Animal Science (13 records), Industrial Crops and Products (eight records), etc. As a final point, the countries with the highest contributions to this kind of research based on number of articles were: India (128 registers), Brazil (76 registers), China (48 registers), United States (43 registers) and Iran (38 registers), inter alia. While in Latin America, the outstanding countries were: Mexico (20 registers), Colombia (six registers), Argentina/Peru (each with five registers).

Some Medicinal Plants with Therapeutic and Nutritional Properties used for Animal Feed In the current chapter, four medicinal plants have been included, which are or could be used for animal feed, according to their therapeutic and nutritional properties. These plants are Artocarpus altilis, Azadirachta indica, Manihot esculenta, and Prosopis juliflora. The description of each plant (or some parts) will be based on its ethnobotanical use, chemical constituents, bromatological information, biological/ pharmacological properties, and application (feed). Artocarpus altilis (Parkinson) Fosberg (A. camansi Blanco, A. communis Forst. & Forst.f., Radermachia incisa Thunb., Sitodium altile Parkins). The breadfruit tree (preferred common name) belongs to the Moraceae family and it is native to Malaysia, Papua New Guinea, and Philippines (Pacific Islands); it is widespread in the tropical/ subtropical regions (Africa, Caribbean, Central and South America, India, etc.) of the world. Its vernacular names are: árbol de pan, artocarpo, broodboom, chataignier, fruta pão, kapiak, khanun, kulur, marure, mazapan, mei, mian bao shu, paparahua, rimas, sa ke, sukun. The trees are up to 20 m long, fast growing, require little care, thrive in a wide range of ecological conditions (from near sea-level to 1,550 m, 15–40ºC, rainfall 1,000–3,500 mm, 70–80% of humidity), and begin to bear fruit (2–3 times/year) in 3–6 years. This tree (with a milky latex found in all its parts) has multiple uses, mainly its nutritious, starchy, and fragrant fruit (weighing up to 1–4 kg), which is globose/ovoid to cylindrical (up to 29 cm long and up to 20 cm wide) (Badrie and Broomes 2010, Jagtap and Bapat 2010, Lim 2012, LuzuriagaQuichimbo et al. 2019, Quattrocchi 2012, Ragone 1997, 2006, 2018). This plant and particularly its fruits have been used as a staple food and traditional crop in the Pacific islands for centuries, but also (fruits, leaves, latex, flowers, seeds, bark, roots), in the ethnomedicine to mitigate diabetes, prevent hunger, and treat headaches, toothaches, ulcers, sprains/fractures/dislocations, hernias, burns, wounds, anemia, diarrhea, mycosis, ear/urinary/venereal infections, dysentery, malaria, mumps, beri-beri, hypertension, asthma, obesity (fat-burning), rheumatism, cirrhosis, tumors/wars/furuncles, insect bites and as a repellent; as well as sedative, emollient, tonic, digestive, diuretic, stimulant. The biological activities determined for their extracts and isolated compounds have been as anticancer/cytotoxic, antioxidant/antiradical, anti-inflammatory, antiplatelet, antiatherosclerotic, antiviral, antiparasitic, antinephritic, angiotensin-converting enzyme inhibitor/hypotensive, UVB skin protection, antitubercular/antimicrobial, repellent/insecticide agents. Additionally, plant leaves and fruits have been used as animal fodder (Akanni et al.

Nutritional Benefits of Medicinal Plants Used for Animal Feed 5

2014, Arung et al. 2009, Boonphong et al. 2007, Badrie and Broomes 2010, Calzavara 1987, Campos Florián 2013, Eccles et al. 2019, Gonçalves et al. 2020, Huaranca Acostupa et al. 2013, Jagtap and Bapat 2010, Jalal et al. 2015, Jamil et al. 2018, Jones et al. 2012, Lan et al. 2013, Lim 2012, Luzuriaga-Quichimbo et al. 2019, Liyanaarachchia et al. 2018, Medina-Larico 2018, Medina-Medina 2014, Mejia and Rengifo 2000, Molina-Ayme 2011, Mozef et al. 2015, Nwokocha et al. 2012, Pradhan et al. 2012, Ragone 1997, Ren et al. 2019, Saad et al. 2021, Sari et al. 2020, Siddesha et al. 2011, Sikarwar et al. 2014, Simanjuntak and Gurning 2020, Soifoini et al. 2021, Turi et al. 2015, Vianney et al. 2020, Wang et al. 2006). The nutritive/chemical constituents of edible fruit (from immature to very ripe) vary widely: the main components are starch [> 50% (skin: 47.6 ± 0.2–62.79 ± 0.09%, stem/heart: 40.6 ± 0.4–63.4 ± 0.2%, pulp: 42.6 ± 0.7–71.23 ± 0.03%) of total carbohydrates (skin: 64.3 ± 0.7–73.6 ± 0.6%, stem/heart: 50.03 ± 0.09–80.7 ± 0.9%, pulp: 71.0 ± 0.8–86 ± 1%)], minerals [Fe (40.4 ± 0.9–80 ± 2 µg/g), Na (36.9 ± 0.3–86 ± 3 µg/g), Mn (4.8 ± 0.3–22.4 ± 0.5 µg/g), K (1.13 ± 0.05–2.8 ± 0.5%)], vitamins [niacin (2.3–4.4 mg)/riboflavin (0.2–0.4 mg)/ascorbic acid (3.6–22.7 mg)], proteins (skin: 4.65 ± 0.01–5.9 ± 0.1%, stem/heart: 6.04 ± 0.03–7.68 ± 0.01%, pulp: 3.85 ± 0.02–4.12 ± 0.01%), crude fats (skin: 2.33 ± 0.01–3.92 ± 0.04%, stem/heart: 1.61 ± 0.06–4.4 ± 0.1%, pulp: 1.14 ± 0.07–2.56 ± 0.06%). In addition, the nutrients and chemical constituents of A. altilis seeds are: carbohydrates (26.1 ± 0.1–72.66 ± 0.01%), crude protein (4.9 ± 0.5–19.96 ± 0.02%), energy (1650 ± 85 kJ/100 g), fatty acids (1.55 ± 0.01–12.79 ± 0.05%), vitamins [ascorbic acid (19 ± 2 ppm), pyridoxine (4 ± 1 ppm), thiamine (3.5 ± 0.8 ppm)] and minerals [K (3.250 ± 0.001–9 ± 2 mg/g), Ca (1.850 ± 0.004–2.90 ± 0.03 mg/g)]. Whilst the representative lipids are: fatty acids [oleic (12–57%), linoleic (26–30%), palmitic (11–21%), stearic (17–18%) and linolenic (15%) acids], phospholipids [phosphatidylserine (205 mg/100 g), phosphatidylcholine (195 mg/100 g), phosphatidylinositol (60 mg/100 g)] and sterols [sitosterol (91%), stigmasterol (5%), campesterol (4%)] (Adekele and Abiodun 2010, Achinewhu and Akpapunam 1985, Aremu et al. 2017, Jagtap and Bapat 2010, Lim 2012, Obasuyi and Nwokoro 2006, Quijano and Arango 1979, Tukura and Obliva 2015, Valencia et al. 2010). More than 130 compounds have been isolated from the different parts of tree, and according to this the main active compounds are flavonoids [e.g., cudraflavones A-C (1), isocyclomulberrin/cyclomulberrin, chaplashin (2), artoindonesianins B (3)-C/V, hydroxiartoflavone A/artoflavone A, sophoraflavone A, morusin (4), isocyclomorusin/ cyclomorusin, artonins E (5)-F/M/P, cyclocommunol, morin, cycloaltilisin 7 (6), cycloartobiloxanthone, artobiloxanthone, isocycloartobiloxanthone (7), hydroxiartocarpin, artocarpetin, artocarpin (8), norartocarpetin (9), cyclochampedol, artogomezianone, cycloartocarpin A (10), altilisin H-J (11/12), apigenin, tangeretin, nobiletin], xanthones [artonol B (13)], chalcones (broussochalcone A, geranyl dihydrochalcones, retrodihydrochalcone, cycloaltilisin 5), stilbenes [oxyresveratrol (14), artoindonesianin F (15)], terpenoids [cycloartenol (16), ursolic acid, β-sitosterol, β-amyrin, cycloart-23-ene-3β,25-diol/ cycloart-25-ene-3β,24-diol], arylbenzofurans (kazinol A, moracin M (17), artoindonesianin B-1), phenolics (curcumin, desmethoxycurcumin, o-methyldehydrodieugenol, dehydrodieugenol, p-coumaric

6

Ethnobotany: Ethnopharmacology to Bioactive Compounds OH

OH HO

HO

O

O

O O

OH OH

O

OH

O (2) - R: -OH (3) - R: OOH

(1) HO O

O

OH

HO

OH

O

HO

O O (11) - R: -H (12) - R: OCH3

O

OH HO

O

OH

O O

O

O

OH

O

O OH

O

O (10) OH

OH O

HO

HO

O R

OH O

(9)

HO

O (6)

O

(8)

OH

OH

HO

O OH

OH O

O

R

(4) - R: --H (5) - R: OH

O

O

(7)

O

OH

R

OH

O

O

R

OH

O (13)

OH (14) - R: -H (15) - R: -CH=CHCH(CH3)2

HO

OH (16)

(17)

acid, vanillin/vanillic acid), and lectins (jacalin, frutalin, frutackin, lectin) (Altman and Zito 1976, Amarasinghe et al. 2008, Boonphong et al. 2007, Chan et al. 2018, Chen et al. 1993, Hakim et al. 2020, Huong et al. 2012, Lan et al. 2013, Lim 2012, Luzuriaga-Quichimbo et al. 2019, Mai et al. 2012, Nguyen et al. 2012, Patil et al. 2002, Shamaun et al. 2010, Sikarwar et al. 2014, Syah et al. 2006, Wang et al. 2006, 2007). In spite of all the nutritional and medicinal benefits attributed to this plant, it contains some antinutritional factors, such as oxalates, phytates, condensed tannins, saponins, lignin, etc., in addition to the bioactive metabolites, which have diminished the acceptability properties (e.g., palatability and digestibility) as animal feed, and therefore, its exploitation as fodder/forage. Table 1 lists the bromatological/chemical analyses of the breadfruit along with some preparation forms of its parts, as well as the nutritional/therapeutic properties on animals. According to Table 1, for most cases, the best palatability/acceptability of the different parts (fruit pulp, leaf and seed meals) of breadfruit that were used as fodder (for chickens, goats, pigs, rabbits) was when the plant part was treated (by cooking and fermentation) to remove/decrease the bitter constituents. Consequently, certain biochemical parameters in blood exhibited alterations, particularly in SGOT (AST), SGPT (ALT), creatinine, glucose, WBC/RBC, related to toxicity due to consumption of untreated breadfruit-based food. Azadirachta indica A. Juss (Antelaea azadirachta L. Adelb., Melia azadirachta L., M. indica Brandis). The Neem tree, as it is commonly known, belongs to the Meliaceae family and it is found distributed in the tropical/ subtropical regions around the world, although it is native to India and Myanmar (Akbar 2020, El-Hawary et al. 2013, Islas et al. 2020, Koriem 2013). Other common names are: azaddarakhte hindi, azadirachta, bead tree, cornucopia, Indian lilac, lian shu, mimba, neemba(chal/da/di/ do/pan/patti/ro/tel), neem pan(patti/phool/tuo), nim, niimu, nym, shereesh, limbo(a) (Quattrocchi 2012). Citizens of certain countries call it “The village pharmacy” or “Divine tree” due to its great health properties (Islas et al. 2020). It is a species of

Table 1. Bromatological analysis of some parts of breadfruit used as animal feed and its nutritional/therapeutic effects. Part used as feed (preparation)

Bromatological/chemical analysis

Nutritional/therapeutic effects on animals

DM (93–94%), OM (92%), CP (5–21%), EE Yorkshire-Landrace x Duroc hybrid pre-fattening pigs fed with 20-25% (3%), ash (8%), NDF (12–14%), ADF (8%), DE unfermented/fermented breadfruit pulp flour (BPF) (14–16 MJ/kg) < av. daily gain (377–428 g/d); < weight gain (16–18 kg); viability 100%

NR

Fruit pulp (flour)

New Zealand White rabbits fed with BFM and L/BFM < weight gain; < av. daily gain

Brea et al. 2014

Leyva et al. 2013 Leyva et al. 2012

CP (4–16%), CF (5–10%), EE (2–3%), ash (4%), NFE (84%), GE (13–16 MJ/kg), NDF (25–34%), ADF (12–14%), DE (10–11 MJ/kg), oxalate (1–2 × 10–6%), phytate (2–8 × 10–2%), tannins (4–5 × 10–3%), TIU (6–18 mg), HU (3–10 mg)

New Zealand White and Flemish giant cross bred rabbits fed with 25% RBFM/CBFM/FBFM [breadfruit meal, raw (R)/cooked (C)/fermented (F)] RBFM: < total weight gain (0.7 kg); < av. daily gain (13 g); < av. daily feed intake (59 g); > mortality; < WBC/RBC CBFM/FBFM: > total weight gain (0.9 kg); > av. daily gain (16 g); ≥ av. daily feed intake (63–67 g); ≤ mortality; > WBC/RBC < [haemoglobin]

Oladunjoye and Ojebiyi 2012 Oladunjoye et al. 2010

CP (16%), ME (13 kJ/kg)

Yorkland x Duroc hybrid fattening pigs fed with 10–30% BPF < av. daily gain (608–707 g/d); ≡ viability (100%)

Ortiz et al. 2011

DM (71–91%), CP (17–80%), CF (6–66%), EE (4–74%), ash (5–80%), GE (13–14 MJ/kg), NDF (26–53%), ADF (12–42%), oxalate (2 × 10–6%), tannins (6 × 10–3%)

Weaner rabbits fed with 22–67% sun dried breadfruit meal (SDBFM) 22% SDBFM: > av. daily feed intake (70 g); > av. daily weight gain (16 g). 44–67% SDBFM: < av. daily feed intake (55–60 g); < av. daily weight gain (14 g). ↑ glucose, ↑ WBC, ↑ SGOT

Oso et al. 2010

Table 1 contd. ...

Nutritional Benefits of Medicinal Plants Used for Animal Feed 7

DM (89%), CP (6-21%), CF (8%), EE (0.7%), NDF (28%), ADF (18%), ME (2855–2896 kcal/ Yorkland x Duroc hybrid pre-fattening pigs fed with 10–30% BPF kg), lig. (6%), cel. (11%), TC (77%), starch < av. daily gain (372–422 g/d); ≡ feed intake and viability (100%) (56%), sucr. (14%), gluc. (14%), fruc. (13%)

References

Bromatological/chemical analysis

Nutritional/therapeutic effects on animals

Anak broiler chickens fed with 10–30% BFM [breadfruit meal, unpeeled raw(UR)/unpeeled cooked (UC)] DM (89–91%), CP (18–22%), CF (1–5%), EE URBFM: ≤ weight gain (30-37 g/b/d); < feed intake (101–111 g/b/d); < (3–7%), ash (2–12%), NFE (58–65%), GE (13– protein intake (24–26 g/b/d). UCBFM: > weight gain for 10%/30% (38–39 –6 17 MJ/kg), oxalate (2 ×10 –0.03%), phytate g/b/d); > feed intake (107–119 g/b/d); < protein intake (24–26 g/b/d). ↑ 5 (0.7–1.1%), tannins (6–7 × 10 %) albumin, ↑ globulin, ↓ uric acid, ↑ creatinine, ↑ cholesterol (URBFM), SGOT (↑ URBFM/↓ UCBFM), SGPT (↑ URBFM/↓ UCBFM) DM (28–92%), CP (1–23%), CF (2–7%), ash Cornish x White Plymoth chickens fed with 20% BPF (3–11%), ME (4–13 MJ/kg), starch (17–58%) ≡ monitored parameters/indicators

References

Adekunle et al. 2006

Valdivié and Alvarez 2003

Afabro chickens fed with 2.5–7.5% breadfruit pulp flour (BPF) ≡ feed intake for 2.5% BPF (4.0 kg), < feed intake for 5–7.5% BPF (3.8– 3.9kg); > weight gain for 2.5–5% BPF (1.8 kg),< weight gain for 7.5% BPF (1.6 kg); < RBC/haemoglobin/haematocrite/cholesterol levels

Atuahene et al. 2002

DM (91–92%), CP (4–13%), CF (6–10%), EE Crossbred Anglo-Nubian goats fed with 57% BPF (1–-5%), ash (5%), NFE (52–74%), ME (12–14 > body weight gain (9.1 ± 0.5 kg); > daily gain (163 g); < total daily av. feed MJ/kg) intake (1 kg—affected by source of carbohydrate); > DM digestibility

Aregheore 2000

DM (884 g/kg), CP (62–202 g/kg), CF (31–111 g/kg), EE (14–35 g/kg), ash (70 g/kg), NFE (628 g/kg), ME (12–13 MJ/kg)

DM (874 g/kg), CP (59–232 g/kg), CFat (14 g/ kg), CF (59–64 g/kg), ash (34 g/kg), NFE (834 g/kg), ME (12 MJ/kg), GE (16 g/kg)

Cobb broiler chicks fed with 12.5–40% BFM 12.5–25% BFM: > av. weight gain (1420–1424 g/b); > av. feed intake (3224– 3246 g/b); < mortality 20–40% BFM: < av. weight gain (489–502 g/b); < av. feed intake (772–798 g/b); > mortality

Ravindran and Sivakanesan 1995

Leaf (flour)

NR

Laying chickens fed with 2–8% breadfruit leaf flour (BLF) > av. ration consumption 2–4% BLF (43–45 g/b/d), < for 6–8% BLF (40–42 g/b/d); > av. weight gain 2–4% BLF (86–87 g), < for 6–8% BLF (82–84 g).

Lestari et al. 2020

Seed (flour)

CP (20–24%), CF (5–8%), EE (7–8%), ME (2000–3000 kcal/kg)

Anak broiler chickens fed with 10–40% BSM (breadfruit seed meal) < weight gain (11–35 g/b); < feed intake (23–97 g/b); ≥ mortality

Nwokoro and Obasuyi 2006a,b

OM: organic matter, DM: dry matter, CP: crude protein, CF: crude fibre, EE: ether extract, ME: metabolizable energy, GE: gross energy, NFE: nitrogen-free extractives, NDF: neutral detergent fibre, ADF: acid detergent fibre, Lig.: lignin, Cel.: celullose, TC: total carbohydrates, sucr.: sucrose, gluc.: glucose, fruc.: fructose, TIU: trypsin inhibitor units, HU: haemagglutinin units, NR: not registered.

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

8

...Table 1 contd.

Nutritional Benefits of Medicinal Plants Used for Animal Feed 9

easy adaptation/propagation even in extreme conditions [e.g., T: 0–44ºC, sub-arid/ sub-humid zones (rainfall 400–1,200 mm/year)] and it does not demand excessive care: low water/fertilizer requirement. This plant and its parts have been used in the traditional Ayurveda, Chinese, Sidha, and Unani medicines for centuries to treat skin/ respiratory/digestive problems, diarrhoea, dysentery, ulcers, chickenpox, malaria, leprosy, rheumatism, chronic syphilitic sores, gonorrhoea and leucorrhoea; as well as for its bioproperties as anticancer, hypoglycaemic, antispasmodic, antibacterial/ antifungal, larvicidal, antiviral, astringent, febrifuge, emetic, anti-inflammatory, antioxidant, analgesic, immunostimulant, hepatoprotective, neuroprotective, cardioprotective, diuretic, etc. In addition, they are powerful insecticides and repellents against insects/nematodes. One of its notable uses is in veterinary medicine as antiparasitic, insecticide, antimicrobial (bacteria/fungi/viruses), snakebite antidote, febrifuge, and to treat mastitis, eczema, ascariasis, and to cure ulcers in goats and cattle. But also, some parts of plants (e.g., leaves) are exploited as regular feed for ruminants (cattle) in dry lands (Akbar 2020, Alzohairy 2016, Álvarez-Caballero and Coy-Barrera 2019, Biswas et al. 2002, Dixit et al. 1986, Dubey and Kashyap 2014, Girish and Shankara Bat 2008, Gupta et al. 2017, Hashmat et al. 2012, Islas et al. 2020, Koriem 2013, Kumar and Navaratnam 2013, Kumar et al. 2016, Ogbuewu et al. 2011, Quattrocchi 2012, Saleem et al. 2018a,b, Seresinhe and Marapana 2011, Waheed et al. 2006). From the phytochemical screening of the tree and its different parts, constituents such as terpenoids, reducing sugars, glycosides, flavonoids, tannins, alkaloids, cyclic sulfides, sterols, and saponins have been identified, some of which have turned out to be biologically active (Biswas et al. 2002, Saleem et al. 2018b). Among the molecules that have been isolated, structurally characterized, and biologically valued from Neem, the most prominent are the limonoids as azadirachtin (18 broad spectrum insecticide/antifeedant, angiogenic/anti-inflammatory properties), nimbin (19 - antifungal/antifeedant/antiviral), nimbolide (20 - anti-inflammatory/ anticancer/antiproliferative), azadiradione (21 - antifungal/antidiabetic), gedunin (22 - antimalarial/antidiabetic), mahmoodin (23 - antibacterial), salannin (24 antibacterial) and naheedin (25 - antibacterial); and no less important constituents as sugiol (26 - antimicrobial), lupeol (27 - anticancer), nimbiol (28 - insecticidal/ antimicrobial), epicatechin (29 - anti-inflammatory), odoratone (30 - insecticidal) and nimbothalin (31 - insecticidal) (Akbar 2020, Biswas et al. 2002, Dubey and Kashyap 2014, He et al. 2020, Isman et al. 1990, Kumar et al. 2010, Lee et al. 2013, Mordue (Luntz) and Blackwell 1993, Morgan 2009, Ponnusamy et al. 2015, Roy et al. 2007, Sarah et al. 2019, Siddiqui et al. 1992). It is worth mentioning that despite all the benefits attributed to this plant, the main active components (e.g., limonoids as nimbidin, azadirachtin, nimbin, salannin, salannolide) it contains are bitter (they need to be removed), which reduces the exploitation potential, since they decrease the palatability required/adequate to be consumed as a feasible food (complete altogether) for animals (Aruwayo and Maigandi 2013, Chinnasamy et al. 1993, Garg and Bhakuni 1984, Gowda and Sastry 2000, Iwu 2014, Kabeh and Jalingo 2007, Kumar et al. 2016, Paul et al. 1996, Pillai et al. 1984, Polasa and Rukmini 1987, Rukmini 1987, Shukla and Desai 1998).

10

Ethnobotany: Ethnopharmacology to Bioactive Compounds

HO O H

O O

O H

HO

O

O OH O

H

O

OH

O

O

O

O O

H O

O

O

O

O

O

O

O H

O

O

O

O

O

O

O

H

O

O

O

O

H

O

H

O

O

O

O (19)

(18) O

OH

O

H O

O O

H O

O

H

O

HO

O

H

O

O

H

H

O O

H

HO

O O O

(22)

(21)

(20)

O

H HO

O

H

O

H

HO

H

O

O

O O

H

H

O

(23)

OH HO

HO

O (28)

(26)

(25)

(24)

O

OH OH

OH (29)

O

O

(27) O

O

OH

O

O O (30)

O

HO

O

(31)

Additionally, some secondary metabolites (e.g., oxalates, tannins, phenolics, lignin, etc.) or even the limonioids themselves from Neem would act as antinutritional factors/antimetabolites (Adjorlolo et al. 2016, Ameen et al. 2012). In this manner, the bromatological analyses of some parts of Neem and its nutritional/therapeutic properties on animals are registered in Table 2. According to the table, for most cases, the best palatability/acceptability of the different parts (seed meal/cake, leaves flour, fruits) of Neem that were used as animal feed (for buffalos, cattles, chickens, fowls, goats, lambs, pigs, quails, rabbits, rams, sheep) was when the plant part was treated and debittered [removal/decrease of bitter components (bioactive secondary metabolites) using solvents (hexane/ether/water), alkali soaking (1–3% NaOH) or 1.5–3% urea/ammoniation]. Likewise, some biochemical parameters in blood chemistry showed alterations, particularly in liver (SGOT (AST), SGPT (ALT), alkaline phosphatase) and rumen (amylase, xylanase, protease, carboxymethylcellulase) enzymes and hypoglycaemic effect, related to toxicity due to consumption of the supplement with untreated Neem. Manihot esculenta Crantz (M. cassava Cook & Collins, M. dulcis (J.F.Gmel.) Baill., M. edule A. Rich., Janipha manihot (L.) Kunth, J. aipi (Pohl) J. Presl, Jatropha dulcis J.F. Gmel, J. mitis Rottb., Mandioca aipi Pohl, M. utilissima Link, etc.). This species belongs to the Euphorbiaceae family and it is native to central South America (although there are records of its use/consumption in the pre-Columbian cultures of Central America) and has been introduced/domesticated in the tropical/ subtropical regions of the world. The plant is a perennial broadleaf shrub with milky sap, with good growth in drastic conditions (e.g., high tolerance to low fertility soils, resistance to drought), and its bulky tuberous root is the main part used as a food source (rich in starch); the leaves are also eaten. Some names by which it is known are: common/sweet cassava(e), manioc, malango, sweet-potato-tree, tapioc(k) a, cassava, casaba(e), (g/h)cuacamote, mandioca, yuca (blanca/rosadita/noventa/ mansa), ayaka, aso, ubi, ege atu, balangai, guasú mandió, khayewa, alicha, alvananki, etc. Some ethnobotanical uses reported for “yuca” bark and leaves are as treatment

Table 2. Bromatological analysis of some parts of Neem used as animal feed and its nutritional/therapeutic effects. Part used as feed (preparation)

Nutritional/therapeutic effects on animals

References

West African Dwarf rams fed with 2.5–10% water-washed neem fruit meal. CP (15–16%), CFat (2.2–2.4%), NDF (44–45%), ≥ weight gain (6–10 kg), < weight gain for T4; > av. daily gain for T2/T3, Jack et al. 2020 ME (2300–2367 kcal/kg) < av. daily gain for T4/T5; > av. feed intake for T2–T4 (608–735 g), < av. feed for T5. Arbor chickens fed with 1–5% Neem seed flour (NSF). H (7.6 ± 0.1–9.03 ± 0.08%), CP (15 ± 1–18 ± 2%), > body weight: animals fed with 1% of NSF; < body weight: animals feed with CF (4.32 ± 0.01–13.3 ± 0.8%), EE (5.3 ± 0.3–8 5% of NSF. Trigueros et al. ± 2%), Ash (8.49 ± 0.02–9.2 ± 0.3%), FNE (46– Fatty acid content: ↓ oleic (43.6 ± 0.6–44.43 ± 0.02%), ↑ linoleic 2015 55%), ME (962–1086 kcal/kg) (21.2 ± 0.1–24.0 ± 0.9%) and ↓ palmitic (20.1 ± 0.2–21.3 ± 0.4%) acids in abdominal fat of broiler chicks. DM (99%), CP (22–23%), CF (56–59%), EE (13– Broiler chickens fed with 3–12% Neem seed kernel meal (NSKM) Muhammad et 16%), ash (1–2%), H (0.9%), ME (2126–2162%) < daily weight gain (34–51 g/b); < daily feed intake (111–122 g/b). al. 2014 Cockerel chicks of Shika-Brown strain supplemented with 75–225 g/kg raw CP (276–302 g/kg; 22–23%), CF (89–104 g/kg), neem kernel (RFK) and 75 g/kg autoclaving neem kernel (AFK) flours. Uko and EE (453–487 g/kg), ash (40–46 g/kg), ME (12 MJ/ < body weight animals fed with RFK/AFK (150–230 g/chick); weight gain: Kamalu 2006 kg), NFE (91–108 g/kg) AFK < RFK; ↓ palatability for AFK; food consumption (g/chick/d): AFK (16) < RFK (23). Japanese quails supplemented with 0–100 g/kg raw neem kernel meal (NKM) CP (382 g/kg), CF (132 g/kg), EE (33 g/kg), ash Elangovan et al. < body weight gain for animals fed with NKM (122–123 g/b.w.); < feed intake (118 g/kg), ME (11–12 MJ/kg) 2000 (419–455 g/b.w.); ↓ palatability > NKM amount. Broiler chicks and rabbits fed with 10–30% NSM, HENSM/ AENSM (hexane/ CP (14–40%), CF (12–40%), EE (0.7–27%), ash Gowda and alcohol extractions), FFNSM, ATNKM (alkali treatment), UANNKM (urea (3–19%), NFE (14–29%) Sastry 2000 and alkali treatment). Poor growth and low feed efficiency Goats supplemented with 22% Neem seed kernel cake treated with 2.5% urea CP (40%), CF (15%), EE (8%), ash (16%), TC (UTNSKC) ≥ body weight gain (5.6 ± 0.6–6.5 ± 0.6 kg), < weight gain (5.0 ± Anandan et al. (35%), NFE (19%), GE (5 kcal/g) 0.5 kg) in female; ≥ av. daily gain (31 ± 3–36 ± 3 g), < daily gain (27 ± 3 g) in 1996 female; < food intake (239 ± 10–267 ± 17 g), > feed intake (299 ± 16 g) in male. Table 2 contd. ...

Nutritional Benefits of Medicinal Plants Used for Animal Feed 11

Seeds (flour)

Bromatological/chemical analysis

Bromatological/chemical analysis CP (16%), CF (10–12%), TDN (65–66%) DM (90–97%), CP (23–25%), CF (5–9%), EE (8–39%), ash (8–9%), NFE (54%)

DM (86–97%), CP (22–24%), CF (4–13%), EE (7–33%), ash (6–9%), NFE (44–57%)

Seeds (cake)

Nutritional/therapeutic effects on animals

References

Angora and NZW rabbits fed with 8–15% UANKM (urea-ammoniated treatment) and 9–18% ATNKM ↓ haemoglobin, ↓ glucose, ↓ ALT, ↑ AST levels Rabbits supplemented with 20% raw Neem seed meal (RNSM) < body weight gain for animals fed with RNSM (5.8 g/b.w.); < daily feed intake (23.1 g/b.w.) Rabbits supplemented with 20% expeller Neem seed cake (ENSC), solvent Neem seed cake (SNSC), hydraulic press Neem seed cake (HNSC) < body weight gain for animals fed with HNSC/ENSC/SNSC (8.0–8.5 g/b.w.), > body weight gain for SNSC/ENSC; < daily feed intake for animals fed with HNSC/ENSC/SNSC (28.5–31.4 g/b.w.), > daily feed intake for SNSC/ENSC Holstein-Friesian x Jersey crossbred cows fed with 4% detoxified neem cake > body weight gain; > milk yield (6.2–7.5 kg/d); < fat milk content (5.3%); > DM intake (9.6 kg/d)

Gowda et al. 1996

DM (90%), OM (88%), CP (12%), EE (1%), CF (27%), ash (12%), NDF (67%), ADF (34%), HC (32%) H (53–59 g/kg), CP (439–516 g/kg), CF (69–85 g/ kg), CFat (19–22 g/kg), Ash (85–90 g/kg) Lambs fed with 20–50% detoxified neem cake (DNC) DM (964–965 g/kg), OM (929 g/kg), CP (124 g/ < daily gain (70–71 g); no negative effect on digestibility, rumen metabolism, kg), EE (8–13 g/kg), ash (71 g/kg), NDF (569–586 hormonal profiles; ↓ content of limonoids; ↓ trypsin inhibitors (457 µg/g) g/kg), ADF (211–216 g/kg), NFC (211–222 g/kg) Ud lambs and rams fed with 5–25% alkali treated Neem kernel cake (ATNKC) > body weight gain for lambs (7.8–8.8 kg), < weight gain 20% ATNKC (24 kg); > av. daily gain for labs (92–105 g/d), < daily gain 20% ATNKC NR (68 g/d); < food intake (573–691 g/d), > feed intake 5% ATNKC (856 g/d). < body weight gain for rams (10–11 kg), > weight gain 8.5% ATNKC (14 kg); < av. daily gain for rams (119–132 g/d), > daily gain 8.5% ATNKC (167 g); < food intake (1058–1133 g) Seed kernel cake treated with 50–80% MeOH TPC (29 ± 3–58 ± 5%), CF (5.0 ± 0.6–8 ± 2%), TC Better nutritional factors: ↑ digestibility (in vitro - 58 ± 1–77 ± 4%), ↓ content (16 ± 2–22 ± 4%) of limonoids (1 and 7), ↓ antinutritional factors (108 ± 1–145 ± 3 TIA/g)

Bawa et al. 2007

Raj et al. 2016

Rao et al. 2016

Aruwayo and Maigandi 2013

Saxena et al. 2010

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

12

...Table 2 contd.

Table 2 contd. ...

Nutritional Benefits of Medicinal Plants Used for Animal Feed 13

Cockerel chickens fed with 10–% Neem seed cake (UNSC - no treated), DM (89–92%), CP (14–21%), CF (4–20%), EE 10–20% treated Neem seed cake (WNSC), 10–20% charcoal supplemented Odunsi et al. (4–5%), ash (3–10%), NFE (39–59%), GE (823– Neem seed cake (CNSC) 2009. 3252 kcal/kg) > body weight gain with 10–20% WNSC (7.4–7.7g/d) and 10% CNSC (7.4 g/d); > feed intake 10–20% WNSC (42–45 g) OM (88–94%), CP (16–37%), EE (4–5%), TC Goats fed with 15–25% water-washed Neem seed cake (WNSC) Kesava Rao et (46–74%) > body weight gain (14 ± 1 kg); ↓ total lipids and glycerides; ↑ free fatty acids al. 2003 Buffalo calves, broiler chicks, cattle fed with NSC, NKC, WWNKC (water CP (12–41%), CF (11–30%), EE (0.4–15%), ash Gowda and washed), ATNKC (alkali treatment), UANNKC (urea and alkali treatment) (6–20%), NFE (27–52%) Sastry 2000 ↓ RBC/WBC/haemoglobin levels, ↓ palatability Mandya x Merino lambs supplemented with 30% Neem seed kernel cake DM (84–90%), CP (20–40%), CF (7–15%), EE (NSKC) and 33% NSKC treated with 2.5% urea (UTNSKC) Musalia et al. (5–9%), ash (10–16%), WSC (1–4%) 2000, 2002 > daily feed intake for animals fed with UTNSKC (612–723 g/d); UTNSKC food had not effect on palatability CP (349–404 g/kg), CF (150–168 g/kg), EE (65– Broiler chickens fed with 13–27% Neem seed kernel cake treated with 1.5– Nagalakshmi et 106 g/kg), ash (146–150 g/kg), NFE (171–276 g/ 2.5% urea (UANKC) al. 1999 kg) < weight gain (818–1077 g/b) CP (234–249 g/kg), CF (88–123 g/kg), EE (64– Broiler chickens fed with 15–30% Neem seed kernel cake treated with 1–2% 74 g/kg), ash (104–163 g/kg), NFE (392–510 g/ NaOH (ANKC) Nagalakshmi et kg), TC (515–598 g/kg), GE (18–19 MJ/kg), ME < weight gain (806–1035 g/b); ≡ daily intake (2441–2481 g/b), < daily intake al. 1996 (10–12 MJ/kg) for 30% ANKC-1H (2441 g/b); ↓ RBC, ↓ WBC, ↑ AST/ALT, ↑ blood urea Buffalo supplemented with 20% NSCK NR NSCK affected xylanase, amylase, urease, but not carboxymethylcellulase and Paul et al. 1996 protease enzymes CP (16–37%), CF (6–12%), EE (4–5%), ash Goats fed with 15–25% WWNKC Verma et al. (4–12%), TC (46–74%), NFE (34–68%), NDF > body weight gain (4.5 ± 0.5–5.2 ± 0.6 kg); > av. daily gain (25 ± 3–29 ± 3 g); 1995 > food intake (326 ± 26–324 ± 27 g) (27–37%), ADF (8–26%) OM (91%), CP (19%), EE (2.5%), ash (9%), TC Pigs fed with 10% WWNKC Sastry and (69%) > daily weight gain (195 ± 33 g); > daily DM intake (946 ± 74 g) Agrawal 1992

Bromatological/chemical analysis OM (83–90%), CP (27–40%), CF (9–12%), EE (4–8%), ash (10–17%), TC (34–59%), NFE (21– 50%) OM (83–90%), CP (28–40%), EE (4–8%), ash (10–17%), TC (34–58%) DM (94–95%), CP (34–35%), CF (11–12%), EE (9–10%), ash (15%), NFE (29–30%) CP (15%), NDF (29 mg/kg), ADF (19 mg/kg) ME (2.8 Mcal/kg) DM (93%), CP (28%), ash (10%), ADL (5%), NDF (32%), ADF (22%) DM (86–88%), CP (18–27%), NDF (38–50%), ADF (27–31%), ash (12–19%)

Leaves (Flour) DM (92%), CP (21%), CF (17%), EE (4%), ash (7%), NFE (44%)

Nutritional/therapeutic effects on animals

Holstein Friesian x Jersey x Hariana crossbred cows fed with 40% WWNSKC > av. daily milk yield (7.6 kg); < fat content (41 g/kg); > DM intake/100 kg Nath et al. 1989 b.w. (2.6 kg/d); ≡ digestibility Buffalo calves fed with 40% WWNSKC Agrawal et al. > growth rate (606 g/d); > nutrient intake (↑ DCP (319 g/d)) 1987 Holstein Friesian male calves fed with 45% treated Neem seed cake (WNSC - water washed) Nath et al. 1983 ≡ daily weight gain (344–403 g). Katahdin x Suffolk x Hampshire sheeps supplemented with 0.25–0.75% Marcos Neem leaf meal Hernández ≥ feed intake T1-T2 (1402–1421 g/d), < feed intake T3 (1382 g/d); > daily and Villegas weight gain (0.30–0.34 g/d); > daily gain T1; ↓ palatability Pedraza 2020 Gumuz goats fed with 25–75% Neem leaf meal (NLM) < body weight gain (2–3 kg), > 100% NLM (4 kg); < daily b.w. gain Dida et al. 2019 (23–38 g/d), > 100% NLM (44 g/d) West African Dwarf sheeps fed with 20-40% NLM Abdul-Kareem < av. daily gain (18–25 g/d); < av. feed intake (4–90 g); > digestibility T2, 2017 < digestibility for T3/T4 Rabbits (Chinchila x New Zealand White) fed with 5–15% Neem leaf meal (NLM) Unigwe et al. < wkly weight gain for 5% and 15% NLM (71.8 g, 73.0 g), > wkly weight gain 2016 for 10% NLM (74.0 g); < wkly feed intake for 5% and 10% NLM (313 g, 312 g), > wkly feed intake for 15% NLM (315 g)

Pearl grey guinea fowl fed with 0.1–0.3% Neem leaf powder (NLP) DM (90%), CP (18–24%), CF (4–8%), EE (3– > body weight gain (1229.7 ± 0.2–1266.2 ± 0.1 g/b/w); > feed intake (3921 ± 9%), ash (6–10%), 14–4009 ± 16 g/b/w) NR

References

Shikka brown laying hens fed with 5–15% NLM ≡ weight gain for T1, < weight gain for T2/T3

Singh et al. 2015 Esonu et al. 2006

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

14

...Table 2 contd.

Leaves

Neem leaves fed ruminants during dry season CP (10–21%), CF (11%), NDF (38%), ADF Adjorlolo et al. ↓ palatability [condensed tannins (9%), crude saponins (3%), lignin (10%), (27%), NFE (54%) 2016 limonoids (0.03%), phenolics (7%)] Santa Ines cross-breeds sheeps fed with fresh neem leaves (FNL) dosed Chandrawathani NR 3 g/kg b.w. et al. 2006 FNL were palatable; < nematode faecal eggs counts.

OM: organic matter, DM: dry matter, H: humidity, CP: crude protein, CF: crude fibre, EE: ether extract, ME: metabolizable energy, GE: gross energy, NFE: nitrogen-free extractives, NDF: neutral detergent fibre, ADF: acid detergent fibre, TC: total carbohydrates, TIU: trypsin inhibitor units, NR: not registered.

Nutritional Benefits of Medicinal Plants Used for Animal Feed 15

16 Ethnobotany: Ethnopharmacology to Bioactive Compounds against wounds/sores/warts, heat stroke/burns, headache, diarrhoea, conjunctivitis, dysentery, fever, prostatitis, snakebite, spasms, respiratory and dermal disorders, abscesses, sprains, diabetes, etc.; as well as for its antioxidant/anti-inflammatory, antiparasitic, antiproliferative/cytotoxic/anticancer, antiseptic, enzyme inhibitory and antimicrobial properties (Ahmed 1977, Anwar and Mohd Bohari 2019, Bahekar and Kale 2015, Bakare et al. 2020, Brañas et al. 2019, Caballero et al. 2016, de Oliveira et al. 2021, Ferranti et al. 2019, Grandtner and Chevrette 2014, MeraAndrade et al. 2018, Mustarichie et al. 2020, Okoro 2020, Pan et al. 2015, Polyorach et al. 2013, Quattrocchi 2012, Sokerya et al. 2009, Sutiningsih et al. 2020, Van Alfen 2014, Yi et al. 2010, Zakaria et al. 2006). The roots have been millennially/widely exploited as human food prepared in different ways: flour, starch, tapioca, soup, alcoholic beverages; however, once the roots are harvested, they have a short shelf life (24–72 h) and become perishable and inedible due to the accelerated process of physiological deterioration. Sometimes the root (as food) and leaves can become toxic due to the presence of cyanogenic glycosides (CG), such as linamarin (32 - 85–95%) and lotaustralin (33 - < amount); i.e., if crop product contains ≤ 100 µg/g fresh weight (FW) it is considered “sweet cassava”, but if concentration is > 100–500 µg/g FW, it is categorized as “bitter cassava”; nonetheless, all cassava organs, except seeds, contain this kind of glycosides. CG concentration depends of the ecological conditions and plant age (Aregheore and Agunbiade 1991, Kamalu 1995, King and Bradbury 1995, Morgan and Choct 2016, Ngiki et al. 2014, Prawat et al. 1995). The secondary metabolites in M. esculenta leaves and roots preliminary identified are flavonoids, coumarins, polyphenols, terpenoids, etc; the flavonoid glycosides widely occurring in the leaves, f.i., rutin (34 - main constituent), nicotiflorin (kaempferol-3-O-rutinoside - 35), myricetin-3-O-rutinoside (36), hyperoside (37), narcissin, robinin, clovin; as well, hydroxycoumarins are also present in the root, e.g., scopoletin (38), scopolin (39), esculetin (40), esculin (41). These hydroxycoumarins could be produced/involved in the postharvest deterioration suffered by the roots. For its part, some simple phenols, phenylpropanoids, xanthones, and lignans were isolated from the cassava stem: coniferaldehyde, syringaldehyde, isovanillin, ficusol (42), ethamivan (43), 38, p-coumaric acid, 6-deoxyjacareubin (44), pinoresinol (45) and balanophonin (46). Finally, some unusual terpenoids [yucalexin B-9 (ent­ beyerane skeleton - 47), yucalexin P-8 (ent-pimarane skeleton - 48), yucalexin A-19 (ent-atisane skeleton - 49)] were isolated from root when it was damaged by cutting/ fungal-infection; likewise, stigmasterol (50), β-sitosterol (51), and campesterol were found in healthy/damaged roots (Bayoumi et al. 2008, 2010, Blagbrough et al. 2010, Buschmann et al. 2000, Lim 2016, Mustarichie et al. 2020, Sakai et al. 1986, Sakai and Nakagawa 1988, Tao et al. 2019, Tanaka et al. 1983, Wheatley and Schwabe 1985, Yi et al. 2010). There are some reports on the use of roots/leaves as animal feed (though, dry leaves can be toxic to the animals), which are found in the Table 3. In addition, the bromatological/chemical analyses, as well as the nutritional/therapeutic effects were included. It is important to note that cassava poses three principal limitations for

Nutritional Benefits of Medicinal Plants Used for Animal Feed 17

OH CN O

HO

CN

O

HO

O

HO HO

OH

HO

HO

OH

OH O

O

HO

OH

O

OH O

OH OH

OH

(33) O

O

O

HO

OH OH

OH OH

OH

O

O

(36) OH

HO O

O

HO

O

O

O

O

O

OH

OH

OH

O

HO

HO

HO

OH

HO

OH

O

O

OH

(37)

OH

OH

(35)

O

OH

O

OH O

OH

O

OH

HO

OH

O

OH

(34)

O

OH

O O

OH

OH

HO

O

O

HO

OH (32)

HO O

O

OH

OH

O

O

O OH

OH

O

OH

OH

HO

(39)

(38)

O

O

(41)

(40) O

HO HO

O

O

O

O

N

O OH

OH

O

O

CHO HO

O

O

OH

OH

OH

O

O

O O

OH O

(42)

(43)

O O

(44)

O O

HO (47)

(46)

OH

O

HO

(45)

O

(48)

HO

HO (49)

HO (50)

(51)

using as animal feed: (i) chemical factors (e.g., presence of cyanogenic glycosides), (ii) nutritional factors (e.g., low protein content), (iii) physical factors (e.g., presentation in powder or pellets) (Oke 1978, Ravindran 1993). Based on Table 3, tuberous roots/leaves of treated/processed cassava (fermented, peeled, sun-dried, pasta) improved palatability, with some different degrees of digestibility for animals under study (broilers, bulls, cattle, chickens/hens, cows, fishes, geese, goats, heifers/steers, lambs, pigs, and rabbits). Nonetheless, in some cases, the quality and yield of milk production increased; and in others, they had weight gain. In certain reports, the content of antinutritional factors could be determined, e.g., cyanide (HCN), lignine, tannins, etc., which justified the decrease in daily intake and weight gain (rejection to feed), related to low palatability (Fasuyi 2005). As a final point, some alterations in blood chemistry were recorded, e.g., SGOT/SGPT/serum thiocyanate (↑), creatinineWBC//RBC/hemoglobin (↓), related to the consumption of the untreated (raw) cassava (roots/leaves). Into the bargain, at the present time, the exploitation of the by-products (bagasse, sieve residues of gari) or wastes/residues (peels, leaves, roots) of the processing of cassava at the agro-/industrial level (e.g., manufacture of flour) are being incorporated as ingredients of fodder for cattle, ruminants, pigs (Adesehinwa 2009, Bizzuti et al. 2021, Kiendrébéogo et al. 2019, Pertiwi et al. 2019, Zendrato et al. 2020, Zheng et al. 2021).

Roots (fresh)

Bromatological/chemical analysis

Nutritional/therapeutic effects on animals

References

DM (351–921 g/kg), OM (934–963 g/kg), CP (13–143 g/kg), NDF (101–192 g/kg), ADF (54–111 g/kg), cyanide (106 ppm)

Thai native beef cattle fed with 1.5–2.0% FCR (fresh cassava roots) and PELFUR/FCR > DM intake for 2.0% FCR/1.5% FCR

Prachumchai et al. 2021

DM (28–87%), OM (93–95%), CP (2–14%), NDF (8–12%), ADF 6–8%), HCN (91%)

Thai native beef cattle fed with 1–1.5 % FCR and 55% concentrate 1.5% FCR > total DM intake, > apparent digestibility; > thiocyanate and urea-N in blood

Cherdthong et al. 2018

DM (20–23%), CP (6–7%), EE (2%), ash (9–14%), NDF Brahman heifers fed with 5–15 % FCR (58–65%), ADF (40–44%), pH (3.70–3.75), lign. (7–8%) > feed intake (2–5 kg)

Maza et al. 2011

DE (3149–3454 kcal/kg), CP (2–18%), EE (0.6–7%), CF (5–12%), ash (5–7%), GE (82–83%)

[(Landrace × Yorkshire) × Duroc] pigs fed with cassava hard pellets (CHP) and 0.2-0.4% cassava CHP: < av. daily gain (0.4 g); < av. daily feed intake (0.7 g) 0.2% cass.: > av. daily gain (540 g); > av. daily feed intake (1462 g); > RBC, < lymphocytes

Sureshkumar et al. 2022

DM (85%), CP (3%), GE (4 Mcal/kg), starch (68%)

Friesian steers fed with 21–42% cassava pellets < feed intake > % cassava pellets; < DM/OM intakes; > OM digestibility; < CF digestibility

Ahmed 1977

Roots (pulp)

DM (18–86%), CP (2–25%), ash (2–9%), EE (0.3–7%), NDF (18–48%), ADF (13–35%), NFC (40–68%), starch (47–78%), TDN (62–63%) GE (17–19 MJ/kg)

Lactating Holstein-Friesian crossbred cows fed with 14–28% cassava pulp 14% cassava: > weight gain for (453 kg); > milk yield (9 kg/d); > fat and protein corrected milk (8 kg/d); > feed efficiency (0.7); > SCC (126)

Kaeokliang et al. 2019

Roots (chips)

Cobb 500 broiler chickens fed with 12.5–50% cassava root chips DM (87%), ME (2878–3073 kcal/kg), CP (4–21%), CF (CRC) (4%), EE (0.1%), NDF (4–8%) 12.5–37.5% CRC: > av. daily gain (47–51 g); > av. daily feed intake (101–107 g)

Yadav et al. 2019

Roots (pellets)

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

18

Table 3. Bromatological analysis of some parts of cassava used as animal feed and its nutritional/therapeutic effects.

Roots (fermented)

Leaves (flour)

Lohman chicks fed with 2.5–10% fermented dried cassava (gathot) 2.5–5% gathot: > weight gain (1002–1047 g/b); ↓ erythrocytes, ↑ leukocytes, ↑ lymphocytes, ↓ AST, ↑ ALT, ↓ triglycerides

Sugiharto et al. 2016

DM (890 ± 9–892 ± 9 g/kg), CP (15.2 ± 0.7–15.5 ± 0.6 g/kg), CF (38.4 ± 0.9–96 ± 3 g/kg), EE (3.0 ± 0.1–3.2 ± 0.1 g/kg), ash (47 ± 1–64 ± 2 g/kg), NDF (245 ± 5–292 ± 7 g/kg), ADL (22.7 ± 0.9–32 ± 2 g/kg), ADF (126 ± 4–155 ± 4 g/kg), GE (13.2 ± 0.4–14.1 ± 0.6 MJ/kg), cel. (105 ± 3–123 ± 4 g/kg), saponins (0.20 ± 0.01–0.24 ± 0.01 g), HCN (2.9 ± 0.6–6 ± 1 ppm)

Marshall broilers fed with 10–20% peeled/unpeeled cassava root meal (P/UCRM) < weight gain (647–1015 g/b); > weight gain (900-1015 g/b) for PCRM; < feed intake (1431–1526 g/b); > feed intake (1526–1531 g/b) for PCRM ↓ hemoglobin, ↓ RBC, ↑ ST (serum thiocyanate)

Akapo et al. 2014

H (96 g/kg), CP (16 g/kg), CF (162 g/kg), CFat (9 g/kg), ash Marshall broiler chicks fed with 10-20% UCRM + 0/6% carbon (61 g/kg), NDF (245 g/kg), ADL (33 g/kg), ADF (134 g/kg), < weight gain (1431–1674 g/b); < feed intake (2834–3141 g/b) GE (16 MJ/kg), ME (15 MJ/kg), cel. (101 g/kg), HCN (4 ppm) ↓ creatinine, ↓ cholesterol, ↑ SGOT, ↑ SGPT, ↑ ST ME (2568–2593 kcal/kg), CP (17–18%)

Laying hens fed with 25–100% CRM > av. weight for 25–50% CRM; < av. weight for 75–100% CRM; < feed intake (101–105 g/b/d)

ME (3 Mcal/kg), CP (19–21%)

Hubbard broiler chicks fed with 20-30% CRM + 0/5% ME ≥ weight gain (1974–2167 g)

Oso et al. 2014 Anaeto and Adighibe 2011 Gomez et al. 1987

Cobb-500 chickens fed with 10–30% cassava leaf meal (CLM) DM (899 g/kg), CP (170 g/kg; 21%), CF (150 g/kg; 7–9%), < av. daily feed intake; < av. daily gain ash (70 g/kg), EE (68 g/kg; 5–6%), NFE (542 g/kg), 20–30% CLM: > total proteins; > creatine kinase GE (4565 kcal/kg), ME (1666–3491 kcal/kg) 10% CLM: < total proteins; < creatine kinase

Bakare et al. 2020

DM (884 g/kg), CP (198–229 g/kg), CF (55–181 g/kg), ash Cobb 500 broilers fed with 10–20% CLM (97 g/kg), EE (66 g/kg), NDF (470 g/kg), ADF (283 g/kg), < feed intake (1022–2619 g/b); < weight gain (730–1578 g/b) ME (12 MJ/kg)

Diarra and Anand 2020

CP (27%), CF (4–5%), Fat (2–3%), DE (3 kcal/kg)

Curimatã-pacu fishes/canela shrimps fed with 10–20% dehydrated cassava leaf meal (DCLM) Fish: > absolute growth rate; < SGR

Soares et al. 2019 Table 3 contd. ...

Nutritional Benefits of Medicinal Plants Used for Animal Feed 19

Roots (flour)

DM (87–90%), ME (2982–3569 kcal/kg), CP (2–18%), CF (3–7%), CFat (2–4%), ash (1–7%)

20

...Table 3 contd. Bromatological/chemical analysis CP (16%), CF (5–7%), NDF (29–35%), ADF (18–22%), ME (11 MJ/kg), HCN (3–5 ppm)

Foliage

Leaves/roots (flour/chips)

Nutritional/therapeutic effects on animals Hainan indigenous geese fed with 5–10% cassava foliage (CF) > body weight (3310 ± 61–3446 ± 64 g); > av. daily feed intake (142 ± 29–165 ± 29 g/b); > av. daily gain (61 ± 13–64 ± 10 g)

References Li et al. 2019

DM (201 ± 15 g/kg), CP (205 ± 2–4 g/kg), ash (57 ± 5 g/kg), Phan Rang lambs fed with 2% fresh cassava foliage (FCF) NDF (431 ± 18 g/kg), ADF (313 ± 35 g/kg), HCN (341 ± > feed intake FCF-7, < feed intake FCF-0/FCF-21; < daily gain (65–76 g/d) 17 ppm)

Hue et al 2012

DM (204 ± 19–968 ± 23 g/kg), CP (22 ± 2–208 ± 3 g/kg), ash (17 ± 1–73 ± 8 g/kg), NDF (63 ± 8–539 ± 39 g/kg), ADF (32 ± 3–342 ± 55 g/kg), tannins (15 ± 4–35 ± 3 g/kg), HCN (51 ± 17–333 ± 16 ppm)

Phan Rang lambs fed with cassava foliage (fresh/wilted/sun-dried) (FCF/WCF/CH) > feed (630–680g/d) and water (492–901 g/d) intakes for WCF/CH; > digestibility for FCF/WCF

Hue et al 2010

DM (26 ± 4–30 ± 3%), CP (21.8 ± 0.5–24 ± 1%), HCN (172–586 ppm)

Goats fed fresh cassava foliage (FCF) and ensiled cassava foliage (ECF) > av. daily weight gain (42 ± 13–59 ± 22 g/d); > CP intake; < DM intake. ECF: < total worm burden

Sokerya et al. 2009

DM (21%)

Zebu bulls fed with cassava aerial parts Apparent digestibility (66–68%); voluntary consumption (4–5 kg/d); digestible DM (2–3 kg/d); consumption index (2)

Ffoulkes et al. 1997

CP (22%), ADSCP (48%), NDF (56%), ADF (43%), NFE (50–63%), HCN (17–289 ppm)

Friesian x Boran crossbred cows fed with cassava silage (root chips: leaves - 4:1) > av. milk yield (8–10%); milk quality: ↑ CP (3.4%), ↑ fat (4%)

Kavana et al. 2005

DM (88–89%), CP (7–12%), CF (6–11%), ash (3–5%), EE (9–10%), NFE (50–63%), HCN (0.2–0.3 ppm)

Anak broilers fed with 10-30% cassava concentrate (CC) (mixing roots:leaves, 1:1, 1:1.5, 1:4) < weight gain (1401–1895 g); < total feed intake (0.1–4 kg); ≥ mortality (3–7%). 10% CC: ↑ WBC, ↑ RBC, ↑ Hemoglobin 20–30% CC: ≤ WBC, ≤ RBC, < Hemoglobin

Eruvbetine et al. 2003

DM (89–92%), OM (87–96%), CP (5–18%), CF (4–20%), ash (4–13%), EE (2–7%), NFE (41–85%)

New Zealand White rabbits fed with cassava feed (30% CRM and 15% CLM) < av. feed intake (81–83 g); < av. daily body gain (17 g); < nutritive value; < N-intake

Abd El-Baki et al. 1993

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

Whole plant (flour/pasta)

DM (27–82%), OM (16–74%), CP (12–19%), NDF (32– 37%), ME (4111–4201 kcal/kg)

Landrace×Yorkshire×Hampshire×Duroc crossbred castrated pigs fed with dry/fresh foliage (30%)/roots (38%) (meal/pasta) > digestibility for pasta base on DM, OM and NDF; < digestibility for dry/fresh meals

Parra et al. 2002

OM: organic matter, DM: dry matter, H: humidity, CP: crude protein, CF: crude fibre, EE: ether extract, ME: metabolizable energy, GE: gross energy, NFE: nitrogen-free extractives, NDF: neutral detergent fibre, ADF: acid detergent fibre, lign.: lignin.

