Bioactive Natural products in Drug Discovery 9811513937, 9789811513930

Table of contents :
Preface
Contents
About the Editors
Part I: Plants Natural Products: Fountainheads for Drug Discovery and Development
1: The Artemisia Genus: Panacea to Several Maladies
1.1 Introduction
1.2 Phytochemistry
1.3 Conservation of Artemisia Species
1.4 Conclusions
References
2: Bacopa monnieri: The Neuroprotective Elixir from the East-Phytochemistry, Pharmacology, and Biotechnological Improvement
2.1 Introduction
2.2 Methodology
2.3 Bioactivity Study
2.3.1 Biological Activities of Plant Extract(s)
2.3.1.1 Pro-cognitive Activity
2.3.1.2 Anti-neurodegenerative Activity
2.3.1.3 Antidepressant and Anti-stress Activity
2.3.1.4 Neuroprotective Activity
2.3.1.5 Cardioprotection
2.3.1.6 Gastrointestinal and Hepatoprotective Activity
2.3.1.7 Antiemetic Activity
2.3.1.8 Anti-epileptic Activity
2.3.1.9 Antioxidant Activity
2.3.1.10 Miscellaneous Activity
2.3.2 Pharmacological Activity of the Active Compounds
2.3.2.1 Bacoside A
Anti-Alzheimer´s Activity
Anti-apoptotic Activity
Anti-epileptic Activity
Antidepressant Activity
Anti-dopaminergic Activity
Anti-inflammatory Activity
Antioxidant Activity
Hepatoprotection
Neuroprotection
Protease Inhibition Activity
Renoprotective Activity
Wound-Healing Activity
2.3.2.2 Bacopaside I
2.3.2.3 Betulinic Acid
2.3.3 Pharmacological Activity of the Polyherbal Formulation(S)
2.3.3.1 Cognition
2.3.3.2 Hepatic Encephalopathy
2.4 Biotechnological Advancement
2.5 Toxicity Study
2.6 Drug Designing
2.7 Structure-Activity Relationship
2.8 Summary
2.9 Conclusion
References
3: Current Knowledge of Cinnamomum Species: A Review on the Bioactive Components, Pharmacological Properties, Analytical and B...
3.1 Introduction
3.2 Botanical Description
3.3 Distribution
3.4 Traditional Use and Polyherbal Formulation of Cinnamon
3.5 Pharmacological Property of Cinnamomum Species
3.5.1 Anti-inflammatory Activity
3.5.2 Antibacterial Activity
3.5.3 Antifungal Activity
3.5.4 Antiviral Activity
3.5.5 Antioxidant Activity
3.5.6 Anticancer Activity
3.5.7 Gastroprotective Activity
3.5.8 Hypoglycemic/Anti-lipidemic Activity
3.5.9 Immunomodulatory Properties
3.5.10 Neuroprotective Activity
3.5.11 Cardioprotective Activity
3.6 Phytochemistry of Cinnamon
3.7 Clinical Study Based on Cinnamon
3.8 Extraction and Isolation of Bioactive Phytochemicals
3.9 Biotechnological Techniques for Large-Scale Multiplication of Cinnamomum Species
3.10 Molecular Markers for Genetic Diversity Assessment of Cinnamomum Species
3.11 Discussion and Conclusion
References
4: Swertia spp.: A Potential Source of High-Value Bioactive Components, Pharmacology, and Analytical Techniques
4.1 Introduction
4.2 Botanical Description
4.2.1 Distribution of Swertia
4.2.2 Morphology of Swertia
4.3 Phytochemistry
4.3.1 Xanthones
4.3.2 Iridoid and Seco-Iridoid Glycosides
4.3.3 Terpenoids
4.3.4 Flavonoids
4.4 Analytical Techniques for Extraction and Quantification of Secondary Metabolites
4.4.1 Extraction Methods
4.4.2 Analytical Techniques
4.5 Pharmacology
4.5.1 Ethnobotanical Uses
4.5.2 Pharmacologically Significant Compounds
4.5.3 Biological Activities
4.5.3.1 Antidiabetic Activities
4.5.3.2 Antioxidant Activity
4.5.3.3 Hepatoprotective Activities
4.5.3.4 Antibacterial Activity
4.5.3.5 Anti-cancerous Activities
4.5.3.6 Neuroprotective Activity
4.5.3.7 Anti-HIV Activity
4.5.3.8 Antimalarial Activities
4.6 Conclusion
References
5: The Genus Calophyllum: Review of Ethnomedicinal Uses, Phytochemistry and Pharmacology
5.1 Introduction
5.2 Morphology and Taxonomy
5.3 Ethnomedicinal Uses
5.4 Phytochemistry
5.4.1 Coumarins
5.4.2 Xanthones
5.4.3 Chromanones
5.4.4 Triterpenes and Steroid
5.4.5 Glycosides
5.4.6 Miscellaneous
5.5 Bioactivities of Genus Calophyllum
5.5.1 Antiviral Activity
5.5.2 Antimicrobial Activity
5.5.3 Inhibition of the Multidrug Transporter P-glycoprotein
5.5.4 Anticancer Activity
5.5.5 Antimalarial Activity
5.5.6 Anti-parasite Activity
5.5.7 Sulphotransferase Inhibitor
5.5.8 Anti-dyslipidaemic Activity
5.5.9 Antioxidant Activity and Anti-inflammatory Activity
5.5.10 Hypotensive Activity
5.5.11 α-Glucosidase Activity
5.5.12 Other Activities
5.6 Conclusions
References
Part II: Plant Derived Natural Products as Leads for Drug Discovery
6: Plant-Derived Quinones as a Source of Antibacterial and Anticancer Agents
6.1 Introduction
6.2 Quinone Mode of Action
6.3 Bioactive Quinones from Natural Resources
6.3.1 Thymoquinone
6.3.2 Plumbagin
6.3.3 Shikonin
6.3.4 Embelin
6.3.5 Emodin
6.3.6 β-Lapachone
6.3.7 Juglone
6.3.8 Salvicine
6.4 Summary and Conclusion
References
7: Drugging Protein-Protein Interaction Interface with Natural Products: A Computational Approach
7.1 Natural Products as Drug Leads
7.2 Protein-Protein Interactions
7.3 Methods in Computational Drug Discovery
7.4 Methods in SBDD
7.4.1 Protein Structure Modelling
7.4.1.1 Homology or Comparative Modelling
7.4.2 Molecular Docking
7.4.2.1 Protein-Protein Docking
7.4.2.2 Protein-Ligand Docking
7.4.3 Molecular Dynamic (MD) Simulations
7.5 Conclusion
References
8: CQDs Derived from Natural Sources: Excellent Bioimaging Agents
8.1 Introduction
8.2 Methods to Prepare CQDs
8.2.1 Chemical Ablation
8.2.2 Microwave Irradiation
8.2.3 Hydrothermal Treatment
8.2.4 Laser Ablation
8.2.5 Electrochemical Carbonization
8.3 Various Natural Precursors for CQD Synthesis
8.4 Functional Groups Present in CQDs
8.5 Shape and Size Determination of CQDs
8.6 UV-Visible Absorption Spectra of CQDs
8.7 Photoluminescence Properties of CQDs
8.8 Excellent Imaging Agents for Biomedical Applications
8.9 Conclusions
References
Part III: Microbial Natural Products: A Quintessential Source for Drug Discovery and Development
9: Microbial Natural Products: Recent Insights into Novel Applications
9.1 Introduction
9.2 Applications
9.2.1 Bioremediation
9.2.2 Biosurfactants
9.2.3 Anti-biofilm Compounds
9.2.4 Drugs
9.2.4.1 Antitumour Drugs
9.2.4.2 Antimicrobial Compounds
9.2.5 Pigments
9.2.6 Probiotics and Nutraceuticals
9.2.7 High-Value Molecules
9.3 Novel Strategies for the Characterisation of Natural Microbial Products
9.4 Conclusions and Future Perspectives
References
10: Bioactive Peptides and Carbohydrates from Natural Products: A Source of Functional Foods and Nutraceuticals
10.1 Introduction
10.2 Plant-Based Bioactive Components as a Source of Nutraceuticals
10.2.1 Bioactive Peptides
10.2.1.1 Maize as a Source of Bioactive Peptide
10.2.1.2 Amaranthus as a Source of Bioactive Peptide
10.2.1.3 Chia as a Source of Bioactive Peptide
10.3 Algae-Based Bioactive Components as a Source of Nutraceuticals
10.3.1 Proteins
10.3.2 Polysaccharides
10.4 Fungal Polysaccharide as a Source of Nutraceuticals
10.4.1 Types and Sources of Bioactive Fungal Polysaccharides
10.5 Animal Protein as a Source of Nutraceutical
10.5.1 Bovine Milk
10.5.2 Antihypertensive Effects
10.5.3 Antithrombosis
10.5.4 Antioxidant
10.5.5 Hypolipidaemic Effects
10.5.6 Immunomodulating Effects
10.5.7 Antidiabetic Effect
10.6 Challenges Associated with the Production of Bioactive Components
10.7 A Novel Mechanism to Increase the Functional Properties of Nutraceuticals
10.8 Conclusion
References
11: Metabolites of Fluorescent Pseudomonads and Their Antimicrobial and Anticancer Potentials
11.1 Introduction
11.2 Fluorescent Pseudomonad Metabolites
11.2.1 Polyketides
11.2.1.1 Pyoluteorin
11.2.1.2 Phloroglucinols
11.2.1.3 Mupirocin
11.2.1.4 Rhizoxin
11.2.2 Peptides
11.2.3 Pyrrole-Type Compounds
11.2.4 Volatiles
11.2.5 Phenazines
11.3 Antimicrobial Activity of Fluorescent Pseudomonad Metabolites
11.4 Anticancer Activity of Fluorescent Pseudomonad Metabolites
11.5 Cancer and Apoptosis
11.5.1 Regulatory Mechanism of Cancer
11.6 Apoptotic Potential of Fluorescent Pseudomonad Metabolites
11.6.1 Phenazine-1-carboxylic Acid (PCA)
11.6.2 5-Methyl Phenazine-1-Carboxylic Acid Betaine (MPCAB)
11.6.3 Phenazine-1-carboxamide (PCN)
11.6.4 2,4-Diacetylphloroglucinol (DAPG)
11.7 Conclusion
References
12: Ganoderma: A Propitious Medicinal Poroid Mushroom
12.1 Introduction
12.2 Herbal History of Ganoderma
12.3 Bioactive Constituents of Ganoderma
12.3.1 Polysaccharides
12.3.2 Triterpenoids
12.3.3 Proteins
12.3.4 Other Compounds
12.4 Biological Activities of Ganoderma
12.5 Antioxidant Activity
12.6 Immunomodulation Activity
12.7 Anticancer Activity
12.8 Anti-inflammatory Activity
12.9 Anti-allergic Activity
12.10 Antidiabetic Effects
12.11 Hepatoprotective Activity
12.12 Antimicrobial Activity
12.12.1 Antibacterial Activity
12.12.2 Antiviral Activity
12.12.3 Antifungal Activity
12.13 Effects on Central Nervous System
12.14 Other Biological Effects
12.15 Conclusions
References
13: Pharmaceutically Important Metabolites from Marine Fungi
13.1 Introduction
13.2 Preferred Habitat
13.3 Food Source
13.4 Classification of Fungi from the Marine Environment
13.5 Environmental Special Effects of Fungi in the Oceanic Atmosphere
13.6 Pharmaceutical Compounds from Fungi
13.6.1 Cladosporium sp.
13.6.2 Penicillium sp.
13.6.3 Nigrospora sp.
13.6.4 Aspergillus sp.
13.6.5 Aspergillus sp.
13.6.6 Stachybotrys sp.
13.6.7 Trichoderma sp.
13.6.8 Fusarium sp.
13.6.9 Pestalotiopsis sp.
13.6.10 Zopfiella latipes
13.6.11 Drechslera dematioidea
13.6.12 Ascochyta salicorniae
13.6.13 Halorosellinia oceanica BCC5149
13.6.14 Phoma herbarum
13.6.15 Exophiala
13.6.16 Chaetomium sp.
13.6.17 Curvularia sp.
13.6.18 Spicellum roseum
13.6.19 Massarina sp.
13.6.20 Aspergillus carbonarius
13.6.21 Aspergillus ustus
13.6.22 Petriella sp.
13.6.23 Aspergillus aculeatus
13.6.24 Aspergillus glaucus
13.6.25 Aspergillus versicolor
13.6.26 Aspergillus sydowii
13.6.27 Cosmospora sp.
13.7 Conclusion
References
14: Endophytic Fungi: A Treasure Trove of Novel Bioactive Compounds
14.1 Introduction
14.2 What Is an Endophyte?
14.3 Endophytic Fungi: A Warehouse of Bioactive Metabolites
14.3.1 Altenusin
14.3.2 Ambuic Acid
14.3.3 Beauvericin
14.3.4 Brefeldin A
14.3.5 Griseofulvin
14.3.6 Azaphilones
14.3.7 Cytochalasa(i)ns
14.3.8 Chaetoglobosin
14.3.9 Phomoxanthone
14.4 Conclusion
References
15: Novel Products from Microalgae
15.1 Introduction
15.2 Microalgae
15.2.1 Chlorella vulgaris
15.2.2 Spirulina
15.2.3 Nostoc
15.2.4 Haematococcus pluvialis
15.2.5 Dunaliella salina
15.3 Value-Added Products from Microalgae
15.3.1 Lutein
15.3.2 Astaxanthin
15.3.3 Zeaxanthin
15.3.4 Beta-Carotene
15.3.5 Lycopene
15.3.6 Fatty Acids
15.3.7 Docosahexaenoic Acid and Eicosapentaenoic Acid
15.3.8 Tocopherols and Sterols
15.3.9 Polysaccharides
15.3.10 Enzymes and Proteins
15.3.11 Vitamins
15.4 Microalgae as Nutraceuticals
15.5 Microalgae and Animal Feed
15.6 Microalgae and Cosmetics
15.7 Microalgae and Biofuel
15.8 Microalgae and Pharmaceuticals
15.9 Antiviral Activity of Microalgae
15.10 Anticancer Activity of Microalgae
15.11 Antimicrobial Activity of Microalgae
15.12 Conclusion
References
16: Lactic Acid Production and Its Application in Pharmaceuticals
16.1 Introduction
16.2 Lactic Acid Pathway
16.3 Biomass for Lactic Acid Production
16.4 Fermentation
16.5 Kinetic Modelling for Lactic Acid Production
16.6 Downstream Processing of Lactic Acid
16.7 Applications of Polylactic Acid
16.8 Conclusions and Future Perspectives
References
17: Microbial Clot Busters: An Overview of Source, Production, Properties and Fibrinolytic Activity
17.1 Introduction
17.2 The Evolutionary Trend in Thrombolytic Therapy
17.2.1 The First Generation of Thrombolytic Drugs
17.2.1.1 Streptokinase
17.2.1.2 Urokinase
17.2.2 The Second Generation of Thrombolytic Drug
17.2.2.1 Anistreplase (Acylated Plasminogen-Streptokinase Activator Complex)
17.2.2.2 Pro-urokinase
17.2.2.3 Alteplase
17.2.3 Third Generations of Thrombolytic Drug
17.2.3.1 Reteplase
17.2.3.2 Tenecteplase
17.2.3.3 Lantoplase
17.2.3.4 Monteplase
17.2.3.5 Pamitelase
17.2.3.6 Desmoteplase
17.2.3.7 Staphylokinase
17.3 Fibrinolytic Agents from Microorganisms
17.3.1 Fibrinolytic Agents from Bacteria
17.3.2 Fibrinolytic Agents from Algae
17.3.3 Fibrinolytic Agents from Actinomycetes
17.3.4 Fibrinolytic Agents from Fungi
17.3.5 Fibrinolytic Agents from Endophytic Fungi
17.4 Conclusion
References
18: Carbohydrate Biopolymers: Diversity, Applications, and Challenges
18.1 Introduction
18.2 Carbohydrate Biopolymers
18.2.1 Cellulose
18.2.2 Starch
18.2.3 Chitin and Chitosan
18.2.4 Carrageenan
18.2.5 Alginate
18.2.6 Other Important Polysaccharides
18.3 Challenges in Applications
18.4 Conclusions
References
Part IV: Important Biotechnological Applications of Natural Products
19: Biotechnological Aspects of Nanoparticles Driven from Natural Products for Drug Delivery System and Other Applications
19.1 Introduction
19.1.1 Nanoparticles from Natural Products
19.1.2 Approaches in Selecting, Screening and Discovery of Natural Products as the Potential for Drug Discovery and Development
19.1.3 Screening and Design
19.1.4 Isolation and Purification
19.1.5 Identification of Biologically Active Material
19.1.6 Structure-Activity and Structure-Property Relationships of Natural Products
19.2 Nanoparticles in Drug Delivery
19.3 Other Applications of Nanoparticles
19.3.1 Nanoparticles in Agriculture
19.3.2 Industrial Applications of Nanoparticles
19.3.3 Nanoparticles in Food Industry
19.3.4 Nanoparticles in Cosmetics
19.3.5 Nanoparticles in Textiles
19.3.5.1 Development of Nanofibres
19.3.5.2 Enhancing Self-Cleaning Properties of Fabrics
19.3.5.3 UV Blocking/Protection
19.3.5.4 Antibacterial and Wrinkle-Resistant Mechanism
19.3.5.5 Anti-static Property and Water-Repelling Properties of Fibres
19.4 Challenges and Nanotoxicity
19.5 Future Perspective and Challenges in the Natural Product Drug Discovery
19.6 Conclusion
References
20: Methods and Techniques for the Chemical Profiling and Quality Control of Natural Products and Natural Product-Derived Drugs
20.1 Introduction
20.2 Natural Product-Based Drug Discovery
20.3 Physicochemical Analysis of Natural Products and Natural Product-Derived Drugs
20.4 Phytochemical Analysis of Natural Products and Natural Product-Derived Drugs
20.5 Quantitative Analysis to Characterize the Phytochemicals of Natural Products and Natural Product-Derived Drugs
20.6 High-Performance Thin-Layer Chromatography
20.7 UV-Visible Spectroscopy
20.8 Infrared Spectroscopy
20.9 Nuclear Magnetic Resonance Spectroscopy (NMR)
20.10 Mass Spectrometry
20.11 Need of Analogue Synthesis of Natural Products
20.12 Conclusion and Future Prospects
References
21: Characterization of Bioactive Secondary Metabolites of Fungal Endophytes from Melghat Forest in Maharashtra, India
21.1 Introduction
21.2 Materials and Methods
21.2.1 Collection of Plant Samples
21.2.2 Isolation of Endophytic Fungi
21.2.3 Production of Secondary Metabolites and Solvent Extraction
21.2.4 In Vitro Antibacterial Activity via Kirby-Bauer (KB) Disk Assay
21.2.5 GC/MS Analysis of the EA Crude Residue
21.3 Results
21.3.1 Isolation of Endophytic Fungi
21.3.2 In Vitro Antibacterial Activity via KB Disc Assay
21.3.3 GC/MS Analysis of the EA Crude Residue
21.4 Discussion
21.5 Conclusion
References
22: Modulation of Cellular Protein Quality Control Pathways Using Small Natural Molecules
22.1 Introduction
22.2 Cellular Protein Quality Control Pathways: Multiple Arms Converging for a Common Goal
22.3 Exploiting Protein Quality Control Pathways for Therapeutics Against Major Human Pathologies
22.4 Natural Molecules as the Modulators of Cellular Proteostasis Mechanisms
22.4.1 Small Molecules Enhancing Cellular Chaperoning Capacities
22.4.2 Natural Modulators of Autophagic Pathway
22.4.3 Targeting Diseases by Regulating Proteolytic Activities of the Proteasome
22.5 Concluding Remarks and Future Perspectives
References
23: Elaborating on the Potential for Mushroom-Based Product Market Expansion: Consumers´ Attitudes and Purchasing Intentions
23.1 Introduction
23.2 The World Market of Mushroom-Based Products: The Relation of Practice and Literature
23.3 An Overview of Mushroom-Based Products
23.4 Potential of Medicinal Mushrooms to Be Used as a Source of Natural Products
23.4.1 Active Chemical Compounds of Medicinal Mushrooms
23.4.2 Mushroom Polysaccharides
23.4.3 Commercial Mushroom-Based Products
23.4.3.1 Krestin
23.4.3.2 Lentinan
23.4.3.3 Ganopoly
23.5 Internal Factors That Shape Consumer Attitudes and Purchasing Behavior Towards Mushroom-Based Products
23.5.1 Sociodemographic Characteristics
23.5.2 Psychographic and Behavioral Characteristics
23.6 External Factors That Shape Consumer Attitudes and Purchasing Behavior Towards Mushroom-Based Products
23.7 Rising the Market Potential for Mushroom-Based Products
23.8 Conclusion
References
24: The Role of Algae in Nutraceutical and Pharmaceutical Production
24.1 Introduction
24.2 Growth Environment of Algae
24.3 High-Value Products from Algae
24.3.1 Role of Algae in Nutraceuticals
24.3.1.1 Vitamins
24.3.1.2 Fatty Acids
24.3.1.3 Polyunsaturated Fatty Acids (PUFA)
Docosahexaenoic Acid (DHA)
Eicosapentaenoic Acids (EPA)
Arachidonic Acid (AA)
24.3.1.4 Carotenoids
24.3.1.5 Sterols
24.3.1.6 Proteins and Enzymes
24.3.2 Role of Algae in Pharmaceuticals
24.4 Bioactivity of Compounds from Algae
24.4.1 Antioxidant Activity
24.4.2 Antiangiogenic, Cytotoxic, and Anticancer Activities
24.4.3 Antiobesity Activity
24.4.4 Antimicrobial Activity
24.4.5 Antiprotozoal Activity
24.5 Market Potential of Algal Products
24.6 Future of Natural Products from Algae
References
25: Microbial Interventions to Induce Secondary Metabolite Biosynthesis in Medicinal and Aromatic Plants
25.1 Introduction
25.2 Secondary Metabolites
25.2.1 Terpenoids
25.2.2 Alkaloids
25.2.3 Benzylisoquinoline Alkaloids
25.2.4 Bisbenzylisoquinoline Alkaloids
25.3 Biosynthetic Pathways in MAPs
25.3.1 The Polyketide Pathway
25.3.2 Mevalonate and Deoxyxylulose-5-Phosphate Pathways for Synthesis of Terpene
25.3.3 Shikimate Pathway
25.3.4 Polyamine Pathway
25.3.5 Mixed Biosynthetic Pathways
25.4 Basic Outline and Variety of Bioactive Molecules
25.5 Plant Growth-Promoting Microorganisms (PGPMs)
25.6 Mechanisms of PGPM-Induced Secondary Metabolite Synthesis in MAPs
25.7 Conclusion and Future Perspectives
References
26: Peptaibols: Antimicrobial Peptides from Fungi
26.1 Introduction
26.2 Early Discovery and Naming
26.3 Characteristics of Peptaibols
26.4 Chain Length and Residue Types
26.5 Classification of Peptaibols
26.6 Biosynthesis of Peptaibols
26.6.1 Initiation or Adenylation
26.6.2 Elongation or Thiolation
26.6.3 Termination
26.7 Detection of Peptaibols Using Modern Techniques
26.8 Structure of Peptaibols
26.9 Mode of Action
26.10 Bioinformatics and Synthetic Peptides
26.11 Applications and Functions of Peptaibols
26.12 Conclusion
References
Index

Citation preview

Joginder Singh Vineet Meshram Mahiti Gupta   Editors

Bioactive Natural Products in Drug Discovery

Bioactive Natural Products in Drug Discovery

Joginder Singh • Vineet Meshram • Mahiti Gupta Editors

Bioactive Natural Products in Drug Discovery

Editors Joginder Singh Department of Microbiology Lovely Professional University Phagwara, Punjab, India

Vineet Meshram Department of Plant Pathology and Weed Research Agricultural Research Organization, The Volcani Centre Rishon Lezion, Israel

Mahiti Gupta Department of Biotechnology Lovely Professional University Phagwara, Punjab, India

ISBN 978-981-15-1393-0 ISBN 978-981-15-1394-7 https://doi.org/10.1007/978-981-15-1394-7

(eBook)

# Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

Natural products are small organic molecules produced naturally by any organism including primary and secondary metabolites. Natural products offer colossal structural diversity and unique biological activities which are the result of biosynthetic processes that have been modulated over millions of years due to natural selections and evolutionary process substantiating their superiority over chemically synthesized compounds. Thus, natural products have been used in both traditional and modern medicines as a panacea for various diseases. Furthermore, natural products also provide template for the synthesis of various drugs followed by synthetic modifications to increase the bioavailability and reduce the side effects of the drugs. Traditional methods used for screening and isolation of natural products were ineffective, cost-intensive, and cumbersome; however, with the advent of modern analytical and high-throughput techniques, isolation and characterization of the natural products can be done rapidly which open up exciting opportunities for the pharmaceutical industries in the field of drug discovery and development. The endeavor of the book entitled Bioactive Natural Products in Drug Discovery is to present details of cutting-edge research in the field of drug discovery and development from bioactive natural products and helps its reader to understand how natural product research continues to make significant contributions in the discovery and development of novel medicinal entities. With 27 chapters contributed by an elite group of researchers working in the forefront of bioprospecting natural products, the book is divided into three modules; the first two modules respectively elaborates the significance and applications of plant and microbial natural products, whereas the third module highlights the important biotechnological applications of the natural products with an intention to unravel their pharmaceutical applicability in modern drug discovery processes. The book covers the biosynthesis, bioactivities, pharmacology, chemical profiling, and structure–activity relationships of various bioactive natural products. Modern emerging areas such as metabolomics, proteomics, nutraceuticals, and drug targeting are also covered. It also includes interesting chapter that deals with the economics, consumers’ attitudes, and intentions in

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Preface

purchasing natural products. It therefore serves as a useful reference book for students and researchers in a wide variety of research fields, including analytical chemistry, biochemistry, biotechnology, ethnobotany, microbiology, pharmacy, and phytochemistry. Phagwara, India Rishon LeZion, Israel Phagwara, India 2020

Joginder Singh Vineet Meshram Mahiti Gupta

Contents

Part I

Plants Natural Products: Fountainheads for Drug Discovery and Development

1

The Artemisia Genus: Panacea to Several Maladies . . . . . . . . . . . . . Bhupendra Koul and Taslimahemad Khatri

2

Bacopa monnieri: The Neuroprotective Elixir from the East—Phytochemistry, Pharmacology, and Biotechnological Improvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Samapika Nandy, Anuradha Mukherjee, Devendra Kumar Pandey, and Abhijit Dey

3

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3

Current Knowledge of Cinnamomum Species: A Review on the Bioactive Components, Pharmacological Properties, Analytical and Biotechnological Studies . . . . . . . . . . . . . . . . . . . . . 127 Devendra Kumar Pandey, Ronni Chaudhary, Abhijit Dey, Samapika Nandy, R. M. Banik, Tabarak Malik, and Padmanabh Dwivedi

4

Swertia spp.: A Potential Source of High-Value Bioactive Components, Pharmacology, and Analytical Techniques . . . . . . . . . 165 Prabhjot Kaur, Devendra Kumar Pandey, Abhijit Dey, Padmanabh Dwivedi, Tabarak Malik, and R. C. Gupta

5

The Genus Calophyllum: Review of Ethnomedicinal Uses, Phytochemistry and Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . 215 Shiv Gupta and Pawan Gupta

Part II

Plant Derived Natural Products as Leads for Drug Discovery

6

Plant-Derived Quinones as a Source of Antibacterial and Anticancer Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 Surbhi Goel, Preeti Singh Parihar, and Vineet Meshram

7

Drugging Protein-Protein Interaction Interface with Natural Products: A Computational Approach . . . . . . . . . . . . 281 Ria Biswas and Angshuman Bagchi vii

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8

Contents

CQDs Derived from Natural Sources: Excellent Bioimaging Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Ranjana Singh, Jyoti Goutam, and Ranjan K. Singh

Part III

Microbial Natural Products: A Quintessential Source for Drug Discovery and Development

9

Microbial Natural Products: Recent Insights into Novel Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Rajnish Kumar Verma and Amita Sharma

10

Bioactive Peptides and Carbohydrates from Natural Products: A Source of Functional Foods and Nutraceuticals . . . . . . . . . . . . . . 335 Gurseen Rakhra, Sumit Kumar Jaiswal, and Gurmeen Rakhra

11

Metabolites of Fluorescent Pseudomonads and Their Antimicrobial and Anticancer Potentials . . . . . . . . . . . . . 355 Kranti Tanguturu, Moumita Mondal, Ankit Banik, Gurusamy Raman, and Natarajan Sakthivel

12

Ganoderma: A Propitious Medicinal Poroid Mushroom . . . . . . . . . 379 Ranjeet Singh, Avneet Pal Singh, Gurpaul Singh Dhingra, and Richa Shri

13

Pharmaceutically Important Metabolites from Marine Fungi . . . . . 411 Vijayalakshmi Selvakumar, Satyender Singh, Karthik Kannan, and Panneerselvam Annamalai

14

Endophytic Fungi: A Treasure Trove of Novel Bioactive Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 Mahiti Gupta and Kamlesh Kumar Shukla

15

Novel Products from Microalgae . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 G. Subashini and S. Bhuvaneswari

16

Lactic Acid Production and Its Application in Pharmaceuticals . . . 467 Ajay Kumar, Joginder Singh, and Chinnappan Baskar

17

Microbial Clot Busters: An Overview of Source, Production, Properties and Fibrinolytic Activity . . . . . . . . . . . . . . . . . . . . . . . . 485 Mahiti Gupta, Sanjai Saxena, and Vineet Meshram

18

Carbohydrate Biopolymers: Diversity, Applications, and Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517 Taranpreet Kaur and Raman Preet Singh

Contents

Part IV

ix

Important Biotechnological Applications of Natural Products

19

Biotechnological Aspects of Nanoparticles Driven from Natural Products for Drug Delivery System and Other Applications . . . . . . 549 Simranjeet Singh, Vijay Kumar, Satyender Singh, Shivika Datta, Sanjay Kumar, Pooja Bhadrecha, Daljeet Singh Dhanjal, and Joginder Singh

20

Methods and Techniques for the Chemical Profiling and Quality Control of Natural Products and Natural Product-Derived Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 Vijay Kumar, Simranjeet Singh, Satyender Singh, Shivika Datta, Daljeet Singh Dhanjal, and Joginder Singh

21

Characterization of Bioactive Secondary Metabolites of Fungal Endophytes from Melghat Forest in Maharashtra, India . . . . . . . . 599 Kishor Suradkar and Dillip Hande

22

Modulation of Cellular Protein Quality Control Pathways Using Small Natural Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Rahul Badhwar and Arun Upadhyay

23

Elaborating on the Potential for Mushroom-Based Product Market Expansion: Consumers’ Attitudes and Purchasing Intentions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 Sonja Veljović and Jelena Krstić

24

The Role of Algae in Nutraceutical and Pharmaceutical Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665 Shristy Gautam and M. Amin-ul Mannan

25

Microbial Interventions to Induce Secondary Metabolite Biosynthesis in Medicinal and Aromatic Plants . . . . . . . . . . . . . . . . 687 Rupali Gupta, Gautam Anand, and Rakesh Pandey

26

Peptaibols: Antimicrobial Peptides from Fungi . . . . . . . . . . . . . . . . 713 V. N. Ramachander Turaga

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731

About the Editors

Joginder Singh is presently working as a Professor at the Department of Microbiology, Lovely Professional University, Punjab, India. His training and research experience prepared him to work with microbial consortium formulation and study its ecology. His particular areas of competence include planning and execution of R&D facilities at scientist level. He is an active member of various scientific societies and organizations, including Indian Science Congress Association, the Association of Microbiologists of India, K. K. Nanda Foundation for Advancement of Plant Sciences, Indian Society of Salinity Research Scientists, Indian Society for Radiation Biology, Hong Kong Chemical, Biological & Environmental Engineering Society, and European Federation of Biotechnology. The Academy of Plant Sciences, India (2016) conferred him certificate of excellence in the field of Microbial Technology. He serves as a reviewer for many prestigious journals and has published more than 60 research and review articles in peer-reviewed journals, edited 4 books, and authored/co-authored 25 book chapters. Vineet Meshram is currently working as a Visiting Scientist at the Department of Plant Pathology and Weed Research, the Volcani Centre, Agricultural Research Organization, Israel. He previously served as an Assistant Professor at the Department of Biochemistry, DAV University, India (2016–2017). He has over 10 years of research experience in microbial secondary metabolites, microbial biochemistry, biological control, mycology, and drug discovery. His research work has resulted in over 15 referred journal articles, 21 abstracts and, 3 book chapters. He is also a founder member of the International Society for Fungal Conservation. In recognition of his contributions, the Mycological Society of India (2012) and European Mycological Society (2015) selected him for a Young Scientist Award. Recently, he has been awarded Karsons’s award (2019) by The Ministry of Agriculture, Agricultural Research Organization, Israel, for his studies on plant-microbe interactions. Mahiti Gupta is an Assistant Professor at the Department of Biotechnology, Lovely Professional University, India. Her research interests are in natural products and drug discovery, enzyme inhibitors, protein purification, and characterization.

