Ethnopharmacology, Phytochemistry and Pharmacology Review of Traditional Chinese Medicine-Ⅰ

Maoxing Li

Science Press Beijing Responsible Editors Litao Kang :

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ISBN - - - - 978 7 03 045639 7 Editorial Board

Editor-in-Chief Maoxing Li Department of Pharmacy General Hospital of Lanzhou Commant PLA Gansu Lanzhou China , , , , Associate Editor Jinhui Wang Department of Pharmacy Affiliated Hospital of Gansu University of Chinese Medicine Gansu Lanzhou China , , , Zhengping Jia Department of Pharmacy General Hospital of Lanzhou Commant PLA Gansu Lanzhou China , , , , Editorial Board Hu Pan Institute of Husbandry and Pharmaceutical Sciences Chinese Academy of Agricultural Sciences , , Gansu Lanzhou China , , Linhong Huang Xi’an Hong-Hui Hospital Xi’an Jiaotong University Medical College Shanxi Xi’an China , , , Ruxue Zhang Department of Pharmacy General Hospital of Lanzhou Commant PLA Gansu Lanzhou China , , , , Xiaofei Shang Institute of Husbandry and Pharmaceutical Sciences Chinese Academy of Agricultural Sciences , , Gansu Lanzhou China , , Xirui He Xi’an Hong-Hui Hospital Xi’an Jiaotong University Medical College Shanxi Xi’an China , , , Yinqian Liu Pharmacy College Lanzhou University Gansu Lanzhou China , , ,

Preface

Medicinal plants are - of course - an integral part of our common human history. There can be no doubt that they are an important part of all cultures past and modern. At the same time we now have scientific tools available to us which allow a study of these resources from a multitude of angles - including for example pharmacology clinical research phyto- , , , , chemistry toxicology anthropology public health and history to name just a few. , , , , Why do we do all these studies In part it is in order to understand our own culture and ? history but many including the author of these lines also think that such research must , , , contribute to a more evidence - based and safer use of such herbal medicines. There are many challenges to overcome and this book offers an overview of key evidence which is available for some of the most important species used in Traditional Chinese Medicine. As always , such research uncovers exciting new pharmacological effects of interesting chemical com- pounds but it also highlights potential risks including toxic effects. So a critical appraisal , , and review of the available evidence on these species is very welcome indeed. And I want to congratulate Prof. Moaxing Li from the Lanzhou General Hospital of PLA and his team / , collaborators for developing these monographs and for bringing them together in this book. The vast majority of the monographs were published in the Journal of Ethnopharmacology - without doubt today the leading journal in the area of ethnopharmacology / medicinal plant research. These reviews provide a careful assessment of the scientific evidence on these medicinal plants and now such research needs to be translated into better products. While the philoso- , phy and many elements of the practice of TCM are unique to the Chinese tradition and phi- losophy the fundamental requirements in terms of sustainability quality and safety are now , , universal. We want and must make sure that we use safe products which do not harm pa- , tients and ideally ones for which a good evidence basis exists. Safety is based on two key , aspects - the use of species which are general considered to be of low risk i． e. safe and ( ) good manufacturing along the value chains of these products. Only if both are fulfilled will we get high quality products. In recent years concerns about adulterations and poor quality have increased tremendously and yes we have to acknowledge that many products sold with health claims , are of poor or inadequate quality. This is also linked to problems with regards to ascertaining a sustainable supply and the overexploitation of resources is a key problem faced by practi- , tioners of TCM and other medical traditions So the review of the evidence provided my , , ProfMoaxing Li and collaborators is an important but just a first step in order secure high i · · ii Ethnopharmacology Phytochemistry and Pharmacology Review of Traditional Chinese Medicine- · · , Ⅰ quality products for consumers in China and beyond. Not only is it a pleasure to congratulate ProfMoaxing Li and collaborators for this excit- ing initiative but we all should hope that it leads to such better products and thus a better use , of Chinese herbal medicine.