Nutritional Benefits of Medicinal Plants Used for Animal Feed 21

22

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Prosopis juliflora (SW.) DC. (Acacia cumanensis Humb. & Bonpl. ex Willd., Algarobia juliflora (Sw.) Heynh., Desmanthus salinarum (Vahl) Steud., Mimosa juliflora Sw., Neltuma bakeri Britton & Rose, P. cumanensis (Willd.), etc.). This species that is found in arid zones is a small, spiny, perennial, non-climbing tree or shrub, of very fast growth, whose leaves and fruits are eaten by grazing animals (cattle/livestock); the tree starts bearing fruit in 3–4 years and its fruit (pods) is a legume, whose pulp is slightly sweet and edible. The plant belongs to the Mimosaceae family and it is native to the southern United States, Central America and the WestIndies, and South America; in addition, the plant is distributed in the tropic/subtropic areas of the world. Their common names are: algarroba(o), bayahón, bate-caica, bee/ bihi, cuji-yaque, cují, espino real, huaranca(u)/(h)guarango, honey lacust/podmes(z) quite, mizquitl, pile, t(h)acco, trupillo, yaque, yaga be/bihi/bii, eterai, angreji/bilayati babul, bavalio, cimaikkaruvel, circar kampa/ mullu, kikar, valaitij, etc. (Grandtner and Chevrette 2014, Quattrocchi 2012, Roth and Lindorf 2002). All parts of P. juliflora are exploited, e.g., wood as charcoal, for building material, furniture, and handicrafts; and undeniably, the leaves and pods are used for medicinal purposes and as food. For example, pod meal can be obtained to prepare bread/cakes/cookies; similarly, alcoholic/non-alcoholic beverages can be made; and some sweets for food industry can be prepared from the gum of the trunk (bark). On the other hand, the ethnobotanical uses reported for “trupillo” bark and leaves are as antiseptic, tonic/digestive, diuretic, painkiller, galatacgogue, and treatment against wounds/sores/warts, diarrhoea, eye inflammation, parasites, purgative, dysentery, respiratory/gastrointestinal disorders, asthma, snakebite prepared in form of paste/poultice, gum, smoke, decoction/infusion, maceration, baths, etc.; and its pharmacological/biological properties demonstrated are anticancer, antidiabetic, anti-Alzheimer, neurotoxic, anti-inflammatory/antioxidant, analgesic, anthelmintic, antibiotic/antimicrobial, antiemetic, haemolytic, antigiardial, amoebicidal, antiparasitic/antiviral, antiulcer, antipyretic, insecticide/larvicidal, and allelophatic; moreover, it has probiotic and nutritional effects. The pods are widely used as animal fodder; however, some of them have been naturally poisoned by the uncontrolled consumption (for long times) of enormous quantities of pods due to biological invasion (Al-Musayeib et al. 2012, Alamgeer et al. 2018, Badri et al. 2017, da Silva et al. 2018, Damasceno et al. 2017, 2018, dos Santos et al. 2013, Elbehairi et al. 2020, Garbi et al. 2014, Gopinath et al. 2013, Henciya et al. 2017, Kandasamy et al. 1989, Mendonça et al. 2020, Pinho et al. 2013, Preeti et al. 2015, Ravikumar et al. 2012, Ruiz-Nieto et al. 2020, Saleh and Abu-Dieyeh 2021, Sathiya and Muthuchelian 2010, Sharifi-Rad et al. 2019, Silva et al. 2007, Sivakumar et al. 2009, Srinivas and Chaturvedi 2019, Sudhakar et al. 2015, Tajbakhsh et al. 2015, Taisma 2017, Umair et at. 2017, Wagh and Jain 2018, Yaseen et al. 2015, Zerihun and Ele 2020). The different parts (leaves, pods, flowers) of plant contain tannins, terpenoids, alkaloids, flavonoids/phenolics, saponins, quinones, etc. Though, molecules type piperidine-alkaloids and phenolic/lignoid have been identified/isolated from leaves/pods, f.i., juliflorine/juliprosopine (52/53 - anti-Alzheimer, antibacterial, antiparasitic), secojuliprosopinal (allelophatic), julifloricine (antibacterial), julifloridine, N-methyljulifloridine, isojuliprosine/juliprosine (54 - antibacterial,

Nutritional Benefits of Medicinal Plants Used for Animal Feed 23

antifungal, antimalarial), prosopine, prosopinine, prosafrinine, prosoflorine (55 - antibacterial), 3´-oxojuliprosopine (allelophatic), 3´´´´-oxo-juliprosopine (56), 3-oxojuliprosine/3´-oxojuliprosine (allelophatic), juliprosinene (antibacterial), prosophylline (57), cassine (58), mesquitol (59 - antioxidant), syringin (60 - allelophatic), lariciresinol (61 - allelophatic). Other molecules such as apigenin, catechins, rutin, palulitrin (62 - anticancer), zerumbone (63) and dehydroabietic acid (64) have also been isolated/identified from pods (Ahmad et al. 1978, 1989a,b, Aqeel et al. 1989, Choudhary et al. 2005, dos Santos et al. 2013, Damasceno et al. 2017, 2018, Henciya et al. 2017, Ibrahim et al. 2013, Nakano et al. 2002, 2004, Silva et al. 2007, Singh and Verma 2012, Singh 2012, Sirmah 2018, Sirmah et al. 2009, 2011, Sivakumar et al. 2009). Based on the main use of mesquite (pods) as human/animal food for its nutritional benefits, in Table 4, the bromatological/chemical analyses of the plant together with the therapeutic/nutritional properties on animals is registered, as well as some forms of preparation of the parts. According to Table 4, some authors mentioned that pods contain phytates, tannins, lignin, saponins, etc., as main antinutritional factors (in addition, to the piperidine-alkaloids), which diminished the acceptability (e.g., palatability and digestibility) as animal feed. Nevertheless, the best palatability of the different parts (pods/seed meals and whole plant) of “trupillo”, used as feedstuff (for broilers, chicks/hens, cows, ewes, fingerlings, goats, lambs, rabbits, rams, sheeps), was when the plant part was treated (by enzymes, fermentation/probiotics, soaking/ autoclaving) to remove/decrease the antinutritional factors; although produced different degrees of digestibility. Consequently, for most cases, the weight gain, feed intake, milk production, eggs fertility, and hatchability improved. If selected biochemical parameters of the blood are considered, they showed some alterations HO

HO

HO N H

N H

H N

N H

H N

HO

HO

HO

N

N H

N H

N H

(52)

(53)

(54) -(55)

HO

O HO N H

N

O

OH

HO

N H

OH

(57)

HO

HO

O

OH HO

O O

HO

O O

OH

O OH

(60)

O

OH O

HO

(61)

HO

HO

(59)

O

O

O

HO

(58)

(56) HO

HO

OH

N H

N H

OH

OH

O

O

O

OH OH

OH

COOH

O (62)

(63)

(64)

OH

24

Table 4. Bromatological analysis of some parts of trupillo used as animal feed and its nutritional/therapeutic effects. Bromatological/chemical analysis

Nutritional/therapeutic effects on animals

References

Seeds (flour)

DM (902–907 g/kg), CP (328–366 g/kg), CFat (95–119 g/kg), CF (37–41 g/kg), ash (28–91 g/kg), NFE (386–445 g/kg), GE (15271–15857 kJ/kg),TP(3.5±0.2–3.70±0.03g/kg),phytate(3.2±0.2–3.4±0.2g/kg), tannins (4.8 ± 0.1–8.3 ± 0.1 g/kg), TIU (25.1 ± 0.4–60.3 ± 0.1 g–1), Lig. (3.4 ± 0.1–3.60 ± 0.05 g/kg)

Rohu fingerlings fed with 20–50% seed meal (raw/ soaking/soaking+autoclaving) (RSM/SSM/SASM) < weight gain (96 ± 6–152 ± 9%); ≤ apparent protein/lipid digestibility (85–91%)

Bhatt et al. 2011

DM (90.04 ± 0.06–92.30 ± 0.06%), CP (17–18%; 14.8 ± 0.1–16.8 ± 0.1%), CF (15%; 21.8 ± 0.1–22.7 ± 0.1%), ash (4.94 ± 0.02–5.03 ± 0.02%), EE (4.26 ± 0.01–4.35 ± 0.02%), ME (11 MJ/kg), GE (14.05 ± 0.06–15.6 ± 0.3%), tannins (22.4 ± 0.2–74.6 ± 0.2 mg/g), phytates (48.4 ± 0.1 ppb), aflatoxin (6.6 ± 0.2 ppb)

New Zealand white rabbits fed with 15-30% mature pods meal [unfermented (UMPM)/fermented (FMPM)] > weight gain (1.3 ± 0.2–1.7 ± 0.2 kg); ≥ feed intake for 15–30% FMPM and 30% UMPM

Odero-Waitituh et al. 2020

DM (92 ± 1%), OM (86 ± 1%), CP (13.0 ± 0.7%), CF (22 ± 1%), EE Local Kilakarisal breed rams fed with pod flour as sole (1.7 ± 0.2%), NFE (57 ± 2%), NDF (43 ± 2%), ADF (30 ± 1%), ADL feed > digestibility; > palatability (2.6 ± 0.3%), ash (5.6 ± 0.7%) DM (92–93%), CP (16%), CF (5–11%), ME (13 MJ/kg) Pods (flour)

KALRO-improved indigenous chickens fed with 10-30% pod meal (PM) ≤ egg production; < weight gain; ↓ IgG value

KALRO-improved indigenous chickens fed with 10–30% PM and 6–16% PM incorporated into feed DM (893–902 g/kg), CP (139–231 g/kg), CF (56–181 g/kg), EE 10–30%: < av. daily gain (9–12 g/d; 16–19 g/d); ≤ av. (64–72 g/kg), ash (64–84 g/kg), ME (13 MJ/kg) DM (898– feed intake (61–71 g/d; 80–93 g/d); < live weight change 910 g/kg), CP (230–234 g/kg), CF (54–65 g/kg), EE (71–81 g/kg), (699–934 g/b; 1228–1491 g/b) ash (81–82 g/kg), NFE (447–457 g/kg), ME (13–14 MJ/kg) 6–16%: < av. daily gain for 6%/16% PM; < av. feed intake (60–63 g/d; 83–88 g/d) DM (91%), CP (12–40%), CFat (3–7%), TDF (9–22%), ash (5– 10%), NFE (23–50%), GE (14–16 kJ/g), TP (0.6), phytate (0.2), tannins (1), saponin (0.4)

Rohu fingerlings fed with 33% pods (raw/fermented/ probiotics) < feed intake; > weight gain for fermented pods; < digestive enzymes activity amylase, protease, lipase) for raw pods, > for the other feed

Chellapandian and Thirumeignanam 2019 Khobondo et al. 2019

Wanjohi 2019

Chovatiya et al. 2018

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

DM (90%), CP (18%), CF (8%), EE (6%), ash (10%), ME (2798–2828 kcal/kg)

White leghorn hens fed with 10–30% pod meal > % eggs fertility (90–93%), > % hatchability for Gulilat et al. 2018 10%/20% PM; > quality of hatched chicks; < mid/late embryonic mortality for 10%/20% PM;

DM (894 g/kg), OM (955 g/kg), CP (147 g/kg), NDF (430 g/kg), ADF (270 g/kg), ash (42 g/kg)

Afar goats fed with 150–450 g pods < DM feed intake (469–509 g/d); < daily gain (26–62 g/d); ↓ WBC, ↓ RBC, ↓ Hob

DM (96%), OM (93%), CP (18%), CF (13%), EE (4%), ash (7%)

Marwari and Sihori breed goasts fed with 50% dried ground pods (DGP)/50% whole/un-ground pods (WUGP) < av. daily gain; < change in body weight

Manhique et al. 2017

Sirohi et al. 2017

Abor acres broilers fed with 10–30% milled mature pods DM (89-90), CP (11-23%), CF (4-18%), ash (3-12%), EE (3%), ME Odero-Waitituh et (MPM) (12-13 MJ/kg), TEP (55-80 mg/g) al. 2016 ≤ av. daily feed intake; < av. daily gain Cobb 500 broilers fed with 5–15% PM (–/+ enzyme) incorporated into feed ≥ feed intake and daily gain; ≥ apparent metabolizable energy and fibre digestibility ↑ RBC, ↑ HB, ↓ creatinine, ↓ AST, ↓ ALT

Al-Marzooqi et al. 2015

DM (89%), OM (98%), CP (12%), NDIP (0.1%), ADIP (0.04%), EE Santa Ines sheeps fed with 15-45% PF incorporated into (1%), TC (85%), NFCcorr (53%), NDFap (30%), ADF (28%), Lig. feed (5%), Cel. (24%), HC (4%) > acceptability (> DM intake); > digestibility

dos Santos et al. 2015

Local male goats fed with 10–40% pod flour (PF) DM (88–94%), CP (13–16%), CF (18–24%), EE (2–5%), ash (2– > feed intake (580–677 g/b/d), ≥ av. body weight gain for 6%) 10%/40% PF

Hintsa et al. 2015

DM (87–90%), CP (13–23%), CF (4–18%), Fat (2–3%), EE (1%), ash (5%), ME (13–14 MJ/kg), GE (19 MJ/kg), Lign. (4%), Cel. (32%), HC (13%), TNSP (28%), tannin (2 g/kg)

Table 4 contd. ...

Nutritional Benefits of Medicinal Plants Used for Animal Feed 25

KALRO-improved indigenous chickens fed with 10– DM (944 g/kg), CP(126 g/kg; 16%), CF (192 g/kg; 5–11%), EE (19 g/kg), 30% PM NDF (459 g/kg), ADF (297 g/kg), ash (44 g/kg), ME (13–17 MJ/kg) < live weight change; ≤ egg production, > production for 10%; < body weight gain

Hassen et al. 2017

Bromatological/chemical analysis

Nutritional/therapeutic effects on animals

Galla goats fed with 100–400 (g/b/d) seedpod flour (SPF) DM (88.4 ± 0.3%), OM (83 ± 3%), CP (18.5 ± 0.3%), ash (5.2 ± ≥ total feed intake (24–40 kg); > total weight gain 0.7%), NDF (52 ± 4%), ADF (29.8 ± 0.1%), ADL (3.2 ± 0.4%) (2–4 kg); ↑ digestibility DM (896–898 g/kg), OM (929–932 g/kg), CP (219–242 g/kg), NDIP (146–200 g/kg), ADIP (15–16 g/kg), EE (112–130 g/kg), TC Santa Ines × Dorper lambs fed with 14–43% PF (560–598 g/kg), NFC (216–246 g/kg), NFCcorr (265–296 g/kg), > intake for 29% PF (TDN: 80 g/kg), < for 14%/43% PF NDF (335–356 g/kg), NDFap (294–306 g/kg), ADF (174–230 g/ kg), Lig. (42–51 g/kg) DM (897–928 g/kg), OM (845–853 g/kg), CP (42–167 g/kg), NDF Afar rams fed with 10–30% pod meal (PM) (371–755 g/kg), ADF (236–472 g/kg), ADL (57–75 g/kg), hemicel. > weight gain (780–990 g); > feed and nutrient intake; (135–289 g/kg), cel. (161–414 g/kg) > digestibility Malpuma rams fed with 13–40% PM incorporated into OM (922 g/kg), CP (183 g/kg), NDF (391 g/kg), ADF (276 g/kg), feed ADL (62 g/kg), ash (78 g/kg), hemicel. (115 g/kg), cel. (215 g/kg) > total DM intake (684–748 g/d); > av. daily gain (34–72 g/kg) Boran x Fresian crossbred cows fed with 10–50% PM incorporated into feed DM (88%), OM (95%), CP (15%), ash (5%), NDF (41%), ADF > total DM intake for 10–30%, < for 50%; ≥ milk yield (28%), Lig. (9%), DOMD (62%) for 10%/30%, < for 20%/50%; > protein content and total solids; ≥ fat content for 10–30% ,< for 50% Awassi ewes (and their lambs) fed with 12–25% pods DM (903–905 g/kg), OM (902–903 g/kg), CP (145 g/kg), NDF > DM intake for 12% pods; < final body weigth for ewes; (396–419 g/kg), ADF (224–250 g/kg), ME (2.5 Mcal/kg) < av. body weight gain for lambs (263–268 g/d); ↑ milk production, ↓ total solids, ↓ fat (g/kg), ↑ fat (g/d) DM (902–922 g/kg), OM (912–936 g/kg), CP (134–138 g/kg), EE Saanen goats fed with 15-47% PM incorporated into feed (19–29 g/kg), NDF (298–348 g/kg), ADF (133–236 g/kg), NDIP > intake for 15%/31% PM (TDN: 980–1010 g/d), < for (46–95 g/kg), ADIP (26–38 g/kg), TC (758–769 g/kg), NFC 47% PF; ≥ digestibility (411–471 g/kg), Lig. (51–54 g/kg)

References Kipchirchir et al. 2014 Pereira et al. 2014 Yasin and Animut 2014 Chaturvedi and Sahoo 2013

Kitaw et al. 2013

Obeidat and Shdaifat 2013 Pereira et al. 2013

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Part used as feed (preparation)

26

...Table 4 contd.

Ali et al. 2012

Girma et al. 2011a, b

Abedelnoor et al. 2009 Obeidat et al. 2008 Mahgoub et al. 2005 Ravikala et al. 1995 Ali et al. 2012

Abedelnoor et al. 2009

OM: organic matter, DM: dry matter, CP: crude protein, CF: crude fibre, EE: ether extract, ME: metabolizable energy, GE: gross energy, NFE: nitrogen-free extractives, NDF: neutral detergent fibre, ADF: acid detergent fibre, Lig.: lignin, HM: hemicellulose, Cel.: celullose, TC: total carbohydrates, TIU: trypsin inhibitor units.

Nutritional Benefits of Medicinal Plants Used for Animal Feed 27

Whole plant

DM (90%), CP (15%), NDF (30%), ADF (17%), ADL (4%), ash Afar sheeps fed with 30% pods (5%) > weight gain (50 g/b/d); > total DM intake (718 g/d) Hubbard Classic chicks fed with 10-30% PM DM (89–92%), CP (15–22%), CF (5–15%), EE (6–7%), NFE < feed intake; > live weight change for 10%, < live weight (47–48%), ash (6–11%), ME (2969–3112 kcal/kg), β-carotene change for 20–30%; > av. daily gain for 10%, < av. daily (82 µg/100 g) gain for 20–30%; ≤ mortality Bovans Brown hens fed with 10–30% PM DM (92%), CP (12–17%), CF (6–14%), EE (6–7%), NFE (50–52%), ≡ final body weight; > BW change for 20%, < for ash (6–14%), ME (2800–2865 kcal/kg), β-carotene (82 µg/100 g) 10%/30%; < egg mass; > egg weight for 30% DM (931–953 g/kg), CP (172 g/kg), CF (228 g/kg), ash (65 g/kg) Local goats and sheeps fed with DPF in vitro digestibility (DMD: 488 g/kg, OMD: 439 g/kg) Awassi lambs fed with 10–20% PM DM (891–894 g/kg), OM (866–918 g/kg), CP (172–174 g/kg), NDF > av. daily gain for 20% PM (273 g), < for 10% PM; (360–367 g/kg), ADF (179–180 g/kg), ME (3 Mcal/kg) ≥ digestibility; > pH DM (862–930 g/kg), CP (120–150 g/kg), EE (26–59 g/kg), ADF Omani native Batina and Dhofari goats fed with 10-30% (199–317 g/kg), NDF (335–402 g/kg), ash (4–79 g/kg) dry Meskit pod flour (DPF) 10–20% DPF: > weight gain (43–76 g/kg), > feed intake (463–500 g/d, 25–26 g/kg b.w.) CP (13%), EE (3–6%), CF (23–27%), NFE (46–56%), ash (5–10%) Lambs fed with 15–30% PM > av. daily gain and feed efficiency for 15% DM (91%), CP (18%), NDF (28%), ADF (18%), ADL (4%), ash Afar sheeps fed with 15% pod + leaf mixture (7%) > weight gain (24 g/b/d); > total DM intake (571 g/d) Local goats and sheeps fed with 5–15% leaves + 10% pods silage (LPS) in vitro digestibility (DMD: 381–541 g/kg, OMD: 247–485 g/kg) DM (390–984 g/kg), CP (188–256 g/kg), CF (210–288 g/kg), ash sheeps - av. live weight: > for 5% LPS, < for 10–15% (93–110 g/kg), ME (11 MJ/kg) LPS; < live body weight change; < growth rate; < DM intake goats - < av. live weight; < live body weight change; < DM intake; > milk production

28

Ethnobotany: Ethnopharmacology to Bioactive Compounds

on RBC, WBC, HB, AST and ALTS levels, which could be related to damage due to both the form and the amounts consumed as food of the untreated/treated plant.

Conclusion According to the plants under study, it could be concluded: (i) if application of any part of the medicinal plant is for animal feed, the potential risk of harm (toxicity/ death) in the animals should be evaluated/determined, because the active principles present in plants could cause any injury to the animals, if they are constantly/ permanently and long-term exposed to this type of food; (ii) for most of the cases, the palatability/acceptability of the feed by the animals was related to the presence of “bitter” bioactive principles, which must be removed (or their content reduced to the minimum amount) or decomposed by any treatment (washing/fermentation/thermal), which could go against whether the plant would be used to take advantage of the therapeutic effect; thus, perhaps a dilemma will arise over its use as a therapeutic (medicine) or a food; (iii) the nutritional versus veterinary potential (as therapeutic treatment) of medicinal plants and their nutritive/bioactive constituents can be better exploited if certain selection criteria (rejection/acceptance) are established, based on types of active/nutritive principles (content of alkaloids, cyanogenic glycosides, tannins/lignin/flavonoids/phenolics, terpenoids/saponins, phytates; content of proteins/fats/carbohydrates), application form (topic/baths/intake), dose (LD50 active principles; palatable/digestible concentration), toxicity (in vitro/in vivo LC50, effects on blood biochemical parameters) and use time (hours, days, months, etc.), and not least, the part of the plant (fruits/seeds/leaves/roots/stems).

Acknowledgements The authors thank: Universidad Santo Tomás de Aquino (sede Bucaramanga) by using of the Bibliometric Unit; Colciencias-SGR [Formación de Capital Humano (N.M.P. and C.P.G., Convocatoria No. 810, 2018 - Departamento de La Guajira)].

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Chapter 2

Resveratrol

Perspectives from Ethnobotanical uses to Health Applications José L. Martinez,1 Onder Yumrutas,2 Maite Rodriguez,3 Miguel Rios,4 Rao Zahid Abbas,5 Luisauris Jaimes4 and Ali Parlar 2,*

Introduction In today’s age, herbal medicines, which have become up to date once again with the helplessness of modern medicines in newly emerging diseases, have become the focus of people, researchers, and pharmaceutical companies. In particular, a war has been started against the SARS-COV-2 (Covid-19) virus, which broke out in Wuhan, China in 2019 and affected the world in a short time. Although efforts to find an effective drug on the one hand and vaccine studies on the other hand accelerate, researchers have turned to bioactive substances of plants to repair the damage caused by Covid-19. Resveratrol, one of these bioactive substances, is especially concentrated in black grapes and their skins. In this context, 3,603 studies have been conducted on resveratrol since 2019. As indicated in Table 1, resveratrol is present in many plant species, such as juice, grape, purple, bilberry, cranberry, blueberry, peanut, and rapeseed (Parlar et al. 2021). Although many modern medications (e.g., anticholinergics, β-adrenergic agonists, steroids, antihistamines, antileukotrienes, and phosphor-diesterase inhibitors) through direct therapy are used to treat asthma to date, a significant number of patients experience repeated asthmatic attacks (Parlar et al. 2021). Vicerrectory of Research, Development and Innovation, University of Santiago de Chile, Santiago, Chile. 2 Departament of Pharmacology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey. 3 School of Chemistry and Pharmacy, Faculty of Medicine, Andrés Bello University, Santiago, Chile. 4 Department of Biology, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile. 5 Department of Parasitology, University of Agriculture, Faisalabad-38040, Pakistan. * Corresponding author: [email protected] 1

Table 1. The studies of plants containing resveratrol. Species

Family

Quantification of resveratrol

Research type

Study

Year

1940

Veratrum grandiflorum (Maxim.) Loes. f

-­

Review

--

Takaoka (“Takaoka, M.J. (1940) of the Phenolic Substances of White Hellebore (Veratrum grandiflorum Loe. fil.). J Faculty Sci Hokkaido Imperial University, 3, 1-16. - References Scientific Research Publishing,” n.d.)

Rumex japonicus Houtt.

-­

Chemical research

UV spectra

Aritomi (Aritomi et al. 1965)

1964

62.1 %

Chemical structure

HPLC

Hillis (Hillis and Inoue 1967)

1967

6.79-2H, d, J = 8Hz

Chemical research

X-rays

Anjaneyulu (Anjaneyulu et al. 1984)

1984

-­

Chemical research

Spectroscopic analysis

Suzuki (Suzuki et al. 1987)

1987

7.30, 3H, d, J = 8.5 Hz

Chemical structure

UV spectra

Lins (Lins et al. 1991)

1991

2300 ppm

Chemical research

GC/MS

Powell (Powell et al. 1994)

1994

1H, d, J = 2.0 Hz

Chemical structure

UV spectra

Tanaka (Tanaka et al. 1998)

1998

30 µM

Chemical research

Enzyme assay

Zhou (Zhou et al. 1999)

1999

Nothofagus fusca Hook. f.

Nothofagaceae

Bauhinia racemosa Lam. Carex fedia var miyabei (Franchet) T. Koyama Parthenocissus tricuspidata (S. et Z.) Planch. Lolium perenne L. Parthenocissus quinquefolia (L.) Planch. Veratrum taliense Loes. f.

Cyperaceae

Table 1 contd. ...

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 45

Measurement method

Quantification of resveratrol

Research type

Measurement method

Study

Year

ED50 values = 10 to 50 μM vs. 5 × 10−8 M 20-hydroxyecdysone)

Chemical research

HPLC

Sarker (Sarker et al. 1999)

1999

6.21, 2H, d, J = 2 Hz

Chemical structure

UV spectra

Adesanya (Adesanya et al. 1999)

1999

7.23 1H, d, J = 16.4 Hz

Chemical structure

UV spectra

Syah (Syah et al. 2000)

2000

161.7 ng/g

Chemical research

UV spectra

Huang (Huang et al. 2000)

2000

429.6 ng/g

Chemical research

Spectroscopic analysis

Tanaka (Tanaka et al. 2001)

2001

16.3 ng/g

Chemical research

chromatographed

Xiang (Xiang et al. 2002)

2002

7.65, d, J = 15.9 Hz

Chemical structure

Ultraviolet (UV) spectra

Shu (Shu et al. 2002)

2002

Ranunculaceae

59 mg/0.18 g

Chemical research

HPLC

Kim (Kim et al. 2002)

2002

Dipterocarpaceae

-­

Chemical research

Spectroscopic analysis

Ito (Ito et al. 2003)

2003

Ericaceae

36 NG/G

Chemical research

LC-MS/MS

Lyones (Lyons et al. 2003)

2003

6.33 (1H, d, J2.5 Hz)

Chemical research

X-rays

Liu (Liu et al. 2004)

2004

Family

Paeonia suffruticosa (Andr.) Kerner Cissus quadrangularis L. Morus macroura Miq. Gnetum hainanense C. Y. Cheng Gnetum parvifolium (Warb.) C. Y. Cheng ex Chun

Gnetaceae

Gnetum montanum Markgr Smilax bracteata Presl Paeonia suffruticosa Andr. Vatica pauciflora (Korth.) Bl. Vaccinium myrtillus Linn. Caragana stenophylla Pojark.

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Species

46

...Table 1 contd.

1H, d, J = 1.5 Hz, H-6

Chemical structure

Ultraviolet (UV) spectra

Xu (Xu et al. 2004)

2004

Grossulariaceae

97.8%

Chemical research

capillary zone electrophoresis

Ehala (Ehala et al. 2005)

2005

0.26–4.67 µG/G

Chemical research

GC/MS

Rimando (Rimando and Barney 2005)

2005

0.288 mg/mL

Chemical research

HPLC

LI (LI et al. n.d.)

2007

Ampelopsis japonica (Thunb.) Makino

5.2 mg/500 mg

Chemical research

HPLC

Kim (Kim et al. 2007)

2007

Ammopiptanthus mongolicus (Maxim. ex Kom.) Cheng f.

7.46 (dd, J ¼ 6.5, 2.0 Hz, 2 H)

Chemical research

X-rays

Tian (Tian et al. 2008)

2008

Arachis hypogaea Linn.

9.49 mg/mL

Chemical research

HPLC

Chukwumah (Chukwumah et al. 2009)

2009

Pinus sylvestris L.

0.529.6 mg/g

Chemical structure

MS/MS

Li (Li et al. 2009)

2009

Medicago sativa L.

0.1 ± 0.08 nmol/g tissue

Chemical research

HPLC

Kineman (Kineman et al. 2010)

2010

23.7 to 105.5 mg % in six different mulberry cultivars.

Chemical research

NMR spectral analysis

Choi (Choi et al. 2013)

2013

62.89 g/L

Chemical research

HPLC

Y (Qi et al. 2012)

2013

2H, d, J = 2.0 Hz.

Chemical structure

NMR spectral analysis

Abbas (Abbas et al. 2014)

2014

0.56 × 10–2 ng/mL

Chemical research

Chemical analysis

Silva (Da Silva et al. 2014)

2014

Ribes nigrum L. Vaccinium haitangense Sleumer Smilax glabra Roxb

Morus alba L. Vigna umbellata (Thunb.) Ohwi et Ohashi Morus nigra L. Ananas comusus (L) Merr.

Bromeliaceae

Table 1 contd. ...

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 47

Myrcinaceae

Aegiceras corniculatum (Linn.) Blanco

Cinamomum spp.

Family

Quantification of resveratrol

Research type

Measurement method

Study

Year

Lauraceae

76.82 g/L

Chemical research

HPLC

Muangthai (Muangthai et al. 2014)

2014

0.009 µg/mL

Chemical research

HPLC

Ji (Ji et al. 2014)

2014

CD spectra

Chen (Chen et al. 2015)

2015

Vitis amurensis Rupr. Cudrania cochinchinensis Lour.

6.30 (1H, dd, J = 8.0, 2.0 Hz, H-8

Vaccinium oxycoccos Linn.

533.4 ng/g

Chemical research

HPLC

Česoniene (Česoniene and Daubaras 2015)

2015

6030 ± 680 µg/g

Chemical research

LC/MS

Soural (Soural et al. 2015)

2015

Pinus koraiensis Sieb. et Zucc.

0.322 mg/mL

Chemical structure

HPLC

Lee (Lee et al. 2016)

2016

Artocarpus lakoocha Roxb.

85.00 mg/kg

Ultraviolet-visible

Borah (Borah et al. 2017)

2017

Vitis vinifera L.

Vitaceae

51.0 ± 7.6 vs 29.6 ± 11.3 µM

Animal research

Antioxidants activity

Gadani (Gadani et al. 2017)

2017

Ornithogalum caudatum Jacq

0.549 mg/g

Chemical research

HPLC

Yuan (Yuan et al. 2018)

2018

Veratrum maackii Regel

0.478 mg/g

Chemical research

HPLC

Wu (Wu et al., 2018)

2018

8000 IU

Animal research

Anti-oxidant activity

Rajkumari (Rajkumari et al. 2018)

2018

65.15-55.35 %

Chemical research

TLC, HPLC

Irnidayanti (Irnidayanti and Sutiono 2019)

2019

Camellia sinensis

Syzygium jambos (L.) Alston Glycine max (Linn.) Merr.

Theaceae

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Species

48

...Table 1 contd.

Rubus chingii Hu Veratrum nigrum L. var. ussuriense Nakai

-­

Review

-­

Review

712.3 ng/g

Smilax scobinicaulis C. H. Wright Alnus spp., Aster tataricus L. f., Syneilesis aconitifolia (Bge.) Maxim, Vaccinium dendrocharis Hand. -Mazz., Vaccinium chaetothrix Sleumer, Vaccinium moupinense Franch., Vaccinium sikkimense C. B. Clarke, Euphorbia humifusa Willd. ex Schlecht., Poa annua L, Festuca ovina L. Stipa tianschanica (Roshev.) Norl, Stipa tianschanica (Roshev.) Norl

-­

Yu (Yu et al. 2019)

2019

-­

Wu (Wu et al. 2018)

2020

Chemical research

HPLC

Borowska (Borowska et al. 2009)

2020

Abstract

Chromatographic

Wang (Wang et al. 2013)

2020

Review

--

Tian (Tian and Liu 2020)

2020

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 49

Vaccinium microcarpum (Turcz. ex Rupr.) Schmalh.

Rosaceae

50

Ethnobotany: Ethnopharmacology to Bioactive Compounds

The use of resveratrol in medicine dates back to ancient times. Resveratrol, which was first used in wound healing, has proven to have anti-cancer, antioxidant, antibacterial, and anti-inflammatory effects in later studies (JK and YJ 2008, Parlar and Arslan 2019). Moreover, after the coronavirus caused a pandemic in 2019, it was investigated whether the effects of resveratrol on the elimination of respiratory difficulties due to fibrosis is caused by the corona virus (Fei et al. 2020), especially in the lungs (S et al. 2019). In addition, long-term and excessive use of some of these drugs, especially nonsteroidal anti-inflammatory drugs (NSAID) and corticosteroids, can cause undesirable side effects, such as gastrointestinal toxicity, addiction, drug resistance, and induction of Cushing´s syndrome (Hodgson 2015). It was investigated whether resveratrol has curative effects in lung diseases, such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and pneumonia.

Asthma and Resveratrol Asthma is a response of the body to a variety of endogenous and exogenous stimuli, characterized by spontaneous airway contraction. About 300 million people worldwide are affected by asthma (Parlar and Arslan 2020). Various cytokines, mast cells, T cells, neutrophils and eosinophils play a role in asthma (Kay 1996). Moreover, asthma is accompanied by mucus secretion, contraction of the smooth muscles of the airway, and edema. The main symptoms are gasping for breath, growling, and coughing. The pathology of asthma is characterized by epithelial fibrosis, hyperalgia and metaplasia of goblet cells, and hyperplasia and hypertrophy of airway smooth muscle cells (Shinagawa and Kojima 2003). In the immune response, plasma proteins and inflammatory cells migrate from blood vessels to airway cells and then into the brongioalveolar fluid (MF et al. 2020). This microvascular escape increases with the severity of inflammation and fills the alveolar space as a result of endothelial loss. In the bronchialveolar fluid, bronchoconstriction occurs as a result of excessive increase in IgE levels of inflammatory mediators, tumour necrosis factor-α (TNF-α), and interchoins (Thakur et al. 2018). It is known that eosinophils play an important role in both innate and acquired immunity (Shamri et al. 2011). In airway inflammation, the amount of eosinophils increases in both serum and bronchialveolar fluid. This increase is associated with the production of IgE, IL-4 and TNF-α (Vuolo et al. 2015, Ghorani et al. 2018). It is very difficult to control the severe form of asthma, even with current therapeutic agents, and relapse is common when treatment is discontinued in children (Yang et al. 2013). Moreover, due to the undesirable side effects of modern drugs, researchers and pharmaceutical companies have turned to naturally-derived herbs to find a more effective treatment for asthma with fewer unwanted side effects. In this context, a lot of research has been done on resveratrol. Due to the anti-inflammatory and anti-oxidative effects of resveratrol, researchers have tried to establish ovalbumin­ induced asthma models in experimental animals and tried to reveal the therapeutic properties of resveratrol by measuring the amounts of inflammatory cytokines and cells in respiratory function tests, brongioalveolar fluid and serum, as well as its

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 51

undesirable side effects. In this context, the ovalbumin-induced animal model plays a key role in allergic asthma. Resveratrol reduces the severity of asthma by inhibiting the activation and degranulation of eosinophils, which play an important role in asthma (YC et al. 2009). Studies have shown that both serum and bronchio-alveolar fluids (BALs) significantly reduce the levels of interleukin and cytokines of immune mast cells, thus reducing airway hyperresponsiveness and airway inflammation (Y and LH 2008). In addition, resveratrol regulates differentiation of T helper-1 to Thelper-2 via Tbet/GATA binding protein 3 (M and B 2016). The contribution of the NF-kB pathway plays an important role in the ameliorating effect of resveratrol on bronchial asthma (SK et al. 2000). In a study, 50 µM/L resveratrol significantly reduced rat airway pathological lesions, while 10 µM/L resveratrol had no effect (Jiang et al. 2019). Moreover, resveratrol significantly reduced HMGB1, TLR4, MyD88 and NF-κB mRNA levels (Jiang et al. 2019). In the ova-induced mouse model of asthma, resveratrol significantly decreased serum TGF-β, IL-4, IL-5 and IL-13 levels and lung total Th2 cell counts (E et al. 2018). Moreover, resveratrol inhibits the progression of asthma by upregulating the phosphatase-tensin homolog and the sirtuin1 signaling pathway. Sirtuin 1 protects the lung against oxidative stress by upregulating the calase, superoxide distumza 1 and 2 genes by causing the receptor γ coactivator 1α activity to be activated by the peroxisome proliferator (G et al. 2015). This transforms growth factor-β1, which binds to the TGF receptor, promotes the synthesis and deposition of the extracellular matrix, and enables it to be activated against the decapentaplegic homologous pathway, resulting in fibrosis. As a result, it leads to the development of epithelial-mesenchymal transition in lung tissues, increased expression of α-smooth muscle actin, and decreased expression of E-cadherin. Resveratrol reduces TGF-β1 expression, suppresses TGF-β1/Smad2/3 signalling, and epithelial-mesenchymal transition process, effectively ameliorating airway structural changes and inflammation (Lee et al. 2017). Stimulation of TNF-α or IL-1 leads to secretion of high mobility group box 1 by immune cells, such as macrophages and mononuclear monocytes and activation of TLR2 and TLR4 (L et al. 2020). Resveratrol reduces serum levels of inflammatory cytokines, such as IL-1, IL-10, and TNF-α by reducing multiple inflammatory cell infiltration into the airway epithelium, airway collagen deposition, and the HMGB1/TLR4/NF­ kB pathway (Jiang et al. 2019). Insulin signalling in the lungs plays an important role in obesity-associated asthma exacerbations. Recently, researchers found that Resveratrol markedly abrogates pulmonary eosinophil infiltration and insulin resistance in obese-associated insulin-resistant mice. Resveratrol also significantly increased the expression of phosphorylated AMP-activated protein kinase, decreased the expression of p47phox and TNF-α, and inhibited the production of reactivated oxygen species in the lung tissues of obese mice (André et al. 2016). In addition, André et al. showed that resveratrol ameliorates allergic airway inflammation and obesityassociated asthma exacerbations by restoring insulin-induced phosphorylation of Akt, insulin receptor substrate 1 and insulin receptor β, reducing JNK and NF-kB signalling pathways (DM et al. 2017). Studies on the use of resveratrol-containing plant species in asthma are given in Table 2.

52

Ethnobotany: Ethnopharmacology to Bioactive Compounds Table 2. The use of plants containing resveratrol in asthma.

Species

Methods of extract

Results

Research type

Study

Year

Shema Zhichuan

Liquid

Plasma viscosity ↓ Lung function ↑

Review

Bo-ning (Ma and Li 2020)

2020

Shegan Mahuang Decoction

Decoction

VEGF ↓

Clinical reseach

Zhang (YQ et al. 2015)

2015

Baihe Gujin

Decoction

Cough ↓

Clinical reseach

Hai-Bo (HB and J 2020)

2020

Pneumonia and Resveratrol It is a pathological reaction characterized by cough and dyspnoea, causing pneumonia, lung, or pulmonary parenchymal infection, which results in lung infection, malaise, and ultimately death. After the new type of coronavirus did not cause a pandemic in Wuhan, China in December 2019, researchers found that the new coronavirus caused severe acute respiratory syndrome. Moreover, they found that the coronavirus binds to the angiotensin-converting enzyme-2 receptor in humans. Moreover, the researchers showed that the nucleotides of both coronavirus types that cause pneumonia are identical (Lu et al. 2020). A study in mice reveals that SARS-CoV causes acute lung injury and eventual death. In 2016, Li et al. suggested that resveratrol inhibits the replication and cytotoxic effect of the SARS virus (Li et al. 2006) and that resveratrol may have a potential therapeutic role in severe acute respiratory syndrome caused by SARS-CoV-2. In cases of pneumonia caused by Serratia marcescens, use of resveratrol for 3 days increased NK cell and macrophage activity, and also decreased the severity and bacterial burden of pneumonia (Lu et al. 2008, Long et al. 2016). Nuclear erythroid-associated factor 2 is a transcription factor involved in the inducible expression of a number of antioxidant and detoxification enzymes, including glutamate-cysteine ligase (J et al. 2018a, S et al. 2018). Moreover, Resveratrol reduced the severity of smoking-induced pneumonia in mice by decreasing DNA binding of NF-κB and increasing heme oxygenase-1 activity (Liu et al. 2014). Besides, emerging studies reported the therapeutic effects of resveratrol in the treatment of asthma in other mouse models. Respiratory syncytial virus (RSV) infections cause lower respiratory tract infections in children and also play an important role in old people with asthma. Recent studies have indicated that RSVmediated airway inflammation and AHR were alleviated by resveratrol via regulating TLR3 expression and suppressing the TRIF signaling pathway in mice. Furthermore, emerging studies have reported therapeutic effects of resveratrol in the treatment of asthma in other mouse models. Respiratory syncytial virus (RSV) infections cause lower respiratory tract infections in children and play an important role in the elderly with asthma. Recent studies have shown that RSV-mediated airway inflammation and AHR are alleviated by resveratrol by regulating TLR3 expression and suppressing the TRIF signaling pathway in mice. Information on the use of some plants containing resveratrol in pneumonia is given in Table 3.

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 53 Table 3. The use of plants containing resveratrol in pneumonia. Species

Methods of extract

Results

Research type

Study

Year

Banxia Houpu

Decoction

Temperature and white blood cell ↓

Clinic research

Zhang (Zhang n.d.)

2016

Shegan Mahuang

Decoction

Temperature and cough ↓

Clinic research

Cheng (Lin et al. 2020)

2020

Sangxing

Decoction

Temperature and cough ↓

Clinic research

Zhao (Zhao et al. 2020)

2020

Qingfei Huatan

Decoction

Temperature and cough ↓

Clinic research

Xue (Xue and Da 2021)

2021

Maxing Shigan

Decoction

Temperature and cough ↓

Clinic research

Li (L et al. 2009)

2009

Sangpi Qingfei

Decoction

Temperature and clinical symptom ↓

Clinic research

Guo (Jiang et al. 2014)

2014

Huatan Sanren

Decoction

Temperature and clinical symptom ↓

Clinic research

Li (Y et al. 2020)

2020

Chronic Obstructive Pulmonary Disease and Resveratrol Chronic obstructive pulmonary disease (COPD) is an irreversible lung disease that causes shortness of breath, cough, nasal congestion, more phlegm, chest tightness, and persistent inflammation. In COPD, excess mucus is secreted as a result of lung parenchyma inflammation. Excessive mucus secretion is caused by cigarette smoke, acute and chronic bacterial and/or viral infection. COPD is a disease that ultimately results in death and affects 9 million people by 2020 (Kim and Criner 2013). Despite modern drugs, there is no drug that completely stops the progression of COPD and has the ability to completely suppress inflammation. Sirtuin 1, a NAD+-dependent type III histone/protein deacetylase that regulates cellular aging, inflammation, and stress resistance, is activated by resveratrol, and thus Sirtulin 1 can reduce COPD. It is known that the decreased expression of AMP-activated protein kinase in COPD is stimulated by Sirtuin 1 (Y et al. 2014) and resveratrol-induced SIRT 1 may be a therapeutic target for COPD treatment. Alveolar epithelial type 2 cell senescence involved in the pathogenesis of COPD is regulated by the SIRT1/p53 signaling pathway. It mediates the protection of alveolar epithelial type 2 cells by activating p53 kinase B and murine double minute 2 signal, whose destabilization is promoted by sirtuin 1 expression by resveratrol (S et al. 2017, 2018). Resveratrol causes the recovery of COPD by suppressing the granulocytemacrophage colony-stimulating factor, which is triggered by TNF-α and IL-6, which have an important role in the inflammatory response. Moreover, resveratrol has been reported to inhibit the T-cell inflammatory response of IL-8 (J et al. 2019). Due to the increase in oxidative stress parameters in COPD, studies conducted so far show that oxidative stress parameters, such as catalase and superoxide dismutase have an important role in lung diseases. In this context, sirtuin 1 activated by resveratrol activates the peroxisome proliferator-activated receptor γ coactivator-

54

Ethnobotany: Ethnopharmacology to Bioactive Compounds

1α. As a result, upregulated antioxidant genes protect the organ against oxidative stress (M et al. 2017, J et al. 2018a, R et al. 2018, Y et al. 2019).

Idiopathic Pulmonary Fibrosis and Resveratrol Idiopathic pulmonary fibrosis (IPF), a chronic and fibrotic lung disease, with excessive accumulation of extracellular matrix proteins characterized by progressive scarring of the lungs, leads to destruction of lung structure and function, impaired gas exchange, and ultimately fatal consequences (Richter et al. 2015, T and S 2018). Bleomycin, used to induce experimental fibrosis, mediates peroxidation of membrane lipids and generation of reactive oxygen species that cause DNA damage (Arslan et al. 2002). IPF causes an immediate inflammatory response. It causes inflammatory cells to produce cytokines, such as TNF-α, interlockin, prostaglandin, and TGF-β. Moreover, TGF regulates mRNA and protein expression of α-SMA via the Smad2/3 pathway. Resveratol contributes to IPF healing by inhibiting TGF-βinduced collagen production and lung fibroblast proliferation (E et al. 2011, YQ et al. 2015). Furthermore, resveratrol inhibits lung fibrosis by decreasing the expression of E-cadherin, collagen I, and α-SMA in the lung through activation of sirtuin-1 (R et al. 2020). Resveratrol inhibits the proliferation and collagen deposition of Kinase-1 fibroblasts activated by TGF-β (J et al. 2017). When epithelial cells become damaged, cytokines, growth factors, and various proteases are secreted, which cause fibroblasts to migrate to the damaged area, activate, and proliferate (Zhao et al. 2020). Studies have shown that by inhibiting the proliferation of fibroblasts, resveratrol mediates the preservation of the integrity of alveolar epithelial type 2 cells and contributes to the preservation of lifespan and health (S et al. 2017, YR et al. 2018).

İschemia/Reperfusion and Resveratrol Ischemia-reperfusion (I/R) of tissue is a serious pathological condition. Surgical procedures can cause disruption of barriers, tissue disruption, and increased permeability of tissues. Moreover, with increased permeability of blood vessels, it causes the migration of plasma proteins, polymorph nuclear leukocytes into the tissue, causing the initiation of the inflammatory process. In addition, some serious cellular mediators in I/R play an important role in the pathogenesis of tissues. We previously reported that resveratrol inhibited the increases in cytokines induced by intestinal I/R in rats (Parlar and Arslan 2019). Intestinal I/R reduces the motility of smooth muscles that are not associated with intestinal cholinergic receptors. Resveratrol improved 24-hour reperfused bowel motility. Cerebral ischemia reduces the uptake of oxygen and glucose to the brain and eventually causes reactive oxygen species, tissue damage, and general metabolic syndrome. Adenosine monophosphate, the sensor of cellular energy metabolism, regulates autophagy, removes damaged mitochondria, and increases energy sources. Resveratrol triggers protein kinase-dependent signaling, which plays a role in the regulation of all these events (N et al. 2020). Renal ischemia/reperfusion, one of the major causes of acute kidney injury, can result in renal failure by causing nephropathy. I/R not only causes kidney damage

Table 4. The use of resveratrol on some diseases. Model

Research type

Study

Year

TNF-α ↓ IL-1β ↓ Intestinal muscle contractility ↑

Animal Research

Parlar (Parlar and Arslan 2019)

2019

Intestinal I/R

NO production ↓ Sirtuin-1 ↑ NF-kB ↑

Animal Research

Dong (W et al. 2013)

2013

Intestinal I/R

CSE/H2S ↓ iNOS/NO ↓

Animal Research

Wang (W. Z et al. 2019)

2019

MPO ↓ NO production ↓ GSH production ↑

Animal Research

Borges (SC et al. 2018)

2018

Intestinal I/R

MDA ↓ Protein level ↓

Animal Research

Yildiz (F et al. 2009)

2009

Intestinal I/R

Tissue protection ↑ MPO ↓ NO production ↓ GSH production ↑

Animal Research

Borges (SC et al. 2016)

2009

Intestinal I/R

nNOS ↓ neuronal population ↓

Animal Research

Borges (SC et al. 2016)

2016

Intestinal I/R

MPO ↓ Thiobarbituric Acid-Reactive ↓

Animal Research

Petrat (F and H 2011)

2011

Cerebral I/R

Behavioural healt ↑ Lamina Propria Lymphocytes ↓ Vascular permeability ↓

Animal Research

Dou (D. Z et al. 2019)

2019

Cerebral I/R

Neurological function improves Adenosine monophosphate-activated protein kinase ↓

Animal Research

Ramírez (N et al. 2018)

2018

Ileum I/R

Resveratrol-loaded nanoparticle/ intestinal I/R

Table 4 contd. ...

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 55

Mechanism of action

Mechanism of action

Research type

Study

Year

Cerebral I/R

Sirtuin-1 ↑

Animal Research

Grewal (AK et al. 2019)

2019

Cerebral I/R

M2 polarization of microglia Reduced neuroinflammation Inhibition miR-155

Animal Research

Ma (M. S et al. 2020)

2020

Cerebral I/R

Cellular redox ↓

Animal Research

Burgos (I et al. 2020)

2020

Cerebral I/R

TLR4 downregulation

Animal Research

Lei (JR et al. 2019)

2019

Myocardial I/R

Inflammasome markers ↓ NF-κB ↓ IL-1β ↓ IL-6 ↓ TNF-α ↓

Animal Research Cell culture

Feng (H et al. 2020)

2020

Myocardial I/R

Myocardial Nrf2 expression ↓

Animal Research

Xu (G et al. 2019)

2019

Myocardial I/R

Lactate dehydrogenase ↓ creatine kinase-MB ↓ alleviate ventricular arrhythmia

Animal Research

Kazemirad (H and HR 2020)

2020

Myocardial I/R

Reduce neutrophil accumulation and TNF-α via modulating TLR4/NFκB signalling

Animal Research

Li (J et al. 2015)

2015

Activating of SIRT1 Inducing protective autophagy Inhibiting Akt/mTOR Activating p38-MAPK

Cell Culture

Wang (J et al. 2018b)

2018

Colon Cancer

Inhibits the invasion and metastasis via AKT/GSK3β/ Snail signalling pathway

Cell Culture

Yuan (L et al. 2019)

2019

Breast Cancer

Inhibits the Migration and Metastasis of MDA­ MB-231 reversing TGF-β1

Cell Culture

Sun (S. Y et al. 2019)

2019

PRMT5 Promotes Apoptosis via Akt/Gsk3β Signalling Induced

Cell Culture

Li (L. Y et al. 2019)

2019

Non-small-cell lung cancer

Human Lung Cancer Cell

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Model

56

...Table 4 contd.

Resveratrol: Perspectives from Ethnobotanical uses to Health Applications 57

and dysfunction, but can exacerbate oxidative stress, inflammation, and apoptosis of I/R (M et al. 2020). Renal I/R causes energy deficiency, oxidative damage, and metabolic dysfunction. In the physiopathology of I/R, it causes increased reactive oxygen species, abnormal lipid metabolism, excess calcium overload, and nitrosoredox imbalance in kidney tissue. It also causes the release of cytokines such as TNF-α. Resveratrol protects the tissue against damage by inhibiting TNF-α in the renal I/R and regulating the impaired energy balance (S et al. 2020). It has been reported that resveratrol protects the heart against I/R damage by upregulating the decreased Nrf2 expression in myocardial I/R damage (G et al. 2019). Information on the use of resveratrol in various disease models is given in Table 4.

Lung Cancer and Resveratrol Lung cancer is a type of cancer that causes a lot of death in men and women around the world. Researchers are trying to find new approaches for cancer, which has not yet found a definitive cure. Since the therapeutic index of anticancer drugs is narrow, their side effects are quite high. Therefore, among the new approaches is the orientation of researchers to plant extracts. In addition, chemoprevention studies are among the new approaches. In this context, resveratrol novel chemoprevention is a phytochemical, which are non-nutritive products of plants. Whether these chemoprevention agents are useful in the prevention of many diseases, including cancer, is being investigated in the world (RH 2004). Resveratrol prevents cancer by suppressing TGF-β-induced epithelialmesenchymal transition, decreasing the rate of hepatic and lung metastases, decreasing E-cadherin expression, increasing vimentin expression, and activating TGF-β1/Smads signaling pathway (Q et al. 2015, Rauf et al. 2017).

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Chapter 3

Coffee and Folk Medicine Mechanisms and Activities

Filipe Kayodè Felisberto dos Santos, Ian Gardel Carvalho Barcellos Silva, Arquimedes Lopes Nunes Filho and Valdir Florêncio da Veiga Júnior*

Introduction Coffee is one of the most consumed beverages around the world, having spread from East to West. It is appreciated both for its pleasant taste and aroma, as well as for its functional properties, which are associated with the presence of carbohydrates, lipids, amino acids, phenolic compounds, and minerals (Lim et al. 2019). Historically, coffee has represented a milestone in the development of several countries, including Brazil, such as the construction of railways and ports for the production flow. Today, Brazil is responsible for 30% of the international market, being the foremost producer of raw coffee beans and the second greatest consumer market for the beverage, with most of the produce coming from the State of Minas Gerais specifically. Combined with this data, it is important to highlight the chemical composition of the coffee beans. There are several studies in the literature on the chemical constituents of coffee, mainly on a pseudo-alkaloid, caffeine, and its proven stimulating effect via direct action on the central nervous system (CNS). Another compound group of importance is the chlorogenic acids, which have high antioxidant activity. Lipids also represent a key set of substances present in the raw coffee bean. In this fraction, the presence of triacylglycerides and the kauran diterpenes occur mainly as cafestol and kahweol (Trugo and Macrae 1984, Trugo et al. 1991, Weusten-Van der Wouw et al. 1994, Chou and Benoxitz 1994, Damodaran et al. 2010, Tsukui et al. 2014, ABIC 2016, Novaes et al. 2019, Debastiani et al. 2019, Jeon et al. 2019, Rahn et al. 2019).

Chemical Engineering Section, Laboratory of Organic Bioprocesses, Military Engineering Institute, Rio de Janeiro, Brazil. * Corresponding author: [email protected]

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This chemical complexity has allowed coffee to be used as a medicinal tool. Many investigations, epidemiological studies, and meta-analyses on coffee consumption have revealed its inverse correlation with that of diabetes mellitus, several forms of cancer, Parkinsonism, and Alzheimer’s disease. This chapter aims to list clearly and objectively, the most recent studies involving the application of coffee and its bioactive chemical compounds in the treatment of the most diverse diseases.

Historical use The origin of coffee plant is not known for sure, but it is known that the coffee tree is a plant native to high-altitude regions of Ethiopia, specifically Kafa and Ennarea. There are some fables that allude to the consumption of this fruit, the first of which states that a shepherd was curious after noticing that his goats were more excited after eating a plant. The shepherd took the coffee seed to the tribe’s monk, who initially showed no faith in such an effect, but soon changed his mind after experiencing the plant’s aroma when burned (Crawford 1850, Smith 1985). The second fable concerns when Kaldi (an Ethiopian goat herder) took the seeds to a monk, who, after preparing a meal with the plant and its seeds, finally tasted it. The stimulating effect upon consumption motivated the religious to adopt the plant as a base for their stimulant, which they used during their night prayers. In general, it is assumed that coffee only entered human history after Yemenis of a Sufi Muslim order began to use the seed as a tea for their prayers. This is because Islam does not allow the consumption of alcohol (Crawford 1850, Allen 2003). In the religious context, Muhammad was the only prophet who showed interest in coffee. Although Yemenis have focused on exporting, for a century and a half, they have not traded this product with Western Europe. As it is linked to Islam, coffee was spread by pilgrims from Hajj to Mecca. Since then, it has been dissipated to Java, India, Persia, Turkey, Morocco, and West Africa. Between 1516 and 1517, the spread of coffee became embroiled in a battle when the ancient Mamluk state of Egypt was dominated by the Ottoman empire, during which it was a preferred product for consumption by imperial and military officers (Crawford 1850, Morris 2018). Countless times, coffee has been a source of dispute by governments and traders due to economic interests and commercial monopolies, in addition to being a strategic piece used by the military and in wars, due to its effect on increasing soldiers’ alertness. All the movement around this commodity, be it political, social, economic, and/or agricultural, motivated the scientific development of coffee. Furthermore, during the second half of the 17th century, it was recognized that coffee could fit another ecological niche as a medicinal aid (Smith 1996, Pendergrast 2010). The followers of galenic Hippocratic medicine, who dominated physiology from the 4th century BC until the 19th century, called coffee “the drink that balanced mood”, as according to the four individual temperaments at the time. Plant extracts were a large part of the therapeutic resources until the 19th century. Coffee, as infusions, capsules, syrups, or injections, was used as a remedy for almost all ailments or diseases, from hernias and rheumatism, to colds and bronchitis. In that same period, it was believed that coffee could also save the body’s nutritional reserves, and between the 19th and 20th centuries, researchers, like the French physiologist M. Gasparin,

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were able to observe that coffee reduced hunger. Friedlieb Ferdinand (1795–1867) accidentally discovered that the belladonna plant stratum would expand its eye pupil. He also discovered caffeine. Only in 1915 was the compound caffeine proven to increase metabolism (Gasparin 1850, Bizzo et al. 2015, Allen 2013). During the 18th century, several studies were carried out to explain the mechanisms of nervous and vasomotor stimulation caused by coffee. Ever since then, a significant number of researchers have endeavoured to study the chemistry and biological action of coffee (Fischer et al. 2019). In the 19th century, coffee was seen as an auxiliary resource in the treatment of various diseases, like cholera and malaria, as it had antiseptic properties. In the first studies of coffee bioactivity, the effects of coffee on the diameter of the artery and the frequency of the heartbeat were evaluated. These observations resulted in 27 publications between 1874 and 1913, in addition to a Nobel Prize in chemistry being won by Fischer for the studies of caffeine and other purines. Although there are discussions related to the effectiveness of coffee in resulting in positive health outcomes, studies using test results with 400,000 individuals have shown the opposite. In 1915, coffee was known to increase the metabolic rate, while in 1960, it was established as a potentiating agent in the energetic category. In the 2000s, caffeine was shown to activate energy metabolism, lipid oxidation, and the release of catecholamines (Fischer et al. 2019). There are studies showing that the use of coffee in specific dosages can treat type 2 diabetes. This is because its composition contains antioxidant substances and chlorogenic acids. Studies also show that coffee could be a potential combatant of the global pendency of obesity, in addition to already demonstrating positive results in the treatment of Alzheimer’s and prostate cancer. In 2009, the presence of a potential substance in the treatment of cancer was found to be present in coffee; this is a phytoestrogen called trigonelline. The existence of terpenes in the composition of coffee also induces cellular apoptosis of human leukemia cells. By-products originating from the toasting process of the coffee beans, such as methylpyridinium, are able to reduce the risk of colon cancer. Studies carried out between 1970 and 2011 showed that coffee intake is directly related to the reduction of the risk of cancer, stroke, and heart failure. However, the consumption of other substances, such as alcohol and tobacco, cut the benefit of coffee (Fischer et al. 2019).