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About the Editors

She is currently working on endophytes and Stevia. She has been honored with a UGC Meritorious Fellowship and a Young Scientist Award. She has published seven research articles in peer-reviewed international and national journals and has authored and co-authored several book chapters. She is a member of numerous scientific societies, including the Indian Science Congress.

Part I Plants Natural Products: Fountainheads for Drug Discovery and Development

The Artemisia Genus: Panacea to Several Maladies

1

Bhupendra Koul and Taslimahemad Khatri

Abstract

The genus Artemisia belongs to the family Asteraceae which has now become the subject of great attraction because of its rich species diversity and phytochemical composition. This genus has a very long history of use in the treatment of human diseases in different parts of the world. This medicinally important genus has promising therapeutic potential which includes antimalarial, anti-parasitic, hepato-protective, anti-nociceptive, anti-inflammatory, anti-ulcerogenic, antimicrobial, antitumour, antioxidant, anticancer, anticonvulsant, anti-leishmanial, anti-diabetic, anti-promastigote, antidepressant and anticonvulsant. A total of 839 chemical compounds (volatile and non-volatile) have been reported in different species of this genus. These chemical compounds can be categorised into major classes such as flavonoids, lignans, terpenes, fatty acids, phenylpropanoids, sterols, fatty esters, phenolics, hydrocarbons and miscellaneous compounds. Strategic conservation of Artemisia species shall continue to provide molecules of pharmaceutical importance in future. Keywords

Secondary metabolites · Herbal drugs · Antimalarial · Artemisinin · Mugwort

B. Koul (*) School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India e-mail: [email protected] T. Khatri Department of Chemistry, Government Science College, Chikhli, Gujarat, India # Springer Nature Singapore Pte Ltd. 2020 J. Singh et al. (eds.), Bioactive Natural Products in Drug Discovery, https://doi.org/10.1007/978-981-15-1394-7_1

3

4

B. Koul and T. Khatri

Abbreviations 2,4-D AA AIDS BAP BC cm DPPH FRAP g HCl HPLC HPTLC IAA KN mg ml MS MTCC NAA TCM μM

1.1

2,4-Dichlorophenoxyacetic acid ascorbic acid acquired immune deficiency syndrome 6-benzylaminopurine before the Christ’s birth centimetre 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity ferric reducing antioxidant power gramme hydrochloric acid high-performance liquid chromatography high-performance thin-layer chromatography indole 3-acetic acid kinetin milligrams millilitre Murashige and Skoog Microbial Type Culture Collection and Gene Bank α-naphthalene acetic acid traditional Chinese medicine micromolar

Introduction

Plants are being used from ancient times as a source of food, fuel and fodder and for medicinal purposes. Thus, they act as a supporting system for the existence of all the living organisms on Earth. The plant kingdom is a reservoir of medicinally important plants which are used to produce effective and non-toxic medicines for human healthcare (Liu et al. 2013). India contributes its maximum income for the production of herbal medicines and thus it is known as the ‘botanical garden of the world’. Andaman and Nicobar Islands, Eastern Himalayas and Western Ghats of India are the major hotspots which constitute nearly 45,000 species of medicinally important flora (Mohanty et al. 2018). The applications of herbs for various purposes have also been mentioned in ancient Hindu scripts of India such as Sushruta Samhita (800–700 BC), Samhita (1000–800 BC), Rigveda (4500–1600 BC) and others (Pal and Jain 1998; Chan et al. 2010; Leonti and Casu 2013; Kapur 2016). During the ancient times, the knowledge regarding the medicinal properties of plants was limited to local people, tribal communities, priests, etc. but in the present time the power of herbal remedies has become widespread (Koul et al. 2017). With

1

The Artemisia Genus: Panacea to Several Maladies

5

the advancements of medical and chemical sciences several synthetic drugs are now available in the market for the treatment of various disorders. As a result, the demand of herbal medicines is continuously increasing day by day among the people because herbal medicines are safe, cost effective and eco-friendly. It has been reported that more than 60% of the commercially important drugs are obtained from plant sources (Cubukcu et al. 1990; WHO 2003). Artemisia is a medicinally important genus belonging to Asteraceae family which is also known as ‘Compositae family’, ‘thistle family’ or ‘daisy family’ and ‘sunflower family’. This genus consists of 474 species which are generally known as ‘mugwort’, ‘tarragon’, ‘worm wood’ or ‘sagebrush’ (Tajadod et al. 2012; Obistioiu et al. 2014). These species are either biannual, annual, perennial, herbs or shrubs. The word ‘Artemisia’ comes from the ancient Greek word ‘Artemis’ ¼ The Goddess (the Greek Queen Artemisia) and ‘absinthium’ ¼ Unenjoyable or without sweetness. The plants possess peculiar bitter taste and pungent smell due to the presence of sesquiterpene lactones and terpenoids (Abad et al. 2012). Some species of this genus are used for the preparations of herbal tea, alcoholic beverages, tonic and medicines while some are cultivated as crops. As the Artemisia spp. are a rich source of volatile and non-volatile bioactive phytoconstituents, these species have been reported to possess numerous therapeutic potential such as the following: antimalarial (Sarab et al. 2011; Mojarrab et al. 2016), antibacterial (Altunkaya et al. 2014; Saxena 2015; Kumar et al. 2017; Wani et al. 2017), anti-diabetic (Ashok and Upadhyaya 2013; Nathar and Yatoo 2014), anticancer (Taherkhani 2014; Martínez-Díaz et al. 2015), antifungal (Obistioiu et al. 2014; Saxena 2015), anti-helminthic (Rajeshkumar and Hosagoudar 2012), hepatoprotective (Mohammadian et al. 2016), trichomonacidal (Nibret and Wink 2010), antiviral (Rajeshkumar and Hosagoudar 2012; Sharma et al. 2014), antispasmodic (Sarab et al. 2011; Joshi et al. 2016), anti-parasitic (Yildiz et al. 2011), anti-arthritis (Kim et al. 2015), anti-rheumatic (Saxena 2015), antihypertensive (Tigno et al. 2000; Sharopov et al. 2012), anti-inflammatory (Sarab et al. 2011; Nikhat et al. 2013), neuroprotective (Lachenmeier 2010), antitumour (Shafi et al. 2012; Mojarrab et al. 2013), antipyretic (Hailu et al. 2013), antioxidant (Bora and Sharma 2011; Mojarrab et al. 2013; Msaada et al. 2015; Mohammadian et al. 2016), anti-fertility (Ashok and Upadhyaya 2013; Singh et al. 2019d), deobstruent (Nikhat et al. 2013), wormicidal (Bizhani 2015), trypanocidal, emmenagogue, diuretic, abortive (Kader and Delseny 2011; Singh et al. 2016; Mishra et al. 2016; Kumar et al. 2016), analgesic (Saxena 2015), acaricidal (Godara et al. 2014), vermifuge, febrifuge, antibiotic, urine stimulant (Saxena 2015), premenstrual syndrome, menopause, dysmenorrhoea and attention-deficit hyperactivity disorder (Adams et al. 2012), immunomodulatory (Zamanai et al. 2015), anti-ulcerogenic (Kim et al. 2017), anti-coccidal (Kostadinovic et al. 2012), diuretic, anti-cholesterolemic, cholagogue, febrifuge and vasodilator (Sajid et al. 2016), anti-plasmodial (Ramazani et al. 2010), bile stimulant (Saxena 2015), anti-hyperlipidaemic (Daradka et al. 2014; Khan 2015), anti-epileptic and anticonvulsant (de Almeida et al. 2013), disinfectant, choleretic, balsamic, depurative, digestive, emmenagogue, anti-leukaemia and anti-sclerosis (Ali and Abbasi 2014), abortifacient (Zadoks 2013), anti-nociceptive (Shoaib et al. 2016), antifeedant (Barrero et al. 2013), insecticidal (Bouzenna and Krichen 2012),

6

B. Koul and T. Khatri

anti-leishmanial (Tariku et al. 2010; Jafroodi et al. 2015), antivenom (Nalbantsoy et al. 2013), anti-herpes virus (Gavanji et al. 2015; Kumar et al. 2015), antidote to insect poison (Mckenna and Hughe 2014) and anti-migraine (Gohari et al. 2013; Kumar et al. 2014). In this chapter we have compiled the information regarding phytochemical constituents, pharmacological activities, commercialised products and conservation of Artemisia species.

1.2

Phytochemistry

Artemisia genus is a source of numerous secondary metabolites which can be categorised into different classes such as oxygenated sesquiterpenes, oxygenated monoterpenes, phenylpropanoids, diterpene hydrocarbons, sesquiterpene hydrocarbons, monoterpene hydrocarbons, saturated fatty acids, azulenes, acyclic alkanes, norisoprenoids, saturated fatty aldehydes, oxygenated diterpenes, unsaturated ketone, unsaturated fatty alcohol, fatty esters, oxygenated hemiterpene, alkyl ketones, saturated fatty alcohol, unsaturated fatty aldehydes, lignan, phenolic acids, aromatic hydrocarbon, alkaloids, sterols, flavonoids, flavonoid glycosides, hydroxyl cinnamic acids, phenolic glycosides, oxygenated triterpenes, butenolides, pyrethroids, benzenoids, alkyne, cyclic hydrocarbons, coumarins (expected flavonoids), ester of caffeic acid and unsaturated fatty acids. Artemisinin is one of the important phytochemicals which has been isolated from two spp. of Artemisia: A. annua L. and A. vulgaris L. (Hussain et al. 2010). A total of 839 phytochemicals have been isolated from 14 different species of Artemisia, viz. A. arborescens (Vaill.) L., A. abrotanum L., A. carvifolia Buch.-Ham. ex Roxb., A. dracunculus L., A. absinthium L., A. indica Willd., A. afra Jacq. ex Willd., A. capillaris Thunb., A. cina Berg ex Poljakov, A. annua L., A. japonica Thunb., A. chamaemelifolia Vill., A. vulgaris L. and A. herba-alba Asso (Brown 2010; Altunkaya et al. 2014; Martínez-Díaz et al. 2015) as shown in Table 1.1. These phytochemicals have been isolated using different techniques such as HPLC-MS, GC-MS, HPLC, X-ray crystallography and 1D and 2D NMR. Oxygenated terpenes and hydrocarbons are the most abundant phytoconstituents found in this genera.

1.3

Conservation of Artemisia Species

All the medicinally important species of this genus have been reported to be in use since ancient times for culinary preparations as well as therapeutic uses as mentioned in Table 1.2. Besides that, various commercialised products of these species in the form of tablets, syrups, oils, creams, etc. are also available in the market for human healthcare (Table 1.3). The species of Artemisia are also reported to accumulate heavy metals (Bhati et al. 2019; Kapoor et al. 2019). Thus they provide a solution to remediate the environment contaminants (Singh et al. 2019a, Kumar et al. 2019a; Singh et al. 2019b; Singh et al. 2019c). They work by the process of either phytoremediation or phytoaccumulation and transformed them into useful by-products (Kumar et al. 2019b; Sidhu et al. 2019; Kumar et al. 2019c; Kumar and

Artemisia absinthium L. (Absinthium, worm wood, green ginger, absinthe worm wood, common worm wood or grand wormwood, louisiana artemisia, cudweed, western mugwort, white sage)

A. absinthium is silver green, perennial, herbaceous plant growing in the temperate regions of Eurasia, Northern Africa and North America. It grows in natural habitat on uncultivated-ground, rocky slopes, sides of footpaths, foot of hills and fields. Stem is erect, 4–12 in. tall branched, firm, leafy, sometimes almost hard

Bioactive compounds present in Artemisia abrotanum L. Artemisinin (5)a Artedouglasia oxide A (1)a a Artedouglasia oxide B (2) cis-Arbusculone (6)b Artedouglasia oxide C (3)a cis-Davanone (7)a Artedouglasia oxide D (4)a cis-β-Terpineol (8)b

Used as condiment/ anthelmintic; antiseptic; antispasmodic; appetizer; carminative; cholagogue; emmenagogue; febrifuge; homeopathy; hypnotic; stimulant; stomachic; tonic; vermifuge/repellent; strewing

Davana ether (9)a Estragole (10)c Lavender lactone (11)b Nordavanone (12)a

o-Cymene (13)f Piperitone (14)b Silphiperfol-5-en-3-ol A (15)a trans-Arbusculone (16)b Whole Herb

(continued)

Abad et al. (2012), Altunkaya et al. (2014) Erel et al. (2012), Lee et al. (2013), Obistioiu et al. (2014), Ozek et al. (2014), Sharopov et al. (2012), Wani et al. (2014)

trans-Piperitol (17)b α-Terpineol (18)b 1,8-Cineole (19)b

References Abad et al. (2012), Ben-Nasr et al. (2013), Obistioiu et al. (2014), Ozek et al. (2014), Suresh et al. (2010), Suresh et al. (2011)

Botanical name/common name Artemisia abrotanum L. (Southernwood, old man, boys love, old man’s worm wood, lover’s plant, European sage, lemon plant, appleringie, garderobe, maid’s ruin, garden sagebrush, our lord’s wood) Part used Whole herb

Table 1.1 Phytochemicals and medicinal properties of selected Artemisia species Medicinal properties/ other uses Used as condiment; tea/anthelmintic; antiseptic; cholagogue; deobstruent; emmenagogue; stomachic; tonic/yellow dye is obtained from branches; hair tonic; incense; pot-pourri; insect repellent

The Artemisia Genus: Panacea to Several Maladies

Botanical description A. abrotanum is a small bush and gains a height of 1.2 m. It grows wild or is cultivated as ornamental plant in gardens in temperate region of Eurasia and Africa and some places of North America because it bears flowers with aroma

1 7

Botanical name/common name

Table 1.1 (continued)

woody at the base. The leaves of the plant are white silver-green in colour having bitter, strong aroma due to presence of compound thujone. A single plant can produce 50,000 seeds. Fibrous roots of plant possess aromatic taste. It is used as herbal medication in Ayurveda, Unani, homeopathy and Siddha. It has long been used as an anti-helminthic (wormwood) and also as an ingredient in the liquor Absinthe. Artemisia absinthium is commonly called as wormwood. The name wormwood implies that it is a powerful worming agent, because of its usage for hundreds of years to expel tapeworms, threadworms and especially roundworms from dogs, cats and humans. Absinth wormwood is used in companion planting to suppress weeds, because its

Botanical description

Medicinal properties/ other uses Part used

References

8 B. Koul and T. Khatri

roots secrete a substance called absinthin (sesquiterpene lactone) that inhibits the growth of surrounding plants. It can repel insect larvae when planted on the edge of the cultivated area. It has also been used to repel fleas and moths indoors. Studies of its effect on the germination of other plants are inconclusive Bioactive compounds present in Artemisia absinthium L. (E)-Nerolidol (43)a Artemisia ketone (20)b Aromadendrene (21)e (E)-Nuciferolisobutyrate Bicyclogermacrene (22)e (44)a Borneol (23)b (E)-Sabinyl acetate (45)b f Camphene (24) (E)-Sabinene hydrate (46)b Carvacrol (25)b (E)-3-Hexenyl butyrate Carvone (26)b (47)b Caryophyllene oxide (27)a Farnesol (48)a h Chamazulene (28) Germacrene B (49)e Chrysanthenyl acetate (29)b Germacrene D (50)e b cis-Chrysanthenol (30) Geranial (51)b cis-Epoxyocimene (31)b Geraniol (52)b b cis-Piperitone epoxide (32) Geranyl acetate (53)b cis-Sabinol (33)b Geranyl butanoate (54)b b cis-Verbenol (34) Geranyl isobutanoate (55)b Cubenol (35)a Geranyl isovalerate (56)b e Curcumene (36) Geranyl propionate (57)b Decanoic acid (37)g Geranyl, 2-methylbutanoate Linalool (66)b Myrtenal (67)b Myrtenol (68)b n-Heneicosane (69)i n-Heptadecane (70)i n-Nonadecane (71)i Nerol (72)b Neral (73)b Neryl acetate (74)b Neryl butanoate (75)b Neryl isobutanoate (76)b Neryl isovalerate (77)b Neryl 2-methylbutanoate (78)b Neryl-3-methylbutanoate (79)b Neryl propionate (80)b p-Cymene (81)f

trans-Caryophyllene (89)e trans-Epoxyocimene (90)b trans-Pinocarveol (91)b trans-Sabinol (92)b trans-Verbenol (93)b Terpinen-4-ol (94)b Terpinolene (95)f Terpinyl propionate (96)b Thymol (97)b Tricyclene (98)f trans-Muurolol (99)a Valerenic acid (100)a Verbenone (101)b Viridiflorol (102)a (Z)-Anethole (103)c

The Artemisia Genus: Panacea to Several Maladies (continued)

α-Muurolene (112)e α-Phellandrene (113)f α-Pinene (114)f α-Terpinene (115)f α-Terpineol (18)b α-Terpinyl acetate (116)b α-Thujene (117)f α-Thujone (118)b β-Bourbonene (119)e β-Citronellol (120)b β-Elemene (121)e β-Ionone (122)j β-Pinene (123)f β-Selinene (124)e β-Thujone (125)b γ-Muurolene (126)e γ-Cadinene (127)e γ-Dehydro-Ar-himachalene

1 9

(58)b Iso-3-thujanol (59)b Lavandulyl acetate (60)b Lavandulyl isobutanoate (61)b Lavandulyl 2-methylbutyrate (62)b Ledol (63)a Limonene (64)f Linalyl acetate (65)b

A. afra is a common species which is widely grown in Africa including north to east areas of Africa, Ethiopia and South Africa. A. afra is dark green in colour having woody stem reaching from 0.5–2 m in height, while leaves are similar to fern. A. afra is a well-known medicinal plant in Africa, and is still used by people of many cultures. The whole plant part including stem, roots and leaves is used in moth repellent, lotions, smoking and insecticide or as

Artemisia afra Jacq. ex Willd (Wild wormwood, African wormwood, wildeals, umhlonyane, mhlonyane, lengana, zengana, nyumba)

Botanical description

Dihydro-chamazulene (38)h (E)-Anethole (39)c (E)-Caryophyllene (40) (E)-Crysantenyl acetate (41)b (E)-Linalool oxide (42)b

Botanical name/common name

Table 1.1 (continued)

None known. The roots, stems and leaves are used as enemas, poultices, infusions, lotions, inhaled (e.g. smoked or snuffed), or as an essential oil/moth repellent/organic insecticidal spray

Perillaldehyde (82)b Piperitenone oxide (83)b Pogostol (84)a Pulegone (85)b Sabinene (86)f Santolina alcohol (87)b Spathylenol (88)a

Medicinal properties/ other uses (Z)-Linalool oxide (104)b (Z)-Nuciferolisobutyrate (105)a (Z)-Sabinyl acetate (106)b α-Copaene (107)e α-Bisabolol (108)a α-Dehydro-arhimachalene (109)e α-Humulene (110)e α-Ionone (111)j Root, stem and leaves

Part used

References

Abad et al. (2012), Maggio et al. (2012), Ozek (2014)

(128)e γ-Isogeraniol (129)b γ-Terpinene (130)f δ-Cadinene (131)e 1,8-Cineole (19)b 3,6-Dihydrochamazulene (132)h 9-Geranyl-p-cymene (133)d

10 B. Koul and T. Khatri

essential oils. A. afra possesses strong, sticky sweet fragrance that emanates when cut or touched. The other common names of A. afra are African wormwood, wild wormwood, wilde-als (Afrikaans), umhlonyane, mhlonyane, lengana, zengana and nyumba. The leaves are used to treat fevers, chest infections, digestive disturbances, coughs, flu, emphysema and asthma-like disorders Bioactive compounds present in Artemisia afra Jacq. ex Willd cis-Carveol (146)b Artemisia alcohol (134)b Artemisia ketone (20)b cis-Lanceol (147)a a Artedouglasia oxide D (4) cis-Muurola-4(14,5 diene) Allo-aromadendrene (135)e (148)a Allo-aromadendrene oxide Decanal (149)k Dihydronerolidol (150)a (136)a b Borneol (23) Davanone D (151)a Bicyclogermacrene (22)e Davana ether (9)a b Bornyl acetate (137) (E)-β-Farnesene (152)e Camphene (24)f (E)-Nerolidol (43)a b Camphor (138) phytol (153)l Carvacrol (25)b Guaiol (154)a b Carvone (26) Geranial (51)b Caryophyllene oxide (27)a Germacrene B (49)e Methyl eugenol (159)c Myrtenal (67)b Myrtenol (68)b Myrtenyl acetate (160)b Neolyratol (161)b Nordavanone (12)a Neral (73)b Neryl acetate (74)b p-Cymene (81)f p-Cymen-8-ol (162)b Pinocarvone (163)b Piperitone (14)b Spathulenol (164)a Santolina alcohol (87)b

trans-Chrysanthenyl acetate (169)b Terpinen-4-ol (94)b trans-Carveol (170)b Thymol (97)b trans-Cadinol (171)a trans-Muurolol (99)a Viridiflorol (102)a (Z)-α-Bisabolene epoxide (172)a α-Thujene (117)f α-Pinene (114)f α-Campholenal (173)b α-Terpineol (18)b

The Artemisia Genus: Panacea to Several Maladies (continued)

α-Copaene (107)e β-Thujone (125)b β-Eudesmene (β-Selinene) (124)e β-Guaiene (181)e β-Bisabolene (182)e β-Pinene (123)f β-Bourbonene (119)e β-Elemene (121)e γ-Terpinene (130)f γ-Gurjunene (183)e γ-Muurolene (126)e γ-Cadinene (127)e (2Z,6E)-Farnesyl acetate (184)a

1 11

Germacrene D (50)e Hotrienol (155)b Isophorone (156)m Isospathulenol (157)a Ledol (63)a Linalool (66)b Limonene (64)f Linalylformate (158)b

A. annua is also known as annual mugwort, sweet sagewort, sweet annie, sweet wormwood or annual wormwood, belonging to the family of Asteraceae, which is grown naturally in Asia (China, India, Pakistan, Japan, Russia, Serbia, Turkey), Europe (Albania, Bulgaria, Montenegro, Romania, Austria, France, Germany, Hungary, Italy, Poland, Slovakia, Spain, Switzerland), South America (Argentina) and North America (USA). A. annua is an annual, hairless, sweetly

Artemisia annua L. (Qing Hao, sweet worm wood, sweet annie, sweet sagewort, annual mugwort, annual wormwood)

Botanical description

Cabreuva oxide B (139)a Chrysanthenone (140)b cis-Sabinene hydrate (46)b cis-(Z)-α-Bisabolene (141)e cis-Jasmone (142)b cis-Piperitol (143)b cis-Pinocamphone (144)b cis-Chrysanthenyl acetate (145)b

Botanical name/common name

Table 1.1 (continued)

Used as condiment/ antibacterial; antiperiodic; antiseptic; carminative; digestive; febrifuge; essential oil; herbicide; flavouring spirits

Santolinatriene (165)f Sabinene (86)f Safranal (166)b trans-p-Menth-2-en-1-ol (167)b trans-Pinocarveol (91)b trans-Verbenol (93)b trans-Chrysanthenol (168)b

Medicinal properties/ other uses α-Bisabolol (108)a α-Bisabolol oxide B (174)a α-Bisabolone oxide A (175)a α-Eudesmol (176)a α-Selinene (177)e α-Amorphene (178)e α-Humulene (110)e α-Guaiene (179)e α-Cubebene (180)e Leaves

Brown (2010), Tzenkova et al. (2010), Abad et al. (2012), Ozek et al. (2014)

References 1-Octen-3-ol (185)n 1-S-cis-Calamenene (186)e 1,3,8-p-Menthatriene (187)f 1,8-Cineole (19)b 8-Cedren-13-ol (188)a (2Z,6E)-Farnesol (189)b

Part used

12 B. Koul and T. Khatri

aromatic plant growth, fernlike leaves and flowers are bright yellow with strong fragrance due to presence of bioactive compound camphor. Artemisinin (antimalarial) is a bioactive compound which is extracted from A. annua, which cures infection of Plasmodium Bioactive compounds present in Artemisia annua L. Cyclohexanecarboxylic acid, Abscisic acid (190)a Abscisic acid methyl ester 3-[[3-(3,4-dihydroxyphenyl)(191)a 1-oxo-2-propenyl]oxy]-4,5Acetone (192)m dihydroxy-1-[[3-(4-hydroxyAcetophenone, 2-43-methoxyphenyl)-1-oxo-2dihydroxy-6-methoxy propenyl]oxy] (309)c af Cyclooctane, 1,4-dipropyl (193) Aesculetin (194)y (310)ah f allo-Ocimene (195) Cyclopentanecarboxylic Amorph-4-en-7-ol (196)a acid, 3-methylene, 1,7,7Amyl 2-methylbutyrate trimethylbicyclo-[2.2.1]hept(197)o 2-yl ester (311)b ac Amyrenone, alpha (198) Cycloprop[7,8]azuleno[3a,4Amyrin, alpha (α-Amyrin) b]oxirene, decahydro(199)ac 1,4a,7,7-tetramethyl-, Amyrin, beta (β-Amyrin) (1R,6aR,7aR,7bS) (312)a ac Cyclopropane, (1-methyl(200) Amyrin, beta (β-Amyrin): 1,2-propadien-1-yl) (313)ah ac Cyclopropene, 3-ethenyl-3acetate (201) Anethole (202)c methyl (314)ah Myrcene alfa hydroperoxide (426)b Myrcenol (427)b Myrtenal (67)b Myrtenol (68)b Nerol (72)b Nerolidol (43)a Neryl acetate (74)b n-Hexanol (428)r n-Hexyl isovalerate (429)o n-Hexyl tiglate (430)o n-Nonyl alcohol (431)r Nonacosan-1-ol (432)r Nonacosane, n (433)i Nonadecane (434)i Nonadecanoic acid (435)g Norannuic acid (436)a Norannuic acid formyl

Xanthoxylin (538)af Ylangene (539)e Yomogi alcohol (540)b Zeatin (541)w Zeatin, dihydro: riboside (542)w α-Aromadendrene (135)e α-Bisabolol (108)a α-Bourbonene (543)e α-Cadinene (544)e α-Cadinol (545)a α-Cedrene (546)e α-Copaene (107)e α-Elemene (547)e α-Epoxyartemisinic acid (548)a α-Epoxydihydroartemisinic (549)a

The Artemisia Genus: Panacea to Several Maladies (continued)

2,6-Octadien-1-ol, 2,6-dimethyl8-[(tetrahydro-2H-pyran-2-yl) oxy] (632)b 2,7,10-Bisabolatriene (633)e 20 ,40 -Dimethyl ether (634)af 20 ,40 ,60 -Trihydroxyacetophenone 20 -methyl ether (635)af 20 -Methyl ether 4’-O-β-DGlucopyranosde (636)af 20 ,40 ,60 -Trihydroxyacetophenone 40 -methyl ether 2-O-β-DGlucopyranoside (637)af 2-Benzyloctanal (638)s 2-Butenoic acid, 3-methyl(1S,2R,4S)-1,7,7trimethylbicyclo[2.2.1]hept-2-yl ester (639)b 2-Butyl-2-octenal (640)s 2-Cyclohexen-1-one, 2-Methyl5-(1-methylcyclopropyl) (641)b

1 13

Botanical description

Cymol ( p-Cymene) (81)f Cynaroside (315)z Cyneol (316)b Daucosterol (317)x Decan-2-one (318)q Decanoic acid (37)g Deoxyarteannuin B (319)a Deoxyartemisinin (320)a Dihydroarteannuin B (321)a Dihydroartemisinic acid (322)a Dihydroartemisinic acid hydroperoxide (323)a Dihydroartemisinic alcohol (324)a Dihydroartemisinic aldehyde (325)a Dihydro-deoxyarteannuin B (326)a Dihydro-epideoxyarteannuin B (327)a Dihydro-seco-cadinane (328)a Dihydroxycadinanolide (329)a Docosan-2-one (330)q Docosanoic acid (331)g Dodecane (332)i Dodecanoic acid (333)g

Botanical name/common name

Anisole (203)af Annphenone (204)af Annuadiepoxide (205)ag Annuic acid, nor (206)a Annulide (207)a Annulide, iso (208)a Apigenin (209)y Aromadendrene epoxide (210)a Arteannuic acid (211)a Arteannuin A (212)a Arteannuin B (213)a Arteannuin B, deoxy EPI (214)a Arteannuin B, dihydro EPI: deoxy (215)a Arteannuin B, dihydro (216)a Arteannuin C (217)a Arteannuin D (218)a Arteannuin E (219)a Arteannuin F (220)a Arteannuin G (221)a Arteannuin H (222)a Arteannuin I (223)a Arteannuin J (224)a Arteannuin K (225)a Arteannuin L (226)a Arteannuin M (227)a Arteannuin N (228)a

Table 1.1 (continued)

ester (437)a Occidentalol (438)a Occidentalol acetate (439)a Occidol (440)a Octacosan-1-ol (441)r Octadecane (422)i Octadecanoic acid (443)g Octadecanoic acid, methyl ester (444)o Octan-1-ol (445)r Octanal (446)k Oleanolic acid (447)x Oleic acid (448)ak Pachypodol (449)y p-Allylanisole (450)c Patuletin (451)y Patuletin-3-O-β-Dglucoside (452)z p-Cymen-8-ol (162)b Penduletin (453)y Pentacosane, n (454)i Pentadecanoic acid (455)g Pentane (456)i Pentanoic acid (457)g Pentanoic acid, tert-butyl ester (458)o Perillaldehyde (82)b

Medicinal properties/ other uses References

2-Decenal (642)s 2-Ethylbutanoic acid, methyl ester (643)o 2-Ethylfuran (644)al 2-Heptanone (645)q 2-Heptenal (646)s 2-Hexenal (647)s 2-Hydroxybenzoic acid, 3-methylbutyl ester (648)o 2-Methoxy-3-(2-propenyl) phenol (649)af 2-Methyl butanoic acid, ethyl ester (650)o 2-Methyl-2-hexanol (651)r 2-Methyl-2-pentanol (652)r 2-Methylbutanoic acid (653)g 2-Methylbutanoic acid anhydride (654)al 2-Methyl-butanoic acid, 2-methylbutyl ester (655)o 2-Methyl propyl propionate (656)o 2-Naphthalenol, decahydro-1methyl-6-methylene-4(1-methylethenyl) (657)a 2-Nonynoic acid, methyl ester (658)o 2-α-Hydroxy-1,8-cineole (659)b 3,3-Dimethyl-1-butene (660)i

Part used α-Farnesene (550)e α-Guaiene (179)e α-Gurjunene (551)e α-Humulene (110)e α-Hydroxysantonin (552)a α-Linolenic acid (553)ak α-Phellandrene (113)f α-Pinene (114)f α-Selinene (177)e α-Terpinene (115)f α-Terpineol (18)b α-Thujene (117)f α-Thujone (118)b β-Bisabolene (182)e β-Cadinene (554)e β-Caryophyllene (555)e β-Cubebene (556)e β-Elemene (121)e β-Eudesmol (557)a β-Farnesene (152)e β-Guaiene (181)e β-Phellandrene (558)f β-Pinene (123)f β-Pinene oxide (559)b β-Sabinene hydrate (560)b β-Selinene (124)e γ-Cadinene (127)e

14 B. Koul and T. Khatri

Arteannuin O (229)a Arteanuic acid, 11(R)dihydro (230)a Artemetin (231)y Artemisia alcohol (134)b Artemisia dihydroxycadinolide 2-A (232)a Artemisia ketone (20)b Artemisia secocadinane (233)a Artemisia triene (234)f Artemisin (235)a Artemisinic acid (236)a Artemisinic acid, methyl ester (237)a Artemisinic acid,6,7-dehydro (238)a Artemisinic acid epoxy (239)a Artemisinic aldehyde (240)a Artemisinin (5)a Artemisinin B (241)a Artemisinin deoxy (242)a Artemisinin, dehydro (243)a Artemisinol (244)a Artemisitene (245)a Artemisyl acetate (246)b Ascaridole (247)b Astragalin (Kaempferol-3-Oglucoside) (248)z Aurantinamide acetate