Prof. Michael Heinrich Centre forPharmacognosy and Phytotherapy / Research Cluster Biodiversity and Medicines UCL School of Pharmacy , 29-39 Brunswick Square , London WC1N 1AX United Kingdom , Introduction

In human history people have relied on plants in order to survive numerous diseases. , After diverse exploration of their observable effects our ancestors distinguished the medicinal , plants from other ones. This knowledge was recorded categorized and inherited over centu- , ries in oral or in a few cases written traditions. Today more than 22 000 plants have been , , used as medicine in different cultures of the world. Thanks to the geographical and climaticdiversity in our enormous country 27000 , species of plants are known to be distribute in China. Our civilization one of the longest and , most glorious culture in the world has developed a unique and the most amazing Traditional , medicinal tradition - TCM . People believe TCM not only can be used as medicine to treat diseases but also as food to nourish and protect our body. , Today more and more researchers find ethnopharmacological clues for developing of new medicine from such local and traditional knowledge. Artemisinin and taxinol were the most famous success in these studies. In the past decades the development of chemistry molecular pharmacology and cell bi- , , ology has led to a rapid increase in the information available on TCM. At the same time sci- , entists also showed enthusiasm to study the phytochemistry and pharmacology of samples from the same species or genus coming from different areas. A thorough review of these studies published in different languages and areas is very important and valuable not only for the experts but also for a novice. The aim of this book is to comprehensive outline the botanical description ethnophar- , macology phytochemistry biological activities and toxicology of ten special species or gen- , , era Leonurus Japonicus Houtt. Eucommia ulmoides Oliv Pedicularis Epimedium Loni- : , , , , cera japonica Thunb Scutellaria Rehmannia glutinosa Oxytropis Phlomis Patrinia and , , , , , , to discuss the possible trend for the further study. Information on these plants was gathered via the internet using Pub Med Elsevier Baidu Scholar Google Scholar Medline Plus ( , , , , , ACS CNKI and Web of Science and libraries for some local books. , ) The common structureof the reviews for every genus includes Introduction 1 Botan- : ( ), ical description 2 ethnopharmacology 3 Phytochemistry 4 Biological activities ( ), ( ), ( ), 5 Toxicity 6 Future perspectives and conclusion 7 and References 8 . In the ( ), ( ), ( ), ( ) first part the common knowledge and study were introduced. In the second part the distri- , , bution botanical description medicinal material description were summarized according to , , flora and record. In the third part the recorded in local and traditional uses as a medicine , , nourishment an invigorator or a roborant were reviewed. In the fourth part the isolated , , , iii · · iv Ethnopharmacology Phytochemistry and Pharmacology Review of Traditional Chinese Medicine - · · , Ⅰ and identified chemical compounds were categorized with their structures and source the part ( or species of plants . At the same time the structures of the major compounds with high ) , contents or high activities are included. In the fifth part the data about bioactivities of the , extracts or compounds in vivo experiments or in vitro experiments and animals or cells are , , , presented analyzed and assessed according to different functions. The relationship of these , bioactivities and the species ethnopharmacology was especially presented. In the sixth part ’ , the serious attention was paid to any information about the toxicity of the extracts or com- pounds. In the seventh part the data about modern pharmacological and ethnopharmacologi- , cal and the species phytochemistry are rivied in order to assess theirpotential as new medi- , cine. At the same time limitations methodological problems and new method arediscussed , , and suggested for further investigation. The references form the last part of each monograh organized alphabetically . ( ) The tenmedicinally important species or genera reviewed in this book were specially se- lected some of them are widely used in TCM and others are indigenous to China especial- , , , ly in the Qing-zang Plateau. These plants have a long tradition of use have therapeutically , relevant effects on modern diseases such as hepatopathy diabetes cancer inflammation , , , , , immunodeficiency ageing and highlight the chemical diversity of such medicines. We hope , , this book will be beneficial for the wider public to understand the plant-based medicines and specifically of the ones used in TCM. For a novice it will serve as an outline of their chosen study object and for researchers it will hopefully spark some ideas for future invention. , Contents