Coffee and its Chemical Complexity Coffee quality is directly related to factors such as climate, soil, irrigation, genus, roasting, drying, etc. However, the flavour, aroma, and biological applicability can be attributed to the chemical constituents present in the red coffee bean. The production of chemical constituents within the bean is also a direct consequence of general planting conditions, such as harvesting, as well as the processing and storage of the final product. Regarding the planting site, coffee beans from C. canephora grown in Brazil have higher amounts of chlorogenic acid compared to the same species grown in Vietnam (Pinheiro 2021, Hall et al. 2015). Coffee consists of volatile and non-volatile substances, which vary from species to species. For example, species of C. arabica L. and C. canephora have different levels of chlorogenic acid, trigonelline,

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caffeine, and lipids (Figure 1). However, depending on the planting location, the percentage of substances can change from specimens of the same species, which will influence the final quality of the product (Sanz et al. 2002, 2001). Several processes are related to the formation of volatile compounds; among them are the Maillard reaction and the Strecker degradation that occur during the roasting step of coffee production. These processes lead to the formation of phenols, hydroxyamino acids, trigonelline, serotonin, carbohydrates, etc. In fact, more than 800 volatile substances have been identified during the roasting of coffee beans, including: furans (38–45%), pyrazines (25–30%), pyridines (3–7%), and pyrroles (2–3%), in addition to other substances, such as carboxylic acids, aldehydes, ketones, and sulfur compounds (Elhalis et al. 2021, Haile et al. 2020, Thammarat et al. 2018). Coffee roasting increases the phenolic content, with the most commonly found phenolic compounds being 4-vinyl guaiacol, guaiacol, and phenol. The formation of the phenolic compounds is directly related to the degradation of chlorogenic acids. Other classes of compounds can be found in lesser quantities, such as carboxylic acids that can be generated by sugar fragmentation, fatty acid degradation, and/or chlorogenic acid degradation (Naranjo et al. 2018, Abdelwareth et al. 2021).

Figure 1. Main bioactive compounds present in coffee beans. Figure 1. Main bioactive compounds present in coffee beans

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Some of the biologically active compounds beneficial to human health are chlorogenic acids, trigonelline, and caffeine. Chlorogenic acid is formed by the esterification reaction between trans-cinnamic acid and quinic acid, resulting in a compound with physiological, pharmacological, and antioxidant functions. This compound has highly important biological activities, which include acting as a neuroprotective, nervous system stimulant, antioxidant, antimicrobial, antiviral, antipyretic, cardioprotective, anti-obesity, antihypertensive, and hepatoprotective (Grzelczyk et al. 2021, Socała et al. 2021, Plazas et al. 2013, Hao-Nan et al. 2020). Trigonelline is synthesized by a one-step reaction from nicotinic acid, which is provided by the NAD cycle (Figure 2). It can be present in green radiant and robust coffee beans, in the range of 0.6–1.3% and 0.3–0.9%, respectively. It has low toxicity compared to caffeine, acting mainly on the CNS, bile secretion, and intestine. During the roasting process, trigonelline undergoes demethylation, causing the formation of niacin, also known as vitamin B3. This vitamin is essential for maintaining cellular health and protecting DNA, contributing to reduce cholesterol levels, controlling diabetes, and it can also prevent diseases, such as cataracts, atherosclerosis, and Alzheimer’s. Vitamin B3 deficiency can trigger the appearance of pellagra, a serious disease that causes darkening of the skin, severe diarrhoea, and dementia (Ribeiro et al. 2021, Sualeh et al. 2020, Santos and Rangel 2015). Caffeine is a bioactive alkaloid compound present in a wide variety of drinks, such as teas, coffees, and soft drinks. Because it is an antagonist of adenosine receptors and an inhibitor of phosphodiesterase 3 (PDE3), it increases alertness and anxiety, in addition to having potential anti-inflammatory and immunosuppressive effects. In vivo studies using animal models, caffeine alone had antidepressant effects, while the combination of caffeine and the antidepressant drug duloxetine resulted in higher levels of the neurotransmitters, norepinephrine, dopamine, and serotonin (Tej et al. 2019, Orbán et al. 2018, Kale and Addepalli 2014). Folic acid (a vitamin present in the coffee drink) acts as an antidepressant, functioning similar to serotonin within

Figure 2. Biosynthesis of trigonelline in coffee plants. Adapted from Ashihara (2006).

Figure 2. Biosynthesis of trigoneline

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the frontal cortex and hippocampus. Some studies have reported that FA has antiinflammatory effects, such as the antidepressant drug imipramine. FA has been shown to induce the proliferation of neural stem cells (NSCs) and neural progenitor cells (NPCs), both precursors of neurons and glia in the fetal and adult CNS. This suggests that FA may be particularly important in the treatment or prevention of depression, as two main causes/effects of depression, stress and increased cortisol production, have been shown to reduce the proliferation of NSCs and NPCs (Grossarth-Maticek and Eysenck 1990, Houghton et al. 2020). Caffeic acid (CA) (Figure 1) has potential antioxidant and anti-inflammatory properties, in addition to acting as a neuroprotective. Phenethyl ester, its derivative, also has its own biological activities, with antioxidant, antiviral, anti-inflammatory, and immunomodulatory function. CA acts resulting in anxiolytic activity, as was observed in in vivo studies using mice submitted to the labyrinth test. This was attributed mainly to indirect modulation of the α1A adrenergic system. Countless studies have shown that both of these compounds have antidepressant, antiinflammatory, antioxidant, and neuroprotective activities (Silva and Lopes 2020, Balaha et al. 2021, Koriem 2020).

Medicinal Applications of Extracts and Isolated Compounds The chemical complexity of coffee and its ethnobotanical impact has attracted the interest of several scientific entities in order for them to understand the constant growth of consumption of this drink and its biological effects. Its chemical compounds play an important role in human health, presenting metabolites with a wide range of pharmacological effects. Cardiovascular diseases, neoplasms, type 2 diabetes mellitus, neurodegenerative diseases, liver disease, depression, and anxiety are examples of the main pathologies in which coffee has become an excellent alternative for pharmacotherapeutic treatment.

Cardiovascular Disease Cardiovascular diseases encompass a group of pathologies in which there is a problem in the heart and blood vessels. It is the leading cause of death in the world: more people die annually from these diseases than from any other cause. It is estimated that 17.9 million people died from cardiovascular disease in 2016, representing 31% of all deaths globally. Of these deaths, it is estimated that 85% occur due to heart attacks and strokes. More than three quarters of deaths from cardiovascular disease occur in low- and middle-income countries. Of the 17 million premature deaths (people under the age of 70) from chronic non-communicable diseases, 82% occur in low- and middle-income countries and 37% are caused by cardiovascular diseases (PAHO—Pan American Health Organization). Epidemiological, clinical, and investigative research studies have been carried out over the decades to determine the relationship between coffee consumption and cardiovascular diseases. The main focus of the research has been whether excessive coffee consumption is associated with an increase in cardiovascular disease. As coffee has an abundance of bioactive compounds, coffee consumption could have positive or negative impacts

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to the consumer. However, the dose at which the drink is being consumed can direct the type of impact it will have. This relationship is similar to when we distinguish between a drug and a poison: what differs is both the amount/concentration at which the compound will be administered to patients and how much it will influence the therapeutic range (Di Giuseppe et al. 2015). A series of meta-analyses reviewed the associations between coffee consumption and cardiovascular disease risk (Cai et al. 2012, Wu et al. 2019, Mostofsky et al. 2012). Overall, they conclude that there is no association between coffee consumption and increased risk of these diseases (Karabudak et al. 2015, Haffner et al. 1985, Richardson et al. 2009). Thus, based on the reviewed data, it can be concluded that moderate caffeine intake (2 to 3 cups or 300 mg/day) is not associated with adverse effects, such as cardiovascular stimulating effects, at least in healthy adults. Long-term coffee consumption actually reduced the risk of cardiovascular disease, especially stroke (Lopez-Garcia et al. 2009, Orozco-Beltran et al. 2017). The current explanation for the possible risk due to the excessive consumption is associated with the presence of the diterpenes, cafestol, and kahweol. The diterpenes are related to the increase in serum cholesterol levels and, therefore, represent a possible threat to cardiovascular health. It is important to note that the concentration of these compounds in coffee depends on the coffee preparation. Boiled coffee has higher concentrations of cafestol/kahweol, because diterpenes are extracted from the coffee beans during the prolonged period of contact with hot water. In comparison, strained/filtered coffee, because the contact with hot water is short, the diterpenes are retained in the filter paper, decreasing the concentration of these compounds. However, the clear involvement of the diterpenes in the deposition of low-density lipoproteins (LDLs) or an oxidation of this lipid fraction is still debatable (Nilsson 2015). Other studies have shown that sitosterol—first identified in coffees by Nagasampag and collaborators in 1971—present in coffee leaf extracts has been used for the prevention of cardiovascular diseases. Clinical tests on rats have resulted in an increase in plasma triacylglycerol and a decrease in blood cholesterol levels. Such results demonstrate that cafestol and kahweol diterpenes are not the only ones responsible for the regulation of cholesterol in the body (Chen 2019).

Cancer Cancer is a disorderly growth of cells, which can invade adjacent tissues or organs at a distance. Dividing rapidly, these cells tend to be aggressive and uncontrollable, causing formation of tumours, which can spread to other regions of the body. The different types of cancer correspond to the various types of cells in the body. When they start in epithelial tissues, such as in the skin or mucous membranes, they are called carcinomas. If it starts in connective tissues, such as bone, muscle, or cartilage, they are called sarcomas. The speed of cell multiplication and the ability to invade neighbouring or distant tissues and organs, known as metastasis, is characteristic of each cancer (INCA 2021). Cancer is among the top 4 death-causing diseases in the world. As the world population has been increasing, the rates of cancer have been growing proportionately,

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partly due to an aging population or changes in habits, such as sedentary lifestyle, inadequate diet, smoking, drug use, excessive exposure to the sun, and irrational use of medications. In the last survey carried out in 2018, there were 18 million new cases of cancer worldwide and 9.6 million deaths. The incidence in men (9.5 million) represents 53% of new cases, being slightly higher than in women, at 47% of new cases (8.6 million). The most common types of cancer in men were lung cancer (14.5%), prostate cancer (13.5%), colon and rectum (10.9%), stomach (7.2%), and liver (6, 3%). In women, the highest incidences were of breast cancer (24.2%), colon and rectum (9.5%), lung (8.4%), and cervix (6.6%) (Bray et al. 2020, Ferlay et al. 2019). Numerous epidemiological studies have focused on the relationship between coffee consumption and a cancer incidence in several locations. A recent meta-analysis suggested that coffee consumption may reduce the total risk of cancer. Due to this data, coffee has been investigated as an alternative treatment for cancer (Yu et al. 2011, Mishra et al. 2016). Cafestol and kahweol have biological functions similar to some anti-cancer drugs, stimulating the detoxification process of cancer cells and inducing the activation of the disorganized division of cells. Chlorogenic acids and their source of polyphenols also contribute to the anti-cancer action due to the antioxidant function and stimulation of the defense of intercellular mechanisms. In addition, CA inhibits the process of DNA hypermethylation, which is a common feature in tumour cells and is a key mechanism for silencing several genes that encode suppressor proteins and DNA repair enzymes. This mechanism is associated with the inactivation of several pathways involved in the tumorigenic process, including limiting the cell cycle, inflammatory response, oxidative stress, and apoptosis (Nkondjock 2009). Lung and gastric cancer Lung cancer is the most prevalent form of cancer around the world, with 2.1 million new cases per year, being more frequent in men with a rate of 14.5% and in women at 8.4%. Smoking is one of the risk factors for this type of cancer, being responsible for 25% of all lung cancer cases worldwide. Kahweol, cafestol, and CA are components described as having antimutagenic activity, the ability to inhibit cancer-promoting agents, and antioxidant potential. It is believed that there is a significant reduction in the incidence of new cases with the consumption of coffee (Tanga et al. 2010, Pasquet et al. 2016). Gastric cancer is the fourth most common cancer and is the second leading cause of cancer death worldwide. Previous studies have found that smoking, alcohol, salt intake, and low intake of fruits and vegetables are known risk factors for the development of stomach cancers. Stensvold and Jacobsen (1994) reported that coffee consumption had a non-significant inverse association with gastric cancer. It has been shown that there is a clear link between coffee consumption and the risk of gastric cancer from a meta-analysis study. Pancreas Pancreatic cancer is among the leading causes of cancer-related deaths worldwide, with a survival rate of less than 5% and a proportion of fatal cases of 99% within 12 months of diagnosis. Coffee consumption was related to the risk of pancreatic cancer. To date, a study from European Prospective Research Cohort on Nutrition

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and Cancer provided evidence that the consumption of coffee, decaffeinated coffee and tea do not present association with pancreatic cancer (Bhoo–Pathy et al. 2013). Colorectal and ovarian The cancer with the third greatest incidence in the world is colorectal cancer. There are around 1.8 million new cases of colorectal cancer each year, affecting men more than women, with respective mortality rates of 10.9% and 9.5% (BRASIL 2021). Coffee contains several anti-cancer substances, including polyphenols, diterpenes, melanoidins, and antioxidants that can be beneficial in improving the survival of patients with this type of cancer. That is, through systemic improvement, these substances can reprogram the metabolic process of cancer or promote an anti-cancer microenvironment that slows down the progression of the tumour (Moreira et al. 2012, Alicandro et al. 2017). Melanoidins can inhibit matrix metalloproteases that play a central role in tumour growth and the development of metastasis. It has been suggested that the presence of diterpenes, such as cafestol and kahweol, in coffee has a protective factor against colorectal cancer through its ability to inhibit reactive species due to significant antioxidant activity and the ability to induce suppressor genes. A study using a rodent model showed that both diterpenes have this potential to inhibit metastasis by interrupting STAT3-mediated transmission, one of the prometastatic genes (Kim et al. 2012, Cavin et al. 2002). Furthermore, polyphenols, such as CA, can inhibit colon cancer metastasis by targeting protein mitogens from activated kinases, which are proteins originating from T cell kinases (Kang et al. 2011). In addition, caffeine can decrease the risk of colorectal cancer by increasing the mobility of the large intestine and inhibiting the growth of cancer cells. Few studies have attempted to verify the relationship between post-diagnosis coffee intake and colorectal cancer outcomes. One of the few recent studies found that increased coffee intake was associated with reduced risk of cancer recurrence and patient death. The study pointed out that 50% of the risk of mortality was reduced in patients who consumed at least 4 cups/day of coffee, compared to those who did not drink coffee (Guercio et al. 2015). In a study by Hu et al. (2018), an inverse association between increased coffee intake and recurrence or mortality in patients with stage III colon cancer was reported. Compared with patients who consumed less than 2 cups/day of coffee, those who drank 2 cups/day of coffee had a 16% lower risk of death, while patients who maintained the intake of 2 cups/day of coffee in pre- and postdiagnostic periods had a 29% reduction in mortality risk. Ovarian cancer is the seventh most common type of cancer and is the greatest cause of cancer death in women. Relatively few studies have been conducted on the effectiveness of coffee in influencing the risk of ovarian cancer. Meta-analyses found that coffee consumption presents a reduced risk and there is a small significant association for daily coffee consumption. Breast Breast cancer is a leading cause of cancer-associated deaths in women. This type of cancer includes changes in the functional aspects of epithelial cells in the breast and is induced by the expression of oncogenes and the decrease in tumour suppressor

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genes. Studies suggest that there is an inverse association between coffee intake and breast cancer risk. A Norwegian study in the 1990s with 14,593 women showed that drinking 5 or more cups of coffee per day led to a statistically significant 50% reduction in the risk of breast cancer compared to those who drank 2 cups or less (Vatten et al. 1990). Years later, in a study by Nkondjock et al. (2006), it was found that the consumption of 6 or more cups of coffee per day in pre-menopausal women, who had BRCA1 and BRCA2 (a habitual protein mutation for the risk of cancer of breast cancer) led to a significant reduction of 70% for the development of cancer. Although the data is not fully convincing, due to the variation in the size of cups and amount of coffee consumed, mechanisms are established and some evidence suggests that regular consumption, at least four cups per day, is related to reduced risk of breast cancer (Nkondjock 2009). Caffeine suppresses the expression of stromal cell-derived factor 1 matrix metalloproteinase-2, and transforming growth factor-α of fibroblasts that are induced in, and associated with, breast cancer. In addition, it also decreases the concentration of the main markers of myofibroblasts, smooth muscle α-actin, and inhibits cancer from migrating/invading other cells. The aforementioned impacts are mediated by the inhibition of regulatory protein kinases 1 and 2 and α-serine/threonine protein kinases due to increased phosphatase production. The reduction of both substances prevents extracellular signalling to initiate the process of metastasis (Yu et al. 2011). A study by Al-Ansari and Aboussekhra (2014) demonstrated that the active breast cells of stromal fibroblasts can return to normal and negatively regulate the procarcinogenic and metastatic properties after ingesting caffeine. Negative regulation is exerted through increased expression of vital tumour suppressor proteins (p16, p21, p53, and Cav-1), which suppress the release of several cancer-causing pro-cytokines. Other studies have reported synergism of caffeine in the treatment with other anti-neoplastic agents. Among them, a study by Niknafs (2011) found that caffeine together with cisplatin form a complex inhibitor of inositol triphosphate kinase, causing the induction of apoptosis in cancer cells by the intracellular release of Ca2+. The association of caffeine and cisplatin caused detachment of the fixation surface in some breast cancer cells and, according to this study, this was beneficial in inducing the death of cancer cells. Beauregard et al. (2015) tried to explore the effectiveness of CA and its derivatives in the apoptotic cascade mediated by p53 protein. The p53 is the most extensively studied tumour suppressor and several forms of stress whose activity involves the activation of its receptor that induces apoptosis by multiple pathways, in order to ensure that the tumour cell proceeds efficiently with its death schedule. This apoptotic dependency on the p53 cascade is potentially very important in the dysregulation of the cell cycle in the processes of carcinogenesis. In studies by Mishra et al. (2016), experimental observations after exposure of MCF7 breast cancer cells to CA and its derivatives showed increased expression of p53. In addition, MDA-MB-231 breast cancer cells, which have a mutation in p53, were able to regulate apoptosis in the presence of CA. Kahweol also has a function that significantly regulates the apoptotic cascade and blocks the proliferation of tumour cells and metastases in various types of human carcinoma cells (Um et al. 2010). Cárdenas et al. (2014) described the effect of kahweol as an inhibitor of tumour cell proliferation and an apoptosis inducer

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in MDA-MB-231 cells. They noted that kahweol increased the generation of reactive oxygen species in human breast cancer cells, which enhanced the cytotoxic effect on these cells, without harming normal cells. With the activation of caspases and release of cytochrome-c, the cytotoxic effect increases the reactive oxygen species and this would be responsible for kahweol’s antitumor activity, which reinforces the inhibitory effects on MDA-MB-231 cells during his experiments.

Type 2 Diabetes and Neuro-degenerative Disorders In particular, long-term coffee consumption is associated with significant dosedependent reductions in the risk of developing type 2 diabetes (Carlstrӧm and Larsson 2018). A systematic review of nine studies compared minimum coffee and low coffee consumption (< 2 cups/day) with heavy coffee consumption (≥ 6 cups/ day) for the risk of developing type 2 diabetes mellitus. These researchers concluded that the risk of developing type 2 diabetes was lower in individuals who drank ≥ 6 cups a day and was also significantly reduced for individuals who consumed 4 to 6 cups daily (O’Keefe et al. 2013). Coffee consumption is also inversely associated with the risk of Parkinson’s disease (Prakash and Tan 2011), and the risk of Alzheimer’s disease is lower in those who regularly consume coffee than in those who do not drink coffee (Carman et al. 2014).

Liver Conditions Studies show that moderate coffee consumption, two cups per day, reduces the risk of liver cancer, both among individuals with and without a history of liver disease (Mascitelli et al. 2008). In this sense, coffee has a protective function against liver cell damage induced by oxidative stress (Goya et al. 2007). Excessive iron concentration in the blood is considered a carcinogenic factor or a promoter of liver cancer, even in patients without hemochromatosis or cirrhosis. It was believed that the polyphenols present in coffee could keep the iron concentration relatively low and, therefore, reduce the risk of liver damage and avoiding liver metastases. Cafestol and kahweol can induce enzymatic phase II reactions, increase liver glutathione levels, and decrease liver DNA adducts that cause carcinogens (Bonkovsky et al. 1996). In addition, coffee consumption inhibits elevated liver transaminases (markers of liver damage), reducing the risk of liver damage and reducing mortality from liver cirrhosis, which is an important disease and is considered a risk factor for the development of cancer. Therefore, coffee appears to reduce the risk of liver cancer, help improve patient survival, and inhibit the capacity for liver metastases (Vecchia et al. 1998, Klatsky et al. 2006, Tverdal and Skurtveit 2003).

Depression and Anxiety Caffeine is the most consumed psychoactive drug worldwide and appears to exert most of its biological effects through antagonism to the adenosine receptor. Adenosine is an endogenous inhibitory neuromodulator that causes feelings of drowsiness and, therefore, induces generally stimulating effects on the CNS (Bae et al. 2014). Based

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on the revised data, moderate caffeine intake (2 to 3 cups or 300 mg/day) is not associated with adverse effects, but a beneficial effect in the area of caffeine-related neuroactivities may potentiate the preventive influence in suicides and in cases of depression. The relative risk of suicide decreased by 13% for each cup of coffee consumed daily (Clarke and Vitzthum 2008).

Conclusion Studies related to the health benefits of coffee and its use in folk medicine still lack greater understanding. Due to its chemical complexity, several factors must be taken into account to evaluate the application of this drink in the treatment of some diseases. Among these factors are the toxicity of some of the compounds within coffee, their bioavailability, and the daily consumption of the drink, as side effects can occur depending on the amount ingested and the method of preparation. Some industrial processes have produced commercial coffees with the removal of some substances, such as caffeine and serotonin amides, for consumers with stomachs that are sensitive to these compounds. However, coffee becomes a viable alternative in the search for natural compounds capable of promoting the health and well-being of modern society.

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Sanz, C., D. Ansorena, J. Bello and C. Cid. 2001. Optimizing headspace temperature and time sampling for identification of volatile compounds in ground roasted Arabica coffee. Journal of Agricultural and Food Chemistry 49(3): 1364–1369. Sanz, C., L. Maeztu, M.J. Zapelena, J. Bello and C. Cid. 2002. Profiles of volatile compounds and sensory analysis of three blends of coffee: influence of different proportions of Arabica and Robusta and influence of roasting coffee with sugar. Journal of the Science of Food and Agriculture 82(8): 840– 847. Silva, H. and N.M.F. Lopes. 2020. Cardiovascular effects of caffeic acid and its derivatives: a comprehensive review. Frontiers in Physiology, 11. Smith, R.F. 1985. A history of coffee. In: Coffee. Springer, Boston, MA. p. 1–12. Smith, S.D. 1996. Accounting for taste: British coffee consumption in historical perspective. The Journal of Interdisciplinary History 27(2): 183–214. Socała, K., A. Szopa, A. Serefko, E. Poleszak and, P. Wlaź. 2021. Neuroprotective effects of coffee bioactive compounds: a review. International Journal of Molecular Sciences 22(1): 107. Stensvold, M.I. and B.K. Jacobsen. 1994. Coffee and cancer: a prospective study of 43,000 Norwegian men and women. Cancer Causes Control 5(5): 401–408. Sualeh, A., K. Tolessa and A. Mohammed. 2020. Biochemical composition of green and roasted coffee beans and their association with coffee quality from different districts of southwest Ethiopia. Heliyon 6(12): e05812. Tanga, N., Y. Wub, J. Maa, B. Wangc and R. Yud. 2010. Coffee consumption and risk of lung cancer: A meta-analysis. Lung Cancer 67: 17–22. Tej, G.N.V.C., K. Neogi and P.K. Nayak. 2019. Caffeine-enhanced anti-tumor activity of anti-PD1 monoclonal antibody. International Immunopharmacology 77: 106002. Thammarat, P., C. Kulsing, K. Wongravee, N. Leepipatpiboon and T. Nhujak. 2018. Identification of volatile compounds and selection of discriminant markers for elephant dung coffee using static headspace gas chromatography—Mass spectrometry and chemometrics. Molecules 23(8): 1910. Trugo, L.C. and R.A. Macrae. 1984. Study of the effect of roasting on the chlorogenic acid compositon of coffee using HPLC. Food Chemistry 15: 219–227. Trugo, L.C., C.A.B. De Maria and C.C. Werneck. 1991. Simultaneous determination of total chlorogenic acid and caffeine in coffee by high performance gel filtration chromatography. Food Chemistry 42: 81–87. Tsukui, A., S.S. Oigman and C.M. Rezende. 2014. Óleo de Grãos de Café Cru: Diterpenos Cafestol e Kahweol. Revista Virtual de Química 6(1): 16–33. Tverdal, A. and S. Skurtveit. 2003. Coffee intake and mortality from liver cirrhosis. Annals Epidemiology 13: 419–423. Um, H.J., J.H. Oh, Y.N. Kim, Y.H. Choi, S.H. Kim, J.W. Park and T.K. Kwon. 2010. The coffee diterpene kahweol sensitizes TRAIL-induced apoptosis in renal carcinoma Caki cells through down-regulation of Bcl-2 and c-FLIP. Chemical-Biological Interactions 186(1): 36–42. Vatten, L.J., K. Solvoll and E.B. Løken. 1990. Coffee consumption and the risk of breast cancer, A prospective study of 14,593 Norwegian women. British Journal of Cancer 62: 267–270. Vecchia, C. La, E. Negri, L. Cavalieri d’Oro and S. Franceschi. 1998. Liver cirrhosis and the risk of primary liver cancer. European Journal of Cancer Prevention 7: 315–320. Weusten-Van der Wouw, M.P.M.E., M.B. Katan, R. Viani, A.C. Huggett, R. Liardon, G. Lund-Larsen Per, S. Thelle Dag, I. Ahola, A. Aro, S. Meyboom and A.C. Beynen. 1994. Identity of the cholesterolraising factor from boiled coffee and its effects on liver function enzymes. Journal of Lipid Research 35: 721–733. Wu, J.N., S.C. Ho, C. Zhou, W.H. Ling, W.Q. Chen, C.L. Wang and Y.M. Chen. 2019. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. International Journal of Cardiology 137: 216–225. Yu, X., Z. Bao, J. Zou and J. Dong. 2011. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer 11: 96.

Chapter 4

Use of Antidiabetic Medicinal Plants with Ethnomedicinal Information in Clinical Trials Focus on Bioactive Compounds Anuar Salazar-Gómez,1 Candy Carranza-Álvarez,2 Fabiola Domínguez3 and Angel Josabad Alonso-Castro4,*

Introduction Traditional medicine continues to play a significant role in the treatment and management of many diseases, including diabetes mellitus. Ethnomedicinal evidence derived from traditional health knowledge could be worth examining for new directions in therapeutic research strategies. An electronic literature search was conducted on clinical trial studies that examined the efficacy of medicinal plants, with ethnomedicinal information about the antidiabetic effect, on type 2 diabetes mellitus (T2DM) patients. The antidiabetic mechanisms of action of isolated compounds were also reviewed. The bibliographic search was done in databases of PubMed, Science Direct, Google Scholar, and SciFinder until June 2021 using

Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, México. 2 Facultad de Estudios Profesionales Zona Huasteca, Universidad Autónoma de San Luis Potosí, Ciudad Valles, San Luis de Potosí, México. 3 Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Metepec, Puebla, México. 4 Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, México. * Corresponding author: [email protected] 1

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the following keywords: “medicinal”, “plant”, “ethnomedicinal”, “diabetes”, and “clinical trial”. Additional information was identified from references located in the retrieved articles. For each species, the accepted name was checked on “The Plant List” database (www.theplantlist.org) and updated when necessary. This chapter highlights the ethnomedicine contribution to clinical trial research, providing a collection of information about the medicinal plants which have been investigated in T2DM patients for their anti-diabetic potential.

Ethnomedicinal Information and the Discovery of NaturalDerived Drugs Ethnomedicine examines the traditional health knowledge of various ethnic groups or communities around the world. Most of these studies are based on the use of herbal medicines derived from indigenous cultural development. Plants have been used as a source of medicines from ancient times, and the documented local knowledge of their medicinal proprieties has contributed to the discovery of drugs (Singh et al. 2020). The ethnomedical approach has the potential to be efficient in the initial phase of the discovery of natural-derived drugs, which avoids unnecessary waste of resources during random screening. Several scientists suggest that efforts based on ethnomedical information provide significant advantages in the planning and implementation of experimental research (Farnsworth 1994), and in some cases, in the appropriate clinical trial design. The discovery of artemisinin from Artemisia annua L. (Asteraceae) represents a successful example of approved drugs that were initially discovered using ethnomedical information. There are many other examples of plant-derived drugs, which were developed based on ethnomedical information (Atanasov et al. 2015). An analysis of 122 plant-derived drugs showed that 80% of these molecules are used in the treatment of diseases for which plants were originally used in ethnomedicine (Fabricant and Farnsworth 2001). The ethnomedical information provides the potential to identify which plants are most likely to be useful in the treatment of certain diseases. There is no doubt that ethnomedicine can guide the research and development of modern drugs. Therefore, it is necessary to transfer ethnomedical information and preclinical data obtained from medicinal plants to an ideal clinical setting to assess their therapeutic potential, which might support their widespread utilization.

Clinical Trial of Medicinal Plants Based on Ethnomedical Claims Related to Diabetes Mellitus Medicinal plants have been used to treat all kinds of illnesses, including chronic diseases, such as diabetes mellitus. Efforts to obtain antidiabetic agents from medicinal plants date back more than ten decades. The discovery of the hypoglycemic activity of galegine, from Galega officinalis L. (Fabaceae) in the 1920s, and the incorporation of metformin (a derivate of galegine) to clinical use were major stimuli for the investigation of the anti-diabetic potential of plant-derived compounds (Zhou

Antidiabetic Plants with Ethnomedicinal Information 83

et al. 2018). In this context, more than 500 species have been reported to have antidiabetic properties (Salehi et al. 2019), and this topic has still attracted the attention of the scientific community. From 2015 to 2019, an increasing trend in preclinical studies has been focusing on the antidiabetic potential of medicinal plants (SalmerónManzano et al. 2020). Most of these studies highlight documented local knowledge of plants as the basis for research, and one of their main objectives is to support the ethnomedical use in various pathological conditions. To avoid discrepancies, it is necessary to confirm in clinical trials the pharmacological effect reported in the preclinical phase (Furman et al. 2020). Thus, how many clinical studies have examined the impact of medicinal plants on diabetes? Despite several studies on the anti-diabetic effect of medicinal plants, only a fraction of the known plant material has been found to lower blood glucose in patients with diabetes mellitus. In 2018, Furman et al. summarized 68 clinical trials examining the effects of plant extracts on blood glucose, with only 46 trials including T2DM patients. Recently, other plants such as Boswellia serrata Roxb. ex Colebr. (Burseraceae) (Mehrzadi et al. 2018), Morus alba L. (Moraceae) (Sohail et al. 2020), and Crocus sativus L. (Iridaceae) (Tajaddini et al. 2021) are now included in this select group. This chapter provides examples of medicinal plants used in clinical trials based on ethnomedical claims related to diabetes. The details of species, part of the plant, and the ethnomedicinal use and clinical intervention studies are detailed in Table 1.

Salacia reticulata S. reticulata (Celastraceae), known as Kothala himbutu (Sinhala), is a large woody climbing shrub widely distributed in Sri Lanka and the Southern region of India. This plant has been used because of its variety of medical benefits, including hypoglycemic and anti-obesity effects (Arunakumara and Subasinghe 2011). In the Kokrajhar district, local elderly people and some diabetic patients consume leaves of this species as a juice to treat diabetes (Das and Mandal 2017). Furthermore, traditional healers residing in the Eastern Province of Sri Lanka use the bark as food to treat T2DM (Sathasivampillai et al. 2018). Previously, Radha and Amrithaveni (2009) demonstrated that daily supplementation with S. reticulata bark powder (two capsules 1 g bark powder along with breakfast for 60 days) showed a lipid-lowering effect and reduced fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and 2-h postprandial blood glucose (2hPG) (Radha and Amrithaveni 2009). This study confirmed the antidiabetic effects of the bark of S. reticulata in a clinical trial.

Morus alba L. M. alba, also known as white mulberry, is a short-lived, fast-growing, small to medium-sized tree mainly distributed in South Europe, North America, East and Southeast Asia, southeastern Australia, and Africa (He et al. 2018). This tree is commonly harvested for both its edible fruit, and its health benefits. Ethnobotanical studies have reported that leaves of M. alba are used by local people in central and northern Morocco as an infusion for diabetic problems (Hachi et al. 2016, Chaachouay et al. 2019).

Species name

Ethnomedicinal information

Clinical intervention studies Study design

Dose, duration, and patient type

References Main outcome measure and results

Adverse effects

Celastraceae

Salacia reticulata

“The leaf of this plant is pasted, and de juice is taken” (Das and Mandal 2017); Bark (Sathasivampillai et al. 2018).

Not mentioned

- Two capsules (1 g bark powder) daily, - 60 d, T2DM patients (n = 20).

HbA1c (↓), 2hrPG (↓) and FBG (↓)

Not mentioned

Radha and Amrithaveni 2009

Moraceae

Morus alba

“Fresh leaves in infusion” (Hachi et al. 2016). Leaf- infusion (Chaachouay et al. 2019).

Open label Randomized Controlled Trial

- 500 mg leaf tablets twice a d, - 90 d, - T2DM patients (n = 40).

HbA1c (↓)

Not mentioned

Sohail et al. 2020

Juglandaceae

Juglans regia

Leaf, bulb, fruit. Infusion, edible. (Rajaei and Mohamadi 2012)

Randomized double-blind, placebo-controlled trial.

- 100 mg leaf extract capsule two times a d, - three mon, T2DM patients (n = 32).

HbA1c (↓), FBG (↓).

Mild adverse events at the beginning of the study (diarrhea, vertigo, and anxiety)

Hosseini et al. 2014

Randomized double-blind placebo-controlled trial.

- 250 mg leaves aqueous extract powder capsules every eight hours, - three mon, T2DM patients (n = 19)

HbA1c (↓), FPG (↓), PPBG (↓).

No adverse effects

Abdoli et al. 2017

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Family

84

Table 1. Clinical trials based on ethnomedical claims related to diabetes mellitus.

Cecropia obtusifolia

“Normally the people drink the infusion of the leaves after boiling between three (approximately 36 g) and five (approximately 60 g) leaves in 1 l water” (Andrade-Cetto and Wiedenfeld 2001).

Not mentioned

- 13.5 g of dried and milled leaves (aqueous extract) daily, - 32 wk, T2DM patients (n = 12).

HbA1c (↓), Glucose levels (↓).

No adverse effects

RevillaMonsalve et al. 2007

Asteraceae

Silybum marianum

“Decoction of Leaves and stem powder of Silybum marianum is taken orally half cup per day for two weeks” (Zain-ul-Abidin et al. 2018)

Randomized Double-blind Clinical Trial

- 200 mg silymarin tablet three times a d, - Four mon, - T2DM patients (n = 51).

HbA1c (↓), FBG (↓)

No adverse effects

Huseini et al. 2006

Randomized, parallel, placebocontrolled, tripleblind study

- 140 mg Silymarin (Livergol ®) thrice daily, - 45 d, - T2DM patients (n = 40).

FBG (↓), insulin (↓), HOMA-IR (↓) QUICKI (↑)

No adverse effects or symptoms

EbrahimpourKoujan et al. 2018

Stem, Leaves (Guo et al. 2017)

Randomized, placebo-controlled, double-blind trial

- 3 g of powder/packet, twice a d, - 12 wk, - T2DM patients (n = 12).

HbA1c (↓), FPG (↓), HOMA-IR (↓). Did not decrease 30and 120 min OGTT postload values

No adverse effects

Huyen et al. 2010

Cucurbitaceae Gynostemma pentaphyllum

Table 1 contd. ....

Antidiabetic Plants with Ethnomedicinal Information 85

Cecropiaceae

Species name

Ethnomedicinal information

Clinical intervention studies Study design

Apocynaceae

Gymnema sylvestre

“Before a +meal, two leaves of this plant are given to the diabetic patients for 48 days for the complete cure of diabetes” (Elavarasi and Saravanan 2012); “Leaf juice or young tender leaves are orally administered. The dose of this drug is taken once in a day in the morning to cure diabetes” (Mishra et al. 2019)

Lamiaceae

Coccinia indica

“Plant juice is given in Single-blind study. the morning and evening” (Jayakumar et al. 2010); “Leaf powder mixed with cow´s milk is taken orally to treat diabetes” (Umapriya et al. 2011)

Randomized, double-blind, placebo-controlled clinical trial

Dose, duration, and patient type

References Main outcome measure and results

Adverse effects

- 300 mg G. sylvestre capsules (Swanson Superior Herbs), - 12 wk, - Patients with Impaired Glucose Tolerance (n = 15)

HbA1c (↓), 2hrPG (↓), insulin sensitivity (↑).

Headache and gastrointestinal symptoms

Gaytán Martínez et al. 2021

- 6 g of leaves powder twice daily, - 60 d, - T2DM patients (n = 15).

HbA1c (↓), FBS (↓), PPBG (↓).

No adverse effects

Junaid et al. 2020

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Family

86

...Table 1 contd.

“Early morning a pinch of the leaf is taken to treat diabetes” (Thirumalai et al. 2021); Leaves/ Powder. “10 g powder is given with water twice a day” (Yaseen et al. 2015)

Randomized Control Trial

- Glibenclamide plus 250 mg leaf extract capsule, - 30 d, - T2DM patients (n = 30).

HbA1c (↓), FBG (↓), PPBG (↓).

No adverse effects

Somasundaram et al. 2012

Salvia officinalis

“Infusion 3 to 4 leaves or 1 handful. Orally, twice to thrice a day” (Skalli et al. 2019)

Randomized placebo-controlled parallel-group study.

- 500 mg leaves powder extract capsules every 8hr, - three mon, - T2DM patients (n = 40).

HbA1c (↓), Fasting glucose (↓)

No adverse effects

Kianbakht and Dabaghian 2013

Abbreviations: decrease (↓); increase (Abbreviations: decrease (↓); increase (↑); glycated hemoglobin (HbA1c); fasting blood glucose (FBG); homeostasis model assessmentinsulin resistance (HOMA-IR); quantitative insulin sensitivity check index (QUICKI); 2-hr postprandial blood glucose (2hrPG); postprandial blood glucose level (PPBG); gastrointestinal (GI); fasting plasma glucose (FPG); oral glucose tolerance test (OGTT).); glycated hemoglobin (HbA1c); fasting blood glucose (FBG); homeostasis model assessment-insulin resistance (HOMA-IR); quantitative insulin sensitivity check index (QUICKI); 2-hr postprandial blood glucose (2hrPG); postprandial blood glucose level (PPBG); gastrointestinal (GI); fasting plasma glucose (FPG); oral glucose tolerance test (OGTT).

Antidiabetic Plants with Ethnomedicinal Information 87

Ocimum sanctum

88 Ethnobotany: Ethnopharmacology to Bioactive Compounds Because of its potential health benefits, M. alba has become the subject of numerous clinical trials (Chan et al. 2016). In a recent open-label randomized controlled trial, 80 T2DM patients received reference drug or 500 mg leaf tablets twice a day (15 min before the breakfast and dinner). After 90 days of M. alba leaf tablets consumption, an improvement in the levels of HbA1c was recorded (Sohail et al. 2020).

Juglans regia L. Juglans regia (Juglandaceae) is commonly found in Southeast Europe and distributed to the Himalayas and Southwest China (Gupta et al. 2019). Local people in Hezar Mountain (Iran) use different parts (leaf, bulb, or fruit) of J. regia as an infusion to treat diabetes (Rajaei and Mohamadi 2012). Following the traditional use of this plant, clinical trials have demonstrated its antidiabetic potential. A study conducted at the Diabetes Care Clinic of Shariati hospital Tehran (Iran) reported that the treatment with 100 mg/kg J. regia leaf extract contained in capsules and administered twice a day (before meal) along with standard anti-diabetic therapy for three months led to significantly decreased in the levels of FBG, HbA1c, triglyceride (TG), and total cholesterol (TC) in 32 T2DM patients (aged 40–65 years) (Hosseini et al. 2014). Another clinical study on the hypoglycemic effects of J. regia leaf aqueous extract in T2DM patients treated with their conventional oral hypoglycemic agents was conducted at the Imam Khomeini Hospital in Tehran (Iran). The study was a randomized double-blind, placebo-controlled trial involving 19 T2DM patients (aged 35–70 years). The results from this study confirmed that FPG, postprandial blood glucose level (PPBG), and HbA1c are markedly suppressed after the ingestion of one capsule every 8 h (750 mg per day) for three months (Abdoli et al. 2017).

Cecropia obtusifolia Bertol. C. obtusifolia (Cecropiaceae) is a tree, commonly known as “Guarumbo”, “Chancarro”, and “Hormiguillo”, and used in Mexican traditional medicine for the treatment of T2DM. The traditional healers and the diabetic people from rural communities of the state of Oaxaca (Eastern Mexico) drink an infusion prepared with leaves (36–60 g) in 1 l water (Andrade-Cetto and Wiedenfeld 2001). Clinical evidence indicates that aqueous extract of the leaves (prepared as recommended by the traditional healers) has shown promising anti-diabetic activity in 12 diabetic patients (aged 44–52 years). Treatment with this preparation for 32 weeks resulted in blood glucose and HbA1c reduction without showing a direct effect on insulin secretion (Revilla-Monsalve et al. 2007).

Silybum marianum (L.) Gaernt S. marianum (Asteraceae), commonly known as milk thistle, is an annual/biennial plant native of the Mediterranean area and naturalized in North and South America as well as in South Australia (Abenavoli et al. 2010). In some localities of South-west

Antidiabetic Plants with Ethnomedicinal Information 89

Pakistan, traditional healers, religious scholars, and experienced housewives consume half a cup per day for two weeks of leaves and steam decoctions for the treatment of T2DM (Zain-ul-Abidin et al. 2018). Several clinical trials of milk thistle and some of its components have been published, especially focused on the control of chronic liver diseases, cancer, and diabetes (Tamayo and Diamond 2007). Silymarin (a milk thistle extract) treatment in 51 T2DM patients for four months had a beneficial effect in lowering the levels of FBG, HbA1c, TC, low-density lipoprotein (LDL), and TG levels. Moreover, SGOT and SGPT were also reduced after Silymarin treatment, thus the authors attributed the results to the antioxidant potential of this extract (Huseini et al. 2006). Recently, in a randomized, parallel, placebo-controlled, triple-blind study involving 20 T2DM patients (aged 25–50 years), 45 days of Silymarin supplementation (140 mg, thrice daily) reduced FBG, serum insulin, homeostasis model assessmentinsulin resistance (HOMA-IR), TG, TG/HDL ratio, and increased the quantitative insulin sensitivity check index (QUICKI) as compared to baseline and placebo group. The HOMA-IR and the QUICKI are commonly used to evaluate insulin resistance, thus Silymarin treatment could improve this pathological condition (EbrahimpourKoujan et al. 2018).

Gynostemma pentaphyllum (Thunb.) Makino G. pentaphyllum (Cucurbitaceae), named Jiaogulan in China, is a perennial creeping plant widely distributed in southwestern China and dispersed throughout India, Nepal, Bangladesh, Sri Lanka, Laos, Myanmar, Korea, and Japan (RazmovskiNaumovski et al. 2005, Li et al. 2019). In Changzhi city (Shanxi province, China), steam or leaves of G. pentaphyllum are used by indigenous people and traditional health practitioners for the treatment of T2DM (Guo et al. 2017). The antidiabetic effect of G. pentaphyllumin was assessed in a randomized, placebo-controlled, double-blind trial (Huyen et al. 2010). In this study, 24 patients (aged 57–70 years), newly diagnosed with T2DM, were treated with G. pentaphyllum tea (6 g daily, 30 min before the breakfast and dinner) or placebo, for 12 weeks. At the end of the study, the levels of FBG and HbA1c, and HOMA-IR were significantly reduced.

Coccinia indica Wight & Arn. Bimbi, C. indica (Cucurbitaceae), is a well-known plant used extensively in Ayurvedic and Unani systems of traditional Indian medicine. This plant grows in Asia, Africa, and Oceania (Deokate and Khadabadi 2011). In South India, local people use Bimbi as a juice preparation in the morning and evening to treat diabetes (Jayakumar et al. 2010). Similarly, elder people in the Palamalai hills located in the Coimbatore district of Tamil Nadu (South India), consume the leaf powder mixed with cow´s milk to treat T2DM (Umapriya et al. 2011). In a single-blind study, consumption of 6 g of leaves powdered twice daily (30 min before food) for 60 days resulted in a reduction of FBG, PPBG, HbA1c, and urine glucose levels in 15 T2DM patients (aged 31–60 years) (Junaid et al. 2020).

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Ethnobotany: Ethnopharmacology to Bioactive Compounds

Gymnema sylvestre (Retz.) R.Br. ex Sm. G. sylvestre (Apocynaceae), commonly known as “Gurmar” (sugar destroyer), is a slow-growing, perennial, woody climber found in India, Africa, Australia, and China. This plant is used for the treatment of diabetes in Ayurvedic system medicine (Khan et al. 2019). In India, two ethnobotanical surveys have verified the use of this species for the treatment of T2DM. Tribal settlements from Kolli hills, (Namakkal district, South India), administer two leaves of this plant before the meal for 48 days for the folk treatment of T2DM (Elavarasi and Saravanan 2012). Similarly, ethnic groups of local people from Khurda, Odisha (Eastern India), administer orally leaf juice or young tender once a day in the morning to treat T2DM (Mishra et al. 2019). A randomized, double-blind, placebo-controlled clinical trial involving patients with impaired glucose tolerance (aged 30–59 years) showed that daily intake of 300 mg G. sylvestre capsules (twice a day, before the breakfast and dinner) for 12 weeks decreased the levels of 2-hPG and HbA1c and enhanced insulin sensitivity. This treatment also reduced weight, body mass index, and LDL levels (Gaytán Martínez et al. 2021).

Ocimum sanctum L. O. sanctum (Lamiaceae), commonly known as tulsi, is an aromatic plant mainly distributed in tropical regions including India. It has been used in Ayurveda for its diverse healing properties (Cohen 2014). The local people in Javadhu hills (South India), use a small portion of leaf early morning to treat diabetes (Thirumalai et al. 2012). In Pakistan, traditional health practitioners and diabetic patients of Islamabad, Khyber Pukhtoonkhwa, and Deserts of Sindh (North Pakistan) recommend the use of 10 g powder leaf with water twice a day (Yaseen et al. 2015). In a randomized control trial with 30 T2DM patients, the administration of 500 mg O. sanctum leaf extract combined with Glibenclamide for 30 days was associated with a sustained reduction in PPBG and HbA1c compared to those who consumed only oral hypoglycemic agents (Somasundaram et al. 2012).

Salvia officinalis L. S. officinalis (Lamiaceae) is a perennial round shrub native to the Middle East and Mediterranean areas and naturalized throughout the world, particularly in Europe and North America. The aerial parts of this plant have been used as a food flavouring and in traditional medicine (Ghorbani and Esmaeilizadeh 2017). A survey conducted by Skalli et al. (2019) in Rabat (Morocco) showed the importance of the consumption of the infusion of one handful or three to four leaves of S. officinalis twice to three times a day in managing diabetes. Kianbakht and Dabaghian (2013) conducted a randomized placebo-controlled parallel-group study on 40 T2DM patients (aged 40–60 years) to evaluate the efficacy of S. officinalis. Patients received 500 mg leaves powder extract capsules every 8 hr for three months and restricted the consumption of carbohydrates and fatty foods. At the end of the study, significant reductions in FBG and HbA1c were found, as well as an improved lipid profile.

Antidiabetic Plants with Ethnomedicinal Information 91 HO

OH

OH

OH

O3S O

OH

OH

OH

-

+

+

S

S

OH

HO

OSO3 OH

HO

2

OH

OH

N H

HO

OH

HO

OH O O

OH

O

HO

O

7

6

O

OH

OH O

O OH

OH

8

O

O

O

OH

O OH

OH

HO

OH

OH

O HO

OH OH

HO

OH

5

HO

O

O

HO

HO

OHO

O

4

OH

3 OH

O

OH

OH

OH

HO

1

OH

HO

-

OH

9

O

HOH2C HO OH

O

HO

OH HO

O

O

O

O

O

OH

HO

OH

HO O

OH HO

11

O HO

OH

CHO

HO

O

O

O

10

12

OH

OR1

OH

HO OH

OH HO

OH HO

O HO

O

HO

O

13

OH OH

O

H

R1

R2

14

Tigloyl

Ac

OH

15

2-methyl butyroyl

Ac

OH

16

2-methyl butyroyl

H

17

Tigloyl

H

OH

O OH

OH

O HOH2C

HO O

OH HO

OH

H

O

OH

OH CH2OR2

OH

18

Figure 1. Chemical structures of compounds 1–18.

Mechanisms of Action of Bioactive Compounds from Medicinal Plants with Antidiabetic Effects in Clinical Trials Many of the molecular mechanisms of action underlying the anti-diabetic effect of natural products remain to be clarified. However, the inhibition of carbohydrate hydrolyzing enzymes or glucose transporters, stimulation of glucose uptake by peripheral tissues, stimulation of insulin secretion by pancreatic β-cells, inhibition of glucose production in the liver, and improvement in mechanisms by peroxisome proliferator active receptor are some mechanisms in which plant-derived compounds are involved. Some of these mechanisms have been reported for compounds isolated from the plants described above (Table 2) and are discussed in the following section.

Salacia reticulata

Morus alba

Juglans regia

Cecropia obtusifolia

Salvia officinalis

No.

Compound

1

Salacinol

2

Kotalanol

3

4

1-deoxynojirimycin

(3S,5R,6R,7E,9S)-3,5,6,9­ Tetrahydroxymegastigman­ 7-ene

Class

Effects and Proposed Mechanisms

Model

Reference

- Competitive inhibition of intestinal α-glucosidase - Inhibition of recombinant human maltase glucoamylase

- Rat small intestinal brush border membrane vesicles (in vitro) - Recombinant human maltase glucoamylase (in vitro)

Yoshikawa et al. 2002 Rossi et al. 2006

Competitive inhibition of intestinal α-glucosidase

Rat intestinal α-glucosidase (in vitro)

Yoshikawa et al. 1998

Inhibition of α-glucosidase

Rat intestinal α-glucosidase enzyme

Han et al. 2018

Inhibition of Intestinal glucose absorption [mRNA and protein expression of SGLT1, Na+/K+-ATP, GLUT2 (↓)]

STZ-diabetic mice

Li et al. 2013

Megastigmane

Glucose uptake (↓)

HepG2 and Caco-2 cells

Forino et al. 2016

- Insulin-sensitive and insulin-resistant 3T3­ F442A adipocytes - HepG2 cells

Alonso-Castro et al. 2008 Ong et al. 2013

Thiosugar sulfonium sulfate

Polyhydroxylated piperidine alkaloid

5

Chlorogenic acid

Phenolic acid

- Glucose uptake stimulation - Activation of AMPK

6

Isoorientin

Flavonoid

Glucose uptake stimulation and inhibition of lipid accumulation.

Palmitate-induced insulin resistant 3T3-L adipocytes

Mazibuko-Mbeje et al. 2020

7

12-O-methyl carnosic acid

Abietane diterpene

PPARγ activation

PPARγ transactivation (in vitro)

Christensen et al. 2010

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Botanical source

92

Table 2. Bioactive compounds isolated from medicinal plants with anti-diabetic effects in clinical trials and their possible mechanisms of action (structures illustrated in

Figure 1).

Silybum marianum

Ocimum sanctum

Gymnema sylvestre

Coccinia indica

Silybin A and B

Flavonoid

Inhibition of hepatic glucose-6­ phosphatase and gluconeogenesis

Rat hepatocytes perfused with different carbohydrates

Guigas et al. 2007

10

[16-Hydroxy-4,4,10,13­ tetramethyl-17-(4-methyl­ pentyl)-hexadecahydro­ cyclopenta[a] phenanthren-3-one]

Tetracyclic triterpenoid

FBG (↓), TG (↓), LDL (↓), TC (↓) and HDL (↑).

Alloxan-induced -diabetic rats (Bioactivity-guided fractionation)

Patil et al. 2011

11

Gylongiposide I

Glucose-dependent stimulation of insulin release

Isolated pancreatic islets from spontaneously diabetic GotoKakizaki rats

Lundqvist et al. 2019

Activation of AMPK, β-oxidation (↑), GLUT4 translocation (↑).

L6 cells

Nguyen et al. 2011

Insulin-releasing action (Gymnemic acid IV)

STZ-diabetic mice

Sugihara et al. 2000

HOMA-IR (↓),(HOMA-β)(↑).

STZ-diabetic rats

Jamwal and Kumar 2019

Potentiated glucose and glibenclamide-induced insulin secretion and protected β -cells against oxidative damage; ERK1/2 phosphorylation (↑).

INS-1 cells

Saponin 12, 13

Damulin A and B

14, 15, 16, 17

Gymnemic acid I−IV

18

Quercetin

Triterpene glycosides

Flavonoid

Youl et al. 2010

Abbreviations: : decrease (↓); increase (↑); Na+-glucose cotransporter 2 (SGLT2); Glucose transporter 2 (GLUT2); Glucose transporter 4 (GLUT4); streptozotocin (STZ); peroxisome proliferator-activated receptor γ (PPARγ); fasting blood glucose (FBG); AMP-activated protein kinase (AMPK); homeostasis model assessmentinsulin resistance (HOMA-IR); homeostasis model assessment of β-cell function (HOMA-β); extracellular signal-regulated kinase 1/2 (ERK1/2); high-fat diet (HFD); phosphatidylinositol 3-kinase (PI3K).

Antidiabetic Plants with Ethnomedicinal Information 93

Gynostemma pentaphyllum

8, 9

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Inhibition of α-glucosidase to Reduce Intestinal Glucose Absorption Inhibition of α-glucosidase is an effective strategy to control postprandial hyperglycemia (PPHG) in individuals with diabetes (Alssema et al. 2021). Salacinol (1), Kotalanol (2), and 1-deoxynojirimycin (DNJ, 3) are three potent a-glucosidase inhibitors identified during the curse of characterization studies on the anti-diabetic activity of medicinal plants. Salacinol and Kotalanol were isolated from the roots and stems of S. reticulata (Yoshikawa et al. 1998, 2002). In vivo experiments showed that Salaciol is effective in the management of PPHG (Yoshikawa et al. 2002). Thus, S. reticulata seems to normalize blood glucose via inhibition of a-glucosidase by these compounds. 2hrPG reduction, along with a significant decrease in HbA1c, was also observed in T2DM patients treated with bark powder of this plant (Radha and Amrithaveni 2009). DNJ, the main hypoglycemic component in M. alba, has attracted considerable interest for its health-promoting properties in non-communicable metabolic diseases (Thakur et al. 2019). Although less is known regarding how DNJ as a pure compound affects clinical parameters in T2DM subjects, consumption of DNJ-enriched young mulberry leaves powder suppressed the rise of PPBG (Kimura et al. 2007). This clinical effect is partially attributed to the a-glucosidase inhibition activity of DNJ demonstrated in both in vivo and in vitro models (Han et al. 2018, Li et al. 2013). Some of the antidiabetic mechanisms of plant extracts and their active compounds include the inhibition of carbohydrate hydrolyzing enzymes, and the reduction in the transport of glucose across the small intestine. In this sense, DNJ also inhibits glucose absorption in the small intestine by inhibiting the expression of sodium glucose transport protein (SGLT1), Na+/K+-ATPase, and glucose transporter 2 (GLUT2). Another natural product with decreasing carbohydrate absorption effects is (3S,5R,6R,7E,9S)-3,5,6,9-Tetrahydroxymegastigman-7-ene (4), a Megastigmane isolated from leaves of J. regia. This compound reduces the cellular uptake of glucose in HepG2 and Caco-2 cells, commonly used as a model system for intestinal permeability (Forino et al. 2016).

Glucose Uptake Stimulation Insulin resistance is a common clinical feature of most types of metabolic disorders such as T2DM, in which insulin‐dependent cells, such as skeletal muscle and adipocytes, fail to properly respond to normal circulatory levels of insulin, resulting in further increases in blood glucose levels (Yaribeygi et al. 2019). Insulin regulation of cellular glucose uptake has been well studied in different cell types and some phenolic compounds are considered modulators of this process (Huang et al. 2015). Isoorientin (5) and chlorogenic acid (6) are the main active phenolic compounds of C. obtusifolia. In vitro studies have demonstrated the glucose uptake stimulation effects of these compounds in adipocytes. Isoorientin probably improves glucose uptake and decreases lipid accumulation in insulin-resistant 3T3-L1 adipocytes via activation of AMP-activated protein kinase (AMPK) (Mazibuko-Mbeje et al. 2020), whereas chlorogenic acid seems to have insulin-like properties in both insulin­

Antidiabetic Plants with Ethnomedicinal Information 95

sensitive and insulin-resistant 3T3-F442A adipocytes (Alonso-Castro et al. 2008). In addition, it has been demonstrated that 5 induced the activation of AMPK, which reduces the expression of glucose-6-phosphatase (G6Pase), thus suppressing glucose production in HepG2 cells (Ong et al. 2013) and decreasing glucose uptake by human intestinal Caco-2 cells (Johnston et al. 2005). Abietane diterpenes are some of the major components occurring in S. officinalis and because of their antidiabetic activity previously described, these compounds seem to be involved in the important spectrum of bioactivity reported for this plant (Rau et al. 2006). 12-O-methyl carnosic acid (7) isolated from dichloromethane extract of S. officinalis is related to the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). Activation of PPAR-γ by antidiabetic thiazolidinedione agents causes insulin sensitization that enhances glucose metabolism (Botta et al. 2018). Plant-derived compounds with agonist activities on PPAR-γ may have important roles in the treatment of hyperlipidemia and T2DM.

Inhibition of Glucose Production in the Liver In T2DM, hepatic gluconeogenesis is a predominant cause of elevated hepatic glucose production and G6Pase is a key element in this metabolic pathway. Therefore, the inhibition of this enzyme is a potential target for normalizing plasma glucose levels (Westergaard and Madsen 2001). Silymarin, an extract of the milk thistle S. marianum, is a general name for a family of flavonolignans isomers including silibinin, isosilibinin, silichristin, and silidianin. Silibinin, also known as Silybin, is the major active component of silymarin and consists of the diastereomers silybin A (8) and B (9) (Soleimani et al. 2019). These compounds can inhibit hepatic glucose6-phosphatase and gluconeogenesis in rat hepatocytes perfused with different carbohydrates (Soleimani et al. 2019).