Dodecanoic acid, ethyl ester (334)o Eicosane (335)i Eicosanoic acid (336)g Elemol (337)a Elemyl acetate (338)a Eleutheroside B-1 (339)ai Elixene (340)e endo-Dehydronorborneol (341)b epi-Cubenol (342)a epi-Deoxyarteannuin B (343)a epi-Globulol (344)a Ethyl formate (345)k Eudesma-4 (15)-11-diene, 5-alphahydroxy (346)a Eugenol (347)c Eugenyl isovalerate (348)c Eupalitin (349)y Eupatin (350)y Eupatorin (351)y Farnesal (352)a Farnesol (48)a Farnesyl pyrophosphate (353)a Fenchol (354)b Fenchone (355)b Flavone, 20 -40 -5-trihydroxy50 -6-7-trimethoxy (356)y Flavone, 30 -5-7-8tetrahydroxy-3-40 -dimethoxy

Perillene (459)b Phellandral (460)b Phenylacetic acid (461)af Phenylpropanoic acid (462)af Phthalate, bis- (hydroxy2-methylpropyl) (463)af Phytene-1,2-diol (464)l Phytene-1-ol-2hydroperoxide (465)l Phytol (153)l Phytone (466)m Pinocamphone (144)b Pinocarveol, trans (91)b Pinocarvone (163)b Pinocarvyl acetate (467)b Piperitone (14)b p-Menth-1-en-5-ol (468)b p-Menth-2,8-dien-1-ol (469)b p-Menth-3-ene (470)f p-Mentha-1(7),5-dien-2ol (471)b p-Mentha-1(7),8-dien-2ol (472)b p-Mentha-1,4(8)-dien-3ol (473)b p-Mentha-2,4-diene (474)f Ponticaepoxide (475)ag Pregeijerene (476)e Propanoic acid, ethyl

γ-Cadinol (561)a γ-Caryophyllene (562)e γ-Elemene (563)e γ-Eudesmol (564)a γ-Gurjunene (565)e γ-Muurolene (126)e γ-Selinene (566)e γ-Terpinene (130)f δ-Cadinene (131)e δ-Elemene (567)e δ-Muurolene (568)e δ-Terpineol (569)b ()-Amorpha-4,11diene (570)e ()-Myrtenyl acetate (160)b ()-Spathulenol (164)a ()-trans-Pinocarveol (91)b ()-α-Thujone (118)b (+)-Germacrene A (571)e (1R,3Z,9S)-Bicyclo [7.2.0]undec-3ene, 4,11,11-trimethyl-8methylene (572)e (2E)-Hexadecene (573)i (2E,4E)-Nonadienal (574)s (E)-3,7-Dimethyl-1,3,6octatriene (575)f (E)-2-Butenoic acid,

The Artemisia Genus: Panacea to Several Maladies (continued)

3,40 ,5,6,7-Pentahydroxyflavone 3,40 ,6,7-Tetramethyl ether (661)y 3,4-Diferuoylquinic acid (662)aj 3,4-Dihydroxybenzoic acid (663)af 3,5-Cycloheptadienone (664)al 3,5-Diferuoylquinic acid (665)aj 3,7-Dimethyl-1,5,7-octatrien-3-ol (666)b 3,7-Dimethyl-2,6-octadienyl, isobutyric acid, ester (667)b 3,7-Octadien-2-ol, 2,6-dimethyl (668)b 3,7-Octadien-2-ol, 2-methyl-6methylene (669)b 30 ,5,7,8-Tetrahydroxy3,40 -dimethoxyflavone (670)y 3-Allyl-6-methoxyphenol (671)c 3-Caffeoyl-4-feruloylquinic acid (672)aj 3-Cedren-12-ol (673)a 3-Cyclohexene-1-methanol 2-hydroxy-α,α,4-trimethyl-, 1-acetate (674)b 3-Feruloyl-5-caffeoylquinic acid (675)aj 3-Hexenyl butanoate (676)o 3-Hexenyl hexanoate (677)o 3-Methyl-1-butanol, acetate (678)o 3-Methylbutanal (679)k 3-Methylbutanoic acid, 3-methyl-

1 15

Botanical description

(357)y Flavone, 3-30 -5-trihydroxy40 -6-7-trimethoxy (358)y Flavone, 3-5-dihydroxy30 -40 -6-7-tetramethoxy (359)y Flavone, 5-hydroxy-3-40 -67-tetramethoxy (360)y Flavone, 5-hydroxy-3-40 -67-tetramenthoxy (361)y Flavone,4-5-50 -trihydroxy-35-6-7-tetramethoxy (362)y Fraxidin, iso (363)ai Friedelan-3-β-ol (364)x Friedelin (365)x Geraniol (52)b Geranyl acetate (53)b Germacrene B (49)e Germacrene D (50)e Globulol (366)a Glucoluteolin (367)z Guaiazulene (368)e Heneicosane (69)i Hentriacontayl triacontanoate (369)o Hepta-3-trans-5-diene-2one,6-methyl (370)m Heptadecane (70)i Heptadecanoic acid (371)g

Botanical name/common name

(249)w Axillarin (250)y Baurenol (251)ac Benzenepropanoic acid,3cyanophenyl ester (252)o Benzoic acid (253)af Benzyl 2-methyl butyrate (254)o Benzyl cinnamate (255)o Benzyl isovalerate (256)o Benzyl phenylacetate (257)o Benzyl valerate (258)o Bicyclo[2.2.2]octa-2,5diene, 1,2,3,6-tetramethyl (259)ah Bicyclo[3.1.1.] hept-2ene, 3,7,7-trimethyl (260)ah Bicyclo[3.1.1]heptan-3-one, 2,6,6-trimethyl-4-methylene (261)m Bonanzin (262)y Borneol (23)b Borneol acetate (263)b Borneol isobutyrate (264)b Bornyl valerate (265)b But-2-en-1-al,3-methyl (266)p Butanal (267)k Cadin-4-en-11-ol-3-iso-

Table 1.1 (continued)

ester (477)o Protocatechuic acid 4-glucoside (478)af Pseudopinene (479)f Purine, 7-8-dihydro: 6-(30 -methylbutylamino)-2-hydroxy (480)w Quercetagetin 3-methyl ether (481)y Quercetagetin3,40 -dimethyl ether (482)y Quercetagetin-30 -40 -6-7tetramethyl ether (483)y Quercetagetin-40 -6-7trimethyl ether (484)y Quercetagetin-40 -methyl ether (485)y Quercetin (486)y Quercetin 30 -glucoside (487)z Quercetin 3-rutinoside (488)z Quercetin-3’-O-beta-Dglucoside (489)z Quercetin-3-methyl ether (490)y Quercimeritrin (491)z

Medicinal properties/ other uses 2-methyl-, 2,2-dimethyl-1(2-methyl-1-propenyl)3-butenyl ester (576)b (E)-2-Hexenol (577)n (E)-3-Hexen-1-ol (578)n (E)-3-Hexen-1-ol, acetate (579)o (E)-Nerolidyl acetate (580)a (Z)-1,3(15),6,10Farnesatetraene (581)e (Z )-2-Nonenal (582)s (Z )-3,7-Dimethyl-1,3,6octatriene (583)f (Z )-3-Hexen-1-ol (584)n (Z )-3-Hexenyl isovalerate (585)o (Z )-3-Hexenyl propanoate (586)o (Z )-3-Hexenyl tiglate (587)o 1,10-Oxy-α-myrcene hydroxide (588)b 1,10-Oxy-β-myrcene hydroxide (589)b 1,10 -Bicyclopropyl, 2,20 -dimethyl (590)ah 1,1-

Part used

References 3-butenyl ester (680)o 3-Methylbutanoic acid, butyl ester (681)o 3-Methylbutanoic acid, ethyl ester (682)o 3-Methylfuran (683)al 3-Methylpentanal (684)k 3-Nonen-2-one (685)q 3-Octen-5-yne, 2,7-dimethyl(686)ag 3-Pinanol (687)b 3-Thujen-10-al (688)b 3-Thujen-2-ol (689)b 3-Undecen-1-yne (690)ag 3α,15-Dihydroxy cedrane (691)a 3α-Hydroxy-4α,5α-epoxy-7-oxo(8[7 ! 6]-abeo-amorphane (692)a 4(15),11-Amorphadien-9-one (693)a 4(15),5,11-Cadinatriene (694)e 4,5-Diferuoylquinic acid (695)aj 4,7(11)-Amorphadien-12-al (696)a 4-Amorphen,3,11-diol (697)a 4-Amorphen,3,11-diol 3-(2-methylpropanoyl) (698)a 4-Amorphene-3,7-diol (3α,7α) (699)a

16 B. Koul and T. Khatri

butyryl (268)a Cadin-4-ene,3-alpha-7alhpa-diyhydroxy (269)a Cadina-4 (15)-11-dien-9-one (270)a Cadina-4 (7)-11-dien-12-al (271)a Camphene (24)f Camphene hydrate (272)b Camphor (138)b Capillene (273)ag Carvacrol (25)b Carvone (26)b Caryophylladienol I (274)a Caryophylladienol II (275)a Caryophyllene oxide (27)a Casticin (276)y Cedra-8(15)-en-9α-ol (277)a Cedra-8(15)-en-9α-ol,acetate (278)a Cedra-8-en-13-ol, acetate (279)a Cedrol (280)a Cedryl acetate (281)a Chlorogenic acid (282)aa Chromene,2-2-6-trihydroxy (283)ai Chromene,2-2-dihydroxy-6methoxy (284)ai Chrysanthenone (140)b Chrysoeriol (285)y Chrysosplenetin

Hex-2-en-al (372)s Hexacosan-1-ol (373)r Hexacosane (374)i Hexadecane (375)i Hexadecanoic acid (376)g Hexadecanoic acid, ethyl ester (377)o Hexadecanoic acid, methyl ester (378)o Hexan-1-ol acetate (379)o Hexan-1-ol, 2-ethyl (380)r Hexanal (381)k Hexane (382)i Hex-cis-3-en-1-ol (383)n Hex-trans-2-en-1-ol (384)n Hexylcyclohexane (385)ah Humulene epoxide I (386)a Humulene epoxide II (387)a Ipsdienol (388)a Isoannulide (389)a Isoaromadendrene (390)a Isobornyl acetate (391)b Isochlorogenic acid A (392)aj Isochlorogenic acid B (393)aj Isochlorogenic acid C (394)aj Isocomene (395)e Isofraxidin (396)ai Iso-menthone (397)b Isophytol (398)l Isoquercitrin (399)z Isorhamnetin (400)y Isorhamnetin 3-glucoside

Quercitrin, iso (492)z Resorcinol, 5-nona decyl:3-O-methylether (493)al Retusin (494)y Rhamnentin (495)y Rhamnocitrin (496)y Rutin (497)z Sabina ketone (498)b Sabinene (86)f Sabinene, cis hydrate (46)b Sabinol (499)b Salicylic acid (500)af Santolina alcohol (87)b Santolinatriene (165)f Scoparone (501)ai Scopoletin (502)ai Scopolin (503)ai seco-Cadinane (233)a Selina-4,11-diene (504)e Silphinene (505)e Sitosterol, beta (506)x Spathulenol (164)a Stigmasterol (507)x Sylvestrene (508)f Tamarixetin (509)y Taraxasterone (510)x Taraxerol acetate (511)x Terpinen-4-ol (94)b Terpinolene (95)f Tetracosane (512)i Dicyclopropylethylene (591)ah 1,3-Pentadiene (592)i 1,4-Cineol (593)b 1,6-Octadien-4-one, 7-methyl-3-methylene(594)b 1,7-Octadien-3-one, 2-methyl-6-methylene(595)b 1,7-Octadiene (596)i 1,8-Cineol (19)b 10-Dodecyn-1-ol (597)ag 10-Epi-γ-Eudesmol (598)a 10-Undecenal (599)s 11R-()Dihydroartemisinic acid (600)a 14Hydroxy-α-humulene (601)a 14-Hydroxy-δ-cadinene (602)a 15-Nor-10-Hydroxyoplopan-4-oic acid (603)a 1-Caffeoyl-5feruoylquinic acid (604)aj 1-Dodecyne (605)ag

The Artemisia Genus: Panacea to Several Maladies (continued)

4-Amorphene-3,7-diol (3α,7α), acetate- (700) 4-Caffeoyl-5-feruloylquinic acid (701)aj 4-Feruloyl-5-caffeoylquinic acid (702)aj 4H-1-Benzopyran-4-one 5-hydroxy-2-(2-hydroxy-3,4-dimethoxyphenyl)-3,7-dimethoxy (703)y 4H-1-Benzopyran-4-one, 2-(2,4-dihydroxyphenyl)-5hydroxy-6,7-dimethoxy (704)y 4H-1-Benzopyran-4-one, 2-(3,5-dihydroxy-4methoxyphenyl)-3-(β-Dglucopyranosyloxy)-5,7dihydroxy (705)y 4H-1-Benzopyran-4-one, 3-hydroxy-6,7-dimethoxy-2(4-methoxyphenyl) (706)y 4-Hydroxy-2-isopropenyl-5methylene-hexan-1-ol (707)b 4-Methyl-2,3-dihydrofuran (708)al 4-Methyl-2-pentanone (709)q 4-Muurolen-10-ol (710)a 4-Penten-1-ol, propionate (711)o 4-Pentenal (712)s 4-Pentene-2-ol (713)n 4-Terpinyl acetate (714)b 4α,5α-Epoxy-6α-hydroxy

1 17

Botanical description

(401)z Jasmone (402)b Kaempferide, Iso (403)y Kaempferol (404)y Kaempferol, 6-methoxy: 3-O-beta-D-glucoside (405)z Kongol (406)a Lavandulyl acetate (60)b Ledene oxide (407)a Ledol (63)a Limonene (64)f Limonene-1,2-epoxide (408)b Linalool (66)b Linalool acetate (67)b Linoleic acid (409)ak Longipinene (410)e Luteolin (411)y Luteolin-7-methyl ether (412)y Maaliene (413)r Mearnsetin (414)y Menthen-4-ol, para (415)b Menthol (416)b Menthol, 2-hydroxy (417)b Methyl 9-octadecenoate (418)o Methyl cinnamate (419)c Methyl cyclopentane (420)ah

Botanical name/common name

(Chrysosplenol B) (286)y Chrysosplenol D (287)y Chrysosplenol E (288)y Chrysosplenol, 30 -methoxy (289)y Cirsilineol (290)y Cirsiliol (291)y Cirsimaritin (292)y cis-Arteannuic alcohol (293)a cis-Calamenene (186)e cis-Carveol (146)b cis-Carvyl acetate (294)b cis-Caryophyllene oxide (295)a cis-Chrysanthenyl acetate (145)b cis-Epoxyocimene (31)b cis-Lanceol (147)a cis-Pinocarveol (296)b cis-p-Menth-2-en-1-ol (297)b cis-Sabinene (298)f Citronellal (299)b Citronellol (300)b Corymbolone (301)a Coumaric acid (302)aa Coumarin (303)ai Cubenol (35)a Cuminal (724)c

Table 1.1 (continued)

Tetracosanoic acid (513)g Tetradecane, 2,5-dimethyl (514)i Tetradecanoic acid (515)g Tetratriacontane (516)i Thujone, iso (517)b Thymol (97)b t-Muurolol (99)a Tomentin (518)y trans,trans-1,3,5Heptatriene (519)i trans,trans-2,4Hexadiene (520)i trans-1,5,9-Decatriene (521)i trans-4-Methyl-2-hexene (522)i trans-5-Hydroxy-2isopropenyl-5methylhex-3-en-1-ol (523)n trans-Arteannuic alcohol (524)a trans-Carveol (170)b trans-Carvyl acetate (525)b trans-Caryophyllene (89)e

Medicinal properties/ other uses 1-Hepten-3-ol (606)n 1-Hepten-6-yne (607)ag 1-Methoxy-2-butyne (608)ag 1-Octanol (609)g 1-Octen-3-ol (185)n 1-Oxo-2β-[3-butanone]3α-methyl6β-[2-propanoic acid]cyclohexane (610)a 1-Oxo-2β-[3-butanone]3α-methyl6β-[2-propanol formylester]cyclohexane (611)a 1-Pentanol (612)r 1α-Aldehyde2β-[3-butanone]3α-methyl6β-[2-propanoic acid]cyclohexane (613)a 1α-Aldehyde2β-[3-butanone]3α-methyl6β-[2-propenoic acid]cyclohexane (614)a 1β,6α-Dihydroxy-4(15)eudesmane (615)a 1β-Hydroxy-4(15),5

Part used

References amorphan-12-oic acid (715)a 5,30 -Dihydroxy, 3,6,7,50 -tetramethoxyflavone (716)y 5-Hydroxy-30 ,40 ,6,7tetramethoxyflavone (717)y 5-Methyl-1-hexanol (718) 5-Methyl-2furancarboxyaldehyde (719)al 5-Nonadecylresorcinol-3-Omethyl ether (720)al 5α-Hydroperoxy-eudesma-4 (15),11-diene (721)a 5α-Hydroxy-eudesma-4(15),11diene (722)a 6,7-Dimethoxy dihydrocoumarin (723)ai 6-Methyl-3,5-heptadien-2-one (724)m 7-Oxabicyclo[4.1.0] heptane, 4-(1,5-dimethyl-4-hexen-1ylidene)-1-methyl-, (1R,4Z,6S)(725)a 8-Tricosanone, 23-hydroxy-2methyl- (726)r 9-Decen-1-ol (727)r 9-Octadecenoic acid, 2,3-dihydroxypropyl ester (728)o

18 B. Koul and T. Khatri

Cuminic alcohol (304)c Cyclocolorenone (305)a Cyclohexanecarboxylic acid, 1,3,4-trihydroxy-5[[3-(4-hydroxy-3methoxyphenyl)-1-oxo-2propenyl]oxy], (306)c Cyclohexanecarboxylic acid, 3,4,5-tris [[3-(3,4-dihydroxyphenyl)-1oxo-2-propenyl]oxy]-1hydroxy (307)c Cyclohexanecarboxylic acid, 3-[[3-(3,4-dihydroxyphenyl)1-oxo-2-propenyl]oxy]1,4,5-trihydroxy (308)c

Methyl eugenol (159)c Methyl hexadecanoate (421)o Methyl salicylate (422)af Mikanin (423)y Mycerene Beta Hydroperoxide (424)b Myrcene (425)f trans-Chrysanthenol (168)b trans-Nerolidol (43)a trans-Ocimene (526)f trans-Pinocarveol (91)b trans-p-Menth-2-en-1-ol (167)b trans-Sabinyl acetate (45)b trans-α-Ocimene (527)f trans-β-Farnesene (152)e Triacontane (528)i Triacontane,-2-29dimethyl (529)i Triacosan-8-on-23-ol,2methyl (530)r Tricosane (531)i Tricyclene (98)f Tridecanal (532)k Tridecane (533)i Tridecane, 5-methyl (534)i Tridecanoic acid (535)g Verbenone (101)b Verbenyl acetate (536)b Verboccidentene (537)e

(E),10(14)germacratriene (616)a 1β-Hydroxy-4(15),5eudesmadiene (617)a 1β-Hydroxy-4(15),7eudesmadiene (618)a 2,2,3-Trimethylbutane (619)i 2,2,6Trihydroxychromene (620)ai 2,2-Dihydroxy-6methoxy-2H-1benzopyran (621)ai 2,3-Dihydro-1,8-cineole (622)b 2,3-Epoxy-7,10bisaboladiene (623)b 2,40 ,50 -Trihydroxy50 6,7- trimethoxyflavone (624)y 2,4-Decadienal (625)s 2,4-Dimethyl-2-pentene (626)i 2,5-Dihydro-3methylfuran (627)al 2,6,10-Farnesatrien-1-ol acetate (628)a 2,6-Dimethyl-1,3,5,7octatetraene (629)f 2,6-Dimethyl-1,5,7octatrien-3-ol (630)b 2,6-Dimethyl-3,5,7octatrien-2-ol (631)b (continued)

1 The Artemisia Genus: Panacea to Several Maladies 19

Medicinal properties/ Botanical description other uses A. arborescens (arborescens None known. Essential means ’woody’ or ’treeoil is medicinal like’), is also known as tree wormwood, old woman or silvery. It is commonly grown in temperate regions of Mediterranean region. The plant is perennial or annual, silvery green-leaved bushy shrub with yellow daisy-like flowers which blossom in late summer Bioactive compounds present in Artemisia arborescens (Vaill.) L cis-Salvene (738)f Linalool (66)b Allo-aromadendrene (135)e Arborescin (729)a cis-Sabinene hydrate (46)b Limonene (64)f n Alcohol perrilique (730) Dehydro-sesquicineole Myrtenol (68)b Aldehyde perrilique (731)s Methyl benzoate (751)af (739)a b o Borneol (23) Diethyl phthalate (740) (7-Epi)-silphiperfol-5Bornyl butyrate (732)b Borneol (23)b ene (752)e e a Bicyclogermacrene (22) Elemol (337) Methyl jasmonate (753)b Bicyclo [2.2.1] heptan-2-ol, Eugenol (347)c Methyl salicylate (421)af t Fargesin (741) Neryl isovalerate (77)b 1,7,7-trimethyl-acetate, Germacrene D (50)e Neophytadiene (754)d (1S-endo) {Bornyl acetate} b a Germacrene-D-4-ol (742) Norcalamenene (755)a (137) Cuminaldehyde (733)c Geranyl isovalerate (56)b p-Cymene (81)f a g Catalponol (734) Hexadecanoic acid (376) Perillaldehyde (82)b Camphene (24)f Himachalol (743)b Phenyl hydroquinone Camphor (138)b Iso-3-thujanol (59)b (756)u Carvotanacetone (735)b Iso chavicolisobutyrate Pulegone (85)b f c () Canfene (736) Terpinolene (95)f (744) Carvacrol (25)b Isobutyl 2-methylbutyrate Terpinen-4-ol (94)b h o Chamazulene (28) Thymol (97)b (745)

Botanical name/common name Artemisia arborescens (Vaill.) L. (Tree wormwood)

Table 1.1 (continued) References Abad et al. (2012), Abderrahim et al. (2010) Araniti et al. (2013), Dhibi et al. (2015), Erel et al. (2012), Militello et al. (2011), Ozek et al. (2014), Younes et al. (2012)

γ-Terpinene (130)f 1,8-Cineole (19)b 1,4-Dihydro-p-menth-2-ene (762)b 2-Methyl butyl-2-methyl butyrate (763)o 2,3-Dimethoxytoluene (764)af 6-Methyl-5-hepten-2-one (765)m 3,4-Dimethyl cinnoline (766)w 2,2,3-Trimethylnaphtalen-1(2H)one (767)m 2.alpha./2.beta-Hydroxycholest4-en-3-one (768)x 3,30 -Dimethyldiphenyl (769)v (3Z)-Hexenyl 2-methyl butanoate (770)o 9,12-Octadecadienoic acid, methyl ester (771)o (E,E)-9,12,15-octadecatrienoic

Part used Whole plant

trans-Sabinol (92)b Toluene (758)af Undecan-2-one (759)q α-Bisabolol (108)a α-Copaene (107)e α-Thujene (117)f α-Pinene (114)f α-Phellandrene (113)f α-Terpinene (115)f α-Thujone (118)b α-Terpineol (18)b α-Humulene (110)e β-Eudesmol (557)a β-Selinene (124)e β-Pinene (123)f β-Phellandrene (558)f β-Thujone (125)b β-Bourbonene (119)e β-Copaene (760)e

20 B. Koul and T. Khatri

Iso-amyl iso-butyrate (746)o Isopentyl butanoate (747)o Junenol (748)a Sabinene (86)f Sesamin (749)t Selina-4(14),7(11)-diene (750)e

Distribution: East Asia—China, Japan, Korea, Manchuria Artemisia capillaris-Thunb. is a bushy perennial shrub that with an average height of 2–4 ft (60–120 cm) Bioactive compounds present in Artemisia capillaris-Thunb. Coumaric acid Apigenin (209)y Apigenin-7-glucoside (774)z (302)aa Caffeic acid (775)aa Catechin (778)y Capillarisin (776)y Epicatechin (779)y Catechin gallate (777)y Epigallocatechin gallate Chlorogenic acid (282)aa (780)y Hesperidin (781)z Hyperoside (782)z Artemesia caruifolia-Buch.Distribution: East Ham. Asia—China, Japan, Himalayas, annual or biennial herb with an average height of 30–150 cm. Branched and glabrous. Leaves at the basal stem generally fall down before anthesis. Leaf blade is elliptic or ovate to oblong, serrate margins

Artemisia capillaris-Thunb. (Yin Chen Hao)

Caryophyllene oxide (27)a cis-Piperitol (143)b cis-Pinene-hydrate (737)b

Isorhamnetin 3-Orobinobioside (783)z Isoquercitrin (399)z Isorhamnetin-3-ogalactoside (784)z Isorhamnetin-3-oglucoside (401)z Kaempferol (404)y Leaves are used as tea; used as anti-asthmatic; anti-phlogistic; depurative; febrifuge; stomachic; tonic; vermifuge/insect repellent

trans-Caryophyllene (89)e trans-Cadinol (171)a trans-Piperitol (17)b trans-Pinene hydrate (757)b trans-Sabinene hydrate (46)b Leaves are edible, antibacterial; anticholesterolemic; antiviral; cholagogue; diuretic; febrifuge; hepatic; vasodilator

2,4-Dihydroxy-6methoxyacetophenone 4-glycoside (786)ab 3,5-Di-O-caffeoylquinic acid (787)aa 3,4-Di-O-caffeoylquinic acid (788)aa Ma et al. (2001)

Naringin (785)z Rutin (497)z Scopolin (503)ai Scoparone (501)ai Quercetin (486)y

Leaves

(continued)

Park et al. (2012)

acid, methyl ester, (Z,Z,Z) (772)o 9,12-Octadecadienoic acid (773)ak

Leaves

β-Cubebene (556)e γ-Cadinene (127)e γ-Himachalene (761)e

1 The Artemisia Genus: Panacea to Several Maladies 21

A. chamaemelifolia is an Used as an insect endangered species of the repellent family Asteraceae, grown in European, Middle Eastern and Asian mountains such as the Alps, Caucasus, Cantabria and Stara Planina, and in Asia Minor and northern Iran. The stems are 30–50 cm (12–20 in.) in length and are erect, cylindrical, dark brown in colour. Leaves are pinnatisect, green coloured and may have minimum amount of hair. Flowers are yellow in colour Bioactive compounds present in Artemisia chamaemelifolia vill. Chrysanthenyl acetate (29)b Myrtenol (68)b Artemisia alcohol (134)b b f Artemisia ketone (20) cis-Sabinene (298) p-Cymene (81)f Bicyclogermacrene (22)e cis-β-Terpineol (8)b Pseudocumene (798)v Borneol (23)b Cuminic aldehyde (724)c Pinocarvone (163)b Bornyl acetate (137)b Davanone D (151)a Sabinene (86)f Camphene (24)f Davana ether (9)a Safranal (166)b Camphor (138)b Eugenol (347)c Santolinatriene (165)f Carvacrol (25)b Germacrene D (50)e Santolinyl acetate (799)b Caryophyllene oxide (27)a Limonene (64)f Spathulenol (164)a Chrysanthenone (140)b Linalool (66)b Terpinen-4-ol (94)b

Artemisia chamaemelifolia vill. (critically endangered)

Botanical name/common Medicinal properties/ name Botanical description other uses Bioactive compounds present in Artemisia caruifolia-Buch.-Ham. Artemitin (789)y Caruilignan B (791)t Caruilignan D (793)t t t Caruilignan A (790) Caruilignan C (792) Diayangambin (794)t

Table 1.1 (continued)

Sesartemin (796)t 3β-Hydroxy-29-norcycloart-24one (797)ac Ozek et al. (2014), Pirbalouti et al. (2013)

α-Terpineol (18)b α-Thujone (118)b β-Bisabolol (801)a β-Elemene (121)e β-Eudesmol (557)a β-Pinene (123)f γ-Terpinene (130)f 1,8-Cineole (19)b

Syringaresinol (795)p Sesamin (749)t

Thymol (97)b trans-Piperitol (17)b trans-Carveol (170)b trans-Caryophyllene (89)e Verbenene (800)f Viridiflorol (102)a α-Bisabolol (108)a α-Copaene (107)e α-Pinene (114)f α-Terpinene (115)f

Leaves

References

Part used

22 B. Koul and T. Khatri

Distribution: East Leaves are digestive in Asia—Russia, Turkestan function; used as A. cina is an edible aromatic febrifuge; used in herb commonly called as homeopathy; vermifuge/ santonica which is used as none known spice and also possesses antiseptic property. The plant has characteristic features including rounded pollen grains with a fibrous layer on it, which is one of the typical characters of Asteraceae family Bioactive compounds present in Artemisia cina Berg & C.F. Schmidt ex Poljakov α-Terpineol (18)b α-Thujone (118)b Artemisia ketone (20)b b f Borneol (23) α-Terpinene (115) β-Pinene (123)f Artemisia dracunculus L. Distribution: Southern Leaves are used as (Tarragon, French tarragon) Europe to Western Asia condiment/antiA. dracunculus L. commonly scorbutic; appetizer; called as tarragon grows to diuretic; emmenagogue; 120–150 cm in height with febrifuge; hypnotic; branching of slender stems. odontalgic; stomachic; Lanceolate leaves which are vermifuge/essential oil; long and broad, glossy green insect repellent in colour with entire margins. French tarragon rarely produces flowers and seeds; however, the flowers are small and grow in capitulate. Plant is a perennial herb which possesses a wide collection of health benefits, used as herbal medicine

Artemesia cina Berg & C.F. Schmidt ex Poljakov (Cina, Santonica)

1,8-Cineole (19)b

β-Thujone (125)b p-Cymene (81)f Leaves

The Artemisia Genus: Panacea to Several Maladies (continued)

Abad et al. (2012), Ben-Nasr et al. (2013), Obistioiu et al. (2014), Ozek et al. (2014)

Ermayanti et al. (2004)

Leaves

1 23

Artemisia herba-alba Asso (White wormwood)

Distribution: Africa (Saharan Maghreb), Asia (Arabian Peninsula area) and Southwestern Europe and Mediterranean Artemisia herba-alba is a chamaeophyte which grows to 20–40 cm. Strongly aromatic leaves which are covered with thin glandular hairs which reflect the sunlight and give a greyish appearence. Sterile shoots have grey, petiolate, ovate to orbicular leaves in outline, while flowering shoots have smaller and abundant leaves. Flowers are sessile, oblong and tapering at the base. Flowering season is fom September to December. 2–5 yellow-coloured hermaphrodite flowers are present on the receptacle

Botanical name/common name Botanical description Bioactive compounds present in Artemisia dracunculus L. trans-Ocimene (526)f Bicyclogermacrene (22)e Artedouglasia oxide A (1)a Bornyl acetate (137)b a Artedouglasia oxide B (2) Chavicol (802)c Artedouglasia oxide C (3)a cis-Davanone (7)a a Artedouglasia oxide D (4) Elemicin (803)c

Table 1.1 (continued) Part used Herniarin (806)ai Hexadecanoic acid (376)g Limonene (64)f Linalool (66)b Nordavanone (12)a

Medicinal properties/ other uses Estragole (10)c Eugenol (347)c (E)-Asarone (804)c (E)-Methylcinnamate (805)c Germacrene D (50)e

Sabinene (86)f trans-Ocimene (526)f Terpinolene (95)f (7-epi)-Silphiperfol-5-ene (752)e α-Terpinene (115)f γ-Decalactone (807)y Abad et al. (2012), Ben-Nasr et al. (2013), Obistioiu et al. (2014), Ozek et al. (2014)

References

24 B. Koul and T. Khatri

Bioactive compounds present in Artemisia herba-alba Asso 1,8-Cineole (19)b cis-Arbusculone (6)a 2(5H)-Furanone, cis-Chrysanthenyl acetate 5,5-dimethyl (808)ad (145)b e Aromadendrene (21) cis-Chrysanthenol (30)b Benzene,1,2,4-trimethyl cis-Davanone (7)a af cis-Jasmone (142)b (809) Bicyclogermacrene (22)e cis-Salvene (738)f b Borneol (23) Cuminal (733)c Bornyl acetate (137)b Davana ether (9)a f Camphene (24) Davana furan (812)a Camphor (138)b Elixene (340)e Caryophyllene oxide (27)a Filifolone (813)b Chrysanthenone (140)b Germacrene-D (50)e Chrysanthenylpropionate Isospathulenol (157)a Linalool (66)b (810)b cis-2-p-Menthen-1-ol (811)b Artemisia indica Willd. A. indica is annual or perennial and grows to a height of 1.2 m (4 ft). It is found in the western Himalayas including China, India, Indo-China, Japan and Malaysia. The leaves and flowering stems of plant possess anti-helminthic, antiseptic and anti-spasmodic activity. The main objectives of the present study were to evaluate the essential oil from Artemisia indica aerial part. The young leaves are cooked and eaten Leaves are used as condiment and colouring rice for food. Used as anthelmintic; antiseptic; anti-spasmodic; emmenagogue; expectorant; ophthalmic; stomachic; tonic/essential oil; incense; insecticide

Myrtenol (68)b Myrtenyl acetate (160)b Norchrysanthemic acid methyl ester (814)ae Nordavanone (12)a o-Isopropenyltoluene (815)c Palustrol (816)a p-Cymen-8-ol (162)b p-Cymene (81)f Pinocarvone (163)b Piperitenone (817)b Piperitone (14)b p-Nitroanisole (818)af Sabina ketone (498)b

Sabinene (86)f Spathulenol (164)a Terpinolene (95)f Thymol (97)b trans-2-p-Menthen-1-ol (819)b trans-Arbusculone (16)a Tricyclene (98)f Verbenene (800)f Verbenone (101)b Viridiflorol (102)a Vulgarol B (820)a α-Amorphene (178)e α-Copaene (107)e α-Phellandrene (113)f Leaves

The Artemisia Genus: Panacea to Several Maladies (continued)

Rashid et al. (2013), Zeng et al. (2015)

α-Pinene (114)f α-Terpinene (115)f α-Terpineol (18)b α-Thujene (117)f α-Thujone (118)b β-pinene (123)f β-Thujone (125)b γ-Terpinene (130)f γ-Vinyl-γ-valerolactone (Lavender lactone) (11)b δ-Cadinene (131)e

1 25

Artemisia japonica-Thunb.

The plant grows wild and is also cultivated in Afghanistan, Bhutan, China, India, Japan, Korea, Myanmar, Nepal, Pakistan, Russia, Taiwan and Thailand. This plant is commonly found in Ladakh area of Kashmir and is grazed by goats and sheep. The young leaves are cooked as a vegetable. A. japonica is also called Japanese wormwood, Pamasi, Ptee in Hindi and Chyenti in Nepali. It is a perennial plant and attains a height of 1 m. The stem is branched erect, glabrous and bears green leaves and yellow flowers

Botanical name/common name Botanical description Bioactive compounds present in Artemisia indica Willd. Curcumene (36)e Limonene (64)f Borneol (23)b Linalool (66)b b Chrysanthenone (140) Myrtenal (67)b Germacrene-D (50)e Piperitone (14)b b Iso-pulegol (821) Sabinene (86)f

Table 1.1 (continued)

trans-Caryophyllene (89)e trans-Pinocarveol (91)b Terpinen-4-ol (94)b α-Pinene (114)f α-Humulene (110)e Young leaves are cooked as vegetables/depurative; digestive; febrifuge; skin; women’s complaints/ incense

Medicinal properties/ other uses

Joshi (2013), Rashmi et al. (2014)

δ-Cadinene (131)e β-Elemene (121)e 1,8-Cineole (19)b

β-Pinene (123)f γ-Terpinene (130)f γ-Himachalene (268)e β-Selinene (124)e γ-Cadinene (127)e Leaves

References

Part used

26 B. Koul and T. Khatri

Artemisia vulgaris L. (Mugwort, common wormwood, felon herb, chrysanthemum weed, wild wormwood)

It is an annual or perennial, shrubby some extent hard in base, perfumed plant, which is found all over the hills of Himalayas in the middle and upper hill forest up to the height of 2000–5000 ft. in India, Sri Lanka, China, Iran and the USA A. vulgaris is commonly called Titeypati, Tuk-gnyel, Dhamanaga, Dona, Nagdamini, Barha and wormwood. It has been used worldwide in folk medicine since ancient times. The whole plant has been used as medicinal in Ayurvedic and ethnobotany. A. vulgaris possesses antibacterial, antifungal and insecticidal property

Bioactive compounds present in Artemisia japonica-Thunb. Aromadendrene (21)e Naphthalene1,2,4a,5,6,8aArtemisia alcohol (134)b hexahydro-4, 7-dimethyl-1Borneol (23)b (1-methylethyl) Germacrene D (50)e {α-amorphene} (178)e Linalool (66)b Sabinene (86)f

Leaves are used as condiment and colouring rice for food. Used as anticonvulsant; antidepressant; antiemetic; antiseptic; antispasmodic; appetizer; carminative; cholagogue; diaphoretic; digestive; diuretic; emmenagogue; expectorant; foot care; haemostatic; nervine; purgative; stimulant; tonic; women’s complaints/insecticide; insect repellent; tinder for fire

Spathulenol (164)b α-Cubebene (180)e α-Phellandrene (113)f α-Pinene (114)f β-Bourbonene (119)e

Leaves

β-Elemene (121)e β-Pinene (123)f γ-Muurolene (126)e γ-Cadinene (127)e γ-Terpinene (130)f

The Artemisia Genus: Panacea to Several Maladies (continued)

δ-Cadinene (131)e α-Eudesmol (176)a α-Muurolol (822)a 6-Isopropenyl-4,8a-dimethyl1,2,3,5, 6,7,8,8a-Octahydronaphthalen-2-ol (823)a 1,8-Cineole (19)b Obistioiu et al. (2014), Ozek et al. (2014)

1 27

n-Pentadecane (830)i n-Hexadecane (375)i n-Nonadecane (71)i Phytol (153)l Phenyl ethyl alcohol (831)af p-Cymen-8-ol (162)b Silphiperfol-5-en-3-ol (15)a Silphiperfol-4,7(14)diene (832)e Sabinene (86)f Santolinatriene (165)f Salvial-4(14)-en-1-one (833)a Spathulenol (164)a Terpinolene (95)f trans-Sabinene hydrate (46)b Terpinen-4-ol (94)b

Medicinal properties/ other uses E-β-farnesene (152)e Z-β-ocymene (834)f α-Terpinene (115)f α-Terpineol (18)b α-Copaene (107)e α-Calacorene (835)e α-Humulene (110)e α-Thujene (117)f α-Pinene (114)f α-Terpinyl acetate (116)b β-Pinene (123)f β-Bisabolene (182)e β-Copaene (760)e β-Chamigrene (836)e β-Selinene (124)e

Part used

β-Bourbonene (119)e β-Elemene (121)e β-Longipinene (837)e γ-Terpinene (130)f γ-Muurolene (126)e γ-Cadinene (127)e δ-Cadinene (131)e δ-Elemene (567)e 1-Octen-3ol (185)n 1,4-p-Menthadien-7-ol (838)b 2-Lanceol acetate (839)a 1,8-Cineole (19)b

References

Oxygenated sesquiterpenesa, Oxygenated monoterpenesb, Phenylpropanoidsc, Diterpene hydrocarbonsd, Sesquiterpene hydrocarbonse, Monoterpene hydrocarbonsf, Saturated fatty acidsg, Azulenesh, Acyclic alkanesi, Norisoprenoidsj, Saturated fatty aldehydesk, Oxygenated diterpenesl, Unsaturated ketonem, Unsaturated fatty alcoholn, Fatty estersO, Oxygenated hemiterpenep, Alkyl ketonesq, saturated fatty alcoholr, unsaturated fatty aldehydess, lignant, phenolic acidsu, aromatic hydrocarbonv, Alkaloidsw, Sterolsx, Flavonoidsy, Flavonoid glycosidesz, Hydroxyl cinnamic acidsaa, Phenolic glycosidesab, Oxygenated triterpenesac, Butenolidesad, Pyrethroidsae, Benzanoidsaf, Alkyneag, Cyclic hydrocarbonsah, Coumarinsai (except flavonoids), Ester of caffeic acidaj, Unsaturated fatty acidsak, Miscellaneousal Volatile constituent

Botanical name/common name Botanical description Bioactive compounds present in Artemisia vulgaris L. Artemisia triene (234)f Eugenol (347)c Artemisyl acetate (246)b E-nerolidol (43)a e Aromadendrene (21) Germacren D-4-ol (732)a Artemisia ketone (20)b Germacrene D (50)e b Artemisia alcohol (134) Humulene epoxide II (387)a Bicyclogermacrene (22)e Hexadecanoic acid (376)g b Borneol (23) Iso-3-thujanol (59)b cis-Arteannuic alcohol Iso-3-thujyl acetate (826)b a Isobornyl acetate (391)b (293) Caryophyllene oxide (27)a Isoborneol (827)b b Camphor (138) Linalool (66)b cis-Chrysanthenyl acetate Ledol (63)a b Longipinocarveol (828)a (145) Dehydro-sesquicineole n-Nonanal (829)k a n-Tridecane (533)i (729) Camphene (24)f Caren-4-ol (824)b Cuminol (825)c

Table 1.1 (continued)

28 B. Koul and T. Khatri

The Artemisia Genus: Panacea to Several Maladies

(27)

(28)

(29)

29

(30)

(31)

(32)

(26)

1

30

B. Koul and T. Khatri

(69)

The Artemisia Genus: Panacea to Several Maladies

(68)

1

31

32

B. Koul and T. Khatri

The Artemisia Genus: Panacea to Several Maladies

33

(152)

1

B. Koul and T. Khatri

(188)

34

1

The Artemisia Genus: Panacea to Several Maladies

35

36

B. Koul and T. Khatri

1

The Artemisia Genus: Panacea to Several Maladies

37

38

B. Koul and T. Khatri

1

The Artemisia Genus: Panacea to Several Maladies

39

40

B. Koul and T. Khatri

1

The Artemisia Genus: Panacea to Several Maladies

41

B. Koul and T. Khatri

(355)

42

1

The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

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The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

(434)

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The Artemisia Genus: Panacea to Several Maladies

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(451)

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B. Koul and T. Khatri

(466)

48

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The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

(493)

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The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

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The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

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The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

The Artemisia Genus: Panacea to Several Maladies

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58

B. Koul and T. Khatri

The Artemisia Genus: Panacea to Several Maladies

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(694)

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B. Koul and T. Khatri

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The Artemisia Genus: Panacea to Several Maladies

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B. Koul and T. Khatri

(756)

(754)

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The Artemisia Genus: Panacea to Several Maladies

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63

(791)

B. Koul and T. Khatri

(788)

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The Artemisia Genus: Panacea to Several Maladies

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(810)

1

B. Koul and T. Khatri

(811)

(812)

66

Species A. absinthium L.

Ethanol extract of plant

Antioxidant

Antibacterial

(continued)

Altunkaya et al. (2014)

Erel et al. (2012) Lee et al. (2013)

Altunkaya et al. (2014)

Erel et al. (2012)

Ahmad et al. (1992) Daradka et al. (2014) Zeraati et al. (2014)

References Ahmad et al. (1992) Yildiz et al. (2011) Erel et al. (2011) Taherkhani (2014)

The Artemisia Genus: Panacea to Several Maladies

Aqueous extract of dried plant sample

Methanol extract of aerial parts Aqueous extract of aerial parts

Aqueous extract of dried plant sample

Disc-diffusion method against Staphylococcus aureus Staphylococcus aureus (ATCC 12600), Bacillus subtilis (ATCC 6051), Pseudomonas aeruginosa (ATCC 10145), Enterococcus faecalis (ATCC 29212), Salmonella typhimurium (ATCC 25241), Escherichia coli (ATCC 11775) α-Tocopherol equivalent assay Phosphomolybdenum and DPPH (1,1-diphenyl-2 picrylhydrazyl radical scavenging activity) assay ABTS (2,20 -azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radicals

Nociceptive assay against male albino mice

Male rabbits with hypercholesterolemia

Methanol extract of aerial parts

Antiinflammatory Hypolipidaemic

Saline extract of shade dried plant parts Methanol extract of aerial parts

Toxocara cati (cat parasite) MCF7 (human breast cancer cell line) cells MTT [3-(4,5-dimethylthiazolyl)-2,5diphenyltetrazolium bromide] assay, HeLa (human cervical cancer) cells Hind paw oedema method against albino mice

Di-ethyl ether extract of flower parts Methanol extract of aerial parts Aqueous extract of air-dried aerial parts

Anti-parasitic Cytotoxicity

Anti-nociceptive

Study model/methodology Tail immersion method against albino mice

Tested substance Methanolic extract of aerial parts

Pharmacological activities Analgesic

Table 1.2 Pharmacological activities of Artemisia species

1 67

A. annua L.

Species

Table 1.2 (continued)

Anti-ulcerogenic Anti-bacterial

Insect repellent

Anti-coccidial

Antiviral

Hepatoprotective Antimalarial Anti-plasmodial

Antimicrobial

Pharmacological activities

Acetonitrile extract of five-week-old seedlings Shade dried aerial parts (steam distillation) Crude ethanol extract of aerial parts Aqueous extract of air-dried plant material Aqueous extract of fresh aerial parts

Essential oil extract of leaves, stem and flowers Hydroalcohlic extract of aerial plant parts Ethyl alcohol leaf extract Methanol, n-hexane, chloroform and water extract of suspension cells Aqueous extract of plant material

Hydroalcoholic plant extract

Tested substance Hydrodistillation of essential oil Essential oil extract of leaves, stem and flowers Methanol extract of powdered plant material Aqueous extract of aerial parts

TMV (tobacco mosaic virus), SRV (sunnhemp rosette virus) Coccidia infections in male chickens due to Eimeria tenella Tribolium castaneum Herbst and Callosobruchusm aculatus L. Indomethacin-induced ulcer in rats Escherichia coli, Enterococcus hirae, Staphylococcus aureus Esclzericlzia coli, Staphylococcus aureus, Streptococcus faecalis, P. aeruginosa, Klebsiella pneumonia, Bacillus subtilis, Bacillus liclzenqomis

Against Plasmodium berghei in mice Plasmodium falciparum

Total antioxidant power and total thiol groups assays Gram positive and gram-negative bacterial strains Staphylococcus aureus, against 20 male Sprague-Dawley rats Staphylococcus aureus (25923), Listeria monocytogenes Male Wistar rats

Study model/methodology DPPH radical scavenging activity DPPH assay

Rasooli et al. (2003)

Tripathi et al. (2000) Dias et al. (2001) Juteau et al. (2003)

Allen et al. (1997)

Khan et al. (1991)

Moslemi et al. (2012) Msaada et al. (2015) Mohammadian et al. (2016) Zafar et al. (1990) Tawfiq et al. (1989)

References Wani et al. (2014) Msaada et al. (2015) Mohammadian et al. (2016) Juteau et al. (2003)

68 B. Koul and T. Khatri

Ethanolic extract of aerial parts Petroleum ether, ethanol, acetone, water extracts of, stems leaves and roots Ethanol extract of leaves

Anti-insect Acaricidal

Anti-microbial

Methanol extract of leaves

Antioxidant

Aqueous extract of air-dried plant material

Chloroform extract of aerial parts and n-hexane extract of plant cell culture Ethanol extract of leaves

Antimalarial

Anti-parasitic

Aqueous extract of air-dried plant material Aqueous extract of fresh aerial parts

Antifungal

Total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP), trolox equivalent antioxidant capacity (TEAC) and DPPH assay ABTS (2,20 -Azino-bis (3-ethylbenzthiazoline6-sulphonic acid) radical-scavenging activity, ORAC (oxygen radical absorbance capacity assay), DPPH (1,1-diphenyl-2 picrylhydrazyl radical-scavenging activity) and metalchelating assays Paper-disc diffusion method against Bacillus subtilis (ATCC 6633), Enterococcus faecalis (ATCC 29212), Staphylococcus aureus (ATCC 6538 and ATCC 25923), Streptococcus pneumonia (ATCC 49619),

298 Farm workers (study model)

HPLC (high-performance liquid chromatography), Rhipicephalus (Boophilus) microplus (study model) Plasmodium falciparum

(continued)

Cavar et al. (2012)

Ogwang et al. (2011) Iqbal et al. (2012)

Liu et al. (1992)

De Souza Chagas et al. (2011)

Rasooli et al. (2003) Maggi et al. (2005) Zhang et al. (2008)

Candida albicans, Saccharomyces cerevisiae Epilachna paenulata and Spodoptera eridania Tetranychus cinnabarinus Bois

Juteau et al. (2003)

Candida albicans, Saccharomyces cerevisiae

1 The Artemisia Genus: Panacea to Several Maladies 69

A. arborescens (Vaill.) L.

Species

Table 1.2 (continued)

Antioxidant

Chemo preventive

Methanol extract of dried leaves

Allelopathic

Ethanol extract of aerial parts Ethanol extract of aerial parts

Aqueous extract of aerial parts

Methanol extract of aerial parts Dimethyl sulphoxide (DMSO) extract of leaves Ethyl acetate extract of aerial parts

Antiviral

Aqueous extract of aerial parts

Methanol extract of aerial parts

Aqueous extract of aerial parts

Powdered leaves

Anti-leishmanial

Antibacterial

Tested substance

Pharmacological activities

Gas chromatography, mass spectrometry; 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay DPPH and FRAP assay MTT assay

Gas chromatography, mass spectrometry, Lactuca sativa L. (study model) DPPH assay

Micrococcus luteus (ATCC 4698), Escherichia coli (ATCC 25922), Haemophilus influenzae (ATCC 49766), Pseudomonas aeruginosa (ATCC 9027 and ATCC 27853) In vitro anti-leishmanial activity against the hamsters infected with Leishmania panamensis Gas chromatography, mass spectrometry, Listeria monocytogenes (study model) Disc diffusion method against Staphylococcus aureus Gas chromatography, mass spectrometry, Enterococcus faecalis, Listeria monocytogenes, Escherichia coli (study model) HSV 1 (Herpes simplex virus type 1) Herpes simplex virus 1, 2 (HSV-1 and HSV-2)

Study model/methodology

Carvalho et al. (2011) Younes et al. (2012) Ornano et al. (2013)

Araniti et al. (2013)

Sinico et al. (2005) Saddi et al. (2007)

Younes et al. (2012)

Militello et al. (2011) Erel et al. (2012)

Mesa et al. (2017)

References

70 B. Koul and T. Khatri

A. Capillaris Thunb.

A. campestris L.

A. asiatica (Pamp.) Nakai ex Kitam.

A. afra Jacq. ex Willd A. tschernieviana Besser A. ludoviciana Nutt.

Antiinflammatory Antioxidant Antitumour Antimicrobial

Antimicrobial

Hexane and dichloromethane extract of volatile oil

Diethyl-ether extract of aerial parts

Water, alcohol and hexane plant extract

Ethanol extract of plant

Phyto-synthesised silver nanoparticles extract of aerial parts Hydrodistilled aerial and ground plant parts Hydro-distilled plant extract

Anti-cancer

Anti-nociceptive

Aqueous extract of leaves

Methanol extract of leaves

Aqueous extract of aerial parts

Antimicrobial

Hepatoprotective Phytotoxicity

DPPH assay, ABTS assay Human adenocarcinoma cell line (HT-29) Broth dilution method was used against different strains of Staphylococcus Salmonella typhi, Klebsiella pneumoniae, E. coli (MTCC 1610), Staphylococcus aureus (MTCC96), Streptococcus mutans (MTCC 890), Bacillus subtilis (MTCC121), Candida albicans (MTCC 1637) and C. glabrata (MTCC3019)

Cytotoxicity assay against HT29 (human colon adenocarcinoma cell line) Hot plate and formalin-induced test against ICR male mice Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Rhodotorula rubra, Candida albicans, Aspergillus fumigatus Gastric ulcers induced in mice

Gas chromatography, mass spectrometry, Wistar rats (study model) GC–MS (gas chromatography, mass spectrometry) and HPTLC (high-performance liquid chromatography) analysis, Lactuca sativa L., Raphanus sativus L., Amaranthus retroflexus L., Cynodon dactylon L. 41 different strains of microbes

The Artemisia Genus: Panacea to Several Maladies (continued)

Joshi (2013)

Cha et al. (2005)

Akrout et al. (2011)

Jeong et al. (2014)

Anaya-Eugenio et al. (2016) Kalemba et al. (2002)

Mangena and Muyima (1999) Khalili et al. (2017)

Araniti et al. (2016)

Dhibi et al. (2015)

1 71

A. spicigera K. Koch

A. abyssinica Sch. Bip. ex A. Rich.

A. caruifolia BuchHam. A. iwayomogi Kitam. A. scoparia Waldst. & Kit.

Species

Table 1.2 (continued)

Methanolic extract of aerial parts

Anti-leishmanial Antioxidant

Antifungal Antioxidant Cytotoxicity

Dichloromethane extract of aerial parts Hydrodistillation of leaves

Methanol extract of aerial parts Methanol extract of aerial parts Methanol extract of aerial parts

Antibacterial

Antitrypanosomal Cytotoxic

Methanol extract of aerial parts

Antimicrobial

Methanol extract of aerial parts

Ethanol extract of whole plant

Tested substance Methanol extract of whole plant

Hexane-ethyl acetate essential oil extract Diethyl-ether extract of aerial parts

Antibacterial

Antitumour activity Cytotoxic

Pharmacological activities Anti-glycation

Erythrocytes and human monocytic leukaemia cells (THP-1) Leishmania aethiopica and L. donovani DPPH method

Broth dilution method: against different strains of Staphylococcus Disc diffusion method against Staphylococcus aureus Candida albicans Radical scavenging assay Inhibit multiplication of MCF7 (human breast cancer cell line) cells and HeLa (human cervical cancer) cells Trypanosoma brucei brucei

Study model/methodology Protein tyrosine phosphatase 1B (PTP1B),a-glucosidase, rat lens aldose reductase (RLAR), and advanced glycation end product (AGE) formation inhibitory assays Human hepatocellular carcinoma cells (Huh7, HepG2) Meth-A (fibrosarcoma) and LLC (lewis lung carcinoma) Tumor Cell Lines Different Staphylococcus strains

Afshar et al. (2012)

Nibret and Wink (2010) Tariku et al. (2010)

Erel et al. (2011)

Erel et al. (2012)

Cha et al. (2005)

Chung et al. (2009)

Ma et al. (2001)

Jang et al. (2017)

References Islam et al. (2014)

72 B. Koul and T. Khatri

Hydrodistillation of leaves

Antimicrobial

Antibacterial Antifungal Antibacterial Antifungal

Antimicrobial

A. pallens Wall. ex DC.

A. herba-alba Asso.

Antioxidant Therapeutic

Ethanol extract of powdered aerial parts

Antimalarial

A. abrotanum L.

Methanol and ethanol extract of whole plant

Hydrodistillation of aerial parts

Ethanol extract of aerial parts

Antibacterial

Hydrodistillation of essential oil

Aqueous extract of air-dried aerial parts Steam-distilled essential oil

Antifungal

Antifungal

Aqueous extract of air-dried aerial parts

Antibacterial

A. fragrans Willd.

A. douglasiana Besser ex Besser

A. khorassanica Podlech

Pseudomonas cepacia Trichosporon beigelii Bacillus stearothermophilus Trichosporon beigelii, Saccharomyces cerevisiae Agar-well diffusion method: different bacterial and fungal strains DPPH and ABTS assay STZ (streptozotocin)-induced diabetic neuropathic rats

Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 29737), Enterobacter cloacae (PTCC 1003), Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), Salmonella typhi (PTCC 1185) Candida albicans (ATCC 10231), Aspergillus niger (ATCC 16404) Colletotrichum fragariae, Botrytis cinerea, Colletotrichum acutatum, Colletotrichum gloeosporioides B. cereus (ATCC 14579), S. aureus (ATCC 29213), P. aeruginosa (ATCC 27853), C. albicans (ATCC 10231), E. coli (ATCC 25922), A. niger (ATCC 16401) Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa Plasmodium falciparum strains

The Artemisia Genus: Panacea to Several Maladies (continued)

El-Marasy et al. (2017)

Mighri et al. (2010)

Cubukcu et al. (1990) Suresh et al. (2010)

Shafaghat et al. (2009)

Setzer et al. (2004)

Meepagala et al. (2003)

Ramezani et al. (2004)

1 73

Aqueous extract of powdered plant

Antioxidant Anticonvulsant

Nociceptive Antiinflammatory

Hydrodistillation of essential oil

Antibacterial

A. echegarayi Hieron.

A. dracunculus L.

Hydrodistillation of essential oil

Antimicrobial

Acetone, petroleum ether and ethanol extract of dried leaves Water and alcoholic extract of aerial parts Hydrodistilled volatile oil

A. kulbadica Boiss.

Antidiabetic

Acaricidal

Aqueous extract of leaves and flowers Hydrodistillation of essential oil

Antioxidant

A. judaica L.

Methanol extract of aerial parts Aqueous extract of leaves and flowers

Antifungal Antibacterial

A. saharae Pomel.

Antioxidant

Methanol extract of aerial parts Methanol extract of aerial parts

Antioxidant Antibacterial

A. sanctonium L.

A. japonica Thunb.

Tested substance Methanol extract of aerial parts

Pharmacological activities Antibacterial

Species A. campestris L.

Table 1.2 (continued)

48 Wistar-albino adult male rats

Disc diffusion assay and micro-well dilution method against seven bacterial species Gas chromatography/mass spectrometry NMRI male mice

Six different bacterial strains

Tetranychus urticae Koch and Phytoseiulus persimilis Diabetes-induced rats

Study model/methodology Disc diffusion method against Staphylococcus aureus Trolox equivalent antioxidant capacity Disc diffusion method against Staphylococcus aureus Candida albicans Escherichia coli, Klebsiella pneumonia, Salmonella typhimurium, Bacillus cereus, Enterococcus faecalis, and Micrococcus luteus Gas chromatography/mass spectrometry, DPPH assay Gas chromatography/mass spectrometry

Sayyaha et al. (2004) Reza et al. (2015)

Aghajani et al. (2009) Laciar et al. (2009)

Pradeep et al. (2014) El-Sharabasy (2010) Nofal et al. (2009)

Zouari et al. (2014)

Erel et al. (2012)

References Erel et al. (2012)

74 B. Koul and T. Khatri

A. vestita Wall. ex Besser A. vulgaris L..

A. argentea L’Hér.

A. nilagirica (C.B. Clarke) Pamp. A. indica Willd.

DPPH assay, FTC (ferric thiocyanate method) DPPH assay Enzymatic and non-enzymatic antioxidant activity

Methanol and chloroform extract of leaves

Antioxidant

Aqueous extract of mature and young leaves and woody litter Essential oil Methanol extract of dried aerial parts

Allelopathic

Against experimentally induced coccidial infection in broiler chicken Lepidium virginicum L., Lolium perenne L.

Crude plant extract

Anti-coccidial

Alcoholic extract of aerial parts

PTZ-induced seizures Elevated plus maze (EPM), light/dark box test (LDB) The tail suspension test, the forced swim test DPPH and FRAP assay

Methanol extract of plant

Antidepressant Antioxidant

Different strains of Leishmania

Ethanolic leaf extract

Antipromastigote Anticonvulsant Anxiolytic

Total phenolic content (TPC), total flavonoid content (TFC), DPPH free radical scavenging assay Hole plate diffusion method (HPD), disc diffusion method (DDM), pour plate method (PPM), agar dilution method (ADM), minimum inhibitory concentration (MIC) against different bacteria and fungi Gas chromatography/mass spectrometry

Hydrodistillation of essential oil

Water, ethanol and water-ethanol extract

Antioxidant

Antimicrobial

Antioxidant

(continued)

Melkania et al. (1982) Bhatt et al. (2007) Karabegovic et al. (2011) Haniya and Padma (2013)

Gouveia and Castilho (2011) Ahad et al. (2017)

Pradeep et al. (2014) Ganguly et al. (2006) Khan et al. (2016)

Behbahani et al. (2017)

1 The Artemisia Genus: Panacea to Several Maladies 75

Species

Table 1.2 (continued)

Methanol extract of aerial parts

Essential oil

Ethanol leaf extract

Aqueous extract of air-dried stem

Cyto-toxicity

Larvicidal

Antimalarial

Antihyperlipidaemic

Antifungal

Antimicrobial

Tested substance Methanol extract of aerial parts

Alcohol, petroleum, benzene and water extract of leaves Chloroform, ethyl acetate, ethanol, aqueous, petroleum ether extract of leaves Methanol extract of dried aerial parts

Pharmacological activities Antibacterial

Male albino Wistar rats

Plasmodium berghei (parasite on male mice)

B. subtilis, S. aureus, E. coli, P. aeruginosa, S. cerevisiae, C. albicans, A. niger MCF7, HeLa, A7R5 (smooth muscle cell line), 293 T (human embryonic kidney cell line) Larvicidal bioassay against Aedes aegypti

Study model/methodology Disc diffusion method against Staphylococcus aureus Disc diffusion method, Staphylococcus aureus, Escherichia coli Candida albicans, Rhizopus japonicus, C. tropicalis, Aspergillus fumigatus

Govindaraj et al. (2013) Bamunuarachchi et al. (2014) Khan (2015)

Karabegovic et al. (2011) Erel et al. (2011)

Hiremath et al. (2011)

References Erel et al. (2012)

76 B. Koul and T. Khatri

1

The Artemisia Genus: Panacea to Several Maladies

77

Table 1.3 List of some commercialized products of Artemisia species Species Artemisia absinthium L.

Artemisia annua L.

Medicine Artemisia combination

Formulations Capsules

Uses Stimulate digestive process/tonifies stomach, liver, nerves and intestine Dietary supplements

Artemisia 100 vegetarian caps

Capsules

Artemisia tablets

Tablets

Artemisia and clove

Syrup

Artemisia combination

Capsules

Improves digestion/soothes digestive tract

Artemisia absinthium plus

Syrup

Anthelmintic

Best Artemisinin

Capsules

Dietary supplements

Artemisia oil

Oil

Assenzio

Cream

Super artimisinin

Tablets

Anthelmintic, deodorant, digestive, insecticide, narcotic, febrifuge, vermifuge Deodorant cream (provides longlasting freshness) Dietary supplements

Artemisia plus

Tablets

Improves immune system and digestion Broad-spectrum herbal supplement

Improves digestion, relieve flatulence, nausea, heart burn, relieve chills and minor fever

Company Knowledge products, The Canadian cleansing company, Richmond Hill, Ontario, Canada Allergy research group LLC, 2300 north loop road, Alameda, California Natural point, Pompeo mariani, Milano, Italy Bioray, 23,172 Alcalde drive, Suite B, Laguna Hills, California Nature’s sunshine products, 2500 west executive parkway, Suite 500, Lehi, Utah, United States Nature’s formulae health products ltd., Kelowna, British Columbia, Canada Doctor’s best, 18100 Von karmen ave., Irvine, California, United States Katyani exports, Road no. 44, Rani bag, Pitampura, New Delhi, India

L’Erbolario, Viale Milano, Lodi, Italy Nurticology, 2300 north loop road, Alameda, California Interclinical laboratories Pvt. Ltd., Alexandria, Australia

(continued)

78

B. Koul and T. Khatri

Table 1.3 (continued) Species

Medicine Artemisia annua pura

Formulations Tonic

Uses Improves gastrointestinal functioning

Intestinal tract defence

Tonic

Improves digestion

Arteether

Injection

Antimalarial

Artemisia capillaris Thunb. Artemisia vulgaris L.

Wormwood oriental

Capsules

Divya arshkalp vati

Tablets

Improves digestion and body detoxification Relief from Constipation, indigestion and hyperacidity

Artemisia pallens Wall.

Davana oil

Oil

Pitta

Oil

Aphrodisiac, stimulator antiinfectious, calmative, mucolyting, emollient Improves digestion, metabolism and energy production

Company Herb pharm, 117 SE Taylor street, Portland, Oregon, USA Herb pharm, 117 SE Taylor street, Portland, Oregon, USA 11/12, Udyognagar, S.V. road, Goregaon (west), Mumbai, India Nature’s health, Las Vegas, USA Patanjali Ayurved Limited unit III, Patanjali food and herbal park, Village Padartha, Laksar road, Haridwar, Uttrakhand, India C-39, second Floor, 13th Street, Madhu Vihar, Patparganj, Delhi, India

Perfect potion pvt. Ltd., Zillmere, Queensland, Australia

Singh 2018a, b; Kumar et al. 2018a; Kumar et al. 2018b). Furthermore, being a reservoir of various phytochemical constituents, this genus is overexploited due to continuously increasing demands of pharmaceutical industries as well as other anthropogenic activities (Kumar et al. 2018c; Datta et al. 2018; Singh et al. 2018; Kaur et al. 2018; Singh et al. 2017). Hence, the conservation of this genus is the need of the hour. Otherwise, it will lead to its biodiversity loss. As discussed in the previous study by Koul et al. 2017, micropropagation or in vitro generation is one of the promising techniques for the mass production of uniform, disease-free and multiple plants which can be used for the production of secondary metabolites (Yildiz et al. 2011; Mckenna and Hughe 2014). Various studies have been conducted for in vitro propagation of important species of this genus which are discussed in Table 1.4.