Stimulation of Insulin Secretion by Pancreatic β-cells Several natural compounds, such as saponins and flavonoids exhibit their antidiabetic effects through stimulating pancreatic insulin secretion. G. pentaphyllum is a perennial creeping herb known to contain dammarane-type triterpene saponins, namely gypenosides (or gynosaponins) (Razmovski-Naumovski et al. 2005). In a bioassay­ guided isolation study designed to identify the specific compound responsible for the insulin-stimulatory effect of G. pentaphyllum, Lundqvist et al. (2019) reported that Gylongiposide I (11), a dammarane-type triterpenoid, increased insulin secretion. On the other hand, the crude saponin fraction from methanol extracts of the dried leaves of G. sylvestre and Gymnemic acid IV (7) (a triterpenoid glycoside derived from this fraction) reduced the blood glucose levels in streptozotocin (STZ)-diabetic mice. Interestingly, 17 did not show α-glycosidase inhibitory activity. This observation as well as increased insulin levels in STZ-diabetic mice following the administration of this compound suggests an insulin-releasing mechanism of action (Sugihara et al. 2000). Quercetin (18) is a flavonoid found in a variety of vegetables and fruits. Several health benefits are attributed to quercetin and preclinical studies suggested that it

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may have therapeutic potential in the treatment of T2DM (Shi et al. 2019). Jamwal and Kumar (2019) reported that quercetin reduced HOMA-IR and increased β-cell sensitivity (HOMA-β) in STZ-induced diabetic rats, suggesting that this compound is responsible for the antidiabetic activity of C. indica. Previous studies have shown that quercetin potentiates glucose and glibenclamide-induced insulin secretion and protects β-cell function and viability from H2O2-induced oxidative damage in INS-1 cells. These effects are mediated by phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), suggesting that the activation of the ERK1/2 pathway plays a crucial role in the action of quercetin (Youl et al. 2010).

Conclusions Ethnomedical studies have contributed to carrying out clinical trials with antidiabetic medicinal plants used mainly in Asiatic traditional medicine. These antidiabetic plants have shown good hypoglycemic actions, alone or in combination with antidiabetic agents like glibenclamide. Most of the active compounds cited in this chapter have been studied for their mechanism of action. However, further preclinical studies are needed to confirm their efficacy. Future studies open the possibility to combine natural-derived compounds with antidiabetic agents to improve the glycemic status of diabetic patients.

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Yoshikawa, M., T. Morikawa, H. Matsuda, G. Tanabe and O. Muraoka. 2002. Absolute stereostructure of potent α-glucosidase inhibitor, salacinol, with unique thiosugar sulfonium sulfate inner salt structure from Salacia reticulata. Bioorg. Med. Chem. 10: 1547–1554. Youl, E., G. Bardy, R. Magous, G. Cros, F. Sejalon, A. Virsolvy et al. 2010. Quercetin potentiates insulin secretion and protects INS‐1 pancreatic β‐cells against oxidative damage via the ERK1/2 pathway. Br. J. Pharmacol. 161: 799–814. Zain-ul-Abidin, S., R. Khan, M. Ahmad, M.Z. Bhatti, M. Zafar, A. Saeed and N. Khan. 2018. Ethnobotanical survey of highly effective medicinal plants and phytotherapies to treat diabetes mellitus II in SouthWest Pakistan. Indian J. Tradit. Knowl. 17: 682–690. Zhou, T., X. Xu, M. Du, T. Zhao and J. Wang. 2018. A preclinical overview of metformin for the treatment of type 2 diabetes. Biomed. Pharmacother. 106: 1227–1235.

Chapter 5

Phytolaccaceae and Petiveriaceae Ethnobotany and Phytochemistry Zilda Cristiani Gazim,1,* Evellyn Claudia Wietzikoski Lovato,2 Bárbara de Souza Arcanjo,1 Maria Graciela Iecher Faria Nunes,1 Suelen Pereira Ruiz Herrig,1 Ana Daniela Lopes,1 Carla Maria Mariano Fernandez,1 Giani Andrea Linde Colauto,3 Nelson Barros Colauto4 and Juliana Silveira do Valle1

Introduction The order Caryophyllales has flowering plants with approximately 12,500 species distributed in 38 families classified after molecular phylogenetic studies (APG 2016). They are of great ecological and evolutionary interest because they have numerous origins of specialized morphological, anatomical, and biochemical attributes,

Graduate Program in Biotechnology Applied to Agriculture, Universidade Paranaense, Umuarama, PR, Brazil. Email: [email protected],https://orcid.org/0000-0003-2217-7280 Email: [email protected], https://orcid.org/0000-0001-5363-2894 Email: [email protected], https://orcid.org/0000-0002-1094-174X Email: [email protected], https://orcid.org/0000-0003-2027-5741 Email: [email protected], https://orcid.org/0000-0001-7324-5533 Email: [email protected], https://orcid.org/000-0002-9463-5378 2 Graduate Program in Medicinal Plants and Phytotherapeutics in Basic Attention, Universidade Paranaense, Umuarama, PR, Brazil. Email: [email protected], https://orcid.org/0000-0002-8511-0086 3 Graduate Program in Food, Nutrition and Health, Federal University of Bahia, Salvador, BA, Brazil. Email: [email protected], https://orcid.org/0000-0003-1220-2032 4 Graduate Program in Food Science, Federal University of Bahia, Salvador, BA, Brazil. Email: [email protected], https://orcid.org/0000-0003-4390-8302 * Corresponding author: [email protected] 1

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constituting the largest diversity of photosynthesizing species after the grasses. Some species of this order are adapted to extreme habitats, such as xeric conditions, salinity, or nitrogen-poor soils, including succulent, halophytic, gypsophilous, and carnivorous plants (Hernández-Ledesma et al. 2015). The family delimitation within the order Caryophyllales still causes taxonomic uncertainty. The family Phytolaccaceae is constantly changing as molecular phylogeny data becomes available, resulting in the inclusion and exclusion of genera or the separation of subfamilies into distinct families (APG 2016). Genera formerly associated with the family Phytolaccaceae have been separated into new families, such as Barbeuiaceae, Gisekiaceae, Lophiocarpaceae, and Stegnospermataceae (APG 2009). Petiveriaceae, which was always considered a subgroup of Phytolaccaceae, was definitively separated into a new family and, more recently, the subfamily Rivinoideae which also belonged to the family Phytolaccaceae, was included in the family Petiveriaceae (APG 2016). According to Christenhusz and Byng (2016), the family Phytolaccaceae consists of five genera (Agdestis Moc. & Sessé ex DC.; Anisomeria D. Don; Ercilla A. Juss.; Nowickea J. Martínez & J.A. McDonald e Phytolacca Tourn. ex L.) and 35 species; whereas the family Petiveriaceae includes nine genera (Gallesia Casar., Hilleria Vell., Ledenbergia Klotzsch ex Moq., Monococcus F. Muell., Petiveria Plum. ex L., Rivina Plum. ex L., Schindleria H. Walter, Seguieria Loefl., and Trichostigma A. Rich.) and 21 species (POWO 2021). The Phytolaccaceae family is pantropical and occurs mainly in South America. They are plants with herbaceous to sub-shrubby habits, rarely arboreal, and preferentially associated with forest environments. According to Judd (2002), the representatives of Phytolaccaceae are typically entomophile (its flowers attract bees, wasps, flies, and butterflies), and its fruits are dispersed by birds (Neves et al. 2006). In Brazil, it is represented by only three species, such as Phytolacca dioica L. Phytolacca rivinoides Kunth & Bouché, and Phytolacca thyrsiflora Fenzl ex J. A. Schmidt (Meirelles 2016), which were selected for this chapter. Some species of Phytolaccaceae contain substances that are used in medicines. The roots and fruits of some Phytolaccaceae contain saponin, which is used as a soap. Due to its fast-growing nature, some species such as P. dioica are often used as shade trees in the tropics (Lee et al. 2013). The Petiveriaceae family is composed of herbaceous, shrubby, or arboreal plants, distributed from tropical to subtropical America (Savolainen et al. 2000). Species of the Petiveriaceae have four tepals, at least four stamens, a gynoecium with one carpel, and a drupe or achene with indehiscent-type fruit, with a slightly lenticular seed and embryonic distinctions (Luz et al. 2016). There is little information about the general characteristics of the Petiveriaceae family, but the species that constitute this family, such as Gallesia integrifolia (Spreng.) Harms, Petiveria alliacea L., and Rivina humilis L. were selected to compose this chapter.

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Petiveriaceae Family Gallesia integrifolia (Spreng.) Harms Botanical synonymy G. integrifolia (Spreng.) Harms was first described by Sprengel in 1821 under the name Thouinia integrifolia Spreng.; and since then, several names have been misused, which could be confusing. Therefore, the current name and its synonyms, as well as eventual typing mistakes or misspellings, must be clarified. Thus, the main species and its synonyms are Gallesia gorarema, Gallesia gorazema (Vell.) Moq., Crataeva gorazema Vell. (Akisue et al. 1986), Gallesia scorododendrum Casar., Gallesia ovata O. C. Schmidt, Gallesia integrifolia var. ovata (O.C. Schmidt) Nowicke and Crataeva gorarema (Guarim Neto and Morais 2003, Rodrigues et al. 2010). Popular Names It is commonly known as “pau-d’alho” or “garlic plant”, “pau-de-mau-cheiro”, “árvore-de-alho”, “ubaeté”, “catinga-de-gambá”, “ibirarema”, “gororema”, “ivirarema”, “jandiparana”, and “arbol-de-ajó” because of the strong garlic scent, peculiar to all parts of the plant, especially on days with great humidity in the air and which generally ensures the nomenclature attributed (Corrêa and Pena 1984, Akisue et al. 1986, Inoue et al. 1984, Cavalho et al. 2006). Other popular names such as “guararema”, “gurarema”, and “guarema”, of Tupi origin (gwra’rema), are also used and mean smelly wood (Ferreira 1986). Etymology The etymology description in the literature is superficial. However, it has been reported that the name “Gallesia” was a homage to Gallesio and “integrifolia” the whole leaf (Pott and Pott 1994). Specie description G. integrifolia (Figure 1) belongs to the family Phytolaccaceae (Durigan et al. 1997) and is native to South America (Brazil and Peru) with reports in all Brazilian regions and part of the Atlantic forest (Inoue et al. 1984, Gonçalves 2016). It is a fast-growing tree, with a straight trunk and thick and large bark, and height between 5 and 30 m (Figure 1b), having its wood widely exploited (Carvalho 2006, Rodrigues et al. 2010). Its leaves are elliptical and shiny (Figure 1a), and the flowers provide essential oil (Lima et al. 2010). Its inflorescence occurs from February to April (summer and early autumn). The flowers are white, arranged in terminal panicles and monochlamids (Figure 1d) (Corrêa and Pena 1984, Carvalho 1994). Its fruits ripen from September to October, when temperatures are lower, corresponding to winter and spring. The fruits are of the samara type, paleaceous, inedible, and difficult to

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6

Figure 1. Gallesia integrifolia (a) leaves, (b) adult specimen, (c) fruits, (d) flowers, and (e) fruiting branch (Source: Authors).

separate from the seeds (Figure 1c and 1e) (Lorenzi 1992, Lima et al. 2010). Its seeds germinate in open fields with low humidity and high luminosity or closed forests with high humidity and low luminosity, which explains its wide geographic distribution (Barros et al. 2005). The presence of this species is an indication of fertile soil (Carvalho 1994, Forzza et al. 2010). This species also has its wood used mainly in sawmills and for energy production, but also for the manufacture of pulp and paper. It is also used as a substitute for the Brazilian pine (Araucaria angustifolia (Bertol.) Kuntze) (Lima et al. 2010). Popular Use Known for its medicinal properties, G. integrifolia is used to treat pathologies, such as rheumatism, bronchitis, asthma, pneumonia, cough, lymphatic system diseases,

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verminosis, otitis, and prostate tumors. In addition, it is indicated as a hypotensive for the treatment of blood pressure reduction, cholesterol level reducers, and leg pain (Akisue et al. 1986, Santos et al. 2014). The barks have been widely used in folk medicine, mostly in the preparation of teas for the treatment of flu, cough, pneumonia, worms, gonorrhoea, prostate tumors, and rheumatism (Lorenzi 1992). Dried stems have been used to make tea and treat bronchitis in traditional Peruvian medicine practice and in Andean culture (Bussmann et al. 2010). The tea from leaves and bark was used to treat coughs, sore throats, and skin infections. In an ethnopharmacological study by Bueno et al. (2019), G. integrifolia was reported with other therapeutic indications, such as back pain, bronchitis, rheumatism, and constipation (Bueno et al. 2019). Chemical composition The presence of sulfur products is a chemotaxonomic characteristic of this species. Sulfur compounds are found in all tissues of leaves, flowers, fruits, and bark, imparting a strong alliaceous odor (Akisue et al. 1986). The presence of sulfur compounds is associated with the plant’s defence system that produces substances in response to the attack of phytopathogens, synthesizing and emitting numerous volatile compounds and attracting its pollinators. The volatiles found in the bark, leaves, flowers, and fruits of G. integrifolia present high amounts of sulfur compounds, justifying the strong alliaceous odour (Raimundo et al. 2021). These authors reported that the essential oils obtained by hydrodistillation and identified by gas chromatography coupled with mass spectrometry (CG/MS) were 99.2% sulfur compounds in fruits (major compounds were 15.5% dimethyl trisulfide, 52.6% 2,8-dithianone, and 14.7% lanthionine), 95.3% sulfur compounds in leaves (major compounds were 14.2% 1,3,5-tritium, 38.9% 3,5-dithiahexanol-5,5-dioxide, and 12.6% n-ethyl-1,3-dithioisoindole), and 95.9% in flowers (major compounds were 17.2% methyl p-tolyl sulfide, 45.3% L-methionine, ethyl ester, and 13.4% n-ethyl-1,3-dithioisoindole). In another study, (Raimundo et al. 2017) evaluated the chemical composition of the volatiles of G. integrifolia leaves, flowers, and fruits, collected by dynamic headspace technique, finding that leaves had 42.4% dimethylsulfide, 40.4% 3-methylbutanal, 8.6% α-terpinolene, and 5.5% ethanol, 2-(methylthio). Flowers had 44.4% methanethiol and 43.7% dimethylsulfide, and fruits had 35.3% 2,3,5-trithiahexane, 20.9% 3,6-dithiaoctan-1,8-diol, 16.3% methanethiol, and 9.1% dimethyl sulfone. Studies from the same research group reported that the fruit essential oil of G. integrifolia obtained by hydrodistillation and identified by CG/MS had 52.6% 2,8-dithianonane, 15.5% dimethyl trisulfide, and 14.7% lenthionine (Raimundo et al. 2018, Bortolucci et al. 2021b). The dried-leaf essential oil of G. integrifolia (adult specimens in Maringá, Paraná, Brazil) were identified by GC/MS by Maia et al. 2013, and major compounds were dimethyl disulfide (53.0%), methyl disulfide (11.3%), and dimethyl trisulfide (2.3%). Barbosa et al. 1999 investigated the fresh bark essential oil of G. gorazema (current name G. integrifolia; Viçosa, Minas Gerais, Brazil) and identified by GC/MS the major sulfur compounds 2,3,5-trithiahexane (11.2%), 2,3,4,5-tetrathiaheptane

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(8.3%), 2,3,5-trithiahexane 5-oxide (15.0%), methyl propyl tetrasulfide (17.6%), 2-[2,2-bis(sulfanyl)ethoxy]ethane-1,1-dithiol (8.8%). These authors also investigated the chemical composition of fresh bark extract obtained with diethyl ether and reported as major compounds disulfide, (methylsulfonyl)methyl (methylthio)methyl (27.2%), and methyl propyl tetrasulfide (17.9%). The essential oil from the fresh inner bark of G. integrifolia stem (adult specimens, Bom Jardim, Nobres, Mato Grosso, Brazil) was obtained and identified by GC/MS. The main compounds were alpha-santalele (18.9%), phytol (11.8%), bis-disulfide (9.9%), methyl-disulfide (6.9%), and alpha-bisabolene (6.3%) (Arunachalam et al. 2017). The phytochemical study of Arunachalam et al. 2016 investigated the chemical composition of the inner bark alcoholic extract (70% ethanol) of G. integrifolia stem (Juruena Valley, Aripuanã, Mato Grosso, Brazil), identified by HPLC, and reported the presence of phenolic compounds such as gallic acid (12.06 μg/mg), rutin (20.98 μg/mg), and morin (8.88 μg/mg). Bortolucci et al. (2020) and Bortolucci et al. (2021a) investigated the alcoholic extract (ethyl alcohol 96 °GL) from the leaves, flowers, and fruits of G. integrifolia. They reported sulfur compounds in flowers (21.7%), highlighting disulfide, bis(2­ sulphhydryl ethyl (12.8%), and in fruits (9.1%), highlighting 2,3,5-trithiahexane (5.0%). In addition to the sulfur compounds, other classes were found, such as Vitamin E (20.1%) in flowers and (18.2%) in fruits; phytol (30.05%) in leaves, (11.0%) in flowers, and (6.9%) in fruits; linoleic acid methyl ester (29.6%) and methyl palmitate (10.3%) in leaves, and ethyl iso-allocholate (10.8%) in fruits. Biological Activities The presence of sulfur in several parts of G. integrifolia can confer insecticidal action to this species, since elemental sulfur is one of the most used chemical compounds for the control of insects and fungi. Therefore, some organic compounds from the sulfide classes also have insecticidal properties, such as aromatic and aliphatic sulfides, oxygenated sulfur compounds (sulfonic acids, sulfones, sulfoxides, sulfites, and sulfates), sulfonamides, thiazine, and thiazole derivatives, and thioacids, thiophenes, and thiourea (Frear 1948, Raimundo et al. 2018). The number of sulfur atoms in the molecule affects biological activity. According to Mann et al. 2011, molecules with three sulfur atoms (trisulfides) provide greater insecticidal potential than disulfides and monosulfides. This statement was corroborated by Huang et al. 2000, who evaluated the effect of two sulfur compounds (methyl allyl disulfide and diallyl trisulfide) isolated from Allium sativum L. essential oil against the insect Sitophilus zeamais Motschulsky that attacks maize. The authors concluded that diallyl trisulfide provided greater activity against the insect larvae and eggs than the compound with two sulfur atoms in the molecule. Raimundo et al. 2021 also put this statement into practice when they investigated the insecticidal action of the essential oil extracted from leaves, flowers, and fruits of G. integrifolia on Aedes aegypti larvae, with greater activity of the leaf (0.0096 μg/mL), flower (0.0209 μg/mL), and fruit (5.87 μg/mL) essential oil. They also reported that the high insecticidal action found in leaves was due to the presence of dimethyl tetrasulfide

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(5.3%) and 1,3,5-trithiane (13.7%) compounds with four and three sulfur atoms in the molecules, respectively. Bortolucci et al. (2021a) also confirmed that the number of sulfur atoms affected the biological activity of crude extracts of leaves, flowers, and fruits of G. integrifolia against A. aegypti larvae. These authors concluded that the presence of disulfide, bis(2-sulfhydryl ethyl) (11.9%), 2,3,5-trithiahexane (6.2%), 1,2,4-trithiolane (1.1%), and 2,4-dithiapentane (1.1%) in crude flower extract may have provided 99.9% mortality of larvae with LC99.9 of 0.032 mg/mL. Bussmann et al. (2010) investigated the antibacterial potential of alcoholic extract of G. integrifolia dried stems against Staphylococcus aureus and Escherichia coli using the agar-diffusion method. The extract showed an inhibition halo of 19 mm greater than the positive control amikacin (7 mm). Studies report that the pharmacological potential of leaves and bark of this species is due to the presence of natural substances, such as sulfur compounds, tannins, essential oils, coumarins, and alkaloids, which are responsible for antitumor, antimicrobial, and antioxidant activities (Barbosa et al. 1999, Anwar et al. 2008, Bussmann et al. 2010). G. integrifolia has also shown bactericidal and fungicidal effects. The essential oil of G. integrifolia fruits has fungicidal activity in pathogenic and food spoilage against Aspergillus fumigatus, Aspergillus niger, Aspergillus ochraceus, Aspergillus versicolor, Penicillium funiculosum, Penicillium ochrochloron, Penicillium verrucosum var. cyclopium, and Trichoderma viride, with minimal fungicidal concentration from 0.02 to 0.18 mg/mL (Raimundo et al. 2018). The antibacterial activity of the methanol extract from the inner bark of G. integrifolia stem was evaluated by Arunachalam et al. (2016) by broth microdilution method, finding the minimum inhibitory concentration against Shigella flexneri (25 µg/mL), Streptococcus pyogenes (100 µg/mL), Escherichia coli (200 µg/mL), Salmonella typhimurium (200 µg/mL), Pseudomonas aeruginosa (400 µg/mL), Staphylococcus aureus (400 µg/mL), and Klebsiella pneumoniae (400 µg/ml). Arunachalam et al. (2017) evaluated the gastroprotective effect of the inner bark essential oil of G. integrifolia stem against lesions induced by acidified ethanol in mice. The results indicated that the essential oil at 5, 20, and 80 mg/kg inhibited gastric lesion formation by 24.2%, 57.4%, and 81.8%, respectively. The antinociceptive effect of ethanolic and chloroformic extracts of G. gorazema (current name G. integrifolia) leaves and dichloromethane of roots, exhibit 57.8%, 37.4%, and 76.0% inhibition, respectively, against constrictions acetic acid-induced abdominal pain in rats (Silva Júnior et al. 2013). The essential oil of G. integrifolia fruits was investigated for cytotoxic potential against human tumour cell lines MCF-7 (breast adenocarcinoma) with GI50 = 66 µg/mL, NCI-H460 (large cell lung carcinoma) with GI50 = 147 µg/mL, HeLa (cervical carcinoma) with GI50 = 182 µg/mL, and HepG2 (hepatocellular carcinoma) GI50 = 240 µg/mL. The non-tumour PLP2 (porcine liver primary cells) was (GI50 > 400 µg/mL), indicating that the essential oil is non-toxic. It also had antiinflammatory activity 3.4 times greater than the control (dexamethasone) with EC50 of 55 µg/mL (Bortolucci et al. 2021b).

108 Ethnobotany: Ethnopharmacology to Bioactive Compounds Toxicity Bortolucci et al. (2021b) investigated the toxicity of essential oil extracted from G. integrifolia fruits on cells extracted from pig liver (PLP2). The results indicated that the essential oil amount to inhibit 50% of cell growth (GI50) was > 400 µg/ mL, compared to ellipticin GI50 = 3.2 ± 0.7 µg/mL. Although there is no toxicity in G. integrifolia fruits, cytotoxicity studies with other plant parts (leaves, flowers, and husk) are still needed.

Petiveria alliacea L. Botanical synonymy Petiveria alliacea L. has several synonyms, such as Petiveria foetida Salisb (POWO 2021), Petiveria corrientina Rojas, Petiveria hexandria Sessé & Moc., Petiveria octandra L., Petiveria paraguayensis Parodi, Petiveria ochroleuca Moq., Petiveria alliacea var. grandiflora (L.) Moq., Petiveria alliacea var. octandra (L.) Moq., Petiveria alliacea L. var. alliacea, Mapa graveolens Vell. (GBIF 2021, SiBBr 2021), and Petiveria alliacea L. var. tetandra (Hassler 2018). Popular names P. alliaceae has a variety of names depending on where it is found, being known as “guiné” and “anamu” in most South American countries, “awogba-arun”, meaning cures many diseases or “arunyanyan” meaning smells good, in the southern part of Nigeria, where it grows in abundance (Gbenga and Oluyemi 2019) and “mapurito” in Trinidad (Taylor 2004, Alegre and Clavo 2007). Other names are also reported such as “mucuraá” (Furtado et al. 1978), “mucura-caá”, “tipi”, “amansa-senhor”, “tipi-verdadeiro”, “gambá-tipi”, “erva-pipi”, “raiz-de-guiné”, “pipi”, “cagambá”, “cangambá”, “embiaiendo”, “embirembo”, “emboaembo”, “emburembo”, “erva­ das-galinhas”, “erva-de-alho”, “gambá”, “gerataca”, “gorana-timbó”, “gorarema”, “gorazema”, “guiné-pipi”, “paraacaca”, “paracoca”, “pau-de-guiné”, “pênis-de­ coelho”, “raiz-de-congonha”, “raiz-de-gambá”, “raiz-de-pipi”, “raiz-do-congo”, “rederal”, “remédio-de-amansar-senhor”, “tipi-branco”, “tipi-do-mato”, “tipi-roxo”, “tipi-verdadeiro” (Rios and Pastore Júnior 2011). Etymology The generic epithet Petiveria was chosen to honour the pharmacist and nature lover Jacob Petiver, and the specific epithet alliacea was related to the taste and smell similar to garlic (Gonçalves 2016). The common name “remédio-de-amansar­ senhor” is due to the use of enslaved people, who knew the toxic effects of this plant and gave it to their masters, hence the meaning of the name (tame remedy lord), as the root is more active than the leaves (Fazolin et al. 2002). Specie description P. alliacea is native to Africa and tropical America (Fazolin et al. 2002), being found from the United States of America to Argentina and occurring in practically all Brazilian states (Hatschbach and Guimarães 1973). It is a herbaceous, perennial

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shrub (Figure 2a), very branchy, with angular slack branches with deep roots that mature after several years, reaching up to a meter high. The roots and leaves have a strong garlic odour, while the fruits are narrowly oblong and 6–8 mm long (Figure 3c) (Berg 1993, Schmelzer and Gurib-Fakim 2008). Its leaves are short petiolate, alternate, stipulated, membranous, sharp at the apex, and narrow at the base, with 5–18 cm in length and 2–7.5 cm in width (Figure 2b), cylindrical, flattened, and crenated achene fruit. The flowers are small with four white or slightly pinkish petals, sessile, gathered in axillary inflorescences and spiky terminals, androceus 13 with four stamens and unicarpellate gynoecium (Figure 2d and 2e) (Berg 1993, Costa et al. 1989).

Figure 2. Petiveria alliacea L. (a) adult specimen; (b) sheets; (c) stem with flower buds; (d) and (e) stem with flowers (Source: Plants of the World Online, Royal Botanic Gardens, Kew. 2021. Licensed under Creative Commons Attribution CC BY).

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Figure 3. Rivina humilis L. (a) stem with flowers; (b) and (f) overview of an adult specimen; (c) and (d) sheets; (e) fruits (Source: Plants of the World Online, Royal Botanic Gardens, Kew. 2021. Licensed under Creative Commons Attribution CC BY).

It is typical of deforestation, secondary forests, and shrublands, and rare in dense vegetation formations (Hatschbach and Guimarães 1973). Its presence is perceived by the strong odour similar to garlic (Cordero 1978). Its fruits have spines that serve as a means of dissemination (Lorenzi and Matos 2002). Popular use According to indigenous medicine, P. alliacea root and leaf have been associated to several therapeutic properties, such as diuretic, antispasmodic, emmenagogue,

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analgesic, anti-inflammatory, anti-leukemic, anti-rheumatic, anthelmintic, antimicrobial, and depurative (Luz et al. 2016). The crude extract or infusion of the roots and leaves are used topically and orally, with the roots being more active than leaves, and are also a menstrual promoter, stimulant, and sweat promoter (LopesMartins et al. 2002). Herbalists and natural medicine practitioners use the plant for edema, arthritis, malaria, poor memory, skin diseases, scabies, and bites (Revilla 2002a). It is also used in oral infections, throat infections (Zoghbi et al. 2000), lung infections, urinary tract (Cordero 1978), constipation (Salinas and Grijalva 1994), heart and liver problems (Barrett 1994), home treatment of tetanus, epilepsy (Cordero 1978), and as an anesthetic (Hoehne 1978). In some areas of tropical America, after macerating, it is used as a repellent for insects, bats, and as an acaricide (Pérez-Leal et al. 2006, Christie and Levy 2013). The burning leaves produce a sour-smelling smoke that has been used to repel mosquitoes (Rios and Pastore Júnior 2011). In Latin America and the West Indies, it is commonly used by healers in ritual ceremonies. In Brazil, Cuba, and tropical Africa, it is important in Yoruba magical rituals due to its hallucinogenic characteristics, especially the roots (Vieira 1992, Alegre and Clavo 2007), and its leaves are used to fight against courses of the evil eye (Furtado et al. 1978). Chemical composition Phytochemical studies of P. alliacea indicate a diversity of biologically active compounds with qualitative and quantitative variations of the major compounds depending on the area and time of harvest. The essential oil chemical composition has petiverin as its primary compound and others, such as saponins glycosides, isoarborinol-triterpene, isoarborinol-acetate, isoarborinol-cinnamate, steroids, alkaloids, flavonoids, and tannins. The root chemical composition has coumarins, benzyl-hydroxy-ethyl-trisulphide, benzaldehyde, benzoic acid, dibenzyl trisulphide, potassium nitrate, b-sitosterol, isoarborinol, isoarborinol-acetate, isoarborinol­ cinnamate, phenol polys, trithiolaniacine, glucose, and glycine (Luz et al. 2016). Aqueous, methanolic, and chloroformic extracts from P. alliaceae roots and leaves indicated the presence of tannins, flavonoids, terpenoids, steroids, saponins, and alkaloids (Gbenga and Oluyemi 2019). Tannins, saponins, flavonoids, and terpenoids were found in leaves, inflorescences, stem bark; steroids in the stems; saponins in the roots; glycosides in inflorescences, infructescence, stem, and root bark, while alkaloids were present only in the inflorescences (Arogbodo 2021). Flavonoids and flavonoid derivatives were found in an ethanol extract from aerial parts of P. alliacea, such as leridal, leridol, 5-O-methylleridol, engeletin, dihydroquercetin, and myricetin. Furthermore, the fractionation of the ethanol extract provided the isolation of 7-demethylleridal, leridal-chalcone, petiveral, and 4-ethylpetiveral. In addition, a homogenate of P. alliacea roots provided several thiosulfinates, such as s-(2-hydroxyethyl) 2-(hydroxyethane) thiosulfinate, s-(2-hydroxyethyl) phenylmethanethiosulfinate, s-benzyl 2-(hydroxyethane)

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thiosulfinate, and s-benzyl phenylmethanethiosulfinate (petivericin) (Silva et al. 2018). In leaves, branches, roots, and inflorescences, yellow essential oil with a strong and unpleasant odour due to allyl sulfide is found (Luz et al. 2016). The chemical composition of essential oils from different parts of P. alliacea and identified by GC have shown some compounds, such as phenylpropanoids, terpenoids, and numerous benzenoids. Five phenylpropanoids have been reported for P. alliacea essential oils, including eugenol, cinnamaldehyde, cis- and trans-stilbenes, and dillapiole. Benzaldehyde, benzyl alcohol, and (z)-3-hexeny benzoate are predominantly found in roots and flowers. The carvacrol constituted the major compound in the stem leave essential oils (Silva et al. 2018). However, these compounds are affected by external factors. In this context, the volatile constituents from the essential oil by hydrodistillation of P. alliacea aerial parts (Martinique) indicated that the most abundant compounds were toluenethiol (23.0%), phytol (40.0%), dibenzyldisulfide (35.3%), and benzaldehyde (31.3%) (Kerdudo et al. 2015). The essential oil extracted from P. alliaceae roots (northeast Brazil) indicated the presence of benzaldehyde (61.5%), dibenzyl disulfide (18.1%), trans-stilbene (14.1%), and cinnamaldehyde (6.5%) (Luz et al. 2016). Biological Activities

Several authors report P. alliacea with a broad-spectrum antimicrobial, antifungal,

antiviral, anticancer, immunomodulatory, and hypoglycemic activity (Ruffa et al.

2002, Williams et al. 2007, Silva et al. 2018, Akintan and Akinneye 2020). Despite

the relevance of this plant in traditional medicine, information about essential oil

yield and phytochemical constituents of leaves, inflorescences, infructescence, stem,

bark, and root is still scarce (Arogbodo 2021).

Antibacterial activity of soft extract and blended extract of P. alliacea extract have been reported against Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli, and the results showed that the blended extract was more active than the soft extract against all bacteria, mainly against P. aeruginosa but less active against E. coli and E. faecalis (Pacheco et al. 2013). Gbenga and Oluyemi (2019) also evaluated the antimicrobial activity of crude extract of P. alliacea and its fractions, such as (A) 100% chloroform extract, (B) 80% chloroform and 20% methanol extract, (C) 60% chloroform, and 40% methanol extract, (D) 40% chloroform and 60% methanol extract (E), and (F) 100% methanol extract. The root methanol extracts showed antibacterial activity against Staphylococcus aureus, Escherichia coli, Micrococcus sp., and Bacillus subtilis. Apart from the crude extract, the fraction (A) was the only one with broad-spectrum activity. The leaf methanol extract against the same bacteria indicated that all fractions acted on E. coli, fractions (C) and (F) on Bacillus subtilis, the fraction (A) on Micrococcus sp. The antifungal activity was evaluated in Penicillium sp., Aspergillus flavus, Colletotrichum sp., Trichoderma sp., and Rhizopus sp. The fractions were active against three fungi: Penicillium sp., Colletotrichum sp., and Rhizopus sp. Root extract was inactive only for Rhizopus sp.

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Hernández et al. (2014) evaluated a fraction of P. alliacea leaves and stems and verified that the extract induced cell death in vitro and tumour regression in vivo in a murine breast cancer model. The results validate, in part, the traditional use of P. alliacea in the treatment of breast cancer, revealing a new way to visualize the biological activity of this species. According to the authors, the effect of the fraction on enzymes in the glycolytic pathway contributes to and explains the antiproliferative and antitumour activities. The use of P. alliacea aqueous extract was reported by Christie and Levy (2013), demonstrating a hyperglycemic effect in normoglycemic rats, but no hypoglycemic activity in diabetic rats. The authors report that the hexane extract did not cause hypoglycemic action in normal rats and could not sustain an initial hypoglycemic action in diabetic rats. Toxicity The toxicity of different extracts of P. alliacea remains to be elucidated. Despite its usefulness and proven biological activity, there are reports that P. alliaceae can cause dermatitis in humans, contaminate the milk and meat of animals that graze on it, and induce abortion (Cardenas and Coulston 1967, Garcia et al. 1967). The consumption of high concentrations may be associated with cholinesterase inhibition, considering the toxicological reaction similar to that produced by carbamates (Revilla 2002b). In addition, it has mutagenic and potentially carcinogenic substances (Di Stasi and Hiruma-Lima, 2002). The lethal dose of leaf extract tested was 3.4 g/kg (Delgado et al. 1997). When offered regularly to animals, it can cause adverse reactions. The plant’s ability to accumulate nitrates can also promote nitrate poisoning in cattle (Más and Lugo 2013). P. alliacea is still considered a weed in coffee, maize, and apple plantations, as well as in grasslands and natural forests (Garcia et al. 1967, Nienaber and Thieret 2003, Vibrans 2009, Randall 2012).

Rivina humilis L. Botanical synonymy

The main synonym of Rivina humilis L. is Rivina brasiliensis Nocca (POWO 2021).

Popular names

R. humilis is commonly called “erva-dos-carpinteiros”, “vermelhinha”, “rivina” (Marchioretto 1989), “bright red pigeon berry” (Khan et al. 2015), “rouge plant”, “coral berry”, “baby pepper”, “blood berry”, “rouge plant”, and “pigeon berry” (Bagga 2017). Etymology The etymological description in the literature is scarce. Still, there are reports of the meaning of the generic epithet Rivina as a tribute to the German botanist Augustus Quirinus Rivinus, and the meaning of the specific epithet humilis is small (Pott and Pott 1994).

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Specie description This is native to Argentina, Bolivia, Brazil, Colombia, Costa Rica, Cuba, Dominican Republic, El Salvador, French Guiana, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Puerto Rico, Southwest Caribbean, South and Southwestern United States of America, Suriname, TrinidadTobago, Uruguay, and Venezuela. It was introduced in Bangladesh, Bermuda, Cape Verde, China, Fiji, Galapagos, Hawaii, India, Ivory Coast, Jawa, KwaZulu-Natal, Malaya, Mauritius, Mozambique, New Caledonia, Northeast and Southeast regions of Australia, Philippines, Reunion, Seychelles, Somalia, Sri Lanka, Sumatera, Taiwan, Tanzania, Thailand, Tonga, Tuvalu, Vanuatu, Vietnam, Zaïre, and Zimbabwe (POWO 2021). In the adult phase, R. humilis are erect herbs or sub-shrubs (Figure 3f) with slender, dichotomous, glabrous branches. It has alternate leaves, membranous, ovate, or deltoid, glabrous to slightly pubescent adaxial and abaxial faces along the ribs (Figure 3c and 3d). Axillary or terminal racemose inflorescences, pedunculated (Figure 3f), with small, hermaphroditic, white to pink flowers (Figure 3a). Globular drupe fruit, fleshy pericarp (Figure 3e), with lenticular seeds (Marchioretto 1989, Pugialli and Marquete 1989). Considered an ornamental plant suitable for growing alone. Its drupes are used as a colouring matter (Marchioretto 1989). Popular use There is no consensus about the popular use of this species and its chemical constituents. On one hand, the consumption of R. humilis can cause coughing, thirst, tiredness with yawns, and subsequent vomiting. On the other hand, the fruits are palatable and have been dissipated by the aborigines as a therapeutic aid for treating cold, diarrhoea, difficulty urinating, flatulence, gonorrhoea, jaundice, and ovarian pain (Ajaib et al. 2013). Chemical Composition The plant’s berries contain a high content of betaine pigments (Khan et al. 2011) in various shades of orange, red, or purple. Food safety studies of red fruit juice from R. humilis (Khan et al. 2011) indicate that these berries can be a dietary or industrial source of betalains (Khan et al. 2012). A betalain betaxanthin humilixanthin (s-hydroxynorvaline-immonium betalamic acid conjugate) was isolated from R. humilis berries by Strack et al. (1987). Betalains are nitrogenous pigments containing betalamic acid as a chromophore. There are two main groups of betalains in nature: the red-violet betacyanins and the yellow-orange betaxanthines. Betalamic acid can spontaneously condense with various amino acids or amine derivatives to produce betaxanthins, or with cyclic 3,4-dihydroxyphenylalanine (cycloDOPA), which may or may not undergo glycosylation and further acylation to produce betacyanins. Betalains, especially betaxanthins, are associated with greater free radical scavenging activity (Khan et al. 2012). In addition, Hidayah et al. (2016) reported that R. humilis leaves extracted with ethanol and partitioned with n-hexane in a chromatographic column had shown steroids. An extensive chemical characterization of the ripe berries (fresh mass) of

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R. humilis was carried out by Khan et al. (2012), and nutritional components were characterized as 6.2 g/100 g carbohydrates, 2.6 g/100 g protein, 0.7 g/100 g lipids, 3.0 g/100 g fiber, 35.5 kcal/100 g. The hexane fraction showed a concentration of 56.6% saturated fatty acids, mainly palmitic acid (30.3%) and stearic acid (9.7%); 43.5% unsaturated fatty acids, primarily oleic acid (23%) and linoleic acid (18.1%). The aqueous extract of the berries presented a total of 196.7 mg/100 g (fresh mass) of organic acids, mainly tartaric (110.4 mg/100 g), citric (37.3 mg/100 g), and oxalic (25.4 mg/100 g) acids. The vitamin profile of the fruits included 5.3 mg/100 g niacin and 0.8 mg/100 g total tocopherols. Furthermore, the content of total phenols was 105.7 mg EAG/100 g, and the content of microelements, such as potassium (845 mg/100 g) and magnesium (43 mg/100 g) was considered high for a berry. Biological Activities It is considered that betalains have various biological activities, including antiinflammatory, anti-carcinogenic, anti-malaria, and neuroprotection activity (Khan et al. 2011). Methanolic extracts of branches with leaves of R. humilis showed antimicrobial activity against Pseudomonas aeruginosa (MIC = 0.75 mg/mL) and Klebsiella pneumoniae (MIC = 0.5 mg/ml) (Salvat et al. 2001). Khan et al. (2012) conducted several antioxidant activity assays of extraction and fractions of betalain from R. humilis berry juice. The 100 µg/mL methanolic extract of R. humilis berries showed 46% hydroxyl radical scavenging activity. There was no increase in the activity when the extract concentration was 500 µg/mL or 1000 µg/mL. The methanolic extracts at 100 µg/mL and 1000 µg/mL exhibited more than 90% lipid peroxidation inhibition by the beta-carotene linoleic acid assay. Protection against lipid peroxidation was also analysed in Wistar rat brain and kidney homogenates preparations. The methanolic extract of R. humilis berries exhibited low antioxidant activity against lipid peroxidation in brain cells, but the 1000 µg/mL extract exhibited 55% lipid peroxidation inhibition in kidney cells. R. humilis berry methanolic extract showed radical DPPH scavenging activity (EC50 = 81.4 µg/mL), as well as the purified betacyanins (EC50 = 0.29 µg/mL) and betaxanthins (EC50 = 0.11 µg/mL), which revealed high antioxidant activity. The ferric reducing power activity was also high for the extract (EC50 = 39.3 µg/mL), betacyanins (EC50 = 2.79 µg/m)L), and betaxanthins (EC50 = 1.34 µg/mL) (Khan et al. 2012). Crude extracts from roots, branches, leaves, inflorescences, and fruits of R. humilis were obtained with petroleum ether, chloroform, and methanol, and evaluated for antioxidant and antimicrobial potential (Ajaib et al. 2013). The chloroform extract of the fruits showed the most significant antibacterial potential against Pseudomonas aeruginosa, with an inhibition halo of 46 ± 2.8 mm, and the petroleum ether extract of the fruits also exhibited high potential against Aspergillus oryzae, exhibiting an inhibition halo of 64 ± 0.5 mm. Regarding total antioxidant activity, the methanolic extract of the fruits showed iron reducing power activity (FRAP) (1.196 ± 0.43 μM Fe2+/mg of sample), higher total phenolic content (16.94 ± 1.2 µM/mL), and also inhibited lipid peroxidation (62.1%) (Ajaib et al. 2013). The steroids found in the n-hexane extract of R. humilis leaves may have

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contributed to the antimicrobial action against Escherichia coli and Staphylococcus aureus with growth inhibition of 1000 ppm (Hidayah et al. 2016). R. humilis berry extract was used as a natural colourant in fruit spreads and beverages to evaluate its effect on physicochemical properties and acceptability of the product. Results showed that 68% colour was retained in rivina-banana spread after six months of storage at 5ºC (Khan et al. 2015), justifying the antioxidant potential of betalains described by Khan et al. (2012). Toxicity R. humilis berry juice that is rich in betalains and contains betaxanthins (209.7 ± 12.2 mg/100 mL) and betacyanins (155.5 ± 7.5 mg/100 mL) was used to feed Wistar male rats in acute, subacute, and subchronic toxicity studies (Khan et al. 2011). The rats received R. humilis berry juice up to 5 g/kg body mass in a single dose and dose-repeated toxicity studies. In the dose-repeated study for 35 days in rats, no significant alterations in feed intake, growth, organ mass, histology, hematological indices, serum, and liver biochemical parameters were observed. Furthermore, dietary feeding with R. humilis berry juice (up to 2% in diet) for 90 days with rats also does not produce alterations of the same parameters. Therefore, the study concluded that R. humilis berry juice is safe to consume (Khan et al. 2011). Methanolic extracts of R. humilis berries, betacyanins (70% pure), and betaxanthins (95% pure) fractions were used in cancer cell cytotoxicity assays (Khan et al. 2012). The extract and fractions were used to treat HepG2 cells for 24 and 48 h in a MTT assay. No cytotoxicity was observed after 24 h treatment with methanolic extract and betacyanins. However, betaxanthins exhibited EC50 = 12.0 µg/mL. After 48 h, the extract did not show cytotoxicity, whereas betacyanins (EC50 = 17.5 µg/mL) and betaxanthins (EC50 = 2.0 µg/mL) showed increased cytotoxicity (Khan et al. 2012).

Phytolaccaceae Family Phytolacca dioica L. Botanical synonymy The main synonyms of Phytolacca dioica L. are Pircunia dioica (L.) Moq., Phytolacca arborea Hort. ex Moq., Phytolacca populifolia Salisb., Phytolacca dioica var. ovatifolia Chodat, Phytolacca weberbaueri H. Walter, and Sarcoca dioica (L.) Raf (POWO 2021). Popular names P. dioica is popularly known as “cebolão”, “ceboleiro”, “umbu”, “imbu”, “ombu”, “bela-sombra”, and “maria-mole” (Carvalho 2018). It is also called “Belhambra” (English) or “Belhambraboom” (African) (Van Wyk et al. 2005). Etymology “Ombu” comes from the Guarani word ïmboú, which means “tree that attracts rain” (Tourkarkissian 1980). The generic epithet Phytolacca has a Greek origin phytón

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that means plant, and Italian lacca that means varnish or shellac. The specific epithet dioica comes from the Greek dis = two and óikos = house (Marchioretto 2020). Specie description P. dioica is an evergreen tree native to South America (Figure 4) found in Argentina, Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, and Uruguay (Wheat 1977). 22 It was introduced in the Americas in Bolivia and Venezuela; in countries on the African continent such as South Africa, Algeria, Botswana, Eritrea, Ethiopia, Libya,

Figure 4. Phytolacca dioica L. (a) bunch of open flowers; (b) adult specimen trunk; (c) a bunch of flower buds; (d) sheets; (e) fruits (Source: Plants of the World Online, Royal Botanic Gardens, Kew. 2021. Licensed under Creative Commons Attribution CC BY).

118 Ethnobotany: Ethnopharmacology to Bioactive Compounds Morocco, Namibia, Sudan, Tunisia, and Zaire (Van Wyk et al. 2005); in Europe such as Cyprus, France, Greece, Madeira, Sicily, and Spain; and in India, Nepal, Sri Lanka, and northeastern and southeastern regions of Australia (POWO 2021). It is a dioecious plant, 15 to 25 m high, with a diameter ranging from 80 to 160 cm (Lorenzi 1992). Due to its domed-shaped crown ideal for shade, P. dioica has been used in parks and town squares and landscaping (Díaz Cillio 2008). It has a thick, simple trunk, becomes knotty, and is swollen at the base with age (Figure 4b). The leaves are fleshy, simple, alternate, oval, glabrous (Figure 4d), with red or pinkish stalks. The flowers are white and small, arranged in inflorescences up to 15 cm long (Figure 4a) (Orwa et al. 2009). Fruits are succulent, yellow, hanging in clusters (Figure 4e), and contain small dark grey seeds (Van Wyk et al. 2005, Alvarez 2019). It does not have a woody trunk, so it cannot be considered a real tree but a herbaceous plant (Chebez and Masariche 2010). Its wood is light and porous and has no known application, and the fruits are appreciated by birds (Lorenzi 1992). Popular use The leaves and fruits are rich sources of triterpenoid saponins and have been described to have molluscicidal (Helaly and Ahmed 2000), anti-inflammatory, and antimicrobial (Mervat et al. 2018) activities. In addition, it is used against diarrhoea, hypertension (Tene et al. 2007, Aumeeruddy and Mahomoodally 2020), and control of obesity (Aumeeruddy and Mahomoodally 2021). The whole dried plant is used against fever as a dewormer and antiseptic. The infusion made with the leaves and root bark is considered emetic, anti-rheumatic, antiseptic, and astringent. The leaves are used to treat headaches and as a coagulant and purgative. Bark ash is used to produce soap due to the high concentration of saponins (Toursarkissian 1980, Alvarez 2019). Its toxicity, when consumed orally, is still under-investigated (Ashafa et al. 2011). Chemical Composition Phytochemical analysis of aqueous extracts of P. dioica leaves and fruits revealed the presence of alkaloids, tannins, saponins, phenolics, lectins, and flavonoids. Steroids were present only in the leaf, and cardiac glycosides were detected only in the fruits (Ashafa et al. 2010). Hexane extract from fresh fruits (Alexandria, Egypt) presents as major compounds 7-phenyl-tridecane (12.7%), 6-phenyl-dodecane (9.1%), 2-phenyl-tridecane (7.5%), 3-phenyl-tri-decane (6.9%), 4-phenyl-dodecane (6.4%), 5-phenyl-undecane (6.2%), 3-phenyl-undecane (5.8%), 2-phenyl-undecane (5.5%), 2-phenyl -dodecane (5.1%), 3-phenyl-dodecane (5.1%), 4-phenyl-un-decane (4.3%), and 4-phenyl-tridecane (3.5%), and were related to aromatic hydrocarbons. Some highly volatile compounds were also detected, such as α-citronellol (2.5%), dodecane (2.3%), methyl-cy-clohexane (1.6%), (+)-nerolidol (1.2%), decane (1.0%), and ci-tronellyl formate (0.4%) (Mervat et al. 2018). The ethanol extract of P. dioica seeds (Italy) was fractionated to obtain the hexane, ethyl acetate, and n-butanol fractions (Di Petrillo et al. 2019). The hexane fraction showed a concentration of approximately 21% saturated fatty acids, mainly palmitic acid (16.6%) and stearic acid (2%); 52% monounsaturated fatty acids, mainly oleic

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acid (50.3%); and 16.0% polyunsaturated fatty acids, mainly linoleic acid (15.3%) (Di Petrillo et al. 2019). The ethyl acetate fraction showed the highest amount of phenolic compounds (396.4 mg GAE/g dry basis) and flavonoids (43.6 mg QE/g dry basis), and two phenolic compounds from the ethyl acetate fraction were identified, a mixture of isoamerican isomers (B1, B2, C1, and C2) and phytolaccoside B (Di Petrillo et al. 2019). Species of the Phytolacca genus are known sources of ribosome-inactivating proteins (RIPs). RIPs are protein synthesis inhibitors that irreversibly inactivate mammalian ribosomes, inhibit protein synthesis in other animals and yeasts, increase resistance against viruses and other parasites in transgenic plants (Iglesias et al. 2016). These proteins were isolated from different plant tissues and may have a seasonal expression (Parente et al. 2008). Three RIP proteins were isolated from P. dioica seeds (PD-S1, PD-S2, and PD-S3) (Parente et al. 1993). Another six RIPs were identified in P. dioica leaves, two did not show seasonal expression (dioicin 1 and dioicin 2), and four showed variable expression (PD-Ls1-1-4) (Parente et al. 2008). Biological Activities The leaves of P. dioica have triterpene saponins with molluscicidal activity and are promising to control and combat schistosomiasis and its disease-transmitting vehicles (Helaly and Ahmed 2000). The hexane extract of fresh fruits has antioxidant activity with DPPH free radical scavenging capacity of 5.2 ± 0.1 μg/mL and by the β-carotene/linoleic acid co-oxidation system method of 6.3 ± 0.1 μg/mL (Mervat et al. 2018). The same extract has antimicrobial activity against the growth of phytopathogenic bacteria evaluated using the disc diffusion method and microdilution in broth. The hexane extract at 1000 μg/mL, 500 μg/mL, and 250 μg/mL presented an inhibition zone of 12.3 mm, 11.3 mm, and 10.6 mm, respectively, against Ralstonia solanacearum. The extract showed an inhibition zone of 12.3 mm against Bacillus pumilus and Pectobacterium carotovorum subsp. carotovorum at 500 μg/mL and 1000 μg/mL, respectively. Against Dickeya solani, extracts at 500 μg/mL and 1000 μg/mL showed an inhibition zone of 10.3 mm and 10.6 mm. The MIC values of n-hexane extracts were 64, 32, 32, 64, and 125 μg/mL against R. solanacearum, Enterobacter cloacae, B. pumilus, P. carotovorum, and D. solani, respectively (Mervat et al. 2018). The fractions of ethyl acetate and n-butanol from seed ethanol extracts presented antioxidant activity equivalent to Trolox (control). The isoamericanol isolate (mixture of isomers B1, B2, C1, and C2) presented an EC50 for ABTS and DPPH of 7.1 and 6.5 µg/mL, respectively, explaining in part the antioxidant activity of the ethyl acetate fraction. The ethyl acetate fraction of seeds (200 μg/mL) and the isoamericanol isolate (B1, B2, C1, and C2) also showed high anti-tyrosinase and anti-xanthine oxidase activity, revealing the potential of this fraction in inhibiting skin pigmentation and reducing oxidative stress (Di Petrillo et al. 2019). The n-butanol extract of P. dioica fruits, rich in saponins, was submitted to acid hydrolysis, and both (extract and hydrolysate) had their antifungal activity evaluated (Liberto et al. 2010). The n-butanol extract did not show antifungal activity. However,

120 Ethnobotany: Ethnopharmacology to Bioactive Compounds the hydrolysed extract showed activity against Candida albicans (MIC = 62.5 μg/mL) and Cryptococcus neoformans (MIC = 31.2 μg/mL). The fractionation of the hydrolysed extract allowed the isolation and characterization of phytolaccagenin, a triterpenoid saponin, responsible for the antifungal activity against C. albicans (MIC = 62.5 μg/mL) and C. neoformans (MIC = 15.2 μg/mL). Three ribosome-inactivating proteins isolated from P. dioica seeds (PD-S1, PD-S2, and PD-S3) exhibited inhibitory activity on protein synthesis in vitro (Parente et al. 1993). RIPs isolated from P. dioica leaves (PD-L1 to PD-L4) inhibited protein synthesis in vitro (Di Maro et al. 1999). Two RIPs isolated from leaves (dioicin 1 and dioicin 2) showed rRNA n-glycosylase activity, being able to damage ribosomes, and adenine polynucleotide glycosylase activity being able to cleave double-strand DNA (endonuclease activity) (Parente et al. 2008). Other investigation of leaf RIPs (dioicin 2, PD-S2 and PD-L4) activities revealed the inactivation of ribosomes from a plant, fungal, and bacterial models, such as Vicia sativa, Saccharomyces cerevisiae, Escherichia coli, and Agrobacterium tumefaciens; depurination of DNA from salmon sperm and RNA from tobacco mosaic virus; endonuclease activity; and different growth inhibitory properties of Penicillium digitatum (Iglesias et al. 2016). Additionally, RIPs isolated from P. dioica leaves demonstrated antiviral solid activity against the tobacco necrosis virus (Bulgari et al. 2020), requiring studies to prove the antiviral capacity in humans and animals. Toxicity In vivo toxicological studies with aqueous extracts of P. dioica leaves and fruits have shown adverse effects on liver and kidney function in rats (Ashafa et al. 2010). The aqueous extracts of leaves and fruits were administered orally for 14 days at different dosages (50, 100, and 200 mg/kg body mass per day), and cell toxicity in the liver and nephrotoxicity with consequent kidney damage were observed (Ashafa et al. 2010). Additional studies in rats revealed that aqueous extracts of leaves and fruits at all concentrations (50, 100, and 200 mg/kg body mass per day) promoted alteration of different hematological parameters, such as reduction in the serum levels of platelets, neutrophils, monocytes, and eosinophils; and dose-dependent lymphocyte increase, suggesting that orally administered P. dioica extracts are not entirely safe (Ashafa et al. 2011). Studies on the cytotoxicity of RIPs isolated from P. dioica leaves (dioicin 2, PD-S2, and PD-L4) demonstrated cytotoxicity to HeLa and COLO 320 (human colon adenocarcinoma) cell cultures exhibiting IC50 values from 1 to 1000 nM. The most sensitive were HeLa cells showing IC50 values from 5.7 to 25 nM, while COLO 320 cells exhibited values between 1300 and > 1500 nM after 72 h of treatment (Iglesias et al. 2016). Furthermore, the COLO 320 and HeLa cells treated with dioicin 2 showed the typical morphological characteristics of apoptosis, dose-dependent activation of the effector caspase 3/7, and nuclear DNA breakdown, suggesting that cell death caused by these proteins occurs by a combination of necrosis and apoptosis (Iglesias et al. 2016).

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Phytolacca rivinoides Kunth & Bouché Botanical synonymy

The main synonyms of Phytolacca rivinoides Kunth & Bouché are Phytolacca

icosandra var. fraseri Moq. and Phytolacca polystyla R.H. Schomb. ex Moq.

(POWO 2021).

Popular names P. rivinoides is popularly known in Brazil as “espinafre-da-guyana” and “tinturera”. In other countries, it is known as “yerba carmín” (Antilles); “epinard doux”, “herbe a la laquê” (French Antilles); “southern poke-weed” (English Antilles); “ink-weed”, “red-ink plant” (Australia); “yerba de oblea” (Canary Islands); “Gaava” (Colombia); “yerba carmine” (Cuba); “southern poke-weed” (United States); “calalu”, “jockatoe” (Jamaica); “epinard de cayenne” (Martinique); “amoli”, “verbachina”, “zvang-ngutu” (Mexico); “altasara”, “bela sombra”, “cargamanta”, “juan de vargas”, “manta-vieja”, “sauco”, “yerba de culebra” (Puerto Rico); “grama”, “magalaya”, “malambo”, “manga larga” (Venezuela); “almorsaca”, “jaboncillo”, “mazorquilla”, “quilete” (Spanish). “Bledo carbonero”, “elyeberry”, “parramatta”, “pokeweed”, “scorpion­ tail”. “Karey” (Jicaque); “lava ropa”, “mazorquilla”, “quelite”, “reventón”, “yiwa chi’na” (Mixteco); “congeraman”, “cóngora”, “conguera-man”, “conguerán”, “conjira”, “elote jabonoso”, “fitolaca”, “k’onguarani”, “kon-garan”, “kongarani”, “konguera”, “konguera blanca”, “konguera prieta”, “konguerai” (Purépecha); and “t’elkox” (Yucatec Maya) (Rios and Pastore Júnior 2011). Etymology The generic epithet Phytolacca is derived from the Greek words φυτόν (phyton), which means “plant”, and the Latin word lacca (varnish or shellac). The specific epithet rivinoides is similar to the Rivina genus, a Phytolaccaceae genus given in honor of A.Q. Rivinus 1652–1723 (Ichaso et al. 1977). Specie description This species is a herb or sub-shrub plant of 0.8 to 2.5 m and has pink stems (Figure 5a and 5b); fragile, angular, striated to furrowed branches with gland-like punctuations. Leaves are membranous (Figure 5d and 5e), lanceolate, elliptical, obovate, with slightly striated petioles, glabrous, dull base, decurrent, apex acuminate; glabrous adaxial and abaxial faces with glands mainly on the adaxial face; peninervia ribs; and smooth margin. Racemose has pink inflorescences, 20–56 cm long, with white hermaphrodite flowers, pink to intense pink, and glabrous pedicels (Figure 5a and 5c); tepals (5) membranous, elliptical, ovate, deciduous in the fruit; 12 to 16 stamens arranged around a hygoginous disc, fillets 2 to 3 mm in length; ovary 12 to 16 carpels united, stylets united at base, free and recurve at apex. The fruit is juicy and grey or reddish-black berry with 2 to 6 mm in diameter (Figure 5b and 5d). Seeds are small, reniform, and black and shiny. As for phenology, in Brazil, this species blooms and bears fruit throughout the year, but predominantly in the months of July, August, September, and October (Marchioretto 2020).

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28

Figure 5. Phytolacca rivinoides Kunth & Bouché (a) inflorescence; (b) fruits; (c) branch with leaves and inflorescence; (d) branch with fruits; (e) fruits (Source: Plants of the World Online, Royal Botanic Gardens, Kew. 2021. Licensed under Creative Commons Attribution CC BY).