Species A. absinthium L.

Inoculum

Callus

Leaf

Shoots Leaf

Callus

Callus

Callus

Leaf Callus Regenerated shoots Leaf

Shoot Leaf

Explant Callus

Plant growth hormone used (mg/l) or (μM) or (%) MS media + BAP (0.88 μM) + NAA (0.27 μM) MS media + Sucrose (0.1%) MS media + BAP (2.22 μM) + NAA (2.69 μM) B5 media + BAP (0.1 mg/l) B5 media + BAP (0.1 mg/l) B5 media + NAA (0.025 mg/l) + BAP (0.1 mg/l) MS media +2, 4-D (0.5 mg/l) + KIN (0.5 mg/l) MS media + BAP (1.0 mg/l) + IAA (0.5 mg/l) MS media + BAP (4.5 mg/l) + NAA (0.5 mg/l) MS media + BAP (1.5 mg/l) + NAA (0.5 mg/l) MS media + IBA (0.5 mg/l) MS media + TDZ (1.0 mg/l) + NAA (1.0 mg/l) MS media + TDZ (1.0 mg/l) + NAA (1.0 mg/l) MS media + TDZ (1.0 mg/l) + NAA (1.0 ng/l) MS media + TDZ (1.0 mg/l) + NAA (1.0 mg/l)

Table 1.4 Tissue culture reports of Artemisia species

Suspension culture

Inoculum culture

Callus induction

Rooting Callus induction

Shoot multiplication

Shoot induction

(continued)

Ali and Abbasi (2014) Ali et al. (2015)

Kour et al. (2014)

Callus induction Callus proliferation

Mannan et al. (2012)

Zia et al. (2007)

References Nin et al. (1996)

Callus development Shoot formation Root induction

Rooting Callus induction

Response Shoot formation

1 The Artemisia Genus: Panacea to Several Maladies 79

A. vulgaris L.

Species

Table 1.4 (continued)

Shoot

Callus

Regenerated shoots Elongated shoot Leaf

Regenerated shoots Callus Regenerated shoots Leaf explants/ callus Shoot regenerated from callus Leaf Callus Shoot tip

Shoots

Explant Nodal segments

B5 medium + vitamins + NAA (0.01 or 0.025 or 0.05) + BAP (0.1) BAP (1.0 mg/l) + 2, 4-D (0.5 mg/l) BAP (3.5 mg/l) + 2, 4-D (0.5 mg/l) MS media + BAP (4.44 μM) + KIN (4.64 μM) + myoinositol (0.1 g/l) + sucrose (3%) MS media + BAP (0.44 μM) + GA3 (1.44 μM) MS media + IAA (8.56 μM) MS media + BAP (1.0 mg/l) + NAA (3.0 mg/l) MS media + BAP (1.0 mg/l) + GA3 (3.0 mg/l) ½ MS media + IAA (0.5 mg/l)

B5 media + BAP (0.1 mg/l) B5 media + NAA (0.025 mg/l) + BAP (0.1 mg/l) B5 medium + BAP (0.1) + Kin (0.1)

Plant growth hormone used (mg/l) or (μM) or (%) MS media + BAP (0.5 mg/l) + KIN (0.25 mg/l) MS media + BAP (0.1 mg/l) + KIN (0.1 mg/l) + NAA (0.1 mg/l) 1/4 MS media + IBA (2.0 mg/l)

Rooting

Shoot induction

Root induction Callus induction

Shoot elongation

Callus Shoot induction Shoot development

Root induction

Callus development/shoot regeneration

Shoot formation Root induction

Root induction

Shoot multiplication

Response Shoot induction

Borzabad et al. (2010)

Sujatha and Kumari (2007)

Koul and Lone (2016)

Shekhawat and Manokari (2015)

References Shekhawat and Manokari (2015)

80 B. Koul and T. Khatri

Shoot induction Stem

A. chamaelifolia vill.

Leaf

A. annua L.

Callus Hypocotyls

Shoot Seeds

A. aucheri Boiss.

Shoot

Callus

Leaf

Meristematic tip

A. dracunculus L.

A. nilagirica (C.B. Clarke) Pamp.

Seeds

A. herba alba Asso.

Encapsulated somatic embryos Shoot tip Callus Shoots

Leaf

MS media + BAP (2.5 mg/l) + NAA (0.5 mg/l) MS media + BAP (3.0 mg/l) + IAA (0.6 mg/l) MS media + BAP (1.0 mg/l) + NAA (1.0 mg/l) + IAA (0.3 mg/l) MS media + IBA (0.1 mg/l) MS media + KIN (2 mg/l) + 2,4-D (0.1 mg/l) + IAA (1 mg/l) MS media+ NAA (0.02 mg/l) + BAP (0.1 mg/l) Modified MS media + NAA (1.0 mg/l) MS media + NAA (5.4 μM) + 2,4-D (4.5 μM)

MS media +2,4-D (0.5 mg/l) + BAP (1 mg/l) + ascorbic acid (50 mg/l) MS media + GA3 (1.5 mg/l) + IAA (0.5 mg/l) + ascorbic acid (40 mg/l) MS media + KIN (0.75 mg/l) MS media + KIN (0.1 mg/l) MS media + IAA (0.1 mg/l) + NAA (0.5 mg/l) MS media + BAP (0.5 mg/l) + GA3 (1.0 mg/l) MS media + IAA (0.1 mg/l) + KIN (0.5 mg/l) MS media + IAA (0.5 mg/l) MS media + BAP (0.4 mg/l)

Suspension culture Callus induction

Callus induction

Rooting Callus formation

Shoot multiplication

Shoot formation

Callus induction

Rooting Shoot induction

Shoot induction.

Shoot induction

Callus Shoot formation Root formation

Germination of synthetic seeds

Embryogenic callus

The Artemisia Genus: Panacea to Several Maladies (continued)

Paniego and Giulietti (1994)

Gharehmatrossian et al. (2014) Nair et al. (1986)

Hristova et al. (2013) Ganesan and Paulsamy (2011)

Lizarazo and Vásquez (2012)

Sarab et al. (2011)

Mohiuddin and Nitin (2016)

Sudarshana et al. (2013)

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Species

Table 1.4 (continued)

Shoots Cotyledon and hypocotyl Leaf primordia

Nodes

Leaf

Stem

Friable callus

Terminal heads of inflorescence Regenerated shoots Leaf

Juvenile or vegetative parts of mature plant

Leaf

Explant Callus

Plant growth hormone used (mg/l) or (μM) or (%) MS media + NAA (1.08 μM) + BAP (13.32 μM) MS media + BAP (4.44 μM) + 2,4-D (4.52 μM) MS media + Aspartic acid (300 μM) + glutamine (700 μM) + arginine (300 μM) + cysteine hydrochloride (30 μM) + NAA (0.5 μM) + GA3 (0.3 μM) + BAP MS media RT vitamins + casein hydrolysate (1.0 g/l) + BAP (1.0 mg/l) MS media + RT vitamins + casein hydrolysate + IBA (5.0 mg/l) MS media +2,4-D (0.25 mg/l) + BAP (0.25 mg/l) MS media + BAP (0.5 mg/l) + NAA (0.5 mg/l) MS media +6-BAP (1.0 mg/l) + IBA (0.2 mg/l) MS media + BAP (1.0 mg/l) + NAA (2.0 mg/l) MS media + BAP (0.8 mg/l) + TDZ (0.8 mg/l) + IBA (0.1 mg/l) MS media + IBA (0.5 mg/l) MS media +2,4-D (4.5 μM) + BAP (11 μM) + NAA (2.7 μM) Regeneration

Root induction Callus formation

Shoot induction

Callus induction

Shoot induction

Jones and Saxena (2013) Tahir et al. (2013)

Huang et al. (2012) Mohammad et al. (2014) Hailu et al. (2013)

Keng et al. (2010)

Callus induction Suspension culture

Mathur and Kumar (1996)

Ferreira and Janick (1996) Gulati et al. (1996)

References

Formation of leafy structures with subsequent Elongation of axillary shoots Roots formation

Shoot regeneration

Callus induction

Response Organogenesis

82 B. Koul and T. Khatri

A. judaica L.

A. scoparia Waldst. & Kitam.

Shoots Seedlings

Regenerated shoot Callus Young inflorescence and leaf explants Regenerated shoots Shoot tip

Leaf

Leaf

Callus

Nodal segments with axillary bud Shoot Stem

MS media + BAP (2.0 mg/l) + NAA (1.0 mg/l) MS media + NAA (2.0 mg/l) MS media + B5 vitamins + NAA (5 μmol/ l) + TDZ (0.25 μmol/l) + BAP (5 μmol/l))

MS media + kanamycin (10 mg/l)

Full-strength MS medi+ combination of GA3 (1.5 μm/l) + BAP (0.5 μm/l) MS media+ BAP (1.5 mg/l) + NAA (0.5 mg/l) MS media + IBA (1.0 mg/l) MS media + BAP (0.5 mg/l) + NAA (1.5 mg/l) MS media + BAP (1.5 mg/l) + NAA (0.05 mg/l) + glutamine (100 mg/ l) + cystine HCl (5 mg/l) + Arginine (50 mg/l) + asparagine (40 mg/l) MS media + BAP (0.5 mg/l) + NAA (1.5 mg/l) MS media + BAP (1.5 mg/l) + NAA (0.05 mg/l) MS media + NAA (0.5 mg/l) Modified MS media + NAA (1.0 mg/l) MS media + BAP (0.5 mg/l) + NAA (0.3 mg/l)

Root induction Shoot organogenesis induced by culturing Etiolated hypocotyls and intact seedlings (16 shoots per seedling)

Shoot induction

Root formation

Root induction Suspension culture Shoot formation

Shoot induction

Callus induction

Shoot induction

Root induction Callus induction

Shoot induction

The Artemisia Genus: Panacea to Several Maladies (continued)

Liu et al. (2003)

Aslam et al. (2006)

Wang et al. (2016)

Dangash et al. (2015)

Gopinath et al. (2014)

1 83

A. petrosa ssp. eriantha

A. amygdalina Decne.

A. cina berg.

Regenerated shoots Cotyledons Callus

Regenerated shoots Regenerated shoots Nodes

Shoot

Regenerated shoots Leaves

A. carvifolia Buch

Explant Shoot tips

Regenerated shoots Regenerated shoots Leaf and stem

Species A. roxburghiana Besser var. purpurascens (Jacq.) Hook.

Table 1.4 (continued)

MS media +2,4- D (1 mg/l) + MS media + BAP (0.4 mg/l) + NAA (0.1 mg/l)

MS media + BAP (10 μM) + NAA (10 μM) MS media +2,4-D (1 μM)

MS media +2,4-D (1 ppm) + Sucrose (30 g/l) + Agar (8 g/l) MS media + KIN (10 mg/l) + NAA (1 mg/l) MS media +2,4-D (2 mg/l) + BAP (1 mg/l) ½ MS media + BAP (3 mg/l)

MS media + BAP (2.5 g/l) + NAA (0.25 g/l) ½ MS media + NAA (0.1 mg/l)

Plant growth hormone used (mg/l) or (μM) or (%) MS media + KIN (13.95 μM) + NAA (0.27 μM) MS media + BAP (8.88 μM) + NAA (0.27 μM) MS media + IBA (4.93 μM)

Callus formation Shoot formation

Root formation

Shoot formation

Root formation

Polyploidy induced

Shoot formation

Callus formation

Root formation

Shoot formation

Root formation

Shoot multiplication

Response Shoot induction

Pace et al. (2004)

Mubashir et al. (2014)

Herawati et al. (2014) Herawati et al. (2015)

Dilshad et al. (2016)

References Banerjee et al. (2010)

84 B. Koul and T. Khatri

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85

Conclusions

Major portion of the population in the developing as well as developed countries believe in the use of herbal drugs in comparison to synthetic drugs, as herbal drugs are safe and eco-friendly. Artemisia genus has been widely used since ancient times because of its various proven and unproven therapeutic potential. Recently, it has taken the attention of pharmacists and scientists to isolate different compounds which can be used for the treatment of various ailments. Being a reservoir of pharmacologically active compounds, this genus has been overexploited by R&D industries for research purpose; hence, it is necessary to sustain the germplasm of this genus. Micropropagation or in vitro regeneration can be deployed so as to multiply the plants at a rapid rate. Moreover, studies should be carried out in order to overexpress the gene responsible for the production of artemisinin compound so as to retard the cost factor for the production of this compound. In spite of a very long history of medicinal use of this genus, further pharmacological work should be carried out in an elaborative manner in order to validate its traditional uses. On the other hand, certain side effects have also been reported due to long-term use of some Artemisia species, so extensive clinical trials and standardisation should be done in order to optimise the dosage level. This chapter summarises the phytochemical constituents, pharmacological activities, commercialised products and micropropagation reports of various Artemisia species, which will serve as a reference tool to the scientists working in this particular field for further investigation of this genus.

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Singh S, Singh N, Kumar V, Datta S, Wani AB, Singh D, Singh J (2016) Toxicity, monitoring and biodegradation of the fungicide carbendazim. Environ Chem Lett 14(3):317–329 Singh S, Kumar V, Upadhyay N, Singh J, Singla S, Datta S (2017) Efficient biodegradation of acephate by Pseudomonas pseudoalcaligenes PS-5 in the presence and absence of heavy metal ions [Cu (II) and Fe (III)], and humic acid. 3 Biotech 7(4):262 Singh S, Kumar V, Chauhan A, Datta S, Wani AB, Singh N, Singh J (2018) Toxicity, degradation and analysis of the herbicide atrazine. Environ Chem Lett 16(1):211–237 Singh S, Kumar V, Singh J (2019a) Kinetic study of the biodegradation of glyphosate by indigenous soil bacterial isolates in presence of humic acid, Fe (III) and Cu (II) ions. J Environ Chem Eng 7:103098 Singh S, Kumar V, Kapoor D, Kumar S, Singh S, Dhanjal DS, Datta S, Samuel J, Dey P, Wang S, Prasad R (2019b) Revealing on hydrogen sulfide and nitric oxide signals co-ordination for plant growth under stress conditions. Physiol Plant. https://doi.org/10.1111/ppl.13002 Singh S, Kumar V, Sidhu GK, Datta S, Dhanjal DS, Koul B, Singh J (2019c) Plant growth promoting rhizobacteria from heavy metal contaminated soil promote growth attributes of Pisum sativum L. Biocatal Agric Biotechnol 17:665–671 Singh S, Kumar V, Singh S, Singh J (2019d) Influence of humic acid, iron and copper on microbial degradation of fungicide Carbendazim. Biocatal Agric Biotechnol:101196. https://doi.org/10. 1016/j.bcab.2019.101196 Sinico C, De Logu A, Lai F, Valenti D, Manconi M, Loy G, Bonsignore L, Fadda AM (2005) Liposomal incorporation of Artemisia arborescens L. essential oil and in vitro antiviral activity. Eur J Pharm Biopharm 59:161–168 Sudarshana MS, Rajashekar N, Niranjan MH, Borzabad RK (2013) In vitro regeneration of multiple shoots from encapsulated somatic embryos of Artemisia vulgaris. L. IOSR J Pharm Pharm Sci (IOSR-JPBS) 6(6):11–15 Sujatha G, Kumari BR (2007) Effect of phytohormones on micropropagation of Artemisia vulgaris L. Acta Physiol Plant 29(3):189–195 Suresh J, Vasavi RA, Rajan D, Ihsanullah M, Khan MN (2010) Antimicrobial activity of Artemisia abrotanum and Artemisia pallens. Int J Pharmacog Phytochem Res 3(2):18–21 Suresh J, Mruthunjaya K, Paramakrishnan N, Naganandhini MN (2011) Determination of artemisinin in Artemisia arbotanum and Artemisia pallens by LC/MS method. Int J Curr Pharm Res 3(1):4952 Taherkhani M (2014) In Vitro Cytotoxic Activity of the essential oil extracted from Artemisia absinthium. Iran J Toxicol 8(26):1152–1156 Tahir SM, Usman IS, Katung MD, Ishiyaku MF (2013) Micropropagation of WormWood (Artemisia annua L.) using leaf primordia. Sci World J 8(1):1–7 Tajadod G, Mazooji A, Salimpour F, Samadi N, Taheri P (2012) The essential oil composition of Artemisia vulgaris L. in Iran. Ann Biol Res 3(1):385–389 Tariku Y, Hymete A, Hailu A, Rohloff J (2010) Essential oil composition, antileishmanial and toxicity study of Artemisia abyssinica and Satureja punctata ssp. punctata from Ethiopia. Chem Biodivers 7:1009–1018 Tawfiq NK, Anderson LA, Roberts MF, Phillipson JD, Bray DH, Warhurst DC (1989) Antiplasmodial activity of Artemisia annua plant cell cultures. Plant Cell Rep 8:425–428 Tigno XT, de Guzman F, Flora AM (2000) Phytochemical analysis and hemodynamic actions of Artemisia vulgaris L. Clin Hemorheol Microcirc 23:167–175 Tripathi AK, Prajapati V, Gupta R, Kumar S (2000) Herbal material for the insect-pest management in stored grains under tropical conditions. J Med Aromat Plant Sci 21:408–430 Tzenkova R, Kamenarska Z, Draganov A, Atanassov A (2010) Composition of Artemisia annua Essential oil obtained from species growing wild in Bulgaria. Biotechnol Biotechnol Equip 24 (2):1833–1835 Wang B, Kashkooli AB, Sallets A, Ting HM, de Ruijter NC, Olofsson L, Brodelius P, Pottier M, Boutry M, Bouwmeester H, van der Krol AR (2016) Transient production of artemisinin in

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Bacopa monnieri: The Neuroprotective Elixir from the East—Phytochemistry, Pharmacology, and Biotechnological Improvement

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Samapika Nandy, Anuradha Mukherjee, Devendra Kumar Pandey, and Abhijit Dey

Abstract

Bacopa monnieri (L.) Wettst. (Scrophulariaceae), commonly known as water hyssop, is an extensively used herb in Ayurveda. The bioactive phytoconstituents like the dammarane-type triterpenoid saponins such as bacosides A, B, and C were reported mostly for neuroprotective, nootropic, and memory-enhancing properties. Furthermore, B. monnieri also acts as a natural antioxidant, which can ameliorate morphine dependence, memory deficit in epilepsy, hepatocarcinogenesis, hepatotoxicity, β-amyloid cytotoxicity, inflammation, and oxidative stress (Singh et al., Physiol Plant. 2019). The neuroprotective role of the plant was manifested against neurodegenerative disorders like Parkinson’s disease (PD), Alzheimer’s disease (AD)-associated dementia, attention-deficit hyperactivity disorder in children, and anxiety. Somer report also found the traces of heavy metals in various species of Bacopa monnieri. Inadequate knowledge regarding underlying mechanism of neuroprotection and associated systematic structure-activity relationship (SAR) studies and development of semisynthetic derivatives of saponins are of high importance to facilitate rational designing of novel drugs based on leads from bacopasaponins. This review systematically summarizes the origin, analysis of the pharmacotherapeutic properties, and structural significance of bioactivities

S. Nandy · A. Dey (*) Department of Life Sciences, Presidency University (Formerly Presidency College), Kolkata, West Bengal, India e-mail: [email protected] A. Mukherjee Moriswar Motilal High Schools, Jaynagar, West Bengal, India D. K. Pandey Department of Biotechnology, Faculty of Technology and Sciences, Lovely Professional University, Phagwara, Punjab, India # Springer Nature Singapore Pte Ltd. 2020 J. Singh et al. (eds.), Bioactive Natural Products in Drug Discovery, https://doi.org/10.1007/978-981-15-1394-7_2

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exerted by the bacopasaponins. Moreover, future research arenas, lacunae in the present understanding, are also highlighted in this work. Together, this book chapter may further direct to the synthetic optimization of bacopasaponins as lead compounds for the designing of efficacious and clinically acceptable analogues. Keywords

Bacoside A · Cognition enhancement · Neurodegenerative disorders · Neuroprotective medicinal plant

2.1

Introduction

Complementary and alternative medicine plays a vital role in modern psychotherapeutics. The neurological and psychiatric disorders are multifactorial ailments associated with memory loss, cognitive deficits, impaired mental function, oxidative stress generated neurological damage, cytotoxicity, etc. (Mathur et al. 2016). The vast majority of currently available psychoactive drugs as herbal remedies are greatly influenced by folklore medicine and an extensive research is being carried out to evaluate their independent neuromodulatory role as well as their synergistic efficacy with combinatorial drugs. Moreover, novel products that could target multiple pathways are always in demand for potential drug designing and, amidst numerous low-toxicity cognition-enhancing botanicals, medicinal Ayurvedic herb Bacopa monnieri L. Edwall. bacopasaponins, a major component of B. monnieri, plays a very important role as a neural tonic, central nervous system (CNS) activator, and memory booster (Chaudhari et al. 2017). In Ayurveda, plants having prabhava (effect) on keeping or retaining intellect are called “medhya rasayana” which includes psycho-neuroscience as well as nutrition-, rejuvenation-, and geriatrics-based promotive therapy. This nootropic herb from Scrophulariaceae is well established in Ayurvedic system of medicine as the mediator of anxiety, poor cognition and concentration, asthma, insanity, and epilepsy (Kirtikar and Basu 1918). Using elevated maze plus and passive avoidance test the potential of “Brahmi ghrita” (BG) has been estimated for retention of learning and memory in BG-untreated, BG-treated (400 and 800 mg/kg, p.o.), and piracetam-treated (500 mg/kg, p.o.) groups. B. monnieri treatment causes cerebral glutamic acid and gamma-aminobutyric acid elevation which is associated with learning (Yadav et al. 2014). Another B. monnieri-containing formulation, “Unmadnashak Ghrita” (UG) composed of Ferula narthex Drude. (6 g), Gardenia gummifera L.f. (6 g), Elettaria cardamomum L. (6 g), B. monnieri (6 g), and cow’s ghee (clarified butterfat) (76 g) exhibited significant neuropharmacological activities against maximal electroshock-induced seizures and pentylenetetrazol-induced convulsions in mice. Besides showing CNS-depressant activity in gross behavioral test and extended pentobarbitone sleeping time, it also antagonizes the CNS-stimulant drug amphetamine (Achliya et al. 2004). Neurodegeneration is a critical condition where both neuropathological conditions and brain aging disrupt the synaptic plasticity,

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responsible for memory formation, stabilization, and strengthening. The degradation of neural networks plays a key role in the onset of cerebrovascular and neurodegenerative diseases with a global mortality rate of 8%. Moreover, cognitive dysfunction and lack of efficient therapeutic alternatives have led to increased incidences of neurodegenerative disorders such as schizophrenia, depression, AD dementia, head injury, PD, neuronal injury-triggered stroke, or trauma. Numerous animal and in vitro studies along with several randomized, double-blind, placebo-controlled clinical trials have potentiated B. monnieri’s nootropic utility in humans and role of bacopasaponins in cognition enhancement. The therapeutic implications are associated with novel methods for extraction, compound isolation, enrichment, purification, and application of crude and/or semi-pure extract or marker compounds (Shinomol and Bharath 2011). Neuromodulatory mechanisms include redox- and enzyme-induced oxidative stress removal, acetylcholinesterase (AChE) inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral vasodilation, and neurotransmitter modulation (Uttara et al. 2009). In the traditional folkloric system, many indigenous medicinal plants are utilized as psychotherapeutic drugs and B. monnieri is the prime of all. The name Brahmi or Jalanimba is mentioned in many ancient therapeutic texts like Charaka Samhita and Sushruta Samhita Atharva-Veda (Encyclopedia on Indian Medicinal Plants. http://www.frlht. org/rasayana/node/47) and with other Sanskrit names, viz. Saraswati (Goddess of knowledge and wisdom of self), Somavati (containing soma or nectar), and Indravalli (energy of Lord Indra) which clearly indicates its precognition efficacy and usage as “medhya-rasayana” or “Prajnasaktivardhak” (intellectual power rejuvenating) drug in Ayurveda (Sharma and Dash 2009). The practice of Ayurveda in the East originated with a holistic approach of alternative medicine practiced by ancient Vedic healers (Baidya). In Ayurveda, the usage of Brahmi is extensive and reported extensively for its role in enhancing longevity (Ayushya), heart (Hrdaya), nervous system rejuvenation (Majja Dhatu Rasayana), strength (Balya), life force (Jivaniya), and sleep (Nidra) and redirecting the flow of vata downwards (Anuloma). There are different ailments like Kustha (leprosy), Pandu (anemic condition), Mahadasha (diabetes), Asra Vikara (blood disorders), Kasa (cough), Visa (poison), Sopha (edema), Jwara (fever), Unmadaharaor Manasavikara (mental retardation), Unmada (insanity), Alaksmi (behavioral deformities), Apasmara (epilepsy), and Ruk (pain) in which Brahmi and other polyherbal medications enriched with Brahmi had been applied as fruitful satvic (sacred) treatment (Nadkarni 2010; Government of India Ministry of Health and Family Welfare Department of Ayush http://www. ayurveda.hu/api/API-Vol-2.pdf). Plant extract and its phytoconstituents can sequester free radicals and neuronal plaque formation as well as other types of oxidative stress associated with it. This chapter summarizes the role of marker and bacopasaponin-enriched extract or lead fraction in the attenuation of different ailments and their possible therapeutic approach.

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Methodology

Neurodegenerative disorders, progressive loss of structural configuration, and functional activity that leads towards death of neurons are often attributed by lifestyle, stress, carcinogenic agents, and oxidative damage. The neurodegenerative disorders, like PD, AD, Huntington’s disease, amyotrophic lateral sclerosis, and attentiondeficit/hyperactivity disorder, are very much prevalent in today’s world. This chapter summarizes the bioactivity, underpinning mechanism of neuroprotection, and possible role of SAR in medicinal plant B. monnieri or Brahmi, its chemical reservoir, mostly enriched with bacopasaponins. The chapter embodies biological activities exhibited by the plant singly or in combination with its active botanicals and/or commercially available drugs; synergistic effect of polyherbal formulation and their ameliorating role are also discussed vividly along with Ayurvedic Brahmicontaining medications. Figure 2.1 represents the chemical structures of bioactive compounds compiled from www.PubChem.com.

2.3

Bioactivity Study

2.3.1

Biological Activities of Plant Extract(s)

2.3.1.1 Pro-cognitive Activity Brahmi has been utilized as a potent nootropic herb from time immemorial, introduced into Western medicine as “memory enhancer,” and clinically screened for pro-cognitive activities, motor skill improvement, and retention of newly acquired characters. Progressive degeneration of neurons and deformities of central and peripheral nervous system are some reasons of life-threatening neurodegenerative disorders. The well-characterized B. monnieri extract (BME), enriched with bacosides A and B, prescribed as KeenMind®-CDRI 08 possesses anxiolytic, nootropic, and adaptogenic effects (Benson et al. 2014, 2015) as evidenced by various randomized, placebo-controlled, double-blind clinical trials (Stough et al. 2012) and was found to improve attention, concentration, and behavior in hyperactive children (Kean et al. 2015) and to aid in attention-deficit hyperactivity disorder (Dave et al. 2014). The standardized extract of B. monnieri inhibits five major isoforms of human cytochrome P450 (CYP) enzymes via noncompetitive, competitive, or weak inhibition that leads to potential herb-drug interaction (Ramasamy et al. 2014). Pre- and post-administration of CDRI-08 also exerted anti-amnesic effect (Konar et al. 2015; Rai et al. 2015). Therapeutic mechanism of BME with concentration of 10, 20, and 40 mg/kg body weight includes restoration of hippocampal neurotransmitters and downregulation of AChE (Pandareesh et al. 2016) like the standard drug piracetam (200 mg/kg body wt, i.p.). The hippocampal dependent learning coupled with enhanced 5HT(3A) receptor expression and higher level of serotonin and acetylcholine level in Wistar rat pups can be achieved by BESEB CDRI-08 (single dose) (Rajan et al. 2011) whereas postnatal PBDE-209-induced memory impairment in male mice pups associated with altered expression of N-methyl-D-aspartate receptor-1

sgmasterol

D-mannitol

Bacoside A3

Brahmic acid

Apigenin

Bacopasaponin C

Betulinic acid

Bacopaside II

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Fig. 2.1 Chemical structures of bioactive compounds

Bacopaside I

Bacoside A

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can also be cured by CDRI-08 (Verma et al. 2015). Another bioactive formulation, BacoMind (31.2, 62.5, 125 μg/mL), protected human lymphocytes against various clastogens in a dose-dependent manner (Deb et al. 2008). Moreover, in cobalt chloride-induced hypoxia mimetic mice, it attenuates hypoxia-induced memory impairment and reversal of altered expression pattern of Hif-1α and Fmr-1 (Rani and Prasad 2015). The add-on BMEs (500 mg/day for 1 month) can reduce schizophrenia psychopathology without any treatment-triggered side effect (Sarkar et al. 2012). The diabetes mellitus-induced memory impairments can be reverted by CDRI-08 (50 or 100 mg/kg bodyweight) by enhancement of spatial memory in streptozotocin DM2 mice which is often correlated with oxidative stress reduction and upregulation of hippocampal AMPA receptor GluR2 subunit gene expression and when applied at a higher dose,
150 mg/kg body weight, it shows antidiabetic efficacy also (Pandey et al. 2015). The BME (10, 20 and 40 mg/kg bodyweight) protectively replenishes crackers’ smoke triggered neuronal and physiological changes via inducible nitric oxide synthase modulation and altered hemeoxygenase-1 expression in rats, exposed to smoke for 1 h for a period of 3 weeks. Smoke-generated oxidative stress, monoamine oxidase activity, and neuronal and physiological impairments are corrected by BME supplementation (Pandareesh and Anand 2014). The vesicular glutamate transporter type 1 in schizophrenic brain indicates the loss of glutamatergic function, aiding in cognitive impairment (Piyabhan and Wetchateng 2013). BME reduces neuronal toxicity and cognitive deficit caused by glutamatergic neurons in the prefrontal cortex, striatum, and cornu ammonis subfield 1 and 2/3 of hippocampus, in sub-chronic rat model of schizophrenia (Piyabhan et al. 2013; Wetchateng and Piyabhan 2015). The alcoholic BME (40 and 80 mg/kg, p.o.) possesses antinociceptive activity. In chronic constriction injury model of neuropathic pain in rat hindpaw, after the sham injury, the behavioral standard of static and dynamic allodynia and cold allodynia was examined on days 3, 7, 14, and 21. Chronic constriction injury-induced static (days 3–21), dynamic (days 14–21), and cold allodynia (days 3–21) plus heat- and mechanohyperalgesia (days 3–21) were effectively ameliorated by tested dosage of plant extract. Standard gabapentin exhibits such protective behavior but at higher dosage (Shahid et al. 2017). In acetic acid-induced gastric constrictions in Swiss albino mice, reduction injury percentage was higher than the reference drug aspirin (Taznin et al. 2015). Pretreatment with selective α-2 receptor blocker yohimbine (1 mg/kg, i.p.) and aqueous BME (80, 120, 160 mg/kg, oral) in experimental mice and rat groups elucidates antinociceptive effects. The acetic acid writhing test has shown 14.50  2.26 and 37.17  2.14 writhes, respectively, under single- and co-treatment condition (Bhaskar and Jagtap 2011).

2.3.1.2 Anti-neurodegenerative Activity AD is a chronic neurodegenerative disease, mostly prevalent among the aged person leading to impaired cognition, lack of brain-oriented functional activity, and behavioral abnormalities, and is often associated with autosomal dominant inheritance (Ballaed et al. 2011; Ryman et al. 2014), presence of amyloid beta (Akiyama 2016), deposition of amyloid plaques and tau protein in neuronal cytoplasm (Masliah et al.