It is dispersed worldwide and is native to Argentina, Belize, Bolivia, Brazil, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, French Guiana, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Peru, Puerto Rico, Suriname, Trinidad-Tobago, and Venezuela (POWO 2021). It is often considered a weed, especially in Australia, where birds eat the fruits and spread the seeds, invading the crops (Rios and Pastore Júnior 2011).

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Popular Use The leaves are boiled and used in cooking as vegetables. In folk medicine, young leaves and stems are used for diabetes treatment, and the root decoction is used as a beverage for syphilis treatment. The root has emetic and antispasmodic properties; it can also be used for skin conditions and burns (Sanz-Biset et al. 2009, Oliveira 2014) and the treatment of scabies caused by mites (Milliken and Albert 1996). It is also used in digestive problems, infections, wounds, musculoskeletal system problems, nutritional disorders, pregnancy, childbirth and puerperium problems, skin disorders, and analgesics. It also serves as a diuretic and against oliguria. The flower decoction is used to treat measles, and roots and fruits with saponins manufacture soaps (Rios and Pastore Júnior 2011). Chemical Composition The root and the fruits have tannin, phytolacin, and phytolactic acid as active principles (Roig y Mesa 1945). The chemical composition of ethanol extracts of P. rivinoides aerial parts (Pichincha Province, Ecuador) showed the presence of triterpenes, such as 3-O-(O-beta-D-glucopyranosyl-(1→3)-O-[beta-D-galactopyranosyl(1→4)]-O-beta-D-glucopyranosyl)serjanic acid 28-O-beta-D-glucopyranosyl ester; 3-O-(O-beta-D-glucopyranosyl-(1→3)-O-[beta-D-galactopyranosyl-(1→3)]-Obeta-D-glucopyranosyl)serjanic acid 28-beta-D-glucopyranosyl ester and 3-O-(O­ beta-D-galactopyranosyl-(1→4)-O-[beta-D-glucopyranosyl-(1→3)]-O-beta-Dglucopyranosyl)serjanic acid (Nielsen et al. 1995). Five monodesmosidic serjanic acid saponins and one monodesmosidic sergulagenic acid saponin were isolated from the aqueous extract of dried fruits of Phytolacca decandra (Purwodadi, Java, Indonesia). However, for the alcoholic extract, three bidesmosidic serjanic acid glycosides were isolated (Treyvaud et al. 2000). Biological Activities

The antioxidant activity of ethanol extract of P. rivinoidesshowed 67 ± 2.6% (100 μg/mL)

by the microsomal lipid peroxidation inhibition method and 68 ± 1.7 % (100 μg/mL)

by the superoxide radical scavenging method generated by the hypoxanthine-xanthine

oxidase, and both activities could be related to the presence of phenolic compounds,

such as tannins and flavonoids (De las Heras et al. 1998). The ethanol extract of

P. rivinoides leaves showed activity against Plasmodium falciparum, a chloroquineresistant strain in vitro, promoting 98% inhibition (10 μg/mL). However, in an in vivo evaluation, the extract (966 μg/mL administered for four days) showed inactive (Muñoz et al. 2000). The ethanol extract of P. rivinoides fruits used by ethnic groups in the Peruvian Amazon was evaluated in vitro against Leishmania amazonensis amastigotes and against Plasmodium falciparum, a chloroquine resistant strain. The anti-leishmania activity had IC50 = 26.3 ± 7.2 μg/mL and the anti-plasmodium had IC50 = 26.4 ± 10.7 μg/mL, which activities are considered moderate (Valadeau et al. 2009). The methanol and water extracts of Phytolacca icosandra fruits showed molluscicidal activity at 200 mg/ml and 25 mg/ml, respectively, after 24 h, against Biomphalaria glabrata, a snail, due to the presence of bidesmosidic saponins in

124 Ethnobotany: Ethnopharmacology to Bioactive Compounds methanol extract and monodesmosidic saponins in the extract aqueous (Treyvaud et al. 2000). Toxicity The mature leaves, fruits, and roots are considered poisonous, mainly the roots and fruits, which should not be used for food colouring due to reports of potential poisoning (Rios and Pastore Júnior 2011).

Phytolacca thyrsiflora Fenzl ex J.A. Schmidt Botanical synonymy The main synonym of Phytolacca thyrsiflora Fenzl ex J.A. Schmidt is Phytolacca thyrsiflora var. reducta Heimerl (POWO 2021). Popular names P. thyrsiflora is popularly known as “caruru-bravo”, “caruru-selvagem” (Rocha and Diaz 1978), “ara’ o” (mbya guaraní); “ombu miri” (ava chiripa); “bredo-bravo”, “bredo-de-veado”, “caruru”, “caruru-açu”, “caruru-assu”, “caruru de cacho”, “caruru de pomba”, “erva pombinha”, “frutas de pomba”, “marando” (Keller 2010). Etymology The name Phytolacca thyrsiflora comes from the Greek thyrsos = thyrsus and from the Latin flos = flower, as its flowers are arranged in thyrsus (Marchioretto 2020). Specie Description P. thyrsiflora (Figure 6) is a herbaceous plant with an average height of 3 m, erect when grown in isolation. They have membranous leaves (Figure 6c), obovate, ovate, elliptical, elliptical-lanceolate, thin petioles, striated to furrowed, glabrous, base acute to decurrent, apex acute to acuminate; glabrous adaxial and abaxial faces with small pits; peninervia ribs, and smooth to slightly wavy margin (Marchioretto 2020). Pannicular, axillary or terminal inflorescences (Figure 6c and 6e), almost erect, with thyrsus flowers, the purple axis of the inflorescences. Flowers (Figure 6b) are white, red, or purple hermaphrodites; stamens in two series, the external one usually abortive or with four stamens, the internal series with 8 to 10 stamens smaller than the tepals, elliptical anthers, ovary 7 to 9 carpels connected at the base, free at the apex, and curved cylindrical stylets. Berry fruit, red, 7 to 9 evolved carpels, fleshy pericarp (Figure 6a and 6d). Seeds are almost reniform, nigrescent, and bright. With regard to phenology, in Brazil this species blooms and bears fruit throughout the year (Marchioretto 2020). Commonly found in forest clearings, deforested areas, cultivated areas, vacant land, in wet or rocky soils (Udulutsch et al. 2007), this is sometimes considered as an invasive plant and a ruderal species (Meirelles 2016). Flowers and fruits grow all year round (Udulutsch et al. 2007). It is native to Brazil, Colombia, Dominican Republic, El Salvador, French Guiana, Guatemala, Guyana, Haiti, Paraguay, Peru, and Venezuela (POWO 2021). In Brazil, it occurs all over the country and in Mexico it is considered an invasive plant of crops (Rzedowski and Rzedowski 2000).

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Figure 6. Phytolacca thyrsiflora Fenzl ex J.A. Schmidt (a) inflorescence with fruits; (b) flowers; (c) branch with leaves and inflorescence; (d) ripened fruits; (e) plant view (Source: Global Biodiversity Information Facility. 2021. Licensed under Creative Commons Attribution CC BY).

Popular Use Traditionally it is used by Guarani ethnic groups from Missions as a facial colouring (Keller 2010). In Brazil, it is considered medicinal. The leaves are edible and used in wounds as plasters; green fruits are used as purgatives (Udulutsch et al. 2007, Messias et al. 2015). The roots contain saponins that are used as molluscicides (Haraguchi et al. 1988). The crushed leaves are used externally to treat malignant ulcers and cancer. The decoction of leaves is used as mouthwashes and gargles for

126 Ethnobotany: Ethnopharmacology to Bioactive Compounds oral and pharyngeal affections. The pulp of the fruits is used as a dye, hence the name egg dye (Marchioretto 2020). Chemical Composition Phytolakoside saponins B and E and the saponin 30-methyl-ester of 3-O-B-D­ glycopyranosyl jaligonic acid were isolated from the butanolic residue of fresh roots. The acid hydrolysis of crude saponins provided sapogenins, phytolacagenin, and jaligonic acid. The leaves contain, in addition to glycosides 7-0-metilkaempferol and kaempferol, two of the new saponins based on serjanic acid. The lignan americanin A was isolated from the seeds (Haraguchi et al. 1988). Biological Activities Betanin isolated from P. thyrsiflora fruits was used in synergism with Lactobacillus nagelii, and the blood glucose levels and lipid profile were evaluated in mice. Simultaneous administration of the components produced great antihyperglycemic and lipid-lowering activities (Rivera et al. 2020). The aqueous extract of P. thyrsiflora leaves has antiviral activity against the tobacco mosaic virus, having the ability to reduce lesions in Nicotiana glutinosa by up to 50% (Duarte and Alexandre 2009). Toxicity Regarding the use of P. thyrsiflora as a nutritional resource, it is possible that this species is confused with edible species of the genus Amaranthus (Amaranthaceae), popularly named “caruru” in the Tupí-Guaraní language, morphologically similar to P. thyrsiflora but reported as a toxic species (Keller 2010). In high doses, P. thyrsiflora leaves, seeds, and roots are highly toxic and cause vomiting and drowsiness to the patient. Two hours after ingestion, vomiting, diarrhoea, spasms, convulsions, and death occur (Marchioretto 2020).

Conclusion This chapter provided an overview of the current ethnobotany and phytochemistry of the family Phytolaccaceae and Petiveriaceae. Many traditional uses are reported but not documented, resulting in unreliable knowledge. Although several studies have identified bioactive compounds with potential application in medicine, in vivo and in vitro studies have not yet been conducted to confirm efficacy. Thus, additional clinical investigations must be completed to verify the safety and validation of ethnomedicinal uses.

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Khan, M.I., P.S. Harsha, A.S. Chauhan, S.V.N. Vijayendra, M.R. Asha and P. Giridhar. 2015. Betalains rich Rivina humilis L. berry extract as natural colorant in product (fruit spread and RTS beverage) development. J. Food Sci. Technol. 52: 1808–1813. Lee, J., S.Y. Kim, S.H. Park and M.A. Ali. 2013. Molecular phylogenetic relationships among members of the family Phytolaccaceae sensu lato inferred from internal transcribed spacer sequences of nuclear ribosomal DNA. Genet. Mol. Res. 12: 4515–4525. Liberto, M.D., L. Syetaz, R.L.E. Furán, S.A. Zacchino, C. Delporte, M.A. Novoa et al. 2010. Antifungal activity of saponin-rich extracts of Phytolacca dioica and of the sapogenins obtained through hydrolysis. Nat. Prod. Commun. 5: 1013–1018. Lima, M.A.O., M.S. Mielke, A.O. Lavinsky, S. França, A.A.F. Almeida and F.P. Gomes. 2010. Crescimento e plasticidade fenotípica de três espécies arbóreas com uso potencial em sistemas agroflorestais. Sci. For. 38: 527–534. Lopes-Martins, R.A.B., D.H. Pegoraro, R. Woisky, S.C. Penna and J.A.A. Sertie. 2002. The antiinflammatory and analgesic effects of a crude extract of Petiveria alliacea L. (Phytolaccaceae), Phytomedicine. 9: 245–248. Lorenzi, H. 1992. Árvores brasileiras: manual de identificação e cultivo de plantas arbóreas nativas do Brasil. Editora Plantarum, Nova Odessa. Lorenzi, H.E. and F.J.A. Matos. 2002. Plantas medicinais no Brasil nativas e exóticas. Editora Plantarum, Nova Odessa. Luz, D.A., A.M. Pinheiro, M.L. Silva, M.C. Monteiro, R.D. Prediger, C.S.F. Maia et al. 2016. Ethnobotany, phytochemistry and neuropharmacological effects of Petiveria alliacea L. (Phytolaccaceae): A review. J. Ethnopharmacol. 185: 182–201. Maia, A.J., K.R.F. Schwan-Estrada, R.V. Botelho, V.A. Jardinetti, C.M.D.R. Faria, A.F. Batista et al. 2013. Bud break and enzymatic activity in buds of grapevines cv. Ives treated with Gallesia integrifolia hydrolate. Acta Physiol. Plant. 35: 2727–2735. Mann, R.S., R.L. Rouseff, J.M. Smoot, W.S. Castle and L.L. Stelinski. 2011. Sulfur volatiles from Allium spp. affect Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae), response to citrus volatiles. Bull. Entomol. Res. 101: 89–97. Marchioretto, M.S. 1989. A família Phytolaccaceae no Rio Grande do Sul. Pesq. Bot. 40: 26–67. Marchioretto, M.S. 2020. Phytolaccaceae in Flora do Brasil 2020. Jardim Botânico do Rio de Janeiro, Rio de Janeiro. Available at: http://floradobrasil.jbrj.gov.br/reflora/floradobrasil/FB12583. Accessed on: 03 Oct. 2021. Más, E.G. and Lugo, M.L.T. 2013. Common weeds in Puerto Rico and U.S Virgin Islands. University of Puerto Rico, Puerto Rico. Meirelles, J. 2016. Flora of the cangas of The Serra dos Carajás, Pará, Brazil: Phytolaccaceae. Rodriguesia. 67: 1443–1445. Mervat, E.H., A.A. Mohamed, M.Z.M. Salem, M.S.M. Abd El-Kareem and H.M. Alie. 2018. Chemical composition, antioxidant capacity and antibacterial activity against some potato bacterial pathogens of fruit extracts from Phytolacca dioica and Ziziphus spina-christi grown in Egypt. Sci. Hort. 233: 225–232. Messias, M., M. Menegatto, A. Prado, B. Santos and M. Guimarães. 2015. Uso popular de plantas medicinais e perfil socioeconômico dos usuários: um estudo em área urbana em Ouro Preto, MG, Brasil. Rev. Bras. Pl. Med. 17: 76–104. Milliken, W. and B. Albert. 1996. The use of medicinal plants by the Yanomami Indians of Brazil. Econ. Bot. 50: 10–25. Muñoz, V., M. Sauvain, G. Bourdy, S. Arrázola, J. Callapa, G. Ruiz et al. 2000. A search for natural bioactive compounds in Bolivia through a multidisciplinary approach. part III. Evaluation of the antimalarial activity of plants used by Altenos Indians. J. Ethnopharmacol. 71: 123–131. Neves, P.D., S.G. Bauermann, A.L.V. Bitencourt, P.A. De Souza, M.S. Marchioretto, S.A.D.L. Bordignon et al. 2006. Palinoflora do Estado do Rio Grande do Sul, Brasil: Phytolaccaceae R. Br. Rev. Bras. Paleontol. 9: 157–164. Nielsen, S.E., U. Anthoni, C. Christophersen and C. Cornett. 1995. Triterpenoid saponins from Phytolacca rivinoides and Phytolacca bogotensis. Phytochemistry. 39: 625–30. Nienaber, M.A. and J.W. Thieret. 2003. Phytoloccaceae. Flora of North America Editorial Committee, New York and Oxford.

Phytolaccaceae and Petiveriaceae Ethnobotany and Phytochemistry 131 Oliveira, S.M. 2014. Flora of the Guianas. Available at: http://portal.cybertaxonomy.org/flora-guianas/ cdm_dataportal/taxon/ab405677- 06fe-4df6-a396-f0896dedd7fb. Accessed on: 03 Oct. 2021. Orwa C., A. Mutua, R. Kindt, R. Jamnadass and A. Simons. 2009. Agroforestree Database: a tree reference and selection guide. Version 4. Agroforestree Database: a tree reference and selection guide. Version 4. Pacheco, A.O., J.M. Morán, Z.G. Giro, A.H. Rodríguez, R.J. Mujawimana, K.T. González et al. 2013. In vitro antimicrobial activity of total extracts of the leaves of Petiveria alliacea L. (Anamu). Braz. J. Pharm. Sci. 49: 241–250. Parente, A., P. De Luca, A. Bolognesi, L. Barbieri, M.G. Battelli, A. Abbondanza et al. 1993. Purification and partial characterization of single-chain ribosome-inactivating proteins from the seeds of Phytolacca dioica L. Biochim. Biophys. Acta Gene Struct. Expr. 1216: 43–49. Parente, A., B. Conforto, A. Di Maro, A. Chambery, P. De Luca, A. Bolognesi et al. 2008. Type 1 ribosomeinactivating proteins from Phytolacca dioica L. leaves: differential seasonal and age expression, and cellular localization. Planta 228: 963–975. Pérez-Leal, R., M.R. García-Mateos, M. Martínez-Vásquez and M. Soto-Hernández. 2006. Cytotoxic and antioxidant activity of Petiveria alliacea L. Rev Chapingo Ser Hortic. 12: 51–56. Pott, A. and V.J. Pott. 1994. Plantas do Pantanal, EMBRAPA-SPI, Brasilia. POWO. Plants of the World Online. 2021. Facilitated by the Royal Botanic Gardens, Kew. http://www. plantsoftheworldonline.org/ Accessed 27 sept. 2021. Pugialli, H.R.L. and O. Marquete. 1989. Rivina humilis L. (Phytolaccaceae), anatomia da raiz, caule e folha. Rodriguésia. 67: 35–43. Raimundo, K.F., W.C. Bortolucci, E.S. Silva, A.F.B. Pereira, O.A. Sakai, R. Piau Júnior et al. 2017. Chemical composition of garlic wood (Gallesia integrifolia) (Phytolaccaceae) volatile compounds and their activity on cattle tick. Aust. J. Crop Sci. 11: 1058–1067. Raimundo, K.F., W.C. Bortolucci, J. Glamočlija, M. Soković, J.E. Gonçalves, G.A. Linde et al. 2018. Antifungal activity of Gallesia integrifolia fruit essential oil. Braz. J. Microbiol. 49: 229–235. Raimundo, K.F., W.C. Bortolucci, I.L. Rahal, H.L.M. Oliveira, R. Piau Júnior, C.F.A.A. Campo et al. 2021. Insecticidal activity of Gallesia integrifolia (Phytolaccaceae) essential oil. Bol. Latinoam. Caribe Plant. Med. Aromat. 20: 38–50. Randall, R.P. 2012. A Global Compendium of Weeds. Perth, Australia. Revilla, J. 2002a. Plantas úteis da Bacia Amazônica. v.2. INPA, Manaus. Revilla, J. 2002b. Plantas úteis da Bacia Amazônica. v.1. INPA, Manaus. Rios, M.N.S. and F. Pastore Júnior. 2011. Plantas da Amazônia: 450 espécies de uso geral. Editora da Universidade de Brasília, Brasília. Rivera, A., E. Becerra-Martinez, Y. Pacheco-Hernández, G. Landeta-Cortés and N. Villa-Ruano. 2020. Synergistic hypolipidemic and hypoglycemic effects of mixtures of Lactobacillus nagelii/betanin in a mouse model. Trop. J. Pharm. Res. 19: 1269–1276. Rocha, A.B. and P. Diaz. 1978. Anatomia e fitoquímica do axofito de Phytolacca thyrsiflora Fenzl ex Schmidt. Rev. Bras. Cienc. Farm. 1: 13–37. Rodrigues, E.R., R. Monteiro and L. Cullen Junior. 2010. Dinâmica inicial da composição florística de uma área restaurada na região do Pontal do Paranapanema, São Paulo, Brasil. Rev. Arv. 34: 853–861. Roig y Mesa, J.T. 1945. Plantas medicinales, aromáticas e venenosas de Cuba. Cultural, Habana. Ruffa, M.J., M. Perusina, V. Alfonso, M.L. Wagnerb, V. Suriano, C. Vicente, R. Campos and L. Cavallaro. 2002. Antiviral activity of Petiveria alliaceae against the bovine viral diarrhea virus. Chemotherapy 48: 144–147. Rzedowski J. and G.C. Rzedowski. 2000. Notas sobre el género Phytolacca (Phytolaccaceae) en México. Acta Bot. Mex. 53: 49–66. Salinas, B.E. and A. Grijalva. 1994. Diagnóstico de Nicarágua. pp. 132. In: Ocampo, R.A. [ed.]. Domesticaticación de plantas medicinales em Centroamérica. CATIE, Turrialba. Salvat A., L. Antonacci, R.H. Fortunato, E.Y. Suarez and H.M. Godoy. 2001. Screening of some plants from Northern Argentina for their antimicrobial activity. Lett. App. Microbiol. 32: 293–297. Santos, M.S., N.S.A. Feijó, T.M. Secco, M.S. Mielke, F.P. Gomes, L.C.B. Costa et al. 2014. Effects of shading on leaf anatomy of Gallesia integrifolia (Spreng) Harms and Schinnus terebinthifolius Raddi. Rev. Bras. Plantas Med. 16: 89–96. Sanz-Biset, J., J. Campos-de-la-Cruz, M.A. Epiquién-Rivera and S. Canigueral. 2009. A first survey on the medicinal plants of the Chazuta valley (Peruvian Amazon). J. Ethnopharmacol. 122: 333–362.

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Savolainen V., M.W. Chase, S.B. Hoot, C.M. Morton, D.E. Soltis, C. Bayer et al. 2000. Phylogenetics of flowering plants based on combined analysis of plastid atpB and rbcL gene sequences. Syst. Biol. 49: 306–362. Schmelzer, G.H. and A. Gurib-Fakim. 2008. Plant Resources of Tropical Africa: Medicinal plants 1. PROTA Foundation. Backhuys Publishers Wageningen, The Netherlands. SiBBr, Sistema de Informação Sobre a Biodiversidade Brasileira. 2021. Available at: https://sibbr.gov.br/. Accessed on: 11 oct. 2021. Silva Júnior, A.J., F. Campos-Buzzi, M.T.V. Romanos, T.M. Wagner, A.F.P.C. Guimarães, V. Cechinel Filho et al. 2013. Chemical composition and antinociceptive, anti-inflammatory and antiviral activities of Gallesia gorazema (Phytolaccaceae), a potential candidate for novel anti-herpetic phytomedicines. J. Ethnopharmacol. 150: 595–600. Strack, D., D. Schmitt, H. Reznik, W. Boland, L. Grotjahn and V. Wray. 1987. Humilixanthin a new betaxanthin from Rivina humilis. Phytochemistry. 26: 2285–2287. Taylor, L. 2004. The healing power of Rainforest Herbs: A guide to understanding and using herbal Medicinals. Square One Publishers, New York. Tene, V., O. Malagón, P.V. Finzi, G. Vidari, C. Armijos and T. Zaragoza. 2007. An ethnobotanical survey of medicinal plants used in Loja and Zamora-Chinchipe, Ecuador. J. Ethnopharmacol. 111: 63–81. Toursarkissian, M. 1980. Plantas medicinales de la Argentina: Sus nombres botanicos, vulgares, usos y distribucion geografica. Ed. Hemisferio Sur S.A., Buenos Aires. Treyvaud, V., A. Marston, W. Dyatmiko and K. Hostettmann. 2000. Molluscicidal saponins from Phytolacca icosandra. Phytochemistry. 55: 603–609. Udulutsch, R.G., M.H.O. Pinheiro, J.L.S. Tannus, P. Dias and A. Furlan. 2007. Phytolaccaceae. pp. 237–246. In: Melhem, T.S., M.G.L. Wanderley, S.E. Martins, S.L. Jung-Mendaçolli, G.J. Shepherd and M. Kirizawa [eds.]. Flora Fanerogâmica do Estado de São Paulo. Instituto de Botânica, São Paulo. Wheat, D. 1977. Successive cambia in the stem of Phytolacca Dioica. Am. J. Bot. 64: 1209–1217. Williams, L.A.D., H. Rosner, H.G. Levy and E.N. Barton. 2007. A critical review of the therapeutic potential of dibenzyWl trisulphide isolated from Petiveria alliacea L. (guinea hen weed, anamu). West Indian Med. J. 56: 17 –21. Valadeau, C., A. Pabon, E. Deharo, J. Albán-Castillo, Y. Estevez, F.A. Lores et al. 2009. Medicinal plants from the Yanesha (Peru): Evaluation of the leishmanicidal and antimalarial activity of selected extracts. J. Ethnopharmacol. 123: 413-422. Van-Wyk, B.E., F. Van-Heerden and B. Van-Oudtshoorn. 2005. Poisonous plants of South Africa. Briza Publications, Pretoria. Vieira, L.S. 1992. Fitoterapia da Amazônia: manual de plantas medicinais (a farmácia de Deus). Agronômica Ceres, São Paulo. Vibrans, H. 2009. Malezas de México Pennisetum purpureum. Available at: http://www.conabio.gob.mx/ malezasdemexico/poaceae/pennisetum-purpureum/fichas/ficha.htm. Accessed on: 03 Oct. 2021. Zoghbi, M.G.B., E.H. Andrade and J.G.S. Maia. 2000. Aroma de flores da Amazônia. Museu Paraense Emílio Goeldi, Belém.

Chapter 6

Beyond Phytochemistry

Comparative Ethnobotany among Oneirogenic Alkaloid Containing Tabernaemontana species from Mexico and the Amazon and the African shrub Tabernanthe iboga (Apocynaceae) Felix Krengel,1 Ricardo Reyes-Chilpa,2,* Karla Paola García-Cruz,2 Olga Lucia Sanabria-Diago,4 Willian Castillo-Ordoñez4 and Laura Cortés-Zárraga3

Introduction Phytochemistry is currently recognized as a powerful tool for understanding the ethnobotanical use patterns that humanity has assigned to certain plant species (Reyes-Chilpa and Jiménez-Estrada 1995, Reyes-Chilpa et al. 2021, Ríos-Castillo et al. 2012). “Plants of the Gods” (Schultes et al. 2001) is a classic and representative work of this research area. The book explains the medical and, above all, entheogenic uses of numerous species on a chemical basis. While many ethnobotanical applications may be unique to a certain territory and/or culture, there are also striking examples of phylogenetically and/or chemotaxonomically related plant species being utilized for similar purposes in distinct world regions that are separated by Facultad de Ciencias. Instituto de Química. 3 Instituto de Biología, Universidad Nacional Autónoma de México. Av. Universidad 3000, Coyoacan, 04510, Ciudad Universitaria. Ciudad de México, México. 4 Universidad del Cauca. Carrera 2A No. 3N 111 Sector Tulcán. Popayán, Cauca, Colombia. * Corresponding author: [email protected] 1 2

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thousands of kilometers of land or sea (Buenz et al. 2018, Saslis-Lagoudakis et al. 2012). It can be reasonably assumed that the pharmacological properties of these plants were discovered independently in most of these cases. The explanation for these multiple discoveries resides in the same groups of secondary metabolites with similar pharmacological activity being present in the respective plant species. For instance, different species of the Papilionoideae subfamily (Fabaceae) that contain rotenoids have been used during centuries, or even millennia, as fish poisons and/or topical insecticides by native peoples in the American and Asian continents. Rotenone and other structurally similar isoflavonoids are currently well known for their piscicidal, insecticidal, and acaracidal properties. In fact, these compounds are the active principles of the respective herbal preparations. In Mexico, both ethnobotanical and historical reports prove that Pachyrhizus erosus (L.) Urb., as well as several species of Tephrosia Pers. and Brongniartia Kunth have been used, probably since pre-Columbian times, for the above-mentioned purposes (AlavezSolano et al. 1996, Béjar et al. 2000, Estrella-Parra et al. 2014, 2016, Pennington 1958, Reyes-Chilpa et al. 1994). Thousands of miles away, in the Amazon basin and Maritime Southeast Asia, the corresponding piscicide and insecticidal herbal preparations have been obtained from Lonchocarpus Kunth and Derris Lour genera, respectively (Duke 1992, Heizer 1953, Higbee 1947, Rickard and Cox 1986, Tobler et al. 2011, Van Andel 2000). Therefore, it can reasonably be assumed that the peoples inhabiting these different world areas discovered the useful toxic properties of rotenoid-containing legume species independently by observation, trial, and error, which are indeed elements of the scientific method. However, does this process of discovery and use of practical knowledge always occur throughout time and space? Or can the knowledge be ignored, lost, or simply not be documented? To what degree do cosmovision-related, sociocultural, and historical factors influence the preservation of knowledge? In this contribution, we apply these questions to several chemotaxonomically related Apocynaceae species that biosynthesize four oneirogenic monoterpenoid indole alkaloids (MIAs) of the ibogan type. These compounds, which in conjunction we termed the CIVI-complex, share the same basic structure (Figure 1) and presumably have similar bioactive properties. We first compiled the ethnobotany (Table 1) of the entheogenic African shrub Tabernanthe iboga Baill. and several Mexican and Amazonian Tabernaemontana L. species (Figures 2–7). We then reviewed the reported alkaloid profiles of these plants, with particular regard to coronaridine, ibogamine, voacangine, and ibogaine (Table 2). We ultimately

Figure 1. Chemical structures of the CIVI-complex alkaloids.

Table 1. Ethnobotany of Tabernanthe iboga and Latin American Tabernaemontana species. Species

Reported ethnobotanical uses Analgesic & anti-inflammatory

Tabernanthe iboga West Africa, Congo, and Gabon

Toothache

Antimicrobial Sleeping sickness (African trypanosomiasis?; root)

CNSrelated Aphrodisiac, neurasthenia, stimulant, (divinatory, magico-religious and/or ritualistic) entheogen (all root)

Dermatological N/A

Others Antihypertensive, antipyretic, arrow poison ingredient (latex), cough medicine, infertility treatment (anti-microbial?), ophthalmic, tonic (all root)

Alper et al. 2008, Mendoza-Marquez 2000, Neuwinger 1996, Pope 1969, Rätsch 2007, Rodríguez-Acosta et al. 2010, Schultes et al. 2001 Tabernaemontana alba

Mexico: Toothache (external application of crushed seeds or latex), body aches (leaves), headache

Mexico: Dermatobi a hominis (Linnaeus Jr. In Pallas, 1781) myiasis, filariasis (external application of latex). Brazil: Anti­ helmintic (Taenia Linnaeus, 1758)

N/A

Mexico: Pimples (external application of latex or leaves), burns, furuncles, skin infections, skin patches (Pityriasis alba), ulcers,warts, wound healing (external application of latex)

Mexico: Dog bites, mumps (external application of latex) Brazil: Antipyretic (leaves and bark), purgative (leaves), tonic (bark)

Table 1 contd. ...

Beyond Phytochemistry 135

Alcorn 1983, Aparicio-Alegría and García 1995, Batis 1994, BDMTM 2009ª, Caballero et al. 1978, Cifuentes and Ortega 1990, Geck et al. 2016, Leonti 2002, Leonti et al. 2001, Mendoza-Marquez 2000

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...Table 1 contd.

Analgesic & anti-inflammatory Tabernaemontana amygdalifolia

Mexico: Pain relief

CNSrelated

Antimicrobial Puerto Rico and Central America: Syphilis (bark infusions)

N/A

Dermatological

Others

Mexico: Topical application of infusions for warts (latex or leaves), skin infections like pellagra (twigs) or exanthemas (latex). Blepharitis, Herpes labialis (latex), wound cleansing and healing, treatment of wounds caused by flies (latex) or poisonous animals (leaves). Puerto Rico and Central America: Ulcers (topical application), warts (latex). Colombia: Warts (latex), cataplasm for tumor treatment and wound healing (leaves)

Mexico: Antidiarrhoeal, antipyretic, purgative (internal application of latex) Puerto Rico and Central America: Antipyretic (bark infusions)

Anderson et al. 2005, Ankli et al. 2002, Barrera-Marín et al. 1976, BDMTM 2009b, Estrada-Lugo et al. 2011, Nieves 2003, Sanabria-Diago 1986, Van Beek et al. 1984 Tabernaemontana donnell-smithii

Mexico: Swellings, sprains (external application of leaves)

Mexico: D. hominis myiasis (external application of latex), Lutzomyia França 1924 bites (Leishmaniasis)

Mexico: Stimulant (latex)

BDMTM 2009c, Caballero et al. 1978, Flores-Guido et al. 2010, Martínez-Alfaro et al. 1995

Mexico: Wound healing (external application or leaf infusions), external tumours

N/A

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Reported ethnobotanical uses

Species

Tabernaemontana undulata

N/A

Brazil: Dysentery (baths with leaves)

Peru: Anguish and psychiatric problems

N/A

Colombia: Vermifuge (tea from leaves boiled and crushed with Manihot esculenta Crantz). Peru: Rheumatic diseases (roots boiled and macerated in water for 15 days)

N/A

N/A

N/A

Colombia: Cardiotonic (whole plant)

N/A

Peru: Anxiolytic (“cardiac sedative”) sacred rituals (infusions of leaves with Ayahuasca), Ecuador: soothing (leaves)

Colombia: Eye injuries (mixture of latex and water), skin ulcers, skin conditions

Peru: Sudorific, tonic, slimming, treatment of syphilis, rheumatic pain (soaked leaves), leishmaniasis, ingredient in arrow poisons, emetic, diuretic (leaves).

Domínguez 2018, Van Beek et al. 1984 Tabernaemontana cymosa

N/A

Domínguez 2018, Van Beek et al. 1984 Tabernaemontana sananho

Ecuador: Headache (inhaling the essence obtained by crushing the bark)

Granda 2015, León-Cárdenas 2017, Santiváñez-Acosta and Cabrera-Meléndez 2013, Van Beek et al. 1984 Table 1 contd. ...

Beyond Phytochemistry 137

138

...Table 1 contd. Reported ethnobotanical uses Analgesic & anti-inflammatory Tabernaemontana siphilitica

N/A

CNSrelated

Antimicrobial

Dermatological

Others

N/A

Colombia: To prevent sleep (latex drops in the eyes) Peru: Physical and emotional strengthening, restorative

N/A

Peru: Rheumatic diseases (grated roots macerated in water)

N/A

N/A

N/A

Colombia: Food source

N/A

N/A

Brazil: Dermatophytosis (stem latex and in rum macerated roots)

Brazil: Indigestion (infusion of the roots), cavities, diabetes, hypercholesterolemia, joint pain, uric acid

Domínguez 2018 , Van Beek et al. 1984 Tabernaemontana markgrafiana

N/A

Sandoval and Chavez 2014 Tabernaemontana catharinensis

N/A

Kujawska and Schmeda-Hirschmann 2021, Nascimento-Magalhães et al. 2019, Saraiva et al. 2015 Tabernaemontana glabra

N/A

N/A

N/A

N/A

Mexico: Treatment of respiratory diseases (latex and leaves)

Mexico: Conjunctivitis (latex)

N/A

N/A

N/A

N/A

Frei-Haller 1997 Tabernaemontana tomentosa

Yetman and Van Devender 2002 N/A = not detected.

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Species

Beyond Phytochemistry 139

Figure 2. Tabernanthe iboga. Fruits and flowers.

Figure 3. Tabernaemontana amygdalifolia. Fruits and flower.

Figure 4. Tabernaemontana alba. Whole plant, fruit, and flowers.

Figure 5. Tabernaemontana arborea. Fruits and flowers.

Figure 6. Tabernaemontana donnell-smithii. Whole plant, fruits, and flower.

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interpreted the registered ethnobotanical uses in the light of the alkaloid contents of the species.

Materials and methods Ethnobotanical and phytochemical information on Tabernanthe iboga and several Tabernaemontana species was collected by using general (Google Scholar, PubMed, Scopus, Web of Science, etc.) and specific (Base de Datos Etnobotánica de Plantas Útiles de México BADEPLAM, UNAM) scientific search engines and databases. Plant names were checked with http://www.theplantlist.org and https://www. tropicos.org. Both accepted names and synonyms were used to search for published reports and studies. Images of live plants and herbarium specimens were obtained from Naturalista (https://www.naturalista.mx/), the herbarium catalogue of the Royal Botanic Garden Edinburgh (https://data.rbge.org.uk/search/herbarium/), and the Herbario Nacional de México (MEXU), accessed via the Portal de Datos Abiertos UNAM (https://datosabiertos.unam.mx/). Chemical structures were drawn with ChemBioDraw Ultra 13.0 (vector).

Results and Discussion Taxonomic classification and distribution of the Tabernanthe and Tabernaemontana genera The genera Tabernaemontana L. and Tabernanthe Baill. (Figure 7) are sister taxa within the tribe Tabernaemontaneae (subfamily Rauvolfioideae, family Apocynaceae; Sennblad and Bremer 2002). The former is considerably more extensive than the latter, which comprises eight species native to Central Africa (Tabernanthe albiflora Stapf, Tabernanthe bocca Stapf, Tabernanthe elliptica (Stapf) Leeuwenb., Tabernanthe iboga Baill., Tabernanthe mannii Stapf, Tabernanthe pubescens Pichon, Tabernanthe subsessilis Stapf, Tabernanthe tenuiflora Stapf; The Plant List 2012). In contrast, the genus Tabernaemontana includes about 100 pantropical shrub and tree species (Alvarado-Cárdenas and Saynes-Santillán 2018) with distribution in Africa, Asia, Oceania, and the Americas (Silveira et al. 2017). Mexico presents a particularly high number of Tabernaemontana species: T. alba Mill., T. amygdalifolia Jacq., T. arborea Rose ex J.D.Sm., T. chamelensis L.O. Alvarado & Lozada-Pérez (endemic), T. citrifolia L., T. divaricata (L.) R. Br. ex Roem. & Schult. (endemic), T. donnell-smithii Rose ex J.D. Sm., T. eubracteata (Woodson) A.O. Simões & M.E. Endress, T. glabra (Benth.) A.O. Simões & M.E. Endress, T. hannae (M. Méndez & J.F. Morales) A.O. Simões & M.E. Endress, T. litoralis Kunth, T. mixtecana L.O. Alvarado et Juárez-Jaimes (from here on all endemic), T. oaxacana (L.O. Alvarado-Cárdenas) A.O. Simões & M.E. Endress, T. ochoterenae L.O. Alvarado & S. Islas, T. riverae L.O. Alvarado & V. Saynes, T. stenoptera (Leeuwenb.) A.O. Simões & M.E. Endress, T. tomentosa (Greenm.) A.O. Simões & M.E. Endress, and T. venusta (J.F. Morales) A.O. Simões & M.E. Endress (AlvaradoCárdenas et al. 2019).

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Figure 7. Herbarium specimens of Tabernanthe iboga1, Tabernaemontana alba2, T. amygdalifolia3, T. arborea4, and T. donnell-smithii5 (top to bottom, left to right).

Ethnobotany of Tabernanthe iboga and Latin American Tabernaemontana species In Central Africa, Tabernanthe iboga is known under the common name iboga and its traditional use is tightly associated with the Gabonese Bwiti practice (Fernández 1982, Pope 1969). Although this species has occasionally been employed in medicinal treatments that do not rely on central nervous system (CNS) activity, its main ethnobotanical uses are related to its aphrodisiac, stimulant, and above all, oneirogenic effects (Table 1), which enable the Bwiti practitioner to communicate with the ancestors and gain insight into the nature of life and death (Fernández 1982, Pope 1969, Ravelec et al. 2007). The spiritual practice and initiatory society of Bwiti arose in the mid-19th century due to the exposure of the coastal Bantu population to the Pygmy peoples inhabiting the interior of the country. Like other traditional practices connected with iboga, it focuses variably on mysticism, warriorship, and healing. Treatments and initiations can serve different and overlapping purposes, such as rites of passage, grieving, and physical, emotional, and spiritual healing. Today, Bwiti is recognized as one of Gabon’s official religions. Its various branches (Dissoumba, Mitsogo, Fang, etc.) are practiced in numerous villages throughout Gabon, extending into Cameroon and Equatorial Guinea (Fernández 1982). In 2005, Gabon’s former President Omar Bongo declared iboga to be a “national cultural heritage” and a “strategic reserve.” This classification placed it under the general protection of Gabon’s culture ministry and international treaties like the Nagoya Protocol, a segment of the UN Convention on Biological Diversity that focuses on access and benefit sharing for traditional knowledge holders in relation to biological

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or genetic resources (Dickinson 2016). With regard to the non-psychoactive medicinal uses of Tabernanthe iboga, the plant is used to treat cough, infertility, hypertension, and fever, among others (Table 1). When comparing the reported predominant ethnobotanical uses of Tabernanthe iboga in African traditional medicine with those of Mexican and Amazonian Tabernaemontana species, it becomes evident that although some New World species do present registered applications related to CNS activity (Table 1), these are rather the exceptions than the rule. In Mexico, for instance, only one species, T. donnell­ smithii, is recorded as a “stimulant” (Caballero et al. 1978). In the Amazonian region, at least three species have been traditionally utilized for their psychoactive properties. The most important is T. sananho Ruiz & Pav., whose leaves are employed in sacred rituals. However, the leaves of this species constitute only one of over 50 possible admixtures to the entheogenic brew Ayahuasca, whose main ingredients are Banisteriopsis caapi (Spruce ex Griseb.) Morton (Malpighiaceae) and one or more N,N-dimethyltryptamine-containing plants (López-Pavillard 2008, McKenna et al. 1986). T. sananho or sananco, as it is commonly referred to, is also used as an ingredient of arrow poisons, as well as to treat memory loss (López-Pavillard 2008, McKenna et al. 1986) and anxiety. In Ecuador, the species is employed to create a soothing effect and to relieve headache. Another species, T. siphilitica (L.f.) Leeuwenb. is used in Peru for emotionally strengthening and restorative reasons, whereas in Colombia, its latex is said to avoid sleepiness (Table 1). Regarding other, non-CNS-related ethnomedical applications of New World Tabernaemontana species, these are mostly associated with dermatological treatments, wound healing, and analgesic properties (Table 1). T. sananho is named sikta in the Kichwa (Quechua) communities in the Ecuadorian Amazon (Pastaza province). It is a highly symbolic species which is widely used as a medicinal, stimulant, and general “cure-all” plant. In Peru, T. sananho leaves are employed as a heart tonic, as well as to treat fever and syphilis. The roots allegedly cure skin pathologies, abscesses, and colds, while the bark is used as a contraceptive and painkiller. Similar applications are reported from the Awaruna, an indigenous group sharing a common Shuar-ancestry with the Kichwas. The treatments and rituals are conducted by a medicine man who prescribes a series of indications that patients must follow to eventually recover their health. Most requirements involve strict fasting, followed by the controlled intake of certain foods, such as roasted banana prepared without any salt or pepper. Fasting can endure from two weeks to three months (Luzuriaga-Quichimbo 2017, Luzuriaga-Quichimbo et al. 2018). Concerning the modes of application and preparation, several differences can be noticed between the African and the Latin American plants. Tabernanthe iboga is mainly ingested to cause stimulant or entheogenic effects. On the other hand, Tabernaemontana species are mostly applied topically to heal wounds and treat dermatological ailments, as well as to cause analgesic effects. Most herbal preparations of Tabernanthe iboga are obtained from the roots (or root bark), and only minor uses are based on the plant’s latex. In Mexican traditional medicine, in contrast, the latex is the most widely used plant material from Tabernaemontana

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species, followed by the leaves, seeds, and twigs. Root or stem bark preparations have only been reported for these species in South and Central America (Table 1). Ethnopharmacological applications can be studied on a national, regional, or local scale. Tabernanthe iboga and Tabernaemontana sananho are representative of the first two cases, respectively, while Tabernaemontana donnell-smithii is only known locally as a stimulant. There is, indeed, only one report from Uxpanapa, State of Veracruz, Mexico, that substantiates the latter claim (Caballero et al. 1978). Actually, T. donnell-smithii, along with T. alba and T. arborea, grows abundantly in the adjacent Los Tuxtlas-region of the same state, but despite several field trips, we have not been able to obtain testimonies from local inhabitants confirming this stimulant or otherwise psychoactive activity (Krengel et al. 2020, 2019a,b, 2016). On the contrary, many people living in Los Tuxtlas state that the above-mentioned Tabernaemontana species have no medicinal applications and are only used for the construction of “living fences” (trees delimiting properties) and agricultural tools, while the latex serves sporadically as adhesive or as a chewing gum substitute. Effectively, all four practices have been recorded by other authors (AvendañoReyes and Acosta-Rosado 2000, Caballero et al. 1978, Flores-Guido et al. 2010, Martínez-Alfaro et al. 1982, Rodríguez-Acosta et al. 2010). In the case of T. amygdalifolia collected in the Mexican state of Yucatán (Krengel et al. 2019a), there is no evidence of medicinal utilization by the local population. To the best of our knowledge, Tabernaemontana species are not sold in the main herbal markets in Mexico City, like the Mercado de Sonora.

Alkaloid profiles of Tabernanthe iboga and Tabernaemontana species from Mexico and the Amazon The alkaloid profiles associated with Tabernanthe iboga and Tabernaemontana species from Mexico and the Amazon are summarized in Table 2. The CIVIcomplex alkaloids are highlighted in bold. The New World Tabernaemontana species that have been reported to be traditionally used for CNS-related purposes are T. donnell-smithii in Mexico, as well as T. sananho, T. siphilitica, and T. undulata Vahl in the Amazonian region. Other species that contain psychoactive ibogan type alkaloids, but are only employed for non-CNS-related medicinal purposes, are T. alba and T. amygdalifolia in Mexico, as well as T. catharinensis A.DC., T. cymosa Jacq., and T. markgrafiana J.F.Macbr. from the Amazon basin. Albeit its significant ibogan type alkaloid content, the Mexican species T. arborea could not be associated with any ethnobotanical applications. The psychoactive properties of Tabernanthe iboga root bark are essentially due to the majority compound ibogaine, although other ibogan type alkaloids, such as coronaridine, ibogamine, ibogaline, tabernanthine, and voacangine have also shown stimulating CNS activity (Van Beek et al. 1984) and probably contribute to the overall effects (Rätsch 2007). With respect to ibogaine, its mechanism of action has not been elucidated completely, and the currently available pharmacodynamic information is insufficient to explain the complex levels of altered consciousness induced by the alkaloid. In fact, ibogaine interacts with a variety of receptors and

MIAs

References

West Africa, Congo, and Gabon Coronaridine, desmethoxyiboluteine, gabonine, ibogaine, ibogaine hydroxyindolenine, ibogaline, ibogamine, ibogamine hydroxyindolenine, iboluteine, ibophylline, iboquine, iboxygaine (kimvuline), iboxyphylline, kisantine, tabernanthine, voacangine, voaphylline

Dickel et al. 1958

Tabernaemontana alba

Apparicine, coronaridine, 10-hydroxycoronaridine, ibogaine, ibogamine, norseredamine, tabersonine, voacangine, vobasine

Collera et al. 1962, Guzmán-Gutiérrez et al. 2020, Krengel et al. 2019a, b, 2016, Van Beek et al. 1984

Tabernaemontana amygdalifolia

Apparicine, demethylaspidospermine, coronaridine, N-acetyl-12-demethoxycylindrocarine, cylindrocarpidine, demethoxycylindrocarpidine, homocylindrocarpidine, 5-oxocylindrocarpidine, 10-oxocylindrocarpidine, ibogaine, ibogamine, O-demethylpalosine, voacangine, voacangine hydroxyindolenine

Achenbach 1967a, b, 1966, Krengel et al. 2019a, Van Beek et al. 1984, Zhu et al. 1990

Tabernanthe iboga*

Mexico

Tabernaemontana arborea

Tabernaemontana donnell-smithii*

Coronaridine, ibogaine, ibogamine, norseredamine, pericyclivine, tabersonine, voacamine, voacangine, isovoacangine, 19-epivoacorine, vobasine, vobasinol Coronaridine, 10-hydroxycoronaridine, ibogaine, ibogamine, quebrachamine, ß-hydroxyquebrachamine, stemmadenine, tabernanthine, tabersonine, voacamine, voacangine, isovoacangine

Chaverri-Chaverri and Cicció-Alberti 1980, Guzmán-Gutierrez et al. 2020, Kingston 1978, Krengel et al. 2020, 2019a, b, 2016, Van Beek et al. 1984 Collera et al. 1962, Krengel et al. 2019a, Walls et al. 1958

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Species/Country

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Table 2. MIAs reported for African Tabernante iboga and Mexican and Amazonian Tabernaemontana species.

Brazil Tabernaemontana undulata*

Quebrachidine, voaphylline, coronaridine, (-)-19-epi-heyneanine, voacangine

Bruneton et al. 1979, Cave et al. 1972

Tabernaemontana catharinensis, T. affinis

Ibogamine, coronaridine, Na-methyl-pericyclivine, tabernanthine, voacangine, affinisine, isomer of voachalotine, isovoacangine, conopharinginine, voachalotine, dehydrovoachalotine, isoconopharinginine, 11-methoxy-voachalotine, voacamine Serpentine, yohimbine, affinisine, affinine, vobasine, coronaridine, (-)-19-epi-heyneanine, coronaridine pseudoindoxyl, olivacine, unidentified iboga base (APA)

Cava et al. 1964, Chaves 1960, Fonteles et al. 1974, Higashi et al. 2021, Weisbach et al. 1963

Colombia/Ecuador/Peru Coronaridine, 7α-hydroxyindolenine, voacangine, tabersonine, condylocarpine, 14,15-dehydro-16-epi-vincamine, heyneanine,10-hydroxycoronaridine, 3-oxotabersonine, 3-oxovoacangine, stemmadenine, stemmadenine-N-oxide, tabersonine-N-oxide, tetrahydroalstonine, voacristine, isositsirikine, 9-(β-D-glucopyranosyloxy)-tetrahydroalstonine Affinine, anhydrovobasindiol, vobasine, 16-epi-vobasinic acid, coronaridine, voacangine, olivacine, voacamine

Achenbach et al. 1997, Benoin et al. 1968, Burnell and Medina 1971, Gorman et al. 1960, Van Beek et al. 1984

Tabernaemontana sananho*

Coronaridine, 3-hydroxycoronaridine, (-)-heyneanine, (-)-ibogamine, voacangine

Delle Monache et al. 1977, Luzuriaga-Quichimbo et al. 2018, Rohini and Mahesh 2015

Tabernaemontana siphilitica

Geissoschizine, tetrahydroalstonine, pleiocarpamine, apparicine, (+)-tubotaiwine, vincadifformine, 12-hydroxyvincadifformine, coronaridine, voacangine, isovoacangine, tetrastaehyne, tetrastachynine, 12,12’-bis-(1l-hydroxycoronaridinyl), bonafousine, isobonafousine

Damak et al. 1976a, b, c, 1980, Ghorbel et al. 1981

Tabernaemontana markgrafiana

Coronaridine, (l9S)-heyneanine, voacangine, ibogamine, 5,6-dehydrocoronaridine, 3R-methoxycoronaridine, 3R-methoxyvoacangine, 10,11-demethoxychippiine, 3-oxocoronaridine, 3-oxovoacangine, 3R/S-hydroxycoronaridine, 7-hydroxyindolenines, coronaridine hydroxyindolenine, voacangine hydroxyindolenine, 0-acetylvallesamine, vallesamine, 19(E)-akuammidine, 19(E)-16R-isositsirikine

Nielsen et al. 1994

* Species reported to be ethnobotanically used for CNS-related purposes.

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Tabernaemontana cymosa, Tabernaemontana psychotrifolia

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transporters known to modulate psychoactive effects. The alkaloid has been found to both activate 5-HT2A (like mescaline and psilocin) and kappa-opioid receptors (like salvinorin A), while inhibiting muscarinic (like hyoscyamine and scopolamine) and nicotinic acetylcholine, as well as N-methyl-D-aspartate (NMDA) receptors (like the synthetic dissociative ketamine). It also binds to sigma receptors, as well as to serotonin and dopamine transporters (Alper 2001, Glick and Maisonneuve 1998, Johnson et al. 2011, Lochner and Thompson 2016, Nichols 2004, Sweetnam et al. 1995, Zorumski et al. 2016). Concerning their alkaloid profiles, Mexican Tabernaemontana species generally resemble Tabernanthe iboga, as the majority compounds always belong to the CIVI-complex. The most obvious difference consists in the strong quantitative predominance of ibogaine in the African but not the Mexican plants. In turn, Amazonian Tabernaemontana species show significant amounts of coronaridine, ibogamine, and voacangine, whereas ibogaine is only present in low concentrations, if at all (Table 2). Thus, at first sight, both qualitative and quantitative differences between the alkaloid profiles of the species revised in this article may explain their different patterns of ethnobotanical use. However, purely phytochemical factors fail to explain why the entheogenic and/or psychoactive properties of ibogan type alkaloid-producing species are of such fundamentally distinct priority in Africa and Latin America. Specifically, why did Mexican indigenous civilizations apparently not include Tabernaemontana species in their otherwise wide range of psychoactive plants with ritualistic applications? And why did indigenous cultures of the Amazon basin utilize T. sananho only as an admixture to Ayahuasca, rather than using the plant on its own?

Beyond phytochemistry: Explaining the different patterns of ethnobotanical use of Tabernanthe iboga and Tabernaemontana species from Mexico and the Amazon A direct ethnobotanical comparison of the Tabernaemontana species of the Americas with the African Tabernanthe iboga may be problematic due to the geographic, historical, and cultural differences implied. Nevertheless, the available phytochemical information can be interpreted in a manner that sheds light on why plants with related secondary metabolism show quite distinct patterns of ethnobotanical use, especially if geographic and cultural boundaries are involved. Although explanations can be based on concrete chemical findings, cultural and historical reasons may be at least equally important. The following hypothesis attempts to offer an approach suited to explain the distinct patterns of ethnobotanical use of American Tabernaemontana species and Tabernanthe iboga. 1. Ibogaine causes unique stimulant and oneirogenic CNS effects that convert Tabernanthe iboga into an authentic “plant of the gods” of the greatest ethnobotanical value in Central African cultures. The same cannot be said for American Tabernaemontana species, either due to their lower ibogaine content, inferior or undesirable CNS activity, toxicity, preferences intrinsic to indigenous

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civilizations, loss of knowledge of the plants’ psychoactive activity in traditional medicine, or simply lack of documentation. 2. The presence of several MIAs with analgesic, anti-inflammatory, dermatological, and antimicrobial properties confers a certain efficacy to herbal preparations of the above-mentioned species for treating related diseases and medical conditions. Nonetheless, their efficacy may be inferior to other locally available plant species, and consequently, neither Tabernaemontana species nor Tabernanthe iboga are extraordinarily valued in traditional American or African medicine, respectively, for these purposes. 3. The ethnobotanical significance of a plant species that contains mostly MIAs of the ibogan type depends to a large degree on cultural aspects and whether the respective human cultures discover and appreciate the CNS effects of these alkaloids. As previously mentioned, the South American species Tabernaemontana sananho contains mainly coronaridine, ibogamine, and voacangine, but no or only little ibogaine, and serves as an admixture to the entheogenic brew Ayahuasca. Therefore, the absence or low content of ibogaine may limit its use as an entheogen by itself. On the other hand, the pre-Columbian use of psychoactive herbal preparations like Ayahuasca and Jurema has been widely reported in large parts of South America (De Souza et al. 2008, Dos Santos et al. 2016), but not in Mexico, although the same or phytochemically similar plant species occur throughout the tropical Americas. The N, N-dimethyltryptamine-containing root and stem barks of Mimosa tenuiflora (Willd.) Poir. (Fabaceae) are the main ingredients for the psychoactive brew Jurema in northeastern Brazil, whereas in Mexico, they are used to treat dermatological problems and burns, and to construct living fences (BDMTM 2009d, De Souza et al. 2008). The same bark in combination with β-carboline alkaloid-containing plant material from, e.g., Banisteriopsis C.B. Rob. (Malpighiaceae) species, capable of inhibiting the monoamine oxidase A (MAO-A), and thus, the degradation of N, N-DMT, would provide an Ayahuasca-like mixture (Dos Santos et al. 2016). The non-existence of reports about the psychoactive use of Ayahuasca- or Jurema-like preparations in pre-Columbian Mexico may simply be attributed to the respective cultures never discovering the CNS-related properties of certain plants growing in their territories. The same reason might explain why neither Mexican nor South American indigenous civilizations used Tabernaemontana species as main ingredients in entheogenic preparations. Regarding Mexican traditional medicine, there is only one record attributing a psychoactive application to a Tabernaemontana species. Nonetheless, this report of the latext of T. donnell-smithii being used as a stimulant (Caballero et al. 1978) is limited to one well-defined location. This species contains predominantly voacangine, besides smaller amounts of ibogamine, coronaridine, and ibogaine (Krengel et al. 2019a). While T. alba, T. amygdalifolia, and T. arborea contain varying quantities of the same alkaloids, none of the Mexican species shows an ibogaine content matching that of Tabernanthe iboga. Hence, the comparatively low amounts of ibogaine in the

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former may not suffice to produce considerable psychoactive effects, supposing that the other three alkaloids of the CIVI-complex do not have CNS-related activities comparable to ibogaine. Taking into account that all four MIAs have shown striking similarities with regard to their chemical structures and pharmacological activities in animal models (Glick et al. 1994, Van Beek et al. 1984), this explanation seems unlikely and has yet to be tested experimentally. Overall, it is remarkable that the stem and root barks of T. alba, T. amygdalifolia, T. arborea, and T. donnell-smithii have not been associated with CNS-related ethnobotanical applications, since all these organs present significant quantities of at least one alkaloid of the CIVI-complex and do not seem to contain overly toxic compounds (Krengel et al. 2016, 2019a). It is, of course, perfectly feasible that indigenous people in Mexico discovered the psychoactive properties of Tabernaemontana species, but that the knowledge was never revealed to outsiders or lost during or after the Spanish colonization of the Americas. The following comparison offers another example that supports the cultural and historical basis of ethnobotanical uses. The alkaloid profiles of the root and stem bark of the African species Voacanga africana Stapf (Apocynaceae) bear astonishing similarities to those of the root bark of the Mexican species Tabernaemontana arborea. In both cases, the concentrations of the predominant monomeric MIAs are in the same range: Voacangine is present in high amounts, whereas the ibogaine and vobasine content is low to intermediate. Bis-indole alkaloids, such as voacamine, can also be found in both species (Chen et al. 2016, Guzmán-Gutiérrez et al. 2020, Kingston 1978, Krengel et al. 2020, Wang et al. 2019). Yet only V. africana has been associated with psychoactive ethnobotanical uses in its native distribution area, which is basically limited to West and Central Africa, including Gabon, and thus overlaps with the geographic distribution of Tabernanthe iboga (Rätsch 2007, Schultes et al. 2001). Regarding Tabernaemontana arborea, there are no reports on ethnomedical applications at all. Hence, sociocultural and historical factors may better than phytochemical information explain why only the African but not the Mexican species has been documented as a traditional stimulant and entheogen. Nonetheless, the fact that the latex of T. donnell-smithii was registered as a stimulant in an indigenous Chinanteco community in Mexico (Caballero et al. 1978) implies that at least some pre-Columbian Mexican cultures knew about the CNSrelated activities of this and probably other Tabernaemontana species. It also indicates that this knowledge has been conserved over the centuries, albeit in rudimentary form. Ergo, the most evident reasons for the lack of reported psychoactive uses of the genus in Mexican traditional medicine are concealment and partial loss of the original knowledge. The Los Tuxtlas region has been inhabited by the Popoluca and the Nahua since 500 and 800 A.D., respectively (Velázquez-Hernández 2015), but there is no evidence of Tabernaemontana species being used for stimulant or entheogenic purposes. Indeed, two recent ethnobotanical studies of Popoluca communities only documented non-psychoactive applications of T. alba (Leonti 2002, Leonti et al. 2001). It should be mentioned, though, that both Popoluca and Nahua communities possess sacred

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spiritual and ritualistic knowledge that has been conserved and transmitted by a small circle of highly respected leaders (Velázquez-Hernández 2015). During the colonial period of Mexico, spiritual practices involving entheogenic plants or mushrooms were persecuted with eagerness by the religious and secular authorities. Most written primary sources of the pre-Columbian era, the so-called códices, were destroyed. Accordingly, it seems reasonable that the historical experience of many indigenous communities would have led them to conceal the use of entheogenic plants from outsiders. Furthermore, the Los Tuxtlas region was once covered by tropical rainforests, but has suffered severe ecological and cultural devastation during the last decades, largely due to governmental policies designed in the 1950s and aimed to convert “uninhabited” land into private property for immigrant mestizo cattle breeders (Durand 2005, Velázquez-Hernández 2015). As a result, knowledge of the psychoactive properties of the local Tabernaemontana species might have been lost. However, this region is currently known all over Mexico as a “land of witchcraft,” due to weird magic ceremonies offered to tourists, which can be interpreted as a phenomenon of cultural erosion. Last but not least, there is another explanation for the different patterns of ethnobotanical use discussed in this article that plausibly combines chemicalbiological and cultural aspects: Pre-Columbian Mexican civilizations possibly had a certain preference for the “classical hallucinogens,” which according to the Hollisterdefinition causes “changes in thought, perception and mood,” but only minimal “intellectual or memory impairment,” “stupor, narcosis or excessive stimulation”, and “autonomic nervous system side effects,” in the absence of “addictive craving” (Glennon 1994). Several representatives of this group, specifically the ergoline derivatives-containing ololiuqui (Turbina corymbosa (L.) Raf. [Convolvulaceae]) and tlitliltzin (Ipomoea violacea L. [Convolvulaceae]), the mescaline-containing peyotl (Lophophora williamsii (Lem. ex Salm-Dyck) J.M. Coult. [Cactaceae]), as well as the psilocybin and psilocin-containing teonanácatl (Psilocybe (Fr.) P. Kumm. [Strophariaceae]) were widely available in pre-Columbian Mexico and continue to be an essential part of the cosmogony and rituals of many indigenous civilizations (Rätsch 2007, Schultes et al. 2001). In Colombia, ethnic groups like the Nasa refer to plants with pronounced psychoactive properties as “plantas maestras.” These “master plants” are thought of as powerful teachers that mediate between the material and the spirit world. They enable the wise men and women of the community to delve into the secrets of the cosmos in a process of teaching-learning that is sustained by ritual acts. Interestingly, the different master plants of the Nasa are often embedded into a hierarchical structure (Peña-Fernández and Sanabria-Diago 2019). Similar phenomena can be observed in Mexico. Among the Mazatecs, the Lamiaceae hierba de la pastora (Salvia divinorum Epling & Játiva) is mainly used in rituals when Psilocybe mushrooms are scarce. The Huichol people regard peyotl as part of their “holy trinity,” together with the deer and the maize (Rätsch 2007, Schultes et al. 2001). The Solanaceae kieri (Datura innoxia Mill. and Datura stramonium L.), on the other hand, is considered a malignant

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and dangerous force in opposition to the benevolent peyotl (BDMTM 2009e). Both S. divinorum and Datura species contain psychoactive compounds which induce dissociative or deliriant CNS effects very different to those of the “classical hallucinogens,” namely the neoclerodane diterpenoid salvinorin A in the former, as well as the tropane alkaloids hyoscyamine and scopolamine in the latter case (Rätsch 2007, Schultes et al. 2001). It should be noted that the effects of ibogaine are also qualitatively dissimilar to other entheogenic drugs. At lower doses, both Tabernanthe iboga root bark and ibogaine act as a stimulant much appreciated by hunters and warriors to suppress fatigue. High to excessive doses are usually taken at Bwiti ceremonies and cause an introversive self-reflective state accompanied by closed-eye visions that resemble more of a dream than the pseudohallucinations and “psychedelic” mindset associated with the “classical hallucinogens,” which is why the term “oneirogenic” is often used in connection with ibogaine. Furthermore, although the substance presents a moderate toxicity, it is certainly more toxic than the “classical hallucinogens” and high amounts tend to severely impair motor activity, while overdoses can paralyze and even kill humans (Alper 2001, Nichols 2004, Ott 1996, Schultes et al. 2001), especially those suffering from cardiovascular diseases (Koenig and Hilber 2015). Pope (1969) states that “The hallucinogenic dose is several times the normal stimulant dose, so that the user must endure intense and unpleasant central stimulation in order to experience the hallucinogenic effects.” From a pharmacodynamic point of view, the entheogenic properties of the “classical hallucinogens” are a consequence of them being agonists of the 5-HT2A serotonin receptor. Ibogaine, on the contrary and as previously mentioned, interacts with a much wider range of receptors and transporters known to modulate psychoactive effects. Thus, it is reasonable to assume that at least the Mexican indigenous civilizations simply preferred the “classical hallucinogens” to ibogan type alkaloid-containing plants, due to a cultural bias towards the former and a natural environment offering many varieties of this type of entheogen. As a matter of fact, nowhere else in the world are so many indigenous uses of psychoactive plants registered as in Mexico (Schultes et al. 2001). Whether or not Tabernaemontana species were utilized ritualistically on a minor scale and this knowledge then forgotten, cannot be answered at this time. In Central Africa, in contrast, the only “classical hallucinogens” available may be represented by Psilocybe species, whereas iboga is by far the most important natural source of entheogenic preparations (Schultes et al. 2001). Clearly, the regional cultures perceived the oneirogenic properties of the latter as something highly desirable and sacred, not minding, or perhaps even appreciating, the strong stimulating effects. The absence or negligible use of “classical hallucinogens” may be explained by the relatively low abundance and variety of appropriate natural sources compared to Mexico, and/or a cultural bias towards iboga, rendering other entheogenic preparations unimportant. It would thus seem that the demand for psychoactive natural sources belonging to the “classical hallucinogens” or ibogaine type alkaloid-containing plants was substantially created by the local natural environment and, above all, sociocultural and historical developments intrinsic to two very distinct culture groups with similar spiritual needs.