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1993), and mutation in presenilin-1, presenilin-2, amyloid precursor protein, and apolipoprotein E genes which are associated with variable onset of AD (Selkoe 2001). Early onset of AD causes paralyzed memory due to functional alteration of median temporal lobe and hippocampus as well as sleep apnea and psychological disturbances (Scoville and Milner 1957). The accelerated demand for herbal products has been increased manyfold to cure neurodegenerative diseases. Several clinical and preclinical trials have shown that BME’s therapeutic potency is often comparable with commercial drugs like donepezil, rivastigmine, and galantamine (Chaudhari et al. 2017). Neurodegeneration induced by cold stress in cells of hippocampus region of Wistar mice brain showed norepinephrine depletion, low packing density, and decreased cell diameter which were reversed with BME treatment (Kumar et al. 2015). Cholinesterase is a family of hydrolase enzyme present in the central nervous system, muscle, and red cells, which catalyzes the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid. AChEpositive neurons are generally diffused cortically, and responses to new and relevant stimuli and abovementioned hydrolysis allow a cholinergic neuron to attain stability after activation (Dzoyem et al. 2014). Anticholinesterases are potential neurotoxins used to terminate acetylcholine-mediated neurotransmission and can modulate protein function, alter cerebral blood flow, and induce tau phosphorylation and amyloid cascade modification which were associated with the treatment of AD progression (Rösler 2002). There are different forms of dementia associated with AD, Creutzfeldt-Jakob disease, PD, and Pick’s disease as well as there are vascular dementia and dementia with Lewy bodies. In vitro spectrophotometric assay with a dose range of 10–1000 μg plant extract exhibited AChE inhibitory activity but more than 50% inhibition was not achieved. In scopolamine-treated group of Swiss albino mice model of dementia, the extract caused decrease in AChE-specific activity, thus promoting cognition (Poirier et al. 1995; Das et al. 2002) as well as AD-induced depletion of neurons (Uabundit et al. 2010). BME can potentiate cerebral blood flow in Wistar mice after 8 weeks of extract administration (Kamkaew et al. 2013). Preservation of cholinergic neurons, improved memory retention, and enhanced synaptic plasticity were among the other effects that combated cognitive dysfunction in olfactory bulbectomized mice after extract pretreatment (Le et al. 2013). PD is often diagnosed with behavioral setbacks, neuronal loss, dopamine production in substantia nigra, and formation of Lewy bodies accumulated with alpha-synuclein protein. The study of herbal products on this disease is few but in transgenic Drosophila fruit fly (PD model) exposure to CDRI-08 improved climbing skills, activity pattern, and oxidative stress restoration and reduced neuronal apoptosis (Jansen et al. 2014). The alcoholic BME (20 and 40 mg/kg bodyweight) can reduce dose-dependent neuronal injury in a 6-OHDAinjured Parkinson’s rat model as experimented by neurobehavioral activity study (rotarod, locomotor activity, grip test, forced swim test, radial arm maze), lesion formation, and lipid peroxidation (Shobana et al. 2012). BME exposure also reduced alpha-synuclein accumulation, prevented dopaminergic cell death, and restored the lipid content in this PD model of Caenorhabditis elegans (Jadiya et al. 2011).

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2.3.1.3 Antidepressant and Anti-stress Activity Prolonged stretch of anxiety, mood swings, lack of interest or concentration, and low self-esteem often led towards clinically alarming period of depression and fatigue. Moreover, the effect of genetic, biological, psychosocial, or seasonal induction of stress directs the onset of mental retardation and psychiatric ailments. Research using animal model of chronic unpredictable stress showed depression that lowered brain-derived neurotrophic factor level and mRNA levels in the hippocampus and frontal cortex and decreased sucrose consumption that were modulated by tested dosage of BME as indicated by locomotor activity and escape latency through open field and shuttle box escape tests (Banerjee et al. 2014). The serotonin and gammaaminobutyric acid play a key role in antidepressant mechanism and in rodent model; oral administration of BME (20–40 mg/kg) acted as good as the standard drug imipramine (Shader and Greenblatt 1995). In another study, bacoside-rich (25% bacoside A) BME demonstrated antidepressant activity similar with anxiolytic drug lorazepam (Bhattacharya and Ghosal 1998; Shankar and Singh 2000). Drug withdrawal syndrome is often associated with prolonged depression and fatigue. In an experiment, Rauf et al. (2014) studied the curative role of BME against morphine withdrawal. The weight-loaded forced swim test screened for anti-fatigue activity. Swimming time was increased by threefold in the BME-supplemented (10 mg/kg body weight) group on day 13th and after 2 weeks of supplementation swimming time, body weight change, lipid peroxidation level, lactic acid, glycogen, antioxidant enzyme activities, and blood parameters were evaluated. In brain, liver, and muscle tissues, malondialdehyde levels decreased by 11.2%, 16.2%, and 37.7%, respectively (Anand et al. 2012). The alcoholic and aqueous extracts of the whole plant possess tranquilizing property in albino rats and dogs, and combinatorial application of alcoholic plant extract and chlorpromazine can improve motor learning in experimental rat model (Prakash 1962). The standardized BME (80 mg/kg) can function as a potent adaptogenic agent, against acute and chronic stress models in male SpragueDawley rats. It causes reversal of stress-induced increase in the ulcer index, adrenal gland weight, plasma glucose, aspartate amino transferase, creatine kinase, and normalized spleen weight (Rai et al. 2003), and thus prevented alterations in the level of plasma corticosterone, monoamine-noradrenaline dopamine, and serotonin in the cortex and hippocampus of rat brain (Sheikh et al. 2007). Promising effect of BME (80 mg/kg p.o.) is observed against mixed anxiety-depressive disorder that reduces motor nerve incoordination (Chatterjee et al. 2010). Aging is a fundamental evolution of human body and mind hallmarked with impaired memory, altered physiological and histopathological degradation, irregular neurotransmitter secretion, spatial recognition and execution inefficiency, and dendritic and synaptic degeneration that leads to neurodegenerative disorders. The formation of malondialdehyde and lipofuscin pigments indicates signs of aging (Simpson et al. 2015). Aging is also associated with abnormal protein formation, imbalance of neurometabolites, development of neurofibrillary tangles, senile plaque formation, and associated neuroinflammation (Braak and Braak 1997). In aged mice, inoculation with D-galactose (0.5 mL/day, s.c., for 20 days) increased the pigment level and

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administration of ethanol leaf extract of B. monnieri (40 mg/kg body weight for 20 days) reduced them significantly (Kalamade et al. 2008).

2.3.1.4 Neuroprotective Activity The pretreatment with the BME prevented H2O2- and acrolein-induced neurotoxicity in the human neuroblastoma cell line (SK-N-SH) and inhibited ROS generation. Further, stress-triggered modifications of redox-regulated proteins (i.e., NF-kappaB, Sirt1, ERK1/2, and p66Shc) were reduced and it restored the mitochondrial membrane potential (Singh et al. 2010). It can reverse aluminum chloride-induced cognitive impairment in adult male Wistar rats when applied synergistically (100 mg/kg) with rivastigmine (5 mg/kg) (Thippeswamy et al. 2013; Nannepaga et al. 2014). The neuropathological damages induced by sodium fluoride (100 and 200 ppm) decreased the level of antioxidant enzymes, cholinesterase, and impaired memory. Different experimental approaches, i.e., akinesia, rotarod (motor coordination), forced swim test (depression), open-field test (anxiety), transfer latency (memory), and antioxidant study, revealed neuroprotective role of BME (100 and 300 mg/ kg) when applied alone or coadministered with sodium fluoride (Balaji et al. 2015). Cholinergic neurons and reduced anticholinesterase activity are associated with hippocampal β-amyloid deposition and stress-induced hippocampal damage. BME improved the total memory score and reversed phenytoin-induced memory impairment in experimental model and nitric oxide-mediated cerebral vasodilation observed after BME treatment (Chaudhari et al. 2017). The protective efficacy of BME evaluated against valproic acid-induced autism in female pregnant rats and therapeutic mechanism includes attenuation of oxidative stress and increased serotonin content. Altered histological structure of cerebellum was also restored; moreover, behavioral abnormality was corrected too by the experimental dosage (Sandhya et al. 2012). 2.3.1.5 Cardioprotection The sedative and tranquilizing property of B. monnieri is correlated with cardioprotective, anticonvulsant, antioxidant, anti-inflammatory, and musclerelaxing activity and directly influences blood supply to brain and thus aids in neuronal function. The herbal products of B. monnieri exerted protective role in ischemia- and reperfusion-induced brain injury and impaired memory and motor balance in experimental mice model (Rehni et al. 2007). Brahmi can reduce infarct size in the ischemic brain, improve the muscle coordination and catalase activity, and thus prevent memory dysfunction as well as associated decrease in levels of nitrite, nitrate, and lipid peroxidation rate (Saraf et al. 2010). The alcoholic extract screened against cardiological ailments has shown protective role in left ventricular contractility and improved heart rate and coronary flow in isolated rabbit heart like drug quinidine (Rashid et al. 1990). The ethanolic extract (30–100 μg/mL) also improves myocardial function following ischemia/reperfusion injury through recovery of coronary blood flow by 63  13% (30 μg/mL) and 216  21% (100 μg/mL). Moreover, contractile force is increased with reduced infarct size (Srimachai et al. 2017).

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2.3.1.6 Gastrointestinal and Hepatoprotective Activity Herbal juice and other dietary supplements of Brahmi are reported for anti-diarrheal activity along with cognition enhancement. Defecation frequency and ulcer formation are reduced manyfold by oral supplementation of BME (Rao et al. 2000; Siraj et al. 2012). CDRI-08 (KeenMind) (20 mg/kg for 10 days) exerted prophylactic effects, healed acetic acid-induced penetrating ulcers, strengthened mucosal barrier, and reduced lipid peroxidation-induced exfoliation in gastric mucosa of rat (Sairam et al. 2001). In normal/NIDDM rats, ulcers were induced by either physical conditions (2 h of cold-restraint stress and 4 h of pylorus ligation) or application of chemical agents like ethanol (1 mL/200 g, oral) or aspirin (200 mg/kg, oral, 4 h). Further, cysteamine (40 mg/200 g) induced formation of duodenal ulcers. BME (50 mg/kg) showed marked ulcer-healing activity in both normal and non-insulindependent diabetes (NIDDM) rats where mucosal defensive mechanism played significant contribution (Dorababu et al. 2004). BME (1000 μg/mL) has in vitro anti-Helicobacter pylori activity and 10 μg/mL increased in vitro prostanoids (PGE and PGI2) in human colonic mucosal incubates resulting in ulcer-healing activity (Goel et al. 2003). The BME (100–1000 μg/mL) can effectively modulate morphine withdrawal symptoms by reducing naloxone-induced contraction in a dosedependent manner (Sumathi et al. 2002). Chronic morphine exposure (10–160 mg/ kg body weight, intraperitoneal, 3 weeks) altered activity and concentration of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, lactate dehydrogenases, gamma-glutamyl transferase, urea, creatinine, and uric acid. Oral pretreatment with BME (40 mg/kg/day 2 h before morphine injection for 21 days) significantly prevented liver and kidney dysfunction (Sumathi and Devaraj 2009). The methanolic bacopaside A3-enriched BME, at doses of 10, 20, and 30 mg/kg, significantly lowered opioid withdrawal-induced depression in mice assayed via forced swimming test (Rauf et al. 2014). Morphine- and street heroin (20 mg/kg for 14 and 21 days)-insulted hepatotoxicity and nephrotoxicity can be ameliorated by methanolic BME (40 mg/kg) which is enriched with bacoside A3 (37.5 μg/mg), bacopaside II (4.62 μg/mg), and bacopasaponin C (1.91 μg/mg). Histopathological and biochemical alterations are reversed by BME pretreatment and it has shown strong anti-radical activity on 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay (Shahid et al. 2016). The methanolic extract of whole plants of B. monnieri (50–400 mg/kg body weight) exerted dose-dependent inhibition of rise in serum glucose concentrations via the oral glucose tolerance tests conducted with glucose-challenged mice (Taznin et al. 2015). 2.3.1.7 Antiemetic Activity The emetic tendency often occurs as the side effect of chronic dehydration, tumor formation, chemotherapy, psychiatric trauma, poisoning, or radiation apart from indigestion. The methanolic (10–40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5–20 mg/kg) can attenuate cisplatin (7.0 mg/kg, i.v.)triggered reproducible emesis without lethality in healthy pigeons when compared with standard N-(2-mercaptopropionyl) glycine (10 mg/kg). The pretreatment with BME reduced dopamine upsurge in the area postrema and brain stem

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( p < 0.05–0.001), as well as 5-HT concentration in intestine ( p < 0.01–0.001), indicating suitability of the plant and its marker for emetogenic chemotherapy (Ullah et al. 2014). The methanolic fraction (10–40 mg/kg, s.c.) and n-butanol fractions of B. monnieri (5–20 mg/kg, s.c.) can ameliorate cisplatin (30 mg/kg, i.p.)-induced emesis in Suncus murinus by 59.4% and 78.9%, respectively. However, in case of palonosetron (0.5 mg/kg, and N-(2-mercaptopropionyl)-glycine) (30–300 mg/kg) retching and/or vomiting expression reduction was 71% and 44%, respectively, which indicates that the BME can be useful therapeutics against chemotherapyinduced emesis in man (Ullah et al. 2017).

2.3.1.8 Anti-epileptic Activity Research has found excessive neuronal activity at the cortex region of brain due to genetic imprint or brain injury, infection, or stroke finally resulting in epileptic seizures. BME can ameliorate pilocarpine-triggered temporal lobe epilepsy and neurotransmitter balance in the cerebral cortex, through modulation of 5-HT2C and NMDA receptor expression in cerebral cortex when compared to standard carbamazepine. Further, the extract can reverse altered glutamate receptor binding in epileptic rats (Khan et al. 2008) and, associated with gamma-aminobutyric acid, is responsible for neural impulse transmission (Gohil and Patel 2010). Increased AChE activity, higher level of insulin and T3 content, as well as decreased malate dehydrogenase activity are observed in the muscle and heart of the pilocarpine-induced epileptic rats. B. monnieri extract and bacoside A treatment prevented the occurrence of repetitive seizures and thus reduced metabolism and excitability in epileptic rats (Mathew et al. 2010). The excitotoxicity is often correlated with increased 5-HT2C receptor function, downregulated NMDA receptor function, elevated mGlu5 and GLAST gene expression, and higher amount of IP3 release as shown by the elevated plus maze test (Krishnakumar et al. 2015). Similar therapeutic approach is observed in pilocarpine-induced temporal lobe epileptic rats by BME (Mathew et al. 2011). 2.3.1.9 Antioxidant Activity Formation of free radicals, histopathological changes, and oxidative stress generated physiological and biochemical abnormality which is closely associated with various kinds of diseases. Crackers’ smoke is a potent risk factor that leads to free radicalmediated oxidative stress in vivo. The BME treatment (10–40 mg/kg body weight) of smoke-exposed rats ameliorates histopathological changes, reactive oxygen species (ROS) levels, lipid peroxidation, acetylcholine esterase activity, and brain neurotransmitter levels to normal. BME supplementation efficiently inhibited hemeooxygenase-1 expression and nitric oxide generation by downregulating inducible nitric oxide synthase expression. Furthermore, smoke-induced depletion of antioxidant enzyme status and monoamine oxidase activity was also replenished by BME supplementation. This suggests that BME ameliorates various impairments associated with neuronal and physiological changes in rats exposed to crackers’ smoke by its potent neuromodulatory, antioxidant, and adaptogenic propensity. Extract of B. monnieri can alter disturbed antioxidant defense status and peroxidative damage indicated by the activity of antioxidant enzymes in kidney, cerebrum,

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cerebellum, and midbrain of streptozotocin-induced diabetic rats (Kapoor et al. 2009). Bacosides are reported for their antioxidant property and enzyme modulation system in the hippocampus, frontal cortex, and striatum to scavenge reactive oxygen species. BME induces expression of heat-shock protein, enzyme CYP 450, and superoxide dismutase as well as alters other endogenous oxidative markers (Bhattacharya et al. 2000; Govindarajan et al. 2005; Shinomol and Bharath 2011). In many cases cytotoxic effects are generated due to oxidative stress. Oral administration of ethanolic extract of B. monnieri at 150 μg/mL dosages can inhibit abnormal proliferation on Dalton’s lymphoma ascites tumor cells and restore hematological parameters to normal (Kumar et al. 1998). The aqueous extract of B. monnieri prevents tumor cell proliferation, malignant ascites fluid accumulation, and in vivo DNA fragmentation of Ehrlich ascites tumor cell lines (Kalyani et al. 2013). The ethanolic extract of dichloromethane fraction enriched with cucurbitacins and betulinic acid possesses in vitro cytotoxic activity against MCF-7 and MDA-MB 231 cell lines (Mallick et al. 2015). Moreover, it prevents benzo[a]pyrene-mediated apoptosis in human keratinocyte cells through autophagy induction (Das et al. 2016). Hydrogen peroxide, a major cytotoxic agent responsible for generating cellular, nuclear, and mitochondrial oxidative stress, can be ameliorated by BME pretreatment. In PC12 and L132 cells, cytoprotection rendered by BME is estimated via cell viability, mitochondrial membrane potential and comet assays, ROS, and lipid peroxidation estimation. Moreover it prevents mitochondrial and plasma membrane damage as confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase leakage assays. The IC50 values of BME against ROS, lipid peroxidation, and protein carbonylation were 1137.08, 1079.65, and 11,101.25 μg/mL in lung tissues and 1296.53, 753.22, and 589.04 μg/mL in brain, respectively (Pandareesh et al. 2016). Further, plant extract is capable of reducing DNA damage in human non-immortalized fibroblasts in a dose-dependent manner (Russo et al. 2003). The BME pretreatment of dopaminergic (N27 cell lines) cells significantly ameliorated rotenone induced neurotoxicity and resultant oxidative dysfunctions in developing brain of experimental mouse model. BME effectively normalized the protein carbonyl content and restored the cytosolic activity of antioxidant enzymes (Shinomol et al. 2012). In the A549 cells, treatment of BME, activated with lipopolysaccharide (LPS), has shown reduced cyclooxygenase2 (COX-2) and cPGES expression (Muszyńska et al. 2016).

2.3.1.10 Miscellaneous Activity Herbal drugs are potent antioxidants with remarkable anti-inflammatory activities. In carrageenan-induced rat paw edema, bioactive BME (100 mg/kg i.p.)-mediated edema inhibition is 82% when compared to indomethacin (3 mg/kg) with 70% inhibition. The in vitro antioxidant activity is attributed to inhibition of COX-2,5lipoxygenase in rat monocytes and ex vivo downregulation of tumor necrosis factorα (Viji and Helen 2008). In another experiment, alcoholic triterpenoid and bacosideenriched fraction of BME inhibited the production of pro-inflammatory cytokines, tumor necrosis factor-α, and interleukin-6 in vitro in lipopolysaccharide-activated peripheral blood mononuclear cells and peritoneal exudate cells (Viji and Helen

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2011). In vitro inhibition of inflammatory pathways was achieved by the tea, infusion, and alkaloid extracts of B. monnieri (Nemetchek et al. 2017). The petroleum ether, chloroform, methanol, and water extracts of B. monnieri were assayed and among all of them alcoholic fraction exhibited potent mast cell-stabilizing potential under in vitro conditions when compared to disodium cromoglycate, a popular mast cell stabilizer (Samiulla et al. 2001). The wound-healing ability of 50% ethanolic plant extract of BME was observed in rats [10 days (incision and deadspace wound models) or 21 days or more (excision wound model)], when administered (25 mg/kg) orally. This effectively enhanced healing, contraction rate, and skin collagen tissue formation. The epithelialization is promoted by both antioxidant and antimicrobial efficacy of tested extract (Murthy et al. 2013). The treatment of rheumatoid arthritis via the application of BME is reported in traditional medicine. In male Wistar rats, arthritis induction was associated with increased paw edema, upregulation of inflammatory mediators, and enhanced serum anti-collagen IgM and IgG levels which are replenished by BME significantly (Viji et al. 2010a, b). The therapeutic efficacy of BME against respiratory disorders can be correlated with its calcium channel-blocking activity. The ethanolic extract (500 and 700 μg/mL) in guinea pig tracheal smooth muscles when compared with standard drug nifedipine (1  106 M) showed significant depression and shift in the calcium concentration-response curves (Channa and Dar 2012).

2.3.2

Pharmacological Activity of the Active Compounds

BME is enriched with myriads of bacopasaponins and their derivatives. Different biochemical and biotechnological approaches are made to detect, isolate, or synthesize novel products with different chemical identity and activity features. The major compound that is mostly responsible for anti-amnestic ability or neuroprotection is bacoside A, assigned as 3-(a-L-arabinopyranosyl)-O-b-D-glucopyranoside-10,20dihydroxy-16-keto-dammar-24-ene (Chatterji et al. 1963). Bacoside A is actually a mixture of four saponins, bacoside A3, bacopaside II, bacopasaponin C, and its jujubogenin isomer along with bacopaside I, another vital component isolated from BM (Gohil and Patel 2010; Deepak and Amit 2013). The ebelin lactone is the cisisomer of the aglycone (Rastogi et al. 1994). Two new dammarane-type triterpene oligoglycosides, bacomosaponins A and B, and three new phenylethanoid glycosides, bacosides A, B1, and B2, were isolated from the whole plant of B. monnieri and it can inhibit aggregation of 42-mer amyloid β-protein, associated with the AD (Ohta et al. 2016). Another pseudojujubogenin-type saponin, bacopasides III, IV, and V, has also been isolated and studied via 2D NMR and other spectral analyses (Chakravarty et al. 2003). From the aerial part of B. monnieri cucurbitacins (bacobitacin A–D), phenylethanoid glycosides (monnieraside I and III and plantioside B), sterol glycoside (bacosterol-3-O-beta-D-glucopyranoside), and phenylethanoid glycoside were isolated (Hou et al. 2002; Bhandari et al. 2006, 2007). Plant extract of B. monnieri also contains bacopaside I and II, bacopasaponin D (pseudojujubogenin glycosides), and bacopasaponins E and F (jujubogenin

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bisdesmosides) (Garai et al. 1996; Mahato et al. 2000; Chakravarty et al. 2001). In vitro cultures of B. monnieri on MS medium fortified with different chemicals (0.1 g/L magnesium sulfate, 0.1 g/L zinc hydroaspartate, 0.1 g/L l-tryptophan, 0.25 g/L serine, 0.5 g/L serine, and 0.5 mg/L anthranilic acid) produce l-tryptophan and serotonin (Muszyńska et al. 2016). Carrageenan-induced hind paw edema assay revealed that triterpenoid- and bacoside-enriched fractions exerted antiedematogenic effect, and in the arthritis model only the triterpenoid fraction exerted an anti-arthritic potential (Viji and Helen 2011). Herbal products alter the activity of membrane transporters (P-glycoprotein) and ATP-dependent drug efflux transporter is responsible for herb-drug interactions. Five individual active constituents have been isolated, i.e., bacopaside I, bacopaside II, bacopasaponin C, bacoside A, and bacoside A3, which act on human MDR1 gene-transfected LLC-GA5-COL150 cell line (Singh et al. 2014). Phytochemical screening of B. monnieri revealed the presence of two new dammarane glycosides of the 20-deoxy derivatives of jujubogenin and pseudojujubogenin which exhibited antileishmanial, antimalarial, antioxidant, and anti-inflammatory activities and mild-to-moderate cytotoxicity towards noncancerous kidney cell lines (Pawar et al. 2007). In vitro cultures of B. monnieri contain l-tryptophan, serotonin, and palmitic acid (Muszyńska et al. 2016). Bioactive bacopasaponins (bacoside A3, bacopaside I, bacopaside II, bacosaponin C, bacosine, and bacoside A mixture) can act on recombinant human monoamine oxidase enzymes (Singh et al. 2014). The individual activity of marker compound and other therapeutic botanicals originated from Brahmi are discussed in the following part.

2.3.2.1 Bacoside A Anti-Alzheimer’s Activity The peptide, amyloid-beta (1–42) (Aβ42), is a key component responsible for AD progression and amyloid toxicity generated altered fibrillation. Preincubation of the peptide with bacoside A caused Aβ42 oligomer assembly into mature fibrils and blocked their membrane interactions. Moreover, co-incubation with PrP (106–126) prevented membrane interactions of the amyloidogenic fragment of the prion protein [PrP(106–126)] (Malishev et al. 2016). Specifically, this indicates possible protective mechanism of bacoside A against AD (Malishev et al. 2017). Anti-apoptotic Activity Bacoside A (10 mg/kg body weight/day, orally, for 12 weeks) can modulate smoking-induced apoptosis in the brain of adult male albino Wistar rats. DNA fragmentation, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining, and transmission electron microscopy analysis detected smoking-induced toxicity which were associated with enhanced heat-shock protein 70 expression which were cured by bacoside A treatment and thus prevented neuronal apoptosis (Anbarasi et al. 2006a). The de novo anti-glioblastoma multiforme drug development is mostly based on triggering physicochemical disturbances in brain tumor cells. Bacoside A can cause remarkable dose-dependent

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tumor-specific physical, non-homeostatic disturbances against this aggressive brain tumor type. The mechanism includes excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A) enzyme which activates calcium release from the smooth endoplasmic reticular networks, followed by macropinocytotic extracellular fluid intake resulting in cell hypertrophy as well as massive macropinosome enlargement that leads to organellar congestion, cell swelling, rounding, and finally membrane rupture of glioblastoma cells (John et al. 2017). Anti-epileptic Activity Bacoside A can suppress the seizure/convulsion in Caenorhabditis elegans at higher temperatures (26–28  1  C) (Pandey et al. 2010). Hippocampus region plays a major role in epileptogenesis, memory, and learning and in pilocarpine-treated temporal lobe epileptic rats application of bacoside A reverses downregulation of abscisic acid and gamma-aminobutyric acid receptors (Mathew et al. 2011). Antidepressant Activity In mouse models of despair tests, bacopaside I (50, 15, and 5 mg/kg) decreased the immobility time without altering locomotor activity and it also possesses significant brain antioxidant activity. Further, it reversed reserpine-induced depressive behaviors, including low temperature and apoptosis, but did not change brain monoamine oxidase A or B activity (Liu et al. 2013). Anti-dopaminergic Activity The methanolic extract of B. monnieri was fractioned in n-butanol and the obtained extract was found to be rich in bacoside A [bacopasaponin C (3.2 mg/mg), bacoside A3 (4.14 mg/mg), bacopaside II (4.4 mg/mg)]. The marker component (5, 10, and 15 mg/kg) applied on mice model 1 h before intraperitoneal morphine treatment (10 mg/kg) and locomotor activity was found to be increased remarkably. In striatal tissue system HPLC- and electrochemical detection-marked n-butanol extract of B. monnieri mediated reduction in dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole acetic acid levels but exerted no effect on dopamine and serotonin. This indicates the role of the plant extract in treating morphine dependence (Rauf et al. 2012). Anti-inflammatory Activity Bacoside A exhibited in vitro inhibition of tumor necrosis factor-α and interlukin-6 along with reduction in the levels of caspases 1 and 3 and matrix metalloproteinase-3 in the cell-free assay (Nemetchek et al. 2017). Antioxidant Activity Bacoside A3-enriched hydroalcoholic plant extract showed radical scavenging activity (inhibition percentage 85, 91.66, 91.66, and 83%) on polymorphonuclear cells as detected in nitroblue tetrazolium assay with functional dose of 200, 100, 50, and 25 μg/mL, respectively. The IC(50) value of BME was 10.22 μg/mL whereas

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quercetin and ascorbic acid showed IC(50) of 111 and 14.16 μg/mL, respectively (Pawar et al. 2001). Cigarette smoke exposure is associated with enhanced lipid peroxidation, increased creatine kinase and all the three isoform (CK-MM, MB, BB) activity in serum, depletion of CK in heart and brain, and membrane leakage which were mitigated by administration of bacoside A (Anbarasi et al. 2005). Smokeinduced oxidative damage and diminished enzymatic and nonenzymatic antioxidant activities as well as alteration in trace element level were studied on adult male albino rats exposed to cigarette smoke for a period of 12 weeks. Concomitant bacoside A (10 mg/kg body weight/day, p.o.) treatment improved the antioxidant status and maintained the levels of trace elements (Anbarasi et al. 2006b). In dichlorvos-intoxicated mice, concomitant administration of bacoside A and bromelain showed significant amelioration of oxidative stress. It reduces thiobarbituric acid-reactive substance level and normalized the level of serum antioxidant enzymes, i.e., catalase, superoxide dismutase, glutathione peroxidase, and reduced glutathione (Agarwal et al. 2016). Hepatoprotection Liver injury caused by d-galactosamine elevated the level of serum marker enzymes in rats. Pretreatment with BME (10 mg/kg body weight/day, oral for 21 days) can ameliorate d-GalN-induced hepatotoxicity and normalized the levels of vitamin C and vitamin E (Sumathi and Nongbri 2008). Chemoprevention is often considered as a defensive mechanism to minimize hepatocarcinogenesis. Administration of N-nitrosodiethylamine can upgrade lipid peroxidation and associated increase in the level of serum tumor marker enzymes and liver injury marker enzymes. Histopathology and electron microscopic study revealed that bacoside A ameliorated hepatocellular carcinoma and restored endogenous enzymatic and nonenzymatic antioxidant activity (Janani et al. 2009, 2010a). The gelatin zymography study has indicated that bacoside A inhibits activity and downregulates expression pattern of matrix metalloproteinases 2 and 9 in N-nitrosodiethylamine-induced hepatocellular carcinoma via its anti-metastasis efficacy (Janani et al. 2010b). Neuroprotection The bacosides play a significant therapeutic role to inhibit chronic neuroinflammation. Oral administration of this dammarane-type triterpenoid saponins, for 3 months, can prevent age-related neurodegeneration in Wistar rat brain by attenuating elevation of pro-inflammatory cytokines, iNOS protein expression, and total nitrite and lipofuscin content in aged and middle-aged rat brain cortex (Rastogi et al. 2012). Wistar male rats exposed to cold stress (18  2  C till it started to sink for 1 month) showed signs of histological degenerations and supplementation of exposed rats with BME (40 mg/kg) helped them to combat stress-incurred neurotoxicity (Kumar et al. 2015). Protease Inhibition Activity Inhibition of metallo-proteases is important for the healing process and bacoside A is reported as a significant protease cleaver. In Swiss albino rats, Staphylococcus

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aureus-ATCC 29737 was inoculated through intracutaneous and intramuscular injection (0.1 mL) as well as topical application. The caseinolytic proteinases were observed at high concentration in control groups. The SDS-PAGE zymogram assay exhibited approximate molecular mass of 35–45 kDa and 75–80 kDa bacoside A (100, 200, and 300 μg) and standard drug nitrofurozone can inhibit the activity of all proteinases (Sharath et al. 2010). Renoprotective Activity Oxidative stress and hyperglycemia play a key role in the development of diabetic nephropathy, which can be attenuated by hydroalcoholic BME (100, 200, and 400 mg/kg) and isolated stigmasterol (5 and 10 mg/kg) in streptozotocin (65 mg/ kg i.p.)-induced diabetes in male Wistar rats where nicotinamide (230 mg/kg, i.p.) is administered (Kishore et al. 2016). Wound-Healing Activity Wound contraction rate and period of epithelization are two key factors involved in the process of wound healing. The excision, incision, and dead-space wound models were applied to create ischemic wounds on Swiss albino rats after intraperitoneal sedation (30 mg/kg body weight). Among four groups of experimental animals, bacoside A-treated group showed days of epithelization (18.30  0.01) almost equal to the standard drug nitrofurozone (18.18  0.04). Further, enhanced tensile strength (538.47  0.14 g) of the incision wound and granuloma formation (89.15  0.08 g) were observed with simultaneous absence of monocytes along with increased crosslinking of collagen (Sharath et al. 2010).

2.3.2.2 Bacopaside I Bacopaside I, a major triterpenoid saponin of BME, is reported for its therapeutic effect against cognitive impairments. In APP/PS1 transgenic mice, BS I ameliorated learning deficits, improved long-term spatial memory, and caused immunostimulated clearance of β-amyloid plaque load (Li et al. 2016). The transient two-vessel occlusion-induced cognitive impairment in mice and oxygen and glucose deprivation-induced hippocampal cell damage are the in vivo model of vascular dementia and in vitro model of ischemia, respectively. Bacopaside I (25 μM) rendered significant neuroprotection against aforementioned cell damage (Le et al. 2015). 2.3.2.3 Betulinic Acid Betulinic acid, a pentacyclic triterpenoid, isolated from B. monnieri, can prevent in vivo and in vitro production of LPS-induced interlukin-6 in blood mononuclear cells and nuclear translocation of p65 NF-kappaB in hPBMCs which may be associated with p38 and ERK MAPK regulation (Viji et al. 2010a,b). It possesses significant antitumor property (Fulda 2008). It also inhibits LPS-triggered COX-2 protein expression, ROS generation, and lactate dehydrogenase and myeloperoxidase activity (Viji et al. 2011).

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Pharmacological Activity of the Polyherbal Formulation(S)

2.3.3.1 Cognition A phytotherapeutic compound, consisting of B. monnieri and Haematococcus pluvialis (astaxanthin) plus phosphatidylserine and vitamin E, was screened via a cohort, noncomparative, multicenter trial to detect its neuroprotective efficacy. This dietary supplement (one tablet daily, oral) improved the state of mild cognitive impairment in subjects (n ¼ 104), aged approximately 71.2  9.9 years, who went through the Alzheimer’s Disease Assessment Scale-cognitive subscale test and the clock drawing test after completion of dietary supplementation for 60 days. Moreover, the dosage shows high tolerability and significant memory enhancement (Zanotta et al. 2014). Perment, a polyherbal formulation consisting of Clitoria ternatea Linn., Withania somnifera Dun., Asparagus racemosus Linn., and B. monnieri, works as a mood elevator and anxiolytic compound. Moreover, its significant antidepressant effect is studied on chronic unpredictable mild stress model of depression in rat (Ramanathan et al. 2011). A randomized double-blind placebo- and active constituent-controlled clinical trial was performed in healthy elderly subjects and senile dementia of Alzheimer’s-type patients of age 60–75 years. The experimental polyherbal formulation (500 mg) contains plant extract of B. monnieri and leaf and fruit extract of Hippophae rhamnoides L. and Dioscorea bulbifera L. bulbils applied with standard donepezil (10 mg, twice per day for 1 year) and age-related cognitive impairment is treated positively (Sadhu et al. 2014). 2.3.3.2 Hepatic Encephalopathy CongoBlend is a cocktail of Gingko biloba, Uncaria tomentosa (Willd.) DC, Centella asiatica (L.) Urban, Rosmarinus officinalis L., and B. monnieri. In a randomized interventional clinical study performed with patients of Child-Pugh B class hepatic encephalopathy (0–2nd stage), one set of patients received standard treatment whereas the other set of patients were treated with a formula CongoBlend (two capsules twice/day) along with standard treatment for 2–5 months; the patients receiving the combined treatment showed significant signs of clinical improvements in terms of psychometric tests, electroencephalography, and serum biochemistry than groups treated with standard drug only (Kaziulin et al. 2006).

2.4

Biotechnological Advancement

Bacopa monnieri is an extensively exploited plant in traditional medicine mostly for its memory-revitalizing potential. The huge demand for Brahmi-based drugs, insufficient seed availability, and commercial value have triggered the need of in vitro clonal propagation to conserve elite genotype of this plant. There are several reports available for in vitro establishment, propagation, and medium-based preservation of B. monnieri. On Murashige and Skoog’s (MS) medium supplemented with 6-benzyladenine (BA) (0.2 mg/L), shoot proliferation as well as rooting was

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achieved and they were successfully acclimatized and culture maintained for genetic stability studies based on molecular markers (Sharma et al. 2016). Micropropagation of the selected plant was achieved on MS and B5 medium supplemented with benzyl aminopurine and nicotinamide acetic acid using leaf and nodal explants and the best result was obtained with 2.0 mg/L BAP. The sustainability of plants was also checked based on its biochemical parameters, like chlorophyll, carbohydrate, protein, and leaves both in vivo and in vitro (Mohapatra and Rath 2005). Agrobacterium-mediated transformation of in vitro Bacopa culture induced bioproduction of Bacopa saponins in crypt-transgenic (Agrobacterium rhizogenes strain LBA 9402 crypt) plants via the overexpression of a proteinaceous elicitor, cryptogein-coding gene. In crypt gene-containing transgenic plants bacopasaponin D (1.4–1.69%) was maximally enhanced whereas in Ri-transformed plants, Ri crypttransformed plants accumulated bacoside A3, bacopasaponin D, bacopaside II, bacopaside III, and bacopaside V. Ri crypt-transformed plants showed expression of rol genes as well as crypt gene and in both Ri- and Ti-transformed roots callus was derived and redifferentiated to roots and shoot bud induction was initiated (Majumdar et al. 2012). In another transformation experiment, same strain (LBA 9402) and A. rhizogenes strain A4 induced callus and shoot bud initiation. Transformed calli indicated the presence of rolAB or rol A, TR, and ags genes along with morphological features of transformed plants. Growth and biomass accumulation were significantly higher in the transformed shoots (twofold) and roots (fourfold). Moreover, in pRi A4-transformed plants, the content of different isoforms of bacopasaponin, viz. bacopasaponin D, bacopasaponin F, bacopaside II, and bacopaside V, was increased significantly while bacoside A3 and bacopasaponin C content was comparable with that of wild-type plants. Significant stimulatory effect on enhanced accumulation of five bacopasaponins indicates efficient endogenous elicitation by Ri T-DNA of A. rhizogenes (Majumdar et al. 2011). The organic supplementation is a popular approach to enhance production of valuable secondary metabolites in in vitro systems. The effects of glycine (0–125 μM), ferulic acid (0–200 μM), phenylalanine (0–200 μM), α-ketoglutaric acid (0–200 μM), and pyruvic acid (0–200 μM) are evaluated for their influence on production of bacoside A, mostly reported for its key role in cognition improvement, and it is detected in shoot and callus biomass of B. monnieri. The shoot induction was obtained on BA (5 μM)-supplemented MS medium and callus biomass obtained from 2,4-dichlorophenoxyacetic acid (1 μM) and 1-naphthaleneacetic acid (5 μM) enriched MS medium. The production of bacoside A in shoot as well as callus is increased manifold by application of 100 μM pyruvic acid (Parale et al. 2010). Methyl jasmonate also enhanced in vitro production of bacoside A, in shoot cultures of B. monnieri (Sharma et al. 2013). Other phytochemicals like saponins (bacopasaponins, D-mannitol, monnierin), sapogenin (jujubogenin, pseudojujubogenin), flavonoids (apigenin, luteonin), alkaloids (brahmine, herpestine, hydrocotyline), and glycosides (asiaticoside, thanakunicide) and compounds like brahmic acid, brahamoside, brahminoside, and isobrahmic acid have been detected in BMEs (Gohil and Patel 2010).

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Toxicity Study

BME showed acute oral toxicity, in female rats, at 5000 mg/kg dosage in a 2-weekbased study, as evidenced by hematology, blood clinical chemistry, and microanatomy (Sireeratawong et al. 2016). Apart from nausea or mild gastrointestinal complaints there are no reliable reports of genotoxicity or teratogenesis in humans (Chaudhari et al. 2017). BacoMind, a bioactive herbal formulation enriched with B. monnieri, showed median lethal dose of 2400 mg/kg in Sprague-Dawley rats under single oral administration. The oral toxicity test conducted for 90 days, along with necropsy and histopathological studies, revealed no sign of significant toxic effect in rats (Allan et al. 2007). The oral administration of 40 and 80 mg/kg showed nociceptive effect and neuroprotection without toxicity response (Shahid et al. 2017).

2.6

Drug Designing

Solubility and permeability are two key factors required for successful drug designing. To check the bioavailability of standardized BME, a phospholipid-based approach was employed and standard BME-phospholipid complex (Bacopa naturosome) was prepared. The saturation solubility, the in vitro dissolution, and the ex vivo permeability were assayed and significant higher (20-fold) aqueous solubility of Bacopa naturosome was confirmed by photomicroscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies. These studies indicated that drugphospholipid complexation may be a fruitful strategy for dissolution, solubility, and permeability enhancement of bioactive botanicals (Saoji et al. 2017). Bacosides, aglycones, and their derivatives were screened for CNS modulation and cognition enhancement via combined in silico and in vitro methods like radioligand receptor binding and AChE inhibition assays where they were docked into 5-HT1A, 5-HT2A, D1, D2, M1 receptors, and AChE. Their drug-like features are examined through AutoDock, Discovery Studio molecular properties, and ADMET descriptors. It was revealed that the aglycones and their derivatives possess better binding affinity as CNS drug and higher level of intestinal absorption and had better blood–brain barrier penetration than bacosides (Ramasamy et al. 2015). Parkinsonism is associated with protein DJ-1, encoded by the PARK7 gene which causes Lewy body formation and α-synuclein aggregation and thus triggers neurodegeneration. In an experiment, bacoside A along with standard psychotherapeutic botanical L-DOPA showed successful docking with DJ-1. According to the docking simulation detected by Discovery Studio, it was found that this active marker compound binds at the active site 4 of DJ1 (Chandrasekar et al. 2013). Though jujubogenin glycosides also interact with the DJ1 its drug likeness was not satisfactory (Sinha et al. 2012). In case of AD, amyloidogenic peptide-mediated plaque formation can be prevented by binding of bacoside ligand-6 with caspases particularly caspase 3 (Johari et al. 2012).

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Structure-Activity Relationship

The study on structure-activity revealed that bacoside A contains sugar chains linked to a steroid aglycone skeleton. It has been reported that biological activity and pharmacokinetic characteristics of triterpenoid saponins are aided by their in vivo transformation to metabolites. The in silico and in vitro screening methods elucidate therapeutic efficacy of parent molecules (bacosides), aglycones (jujubogenin and pseudojujubogenin), and their derivatives (ebelin lactone and bacogenin A1). These triterpenoid saponins also enhance nerve impulse transmission via membrane dephosphorylation, with a concomitant increase in protein expression and RNA turnover in specific regions of brain (Singh et al. 1988). Among the phytoconstituents of B. monnieri, ebelin lactone showed the strongest binding energy, highest blood–brain barrier penetration, and binding affinity towards M1 and 5-HT2A receptors (Ramasamy et al. 2015). Two structurally related bacopasides (I and II) influenced differential inhibition of water and ion channel activities of mammalian aquaporin-1 (Pei et al. 2016).

2.8

Summary

Amidst the vast area of therapeutic applications, neuropharmacological attributes of Brahmi are overwhelming and a promising area for research and pro-cognitive drug designing. Oxidative stress and associated functional deformities of CNS are responsible for the onset of myriads of neurodegenerative disorders. BME supplementation has paved therapeutic avenue for many ailments, experimentally screened for the mechanism of action and rendered cognitive potential and reviewed for its antidepressant, anti-epileptic, anti-inflammatory, antiaging, cardio-hepatoneuroprotection-facilitating activities. B. monnieri may improve higher order cognitive processes, critically dependent on the input of information from our environment such as learning and memory. Modern medicine-based psychoactive drugs have met with limited success while combating globally increased rate of neurodegenerative diseases. Cognitive impairments are prevalent among aged population because aging is associated with neuronal cell damage, lowered synaptic activity, and susceptibility towards oxidative damage (McPhee et al. 2016). Therefore, there is a growing demand for novel products and to improve the mental capabilities either singly or in combination with conventional drugs. The antiradical activity of Brahmi-derived formulations is functional against cytotoxicity incurred by AD where cells of prefrontal cortex, hippocampus, and striatum are protected and also effective against nitric oxide-mediated cerebral vasodilation (Chaudhari et al. 2017). Dietary supplementation (0.5 and 1% for 4 weeks) modulates endogenous oxidative stress markers, redox status, enzymatic defense response, protein oxidation, and cholinergic function in different brain regions of prepubertal mice (Shinomol 2011; Simpson et al. 2015). Neuroimaging studies have identified shrinkage of cortical, frontal, and temporoparietal volume; white matter hyper-intensities; and higher levels of cortical atrophy occurring in the aged brain; increasing age thus impacts

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cognitive functioning negatively (MacLullich et al. 2002; Looi and Sachdev 2014). Such supplementation theoretically helps to enhance and strengthen synaptic changes and brain connectivity acquired through cognitive training. These B. monnieri-dependent improvements may be aided by specific neuromolecular mechanisms (i.e., synaptogenesis) and may also be attributed by upregulation of calcium-dependent kinases in the synapse and postsynaptic cell as evidenced by various animal models (McPhee et al. 2016). Overall enhancement of logical memory and paired associate learning and recovery from cognitive impairment in various experimental models are achieved through application of BM and its active constituents without severe neurological, hematological, or histopathological damage of vital organs (Chaudhari et al. 2017).

2.9

Conclusion

The psychotherapeutic efficacy of BM plant extract and active constituent bacosides is responsible for exerting the nootropic ability in both animals and humans. Several clinical and preclinical trials have been conducted to target the main functional compound, their bioavailability, structure-function interrelation, and structure analyses. In case of many psychiatric disorders, several similarities have appeared related with atypical protein expression, histopathological damage on a subcellular level, and ultimate aberrant cell death. So studies on these similarities are of immense importance in terms of therapeutic efficacy and parallel drug discovery. Both the botanical and herbal extract-attributed bioactivities have been studied with care and their possible role in neuroprotection is discussed. The delivery of such active compounds to target tissue is an onerous task where nanoscience and phospholipid-mediated transport can influence the drug delivery. Different animal models, cell lines, and in silico studies were performed to elucidate possible neuroprotection though the undercurrent mechanism is still at infancy in many levels. Moreover, variable kinds of bacopasaponins and their true therapeutic role are yet to be explored which can be overcome by constant research and clinical trials. Regulation of oxidative stress, use of neuroimaging techniques, and effective usage of dietary Brahmi-based supplementation and long-term toxic implication of these products will assist in combating elderly cognitive impairments and globally increased stress level.

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functioning in cognitively healthy elderly people: the Australian Research Council longevity intervention (ARCLI) study protocol (ANZCTR12611000487910). Nutr J 11(1):11 Sumathi T, Devaraj SN (2009) Effect of Bacopa monnieri on liver and kidney toxicity in chronic use of opioids. Phytomedicine 16(10):897–903 Sumathi T, Nongbri A (2008) Hepatoprotective effect of Bacoside-A, a major constituent of Bacopa monnieri Linn. Phytomedicine 15(10):901–905 Sumathi T, Nayeem M, Balakrishna K, Veluchamy G, Devaraj SN (2002) Alcoholic extract of ‘Bacopa monnieri’ reduces the in vitro effects of morphine withdrawal in Guinea-pig ileum. J Ethnopharmacol 82(2–3):75–81 Taznin I, Mukti M, Rahmatullah M (2015) Bacopa monnieri: an evaluation of antihyperglycemic and antinociceptive potential of methanolic extract of whole plants. Pak J Pharm Sci 28 (6):2135–2139 Thippeswamy AH, Rafiq M, shastry Viswantha GL, Kavya KJ, Anturlikar SD, Patki PS (2013) Evaluation of Bacopa monnieri for its synergistic activity with rivastigmine in reversing aluminum-induced memory loss and learning deficit in rats. J Acupunct Meridian Stud 6 (4):208–213 Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K (2010) Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. J Ethnopharmacol 127(1):26–31 Ullah I, Subhan F, Rudd JA, Rauf K, Alam J, Shahid M, Sewell RD (2014) Attenuation of cisplatininduced emetogenesis by standardized Bacopa monnieri extracts in the pigeon: behavioral and neurochemical correlations. Planta Med 80(17):1569–1579 Ullah I, Subhan F, Lu Z, Chan SW, Rudd JA (2017) Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew). J Pharmacol Sci 133 (4):232–239 Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74 Verma P, Gupta RK, Gandhi BS, Singh P (2015) CDRI-08 attenuates REST/NRSF-mediated expression of NMDAR1 gene in PBDE-209-exposed mice brain. Evid Based Complement Alternat Med 2015:1 Viji V, Helen A (2008) Inhibition of lipoxygenases and cyclooxygenase-2 enzymes by extracts isolated from Bacopa monnieri (L.) Wettst. J Ethnopharmacol 118(2):305–311 Viji V, Helen A (2011) Inhibition of pro-inflammatory mediators: role of Bacopa monnieri (L.) Wettst. Inflammopharmacology 19(5):283–291 Viji V, Kavitha SK, Helen A (2010a) Bacopa monnieri (L.) Wettst inhibits type ii collagen-induced arthritis in rats. Phytother Res 24(9):1377–1383 Viji V, Shobha B, Kavitha SK, Ratheesh M, Kripa K, Helen A (2010b) Betulinic acid isolated from Bacopa monnieri (L.) Wettst suppresses lipopolysaccharide stimulated interleukin-6 production through modulation of nuclear factor-κB in peripheral blood mononuclear cells. Int Immunopharmacol 10(8):843–849 Viji V, Helen A, Luxmi VR (2011) Betulinic acid inhibits endotoxin-stimulated phosphorylation cascade and pro-inflammatory prostaglandin E2 production in human peripheral blood mononuclear cells. Br J Pharmacol 162(6):1291–1303 Wetchateng T, Piyabhan P (2015) Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and neuronal density in the prefrontal cortex, striatum and hippocampus in sub-chronic phencyclidine administration rat model of schizophrenia. J Med Assoc Thai 98:S56–S63 Yadav KD, Reddy KRC, Kumar V (2014) Beneficial effect of Brahmi Ghrita on learning and memory in normal rat. Ayu 35(3):325 Zanotta D, Puricelli S, Bonoldi G (2014) Cognitive effects of a dietary supplement made from extract of Bacopa monnieri, astaxanthin, phosphatidylserine, and vitamin E in subjects with mild cognitive impairment: a noncomparative, exploratory clinical study. Neuropsychiatr Dis Treat 10:225

Current Knowledge of Cinnamomum Species: A Review on the Bioactive Components, Pharmacological Properties, Analytical and Biotechnological Studies

3

Devendra Kumar Pandey, Ronni Chaudhary, Abhijit Dey, Samapika Nandy, R. M. Banik, Tabarak Malik, and Padmanabh Dwivedi Abstract

Cinnamon (Ceylon cinnamon or true cinnamon) is a popular, expensive aromatic condiment and flavoring agent cum medicinal plant that houses a major number of pharmaceutically active aromatic essential oils and its principal compound cinnamaldehyde, and its derivatives cinnamic acid, cinnamate, etc. In addition to its culinary use, in ancient Ayurvedic texts as well as in folkloric medicine, this plant and precisely the bark and bark powder have been reported as a remedy for respiratory, digestive, and gynecological ailments. It has been evaluated clinically and preclinically for its prominent antioxidant, anti-inflammatory, antidiabetic, antimicrobial, anticancer, lipid-lowering, and cardio- and neuroprotective efficacies. Commercially this plant is highly valued in the pharmaceutical and cosmetic industry. We have summarized the recent relevant scientific evidence on the botanic characterization, distribution, traditional uses, pharmacological

D. K. Pandey (*) · R. Chaudhary Department of Biotechnology, Lovely Faculty of Technology and Sciences, Lovely Professional University, Phagwara, Punjab, India e-mail: [email protected] A. Dey · S. Nandy Department of Life Sciences, Presidency University, Kolkata, West Bengal, India R. M. Banik School of Biochemical Engineering, Varanasi, India T. Malik Department of Biochemistry, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia P. Dwivedi Department of Plant Physiology, Institute of Agriculture Sciences, Banaras Hindu University, Varanasi, UP, India # Springer Nature Singapore Pte Ltd. 2020 J. Singh et al. (eds.), Bioactive Natural Products in Drug Discovery, https://doi.org/10.1007/978-981-15-1394-7_3

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activities, phytochemistry, qualitative and quantitative estimation and extraction of important secondary metabolites, genetic diversity assessment, biotechnological breakthroughs, cultivation, and propagation along with industrial application and clinical studies of Cinnamon species to assess future perspectives for Cinnamon as a pharmacologically leading genus of interest. Secondary metabolite extraction, isolation, and identification using HPTLC, LC-MS, HPLC, and GC-MS, along with genetic diversity assessment through molecular markers and biotechnological advancement (in vitro culture, embryo rescue, genetic transformation, molecular marker-based polymorphism assessment) contributing collectively to cinnamon improvement programs, are conclusively studied and reported in association with phytochemical and pharmacological discoveries via clinical and preclinical trials. The implementation of collective knowledge of research in areas of chemical biology, biotechnology, and pharmacology will directly benefit cost-effective breeding and cultivation program and establishment of encyclopedic database on various fields associated with Cinnamon research, aid in selection of industrially profitable elite germplasm with improved screening and harvesting protocols for Cinnamon-derived components, and elucidate a vast role of Cinnamon as an integral compound of complementary and alternative medicine. Keywords

Cinnamon · Cinnamomum zeylanicum · Cinnamaldehyde · Cinnamon oil · Cinnamon bioactivity

3.1

Introduction

The overwhelming acceptance of herbalism and emergence of complementary and alternative medicine have widened the scope of research on medicinal and aromatic plants (MAPs), of which “Cinnamomum” is an important and popular genus. Though Cinnamomum zeylanicum and Cinnamomum cassia of the family Lauraceae are mainly harvested for spice in different cuisines there are other species of Cinnamomum, like Cinnamomum burmannii, Cinnamomum verum, Cinnamomum tamala, and Cinnamomum loureiroi. Apart from bark, the bark oil (cinnamon oil), bark oleoresin, and aromatic leaf oil are other important value-added commercial products harvested from cinnamon. The term “cinnamon” represents brown color of the bark which is mainly utilized as spice and therapeutic agent. It is one of the oldest herbal medicines and old world spice. Cinnamon, native to the Caribbean region, South America, and Southeast Asia, is commonly known as “daalchini” in Indian household, and it is one of the essential, highly prized components in royal Indian cuisine and extensively used in other parts of the world for its signature flavor and aroma. Ceylon cinnamon is the high-quality cinnamon that is exported from its native country Sri Lanka. In addition to its culinary uses, from ancient period

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Current Knowledge of Cinnamomum Species: A Review on the Bioactive. . .

129

cinnamon has been used as a stomachic and carminative, acted against arthritic pain, cough, bronchitis, and sore throats (Teuscher et al. 2005). In present days it has been evaluated for potential antidiabetic, anti-inflammatory, antioxidant, and antiproliferative properties (Bhati et al. 2019; Kapoor et al. 2019; Singh et al. 2019a). The main chemical constituent of cinnamon bark is cinnamaldehyde, cinnamyl alcohol, cinnamic acid, and coumarin (He et al. 2005). Transcinnamaldehyde is the main bioactive compound of C. cassia and C. burmannii while eugenol is the major component in C. zeylanicum, C pauciflorum, and C. burmannii (Wang et al. 2007, 2009). The cinnamon oil consists of several volatile compounds containing aldehyde (trans-cinnamaldehyde, benzaldehyde, acetaldehyde, etc.), ketone (coumarin), alkane (dodecane), and carboxylic acid (acetic acid) (Wang et al. 2009). The essential oil has also been investigated for various medicinal properties like antidiabetic activity (Asolkar et al. 1992; Chakraborty and Das 2010), antioxidant activity (Mathew and Abraham 2006; Singh et al. 2019b), anti-inflammatory activity (Kirtikar and Basu, 1975), and antimicrobial property (Tzortzakis 2009; Singh et al. 2019c, d; Kumar et al. 2019). The main goal of this chapter is to look through different aspects of cinnamon research and compilation of extensive database. For this purpose we have searched different scientific databases (PubMed, Google Scholar, MEDLINE, EMBASE, NOPR, NISCAIR, SpringerLink, etc.) and comprehensively collected, cross checked, and analyzed the huge information obtained by using the search strings as follows: “cinnamon” “Cinnamomum,” “cinnamon oil,” “cinnamon bioactivity,” “cinnamaldehyde,” “medicinal property of spice,” etc. In addition, we have gathered information from ancient text, monographs, and books. A total of 227 references are cited in this elaborative study and we have tabulated information of bioactivity of chemical components and extraction methodology of different volatile compounds in Tables 3.1 and 3.2. The chemical structures are drawn using ChemSpider software and details of Cinnamomum botany, distribution, traditional usage, pharmacological property, knowledge of phytochemicals, extraction and estimation process of different compounds, biotechnological advancement of cinnamon research, and clinical studies performed till date are critically discussed.

3.2

Botanical Description

The genus Cinnamomum is comprised of 250 species belonging to Lauraceae family. The plants of the family are generally evergreen small- to medium-sized trees or aromatic shrub (Jantan et al. 2003, 2008) distributed throughout tropical and subtropical regions of North America, Central America, Asia, Oceania, and Australia. The mostly harvested plant for spice cinnamon is Cinnamomum zeylanica which is a shrub found in regions with varying altitudes. This tree can grow up to 7 m, scabrous aromatic bark is its main value-added product, and the leaf is also used in culinary for its flavor-adding capacity. The side branches are grown for 3 years to obtain quality cinnamon bark, marketed as small pieces or powder. Leaves are

20 mg/kg bw

40 mg/kg

20 mg/kg bw

20 mg/kg

5, 10 and 20 mg/kg b.w. 10, 20, 50, 100 μM 10 μM

Cinnamaldehyde

Cinnamaldehyde

Cinnamaldehyde

Cinnamaldehyde

Cinnamaldehyde

Cinnamaldehyde

Antidiabetic

NF-E2-related factor 2 activation", ROS#

Mitochondrial membrane permeability # Plasma Insulin", hepatic glycogen", HDL ", plasma enzyme", HbA1C#, serum total cholesterol#, triglyceride# Serum RBP4 #, tissue GLUT4 protein expression " Insulinotropic effect", pyruvate kinase ", phosphoenolpyruvate carboxykinase " FBG ", insulin" body weight", GLUT-4 expression ", TNF-α expression# Antioxidant defense ", pancreatic β-cell damage # Glut4 expression",

40 μM

Cinnamaldehyde

Cinnamaldehyde

Mechanism Biofilm formation#

Dosage 0.1, 0.25, 0.5%

Chemical compound Trans-cinnamaldehyde

Activity Anti-biofilm formation Anticancer

Male C57BL/6 J mouse aortic rings, HUVEC cell line

C2C12 skeletal muscle cells

STZ-induced diabetic rats

C57BLKS/J db/db mice

STZ-induced diabetic rats

Diabetic rat

Human promyelocytic leukemia cells STZ-toxicated male diabetic Wistar rats

Cell line/animal model/assay Uropathogenic E. coli

Table 3.1 Summary of bioactivity of different phytochemicals along with experimental details, dosage, and mode of action

Subash-Babu et al. (2014) Nikzamir et al. (2014) Wang et al. (2015)

Li et al. (2012)

Anand et al. (2010)

Zhang et al. (2008)

References Amalaradjou et al. (2010) Ka et al. (2003) Subash Babu et al. (2007)

130 D. K. Pandey et al.

Growth inhibition"

Growth inhibition" Fungal cell wall synthesis#, chitin synthase# Cellular ATP concentration #

50 μL

1–1000 μg/mL 2 μL 5 mM and 30 mM, respectively 2.10–3.15 mg/l

Cinnamaldehyde

Trans-cinnamaldehyde

Eugenol, cinnamaldehyde

Cinnamaldehyde, eugenol

Membrane fatty acid alteration "

Prostaglandin E2 #

Cinnamaldehyde, eugenol, pyrogallol Cinnamaldehyde

Antiinflammatory Antibacterial

27.2–54.4 mg/ g food and 6.8–13.6 mg/g food, respectively

Fructosamine#, total cholesterols#, triglycerides#, leptin#, TNF α#, malondialdehyde# NO# Contact toxicity", larval death"

Cinnamaldehyde

20 mg/kg

Antifeedant

Cinnamaldehyde

E. coli O157:H7, Salmonella cholera serovar typhimurium, Pseudomonas fluorescens, Brochothrix thermosphacta, Staphylococcus aureus

Listeria monocytogenes

Streptococcus mutans ATCC 25175, S. sanguis, S. mitis, S. milleri, Peptostreptococcus anaerobius ATCC 14956, Prevotella buccae, P. oris, P. intermedia Malassezia furfur, Candida albicans Saccharomyces cerevisiae

COX-2 enzymatic assay

Tribolium castaneum (Herbst) and Sitophilus zeamais Motsch

Fatty-sucrose diet/STZ female albino rat

Current Knowledge of Cinnamomum Species: A Review on the Bioactive. . . (continued)

Ferhout et al. (1999) Bang et al. (2000) Gill and Holley (2004) Di Pasqua et al. (2006)

Hosni et al. (2017) Didry et al. (1994)

Huang and Ho (1998)

Wang et al. (2015)

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Antiinflammatory

Activity

Growth inhibition" Growth inhibition"

100–3200 mg/L 50 μL/mL 0.31 mg/mL

Eugenol and cinnamaldehyde

Cinnamaldehyde

Up to 45 mg/kg

Growth inhibition"

100 μg/ml

Cinnamaldehyde, α-methyl cinnamaldehyde, (E)-2methylcinnamic acid, eugenol, isoeugenol Cinnamaldehyde, eugenol

Cinnamaldehyde

Growth inhibition"

75–600 μg/mL

Cinnamaldehyde

Cytoplasmic content leakage and condensation", cell distortion ", membrane integrity#, Age-related NF-κB activation#, inflammatory iNOS#, COX-2#

Mechanism Antibiotic resistance#

Dosage 20 μg/mL

Chemical compound Trans-cinnamaldehyde

Table 3.1 (continued)

In vitro assay

Aeromonas hydrophila, Enterococcus faecalis E. coli (ATCC 8735), Staphylococcus aureus (ATCC 3101)

E. coli CGMCC 1.487

Staphylococcus aureus, E. coli, Enterobacter aerogenes, Proteus vulgaris, Pseudomonas aeruginosa, Vibrio cholera, V. parahaemolyticus, Salmonella typhimurium), and four species of Candida, dermatophytes (Microsporum gypseum, Trichophyton rubrum, T. mentagrophytes) Lenzites betulina, Laetiporus sulphureus

Cell line/animal model/assay Clostridium difficile

Kim et al. (2007)

Pei et al. (2009) Sanla-Ead et al. (2007) Shen et al. (2015)

Cheng et al. (2008)

References Shahverdi et al. (2007) Ooi et al. (2006)

132 D. K. Pandey et al.

DNA-binding ability of LuxR protein#

150 μM

Cinnamaldehyde

Cinnamaldehyde

20 mg/kg/day

Cinnamaldehyde

Cardioprotection

Quorum-sensing activity

Vasorelaxation", prostaglandin F2α contraction# Vascular contractility "

1 μM to 1 mM

Eugenol and cinnamaldehyde

Anti-ulcerogenic

2 μg/mL

250, 500 mg/kg oral; 50,100 mg/kg i.p.

Cinnamaldehyde

Inducible error-prone DNA repair" Coagulation time", collagen- and thrombininduced platelet aggregation# Growth inhibition"

Antithrombotic

440 identified peptaibol sequences, only few sequences have their high-resolution structures deciphered (Degenkolb et al. 2008) and detailing the source of peptaibols is beyond the scope of this chapter. In the following sections, we shall see more details about these peptaibols.

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Peptaibols: Antimicrobial Peptides from Fungi

Alanine

Amino isobutyric acid

715

Valine

Isovaline

Fig. 26.1 Comparative depiction of nonstandard amino acids α-aminoisobutyric acid and isovaline with alanine and valine, respectively

26.3

Characteristics of Peptaibols

Peptaibols are linear polypeptide antibiotics which contain 5–20 amino acid residues with molecular weights in the range of 500–2200 Da. They contain high amounts of the marker α-aminoisobutyric acid (Aib) residues; possess non-proteinogenic (Aib, b-Ala, MePro, Hyleu, Hyp, d-Iva) (Reusser 1967) and/or lipoamino acids (2-amino4-methyldecanoic acid (AMD)) and 3-aminipropionic acid (APA) (Mori et al. 1982) (Fig. 26.1); and are characterized by the presence of an N-terminus which is acylated, and an acetylated or free amide bonded to amino alcohol at the C-terminus (Yohko et al. 1998; Berg et al. 1999; Toniolo et al. 2001; Degenkolb et al. 2007; Daniel and Filho 2007). The C-terminus besides being amino alcohol can be sometimes –NH2, –RONH2, sugar alcohol, 2,5-dioxopiperazine, or free amino acid (Harman et al. 2004; Degenkolb et al. 2007). Furthermore, all the known peptide antibiotics fall prey to the proteases of either host or pathogen and hence may not be effective in action. Peptaibols, on the other hand, are very stable and are resistant to proteases. This makes them exclusive and hence more effective in treating many diseases (Kluver et al. 2006). Peptaibols, also, give less time to the microorganisms to react as the mode of action is quick when compared to the conventional antibiotics (Eid et al. 2010; Park et al. 2011). Based on the above unique characteristics they are novel and could not be clubbed with any other class of bioactive peptides.