Beyond Phytochemistry 151

In the New World, the number and cultural importance of natural hallucinogens reached amazing heights in the past, and in some places, their relevance remains undiminished to this day. Currently, it is no exaggeration to say that particularly in certain Mexican and South American cultures, hallucinogens obtained from natural sources continue to be an integral part of daily life. The indigenous cultures of the Amazon basin do not have a written history and preserve their ancestral sacred knowledge through oral tradition and legends, passed on from the elderly to the younger generations (Sayin 2014). However, we do not exactly know when and how the rituals involving psychoactive plants originated in Amazon regions of Colombia, Ecuador, Peru, Brazil, and Bolivia (Fábregas et al. 2010, Krippner and Sulla 2011). It is noteworthy that novel medicinal applications for MIAs have appeared. In Bolivia, the Centro Boliviano de Solidaridad VIDA has used ibogaine since 2017 as the first step in its addiction recovery program (Politi 2018). In Brazil, specifically in the state of Sao Paulo, the local government has decreed that ibogaine can be administered in a medical environment with adequate protection for the patients (Politi et al. 2019). Studies conducted in the same country have proven that the supervised use of ibogaine accompanied by psychotherapy can facilitate prolonged periods of abstinence from several drugs of abuse (Schenberg et al. 2014). Regarding Tabernaemontana species, T. catharinensis has shown promising antitumour activity associated with the MIAs coronaridine and heyneanine (Rizo et al. 2013). Comparable effects have been reported for ibogamine and ibogaine obtained from T. divaricata (Pratchayasakul et al. 2008), as well as for voacangine (Xiao et al. 2020). Recently, the pharmacological potential of Tabernaemontana species to treat neurological disorders has been related to the ibogan type alkaloids they produce. Furthermore, due to the importance of natural product analogues, many strategies for modifying naturally occurring secondary metabolites have been explored in order to obtain new molecules with useful bioactivities. For instance, precursor-directed biosynthesis (PDB) has been applied to T. catharinensis plantlets to produce alkaloid derivatives capable of inhibiting enzymes that play a crucial role in dementia, such as acetylcholinesterase and butyrylcholinesterase (Musquiari et al. 2021).

Acknowledgements This research was supported by the grant IG200321 from PAPIIT-DGAPA-UNAM. We are grateful to María Claudia Martínez-Martinez of GELA (Grupo Etnobotánico Latinoamericano) for her assistance in preparing this contribution.

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McKenna D.J., L.E. Luna and C.R.N. Towers. 1986 Ingredientes biodinámicos en las plantas que se mezclan al ayahuasca. Una farmacopea tradicional no investigada. América Indígena, XLVI(1): 73–99. Musquiari, B., E.J. Crevelin, B.W. Bertoni, S.d.C. et al. 2021. Precursor-directed biosynthesis in Tabernaemontana catharinensis as a new avenue for Alzheimerʼs disease-modifying agents. Planta Medica 87(01/02): 136–147. Nascimento Magalhães, K., W.A.S. Guarniz, K.M. Sá, A.B. Freire et al. 2019. Medicinal plants of the Caatinga, northeastern Brazil: Ethnopharmacopeia (1980–1990) of the late professor Francisco José de Abreu Matos. Journal of Ethnopharmacology 237: 314–353. Neuwinger, H.D. 1996. African ethnobotany: poisons and drugs. Chemistry, pharmacology, toxicology. Chapman & Hall, Weinheim. Nichols, D.E. 2004. Hallucinogens. Pharmacol. Ther. 101: 131–181. https://doi.org/10.1016/B978-0-12­ 418679-8.00017-4. Nielsen, H.B., A. Hazell, R. Hazell, F. Ghia and K.B.G. Torssell. 1994. Indol alcaloides y terpenoides de Tabernaemontana markgrafiana. Fitoquímica 37(6): 1729–1735. Nieves, A. 2003. Estudio etnobotánico de los huertos familiares Mayas en el ejido X-Maben, Quintana Roo. Universidad de las Américas. Ott, J. 1996. Pharmacotheon. Entheogenic drugs, their plant sources and history., 2nd ed. Natural Products Co., Kennewick, WA. Pennington, C.W. 1958. Tarahumara fish stupefaction plants. Economic Botany 12(1): 95–102. Peña-Fernández, V. and O.L. Sanabria-Diago. 2019. Aprendiendo de la naturaleza. Kwesx Fi’zenxis Uyna. Sello Editorial de la Universidad del Cauca. Primera edición. Popayán, Colombia. 168 pp. ISBN: 978-958-732-378-8. Politi, M. 2018. Healing and Knowledge with Amazonian Shamanic Diet. Psychedelic Plant Medicine. Recovered from https://chacruna. net/healingknowledge-amazonian-shamanic-diet. Politi, M., F. Friso and J. Mabit. 2019. Plant based assisted therapy for the treatment of substance use disorders. Part 2. Beyond blurred boundaries. Revista Cultura y Droga, 24(28): 19-42. DOI: 10.17151/culdr.2019.24.28.2. Pope, H.G. 1969. Tabernanthe iboga: an African narcotic plant of social importance. Econ. Bot. 23: 174– 184. https://doi.org/10.1007/BF02860623. Pratchayasakul, W., A. Pongchaidecha, N. Chattipakorn and S. Chattipakorn. 2008. Ethnobotany & ethnopharmacology of Tabernaemontana divaricata. Indian Journal of Medical Research 127(4): 317–336. Rätsch, C. 2007. Enzyklopädie der Psychoaktiven Pflanzen: Botanik, Ethnopharmakologie und Anwendungen, 8th ed. AT Verlag, Aarau. Ravelec, V. and A. Mallendi, Paicheler. 2007. Iboga: The Visionary Root of African Shamanism. Park Street Press, Rochester, VT. Reyes-Chilpa, R., F. Gómez-Garibay, L. Quijano, G.A. Magos-Guerrero and T. Ríos. 1994. Preliminary results on the protective effect of (-)-edunol, a pterocarpan from Brongniartia podalyrioides (Leguminosae), against Bothrops atrox venom in mice. J. Ethnopharmacol. 42: 199–203. https://doi. org/10.1016/0378-8741(94)90086-8. Reyes-Chilpa, R. and M. Jiménez-Estrada. 1995. Química de las plantas alexíteras. Interciencia (Venezuela) 20(5): 257–264. Reyes-Chilpa, R., S. Laura Guzmán-Gutiérrez, M. Campos-Lara et al. 2021. On the first book of medicinal plants written in the American Continent: The Libellus Medicinalibus Indorum Herbis from Mexico, 1552. A review. BLACPMA 20(1): 1–27. https://doi.org/10.37360/blacpma.21.20.1.1. Rickard, P.P. and P.A. Cox. 1986. Use of Derris as a Fish Poison in Guadalcanal, Solomon Islands. Econ. Bot. 40: 479–484. https://doi.org/https://doi.org/10.1007/BF02859661. Ríos-Castillo T., L. Quijano and R. Reyes-Chilpa. 2012. Algunas reflexiones actuales sobre la herbolaria prehispánica desde el punto de vista químico. Rev. Latinoamer. Quím. 40 (2): 41–64. http://www. scielo.org.mx/pdf/rlq/v40n2/v40n2a1.pdf. Rizo, W.F., L.E. Ferreira, V. Colnaghi et al. 2013. Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A. DC in a human laryngeal epithelial carcinoma cell line (Hep-2). Genetics and molecular biology 36(1): 105–110.

Beyond Phytochemistry 157 Rodríguez-Acosta, M., F.A. Jiménez-Merino and A.J. Coombes. 2010. Plantas de importancia económica en el estado de Puebla. Herbario y Jardín Botánico (Benemérita Universidad Autónoma de Puebla, BUAP), Puebla. Rohini, R.M. and D. Mahesh. 2015. Evaluation of anti-inflammatory and antinociceptive activity and isolation of two new alkaloids from leaves extract of Tabernaemontana sananho. J. Chem. Pharm. Res. 7(1): 31–36. Sanabria-Diago, O.L. 1986. El uso y manejo forestal en la comunidad de Xul, en el sur de Yucatán. Etnoflora Yucatanense. Fascículo 2. Instituto Nacional de Investigaciones sobre Recursos Bióticos, Xalapa, Veracruz, México. Sandoval, C. and J. Chavez. 2014. Uso alimenticio de especies vegetales por las comunidades indígenas de Colombia: Una revisión de literatura. Agroecol. Cienc. Tecnol. 2(1): 1–6. Santiváñez Acosta, R. and J. Cabrera Meléndez. 2013. Catálogo Florístico De Plantas Medicinales Peruanas. El Centro Nacional De Salud Intercultural (CENSI). Perú. Saraiva, M.E., A.V.R. de Alencar Ulisses, D.A. Ribeiro et al. 2015. Plant species as a therapeutic resource in areas of the savanna in the state of Pernambuco, Northeast Brazil. Journal of Ethnopharmacology 171: 141–153. Saslis-Lagoudakis, C.H., V. Savolainen, E.M. Williamson et al. 2012. Phylogenies reveal predictive power of traditional medicine in bioprospecting. Proc. Natl. Acad. Sci. U. S. A. 109: 15835–15840. https://doi.org/10.1073/pnas.1202242109. Sayin, H.U. 2014. The consumption of psychoactive plants during religious rituals: The roots of common symbols and figures in religions and myths. NeuroQuantology 12(2): 276–296. Schenberg, E.E., M.A. de Castro Comis, B.R. Chaves and D.X. da Silveira. 2014. Treating drug dependence with the aid of ibogaine: A retrospective study. Journal of Psychopharmacology 28(11): 993–1000. Schultes, R.E., A. Hofmann and C. Rätsch. 2001. Plants of the Gods: Their Sacred, Healing, and Hallucinogenic Powers, 2nd ed. Healing Arts Press, Rochester, VT. Sennblad, B. and B. Bremer. 2002. Classification of Apocynaceae s.l. According to a new approach combining Linnaean and phylogenetic taxonomy. Syst. Biol. 51: 389–409. https://doi. org/10.1080/10635150290069869. Silveira, D., A.F. de Melo, P.O. Magalhães and Y.M. Fonseca-Bazzo. 2017. Tabernaemontana species: promising sources of new useful drugs. In: Studies in Natural Products Chemistry; Elsevier: Amsterdam, The Netherlands 54: 227–289. Sweetnam, P.M., J. Lancaster, A. Snowman et al. 1995. Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine’s putative anti-addictive activity. Psychopharmacology (Berl). 118: 369–376. https://doi.org/10.1007/BF02245936. The Plant List. 2012. Tabernanthe. http://www.theplantlist.org/tpl1.1/search?q=tabernanthe(accessed 1.29.19). Tobler, M., Z.W. Culumber, M. Plath, K.O. Winemiller and G.G. Rosenthal. 2011. An indigenous religious ritual selects for resistance to a toxicant in a livebearing fish. Biol. Lett. 7: 229–232. https://doi. org/10.1098/rsbl.2010.0663. Van Andel, T. 2000. The diverse uses of fish-poison plants in Northwest Guyana. Econ. Bot. 54: 500–512. https://doi.org/10.1007/BF02866548. Van Beek, T.A., R. Verpoorte, A.B. Svendsen, A.J.M. Leeuwenberg and N.G. Bisset. 1984. Tabernaemontana L. (Apocynaceae): A review of its taxonomy, phytochemistry, ethnobotany and pharmacology. J. Ethnopharmacol. 10: 1–156. https://doi.org/10.1016/0378-8741(84)90046-1. Velázquez-Hernández, E. 2015. Los recorridos de San Pedro y Santiago Apóstol: un elemento central en la recreación de la territorialidad Nahua-Popoluca. EntreDiversidades. Revista Ciencias Sociales y Humanidades 4: 35–57. Walls, F., O. Collera and A. Sandoval. 1958. Alcaloides de Especies de Stemmadenias. I.–Los Alcaloides de S. donnell-smithii y S. galeottiana. Boletín del Inst. Química de la Univ. Nac. Autónoma México X: 54–71. Wang, Y.Q., H.X. Li, X.C. Liu et al. 2019. One bis-indole alkaloid-voacamine from Voacanga africana Stapf: biological activity evaluation of PTP1B in vitro utilizing enzymology method based on SPRi expriment. Nat. Prod. Res. 33: 3459–3463. https://doi.org/10.1080/14786419.2018.1480623.

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Chapter 7

Phytochemistry and Bioactivity from Huperzias, used by Healers from Saraguro Community, in the Southern Ecuadorian Andes María-Elena Cazar,1,* Chabaco Armijos2 and Omar Malagón Avilés2

Plant biodiversity and cultural heritage from the Ecuadorian Southern Andes The use of molecules derived from plants secondary metabolites in medicine is extensive. The plant kingdom has provided key chemotherapy agents, painkillers, antimalarial, antidiabetic and cardiovascular disease drugs, among others (Antonelli et al. 2019). Of the estimated 350,000 vascular plant species known to science, 7% (c. 26,000) have documented medicinal use (MPNS 2020). There is a strong bond between medicinal plants and traditional knowledge. Many medicinal species are used by people in the region of origin, who have been their primary custodians and often hold unparalleled local knowledge (Howes et al. 2020). Many inhabitants of Latin American countries rely on medicinal plants for primary healthcare. This fact is associated with the high plant biodiversity of this region. The use of medicinal plants generally increases with the species richness of the local flora (De la Torre et al. 2012). Biotechnology and Biodiversity Group. Department of Applied Chemistry and Production Systems. Chemical Sciences Faculty. Universidad de Cuenca. Av. 12 de Abril s/n, Cuenca, Ecuador. 2 Chemistry and Exact Sciences Department. Universidad Técnica Particular de Loja. San Cayetano Alto. Loja, Ecuador. * Corresponding author: [email protected] 1

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The Andes Mountains naturally divide Ecuador in three distinct regions: in the western side, a coastal area of plains and adjacent low mountains (Costa), a central area of mountain ridges and valleys (Sierra) and on the eastern side the Amazonian lowlands (Oriente) (Van den Eynden et al. 2003). These geographical and climatic conditions generate unique ecosystems: mangrove in the Costa, humid cloud forest and highlands grasslands (páramos), in the Sierra and montane rainforest in the Oriente, among many others. About 15,900 species of vascular plants have been reported from Ecuador to date, but new species continue to be described (Jørgesen et al. 2019). Anthropic activities like agriculture, timber logging, and cattle farming threaten constantly the original vegetation of the Sierra: intermontane shrubs and forest vegetation. The scientific efforts drives to characterize plant biodiversity, linked with its cultural heritage. Southern Ecuadorian Andes harbours a great natural and cultural diversity. In the limits of Ecuador and Perú, Loja province occupies 4% of the national territory (11,042 km2). In 2010, the total population of this province was estimated to be 444,966 habitants, from which 96% were “mestizo” Spanish speakers, and 3.7% Saraguro indigenous people, who speak Spanish and Kichwa languages (INEC 2010).

Saraguro people: origin, organization and healing practices The origin of the Saraguros was determined recently. After the conformation of the Tahuantinsuyo, the Incas forced some tribes to migrate to a distant region, as a tactical strategy implemented by the king Tupac Yupanqui, in order to secure the peace among the Empire. These tribes were known as mitimaes. Saraguros are part of these groups, who forcedly travelled from the Bolivian Highland Plateau to Southern Ecuador, where they settled down until nowadays (Ogburn 2008, Andrade et al. 2017). Saraguros, highlighted as one of the best-organized ethnical groups in Ecuador, preserves their traditional dressing, language, religion, social habits, and medicinal practices. Medicinal plants are a useful resource for the health care systems of this community. Plant used as therapeutic agents are still in practice, supporting the health care system for the members of the community (Finerman 1984). The healers developed an organization, known as “Hampiyachakkuna”, to maintain the ancient medical treatments of the Saraguros. For them an illness is not only provoked by physiological imbalances, but for supernatural causes. The “Yachaks” or “visionaries” treat specifically the illness of supernatural nature. Their work differs from the rest of the local healers: midwives (parteras), herbalists (hierbateros), and bone-healers (sobadores) (Armijos et al. 2012). Yachaks not only use plants to cure supernatural ailments, they also make use of several plants for its sacred and magical powers. These plants are used in magicalreligious healing rituals, where the healer reaches an ecstatic state of consciousness, communicating with the gods and the supernatural world. Under this condition, the yachak acquires the power to recognize patient´s diseases and to determine possible cures for the illness (Armijos et al. 2014).

Huperzias used by an Andean Community Healers 161

Bioactive Huperzia species from the Saraguro community A representative number of plants from the genus Huperzia form part of the Chinese pharmacopeia to treat memory and cognitive disorders. Huperzia serrata, has been used for centuries in China for the treatment of contusions, strains, swelling, and schizophrenia. The alkaloids Huperzine A and B are the bioactive principles from that species, proved as potent, reversible and selective inhibitors of acetylcholinesterase (AChE) activity. Huperzine A and some synthetic derivatives are currently tested as candidates as new pharmacological treatment for Alzheimer disease (Ma et al. 2007). Plants from the genus Huperzia belong to the Lycopodiaceae family. They are widely distributed in Ecuadorian paramos, in association with other plants as shrubs. According to the Vascular Plants Catalog from Ecuador, this family is represented in this country by 67 species, distributed in three genera: Huperzia, Lycopodium, and Lycopodiella (Jørgensen, 1999). At Saraguro, the genus Huperzia (Lycopodiaceae) comprise several wild sacred plants, known as wamingas and trencillas. Yachaks mix these plants with others whose alkaloid active principles are well known: “San Pedro” cactus (Echinopsis pachanoi), several species of “wanduk” or “floripondio” (Brugmansia spp. Pers.) and tobacco (Nicotiana tabacum L.), to cure and remove negative energies (Armijos et al. 2012). Some members of this genus are used to treat parturition disorders, and the whole plant is believed to act as a central nervous system stimulant for young children with motor problems, improving their resistance to the labour (Navarrete et al. 2006). The information from the phytochemistry and bioactivity of members from the genus Huperzia, traditionally used by the Saraguros, in Southern Ecuador, comes from the studies from academics from Universidad Técnica Particular de Loja (UTPL). For several years, members of the Chemistry and Exact Sciences Department developed ethnomedicinal and phytochemical studies, in agreement with the Saraguro Healers Council, with the valuable contribution of yachaks. Armijos et al. (2016a), interviewed ten Saraguro yachaks, to report the importance of Huperzias in their health practices. H. brevifolia, H. columnaris, H.compacta, H. espinosana, H. tetragona, H. weberbaureueri are currently used as purgative agents and for curing supernatural diseases. Healers use these plants as purgative agents, to treat supernatural diseases and to prepare psychotropic products, for ritual ceremonies. In the phytochemical analysis, a methanolic extract was prepared and acidified, yielding two fractions: an acid, alkaloid solution and a precipitate enriched in flavonoids and triterpenes. A direct GC-MS analysis in the alkaloid-enriched fraction demonstrated the presence of lycodine (1), lycopodine (2), 6-OH-lycopodine (3), des-N-methyl-α-obscurine (4) and flabelline (5) in H. tetragona. H. compacta alkaloids include lycopodine and 6-OH lycopodine. The non-alkaloid fraction from H. espinosana yielded selgin (6), a rare flavonoid previously isolated from Huperzia selago (Voirin and Jay 1978). H. brevifolia, H. tetragona, and H. compacta produced tricin, a flavonoid with promising bioactivity and potential as a chemopreventive agent, based on in vivo studies (Li et al. 2016). The high productivity of tricin in members of Huperzia genus was reported for Armijos and coworkers, with a method

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Table 1. Traditional uses, biological activity from extracts, and characterization of alkaloid and nonalkaloid fractions from three Huperzia species. Plant

Huperzia compacta

Huperzia tetragona

Ethnobotanical uses/preparation/ application

Pharmacological effect of secondary metabolites

Water decoction for purgative effects.

Alkaloids: lycopodine, 6-OH-lycopodine

For treating shuka (fright), espanto (startle), mal aire (exposure to bad air), vaho de agua (exposure to water­ vapours).

Biological activities: Lycopodine, from Lycopodium clavatum (Lycopodiaceae) induce apoptosis in prostate cancer cells within 12 h of treatment in vitro, at a dose of 148 µM (Bishayee et al. 2013)

To prepare the effective psychoactive preparations, the healer cooks or macerates in alcohol mixtures of H. compacta with hallucinogenic plants. The mixture is administrated by inhalation through the nostrils, or it is drunk or blown over patients.

Purgative For treating supernatural illness: espanto and susto, shuka, mal aire, vaho de agua and mal hecho (witchcraft). Psychoactive

Huperzia espinosana

Purgative For treating espanto and susto, mal aire.

Non-alkaloids: Tricin (5, 7, 4′-trihydroxy3′,5′-dimethoxiflavone), 21-episerratenediol Biological activities: Tricin is a widespread compound, present in many plants. Li et al. (2016), report its DPPH scavenging activity (EC50 = 90.39 mg/mL) and antiinflamatory activity, on induced paw edema in rats (50%). 21-episerreatenediol, isolated from Lycopodium serratum, induce apoptosis in cultured human promyelocytic leukemia HL­ 60 cells (IC50 = 15.9 µM) (Ham et al. 2012) Alkaloids: lycodine, lycopodine, 6-OH­ lycopodine, des-N-methyl-α-obscurine, flabelline Biological activities: Lycopodine, from Lycopodium clavatum, displayed antiinflammatory effects in rats (24% of inhibition dose 500 mg/kg) (Orhan et al. 2007) Non-alkaloids: Tricin (2.77 % on dried plant) Non-alkaloids: selgin (5,7,3′,4′-tetrahydroxy5′-methoxyflavone), tricin. Biological activities: Selgin, isolated from Crossostephium chinense, displayed α-glucosidase inhibition (34,36 µM) (Wu et al. 2009)

to quantify this flavonoid in plant tissues (Armijos et al. 2016b). Table 1 summarizes the main ethnobotanical uses, secondary metabolites isolated, and the reported bioactivities from three selected Huperzia species. Huperzia compacta and Huperzia tetragona are used to treat spiritual disorders, such as “mal aire”, “espanto”, and “susto”. The traditional uses would be related to its richness in alkaloids. Yachaks use H. tetragona in their hallucinogenic preparations, to reach a mental state that allow them to find explanations and treatments to illness, a state called “visionar”. The alkaloid content from this species is also associated to their use as laxatives. The purgative action is considered very important by Saraguro healers, either as an internal organic purification or an external spiritual action. In fact, according to the Saraguro worldview, the internal body purification results

Huperzias used by an Andean Community Healers 163

in toxin elimination, while the external spiritual action opens and discharges the mind. Consequently, the use of a purgative removes bad energies and evil spirits from one´s body. Additionally, the traditional use of H. tetragona, H. compacta and H. espinosana against liver and kidney diseases, fever, inflammation, and colds has been mentioned in studies concerning practices of healers and midwifes in the South Ecuador areas of Vilcabamba, Catamayo, Palanda, and Amaluza (Armijos et al. 2016b). The latter uses would be related to the species richness in non-alkaloid compounds, which displays promising antioxidant, anti-inflammatory, and enzymeinhibition activities.

Phytochemicals from Saraguro’s Huperzias: Pharmacological Properties and Potential in Drug Development The traditional use of members of the genus Huperzia is mainly in ailments possibly related to nervous disorders. Monoamine oxigenases (MAO) are copper and flavine containing enzymes that catalyze the oxidative breakdown of monoamines, specifically monoamine neurotransmitters. Their inhibition prevents the breakdown of molecules, such as serotonin, melatonin, epinephrine, and norepinephrine, increasing its availability to neurons. Acetylcolinesterase (AChE) degrades acetylcholine from the synaptic receptor, terminating signal transmission. Both enzymes are connected with neurodegenerative disorders, like Alzheimer’s and Parkinson disease. AChE, an important component of cholinergic synapses, colocalizes with β-amyloid peptide deposits of Alzheimer´s brain, promoting and accelerating its aggregation, together with lowering amounts of acetylcholine available in the brain. Treatments targeting these two enzymes efficiently slow the disease progression. MAO inhibitors are current medications to treat depression. In this scenario, the discovery of new AChE and MAO inhibitors from natural sources will provide novel alternatives to treat neurodegenerative diseases (Sengupta et al. 2011). From the reported Huperzias alkaloids, huperzine A showed a beneficial impact on cognitive functions of Alzheimer’s disease patients (Yang et al. 2013). However, the relatively modest effect of huperzine A-like compounds, compared to reported observation of plant traditional uses, drive the attention to the verification of the biological effect of alkaloid enriched fraction from members of the genus Huperzia as inhibitors of AChE and MAO. H. brevifolia and H. espinosana extracts displayed significant effects in the inhibition of MAO activity at a concentration of 50 mg/mL (62 and 75%, respectively). H. tetragona and H. compacta alkaloid-enriched fractions display inhibition towards AChE (IC50 of 62.4 and 0.036 mg/mL, respectively). The bioactive alkaloids characterized in the Huperzias used by Saraguro yachak: lycopodine, lycodine, flabelline and α-obscurine were detected in extracts of Lycopodium clavatum and Lycopodium thyoides, species with the ability to inhibit AChE at in vitro and in vivo assays (Konrath et al. 2012). The bioactivity of the Huperzia extracts and compounds display the potential of the Lycopodiaceae family as producers of efficient anti­ neurodegenerative substances. The alkaloid and non-alkaloid bioactive compounds chemical features from three selected Huperzia species are presented below.

164 Ethnobotany: Ethnopharmacology to Bioactive Compounds

H3C

H3C

H3C

R H

H

H N H

N

N

N

O

NH

H3C

H

O

(2) R = H (3) R = OH

(1) H3C

(4)

H3C O

H N

OH

O NH

HO

CH3

O

OH

OH

O

(5) (6)

Figure 1. Alkaloid and non-alkaloid bioactive metabolites from Ecuadorian Huperzias: (1) lycodine, (2) lycopodine, (3) 6-OH lycopodine, (4) des-N-methyl-α-obscurine, (5) flabelline, and (6) tricin.

Conclusions and Future Perspectives The purpose of this chapter was to highlight the rich ethnobotanical knowledge around the genus Huperzia, used by healers (yachak) of the indigenous Saraguro community, located in the Southern Ecuadorian Andes. Members of the Applied Chemistry Department, at Universidad Técnica Particular de Loja, built a steady scientific collaboration with the Saraguro community, in accordance with the Nagoya Protocol and associated Access and Benefit Sharing legislation. The revision of the current knowledge of ethnobotany and phytochemistry from Huperzias, used in folk medicine by the Saraguro community, highlight its potential as a source of bioactive compounds, promising the treatment of Alzheimer’s disease. The yield of tricin and selgin is an important feature from these plants, since the bioactivity of these molecules could lead to promising pharmacologic agents. The group from UTPL continues its prolific work in this genus, isolating new hydroquinolinic alkaloids, with a partial structure characterization so far (Malagón et al. 2016). It is undoubted that we will have new information about the metabolic profile of members from the Lycopodiaceae family in the near future.

References Andrade, J., H. Lucero and C. Armijos. 2017. Ethnobotany of Indigenous Saraguros: Medicinal Plants used by Community Healers “Hampiyachakkuna” in the San Lucas Parish, Southern Ecuador. BioMed Research International, Article ID 9343724, 20 pages, 2017. https://doi.org/10.1155/2017/9343724. Antonelli, A., R.J. Smith and M.S. Simmonds. 2019. Unlocking the properties of plants and fungi for sustainable development. Nature Plants 5(11): 1100–1102. Armijos, C., M. Lozano, F. Bracco, G. Vidari and O. Malagón. 2012. Plantas sagradas y psicoactivas usadas por los Saraguros en la región sur de Ecuador. 1st. Edition. UTPL. ISBN 978-9942-08-178-0.

Huperzias used by an Andean Community Healers 165 Armijos, C., J. Cota and S. González. 2014. Traditional medicine applied by the Saraguro yachakkuna: a preliminary approach to the use of sacred and psychoactive plant species in the southern region of Ecuador. Journal of Ethnobiology and Ethnomedicine, 10,26. Armijos, C., G. Gilardoni, L. Amay, A. Lozano, F. Bracco, J. Ramírez, N. Bec, C. Larroque, P. Vita Finzi and G. Vidari. 2016a. Phytochemical and ethnomedicinal study of Huperzia species used in the traditional medicine of Saraguros in Southern Ecuador; AChE and MAO inhibitory activity. Journal of Ethnopharmacology 193: 546–554. Armijos, C., J. Ponce, J. Ramírez, D. Gozzini, P. Vita Finzi and P. Vidari. 2016b. An unprecedent high content of the bioactive flavone tricin in Huperzia medicinal species used by the Saraguro in Ecuador. Natural Product Communications 11(3): 273–274. Bishayee, K., D. Chakraborty, S. Gosh, N. Boujedani and A. Khuda-Bukhsh. 2013. Lycopodine triggers apoptosis by modulating 5-lipooxigenase, and depolarizing mitochondrial membrane potential in androgen sensitive and refractory prostate cancer cells withoud modulating p53 activity: signaling cascade and drug-DNA interaction. European Journal of Pharmacology 698: 110–121. De la Torre, L., C. Cerón, H. Balslev and F. Borchsenius. 2012. A biodiversity informatics approach to ethnobotany: Meta-analysis of plant use patterns in Ecuador. Ecology and Society, 17, 15. Finerman, R. 1984. A matter of life and death: Health care change in an Andean community. Social Science & Medicine 18(4): 329–334. Ham, Y., W. Yoon, S. Park, Y. Jung, D. Kim, Y. Jeon, W. Wijesingje, S. Kang and K. Kim. 2012. Investigation of the components of Lycopodium serratum extract that inhibits proliferation and mediates apoptosis of human HL-60 leukemia cells. Food and Chemical Toxicology 50: 2629–2634. Howes, M.J.R., C.L. Quave, J. Collemare, E.C. Tatsis, D. Twilley, E. Lulekal, A. Farlow, L. Lo, M.E. Cazar, D. Leaman, T. Prescott, W. Millikenm, C. Martin, M. De Canha, N. Lall, H. Qin, B. Walker, C. Vásquez-Londoño, B. Allkin, M. Rivers, M. Simmonds, E. Bell, A. Battison, J. Feliz, F. Forest, C. Leon, C. Williams and E. Nic Lughadha. 2020. Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi. Plants, People, Planet 2(5): 463–481. INEC. 2010. Ecuador en Cifras. Censo de Población y Vivienda. Published on https://www.ecuadorencifras. gob.ec/censo-de-poblacion-y-vivienda/. Jørgensen, P.M. 1999. Lycopodiaceae. pp. 148–152. In: Jørgensen, P.M. and S. León-Yánez (eds.). Catalogue of the Vascular Plants of Ecuador. Monogr. Syst. Bot. Missouri Bot. Gard. 75. Konrath, E., B. Medeiros, P. Santana, C. dos Santos Passos, A. Simoes-Pires, M. Ortega, A. Goncalves, J.L. Cabrera, J. Fonseca and A. Henriques. 2012. Investigation of the in vivo and ex vivo acetylcholinesterase and antioxidant activities of traditionally used Lycopodium species from South America on alkaloid extracts. Journal of Ethnopharmacology 139: 58–67. Li, M., Y. Pu, G. Yoo and A. Ragauskas. 2016. The occurrence of tricin and its derivatives in plants. Green Chemistry 18L 1439–1454. Ma, X., C. Tan, D. Zhu, D.R. Gang and P. Xiao. 2007. Huperzine A from Huperzia species—an ethnopharmacological review. Journal of Ethnopharmacology 113: 15–34. Malagón, O., J. Ramírez, J. Andrade, V. Morocho, C. Armijos and G. Gilardoni. 2016. Phytochemistry and Ethnopharmacology of the Ecuadorian Flora. A review. Natural Product Communications 11(3): 297–314. MPNS Version 9. 2020. Medicinal Plant Names Services, the Royal Botanic Gardens, Kew. http://www. kew.org/mpns. Navarrete, H., G. León, J. González, D.K. Avilés, J.S. Lecaro, F. Mellado, J. Alban and B. Øllgard. 2006. Helechos. pp. 385–411. In: Kvist, L.P., F. Borchesenius, H. Barslev [Eds.]. Botánica Económica de los Andes Centrales. Universidad Mayor de San Andrés, La Paz. Ogburn, D. 2008. Becoming Saraguro: Ethnogenesis in the context of Inca and Spanish colonialism. Ethnohistory 55(2): 287–319. Orhan, I., E. Küpeli, B. Şener and E. Yesilada. 2007. Appraisal of anti-inflammatory potential of the clubmoss Lycopodium clavatum L. Journal of Ethnopharmacology 109: 146–150. Sengupta, T., J. Vinayagam, N. Nagashayana, B. Gowda, P. Jaisankar and K.P. Mohanakumar. 2011. Antiparkinsonian effects of aqueous methanolic extract of Hyoscyamus niger seeds result from its

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monoamine oxidase inhibitory and hydroxyl radical scavenging potency. Neurochemical Research 36(1): 177–186. Van den Eynden, V., E. Cueva and O. Cabrera. 2003. Wild foods from Southern Ecuador. Economic Botany 57(4): 576–603. Voirin, B. and M. Jay. 1978. Apport de la Biochimie Flavonique á la Systematique du Genre Lycopodium. Biochemical Systematics and Ecology 6: 95–97. Wu, Q., X. Yang, L. Zou and D. Fu. 2009. Bioactivity guided isolation of alpha-glucosidase inhibitor from whole herbs of Crossostephium chinense. Zhongguo Zhong Yao Za Zhi 34: 2206–2211. Yang, G., Y. Wang, J. Tian and J.P. Liu. 2013. Huperzine A for Alzheimer’s disease: a systematic review and meta-analysis of randomized clinical trials. PloS one 8(9): e74916.

Chapter 8

The Genus Alepidea

A Review of its Medicinal Uses, Phytochemistry and Pharmacological Activities Alfred Maroyi,1,* Ruvimbo Jessy Mapaya,2 Ahmad Cheikhyoussef 3 and Natascha Cheikhyoussef 4

Introduction The genus Alepidea F. Delaroche belongs to the Apiaceae or Umbelliferae family, commonly known as celery (Apium graveolens L.), carrot (Daucus carota L.), or parsley (Petroselium crispum (Mill.) Fuss family. The Apiaceae family consist of approximately 434 genera and 3750 species (Duran et al. 2010) which are mainly aromatic herbs, annual or perennial, often with tuberous rootstock, occasionally shrubs or trees. The genus Alepidea comprises 32 species with its centre of diversity in southern Africa (De Castro and Van Wyk 1994, Van Wyk et al. 2013a, Hutchinson et al. 2017). The genus name Alepidea means “without a scale”, based on the Greek prefix “a” meaning without, and the word “lepis” meaning “a scale” (Maroyi 2021). Some species belonging to the genus Alepidea have been used as traditional medicines in southern Africa (Watt and Breyer-Brandwijk 1962, Hutchings et al. 1996). Such medicinal plants have played an important role as primary sources of traditional medicines for centuries and still continue to provide humankind with new pharmaceutical drugs and health products. Research done by Van Wyk et al. (2013b) showed that 50% of pharmaceutical drugs and health products in clinical use in the world are derived from natural products isolated from plants. Department of Botany, University of Fort Hare, Alice, South Africa.

Department of Applied Biosciences and Biotechnology, Midlands State University, Gweru, Zimbabwe.

3 Science and Technology Division, Multidisciplinary Research Centre, University of Namibia, Windhoek,

Namibia. 4 Ministry of Higher Education, Technology and Innovation, Windhoek, Namibia. * Corresponding author: [email protected] 1 2

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Some of these examples include aspirin derived from a compound called salicin isolated from Salix alba L. (family Salicaceae), artemisinin from Artemisia annua L. (Asteraceae), colchicine isolated from Colchicum autumnale L. (Colchicaceae), opium obtained from Papaver somniferum L. (Papaveraceae), paclitaxel from Taxus brevifolia Nutt. (Taxaceae), quinine, an alkaloid obtained from Cinchona pubescens Vahl (Rubiaceae), and silymarin from Silybum marianum (L.) Gaertn. (Asteraceae) (Van Wyk et al. 2013b). Therefore, ethnopharmacological research in the past 100 years has focused on isolation, identification, and characterization of phytochemical compounds along with their pharmacological activities. Research into the medicinal uses, phytochemistry, and pharmacological properties of Alepidea species offers tremendous potential for developing new pharmaceutical health products and drugs. Moreover, Van Wyk (2017) argued that the roots of Alepidea species, such as A. amatymbica Eckl. & Zeyh. and A. cordifolia B.-E. Van Wyk have potential in the development of new commercial medicinal products, which can be used against chest ailments, colds, and influenza. This study therefore, aims at providing comprehensive information on the medicinal uses, phytochemical, and pharmacological properties of Alepidea species.

Materials and Methods Several electronic databases were searched, which included Web of Science, SciELO, Elsevier, SpringerLink, PubMed, Google Scholar, Springer, Science Direct, Scopus, Taylor and Francis. Additional information was obtained from pre-electronic sources, such as books, book chapters, scientific journals, theses, dissertations, and other grey literature obtained from the University library. The relevant terms included ethnobotany, medicinal uses, traditional uses, phytochemistry, pharmacology and toxicity of the extracts, and phytochemical compounds isolated from the genus Alepidea. The Alepidea species names were authenticated using The Plant List managed by the Royal Botanic Gardens, Kew and the Missouri Botanical Garden (http://www.theplantlist.org/). Plant authorities were also authenticated through this process. All research articles published till September 2021 which were aligned with the scope of the study were included in this chapter.

Results and Discussion Taxonomy Species of the genus Alepidea are perennial rhizomatous herbs with simple leaves with ciliate or bristly leaf margins and capitate inflorescences surrounded by showy bracts. Estimates of the number of species in the genus Alepidea vary from 28 to 36. Majority of authors cite 28 species (De Castro and Van Wyk 1994, Olivier et al. 2008, Van Wyk et al. 2008, Van Wyk et al. 2013a). However, “The Plant List” contains 56 species, including 36 accepted names, 19 synonyms, and one unresolved name, and this classification was used in the present review (see Table 1) in conjunction with taxonomical account of the genus by Hutchinson et al. (2017). More than half (59.4%) of Alepidea species are endemic to South Africa, while 34.4% of the species are near endemics, recorded in Eswatini, Lesotho, and/or South Africa (Table 1).

The Genus Alepidea 169 Table 1. Scientific names of Alepidea species. Scientific name

Distribution

A. acutidens Weim. var. acutidens

South Africa

A. acutidens Weim. var. dispar Weim.

South Africa

A. amatymbica Eckl. & Zeyh. var. amatymbica

Lesotho and South Africa

A. amatymbica Eckl. & Zeyh. var. aquatica (Kuntze) Weim.

South Africa

A. amatymbica Eckl. & Zeyh. var. microbracteata South Africa Weim. A. angustifolia Schltr. & H. Wolff

South Africa

A. attenuata Weim.

Eswatini and South Africa

A. basinuda Pott var. basinuda

South Africa

A. basinuda Pott var. subnuda Weim.

South Africa

A. calocephala Schltr. & H. Wolff

South Africa

A. capensis (P.J. Bergius) R.A. Dyer var. capensis

South Africa

A. capensis (P.J. Bergius) R.A. Dyer var. tenella (Schltr. & H. Wolff) Weim.

South Africa

A. cirsiifolia Schltr. & H. Wolff

South Africa

A. comosa Dümmer

Eswatini and South Africa

A. concinna Dümmer

South Africa

A. cordifolia B.-E. Van Wyk

Eswatini, Lesotho, Mozambique, South Africa and Zimbabwe

A. delicatula Weim.

South Africa

A. duplidens Weim.

South Africa

A. galpinii Dümmer

Lesotho and South Africa

A. inflexa S.-L. Hutchinson & Magee

South Africa

A. insculpta Hilliard & B.L. Burtt

South Africa

A. jenkinsii Pott

South Africa

A. longeciliata Schinz ex Dümmer

South Africa

A. longipetiolata Schltr. & H. Wolff

South Africa

A. macowani Dümmer

South Africa

A. multisecta B.L. Burtt

South Africa

A. natalensis J.M. Wood & M.S. Evans

Lesotho and South Africa

A. peduncularis A. Rich.

Democratic Republic of Congo (DRC), Eswatini, Ethiopia, Kenya, Malawi, Mozambique, Somalia, South Sudan, South Africa, Sudan, Tanzania, Uganda, Zambia, and Zimbabwe

A. pilifera Weim.

Lesotho and South Africa

A. pusilla Weim.

Lesotho and South Africa

A. reticulata Weim.

Lesotho and South Africa

A. schlechteri H. Wolff

South Africa Table 1 contd. ...

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...Table 1 contd. Scientific name

Distribution

A. serrata Eckl. & Zeyh. var. cathcartensis (Kuntze) Weim.

South Africa

A. serrata Eckl. & Zeyh. var. serrata

South Africa

A. setifera N.E.Br.

Eswatini, Lesotho and South Africa

A. stellata Weim.

South Africa

A. thodei Dümmer

Lesotho and South Africa

A. woodii Oliv.

Lesotho and South Africa

A. wyliei Dümmer

South Africa

Source: De Castro and Van Wyk 1994, Olivier et al. 2008, Van Wyk et al. 2008, Van Wyk et al. 2013a, Hutchinson et al. 2017.

Alepidea peduncularis A. Rich. has been recorded in rocky hillsides, montane forest, and often burnt grassland and woodland at altitudes ranging from 1000 to 3800 m above sea level from the Democratic Republic of Congo, Sudan and Ethiopia south to South Africa (Jansen 2004). Alepidea cordifolia B.-E. Van Wyk has been recorded in open grassland or on forest margins, often amongst rocks and/or along streams in South Africa, Lesotho, northwards to Eswatini, Mozambique, and Zimbabwe (Van Wyk et al. 2008). Close to a quarter of Alepidea species (22.5%) are threatened with extinction mainly because they are endemic, naturally rare, experiencing significant habitat loss, or are overexploited as traditional medicines (Table 2). The IUCN Red List Categories and Criteria version 3.1 of threatened species (http://www.iucnredlist.org) was used in the assessments of threatened Alepidea species (Raimondo et al. 2009, Van Wyk et al. 2013a). According to Victor and Keith (2004), a species categorized as Least Concern (LC) under the IUCN Red List Categories and Criteria version 3.1 can additionally be flagged as of conservation concern either as rare, critically rare, or declining (see A. delicatula Weim. and A. insculpta Hilliard & B.L. Burtt in Table 2). Anthropogenic factors, such as agriculture, introduction of alien species, urbanization, and excessive exploitation for traditional medicines appear to be the major threats to the survival of Alepidea species, and therefore, effective holistic conservation measures are required.

Vernacular Names and Medicinal Uses Alepidea species are known by various vernacular names in different geographical areas in eastern, central, southern, and northern Africa (Table 3). Insight into the societal value of Alepidea species can be gained by examining these vernacular names. People rarely name plant species that they do not use. According to Dold and Cocks (2012), vernacular name “ikhathazo” often associated with several Alepidea species in South Africa means “difficulty” or “trouble”, implying that the usage of the species enables the user to overcome difficulties. The species name “amatymbica” is named after the amaThembu people of the Eastern Cape province

Table 2. Alepidea species that are threatened or are of conservation concern. IUCN status

Country

Conservation concerns and threats

Reference(s)

Endangered A2d

Lesotho, South Africa, Zimbabwe

Species highly sought-after as traditional medicine and its population declining due to harvesting pressures for medicinal plant trade and habitat loss.

Williams et al. 2000, Raimondo et al. 2009

A. attenuata

Near Threatened B2ab(i,ii,iii,iv,v)

Eswatini and South Africa

This species is rare and confined to highly threatened habitat. Species population is declining due to habitat loss, fragmentation, agriculture, disturbances, and alien plant invasion.

Raimondo et al. 2009

A. basinuda var. subnuda

Endangered B1ab(i,ii,i ii,iv,v)+2ab(i,ii,iii,iv,v)

South Africa

This taxon is threatened by habitat loss, alien invasive plants, and fire.

Raimondo et al. 2009, Van Wyk et al. 2013a

A. cordifolia

Endangered A2bd

Eswatini, Lesotho, Mozambique, South Africa, and Zimbabwe

Species threatened due to harvesting pressures for medicinal plant trade, habitat loss, and fragmentation.

Talukdar 2002, Maroyi 2008

A. delicatula

Rare

South Africa

Rare and confined to high altitude habitats.

Raimondo et al. 2009

A. insculpta

Rare

Lesotho and South Africa

Rare and confined to subalpine grassland on high basalt ridges.

Raimondo et al. 2009

A. longeciliata

Endangered A2c

South Africa

Species population declining due to habitat loss as a result of agriculture, urbanisation, and mining.

Van Wyk et al. 2013a

A. macowani

Vulnerable A2ad; B1ab(v)

South Africa

Species is naturally rare and over-collected for the traditional medicine trade.

Raimondo et al. 2009

A. multisecta

Vulnerable D2

South Africa

Species potentially threatened by competition from alien invasive plants.

Raimondo et al. 2009

The Genus Alepidea 171

Alepidea species A. amatymbica

Country

References

South Africa

Maroyi 2008, Moffett 2010, Van Wyk and Gericke 2018

Eswatini and South Africa

Long 2005

South Africa

Moffett 2010, Hughes et al. 2015

Eswatini, Lesotho, Mozambique, South Africa, and Zimbabwe

Gelfand et al. 1985, Maroyi 2008, Van Wyk and Gericke 2018

South Africa

Fox and Norwood Young 1982, Pooley 2003

Eswatini and South Africa

Hutchings et al. 1996, Long 2005

Lesotho and South Africa

Moffett 2010, Van Wyk and Gericke 2018

South Africa

Pooley 2003

A. amatymbica var. amatymbica Kafferkalmoes, kalmoes, kalmus, slangwortel (Afrikaans), black calmus, star-flowered kalmoes (English), lesoko, lesoku, lesokwane, lesooku (Sotho), ikhathazo, iqwili (Xhosa), and ikhathazo (Zulu) A. attenuata Kalmus (Afrikaans) and likhatsato (Swazi) A. capensis var. capensis Katazo (Afrikaans), lethoka (Sotho) and iqwili (Zulu) A. cordifolia Giant alepidea (English), kataza, katazo (Shona), lesoko (Sotho), inkhatsankhatsa, likhatsato (Swazi) and ikhathazo (Xhosa) A. natalensis Natal Star Flower (English) and ikhokwana (Zulu) A. peduncularis Kalmus (Afrikaans), cocwane, likhatsato, likhatsatwana, likhokhwane, linjata (Swazi), ikhokhane, ikokwane and ikhokhwane (Zulu) A. pilifera Lesokoana and lesokwana (Sotho) A. pusilla Dwarf star flower (English) A. serrata var. cathcartensis

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Vernacular name(s), language or geographical region in brackets

172

Table 3. Vernacular names of Alepidea species.

Lesokwana (Sotho)

South Africa

Moffett 2010

South Africa

Moffett 2010

Eswatini, Lesotho and South Africa

Moffett 2010, Van Wyk and Gericke 2018, Mogale et al. 2019

Lesotho and South Africa

Moffett 2010

Lesotho and South Africa

Pooley 2003

A. serrata var. serrata Lesokwana (Sotho) A. setifera Kalmus (Afrikaans), likhatsatwana (Swazi), lesokoana, lesokwana and lesoko (Sotho) A. thodei Lesokoana (Sotho) A. woodii Wood’s star flower (English)

The Genus Alepidea 173

174 Ethnobotany: Ethnopharmacology to Bioactive Compounds in South Africa, where the species occurs and is widely used as traditional medicine (Nonjinge et al. 2019). A survey of literature shows at least 13 vernacular names for A. amatymbica var. amatymbica, followed by A. peduncularis (8), A. cordifolia (6), A. setifera (5), with A. attenuata, A. capensis var. capensis, A. natalensis, A. pilifera, A. pusilla, A. serrata var. cathcartensis, A. serrata var. serrata, A. thodei, and A. woodii, with vernacular names ranging from one to three (Table 3). This long list of names indicates that local people in these countries have an active interest in Alepidea species. The traditional uses of Alepidea species are referred to in many folkloric and ethnobotanical studies done in east, central, and southern Africa, where the species are still used as primary sources of traditional medicine (Table 4). Respiratory infections (asthma, chest complaints, chest pains, chronic cough, colds, cough, influenza, pneumonia, sore throat, and tuberculosis) and gastro-intestinal disorders (abdominal cramps, abdominal pains, constipation, diarrhoea, dysentery, stomach ache, and stomach pains) (Table 5) are the most commonly treated human ailments. The species are also used for non-medicinal purposes, such as charm and magical rituals, good luck, protection purposes, or as incense to communicate with the ancestors (Table 4). In most ethnobotanical studies, Alepidea species are used alone, but often mixed with other species. For example, in South Africa, the rhizomes of A. amatymbica are mixed with those of Gunnera perpensa L. as traditional medicine against stomach ache (Hutchings et al. 1996, Maroyi 2016). In Lesotho and South Africa, the rhizomes and roots of either A. amatymbica or A. cordifolia or A. pilifera or A. setifera are mixed with Cannabis sativa L. and used against asthma (Afolayan and Lewu 2009, Moffett 2010). In South Africa, the roots of A. amatymbica are mixed with bark of Pterocelastrus echinatus N.E.Br., P. rostratus (Thunb.) Walp., and P. tricuspidatus (Lam.) Walp. as traditional medicine against respiratory infection (Hutchings et al. 1996). Alepidea amatymbica is an ingredient of a multipurpose herbal concoction called “sejeso”, which is sold in informal street herbal medicine markets, herbal medicine shops, supermarkets, and pharmacies in South Africa. Ndhlala et al. (2010) and Madikizela et al. (2017) reported the use of “sejeso” for heartburn, stomach ache, stomach cramps, indigestion, constipation, vomiting, and loss of appetite. This herbal concoction “sejeso” is prepared from five plant species, which include A. amatymbica, Elephantorrhiza burkei Benth. (family Fabaceae), Senegalia caffra (Thunb.) P.J.H. Hurter & Mabb. (Fabaceae), Peltophorum africanum Sond. (Fabaceae), and Hypoxis obtusa Burch. ex Ker Gawl. (Hypoxidaceae) (Madikizela et al. 2017).

Phytochemistry Alepidea chemistry is considerably diverse, with kaurene derivatives as the predominant phytochemical constituents (Table 6). Kaurene derivatives have been identified from more than a third (34.4%) of Alepidea species, and these include A. amatymbica, A. capensis, A. comosa, A. galpinii, A. insculpta, A. natalensis, A. peduncularis, A. serrata, A. setifera, A. thodei, and A. woodii (Rustaiyan and Sadjadi 1987, Holzapfel et al. 1996, Somova et al. 2001, Muleya et al. 2017). Similarly,

Table 4. Medicinal uses of Alepidea species. Scientific name

Plant part

Country/region

Reference(s)

Appetite booster

Root decoction taken orally

South Africa

Omoruyi et al. 2012

Belching

Rhizome and root infusion taken orally

South Africa

Njume et al. 2011

Charm and ritual (good luck and protection)

Rhizome, root and whole plant used

South Africa

Moffett 2010, Rasethe et al. 2019

Cleansing blood

Root decoction taken orally

South Africa

Omoruyi et al. 2012

Cryptococcal meningitis

Rhizome and root infusion taken orally

South Africa

Otang et al. 2012

Diabetes mellitus

Root and whole plant decoction taken orally

South Africa

Rasethe et al. 2019

Fever

Rhizome infusion taken orally

South Africa

Maroyi 2017, Semenya and Maroyi 2018a,b, 2019a

Fungal infections

Rhizome and root infusion taken orally

South Africa

Otang et al. 2012

Gastro-intestinal problems (abdominal cramps, abdominal pains, constipation, diarrhoea, dysentery, stomach ache and stomach pains)

Rhizome and root decoction taken orally

South Africa

Cocks and Dold 2006, Philander 2011, Maroyi 2017

Stomach ache

Rhizomes mixed with those of Gunnera perpensa L. South Africa

Hutchings et al. 1996, Maroyi 2016

Headache

Rhizome and root decoction taken orally

South Africa

Wintola and Afolayan 2010, Van Wyk and Gericke 2018

Inflammation

Rhizome and root decoction applied topically

South Africa

Komoreng et al. 2017

Oesopharyngeal candidiasis

Rhizome and root infusion taken orally

South Africa

Otang et al. 2012

Pain

Rhizome and root decoction applied topically

South Africa

Komoreng et al. 2017

Poison antidote

Root infusion taken orally

South Africa

Cocks and Dold 2006

Purgative

Rhizome and root decoction taken orally

South Africa

Watt and Breyer-Brandwijk 1962, De Castro and Van Wyk 1994

A. amatymbica

The Genus Alepidea 175

Table 4 contd. ...