26.4

Chain Length and Residue Types

Majority of the sequences are found to be either 16 residues or more in length with a helical conformation (Whitmore and Wallace 2004). The preference for this chain length is thought to be an important feature related to the transmembrane permeabilization function of the peptaibol. However, there are peptaibols with a chain length of 11 residues also. These are thought to have different types of membrane insertion model. In order to facilitate spanning of the bilayer, these are proposed to stack in a pairwise fashion in the center of the membrane with their N-terminus. An observation of the peptaibol sequences shows an inclination of more

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than 69% of sequences towards even-numbered chain lengths (de la Fuente-Núñez et al. 2013). The Aib content, which forms one of the major contents of the peptaibols, ranges from 14% to 56%. Aib, which promotes the formation of a hydrophobic helix in peptaibols, plays a crucial role in stabilizing the longer helices and their percentage is directly proportional to the total length of the peptaibol molecule. Interestingly, in the long peptaibols, Aib cannot be found at positions 18, 19, or 20 (de la FuenteNúñez et al. 2013). Glutamine, the second most occurring polar residue (10%), occurs in 86% of the entries. It occupies position 6 or 7 in the peptide chain. Glutamine, at any of the mentioned positions, is supposed to play a crucial role in controlling the ion flow through the transmembrane pore (Nagaoka et al. 1996). As mentioned above, infrequent distribution of aromatic amino acids in peptaibols and exclusively at either the N- and C-termini shows strong positional bias in their distribution. This helps in stabilization of the membrane in the bilipid layer (Schiffer et al. 1992; Wallace and Janes 1999). In peptaibols, residues other than Aib or glutamine are nonpolar or aliphatic in nature, and a very few (4%) polar amino acids can be found. The aliphatic residue helps in maximizing hydrophobic interactions and helps in the formation of channels by insertion of peptaibols into the membrane (Duclohier 2007). Although there is no particular pairwise distribution seen in these molecules, few residues follow certain trend. Prolines are always found after Aib while hydroxyprolines (Hyp) are found after Aib or Iva unlike more hydrophobic valine and leucine, which do not pair with Aib. Glycine frequently precedes leucine. These pairings only help us to understand the bias in synthesizing these peptides. In nature, we see the kinks being formed in β-helices due to the presence of pattern X-Pro-GlyX. However, in these peptides, different from the usual, we see a slightly different motif Pro-X-X-Gly or Gly-X-X-Pro (X represents any amino acid) which tends to form distortions but cannot produce turns (Whitmore and Wallace 2004).

26.5

Classification of Peptaibols

The commonly used classification of peptaibols is based on their chain length. The 17–21-amino acid sequences are grouped into long-chain peptaibols while 11–16and 5–10-amino acid sequences as medium-chain and short-chain peptaibols, respectively. Another classification is based on the type of residues present at the N-terminus. As known, the majority of peptaibols contain Aib along with the C-terminus having 2-amino alcohol (Degenkolb et al. 2007, 2008). If the acylation of the N-terminus is by cis-dec-4-enoic acid or octanoic or decanoic acid, these are referred to as subfamily lipopeptaibols and are strongly lipophilic in nature (Toniolo et al. 2001). SF3, the peptaibol subfamily 3, commonly referred to as amino lipopeptides or lipoaminopeptides has saturated or unsaturated, a- or g-methyl-branched or unbranched C4–C15 fatty acids replacing its N-terminus.

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Peptaibols: Antimicrobial Peptides from Fungi

717

A classification method based on sequence identity and to a lesser extent on sequence length was done by Chug and Wallace in (2001) (Table 26.1). This classification was based on the 200 odd sequences which were available at that time using Clustal W. This homology grouping into subfamilies based on the functionally important residues helped in clustering peptaibols with similar functional properties. Sequences with >50% homology were clustered into nine distinct subfamilies as shown in Table 26.2. Although the classification is based on close homology, Degenkolb and Bruckner (2008) have expressed their reservations and suggested a revision of the subfamilies as many more new sequences have been added to the database.

26.6

Biosynthesis of Peptaibols

Peptaibols are peptides that are non-peptinogenic or not ribosomally synthesized as it cannot incorporate amino acid like Aib. This means they are synthesized in a way that is independent of messenger RNA. Studies suggest that these are synthesized by one or more specialized multienzyme complex modular synthetases called non-ribosomal peptide-synthetase enzymes (NRPS) which are capable of incorporating rare amino acids (Wiest et al. 2002). Usually for a peptide, the NRPS genes are arranged either in gene clusters or in an operon. Ciclosporin is the first NRP to be isolated from fungi (Borel et al. 1996). Addition of an additional amino acid is the responsibility of these NRPS enzymes which are organized in the form of modules. Each module is composed of several domains with specific functions. A study on Trichoderma reesei revealed the presence of two peptaibol synthetase genes (NRPS1 and NRPS2) involved in the synthesis of two peptaibol fractions—a 20-residue paracelsin and a 11-residue hypojecorin, together with four minor peak groups (Mikkola et al. 2012). Each module starts from N-terminus to C-terminus and consists of three main steps as follows:

26.6.1 Initiation or Adenylation Adenylation occurs at the A-domain wherein the activation of the first amino is by an ATP. This activated amino acid is then loaded onto the peptide carrier protein (PCP) domain which has serine-attached 40 -phospho-pantethine (40 PP) side chain. Amino acids can be formylated or methylated by F-domain or methylated by N-methylation domain, respectively.

26.6.2 Elongation or Thiolation Once specific amino acids are loaded onto the PCP domains by each module, an amide bond is formed between the thioester groups of the growing peptide chain from the previous module with the amino group of the current module by a process

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Table 26.1 Representation of the nine subfamilies as described by Chug and Wallace (2001)

Subfamily SF-1

SF-2

SF-3

SF-4

SF-5

SF-6

SF-7

SF-8 SF-9

Chain length and no. of sequences Characteristics 17–20 residues Long peptides; 120 sequences n6/n7—Gln; n18–19—Glu-Gln or Gln-Gln pair; n13/n14—Pro; n11—Gly (80%) 14–16 residues The aromatic 30 sequences residue (phe) at Cand N-termini; n6—Gly; n11— Glu; n10 and n13—Pro/Hyp 14–16 residues Aromatic residue at 15 sequences C- and N-termini; n6—Thr; n3 and n11—Gln 11 or n2—Gln or Asn; 14 residues n5/n9/n13—Pro 5 sequences (in 14-residue peptide) and n9– n13 (in 11-residue peptide); no aromatic/charged aa 7 or Glycine-rich 11 residues peptides; has Pro, 5 sequences Gln, or charged aa 15 residues n1—trp 3 sequences (hydrophobic aromatic) n14— Gln; n15—Leu; No Pro/Hyp 11 residues n11—Leu; n5/6/ 3 sequences 7—Gln; n2—Pro, n3—aromatic aa; may have ethylnorvaline aa (unusual aa) 14 residues 4 Hyp aa; no 1 sequence charged aa 5 residues No Pro, Gln, or 1 sequence charged aa

Examples Alamethicin; Chrysospermins; Boletusin

Antiamoebin-I; Emerimicin-IV; Bergofungin-D

L1-ZervamicinF; Emerimicin-IIA; XR586

Harzianin-HC-I; HarzianinHC-XV; Trichorovin-TVXIIa; Hypomurocin-HMA2

References Molle et al. (1991), Dornberger (1995), Lee et al. (1999a, b) Shenkarev et al. (2013), Benedetti et al. (1983), Berg et al. (1999) Balaram et al. (1992), Benedetti et al. (1983) Song et al. (2011)

Trichogin-A-IV; Trikoningin-KB-I; Trikoningin-KB-I1 Ampullosporin; TylopeptinA; Tylopeptin-B

Song et al. (2011)

LP237-F5LP237-F7LP237F8

Degenkolb and Bruckner (2008)

Clonostachin

Chikanishi et al. (1997) Hulsmann et al. (1998)

Peptaibolin

Song et al. (2011)

n position of amino acid in the peptide chain, aa amino acid(s) Unique characteristics of each subfamily are shown in the table along with few examples

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Peptaibols: Antimicrobial Peptides from Fungi

719

Table 26.2 Peptaibol sequences representing each of the nine subfamilies showing the positional arrangement of Aib Peptaibol Alamethicin Antiamoebin I EmerimicinIIA Harzianin-HCI Trichogin-AIV Ampullosporin LP237-F5 Clonostachin Peptaibolin

Sequence Ac Aib Pro Aib Ala Aib Aib Gln Aib Val Aib Gly Leu Aib Pro Val Aib Aib Glu Gln Phe OH Ac Phe Aib Aib Aib Iva Gly Leu Aib Aib Hyp Gln Iva Hyp Aib Pro Phe OH Ac Trp Ile Gln Aib Ile Thr Aib Leu Aib Hyp Gln Aib Hyp Aib Pro Phe OH Ac Aib Asn Leu Aib Pro Ser Val Aib Pro Aib Leu Aib Pro Leu OH Oc Aib Gly Leu Aib Gly Gly Leu Aib Gly Ile Leu OH Ac Trp Ala Aib Aib Leu Aib Gln Aib Aib Aib Gln Leu Aib Gln Leu OH Oc Aib Pro Tyr Aib Gln Gln Aib EtNor Gln Ala Leu OH Aib Hyp Leu Iva Hyp Leu Iva Hyp Aib Iva Aib Hyp Iva Ile OCH(CH(OH)CH2OH)CH (OH) CH(OH) CH2OH Ac Leu Aib Leu Aib Phe OH

References Molle et al. (1991) Shenkarev et al. (2013) Benedetti et al. (1983) Song et al. (2011) Song et al. (2011) Song et al. (2011) Degenkolb and Bruckner (2008) Chikanishi et al. (1997) Hulsmann et al. (1998)

called condensation. This is catalyzed by the condensation domain (C-domain). The extended peptide gets coupled to the ongoing PCP domain. Sometimes, condensation results in cyclization (formation of cyclic peptides by cyclic domains) for the formation of oxazolidines and thiazolidines or epimerization for the formation of D-configuration. For each elongation module, the above cycle is repeated.

26.6.3 Termination The peptides are released by R-domain wherein the thioester bond is reduced to form terminal aldehyde or alcohol. This mechanism results in a diverse chemical variety of peptide products containing hydroxy-, l-, d-, or unusual amino acids, which are processed further and modified by glycosylation, N-methylation, halogenation, hydroxylation, acylation, halogenation, or heterocyclic ring formation. After secretion of these molecules, they lose either amine group or terminal amino acid resulting in heterogeneity (Neuhof et al. 2007; Degenkolb et al. 2012). For the synthesized molecule to become functional it has to undergo priming and deblocking processes. In priming, the 40 PP transferases attach the 40 -PP side chain of acyl-CoA molecules to the PCP domain and in deblocking the associated specialized thioesterases (TE-II) remove the S-attached acyl groups. The whole process is illustrated in Fig. 26.2. The adenylation, A-domains, usually has broad substrate specificity which determines the specific amino acid that is to be incorporated into a module. Ten

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V. N. Ramachander Turaga Initiation / Adenylation Aminoacid activation with ATP by A-domain and loaded on to peptide carrier protein (PCP) domain

Elongation / Thiolation Amide formation between two thioester groups of two amino acids and / or cyclization

Termination R-domain reduces thioester to aldehyde or alcohol and Peptides are released

Processing Glycosylation, Acylation, Halogenation, Hydroxylation

Priming and deblocking Peptide becomes functional when 4'-phospho-pantetheine (4’PP) molecules gets attached to the PCP-domain (Priming) and the S-attached acyl group removed (Deblocking)

Fig. 26.2 Flowchart depicting the steps involved in the biosynthesis of active peptaibol

amino acids that control substrate specificity can be considered the “codons” of non-ribosomal peptide synthesis. Similarly, the condensation, C-domain, functions as a filter for the epimerized isomer, if it is located behind an epimerase (E-domain) and is believed to have substrate specificity. To predict the substrate specificity from the DNA sequence data, computational methods like NRPSpredictor2 (Rottig et al. 2011) and SANDPUMA (Chevrette et al. 2017) have been developed. In the above process involving synthetase complexes, there exists an internal pseudosymmetry. A study of the single synthetase gene from Trichoderma virens revealed to have 18 modules which synthesize different peptaibol isoforms produced by this organism. Each of the modules is for an amino acid residue in the longest peptaibol made by T. virens (Wiest et al. 2002). These modules are understood to have multiple specificities and hence are able to produce a large number of sequence variants. In the synthesis of shorter peptaibols, it is concluded that the synthetase gene uses fewer modules only. The in vivo synthesis of peptaibols via NRPS is a consequence of its significant bias towards even numbers of residues and pairwise distributions of amino acids. This biosynthesis of non-ribosomal peptides shares characteristics with the biosynthesis of polyketides and fatty acids (Wang et al. 2014).

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Detection of Peptaibols Using Modern Techniques

Peptaibiomics is defined as the study of characterization of peptaibols in entirety under specific culture conditions called peptaibiome (Krause et al. 2006). In the initial days, when sophisticated techniques and instruments were unavailable, the only biochemical method which was used to identify the peptaibols was paper chromatography. However, with the advent of new techniques, the peptide chain length, their composition, nature of amino acids present, overall charge of the molecule, and structure of the various peptaibols discovered became evident. Circular dichroism (CD) was used to decipher the structure of these peptaibols. However, the structural information using CD spectroscopy was less detailed under various solvent conditions. Moreover, it was observed that these peptaibols had helical structure in common with little dependence on solvents as their structure is constrained due to the extensive hydrogen bonds within the molecule (de la Fuente-Núñez et al. 2013). In the late 1990s and at the start of the new century, availability of sophisticated instruments like intact cell MALDI-TOF-MSH (IC-MS) and HPLC-MS combined with rapid sequencing techniques contributed significantly to the peptaibiomics. IC-MS further simplified the screening and elucidation of the peptaibol structure by using a single loop of fungal mycelium. HPLC-MS/MS on triple quadrupole is used to identify the trace amounts of these peptaibols and it brought down the sensitivity to femtograms with high specificity. Using these techniques, the peptaibol biosynthesis dynamics and degradation which are time dependent were demonstrated in T. ghanense CBS 936.69 for the extremely micro-heterogeneous trichobrachins (Krause et al. 2007). Overall, the new techniques have revolutionized the field of peptaibiomics by rapid identification of the peptaibols, their structure and plausible mode of action.

26.8

Structure of Peptaibols

As many peptaibol sequences from fungal species became available, and these could not be compared with known peptide antibiotics due to nonstandard amino acids, they initially did not find place in any database. This necessitated the need for the creation of a new database. Hence, http://www.cryst.bbk.ac.uk/peptaibol is the database that was developed to accommodate this unusual class of sequences (Whitmore 2004; Parisa et al. 2016). Later, the known NMR structures of family members also got incorporated. At present, the peptaibol database lodges the structure and sequence information of about 307 natural peptaibols. Furthermore, there exists a separate database for many chemically synthesized peptaibols (Daniel and Filho 2007). Upon analyzing the sequence available in the Peptaibol database, many features related to the positional arrangement of amino acids and their significance in their structure and action can be well understood in detail. All peptaibol to date is determined to be highly helical in structures. This is attributed to the high amounts

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of the Aib present in all the analyzed sequences which amount close to 40% of all the residues (Whitmore and Wallace 2004). The Aib C-alpha atom’s second methyl group causes steric constraints which force the peptide molecule to form the helical structure. The bend and kink formation in these structures is facilitated by the presence of residues like Iva (isovaleric acid or alpha-ethyl alanine) and amino acids like proline or hydroxyproline in the sequence. However, these kinks or bends are not observed in all peptaibols with imino acids as seen in case of trichotoxin, which is essentially a straight helix despite having a central proline [http://peptaibol.cryst.bbk.ac.uk/trichotoxin1.htm] (Jaworski and Brückner 1999; Chug et al. 2002; Kahne et al. 2005). Peptaibols have only polar residue in glutamine. The number of glutamine residues and their position in the sequence are directly related to the functional properties of these peptaibols and formation of ion channel. The amphipathic nature of these peptaibols is attributed to the polar and nonpolar amino acid residues (glutamine and high Aib). The aromatic amino acids form only 4% of the residues and if present are clustered at either N-termini or C-termini (Wallace and Janes 1999).

26.9

Mode of Action

The mode of action of all the peptide antibiotics seems to be almost the same and is dependent upon the bacterial cell membrane interaction (Hancock and Rozek 2002). The lipopolysaccharides of Gram-negative bacteria and lipoteichoic acids are on the surface of the Gram-positive bacteria or they are usually negatively charged. In the first step, the peptaibols being cationic, i.e., having +ve charge, get electrostatically bound to the outer membrane of the microbes which are anionic, i.e., vely charged. As peptaibols are amphipathic in nature, they self-associate to form a helical bundle with exterior hydrophobic residues and interior water-filled hydrophilic residues. These amphipathic molecules get in touch with their exterior hydrophobic residues with the lipid fatty acid chains of bacterial membrane leaving it permeable in a selfassisted process uptake. This process is driven by the electrostatic and hydrophobic interactions wherein the peptides enter the interfacial region of the cytoplasmic membrane. This is selectively facilitated by the negatively charged bacterial cells over the host eukaryotic cells whose lipids are uncharged. Though the exact mechanism of how the peptides enter into the cell membrane is unclear, many prominent models like the barrel-stave (Ehrenstein and Lecar 1977), carpet (Pouny et al. 1992), toroidal pore (Wu et al. 1999), and aggregate models (Wu et al. 1999) have been proposed. Different types of intermediates are proposed in these models which lead to any of the events like micellization, transient ion channel formation, or dissolution of the membrane. Thus, we can categorize the antibacterial action of these peptaibols broadly as either membrane acting or non-membrane acting. The membrane permeabilizing action which is thought to be the main characteristic of all the cationic antibacterial peptides, could be carried out using any of the cationic

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amphiphilic peptides, if applied in right concentrations (Patrzykat et al. 2002; Zhang et al. 2001).

26.10 Bioinformatics and Synthetic Peptides To identify the full potential of peptaibols, as mentioned above, study of its mode of action is very important (Hancock and Chapple 1999). As one cannot test each and every peptide against all the microbes, it remains elusive to use the right peptaibol against the target bacterium. This is possible with the study of bioinformatics and by synthesis and/or simulation of these synthetic peptides. Bioinformatic studies on peptide sequences gives an overall view with respect to their amino acid content, their position, and their significance in structure and action. As significance of individual amino acid is deduced, one can now use a variety of databases to design synthetic peptides based on the naturally occurring peptides without deviating from the amphipathic alpha-helical structure. This may be used to reduce the unwarra nted effects of these peptides, e.g., cytotoxicity on human cells. Bessalle et al. (1990) using the knowledge of bioinformatics synthesized peptides called “modellins.” However, these were based on small peptide antibiotics other than peptaibols. They demonstrated that synthetic peptides (not peptaibols) with low toxicity and improved antibacterial activity could be developed, e.g., cecropins and cecropin-melittin hybrids (Boman et al. 1989), which appear in the patent literature. This type of peptide synthesis based on molecular modeling can be extended to peptaibols for synergistic and broader applications.

26.11 Applications and Functions of Peptaibols Peptaibols have membrane-modifying biological activity which is attributed to their channel-forming capability in the membranes of the organisms leading to cytoplasmic leakages resulting in cell death (Boheim 1974; Balaram et al. 1992; Peltola et al. 2004; Shi et al. 2010). This is attributed to their amphipathic nature and helical structure aiding in this process. Such an activity resulted in their effective control of bacterial, fungal, protozoan, and helminth growth besides insecticidal activity on mosquito larvae (Szekere et al. 2005; Matha et al. 1992). Also, they can lead to ultrastructural modification of mitochondria leading to pathological effects (Reed and Lardy 1975; Kumar et al. 1991; Bruckner and Toniolo 2013; Nagaraj et al. 2001). Of all the subfamily groups, SF1 has a maximum number of peptaibols with >80% sequence identity. However, it is observed that these subtle differences resulted in varied activities of each peptaibol molecule clearly making each peptide sequence a unique one. Alamethicin, the widely studied member of the SF1, forms channels in bovine adrenal chromaffin cells and transports Ca2+, Mn2+, and Ni2+ ions (Dathe et al. 1998; Fonteriz et al. 1991). Antiamoebin of SF2 exhibited an antiamoebic activity (Thirumalachar 1968). Members of SF3 and SF4 like

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XR586 (Benedetti et al. 1983) and heptaibin (Ishiyama et al. 2000) showed antibacterial activity and antifungal activities. In SF5, the trikoningins and trichorzins act against Staphylococcus aureus (Piazza et al. 1999; Goulard et al. 1995). Tylopeptins of SF6 and peptaibolin of SF9 exclusively act against Grampositive bacteria (Lee et al. 1999a, b) while ampullosporin is found to be neuroleptic in mice (Ritzau et al. 1997). Furthermore, ADP-dependent human platelet aggregation was shown to be the result of clonostachin, a SF8 member (Chikanishi et al. 1997). The lipaminopeptide, integramide A’s complete chiral sequence, has been deciphered (Singh et al. 2002; Maes et al. 2012). It has got the largest number of Iva amino acids than any other peptaibols. It’s C-terminus is found to be with free glycine and is the only peptaibol to be effective against HIV integrase I (Maes et al. 2012). Peptaivirins A and B and chrysospermins B and D inhibit tobacco mosaic virus (Yun et al. 2000; Kim et al. 2000). Chrysospermins B and D with Aib and Iva at position 5, respectively, have a cytotoxic effect on cancer cells (Kim et al. 2000; Huang et al. 1995). Peptaibols with antimalarial activities have also been recorded (Nagaraj et al. 2001). Also, activity against viruses and mammalian cells has been demonstrated (Luo et al. 2010; Shi et al. 2010). Synergistic approaches using two or more peptaibols have resulted in effective treatment of few diseases. For instance, in the case of leishmaniasis, use of peptaibols antiamoebin and suzukacillin resulted in the effective destabilization of the mitochondrial membrane (Fragiadaki et al. 2018).

26.12 Conclusion Peptaibols, mainly isolated from soil fungi and especially from Trichoderma species, are active against a variety of disease-causing organisms. These are different from other short peptide antibiotics by the presence of the nonnatural amino acid Aib. The presence of the Aib gives these peptides the helical structure which plays an import role in permeabilizing the cell membrane and forming ion channels, thus killing the cells or microorganisms. Although more than 440 peptaibols (~317 from database and remaining from literature) are discovered to date (Degenkolb et al. 2008), the knowledge what we have is only a tip of an iceberg. Their discovery from specialized habitats such as fungicolous (Huang et al. 1995a, b, 1996; Grafe et al. 1995; Dornberger et al. 1995; Ritzau et al. 1997; Kronen et al. 2001; Hulsmann et al. 1998; Iida et al. 1999; Wilhelm et al. 2004), coprophilous (Jaworski and Brückner 2000; Nina et al. 2006), entomopathogenic (Krasnoff et al. 2005; He et al. 2006), and marine habitats (Mohamed-Benkada et al. 2006; Ruiz et al. 2007; Landreau et al. 2002; Boot et al. 2006; Poirier 2007a, b) hints us at the existence of myriads of peptaibols in nature which are unique to the organism from which they are isolated with a specific function. However, which signal prompts the organism to produce a variety of these peptaibols still remains a research subject. The availability of sophisticated and advanced techniques along with bioinformatics would further help to discover novel molecules and decipher their structure and bioactivity. Developing synthetic peptide simulation using bioinformatics would

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also give impetus in understanding their structure with new functions. Synergistic effect of two or more peptaibols in the successful treatment of diseases has opened up a new area yet to be explored by the researchers. The presence of Aib imparting resistance to the proteases of host or pathogen, makes these exclusive peptide antibiotics, peptaibols, to be chosen over conventional antibiotics and with all certainty they would play an important role in future applications.

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Index

A Algaculture, 666, 667 Alkaloids, 6, 28, 109, 115, 198, 246, 380, 381, 416, 422, 438, 454, 455, 551, 591, 621, 623, 625, 688–693, 697, 699, 700 Amravati, 599, 601 Anticancer activity, 142–143, 195, 236, 247, 254, 257, 258, 260–263, 266, 338, 358, 362–365, 369, 394–395, 431, 436, 442, 463–464, 557, 649, 658, 675, 676 Anticancer potential, 256, 265, 355–369 Antimalarial, 5, 13, 68, 69, 73, 76, 78, 110, 139, 167, 198, 202, 215, 232, 236, 238, 249, 250, 255, 262, 434, 438, 441, 587, 594, 674, 692, 693, 724 Antimicrobial activity, 152, 233, 255, 256, 260, 262, 266, 267, 319, 321, 323, 363–364, 392, 397–398, 417, 442, 463, 464, 553, 560, 561, 566, 567, 601, 604, 605, 675–677, 701 Antimicrobial potential, 556, 604 Anti-proliferative activity, 142, 236, 256, 257, 421, 431, 437, 441 Antiviral activity, 141, 232–233, 246, 322, 397, 398, 438, 463, 674, 677 Applications, 4, 99, 142, 187, 282, 304, 316, 341, 364, 422, 428, 452, 468, 509, 518, 550, 592, 613, 646, 667, 689, 723 Artemisinin, 6, 7, 13, 15, 77, 85, 215, 594, 618, 690, 699, 701 Autophagy, 103, 260, 356, 365, 387, 611, 613, 614, 616, 620–622 B Bacoside A, 100, 104, 107, 109–113, 115–117 Basidiomycota, 413

Bioactive compounds, 7, 9, 11, 13, 20–28, 101, 129, 147, 166, 182, 184, 186, 194, 196–199, 201, 202, 218, 234, 320, 343, 369, 380, 381, 413, 416, 417, 427–442, 454, 456, 462, 464, 499, 509, 550, 600, 605, 621, 622, 649, 674, 676, 677, 689, 702, 703 Bioavailability, 116, 118, 215, 216, 255, 347, 557, 558, 561, 564, 565, 570, 594 Biofuels, 325, 452, 453, 462, 464, 468 Bioimaging, 303–310 Biomedical applications, 310, 322, 364, 519, 527, 529, 552, 568 Biosensing, 564 Biosensor, 304, 528, 531, 552, 558, 561, 566 C Cancer, 67, 142, 195, 233, 246, 307, 321, 336, 356, 380, 418, 431, 455, 523, 552, 587, 600, 611, 644, 673, 688, 724 Carbon quantum dots (CQDs), 303–310 Cardiovascular disorders (CVDs), 336, 486–488, 497, 498, 509, 651, 688 Chaperones, 611, 612, 614, 616–620, 626 Cinnamaldehyde, 129–133, 135, 139–147, 149, 150, 152, 559, 691 Cinnamomum zeylanicum, 128, 129, 134–136, 138, 140–142, 144, 145, 147, 150, 151 Cinnamon, 128, 559 Cinnamon bioactivity, 129, 152 Cinnamon oil, 128, 129, 139, 140, 142, 147–150 Cognition enhancement, 99, 106 Compounds, 7, 99, 129, 166, 215, 246, 282, 316, 336, 356, 380, 412, 428, 452, 468, 497, 550, 587, 600, 617, 644, 666, 688

# Springer Nature Singapore Pte Ltd. 2020 J. Singh et al. (eds.), Bioactive Natural products in Drug Discovery, https://doi.org/10.1007/978-981-15-1394-7

731

732 Computer-aided drug design (CADD), 282–284 Consumption, 104, 144, 148, 459, 473, 496, 559, 644–647, 651–655, 657, 658, 674, 677 Coumarins, 6, 18, 129, 147, 149, 218, 219, 227, 232, 233, 236–238, 246, 618, 690 D Diagnosis, 266, 558 Downstream processing, 475–479, 482, 533 Drug delivery, 118, 152, 304, 468, 479–481, 519, 523, 526, 528–530, 552, 553, 556–560, 563 Drugs, 5, 98, 138, 166, 215, 246, 282, 304, 316, 343, 356, 397, 412, 428, 452, 468, 487, 519, 550, 586, 600, 612, 650, 666, 688, 714 E Environmental applications, 519, 526, 529, 531 Environment-friendly, 305 Expansion, 286, 327, 421, 518, 643–658 Extraction, 99, 129, 167, 316, 341, 381, 475, 532, 550, 590, 601, 617, 647, 676, 692 F Fibrinolytic agents, 487, 496–509 Fluorescence, 309, 369, 504 Fluorescent pseudomonads, 355–369 Fungi, 75, 140, 217, 266, 316, 340, 358, 380, 412, 428, 463, 487, 553, 594, 600, 625, 651, 714 G Ganoderma, 140, 341, 343, 379–399, 502, 507, 648, 650, 651 H Herbal drugs, 85, 108, 138, 166, 167, 182, 202, 586, 688 HIV-inhibitors, 141 I Industrial applications, 524, 563–564 Isovaline, 715 L Lactic acid, 104, 463, 467–485

Index Lentinan, 341, 343, 650–651 Lignocellulosic biomass, 468, 472 M Marine, 316, 339, 412, 429, 464, 487, 530, 566, 586, 617, 670, 724 Market, 5, 6, 150, 152, 323, 324, 336, 339, 349, 462, 491, 492, 495, 497, 586, 587, 590, 643–678, 688 Medicinal mushrooms, 381, 647–651 Melghat forest, 599–605 Microalgae, 316, 317, 340, 451–465, 666–668, 674, 675, 677, 678 Microorganisms, 316–320, 323–327, 380, 393, 428, 429, 436, 438, 452, 468, 487, 496–509, 531, 532, 550, 552–554, 568, 569, 586, 600, 604, 611, 617, 689, 698–704, 715, 724 Models, 67, 102, 130, 201, 237, 252, 284, 337, 394, 472, 486, 615, 649, 715 Molecular dynamics (MD) simulation, 284, 287, 292–295 Mugwort, 5, 7, 12, 27, 690 Mushroom-based product, 643–658 N Nanoparticle, 71, 264, 304, 337, 481, 523, 524, 526, 529, 530, 550 Natural molecules, 609–626 Natural products, 144, 152, 180, 185, 186, 215, 216, 251, 281–295, 315–327, 335–349, 365, 413, 420, 428, 549–571, 585–595, 644–646, 648–655, 658, 667, 668, 674, 677, 678, 687–689, 693 Natural sources, 238, 303–310, 316, 324, 455, 519, 555, 594, 611, 617, 618, 620, 621, 625, 626 Neurodegeneration, 98, 103, 112, 116, 200, 611–616, 620 Neurodegenerative disorders, 99, 100, 104, 117, 195, 623 Neuroprotective medicinal plant, 100 Nigrospora oryzae, 416, 433, 438, 601–605 Non-analogous compounds, 429–430 Nutraceuticals, 141, 149, 319, 323–324, 335–349, 452, 460–461, 522, 564, 565, 644–647, 649, 665–678 P Peptaibols, 713–725 Peptide antibiotics, 714, 715, 721–724

Index Pharmaceutical, 78, 152, 167, 171, 194, 195, 233, 246, 316, 317, 319, 321, 323, 325–327, 343, 349, 388, 411–422, 428, 452, 453, 455, 457, 460, 462–463, 465, 467–482, 518–520, 525, 526, 529, 531–533, 554, 555, 586, 587, 594, 605, 645–649, 665–678, 692, 693 Pharmacology, 97–118, 165–202, 215–238, 320, 550 Pharmacy, 322, 678 Phytochemical analysis, 218, 590 Phytochemicals, 6, 7, 78, 110, 115, 129, 130, 143, 147–150, 166, 171, 202, 218, 227, 238, 246, 266, 324, 337, 339, 590–592, 600, 688, 698, 702, 703 Plant growth-promoting microorganisms (PGPMs), 698–703 Plant-microbe interaction, 702 Polylactic acid (PLA), 471, 479–482 Polypore mushrooms, 380 Polysaccharides, 145, 318, 339, 380, 453, 518, 553, 648, 669 Probiotics, 323–324, 337, 565, 647 Products, 6, 98, 128, 167, 215, 247, 282, 316, 336, 358, 380, 413, 428, 452, 473, 498, 519, 550, 586, 605, 617, 644, 666, 688, 719 Protein-protein interaction (PPI), 281–295 Proteostasis, 611, 613, 617–626

733 Secondary metabolites, 6, 78, 166, 182–187, 218, 226, 232, 238, 246, 316, 321–323, 326, 357, 412, 413, 417, 420, 422, 428, 431, 432, 436, 439, 441, 462, 464, 497, 509, 550, 551, 571, 595, 599–605, 621, 674, 687–704 Secondary metabolites and terpenoids, 691–692, 694, 697, 702 Streptokinase, 486–493, 496, 497, 500, 505 Structure-based drug design (SBDD), 284–295 Sustainability, 115 Swertia, 165–202 T Thymoquinones, 248–255, 266, 559 Tissue plasminogen activators (t-PA), 487, 488, 491–495, 498, 507, 509 U Ubiquitin proteasome system (UPS), 613, 615, 616, 621, 624, 626 V Virtual screening, 282, 284, 292 Vitex negundo, 138, 600

R Reactive oxygen species (ROS), 105, 107, 108, 113, 130, 142, 200, 237, 247, 248, 252, 254, 256–260, 263, 265, 266, 344, 364, 368, 389, 395, 675

X Xanthones, 171, 172, 178, 180, 184, 187, 194–196, 199, 201, 202, 218, 219, 226, 228, 229, 236–238, 414, 417, 625 Xylarinase, 503, 508

S Schizophyllan, 341, 343, 649, 650

Z Zein peptides, 337