176

...Table 4 contd. Plant part

Country/region

Reference(s)

Respiratory infections (asthma, chest complaints, chest pains, chronic cough, colds, cough, influenza, pneumonia, sore throat and tuberculosis)

Rhizome, root and whole plant decoction taken orally

South Africa

Semenya and Maroyi 2018b,c, 2019a,b, 2020

Asthma

Rhizomes and roots mixed with leaves or whole plant of Cannabis sativa L.

South Africa

Afolayan and Lewu 2009, Moffett 2010

Respiratory infections

Roots mixed with bark of Pterocelastrus echinatus N.E.Br., P. rostratus (Thunb.) Walp. and P. tricuspidatus (Lam.) Walp.

South Africa

Hutchings et al. 1996

Rheumatism

Rhizome and root decoction taken orally

South Africa

Moffett 2010, Semenya and Maroyi 2018a

Skin infections (pimples and skin disorders)

Rhizome and root infusion taken orally

South Africa

Afolayan et al. 2014, Maroyi 2017

Ulcers

Rhizome and stem decoction taken orally

South Africa

Philander 2011, Bhat 2013

Weight loss

Root decoction taken orally

South Africa

Afolayan and Mbaebie 2010

Wounds

Rhizome and root infusion taken orally

South Africa

Wintola and Afolayan 2010, Asowata-Ayodele et al. 2016

Charm and ritual (incense to communicate with the ancestors)

Roots and stems used

South Africa

Hughes et al. 2015

Human immunodeficiency virus (HIV) opportunistic infections

Root and stem decoction taken orally

South Africa

Hughes et al. 2015

Respiratory problems (asthma, bronchitis, chest pain, cough and tuberculosis)

Root and stem infusion taken orally

South Africa

Hughes et al. 2015, Semenya and Maroyi 2019c

A. capensis

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Scientific name

A. cordifolia Charm and ritual (good luck and protection)

Rhizome and root decoction taken orally

Eswatini, Lesotho, and Zimbabwe

Jacot Guillarmod 1971, Gelfand et al. 1985, Long 2005

Fever

Root infusion taken orally

Lesotho

Jacot Guillarmod 1971, Moteetee and Van Wyk 2011

Gastro-intestinal problems (abdominal pains and diarrhoea)

Rhizome decoction taken orally

Zimbabwe

Gelfand et al. 1985, Mavi 1996

Headache

Rhizome and root infusion taken orally

Eswatini, Lesotho, South Africa, and Zimbabwe

Chinemana et al. 1985, Long 2005, Moffett 2010

Malaria

Root decoction taken orally

Mozambique

Bandeira et al. 2001, Fowler 2006

Painful joints

Root decoction applied topically

Lesotho

Jacot Guillarmod 1971, Moteetee and Van Wyk 2011

Repel bees

Rhizome used

Zimbabwe

Gelfand et al. 1985, Hutchings et al. 1996

Respiratory infections (asthma, chest pains, colds, cough and influenza)

Rhizome and root decoction taken orally

Eswatini, Lesotho, South Africa and Zimbabwe

Jacot Guillarmod 1971, Long 2005, Van Wyk 2017

Asthma

Rhizome and roots mixed with leaves or whole plant of C. sativa

Lesotho and South Africa

Moffett 2010

Rheumatism

Root decoction applied topically

Eswatini

Long 2005

Fever (febrile)

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi 2009

Gastro-intestinal problems (abdominal cramps and diarrhoea)

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi et al. 2009a,b

Respiratory infections (asthma, colds, cough and influenza)

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi et al. 2009a,b

Snake bite

Rhizome and root decoction applied topically

South Africa

Hutchings 1989, Mulaudzi 2009

Venereal diseases

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi 2009

A. natalensis

The Genus Alepidea 177

Table 4 contd. ...

178

...Table 4 contd. Country/region

Reference(s)

Fever (febrile)

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi 2009

Gastro-intestinal problems

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi 2009

Respiratory infections (chest pains and cough)

Rhizome and root decoction taken orally

South Africa

Watt and Breyer-Brandwijk 1962, Hutchings 1989

Snake bite

Rhizome and root decoction applied topically

South Africa

Hutchings 1989, Mulaudzi 2009

Venereal diseases

Rhizome and root decoction taken orally

South Africa

Hutchings 1989, Mulaudzi 2009

Charm and ritual

Rhizomes and roots used

Lesotho

Moffett 2010

Fever

Root decoction taken orally

Lesotho

Jacot Guillarmod 1971, Moteetee and Van Wyk 2011

Headache

Rhizome and root decoction taken orally

Lesotho and South Africa

Watt and Brandwijk 1927, Moffett 2010

Respiratory infections (asthma, chest pains, colds and cough)

Rhizome and root decoction taken orally

Lesotho and South Africa

Watt and Breyer-Brandwijk 1962, Jacot Guillarmod 1971

Asthma

Rhizomes and roots mixed with leaves or whole plant of C. sativa

Lesotho and South Africa

Moffett 2010

Charm and ritual

Roots used

South Africa

Moeng 2010, Mogale et al. 2019

Fever

Root infusion taken orally

Lesotho

Jacot Guillarmod 1971, Moteetee and Van Wyk 2011

Headache

Root infusion taken orally

Lesotho

Watt and Brandwijk 1927

Respiratory infections (chest pains, colds, cough and influenza)

Root decoction taken orally

Lesotho and South Africa

Jacot Guillarmod 1971, Maroyi 2017

A. peduncularis

A. pilifera

A. serrata

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Plant part

Scientific name

Toothache

Root decoction applied topically

South Africa

Mogale et al. 2019

Charm and ritual

Rhizomes and roots used

Lesotho

Moffett 2010

Headache

Rhizome and root taken orally

Lesotho

Moffett 2010

Respiratory infections (chest pains, colds and cough)

Rhizome and root decoction taken orally

Lesotho

Watt and Breyer-Brandwijk 1962, De Castro and Van Wyk 1994

Asthma

Rhizome and roots mixed with leaves and whole plant of C. sativa

Lesotho and South Africa

Moffett 2010

Root decoction taken orally

Lesotho

Moteetee et al. 2019

A. setifera

A. thodei Respiratory infections

The Genus Alepidea 179

180

Ethnobotany: Ethnopharmacology to Bioactive Compounds Table 5. Major ailment categories and uses reported. Ailment category or use

Number of use reports

Venereal diseases

3

Antidote and snake bite

4

Fungal infections

5

Headache

7

Fever and malaria

8

Wounds

8

Charm and ritual

9

Rheumatism

12

Gastro-intestinal problems

27

Respiratory infections

41

Okem et al. (2014) and Mangoale and Afolayan (2020) identified alkaloids, flavonols, flavonoids, phenols, proanthocyanidin, saponins, and tannins from the rhizomes and roots of A. amatymbica.

Pharmacological Activities The majority of pharmacological studies evaluated antibacterial, antifungal, anti-HIV, anti-inflammatory, anti-hypertensive, antioxidant, antiplasmodial, antiprotozoal, cardiovascular, diuretic, and cytotoxicity activities. Therefore, evidence of the biological efficacies of various extracts of Alepidea species have been demonstrated using in vitro models, and there is need for testing the clinical relevance and biological potential of the species through appropriate in vivo tests, preclinical and clinical trials.

Antibacterial activities The antibacterial activities of ethanol extract of A. amatymbica leaves and rhizomes against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae using the micro plate method were evaluated by Stafford et al. (2005). The extract exhibited activities against the tested pathogens, with minimum inhibitory concentration (MIC) values ranging from 1.6 mg/ml to 3.1 mg/ml (Stafford et al. 2005). The antibacterial activities of methanol and acetone extracts of A. amatymbica roots, stems, leaves and rhizomes against Serratia marcescens, Staphylococcus epidermidis, Klebsiella pneumonae, Micrococcus kristinae, Bacillus cereus, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Streptococcus pyrogenes, and Salmonella pooni using the agar dilution method were assessed by Afolayan and Lewu (2009). The extracts showed activities against Staphylococcus epidermidis, Bacillus cereus, Staphylococcus aureus, and Streptococcus pyrogenes, with MIC values ranging from 5.0 mg/mL to 10.0 mg/mL (Afolayan and Lewu 2009). The antibacterial activities of aqueous, 80.0% ethanol, dichloromethane and petroleum ether of A. amatymbica rhizomes against Bacillus subtilis, Staphylococcus

The Genus Alepidea 181 Table 6. Phytochemical compounds isolated from Alepidea species. Phytochemical compound A. amatymbica 14-acetoxy ent-kaur-16-en-19-oic acid 14-acetoxo-12-oxokaur-16-en-19-oic acid 14-oxokaur-16-en-19-oic acid 16-hydroxy-kaur-6-en-19-oic acid 3β-acetoxywedelia-seco-kaurenolide 11α-acetoxy-ent-kaur-16-en-19-oic acid 16α-methoxy-ent-kaur-11-en-19-oic acid Alkaloids Caffeic acid Dehydrokaurenoic acid ent-9,(11)-dehydro-16-kauren-19-oic acid ent-12-oxo-9(11),16-kauradien-19-oic acid ent-13-hydroxy-16-kauren-19-oic acid ent-16-kauren-12-on-19-oic acid ent-16-kauren-19-oic acid ent-kaur-16-en-19-oic acid ent-kaura-9(11),16-dien-19-oic acid Flavonoids Hydroxykaurenoic acid Kaempferol Kaurene hydrate Kaurenoic acid Lactone Quercetin (R)-3'-O-β-D-glucopyranosylrosmarinic acid Rosmarinic acid Saponin Tannin Total flavonols Total phenolics Total proanthocyanidin Trachyloban-19-oic acid Wedelia seco-kaurenolide A. capensis Dehydrokaurenoic acid Kaurenoic acid Lactone A. comosa Caffeic acid Dehydrokaurenoic acid Hydroxykaurenoic acid Kaurenoic acid (R)-3'-O-β-D-glucopyranosylrosmarinic acid

Plant part Root Root Root Root Aerial parts Rhizome Rhizome Rhizomes Roots Roots Rhizomes Aerial parts Root Roots Aerial parts, rhizomes and roots Rhizome Rhizome Roots Roots Leaves Roots Roots Roots Leaves Roots Aerial parts and roots Rhizomes Rhizomes Rhizomes Rhizomes and roots Rhizomes Rhizome Rhizome Roots Roots Roots Roots Roots Roots Roots Roots Table 6 contd. ...

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...Table 6 contd. Phytochemical compound

Plant part

Rosmarinic acid A. galpinii Dehydrokaurenoic acid Kaurene hydrate Kaurenoic acid A. insculpta Dehydrokaurenoic acid Kaurene hydrate Kaurenoic acid A. natalensis Dehydrokaurenoic acid Kaurene hydrate Kaurenoic acid Lactone Wedelia seco-kaurenolide A. peduncularis Caffeic acid Dehydrokaurenoic acid Hydroxykaurenoic acid Kaurenoic acid Lactone (R)-3'-O-β-D-glucopyranosylrosmarinic acid Rosmarinic acid A. serrata Dehydrokaurenoic acid Kaurenoic acid Lactone A. setifera Dehydrokaurenoic acid Kaurenoic acid A. thodei Kaurenoic acid A. woodii Kaurenoic acid

Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots Rhizomes Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots Roots

aureus, Escherichia coli, and Klebsiella pneumoniae using micro-dilution bioassay with neomycin (0.1 mg/ml) as a positive control were evaluated by Mulaudzi et al. (2009c). The extracts demonstrated activities against tested pathogens, with MIC values ranging from 0.4 mg/ml to 3.1 mg/ml (Mulaudzi et al. 2009c). The antibacterial activities of aqueous, ethyl acetate, methanol, ethanol, and acetone extracts of A. amatymbica against Helicobacter pylori using the agar well diffusion method with metronidazole and amoxicillin as positive controls were assessed by Njume et al. (2011). The extracts exhibited activities against tested pathogens, with zone of inhibition ranging from 6.1 mm to 8.5 mm (Njume et al. 2011). The antibacterial

The Genus Alepidea 183

activities of ethanol extracts of A. amatymbica roots against Escherichia coli and Staphylococcus aureus using the microdilution assay with neomycin as the positive control were evaluated by Okem et al. (2014). The extracts showed activities against Escherichia coli and Staphylococcus aureus with MIC values of 0.2 mg/mL and 0.4 mg/mL, respectively (Okem et al. 2014). The antibacterial activities of hexane, crude, methanol, dichloromethane, acetone, and ethyl acetate extracts of A. amatymbica roots against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa using serial dilution microplate assay with gentamycin as a positive control were assessed by Muleya et al. (2015). The extracts demonstrated activities against the tested pathogens with MIC values ranging from 150.0 µg/ml to 650.0 μg/ml (Muleya et al. 2015). The antibacterial activities of aqueous and 70% acetone extracts of A. amatymbica whole plant parts against Shigella flexneri, Campylobacter jejuni, Staphylococcus aureus, and Escherichia coli using the microtitre plate method with streptomycin and neomycin as positive controls were evaluated by Madikizela et al. (2017). The extracts exhibited activities against tested pathogens, with MIC values ranging from 0.8 mg/ml to 12.5 mg/ml (Madikizela et al. 2017). The antibacterial activities of the compounds ent-13-hydroxy-16-kauren­ 19-oic acid, 16-hydroxy-kaur-6-en-19-oic acid, 14-acetoxy ent-kaur-16-en-19-oic acid, 14-oxokaur-16-en-19-oic acid, and 14-acetoxo-12-oxokaur-16-en-19-oic acid isolated from A. amatymbica roots against Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli using microtitre plate method were assessed by Muleya et al. (2017). The compounds showed activities against the tested pathogens with MIC values ranging from 50.0 µg/ml to 1250.0 µg/ml (Muleya et al. 2017). The antibacterial activities of aqueous, 80.0% ethanol, dichloromethane, and petroleum ether of A. natalensis leaves and rhizomes against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae using microdilution bioassay with neomycin (0.1 mg/ml) as a positive control were assessed by Mulaudzi et al. (2009c). The extracts demonstrated activities against the tested pathogens, with MIC values ranging from 0.8 mg/ml to 12.5 mg/ml (Mulaudzi et al. 2009c).

Antifungal Activities The antifungal activities of methanol and acetone extracts of A. amatymbica roots, stems, leaves, and rhizomes against Aspergillus niger, Aspergillus flavus and Penicillium notatum using the agar dilution method were evaluated by Afolayan and Lewu (2009). The extracts exhibited activities against the tested pathogens, with extracts showing more than 50.0% inhibition at 5.0 mg/mL (Afolayan and Lewu 2009). The antifungal activities of aqueous, 80.0% ethanol, dichloromethane and petroleum ether of A. amatymbica rhizomes against Candida albicans using the micro-dilution bioassay with amphotericin B as a positive control were assessed by Mulaudzi et al. (2009c). The extracts showed activities against tested pathogen, with the MIC and minimum fungicidal concentration (MFC) values ranging from 0.2 mg/ml to 6.3 mg/ml (Mulaudzi et al. 2009c). The antifungal activities of hexane, crude, methanol, dichloromethane, acetone, and ethyl acetate extracts of A. amatymbica

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roots against Aspergillus fumigatus and Candida albicans using the serial dilution microplate assay with amphotericin B as a positive control were evaluated by Muleya et al. (2015). The extracts demonstrated activities against the tested pathogens, with MIC values ranging from 150.0 µg/ml to 650.0 μg/ml (Muleya et al. 2015). The antifungal activities of aqueous, 80.0% ethanol, dichloromethane and petroleum ether of A. natalensis leaves and rhizomes against Candida albicans using the micro-dilution bioassay with amphotericin B as a positive control were assessed by Mulaudzi et al. (2009c). The extracts exhibited activities against the tested pathogen, with MIC and MFC values ranging from 0.2 mg/ml to 6.3 mg/ml (Mulaudzi et al. 2009c).

Anti-HIV activities The anti-HIV activities of aqueous extracts of A. amatymbica aerial parts and roots as well as the phytochemical compound rosmarinic acid isolated from the species against CXCR4-tropic (NL4-3) and CCR5-tropic (NL-AD87) wild-type viruses using the cell-based replicative assay were evaluated by Louvel et al. (2013). The extract showed moderate activities against the tested viruses, with the half maximal effective concentration (EC50) value of 22.0 μg/mL against the HIV-1 strain NL43 and 85.0 μg/mL against NL-AD87. The phytochemical compound rosmarinic acid exhibited EC50 value of 30.0 μM and 47.0 μM against NL4-3 and NL-AD87, respectively (Louvel et al. 2013).

Anti-inflammatory Activities The anti-inflammatory activities of ethanol extracts of A. amatymbica leaves and rhizomes using the cyclooxygenase (COX-1) inhibition assay were assessed by Stafford et al. (2005). The COX-1 inhibition exhibited by the leaf and rhizome extracts ranged from 77.0% to 96.0% (Stafford et al. 2005). The anti-inflammatory activities of aqueous, 80.0% ethanol, dichloromethane, and petroleum ether of A. amatymbica rhizomes using the enzyme-based cyclooxygenase assays COX-1 and COX-2 with indomethacin as a positive control were evaluated by Mulaudzi et al. (2009c). The COX-1 and COX-2 inhibition exhibited by the dichloromethane and petroleum ether extracts were higher than 90.0% (Mulaudzi et al. 2009c). The anti-inflammatory activities of acetone extracts of A. amatymbica roots against 15-soybean lipoxygenase enzyme were assessed by Muleya et al. (2015). The inhibition activity of 15-soybean lipoxygenase enzyme by the crude extracts of A. amatymbica at concentration of 25.0 μg/ml was 55.0% (Muleya et al. 2015). The anti-inflammatory activities of the phytochemical compounds ent-13-hydroxy-16­ kauren-19-oic acid, 16-hydroxy-kaur-6-en-19-oic acid, 14-acetoxy ent-kaur-16-en­ 19-oic acid, 14-oxokaur-16-en-19-oic acid and 14-acetoxo-12-oxokaur-16-en-19-oic acid isolated from A. amatymbica roots using 15-soybean lipoxygenase inhibition assay were evaluated by Muleya et al. (2017). The inhibition activities of 15-soybean lipoxygenase enzyme exhibited by the phytochemical compounds ranged from 40.0% to 80.0%, and EC50 values ranged from 19.1 µg/ml to 81.2 µg/ml (Muleya et al. 2017).

The Genus Alepidea 185

The anti-inflammatory activities of aqueous, 80.0% ethanol, dichloromethane and petroleum ether of A. natalensis leaves and rhizomes using the enzyme-based cyclooxygenase assays COX-1 and COX-2 with indomethacin as a positive control were assessed by Mulaudzi et al. (2009c). The COX-1 and COX-2 inhibition shown by the dichloromethane and petroleum ether extracts were higher than 75.0% (Mulaudzi et al. 2009c).

Anti-hypertensive Activities The anti-hypertensive activities of the phytochemical compounds diterpene kaurenoids ent-kaur-16-en-19-oic acid, ent-kaura-9(11),16-dien-19-oic acid, trachyloban-19-oic acid, 16α-methoxy-ent-kaur-11-en-19-oic acid, 11α-acetoxy-entkaur-16-en-19-oic acid, and wedelia seco-kaurenolide isolated from A. amatymbica by measuring the blood pressure in conscious rats using the tail cuff method were evaluated by Somova et al. (2001). The phytochemical compounds exhibited the anti-hypertensive activities (Somova et al. 2001).

Antioxidant Activities The antioxidant activities of hexane, crude, methanol, dichloromethane, acetone, and ethyl acetate extracts of A. amatymbica roots using the 2,2′-azino-bis(3ethylbenzothiazoline)-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assays with trolox and ascorbic acid as positive controls were assessed by Muleya et al. (2015). The extracts exhibited activities with EC50 values ranging from 1.3 µg/ml to 152.0 µg/ml in ABTS and EC50 values ranging from 4.2 µg/ml to 36.3 µg/ml in DPPH (Muleya et al. 2015). The antioxidant activities of aqueous, methanol, and acetone extracts of A. amatymbica rhizomes using ABTS, DPPH, ferric reducing antioxidant power (FRAP), hydrogen peroxide (H2O2) and nitric oxide (NO) assays with vitamin C and butylated hydroxytoluene (BHT) as positive controls were evaluated by Mangoale and Afolayan (2020). The extracts showed concentration-dependent increase in inhibition, which were comparable to activities exhibited by the positive controls with half maximal inhibitory concentration (IC50) values ranging from 0.0004 mg/mL to 2.7 mg/mL (Mangoale and Afolayan 2020).

Antiplasmodial Activities The antiplasmodial activities of aqueous, dichloromethane and dichloromethane : methanol (1:1) extracts of A. amatymbica whole plant parts against Plasmodium falciparum strain D10 using the parasite lactate dehydrogenase (pLDH) assay were assessed by Clarkson et al. (2004). The dichloromethane : methanol (1:1) extract exhibited moderate activities with IC50 value of 12.5 µg/ml (Clarkson et al. 2004). The antiplasmodial activities of dichloromethane and dichloromethane: methanol (1:1) extracts of A. amatymbica whole plant parts against Plasmodium falciparum with benznidazole chloroquine (IC50 = 0.05 µM) as a positive control using the [G-3H]-hypoxanthine incorporation assay were evaluated by Mokoka et al. (2011). The dichloromethane and dichloromethane : methanol (1:1) extracts exhibited

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activities with IC50 values of 2.7 µg/mL and 3.7 µg/mL, respectively (Mokoka et al. 2011).

Antiprotozoal Activities The antiprotozoal activities of dichloromethane and dichloromethane : methanol (1:1) extracts of A. amatymbica whole plant parts against Trypanosoma cruzi, Trypanosoma brucei rhodesiense and Leishmania donovani with benznidazole (IC50 = 0.5 µg/mL), melarsoprol (IC50 = 0.03 µM) and miltfosine (IC50 = 0.2 µg/mL) as reference drugs were assessed by Mokoka et al. (2011). The determination of the activities of the extracts against these pathogens was done using Almar Blue and resazurin assays. The extracts exhibited activities with IC50 values ranging from 5.0 µg/mL to 99.5 µg/mL (Mokoka et al. 2011).

Cardiovascular Activities Somova et al. (2001) evaluated the cardiovascular activities of the phytochemical compounds diterpene kaurenoids ent-kaur-16-en-19-oic acid, ent-kaura-9(11),16­ dien-19-oic acid, trachyloban-19-oic acid, 16α-methoxy-ent-kaur-11-en-19-oic acid, 11α-acetoxy-ent-kaur-16-en-19-oic acid and wedelia seco-kaurenolide isolated from A. amatymbica by assessing the coronary flow on isolated rat heart and by testing the potential coronary vasodilating effects. The phytochemical compounds exhibited the cardiovascular activities (Somova et al. 2001).

Diuretic Activities Somova et al. (2001) evaluated the diuretic activities of the phytochemical compounds diterpene kaurenoids ent-kaur-16-en-19-oic acid, ent-kaura-9(11),16­ dien-19-oic acid, trachyloban-19-oic acid, 16α-methoxy-ent-kaur-11-en-19-oic acid, 11α-acetoxy-ent-kaur-16-en-19-oic acid, and wedelia seco-kaurenolide isolated from A. amatymbica by using the Lipschitz test in rats. The phytochemical compounds exhibited the diuretic activities (Somova et al. 2001).

Cytotoxicity Activities Muleya et al. (2017) evaluated the cytotoxicity activities of the phytochemical compounds ent-13-hydroxy-16-kauren-19-oic acid, 16-hydroxy-kaur-6-en-19-oic acid, 14-acetoxy ent-kaur-16-en-19-oic acid, 14-oxokaur-16-en-19-oic acid and 14-acetoxo-12-oxokaur-16-en-19-oic acid isolated from A. amatymbica roots against the dermal mesenchymal stem cells line and monkey Vero cells. The phytochemical compounds exhibited activities against both the dermal mesenchymal stem cells line and monkey Vero cells, with IC50 values ranging from 20.0 µg/mL to 55.0 µg/mL (Muleya et al. 2017).

Conclusion Different species of Alepidea are used in folk medicine for various human ailments and diseases. This review revealed that some species are characterized by

The Genus Alepidea 187

promising biological activities, which include antibacterial, antifungal, anti-HIV, anti-inflammatory, anti-hypertensive, antioxidant, antiplasmodial, antiprotozoal, cardiovascular, diuretic, and cytotoxicity effects. There is therefore, need for further research focusing on in vivo evaluations in order to establish the clinical efficacy of the species extracts. Detailed studies focusing on the phytochemical, pharmacological, and toxicological properties of Alepidea species are also recommended.

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Hutchinson, S.-L., B.-E. Van Wyk and A.R. Magee. 2017. A taxonomic revision of the Alepidea setifera group (Apiaceae, Apioideae), the description of a new species, A. inflexa, and the reinstatement of A. jenkinsii. S. Afr. J. Bot. 111: 1–11. Jacot Guillarmod, A. 1971. Flora of Lesotho. Cramer, Lehre. Jansen, P.C.M. 2004. Alepidea peduncularis Steud. ex A. Rich. pp. 40–41. In: Grubben, G.J.H. and Denton, O.O. [eds.]. Plant Resources of Tropical Africa 2: Vegetables. Backyhuys Publishers, Leiden, Netherlands. Komoreng, L., O. Thekisoe, S. Lehasa, T. Tiwani, N. Mzizi, N. Mokoena et al. 2017. An ethnobotanical survey of traditional medicinal plants used against lymphatic filariasis in South Africa. S. Afr. J. Bot. 111: 12–16. Long, C. Swaziland’s Flora: siSwati Names and Uses. Swaziland National Trust Commission; 2005. Available at: http://www.sntc.org.sz/index.asp, accessed on 15 August 2021. Louvel, S., N. Moodley, I. Seibert, P. Steenkamp, R. Nthambeleni, V. Vidal et al. 2013. Identification of compounds from the plant species Alepidea amatymbica active against HIV. S. Afr. J. Bot. 86: 9–14. Madikizela, B., A.R. Ndhlala, K.R.R. Rengasamy, L.J. McGaw and J. Van Staden. 2017. Pharmacological evaluation of two South African commercial herbal remedies and their plant constituents. S. Afr. J. Bot. 111: 291–298. Mangoale, R.M. and A.J. Afolayan. 2020. Comparative phytochemical constituents and antioxidant activity of wild and cultivated Alepidea amatymbica Eckl & Zeyh. BioMed. Res. Int. Volume 2020, Article ID 5808624. Maroyi, A. 2008. Ethnobotanical study of two threatened medicinal plants in Zimbabwe. Int. J. Biod. Sci. Manag. 4: 148–153. Maroyi, A. 2016. From traditional usage to pharmacological evidence: Systematic review of Gunnera perpensa L. Evidence-Based Compl. Alt. Med. Volume 2016, Article ID 1720123. Maroyi, A. 2017. Diversity of use and local knowledge of wild and cultivated plants in the Eastern Cape province, South Africa. J. Ethnobiol. Ethnomed. 13: 43. Maroyi, A. 2021. A review of medicinal uses, phytochemistry and pharmacological activities of Alepidea species. Int. J. Sci. Technol. Res. 10: 382–391. Mavi, S. 1996. Medicinal plants and their uses in Zimbabwe. pp. 67–73. In: Norman, H., I. Snyman and M. Cohen [eds.]. Indigenous Knowledge and its Uses in Southern Africa. Human Sciences Research Council, Pretoria, South Africa. Moeng, E.T. 2010. Analysis of Muthi Shops and Street Vendors on Medicinal Plants of the Limpopo Province. M.Sc. Thesis, University of Limpopo, Mankweng, South Africa. Moffett, R. 2010. Sesotho Plant and Animal Names and Plants Used by the Basotho. Sun Press, Bloemfontein, South Africa. Mogale, M.M.P., D.C. Raimondo and B.-E. Van Wyk. 2019. The ethnobotany of Central Sekhukhuneland, South Africa. S. Afr. J. Bot. 122: 90–119. Mokoka, T.A., S. Zimmermann, T. Julianti, Y. Hata, N. Moodley, M. Cal et al. 2011. In vitro screening of traditional South African malaria remedies against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. Pl. Med. 77: 1663–1667. Moteetee, A. and B.-E. Van Wyk. 2011. The medical ethnobotany of Lesotho: A review. Bothalia 41: 209–228. Moteetee, A., R.O. Moffett and L. Seleteng-Kose. 2019. A review of the ethnobotany of the Basotho of Lesotho and the Free State province of South Africa (South Sotho). S. Afr. J. Bot. 122: 21–56. Mulaudzi, R.B. 2009. Seed germination and medicinal properties of Alepidea species. M.Sc. Thesis, University of KwaZulu-Natal, Pietermaritzburg, South Africa. Mulaudzi, R.B., M.G. Kulkarni, J.F. Finnie and J. Van Staden. 2009a. Optimizing seed germination and seedling vigour of Alepidea amatymbica and Alepidea natalensis. Seed Sci. Technol. 37: 527–533. Mulaudzi, R.B., M.G. Kulkarni, J.F. Finnie and J. Van Staden. 2009b. Seed germination of Alepidea species: Heavily traded and threatened medicinal plants in South Africa. Afr. J. Trad. Compl. Alt. Med. 6: 345–346. Mulaudzi, R.B., A.R. Ndhlala, J.F. Finnie and J. Van Staden. 2009c. Antimicrobial, anti-inflammatory and genotoxicity activity of Alepidea amatymbica and Alepidea natalensis (Apiaceae). S. Afr. J. Bot. 75: 584–587.

The Genus Alepidea 189 Muleya, E., A.S. Ahmed, A.M. Sipamla, F.M. Mtunzi and W. Mutatu. 2015. Pharmacological properties of Pomaria sandersonii, Pentanisia prunelloides and Alepidea amatymbica extracts using in vitro assays. J. Pharmacogn. Phytoth. 7: 1–8. Muleya, E., B.J. Okoli, F.M. Mtunzi and M.J. Sekomeng. 2017. Diterpenoids of Alepidea amatymbica Eckl. & Zeyh: Studies of their cytotoxic, antimicrobial and lipoxygenase inhibitory activities. MOJ Biorg. Org. Chem. 1: 103‒111. Ndhlala, A.R., R. Anthonissen, G.I. Stafford, J.F. Finnie, L. Verschaeve and J. Van Staden. 2010. In vitro cytotoxic and mutagenic evaluation of thirteen commercial herbal mixtures sold in KwaZulu-Natal South Africa. S. Afr. J. Bot. 76: 132–138. Nonjinge, S., B.B. Tarr and L. Zondi. 2019. Alepidea amatymbica Eckl. & Zeyh. Available at: http://pza. sanbi.org/alepidea-amatymbica, accessed on 15 August 2021. Njume, C., A.J. Afolayan and R.N. Ndip. 2011. Aqueous and organic solvent-extracts of selected South African medicinal plants possess antimicrobial activity against drug-resistant strains of Helicobacter pylori: Inhibitory and bactericidal potential. Int. J. Mol. Sci. 12: 5652–5665. Okem, A., C. Southway, W.A. Stirk, R.A. Street, J.F. Finnie and J. Van Staden. 2014. Heavy metal contamination in South African medicinal plants: A cause for concern. S. Afr. J. Bot. 93: 125–130. Olivier, D., B.-E. Van Wyk and F. Van Heerden. 2008. The chemotaxonomic and medicinal significance of phenolic acids in Arctopus and Alepidea (Apiaceae subfamily Saniculoideae). Biochem. Syst. Ecol. 36: 724–729. Omoruyi, B.E., G. Bradley and A.J. Afolayan. 2012. Ethnomedicinal survey of medicinal plants used for the management of HIV/AIDS infection among local communities of Nkonkobe Municipality, Eastern Cape, South Africa. J. Med. Plants Res. 6: 3603–3608. Otang, W.M., D.S. Grierson and R.N. Ndip. 2012. Ethnobotanical survey of medicinal plants used in the management of opportunistic fungal infections in HIV/AIDS patients in the Amathole District of the Eastern Cape province, South Africa. J. Med. Plants Res. 6: 2071–2080. Philander, L.A. 2011. An ethnobotany of Western Cape Rasta bush medicine. J. Ethnopharmacol. 138: 578–594. Pooley, E. 2003. Mountain Flowers: A Field Guide to the Flora of the Drakensberg and Lesotho. Natal Flora Publications Trust, Durban, South Africa. Raimondo, D., L. Von Staden, W. Foden, J.E. Victor, N.A. Helme, R.C. Turner et al. 2009. Red List of South African Plants. Strelitzia 25. South African National Biodiversity Institute, Pretoria, South Africa. Rasethe, M.T., S.S. Semenya and A. Maroyi. 2019. Medicinal plants traded in informal herbal medicine markets of the Limpopo province, South Africa. Evidence-Based Compl. Alt. Med. Volume 2019, Article ID 2609532. Rustaiyan, A. and A.S. Sadjadi. 1987. Kaurene derivatives from Alepidea amatynsia. Phytochem. 26: 2106–2107. Semenya, S.S. and A. Maroyi. 2018a. Therapeutic plants used by traditional health practitioners to treat pneumonia in the Limpopo province, South Africa. Latin Amer. Caribb. Bull. Med. Aromatic Plants 17: 583–603. Semenya, S.S. and A. Maroyi. 2018b. Data on medicinal plants used to treat respiratory infections and related symptoms in South Africa. Data Brief 21: 419–423. Semenya, S.S. and A. Maroyi. 2018c. Plants used by Bapedi traditional healers to treat asthma and related symptoms in Limpopo province, South Africa. Evidence-Based Compl. Alt. Med. Volume 2018, Article ID 2183705. Semenya, S.S. and A. Maroyi. 2019a. Source, harvesting, conservation status, threats and management of indigenous plant used for respiratory infections and related symptoms in the Limpopo province, South Africa. Biodiversitas 20: 790–811. Semenya, S.S. and A. Maroyi. 2019b. Ethnobotanical survey of plants used by Bapedi traditional healers to treat tuberculosis and its opportunistic infections in the Limpopo province, South Africa. S. Afr. J. Bot. 122: 401–421. Semenya, S.S. and A. Maroyi. 2019c. Source of plants, used by Bapedi traditional healers for respiratory infections and related symptoms in the Limpopo province, South Africa. J. Biol. Sci. 19: 101–121. Semenya, S.S. and A. Maroyi. 2020. Ethnobotanical survey of plants used to treat respiratory infections and related symptoms in the Limpopo Province, South Africa. J. Herbal Med. 24: 100390.

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Somova, L.I., F.O. Shode, K. Moodley and Y. Govender. 2001. Cardiovascular and diuretic activity of kaurene derivatives of Xylopia aethiopica and Alepidea amatymbica. J. Ethnopharmacol. 77: 165– 174. Stafford, G.I., A.K. Jäger and J. Van Staden. 2005. Effect of storage on the chemical composition and biological activity of several popular South African medicinal plants. J. Ethnopharmacol. 97: 107– 115. Talukdar, S. 2002. Lesotho. pp. 21–30. In: Golding, J.S. [ed.]. Southern African Plant Red Data Lists. Southern African Botanical Diversity Network Report No. 14, SABONET, Pretoria, South Africa. Van Wyk, B.-E. 2017. A review of African medicinal and aromatic plants. pp. 19–60. In: Neffati, M., H. Najjaa and A. Mathé [eds.]. Medicinal and Aromatic Plants of the World: Africa Volume 3. Springer, Leiden, Netherlands. Van Wyk, B.-E., A. De Castro, P.M. Tilney, P.J.D. Winter and A.R. Magee. 2008. A new species of Alepidea (Apiaceae, subfam Saniculoideae). S. Afr. J. Bot. 74: 740–745. Van Wyk, B.-E., P.M. Tilney and A.R. Magee. 2013a. African Apiaceae: A Synopsis of the Apiaceae/ Umbelliferae of Sub-Saharan Africa and Madagascar. Briza Academic Books, Pretoria. Van Wyk, B.-E., B. Van Oudtshoorn and N. Gericke. 2013b. Medicinal Plants of South Africa. Briza Publications, South Africa. Van Wyk, B.-E. and N. Gericke. 2018. People’s Plants. A Guide to Useful Plants of Southern Africa. Briza Publications, Pretoria. Victor, J.E. and M. Keith. 2004. The Orange list: A safety net for biodiversity in South Africa. S. Afr. J. Sci. 100: 139–141. Watt, J.M. and M.G. Brandwijk. 1927. Suto (Basuto) medicines. Bantu Studies 3: 73–100. Watt, J.M. and M.G. Breyer-Brandwijk. 1962. The Medicinal and Poisonous Plants of Southern and Eastern Africa. Livingstone, London. Williams, V.L., K. Balkwill and E.T.F. Witkowski. 2000. Unravelling the commercial market for medicinal plants and plant parts on the Witwatersrand, South Africa. Econ. Bot. 54: 310–327. Wintola, O.A. and A.J. Afolayan. 2010. Ethnobotanical survey of plants used for the treatment of constipation within Nkonkobe Municipality of South Africa. Afr. J. Biotechnol. 9: 7767–7770.

Chapter 9

Genus Salvia

Its Secondary Metabolites and Roles in the Treatment of Common Cancer Types in Men and Women Onder Yumrutas,1,* José L. Martinez,2 Ali Parlar,1 Bernardo Morales,3 Pınar Yumrutas4 and Luisauris Jaimes3

Introduction Today, medicinal plants are being constantly researched for the treatment or prevention of many diseases by scientists all over the world. Considering the publications on plants in the literature, it can be said that the number of plants that can be used as medicinal plants is quite high. While many of these plants are mostly used as tea and spice in all societies, they are also used directly or in the form of drugs due to their medicinal properties. One of the best-known families of medicinal plants is Lamiaceae. There are important genus such as Salvia, Thymus, Thymbra, Teucrium, Origanum, Sideritis, Satureja, Ajuga, Ziziphora, Moluccella, Ocimum, etc., in the Lamiaceae. Perhaps the best known of them is the genus Salvia. The genus Salvia, which includes aromatic and perennial species, is represented by approximately 1,000 species (Walker et al. s. d.). They have different dye, different flower type, and colour. They have the

Departament of Pharmacology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey. Vicerrectory of Research, Development and Innovation, University of Santiago de Chile, Santiago, Chile. 3 Department of Biology, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile. 4 Department of Respiratory Biology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey. * Corresponding author: [email protected] 1 2

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essential oils composed of important phytochemicals (Yumrutas et al. 2012, Lim Ah Tock et al. 2020, Cuomo et al. 2020). Salvia species are generally consumed as tea and spices. Salvia officinalis (sage), a species belonging to the genus Salvia, is especially well known and mostly consumed as tea (Ahmad Ghorbani 2017). They are also used for digestive problems, liver (Lima et al. 2007), respiratory diseases, spasm, antidepressant, heart and nervous system diseases, and so on. Also, some Salvia species are suitable for cosmetic uses (Dweck 2000). In many studies, the essential oils, extracts with different polarities, terpenoids, and phenolic compounds of these species have been mentioned and there are many reports about phytochemicals responsible for their bioactivities, including anticancer (Yumrutaş et al. 2018), antioxidant (Yalcin et al. 2017), antimicrobial (Elshafie et al. 2018), antifungal (Abu-Darwish et al. 2013), analgesic (Coffeen and Pellicer 2019), anti-inflammatory (Çadirci et al. 2012), wound healing (Ozay et al. 2021). The type and variety of phytochemicals of these plants may vary in terms of climate, environmental factors, and developmental periods, as well as their genetic characteristics. Cancer is the second leading cause of death after heart disease today (WHO 2018). Cancer is a type of disease that occurs as a result of abnormal and rapid division of cells, and mostly follows an invasive and metastatic pathology in tissues. While the main factors causing cancer are cigarettes, alcohol, obesity, exposure due to working conditions, and radiation, cancer can also occur due to genetic reasons. Also, viruses are known to cause some types of cancer, such as cervical cancer. In addition to these, it is thought that the Sar.Cov.2 virus, which affected the whole world negatively and caused the death of approximately 6 million people, may increase the number of cancer cases in the future. In 2020, it was estimated that there were19.3 million new cancer cases, excepting basal cell carcinoma, and ten million deaths due to the cancer (Sung et al. 2021). It is estimated that in the United States alone, approximately 1.9 million people will be diagnosed with cancer in 2021 and 600,000 of these will die (Siegel et al. 2021). Considering the cancer cases all over the world, it can be thought that this number is much higher and is constantly increasing. Lung, prostate, colorectal, stomach, and liver cancer in men and breast, colorectal, lung, cervical, and thyroid cancer in women are the most common cancer types (WHO 2018). The main purpose of cancer treatment is to prolong patient survival. Although chemotherapy, radiotherapy, immunotherapy, cancer vaccinations, photodynamic therapy, and surgical methods are used in treatment for cancer (Iqbal et al. 2017), the treatment with these methods is limited and the need for complementary treatments is increasing day by day. Among these complementary therapies, the most preferred method is the use of plants or compounds isolated from them against cancer. Phytochemicals have clinical use as chemotherapeutic agents used in the treatment of cancer, and new ones are constantly being added to these substances. Taxanes such as paclitaxel and docetaxel, Vinca alkaloids such as norelbine, vindesine, vincristine and vinblastine, campothecin derivatives such as topotecan, cephalotaxus alkaloids such as homoharringtonin, cyanidin glycosides such as berberine, combretastatin,

Genus Salvia 193

ellipticine, colchicine, cyanidin-3-sideglucidin, cyanidin-3-or glycosides are examples of some chemicals used in cancer treatment (Iqbal et al. 2017). In general, chemicals with potential to be anticancer agents are investigated in in vivo and in vitro test systems. These chemicals are mainly testing cancer cell lines on including A549 (lung), MCF7 (breast), PC3, LNCaP and DU145 (prostate), HeLa (cervix), Caco2, HT29 and HTC116 (colorectal), SGC-7901 (gastric), HL­ 60 (leukemia), and so on. Whether or not a compound has anticancer activity can be evaluated after performing the cell tests, such as viability, apoptosis, cell cycle, metastasis, invasion, and drug resistance tests. In anticancer studies, the viability of cancer cells and inhibition of proliferation are usually tested first. Then, suppression of signal pathways, such as PTEN/PI3K/AKT/MTOR, JACK/STAT/SOCS, TGF1B/SMADS, MAPK/ERK1/ERK2 and EGFR, stimulation of proapoptotic proteins such as BAX/BAD/BIM/BAK, suppression of proteins such as BCL2,BCLXL and MCL1, induction of apoptosis by activating intrinsic/extrinsic apoptotic factors and caspase cascade, cell cycle arrest by suppression of compounds such as cyclin-D1, suppression of some enzymes such as COX-2, topoisomrease-I and topoisomeraseII, MMP-2 and MMP-9 are investigated for anticancer activities.

Effects of Compounds obtained from Salvia species on Cancer As mentioned above, addition to Salvia species have been used in tea and spices for many years, and they have attracted the attention of many scientists working on cancer due to their lack of toxic effects and their phytochemicals. One of the most important reasons for this is that Salvia species are represented by many different species in many geographies of the world, and they are already used naturally and they contain a very large phytochemical source. It has been reported in the literature that various extractions of the aerial and root parts of Salvia species and their isolated substances can be used in the prevention/ treatment of many important cancer types. Salvia species have important cancer anticancer activities, and this activity varies according to the extraction and isolation method, cancer type, and application method. Anticancer activities of important phytochemicals obtained from essential oils and extracts of Salvia species are given in detail in Table 1. The main task of terpenes, phenolics, and many other compounds in Salvia species, as in all plants, is for defense and reproduction. Among the most important phytochemicals of Salvia species are phenolic compounds. Phenolic compounds are secondary compounds containing a hydroxyl group in the aromatic benzene ring. Many plant species, including members of the Salvia genus contain the phenolic compounds, such as flavonoids, flavonols, flavones, flavanones, flavanols, anthocyanins, isoflavones, and phenolic acids (Karakaya 2004). These compounds have been determined to have the bioactivities, such as antioxidant (Rice-Evans et al. 1997), antimicrobial (Ezoubeiri et al. 2005), anticancer (Roleira et al. 2015, Yumrutaş et al. 2018), antidiabetic (Chen et al. 2018), and antihyperlipidemia (Rekha et al. 2019).

No.

Name

Isolated compounds

Portion

Effects

Cancer types

References

1

Salvia miltiorrhiza (Budge)

Polysaccharide

Root

Extraction-isolation

Splenocyte proliferation, promoted anti-inflammatory cytokines (IL-2, IL-4 and IL-10) production, inhibited pro-inflammatory cytokine (IL-6 and TNF-) secretion, augmented the killing activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), and increased phagocytotic function of macrophages

Gastric cancer (rat-in vivo)

(Wang et al. 2014)

2

Salvia miltiorrhiza

Polysaccharide (arabinose, galactose, glucose, rhamnose and galacturonic acid)

Root

promote proliferation of t-lymphocytes of cancer patients, up-regulation of cytokines (IL-4, IL-6 and IFN-γ), evaluated expression of TLR1, TLR2 and TLR4, elevated protein expression of p-JNK and p-ERK; increased protein expression of IKKα, and IKKβ and decreased IκBα levels

Periferic blood of patients with lung, colon, and liver cancers and their tumour cell lines

(Chen et al. 2017)

3

Salvia officinalis L.

Carnasol, Luteolin,, Cirsiliol

Aerial parts

Antiproliferative activity, STAT3 inhibitory activity, activated cytolytic activity of NK cells

Liver, Lung

(Yanagimichi et al. 2021)

Methanol

194  Ethnobotany: Ethnopharmacology to Bioactive Compounds

Table 1.  Extraction type, isolated or screened substances, mechanism of action of Salvia species with anticancer activity.

4

Salvia miltiorrhiza

Cryptotanshinone

5

Salvia miltiorrhiza

Tanshinone

Roots

6

Salvia corrugata Vahl

Fruticulin C, 7a-methoxy­ 19-acetoxy-royleanone, 7a,19-diacetoxy­ royleanone ,7-dehydroxy­ conacytone,fruticulin A, demethyl-fruticulin A and 7a-O­ methyl-conacytone

Aerial parts

induced ovarian cancer A2780 cells apoptosis by activating caspase cascade, suppress migration and invasion of ovarian cancer cells and dramatically inhibited MMP-2 and MMP-9 expression

Ovarian cancer

(Jiang et al. 2017)

Methanol extract

inhibited the proliferation of NSCLC in a dose-dependent manner and induced both early and late apoptosis, G2/M phase arrest, increased expression of p53 and p21, actived caspase-3/9 and PARP1, decreased expression of the antiapoptotic protein Bcl-2, Bcl-xl and increased expression of the pro-apoptotic protein Bax, increase expression levels of PTEN, and reduce the phosphorylated levels of Akt (protein kinase B)

Lung cancer

(Ye et al. 2017)

Dichloromethane

quinone reductase induction activity and histone deacetylase inhibition

Cervical cancer

(Giacomelli et al. 2013)

195

Table 1 contd. ...

...Table 1 contd. Name

Isolated compounds

Portion

Extraction-isolation

Effects

Cancer types

References

7

Salvia involucrata Cav

Involucratin A (1), involucratin B (2), and involucratin C (3), clerodane compounds (5 R ,7 R ,8 S ,9 R ,10 R ,12 R)7-hydroxycleroda-1,3,13(16),14­ tetraene-17,12;18,19-diolide (4) , (–)-hardwickiic acid (5), 1-deoxybacrispine (6), 7 α-hydroxybacchotricuneatin A (7), and kingidiol (8), along with the flavonoid salvigenin, and a mixture of ursolic and oleanolic acids were also isolated.

Aerial parts

Dichloromethane

Antiproliferative activity

Breast, leukemia, glioblastoma, lung adinocarcinoma, colon, prostate cancers

(Bustos-Brito et al. 2021)

8

Salvia multicaulis Vahl

Salvimulticanol and salvimulticaoic acid

Aerial parts

DichloromethaneMetanaol

Antiproliferative activity

Leukemia

(Hegazy et al. 2018)

9

Salvia russellii (benth)

Russelliinosides, β-sitosterol, 18-hydroxyferruginol, daturaolone and oleanolic acid), ursolic acid, cirsimaritin, eupatorin, and salvigenin

Aerial parts

Dichloromethane

Antiproliferative activity

Breast and lung cancers

(Hafez Ghoran et al. 2021)

Salvia multicaulis

11,12,14-trihydroxy-19(4→3)abeo-3,5,8,11,13-abietapentaen2,7-dione (salvimulticanol), 11,12,14-trihydroxy-3,7­ dione-2,3-seco-4(18),8,11,13abietatetraen-2-oic acid (salvimulticaoic acid), 2-oxocandesalvone, candesalvone B,6-β-hydroxycandesalvone B, candesalvone B methyl ester

Aerial parts

CH2Cl2:MeOH

Antiproliferative activity, antimulti drug resistant activity

Breast, colon, glioblastom, leukemia

(Hegazy et al. 2018)

No.

10

Roots

Etanol, petrolium ether, methanol, acetone fractions

Antiproliferative activity

Lung, colon, breast, leukemia, liver

(Zheng et al. 2020)

Roots

Methanol extract, n-hexane, CH2Cl2 and EtOAc fractions

Apoptosis induction, increase of caspase 3 and 8 expressions

Cervical

(Parsaee et al. 2013)

Salvianolic acid A

Induced cell apoptosis and inhibited cell migration and invasion via regulation of p53, Bax/Bcl-2, cytocytosol and F-actin, Up-regulation of p-PTEN and suppression of PI3K/AKT signaling pathway

Lung cancer

(Bi et al. 2017)

Salvia miltiorrhiza

Cryptotanshinone

induced mitocondrial apoptosis, and cell cycle arrest (in G2 phase) in GC cells via ROS-mediated MAPK and AKT signaling pathways

Gastric

(Liu et al. 2017)

S. aurea L., S. judaica Boiss, S. viscosa Jacq

Caryophyllene oxide, carvacrol (main compounds for all of them)

Increased ROS level from mitokondria, induction of apoptosis via decreasing Bcl-2 expression and activation of Caspase 9 and 3,

Prostate

(Russo et al. 2018)

11

Salvia deserta Schangin

12

Salvia chorassanica Bunge

13

Salvia miltiorrhiza

14

15

Horminone, taxoquinone, 7α-O-methylhorminone, 7β-O-methylhorminone, 7α-ethoxyroyleanone, 8α,9αepoxy-6-deoxycoleon U, 6,7-dehydroroyleanone, 6α-methoxy-7-oxoroyleanone, Salvidesertone E, salvidesertone F

Aerial parts

Essential oil

197

Table 1 contd. ...

...Table 1 contd. No.

Name

Isolated compounds

Portion

Extraction-isolation

Effects

Cancer types

References

16

Salvia triloba L.

1,8-cineole, B-pinene, B-caryophyllene, camphor (main compounds)

Aerial parts

Methanol

Induction of apoptosis, increased caspase 3/7 activation,induced DNA fragementation, decreasion in levels of ENA-78, bFGF, EGF, IL-8, IL-8, IFN-gama, PIGF, TIMP-1 and TIMP-2, angiogenin, RANTES, PDGF, MCP-1, LEPTIN, VEGF (angiogenic markers)

Prostate

(Atmaca et al. 2016)

17

Salvia chloroleuca Rech. f. & Aellen

Roots

Methanol, n-Hexane, CH2Cl2, and EtOAc fractions

G1 cell cycle arrested, induction of apoptosis-DNA fragmentation, ROS induction

Breast

(TayaraniNajaran et al. 2013a)

18

Salvia miltiorrhiza

Acetonitrile

Inhibition of cell growing,

Prostate

(Lee et al. 2017)

19

Salvia miltiorrhiza

Dihydrotanshinone

Induction of apoptosis (increased activation of caspase 9 and 3 and release of cytochrome C

Brain

(Cao et al. 2017)

20

Salvia rosmarinus Spenn.

Rosmarinic acid, luteolin-7glucoside,rutin, ursolic acid, carnosol, and carnosic acid, Hesperidin, Isorhamnetin-3O-hexoside, Hispidulin-7glucoside,Dihydroxydimethoxy flavone, Genkwanin, Kaempferol, Rosmaridiphenol, 12-O-methylcarnosic acid

Antiproliferative activity, inducing of apoptosis

Breast

(Brindisi et al. 2020)

Leaves

Methanol-ultrasoundmaceration

21

Salvia atropatana Bunge.

Atropatanene, 7αacetoxyroyleanone, saprorthoquinone and aethiopinone

Roots

Methanol, petrolium ether, ethylacetate, n-butanol, water fractions

Increase of Bax and cleavage of PARP protein levels and in amount of cells arrested in G1 phase

Prostate, breast

(Shakeri et al. 2021)

22

Salvia lachnocalyx Hedge

15-deoxyfuerstione, horminon, oxide, microstegiol, 14-deoxycoleon U

Roots

Dichloromethane, cilica gel fractions

Cytotoxic acitivity via ınhibition topoisomerase I

Breast, leukemia

(Mirzaei et al. 2020)

23

Salvia pilifera Montbet & Aucher Ex Bentham

Fumaric acid, gallic acid, gallicatechin, catechin, oleorufein, caffeic acid, syringic acid, ellagic acid

Aerial parts

Methanol

Antiproliferative, induction of apoptosis,

Prostate

(Yumrutaş et al. 2018)

24

Salvia leriifolia Benth

camphor, 1,8-cineole, camphene, a-pinene

aerial parts

essential oil

Antiproliferative

Lung, colon, melanoma, breast, prostat, renal carcinomas

(Loizzo et al. 2010)

25

Salvia acetabulosa L.

α-Pinen, 1,8-cineole, camphor

Aerial parts

Essential oil

Antiproliferative

Lung, colon, melanoma, breast, prostat, renal carcinomas

(Loizzo et al. 2010)

26

Salvia africana­ lutea L.

Labda-8(17),12E,14-triene2R,18-diol, 2R-Hydroxylabda8(17),12E,14-trien-18-oic acid, Methyl 2R-hydroxylabda­ 8(17),12E,14-trien-18-oate, ursolic acid, carnasol, (+)-trans­ ozic acid, rosmadial

Aerial parts

Ethanol-petroleum ether

Antiproliferative

Breast

(Ahmed A. Hussein et al. 2007)

27

Salvia amarissima Ortega

Teotihuacanin

Aerial parts

Antiproliferative,modulator of multidrug resistance

Breast, colon, cervix

(Bautista et al. 2015) Table 1 contd. ...

...Table 1 contd. No. 28

29

30 31

Name

Isolated compounds

Portion

Extraction-isolation

Effects

Cancer types

References

Salvia triloba L. Salvia hormium L. Salvia dominica L. Salvia syriaca L. Salvia sahendica Boiss. & Buhse

Crude extract

Aerial parts

Ethanol

Antiproliferative activity, antiangiogenic activity

Breast

(Zihlif et al. 2013)

Sclareol, oleanolic acid, B-stosterol, salvigenin, 3a-hydroxy-11a,12aepoxyoleanan-28,13B-olide Castanol (A,B,C), Neotanshinlactone, methyltanshinoate

Aerial parts

n-hexane, ethanol fractions

Antiproliferative activity

Breast

(Tabatabaei et al. 2017)

Whole plant

Acetone, water, and ethylacetate fraction

Antiproliferative activity

Lung, breast, liver, colon

(Pan et al. 2012)

11α-Hydroxyleukamenin E, 11β-Hydroxyleukamenin E, 11-oxoleukamenin E, 3-Oxo11α-hydroxyleukamenin E, 3-Deacetyl-11-oxoleukamenin E, 3,11-Dioxoleukamenin E, 11,12-Didehydroleukamenin E, 11α,12α-epoxyleukamenin E,18-Deacetyl-4-epi-henryine A, 4-epi-henryine A, leukamenin E, 7α,14β-Dihydroxy-17βmethoxymethyl-3β-acetoxyent-kaur-11,15-dione, 7α, 14β-Dihydroxy-17α-ethoxymethyl3β-acetoxy-ent-kaur-11,15dione, 7α,14β-Dihydroxy17β-ethyoxymethyl-3βacetoxy-ent-kaur-11,15-dione, 7α,14β-Dihydroxy-17α-methoxymethylent-kaur-3,11,15-trione

Whole plant

Ethanol, petroleum ether, CHCl3, EtOAc, and n-BuOH,

Antiproliferative activity

Lung, breast, liver, colon

(Zheng et al. 2013)

Salvia castanea Diels f. pubescens Stib. Salvia cavaleriei H.Lév.

32

Salvia digitaloides Diels

33

Salvia disermas L.

34

Salvia dominica

Dihydroneotanshinlactone, 16,17-dinorpisferal A, neotanshinlactone, tanshinone IIA, cryptotansinone, dihydrotanshinone, tanshinone I Rosmarinic acid, caffeic acid, salvigenin, luteolin, luteolin 7-O-β-arabinoside, luteolin 7-O-β-glucoside, ocotillol II

Root

Acetone

Antiproliferative activity

Lung, liver, pancreas, breast, leukemia

(Xu et al. 2010)

Leaves

Ethanol, water and methanol fractions

Liver

(Hawas et al. 2009)

23,6R-epoxy-labd-8,13(14),17trien-16(R),19-olide, 8R,15(S)dihydroxy-23,6R-epoxy- labd13(14),17-dien-16(S),19-olide, 8R,15(S)-dihydroxylabd13(14),17-dien-23,6R-16(S),19diolide, 8R,15(S),23Rtrihydroxy23,6R-epoxy-labd-13(14),17dien-16(S),19-olide, 8R,15(S) -dihydroxy,23R-O-ethyl23,6Repoxy-labd-13(14), 17-dien16(S),19-olide, 8R-hydroxy,23RO-ethyl-23,6Repoxy-labd-13(14), 17-dien-16(R),19-olide, 6R,8R,15(S),23-tetrahydroxylabd-13(14),17-dien-16(S),19olide, 8R,23-trihydroxy-labd13(14),17-dien-16(R),19-olide, 6R,8R,15(S),trihydroxylabd-13(14),17-dien-16(S),19olide, 6R,8R,15(S)-trihydroxy23-carbossi-labd-13(14),17-dien16(S),19-olide

Aerial parts

Hexane, chloroform, methanol

Anti-initiating activity through modulation of the carcinogen metabolism, prevention of excessive ROS production, Induction of phase II drugmetabolizing enzymes such as GST, quinine reductase (QR) or mEH, inhibition of CYP1A activity Inhibition of Tubulin Tyrosine Ligase

Breast, kidney

(Piaz et al. 2009)

Table 1 contd. ...

...Table 1 contd. No.

Name

Portion

Extraction-isolation

Effects

Cancer types

References

Aerial parts

Methanol, n-hexane fractions

Antiproliferative activity, induction of apoptosis, inhibition of excessive ROS production and antioxidant activity

Breast, colerectal

(Tundis et al. 2017)

2α, 3β, 11α –trihydroxy-olean-12ene , 2α, 3β, 11α-trihydroxyolean-18-ene, 2α- acetoxyurs-12-ene-3β, 11α, 20β-triol, 3-keto-urs-12-ene-1β, 11α, 20β -triol, 2α, 3β-diacetoxy-urs12-ene-1β, 11α, 20β -triol, and 3β-acetoxy-urs-12-ene-1β, 11α, 20β –triol

Aerial parts

CH2Cl2, n-hexane/ EtOAc /MeOH fractions

Antiproliferative activity, α-glucosidase inhibitory activity

Breast

(Zare et al. 2020)

Salvia heldreichiana Boıss. Ex Bentham

Spathulenol, caryophyllene oxide,

Aerial parts

Essential oil

Antiproiferative

Prostate, breast, melanoma

(Ayşe Erdogan et al. 2013)

38

Salvia hispanica L.

Musilage Oligosaccharide

Seed

Water, n-BuOH, MeOH

Antiproliferative

Breast, colon, cervix

(RosasRamírez et al. 2017)

40

Salvia officinalis

Leaves

Ethanol

Induction of apoptosis in L1210 cells by activation of caspases, 8, 9 and 3, decay of mitochondrial membrane potential

Leukemia

(Jantová et al. 2014)

Isolated compounds

35

Luteolin, luteolin-7-O-glucoside, Salvia fruticosa rutin, salvigenin, viridiflorol, Mill subsp. Thomasii (Lacaita) B-pinene, 1,8-cineole

36

Salvia grossheimii Sosn.

37

41

Salvia officinalis

12-methylcarnasol, carnasol, 7b-metoxyrosmanol, 7a-metoxyrosmanol, isorosmanol, epirosmanol

Aerial parts

Methanol

Antiproliferation activity, acetylcholine esterase inhibitory activity, melanin synthesis inhibitory activity

Melanoma

(Sallam et al. 2016)

42

Salvia austriaca Jacq.

7-(2-oxoexhyl)-11-hydroxy-6, 12-dioxo-7,9(11),13-abietatriene

Roots

n-hexane, ethyl acetate fractions

Antiprolifrative

Melanoma, leukemia

(Kuźma et al. 2012)

43

Salvia miltiorrhiza

Danshen and dihydroisotanshinone I

Roots

Inhibit the migration of both androgendependent and androgen-independent prostate cancer, diminished the ability of prostate cancer cells to recruit macrophages and reduced the secretion of chemokine (C-C motif) ligand 2 (CCL2) from both macrophages and prostate cancer cells, inhibition of protein expression of p-STAT3, decrease of the translocation of STAT3 into nuclear chromatin, suppression of tumour epithelial– mesenchymal transition genes (RhoA and SNAI1)

Prostate

(Wu et al. 2017)

Table 1 contd. ...

...Table 1 contd. No.

Name

Isolated compounds

Portion

Extraction-isolation

Effects

Cancer types

References

44

Salvia miltiorrhiza

Trijuganone C

Roots

Hexane

Antiproliferative activity, induction of chromatin condensation and DNA fragmentation, activation of caspase 3, caspas8, caspase9 and PARP, activation of bax and bid, induce of cytochrome c release,

Leukemia

(Uto et al. 2018)

46

Salvia chorassanica Bunge

Taxodione, ferruginol and 6-hydroxysalvinolone

Roots

Methanol, n-hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc) and water (H2O

Antiproliferative activity, induction of apoptosis, enhanced expression of the pro-apoptotic protein Bax, cleaved caspase-3 and cleaved PARP, DNA fragmentation,

Leukemia

(TayaraniNajaran et al. 2013b)

48

Salvia miltiorrhiza

Dihydroisotanshinone I

Roots

Ethanol

Anti-proliferative activity, inhibition the of migration, induction of apoptosis, repressed the protein expression of Skp2 (S-Phase Kinase Associated Protein 2) and the mRNA levels of its related gene, Snail1 (Zinc finger protein SNAI1) and RhoA (Ras homolog gene family, member A), colon cancer cells recruitment ability of macrophage by decreasing CCL2 secretion in macrophages

Colorectal

(Lin et al. 2017)

49

Salvia officinalis

Manool

Leaves

Dichlorometane, metanol, water, hexane fractions

Antiproliferative activity

Melanoma, breast, hepatocellular, servical, glaoblastoma

(Francielli et al. 2016)

50

Salvia tiliifolia Vahl.

Tiliifolin A, B, C, D, E

Aerial parts

Acetone, EtOH, water, petrolium ethere, methanol, 2-propanol fractions

Antiproliferative activity

Lung, hepatocellular, leukemia, breast, colon

(Fan et al. 2017)

51

Salvia lachnostachys Benth

Crude extract

Leaves

Ethanol

Decreased hepatic and tumor SODactivity, tumor IL-10 levels and Cyclin D1 expression, and increased tumor reduced glutathione, N-acetylglucosaminidase, reactive oxygen species, lipid peroxidation, TNF-α levels and Nrf2 expression

Solid Ehrlich carcinoma

(Corso et al. 2019)

52

Salvia leriaefolia Benth.

Salvialeriafone, Salvialerial, Salvialerione, salvicanaric acid, dehydroroyleanone, and cariocal

Aerial parts

Ethanol, water, hexane, chloroform, ethyl acetate, and n-butanol fractions

Antiproliferative activity

Cervical, prostate

(Choudhary et al. 2011)

53

Salvia leriifolia Benth.

6β,13β-dihydroxylabd8(17),14-diene-19-oic acid, 13-hydroxylabd­ 8(17),14-diene-6β,19-olide, 8(17),12E,14-labdatrien-6,19olide

Aerial parts

Hexane

Antiproliferative activity

Breast, prostate

(Farimani et al. 2016)

205

Table 1 contd. ...

...Table 1 contd. No.

Name

Isolated compounds

Portion

Extraction-isolation

Effects

Cancer types

References

Caryophyllene oxide, β-caryophyllene, α-copaene, β-pinene, γ-terpinene, pulegone , terpinen-4-ol, camphor (for Sb), γ-muurolene , 1-epi-cubenol, trans-pinocarvyl acetate, α-thujone, α-Pinene , p-cymene (for Sr) Crude extract, clerodermic acid

Aerial parts

Essential oil

Antiproliferative activity, induction of apoptosis, induce of DNA fragmentation

Melanoma

(Cardile et al. 2009)

Aerial parts

n-hexane, dichloromethane, and methanol

β-Ursolic acid

Aerial parts

Lung Antiproliferative activity, suppression of HIF-1, increase in sub-G0/G1 phase, induction of apoptosis, fragmentation of DNA Melanoma Antiprotease activity due to the strongest inhibition activity on urokinase and cathepsin B, Antimetastatic acitivity Antiproliferative activity Colon, ovarian, breast, lung,

54

Salvia bracteata Banks & Sol, Salvia rubifolia Boiss

55

Salvia nemorosa L.

56

Salvia officinalis

57

Salvia pachyphylla Pachyphyllone, carnosol, rosmanol, 20-deoxocarnosol, Epling ex Munz , carnosic acid, isorosmanol, S. clevelandii 7-methoxyrosmanol, 5,6-didehydro-O-methylsugiol, 8â-hydroxy-9(11),13-abietadien12-one, 11,12-dioxoabieta8,13-diene, and 11,12-dihydroxy-20-norabieta5(10),8,11,13-tetraen-1one (for SP), rosmadial, 16-hydroxycarnosol, abieta8,11,13-triene, taxodone, carnosol, rosmanol, and carnosic acid (for SC)

Whole plant

Acetone, n-hexane/ethyl acetate fractions

(Babak Bahadori et al. 2018) (Jedinák et al. 2006)

(Iván C.  Guerrero et al. 2006)

58

Salvia plebeia R.Br.

Crude extract, cosmosiin, homoplantaginin, apigenin, and hispidulin

Aerial part

Ethanol, methylene chloride, ethyl acetate , and n-butanol fractions

Anticancer activity via blocking of the interaction of PD-1 with its ligands PD-L1 (programmed cell death ligand 1) and PD­ L2, increased infiltration of CD8+ T-cells

Colon

(Choi et al. 2020)

59

Salvia przewalskii Maxim

Salviprzols A and B,

Root

70% aqueous acetone, CHCl3, petroleum ether/acetone, ethanol methanol fractions

Antiproliferative

Leukemia, hepatocarcinoma, lung, breast, pancreas

(Xue et al. 2014)

60

Salvia pseudorosmarinus Epling

12-deacetylsplendidin C, pseudorosmaricin, 2-dehydroxysalvileucanthsin A, jewenol A

Aerial parts

n-hexane,CHCl3, CHCl3-MeOH (9:1), and MeOH fractions

Anticancer activity via inhibition of the serine hydrolase monacylglycerol lipase (MAGL)

In vitro model

(De Leo et al. 2018)

61

Salvia tebesana Bunge

Tebesinone A, tebesinone B, aegyptinone A, aegyptinone B,

Root

Metanol, petroleum ether, dichloromethane, butanol and water fractions

Antiproliferative activity

Breast, melanoma, prostate, colon

(Eghbaliferiz et al. 2018)

62

Salvia urmiensis Bunge

Urmiensolide B, urmiensic acid,

Aerial parts

n-hexane,EtOAc,MeOH fractions

Antiproliferative activity

Lung, breast

(Farimani et al. 2015)

63

Salvia eremophila Boiss.

3B,20-dihydroxylupane-28oic acid, carnosol, rosmanol, isorosmanol, 5-hydroxy-7,4’­ dimethoxy flavone

Aerial parts

Hexane, methanol, ethanol fractions

Antiproliferative activity

Breast, leukemia,liver,

(Farimani et al. 2012)

64

Salvia kronenburgii Rech.f.

Eucalyptol, linalool oxide, 2,2,4trimethyl pentanediol1,3diisobutyrate

Whole plant

Methanol

Antiproliferative activity, apoptosis induction due to DNA fragmentation

Breast

(Çebi et al. 2019)

208

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Phenolics of Salvia species Suppressing Cancer Cells It can be said that there is a negative relationship between consumption of foodderived phenolic compounds and the pathogenesis of cancer. As well as the antioxidant activities of phenolic compounds, these compounds can contribute to the prevention and regression of cancer by directly or indirectly acting on the mechanisms that cause cancer formation. It has been determined that Rosmarinic acid, an important phenolic compound, may play a role in the prevention of colitis-associated colon cancer by suppressing NF-kB and STAT3 activation and TLR4-myeloid differentiation factor 2 complex (Jin et al. 2021). It has been determined that dihydroxy-cinnamic acid induces apoptosis in parallel with the increase of caspase-3 in colon and cervical cancer cells through inhibition of histone deacetylase, and causes cell arrest in S and G2/M phases (Anantharaju et al. 2017). Gallic acid has been reported to exhibit anticancer activity by causing arrest of colon cancer cells in the sub-G1 phase and activating apoptosis by inducing ROS (Subramanian et al. 2016). Ferulic acid has been determined to inhibit cell invasion due to decrease in MMP-9 expression, decrease the synthesis of autophagy proteins such as LC3-II, Beclin1 and Atg12­ Atg5, suppress cell cycle proteins such as cyclin D and E, and regulate the cell cycle by increasing the level of proteins such as p53 and p21 (Gao et al., 2018). In addition, hesperidin induces apoptosis by providing BCL2/BAX modulation and increasing caspase 3 in colon cancer cells (Park et al. 2008). Moreover, Kaempferol induces apoptosis in ovarian cancer cells by causing an increase in caspase3 and caspase7 levels due to a decrease in BCL2 and an increase in P53, Bax, and Bad levels (Luo et al. 2011). In many studies, the above-mentioned phenolics were determined by different extraction methods of root, leaf, stem, and flower parts of Salvia species, and tested in anticancer studies. The types and amounts of these phenolic compounds vary considerably from species to species. In the anticancer study using Salvia pilifera extract and chloregenic and caffeic acid, it was determined that the extract and phenolic acids induced apoptosis in prostate cancer cells (Yumrutaş et al. 2018). Salvianolic acid-A isolated from the roots of S. miltiorhiza induces apoptosis, inhibits migration and invasion by the regulation of p53, Bax/Bcl-2, cytocytosol, and F-actin, increases PTEN expression and suppression of PI3K/AKT signaling pathway (Bi et al. 2017). Salvia rosmarinus methanol extract including rosmarinic rosmarinic acid, luteolin-7-glucoside, rutin, ursolic acid, carnosol, and carnosic acid, hesperidin, isorhamnetin-3-O-hexoside, hispidulin-7-glucoside, dihydroxydimethoxy flavone, genkwanin, kaempferol, rosmaridiphenol ve 12-O-methylcarnosic acid reduced the proliferation of breast cancer cells and played a role in inducing apoptosis by suppressing the MAPK/NF-kB pathway (Brindisi et al. 2020). Luteolin obtained from Salvia diserma has anti-initiating activity through modulation of the carcinogen metabolism, prevention of excessive ROS production, Induction of phase II drugmetabolizing enzymes such as GST, quinine reductase (QR) or mEH, inhibition of CYP1A activity (Hawas et al. 2009).

Genus Salvia 209

Terpens of Salvia species Suppressing Cancer Cells Terpenes are compounds with a branched 5-carbon skeleton of isoperene. Terpenes are simple hydrocarbons and may have oxygen-containing compounds, such as hydroxyl, carbonyl, ketone, or aldehyde groups (Muhseen and Li 2019). Terpenoids, which are its subunit, are a modified compound with many functional groups in which the oxidative methyl moves or is displaced in different positions. Cryptotanshinone, obtained from the roots of Salvia miltiorrhiza, is a quinoide diterpene. Cryptotanshinone induces a decrease in BcL2 level and increase in Bax level in ovarian cancer cells. It also induces apoptosis by induction of caspase 3 and 9 and inhibits angiogenesis by suppressing MMP2 and MM9 (Jiang et al. 2017). It has been determined that abietane type-diterpene quinones Tanshinone obtained from Salvia miltiorrhiza roots have a dose-dependent antiproliferative effect on lung cancer cells. Tanshinone exhibits an anticancer activity by inducing early and late apoptosis by increasing Caspase 3, Caspase 9, and Bax levels and decreasing BCL-2 and Bcl-xl expression, by suppressing the PI3K/AKT signaling pathway involved and by arresting cells at the G2/M checkpoint in lung cancer cells (Ye et al. 2017). In another study, it was determined that trijuganone C obtained from the roots of S. miltiorhiza caused an increase in the levels of caspase8, caspase3, caspase 9, and PARP, an increase in the level of bax and bid proapoptotic proteins, and the release of cytochrome C in leukemia cells (Uto et al. 2018). Dihydrotanshinone, which is also isolated from the same plant, stimulates mitocontrial cytochrome-C release in brain cancer cells and increases the level of caspase 3 and 9 (Cao et al. 2017). Diterpenes obtained from aerial parts of S. Corrugata (fruticulin C, 7a-methoxy-19-acetoxy­ royleanone, 7a,19-diacetoxy-royleanone, 7-dehydroxy-conacytone, fruticulin A, demethyl-fruticulin A and 7a-O-methyl- conacytone) have been reported to exhibit anticancer activity with quinone reductase induction activity and histone deacetylase inhibition in cervical cancer cells (Giacomelli et al. 2013). Salvimulticanol and salvimulticaoic acid obtained from the aerial parts of S. multicaulis are abietane diterpenoids and it has been determined that they reduce the viability of leukemia cancer cells (Hegazy et al. 2018). Dammarane-type triterpenoid saponins Russelliinosides A and B from S. russellii have been found to inhibit proliferation of breast and lung cancer cells (Hafez Ghoran et al. 2021). Cryptotanshinone (isolated from S. miltiorhizza), which is an abietane diterpenoid, reduces the proliferation of gastric cancer cells, induces mitocontrial apoptosis by suppressing ROS-mediated MAPK and AKT signaling pathways, and arrests cells in G2 phase (Liu et al. 2017). In addition, p-JNK and p-p38 levels increased and p-ERK and p-STAT3 protein expression decreased after Cryptotanshinone administration in gastric cancer cells. Moreover, essential oils of S. aurea, S. judaica, and S. viscosa (caryophyllene oxide, carvacrol, main compounds for all of them) and S. triloba (1,8-cineole, B-pinene, B-caryophyllene, camphor, main compounds) induce apoptosis by increasing caspase 3 and 7 activity in prostate cancer cells (Russo et al. 2018, Atmaca and Bozkurt 2016) and reduce the level of angiogenic markers, such as ENA-78, bFGF, EGF, IL-8, IL-8, IFN-gamma, PIGF, TIMP-1 and TIMP-2, angiogenin, RANTES, PDGF, MCP-1, LEPTIN, and VEGF (Atmaca and Bozkurt 2016).

210

Ethnobotany: Ethnopharmacology to Bioactive Compounds

It has been determined that abiatene diterpenoids atropatane, saprorthoquinone and aethiopinone obtained from S. atropatana roots show cytotoxic activity on prostate cancer cells and also induce apoptosis with the increase of BAX, PARP and Caspase 3 levels, and cause the arresting in G1 of cell cycle (Shakeri et al. 2021). Together with these, diterpenoid 15-deoxyfuerstione, horminon, oxide, microstegiol, 14-deoxycoleon U obtained from S. lachnocalyx roots prevent proliferation of breast and leukemia cancer cells and also inhibit topoisomerase I activity (Mirzaei et al. 2020). It was determined that 24 sesterterpenes obtained from S. dominica exhibited anticancer activity as Tubulin Tyrosine Ligase inhibitör (Piaz et al. 2009). It has been determined that the diterpenoids taxodione, ferruginol and 6-hydroxysalvinolone obtained from S. chorassanica prevent the proliferation of leukemia cells, increase the levels of BAX, PARP and Caspase 3, and provide DNA fragmentation (TayaraniNajaran et al. 2013b). Diterpene manool from S. officinalis has been found to inhibit the proliferation of melanoma, breast, liver, cervical, and glaoblastoma cancers (Francielli et al. 2016). The neo-clerodane diterpenoid Tiliifolin E from S. tiliifoli has been found to inhibit the proliferation of lung, liver, leukemia, breast, and colon cancers (Fan et al. 2017). It has been proven that clerodane diterpene clerodermic acid obtained from Salvia nemorosa exhibits antiproliferative activity on lung cancer cells, suppresses HIF-1, arrests cells in sub-G0/G1 phase, induces apoptosis, and provides DNA fragmentation (Babak Bahadori et al. 2018). In the above table, anticancer effects of Salvia have been shown in species on cancer cells. However, almost all of the Salvia species mentioned have been only tested on cancer cells in cell culture. However, information on the effects of substances or extracts isolated from the above-mentioned Salvia species in living systems is very limited. Extracts or compounds of these plants should be tested in in vivo conditions for use in the treatment of cancer. It is necessary to determine tissues and other biochemical parameters, especially in order to determine their chronic and acute toxicities.

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Chapter 10

Molecular Basis of Ethnobotany and the Quest for Flavonoids An Analytical Journey

Cecilia B. Dobrecky,1,2 Marcelo L. Wagner,1,6,* Pablo A. Evelson3,4 and Silvia E. Lucangioli2,5

Introduction Plants have been inextricably intertwined with the history of humanity. In ancient times, they were used as an inexhaustible supply of treatment for several ailments. Moreover, plants have determined the very course of civilization, shaped the trajectory of human cultures, and changed the fates of entire nations (Balick and Cox 1996). Ever since, natural products’ unique chemistry has become an inspiration for their synthetic counterparts. Even now, many plant species remain to be studied and they could still provide answers to our most pressing questions. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacobotánica. Buenos Aires. Argentina. C1113AAD. Email: [email protected] 2 Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica. Cátedra de Tecnología Farmacéutica I. Buenos Aires. Argentina. C1113AAD. Email: [email protected] 3 Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Analítica y Fisicoquímica. Cátedra de Química General e Inorgánica. Buenos Aires. Argentina. C1113AAD. Email: [email protected] 4 Universidad de Buenos Aires. CONICET. Instituto de Bioquímica y Medicina Molecular (IBIMOL). Facultad de Farmacia y Bioquímica. Buenos Aires. Argentina. C1113AAD. 5 Universidad de Buenos Aires. CONICET. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica. Buenos Aires. Argentina. C1113AAD. 6 Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Museo de Farmacobotánica “Juan Aníbal Domínguez”. Buenos Aires. Argentina. C1113AAD. * Corresponding author: [email protected] 1

Molecular Basis of Ethnobotany and the Quest for Flavonoids 217

Ethnobotany is a specific field in which the inter-relations between people and plants are investigated and involve a multidisciplinary approach that reunites anthropology, archeology, botany, ecology, economics, medicine, religion, culture but also ethnopharmacology, pharmacognosy, and phytochemistry (Popović et al. 2016, Leonti et al. 2020). Ethnobotany should not be considered just as a stroll down memory lane, but also as a glimpse of the future. In this regard, efforts are constantly made to translate this “intuitive” knowledge into scientific language. Flavonoids, one of the largest and most widespread groups of “specialized metabolites” (formerly known as secondary metabolites), are ubiquitous in the plant kingdom and usually come into play when science turns its eyes to nature in search for answers. They exert a plethora of biological activities, such as antioxidant, antiinflammatory, antibacterial, antiviral, among others, which make them potential drug candidates. These outstanding features have propelled the development of different analytical strategies and instrumental methodologies to unravel their chemical structure in the context of complex matrices, such as plant extracts or intact organs. The aims are directed to simplify and standardize sample preparation, to effectively identify known analytes in an expedite manner while focusing on finding and characterizing new compounds. However, phytochemical screening and structure elucidation are just some pieces of the puzzle. Emerging and attractive analytical methodologies have been devised to search for flavonoid biological targets and their underlying mechanism of action. The ultimate goal is to find the link between structure and bioactivity. And so, the quest begins…

All Aboard A Brief Glossary on Analytical Jargon While the complex nature of herbal medicines offers an undeniable advantage in therapeutics, it poses a challenge from an analytical standpoint. In this sense, there is a growing vocabulary based on the strategic way to tackle the chemical characterization of a plant extract. With the surge of the “omics” revolution, new words have been coined and applied to different contexts. The term ‘‘metabolome” is generally referred to metabolites with molecular weight under 1,500 Da (Deborde et al. 2017). The term “metabolomics” was first described in the seminal work of Oliver Fiehn, as the “link between genotypes and phenotypes”. In its original conception, metabolomic approaches are devised to avoid the exclusion of any metabolite by means of a careful sample preparation and the use of powerful analytical tools. In this sense, it is essentially a “non-targeted” approach for small molecules. It is important to bear in mind that “metabolomics” involves not only instrumental analysis, but data analysis as well (Fiehn 2002). Metabolomics approaches are classified into two main categories: “metabolic foot/fingerprinting” or “profiling” (Deborde et al. 2017). The former is not initially intended for identifying a particular metabolite, but it is aimed to provide a rapid “snapshot” of the metabolic composition for discriminant analysis and/or sample comparison, and high throughput analytical techniques are needed for this purpose (Hubert et al. 2017). While fingerprinting is often applied to crude extracts,

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footprinting makes use of the extracellular fluid metabolome, such as growth medium of plant cell suspension or callus, root exudate medium. In any case, this strategy involves a quick and simple plant matrix extraction, followed by rapid NMR acquisition, processing, and handling of NMR features (Deborde et al. 2017). It is usually regarded as the kickoff to “metabolic profiling”, which consists of the identification and quantification of a selected group of metabolites. If a candidate metabolite or group of metabolites are chosen based on previous knowledge or by means of preliminary strategies, extraction and/or detection methods could be optimized for a “targeted analysis” (Hubert et al. 2017). In short, the difference between “targeted” and “non-targeted” depends, essentially, on the background information of the plant material to be studied. Metabolomics is a nonselective, universally applicable, comprehensive, analytical, and cheminformatics methodology that has been developed to study the total metabolic processes within organisms through the identification and quantification of metabolites. The aim is to get complete metabolite fingerprints, spot differences between metabolites, and devise hypotheses to explain such variations. A significant distinction between metabolomics and dereplication is that metabolomics research usually aims to identify all metabolites involved in metabolic processes, whereas dereplication is the process of distinguishing novel compounds from those that have already been studied (Zani and Carroll 2017, Wolfender et al. 2019). Putative or partial metabolite identification from metabolite profiles or fingerprints of complex extracts is referred to as “annotation” (Wolfender et al. 2019). Dereplication was initially conceived to describe “a process of quickly identifying known chemotypes” (Hubert et al. 2017) and since then, it has evolved in a complex manner. It has been used in different strategies from major compound identification and the expedition of activity-guided fractionation to the chemical profiling of collections of extracts (Wolfender et al. 2019). Secondary metabolites were regarded as low molecular weight compounds, generally non-essential for the basic metabolic processes of the plant. Interestingly, this initial definition has evolved, and secondary metabolites are now regarded as “specialized metabolites” with the following features: (i) some of them are involved in the plant reproduction and protection against UV and reactive oxygen species, such as polyphenols (ii) some of them are restricted to certain species, and thus called specialized. They are derived from primary metabolism and, only specialized metabolites with a molecular weight under 1,500 Da are included in the metabolome. They belong to different families, such as phenolics, alkaloids, terpenoids, polyketides, cyanogenic glycosides, glucosinolates, coumarins, tannins, benzoxazinoids. Most are derived from the isoprenoid, phenylpropanoid, alkaloid or fatty acid/polyketide pathways. Phenolics are the main family. The evolutionary process is in part the driving force for this rich diversity, through the acquisition of improved defense against microbial attack or insect/animal predation. Given that specialized metabolites are present in rather low concentrations in crude plant extracts, they pose a challenge for metabolomics (Deborde et al. 2017).

Molecular Basis of Ethnobotany and the Quest for Flavonoids 219

Analytical Methods Figure 1 summarizes MS and NMR strategies that will be addressed throughout this chapter.

Figure 1. MS and NMR strategies applied to plant analysis, either by direct analysis on tissues or by means of sample pretreatment.

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Stand-alone Configurations Mass Spectrometry and Nuclear Magnetic Resonance: The People’s Choice Undoubtedly, MS and NMR are positioned as the reference methodologies for plant metabolomics. In line with this, many developments have been directed at analyzing intact organs or tissues or facilitating sample preparation.

MS The mass accuracy and resolving power of high-resolution mass spectrometry (HRMS) has strikingly enhanced the detection and identification of compounds in complex matrices and boosted the relevance of stand-alone MS methods. In this sense, direct infusion mass spectrometry (DIMS) can provide a significant increment in the analytical throughput compared to LC-MS, but advanced data mining techniques are required for the rapid identification of numerous peaks resulting from direct injection of complex samples (Nagy et al. 2021). When it comes to mass analyzers, a general classification could be made, namely high and low resolution (or nominal mass) instruments and the basis for such distinction lies in the resolving power. In this sense, high resolution mass spectrometers generally provide resolving power greater than 10,000 (such as timeof-flight analyzers, TOF), while ultra-high-resolving power instruments are above 100,000 (as is the case with Fourier transform instruments, such as Orbitrap and ion cyclotron resonance). Low resolution instruments comprise triple quadrupole (QqQ) and ion trap (IT) configurations (De Villiers et al. 2016). There are three-dimensional quadrupole ion traps, so-called “dynamic” traps and “static” traps in ion cyclotron resonance mass spectrometers like Fourier Transform Ion Cyclotron Resonance (FT-ICR) or Orbitrap. It enables to perform analysis in a unique mode, such as extended MS/MS and allows remeasurement of selected ions, which is not possible using other types of analyzers. The ion traps are characterized by relatively high resolution (up to 200 kDa for Orbitrap). They are well suited for pulsed ionization method, such as matrix-assisted laser desorption/ ionization (MALDI), but they have limited dynamic range and they are a poor choice for quantitative analysis. Furthermore, both the FT-ICR and Orbitrap analyzers act as detectors for the ions, and there is no need to use an additional detector, which is necessary in other techniques (Wojtanowski and Mroczek 2020). To sum up, QqQ instruments show high sensitivity and selectivity, but they are generally restricted to structural elucidation in targeted metabolomics. Ion trap is useful for the identification of unknown compounds, but the co-extracted ions hamper the proper selection of diagnostic ions. As Q-TOF allows accurate mass measurements, it is a better alternative to QqQ or ion trap for identifying unknown compounds (López Fernández et al. 2020). Another aspect to be considered is related to the use of single or multistage systems, that is, the fragmentation of the parent ion to provide a distinctive pattern. This can be achieved in time (as in ion trap instruments) or in space, by combining multiple mass analyzers. In some cases, tandem mass spectrometry becomes

Molecular Basis of Ethnobotany and the Quest for Flavonoids 221

crucial for elucidation purposes. Hybrid instruments are available, such as QqQ, quadrupole-linear-ion trap, Q-TOF, ion-trap TOF, quadrupole and linear-ion trap Orbitrap, and quadrupole and linear-ion trap-ICR instruments (the latter is scarcely used for flavonoid analysis). Mass range is another parameter to bear in mind. This is particularly limited for quadrupole, ion trap and Orbitrap while TOF systems achieve the highest (Table 1) (adapted from De Villiers et al. 2016). The so-called “soft ionization” methods, such as electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) are by far the most popular and suitable techniques for flavonoid analysis. Particularly, ESI and its variant, heated electrospray (HESI) ionization source are the most favoured and widespread used interfaces in HRMS instruments coupled to LC techniques. The heated probe is reported to provide better desolvation and enhanced sensitivity. ESI-based ambient ionization techniques are suited for the analysis of both small molecules and macromolecules with moderate polarity, due to the formation of single and multiple charged molecular ions, whereas APCI techniques are directed to the analysis of less polar and small molecules, with the generation of single charged molecular ions (Álvarez-Rivera et al. 2019). Negative ionization has proven to be more sensitive than positive ionization for all ionization sources, with ESI being the most sensitive. Due to their acidic nature, flavonoids usually give higher ion abundances upon deprotonation in the negative ESI mode than via protonation in the positive mode (Fossen and Andersen 2005). This is related to an increase in chemical noise seen in positive ionization rather than ionization efficiency per se. On the other hand, positive ionization gives more structural information because of a more extensive fragmentation. For negative mode ESI ionization, optimal mobile phases include 0.1% formic acid in most cases, 10 mM ammonium acetate (pH 4) or 0.5% acetic acid, whereas for positive mode, 0.2–0.75% formic acid is preferred (De Villiers et al. 2016). The direct infusion of samples in the MS interface (DIMS) has primarily been used for fingerprinting in metabolomics studies rather than dereplication and comprehensive identification of compounds in an extract. It is generally used with atmospheric pressure ionization sources, such as ESI or APCI and samples can be either infused through a syringe pump, by means of nano-infusion devices or directly injected into the ultra-high performance liquid chromatography (UHPLC)–MS flow using short columns. Preferably, acquisition of MS spectra fingerprints is carried out Table 1. Mass analysers features. Resolving power (FWHM)2 × [×103]

Mass range m/z (upper limit)

Mass accuracy (ppm)

QqQ

-­

2000 – 3000

-­

IT1

-­

2048 – 6000

-­

TOF1

10 – 60

100,000

10 to 100 nM (Emwas et al. 2019). Several strategies have been devised to expand the boundary of NMR applications from instrumental improvements, such as high magnetic fields, cryoprobe technologies, pulse sequences for solvent suppression, dynamic nuclear polarization (DNP), and µCoils combined with photochemically induced dynamic nuclear polarization (photo-CIDNP) to data processing ones such as deconvolution approaches to better quality of the data, expanding the chemical coverage, and increasing the number of detectable metabolites (Selegato et al. 2019). According to the magnitude of the magnetic field strength, NMR can be divided into three categories: high field NMR (> 1.0 T), midfield NMR (between 0.5 T and 1.0 T), and low field (< 0.5 T) (Cao et al. 2021). Ultra-high-field NMR spectrometers are being developed that combine a novel hybrid design with advanced high-temperature superconductor in the inner sections and low-temperature superconductor in the outer sections of the magnet. These magnets offer better resolution with higher sensitivity and allow the detection of more metabolites in a single experiment (Emwas et al. 2019) with high nanomolar detection limits and it could bring NMR concentration sensitivity to within a factor of ~ 10 of what is routinely achievable by mass spectrometry (Wishart 2019). Cryogenic probes work at very low temperatures (e.g., 20 K) in order to reduce the noise produced by electron thermal motion and thus increase sensitivity. Microprobes can work with minute sample requirements, such as a few microliters (Salem et al. 2020). Another avenue for improving NMR sensitivity is spin hyperpolarization that makes use of the magnetic moment of unpaired electrons to polarize nuclear spins. Once the step is completed, the sample is transferred to the NMR to collect the enhanced (> 1000-fold) signal (Salem et al. 2020). Miniaturized coils are used to enhance the amplitude of the NMR signal and allow the analysis of mass-limited samples.

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Table 2 summarizes NMR main features, limitations, and avenues for their improvement (adapted from Emwas et al. 2019). NMR is widely employed for metabolite fingerprinting of crude natural extracts as it does not require prior chromatographic separation and it is also simple and reproducible. It allows the simultaneous detection of primary metabolites (organic acids, amino acids, and sugars) and also secondary metabolites (mainly alkaloids, terpenoids, and flavonoids) (Salem et al. 2020). Liquid-state NMR is a versatile tool to characterize soluble compounds present in polar, semi-polar, or apolar extracts of plant sample extracts or semi-purified fractions, but also in plant ‘‘biofluids” (Deborde et al. 2017). As for 1H NMR, a combination of the chemical shifts (d, the nature of the chemical environment in which a particular nucleus is located), spin–spin coupling (the number and nature of nearby nuclei, which provides connectivity information, described by coupling constants, J), and peak intensity (concentration of protons) Table 2. Summary of the most relevant advantages and limitations of NMR. Parameter

Comments

Reproducibility

High. One of NMR superlative features.

Sensitivity

Inherently low but improved with multiple scans, high magnetic fields, cryo and microprobes, and hyperpolarization methods.

Selectivity

Generally used for non-discriminatory analysis. Peak overlapping is a major challenge. Spectral overlap can be effectively reduced by increasing spectral dimensionality but with longer experimental duration (Le Guennec et al. 2014)

Sample detection

All metabolites at a sufficient concentration can be observed in one 1D 1H experiment.

Sample preparation

Relatively simple. Requires the addition of deuterated solvent and transfer to an NMR tube. A relatively simple procedure for sample pre-treatment is provided in Selegato et al. 2019. High-resolution magic-angle spinning allows direct sample analysis in tissues.

Sample recovery

Multiple analysis can be performed on the same sample for its non-destructive nature.

Quantitative analysis

Intrinsically quantitative because signal intensity is directly proportional to metabolite concentration and number of nuclei in the molecule. A 5 timedelay of the spin-lattice relaxation time (T1) of the slowest relaxing nuclei is essential for baseline stability and improve signal integration accuracy (Salem et al. 2020).

Analytical strategy

It can be used for targeted and untargeted analysis, though less used for the former.

Hyphenation

LC-NMR hyphenation is less straightforward than LC-MS due to the low intrinsic NMR sensitivity (Wolfender et al. 2015). Different strategies have been applied to overcome this limitation: continuous flow, direct stop-flow and loop/cartridge storage (Gebretsadik et al. 2021)

Mixture analysis

Simplification of the abundant 1H NMR spectra through diffusion or relaxation filters or by using Diffusion ordered spectroscopy (DOSY) also called “NMR chromatography”. It can be performed in 1D, 2D, or 3D modes (Salem et al. 2020).

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provides important structural information for the identification of any compound of interest, and this can be achieved in a short time (5–10 minutes for 64–128 scans). For flavonoids, valuable information can be obtained on the relative number of hydrogen atoms, which helps in identifying the aglycone and acyl groups, the number of monosaccharides, and the anomeric configuration of monosaccharides (Pinheiro and Justino 2012, Wolfender et al. 2015). Given that sometimes 1H experiments are insufficient, 1D 13C NMR offers an attractive alternative for its broad 13C chemical-shift dispersion (~ 200 vs ~ 10 ppm for 1H) along with relatively narrow spectral lines, direct detection of carbon multiplicity and scaffold outline, including quaternary carbons. Moreover, 13C presence in all metabolites (1.1% natural abundance) provides spectral diversity to identify, distinguish, and structurally characterize biomarkers (Dey et al. 2020, Ismail et al. 2021). It is particularly useful for carbohydrates, major organic acids, and polymers, but can also be used in plant metabolomics to discriminate botanical and geographical origins (Deborde et al. 2017). 13C application has been hampered by a ~ 5880-fold sensitivity disadvantage (due to its natural abundance and gyromagnetic ratio) over 1H. Sensitive improvements by means of 13C enriched tracers yields ~ 100 times better sensitivity. However, the focus is usually directed to specific metabolic pathways and the resulting spectra can be complicated by undesired 13C-13C couplings (JCC) (Dey et al. 2020). Hyperpolarization methods provide nonequilibrium 13C polarization with a > 10000 sensitivity increase for natural abundance carbon sites. However, there are only limited applications to metabolomics or flavonoids. For the identification of signals of unknown (new or less common) compounds, it becomes necessary to perform 2D NMR experiments, in which much information regarding the atom connectivities of the metabolites within a complex mixture can also be obtained and in some cases, complete de novo metabolite identifications can be achieved. 2D NMR spectra are mainly produced as contour maps and can be carried out as homonuclear and heteronuclear experiments. The first one, such as 1 H-1H COSY (correlation spectroscopy) allows determination of the protons that are spin-spin coupled and the spectrum shows couplings between neighbouring protons revealed as crosspeaks and it is particularly useful for assigning all sugar protons; 1H-1H TOCSY (total correlation spectroscopy) experiments offer more information than COSY as they identify protons belonging to the same spin system. This experiment is particularly useful for assignments of overlapped flavonoid sugar protons in the 1D 1H spectrum, since each sugar ring contains a discrete spin system separated by oxygen. 1H-1H nuclear Overhäuser enhancement spectroscopy (1H-1H NOESY), in which protons that are close to each other in space may be observed as crosspeaks, and rotating frame Overhäuser effect spectroscopy (1H-1H ROESY) is useful for the determination of signals arising from protons that are close in space, but not necessarily connected by chemical bonds. Regarding 1H-13C heteronuclear experiments, the heteronuclear single quantum coherence spectroscopy (HSQC) is a 2D experiment that correlates 13C nuclei with 1H nuclei within a molecule by means of one-bond coupling between them (Fossen and Andersen 2005) and has the advantage of high ppm ranges in the carbon dimension (Jiang et al. 2020). The (heteronuclear multiple bond correlation) HMBC correlates proton nuclei with

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carbon nuclei that are separated by more than one bond (Fossen and Andersen 2006), but it is not so used for metabolites studies (Jiang et al. 2020). TOCSY and COSY are the most used homonuclear methods for metabolomics studies. It is noteworthy that homonuclear 2D 1H-1H NMR is more sensitive than heteronuclear 1H-13C NMR experiments, with TOCSY being one of the most favoured methods in metabolomics. 2D NMR application to metabolomics is hampered by two factors. The acquisition time is significantly extended compared to 1D NMR, due to the need to replicate various 1D sub-experiments to get 2D spectra with adequate resolution, and this may render this method impractical when a large group of samples is to be tested. Another consideration derived from experiment duration is related to spectrometer instabilities, which impair quantitative measurements precision (Martineau and Giraudeau 2019). Consequently, high-throughput studies make limited use of 2D NMR, and they usually employ short evolution times in the indirect dimension, which results in overlap and loss of information (Le Guennec et al. 2014). The second restriction is related to data processing, which is far more complex for 2D NMR (Jiang et al. 2020, Martineau and Giraudeu 2019). There are some alternatives that have been proposed to reduce experiment duration that imply a certain loss of sensitivity and resolution whose consequences are well described and understood. To this purpose, nonuniform sampling (NUS) and ultrafast NMR (UF-NMR) have been applied to metabolomics. The former acquires only a fraction of the indirect data points and rebuilds the spectra by non-Fourier methods (Schlippenbach et al. 2018). UF-NMR can record any 2D experiment in a fraction of a second. It employs specific pulse programs and processing routines, but can provide high repeatability compared to conventional 2D NMR, for being less susceptible to hardware instabilities. An example of such an application refers to ultrafast COSY spectra obtained during a chromatographic run performed on a mixture of three selected flavonoids: naringin, epicatechin, and naringenin (Queiroz Júnior et al. 2012, Giraudeau and Frydman 2014). Diffusion ordered spectroscopy (DOSY) is intended for the analysis of intact complex mixtures in solution and relies on the difference in the transitional diffusion coefficient between molecules of different molecular sizes. Modern diffusion NMR experiments are usually performed using variants of pulse gradient spin or stimulated echo (PGSE) experiments and a pseudo two-dimensional spectrum is produced, in which individual NMR signals are correlated with the calculated diffusion coefficients. The diffusion coefficient depends on molecular properties, such as size, molecular weight, and shape, but also solvent viscosity and temperature. When signals overlap, more advanced processing methods and at least a 30% difference in diffusion coefficient are needed. In some cases, however, multivariate analysis allows a few percents to work. When diffusion coefficients are very similar, a matrix manipulation where diffusion of these analytes could be performed to alter their diffusion behaviour. This is called matrix-assisted DOSY (MAD) and is somewhat similar to chromatography, since it relies on differential interaction of binding of the analytes with the matrix. MAD is usually called chromatographic DOSY, especially when a chromatography phase is used as matrix (Gramosa et al. 2016, Day 2020). A distinction should be made between MAD (or chromatographic NMR) and NMR

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chromatography, the latter referring to an on-line technique in which the outlet from a chromatography separation system is connected to an NMR spectrometer. The choice of additive used in MAD is restricted by some requirements that need to be fulfilled. There must be some interaction between the analyte(s) and the matrix to alter a modulation of the observed diffusion coefficient that needs to be carefully balanced, so that the exchange between free and interacting state is rapid both on the NMR chemical shift and diffusion labelling timescale. Also, a limited disruption to the NMR spectrum should be caused (Day 2020). MAD is devised to exploit differential chemical interactions with a slow diffusion matrix to resolve flavonoid mixtures in mixed solvents. Analyte interaction with the matrix modifies the average diffusion coefficients as mixture components bind to the matrix in different fashions; even spectral overlap can be resolved by chemical shift changes. Additives broadly include chromatographic stationary phases, such as silica supports, surfactants, and polymers. Surfactants forming micelles are probably the most used in MAD. Ionic surfactants such as sodium dodecyl sulphate (SDS) and non-ionic like Brij (78, 98, 700) or polyoxyethylene 20 and polymers such as polyethylene glycol and poly vinyl pyrrolidone have been employed for resolving complex flavonoid mixtures. (Gramosa et al. 2016, Day 2020). Some applications of MAD are provided by Cassani et al. 2012, who employed 80 mM SDS in 50% v/v DMSO-d6-D2O to effectively resolved a mixture of flavone, fisetin, catechin, and quercetin. Álvarez et al. (2016) also used SDS normal micelles in binary aqueous solution (180 mM SDS DMSO­ d6-D2O) to resolve two flavonoid glycosides, kaempferol-O-α-L-rhamnopyranoside and quercetin-3-O-α-L-arabinofuranoside. They combined MAD and PGSE. Vieira et al. 2014 demonstrated that Brij 98 showed improved selectivity over SDS. For a flavonoid mixture of quercetin, fisetin, and catechin, 10 mM of Brij 98 in 50% DMSO-d6 50% D2O (v/v) improved earlier results on SDS. There is yet another approach called 3D diffusion experiments. These can be performed by concatenating a conventional 2D pulse sequence with a diffusionencoding sequence, such as COSY-DOSY in which a COSY sequence is followed by a diffusion-encoding step. An alternative strategy for designing 3D diffusion experiments is to incorporate diffusion encoding into the conventional 2D experiment (an approach known as iDOSY). Either way, 3D DOSY experiments have not been much employed because of the lack of proper processing tools. Dal Poggetto et al. have explored the potential of 3D diffusion experiments through a free and open-source package called MAGNATE. The authors also establish a valuable nomenclature distinction as they refer to the general term “diffusion NMR” rather than DOSY or PGSE, which are specific subsets of NMR methods for the study of diffusion (Dal Poggetto et al. 2018). High-resolution magic-angle spinning (HR-MAS NMR) is a useful tool that allows direct chemical insight of the metabolites in a heterogenous sample, such as plant tissue. It is a combination of solid (magic angle spinning) and solution-state NMR techniques. The possibility of identifying compounds in complex samples is important for quality control purposes of medicinal plants. Flores et al. worked with plant tissues (Passiflora alata Curtis, Eugenia uniflora L, Malpighia emarginata SD), different solvents and metabolites (such as flavonoid glycosides) and pointed

Molecular Basis of Ethnobotany and the Quest for Flavonoids 229

out the lack of standard procedures from sample preparation to NMR spectra acquisition and focused on the main parameters that are to be considered to achieve high reproducibility and reliable data (Flores et al. 2019).

Hyphenation: It Takes Two (or more) to Tango “Hyphenation” is a term coined initially by Hirschfeld (Hirschfeld 1980) that has become a catchword in separation science and is based on the combination of chromatography (as a separation technique) and spectroscopy (as a detection technique). These techniques, due to the simultaneous benefits from both approaches, led to higher selectivity for qualitative and quantitative analysis of unknown compounds in complex natural extracts or fractions (Patel et al. 2010, Azqhandi et al. 2020). When multiple hyphenations take place, a second approach called hypernation is preferred. This means that one is now “one higher than”, or hyper, hyphenation (Wilson and Brinkman 2003). Although there are many chromatographic techniques involved in hyphenation, special emphasis will be made on HPLC coupled to MS or NMR, as it is the most widely employed. The coupling of UHPLC with diode array detection and MS have become the tool­ of-the-trade for profiling flavonoids in complex matrices. Given that most UHPLC separations are performed on columns of 2.1 mm internal diameter (i.d.) or lower and that optimal flow rates vary between 0.2–0.5 mL/min, this is clearly beneficial from the perspective of MS hyphenation. The choice of instrument is almost exclusively dependent on the strategy for plant extract analysis. In general, high-resolution accurate-mass multistage mass spectrometry (UHPLC-DAD-HRAM/MSn) is extensively used for flavonoid analysis. The strategy for plant extract analysis is of paramount importance in selecting the instrument to be used. If a targeted analysis is to be executed, that is, if there is a previous knowledge on the nature of the analyte under study, then QqQ in multiple reaction mode (MRM) or IT are suitable. For an untargeted strategy, resolving power becomes critical and in this sense, the hybrid Q-TOF-MS instruments have been largely adopted as powerful tools in the analysis of complex plant extracts, due to their capability of providing accurate mass data, structural information from HR-MS/MS fragmentation, and it still provides the best compromise between high efficiency and fast separation. Orbitrap systems are being increasingly used for high throughput screening analysis of secondary metabolites. Hybrid Q-Orbitrap-MS instruments combine high mass resolving power, provided by orbitrap mass analyser, with the selectivity of the quadrupole. Thus, multiple precursor ions can be fragmented in a high-energy collision cell, and the product ions can be accurately detected with very low mass error (< 3 ppm), in a wide dynamic range of concentrations (Álvarez-Rivera et al. 2019). As previously mentioned, IM can separate ions in the gas phase based on their different mobility in an inert buffer gas. The ions velocity in an electrical field is dependent on size, structure, and charge. Therefore, even isobaric (i.e., structures with the same nominal m/z ratio) or isomeric compounds can be resolved. This is particularly useful for plant extracts due to their intrinsic convoluted nature, that is, the close coelution of isomeric species. It can be used alone or in combination

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with LC and coupled to a mass analyser with high acquisition rates like TOF or Orbitrap (Ganzera and Sturm 2018). The timescale of UHPLC (in seconds), IMS (in milliseconds) and TOF-MS (in microseconds) are compatible with the requirements of high throughput analysis of complex mixtures (McCullagh et al. 2019). A list of the most recent reports on the use of LC-MS is listed in Table 3. The main technological advances of LC-NMR involve the use of super conducting magnets, solvent suppression programs, strong field superconducting magnets, microprobes, and cryoprobes technologies that have improved the sensitivity and resolution for NMR metabolomics (Gebretsadik et al. 2021). Hyphenation of LC to NMR can be performed mainly in three modes: continuous flow (measurement under dynamic conditions), direct stop-flow, and loop/cartridge storage (measurement under static conditions). Online-flow mode is perhaps the easiest set up as it does not require synchronization between the separation and detection system. The outlet of the LC detector is directly connected to the NMR probe and peaks spectra are acquired while eluting. This strategy is primarily used for the dereplication of complex mixtures. Strong signals resulting from the LC solvents are usually suppressed through dedicated pulse sequences Despite the instrumental simplicity, it has poor sensitivity because the eluted peak is only limited exposed in the detection cell. Stop-flow mode also implies the connection between the LC detector and the NMR probe but once the eluted peaks reach the NMR cell, the operating conditions (pump flow) are stopped until the spectra are acquired. Then, working conditions are restarted until the next peak reaches the NMR detection again. In a variation called time-slice mode, the flow is interrupted at regular and preset intervals, and this is particularly useful for analytes with similar retention times. In this mode, improved line shape quality and efficient solvent suppression signals provide additional structural information for a given LC peak, and 2D spectra can be recorded for the most abundant compounds. This method enables the dereplication of the minor and major components of a complex extract. In the loop/ cartridge storage mode, a solid-phase extraction system that works as an enrichment device is placed between the LC detectors and the NMR flow probe (Gebretsadik et al. 2021). The analyte is captured onto a solid sorbent and the HPLC mobile phase is removed. Then, the SPE cartridge is dried under a nitrogen flow, and the retained compound is eluted with an adequate mixture and volume of deuterated solvents for direct transfer to the NMR flow cell. This step becomes critical and careful parameter optimization needs to be performed. The advantages of this array become evident as it is possible to perform multiple trappings of the same peak by repeated injections of the sample while avoiding column overloading and maintaining optimal LC separation. As deuterated solvents are used for the SPE cartridge alone, the use of solvent suppression signal sequences is limited. The increased sensitivity achieved in this way is suitable for de novo compound identification and complex mixtures (Salem et al. 2020). The ability to accumulate multiple analytes using storage loops (peak parking) and SPE cartridges (peek trapping) has improved the sensitivity to the nanogram level. For a thorough list of NMR applications, the reader is referred to Gebretsadik et al. 2021.

Table 3. Mass spectrometry strategies applied to flavonoids. Flavonoids

Ionization source

Detector

Stationary phase

Mobile phase

References

Passiflora sp.

6‐C and 8‐C‐glycosylflavone isomer orientin/isoorientin and vitexin/isovitexin pairs

ESI –/+

IM-collision induced dissociation

Acquity UPLC BEH 1.7 µm (2.1 × 50 mm)

0.1% aq. Formic acid and 0.1% acetonitrile

McCullagh et al. 2019

Citrus fruits

Polymethoxylated flavones

ESI –/+

QqQ

HSS C18 1.8 µm (2.1 × 100 mm)

0.1% aq. Formic acid and methanol

Zhao et al. 2019

Butea menosperma

Apigenin, apigenin derivatives, genistin,

ESI –

Q-TOF

Hypersil Gold 3 µm (100 × 2.1)

0.1% aq. Formic acid and ammonium formiate and acetonitrile

Farooq et al. 2020

Artocarpus heterophyllus

Prenylated flavonoids

ESI –/+

Q-TOF Linear Trap Quadrupole-Orbitrap

Acquity UPLC BEH 1.7 µm (2.1 × 50 mm)

30% water and 70% methanol. Gradient

Ye et al. 2019

Lotus plumule

Apigenin, luteolin derivatives

ESI +

Q-Orbitrap

Hypersil Gold 1.9 µm (100 × 2.1)

0.1% aq. Formic acid and acetonitrile

Liu et al. 2019

Passiflora sp.

6‐C and 8‐C‐glycosylflavone isomer orientin/isoorientin and vitexin/isovitexin pairs

ESI –/+

IM-collision induced dissociation

Acquity UPLC BEH 1.7 µm (2.1 × 50 mm)

0.1% aq. Formic acid and 0.1% acetonitrile

McCullagh et al. 2019

Citrus fruits

Polymethoxylated flavones

ESI –/+

QqQ

HSS C18 1.8 µm (2.1 × 100 mm)

0.1% aq. Formic acid and methanol

Zhao et al. 2019

Butea menosperma

Apigenin, apigenin derivatives, genistin,

ESI –

Q-TOF

Hypersil Gold 3 µm (100 × 2.1)

0.1% aq. Formic acid and ammonium formiate and acetonitrile

Farooq et al. 2020

Artocarpus heterophyllus

Prenylated flavonoids

ESI –/+

Q-TOF Linear Trap Quadrupole-Orbitrap

Acquity UPLC BEH 1.7 µm (2.1 × 50 mm)

30% water and 70% methanol. Gradient

Ye et al. 2019

Lotus plumule

Apigenin, luteolin derivatives

ESI +

Q-Orbitrap

Hypersil Gold 1.9 µm (100 × 2.1)

0.1% aq. Formic acid and acetonitrile

Liu et al. 2019

Molecular Basis of Ethnobotany and the Quest for Flavonoids 231

Sample

232

Ethnobotany: Ethnopharmacology to Bioactive Compounds

Figures 2, 3, and 4 depict examples of hypernation in which more than two equipment arrays are used to study complex samples (adapted from Gathungu et al. 2020). Figure 2 shows the online coupling of LC-MS-NMR in series, where the LC eluent passes through the NMR and then to the MS; in parallel, the LC eluent splits between the MS and the NMR, where a higher flow is needed due to its lower sensitivity. Figure 3 depicts the LC-MS-SPE-NMR instrumentation set­ up. Figure 4 shows a typical LC-MS offline NMR array. For in-depth reading and further examples, the reader is referred to Gathungu et al. 2020. A recent example is provided by Bhatia et al. 2019, who have developed an integrated UHPLC-QTOF­ MS/MS-SPE-NMR system for higher-throughput metabolite identification. This array is less labour intensive and more cost-effective than conventional approaches and was applied to the purification and identification of flavonoid glycosides for which no commercial standards are available.

Data Processing: The Key to the Kingdom “Data does not equal information; information does not equal knowledge; and, most importantly of all, knowledge does not equal wisdom. We have oceans of data, rivers of information, small puddles of knowledge, and the odd drop of wisdom” (Henry Nix). Although it is beyond the scope of the present chapter to describe in detail all the data processing developments and findings, it is mandatory to acknowledge its relevance in the challenging analysis of complex mixtures, such as plant extracts. Some very interesting insights to this respect were highlighted at the 304th Royal Society of Chemistry Faraday Discussion on “Challenges in analysis of complex natural mixtures” in May 2019 and brilliantly summarized by Dr. Royston Goodacre.

Figure 2. Online coupling of LC-MS-SPE-NMR in series and parallel.

Molecular Basis of Ethnobotany and the Quest for Flavonoids 233

Figure 3. LC-MS-SPE-NMR instrumentation set-up.

Figure 4. LC-MS/Offline set-up.

They concluded that systems chemical analysis for understanding complex systems is a multidisciplinary subject which is only really achieved by combining many different methods, as they supply complementary information needed to identify an unknown substance. Integration of multiple analytical approaches with appropriate informatics (statistics, chemometrics, or some machine learning approach) is needed

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for molecular identification. The appropriate integration of data processing tools will allow to shed some light to the “dark matter”. This term refers to instances where there is data but no reference structure, but also to small and large molecules that are not even measured by the analytical method and so go undetected.

From Here on Out We have come a long way since the doctrine of signatures and the belief that body ailments could be treated based on their similarities to herbal parts. However, there is still a need to provide scientific support to herbal medicines’ traditional use. Despite the great advancements in the technological field applied to analytical methodologies, the comprehensive understanding of the unique chemistry of plant extracts remains a challenge. Flavonoids are an inexhaustible source of information in this regard. It takes a multidisciplinary approach to gather all the pieces of the puzzle and the right data processing tools to unravel the mystery. Schrödinger’s cat paradox could also be applied to this case. If we fail to acknowledge the need to understand plant analysis as a holistic matter, our limited knowledge only allows us to grasp parts of a whole and as a result, we draw incomplete or even wrong conclusions. Hence, based on the minute information we have, we would be right; if seen as a whole, we would be wrong. Both states are possible until we open the box, that is, until we put the pieces together. “Raw data is nothing but a poor relative of information and information is itself a giant leap away from knowledge” (after Goodacre 2019). As pointed out by Wolfender et al. 2019, there is an unparalleled need “to think like a large community rather than as individual islands of knowledge”, so that data is findable, accessible, interoperable, and reproducible to illuminate the “dark matter” in the field of plant extract chemistry. To be continued…

Acknowledgements The authors would like to thank the University of Buenos Aires and CONICET for their financial support.

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Index

A

H

Alepidea 167–172, 174, 175, 180, 181, 186, 187

Analytical methods 219, 234

Animal feed 1–4, 6, 7, 10, 11, 16–18, 23, 24, 28

Anticancer activity 193, 194, 207–210

Anti-diabetic 82, 83, 88, 91, 92, 94

Antiproliferative activity 194, 196–198, 200–202,

204–207, 210

Apiaceae 167

Huperzia 159, 161–164

Hyphenation 225, 229, 230

B Bioactive chemical compounds 66

Bioactivity 159, 161, 163, 164

Biological activities 106, 112, 115, 119, 123, 126

C Cancer 191–198, 200, 202–204, 206, 208–210

Caryophyllales 101, 102

Chromatography 221, 225, 227–229

Clinical trial 81–86, 88–92, 96

Coffee 65–76

Covid-19 44

D Data analysis 217

Diabetes 81–84, 86–90, 94

E Ethnobotanical uses 44

Ethnobotany 168

Ethnomedicine 82

F Flavonoids 216, 217, 221–223, 225–229, 231,

232, 234

Folk medicine 90

I

Ibogaine 134, 143, 144, 146–148, 150, 151

L Lamiaceae 191

M Major compounds 105, 106, 111, 112, 118

Mass spectrometry 220, 223, 224, 229, 231

Medicinal plant 1–4, 28, 81–83, 91, 92, 94, 96,

191

N Nuclear magnetic resonance 220

P Petiveriaceae 101–103, 126

Phenolic 192, 193, 208

Phytolaccaceae 101–103, 116, 121, 126

Popular use 104, 110, 114, 118, 123, 125

R Resveratrol 44–46, 48, 50–55, 57

S Salvia 191–210

Saraguros 160, 161

Secondary metabolites 159, 162

Signal pathway 193, 197, 208, 209

Southern Africa 167, 174

Structure elucidation 217, 224

240

Ethnobotany: Ethnopharmacology to Bioactive Compounds

T

U

Tabernaemontana 133–151

Tabernanthe iboga 133–135, 139–144, 146–148,

150

Terpen 209

Therapeutic/Nutritional properties 1, 23

Traditional medicine 167, 170, 171, 174

Treatment 66, 67, 70, 72, 74, 76, 191–193, 210

Umbelliferae 167

V

Voacangine 134, 143–148, 151