Preface Introduction Chapter 1 Ethnopharmacology phytochemistry and pharmacology of , Leonurus japonicus Houtt 1 …………………………………………… ( ) 1． 1 Introduction 1 ……………………………………………………………………… ( ) 1． 2 Botany and ethnopharmacology 2 ………………………………………………… ( ) 1． 2． 1 Botany 2 ……………………………………………………………………… ( ) 1． 2． 2 Ethnopharmacology 2 ………………………………………………………… ( ) 1． 3 Phytochemistry 5 ………………………………………………………………… ( ) 1． 3． 1 Alkaloids 6 …………………………………………………………………… ( ) 1． 3． 2 Diterpenes 6 ………………………………………………………………… ( ) 1． 3． 3 Flavones 7 …………………………………………………………………… ( ) 1． 3． 4 Spirocyclic nortriterpenoids 7 ……………………………………………… ( ) 1． 3． 5 Sesquiterpene glycosides 7 ………………………………………………… ( ) 1． 3． 6 Megastigma 7 ………………………………………………………………… ( ) 1． 3． 7 Phenylethanoid glycosides 8 ………………………………………………… ( ) 1． 3． 8 Nonapeptides 8 ……………………………………………………………… ( ) 1． 3． 9 Essential oils 8 ……………………………………………………………… ( ) 1． 3． 10 Others 9 …………………………………………………………………… ( ) 1． 4 Pharmacology 15 ………………………………………………………………… ( ) 1． 4． 1 Effects of chemical compounds 15 ………………………………………… ( ) 1． 4． 2 Effects of crude extract 18 ………………………………………………… ( ) 1． 5 Analysis of active constituents and quality control 31 …………………………… ( ) 1． 6 Toxicity 33 ………………………………………………………………………… ( ) 1． 7 Conclusion 34 ……………………………………………………………………… ( ) 1． 8 Acknowledgements 36 …………………………………………………………… ( ) 1． 9 References 36 ……………………………………………………………………… ( ) Chapter 2 Ethnopharmacology phytochemistry and pharmacology of , Eucommia ulmoides Oliv 41 …………………………………………… ( ) 2． 1 Introduction 41 …………………………………………………………………… ( ) 2． 2 Botanical description and ethnopharmacology 41 ………………………………… ( ) 2． 3 Phytochemistry 43 ………………………………………………………………… ( ) 2． 3． 1 Lignans 52 …………………………………………………………………… ( ) v · · vi Ethnopharmacology Phytochemistry and Pharmacology Review of Traditional Chinese Medicine - · · , Ⅰ

2． 3． 2 Iridoids 52 …………………………………………………………………… ( ) 2． 3． 3 Phenolics 53 ………………………………………………………………… ( ) 2． 3． 4 Steroid and terpenoids 53 …………………………………………………… ( ) 2． 3． 5 Flavonoids 53 ………………………………………………………………… ( ) 2． 3． 6 Other compounds 53 ………………………………………………………… ( ) 2． 3． 7 Variance of major components 54 …………………………………………… ( ) 2． 4 Biological activities 54 …………………………………………………………… ( ) 2． 4． 1 Anti-hypertensive activity 56 ………………………………………………… ( ) 2． 4． 2 Hypolipidemic activity 57 …………………………………………………… ( ) 2． 4． 3 Anti-obesity activity 58 ……………………………………………………… ( ) 2． 4． 4 Anti-diabetic activity 58 …………………………………………………… ( ) 2． 4． 5 Effect on bone metabolism 59 ……………………………………………… ( ) 2． 4． 6 Anti-inflammatory anti-viral and anti-bacterial activities 60 , ……………… ( ) 2． 4． 7 Neuroprotective activity 61 ………………………………………………… ( ) 2． 4． 8 Antioxidative activity 61 …………………………………………………… ( ) 2． 4． 9 Improving erectile function 63 ……………………………………………… ( ) 2． 4． 10 Anti-fatigue activity 63 …………………………………………………… ( ) 2． 4． 11 Anti-aging activity 63 ……………………………………………………… ( ) 2． 4． 12 Anti-tumor activity 64 ……………………………………………………… ( ) 2． 4． 13 Hepatoprotective activity 64 ……………………………………………… ( ) 2． 4． 14 Enhancing immune-function 65 …………………………………………… ( ) 2． 5 Toxicity 65 ………………………………………………………………………… ( ) 2． 6 Future perspectives and conclusion 65 …………………………………………… ( ) 2． 7 Acknowledgements 66 …………………………………………………………… ( ) 2． 8 Reference 66 ……………………………………………………………………… ( ) Chapter 3 Phytochemistry and pharmacology of the genus Pedicularis 73 …………………………………………………………………………… ( ) 3． 1 Introduction 73 …………………………………………………………………… ( ) 3． 2 Chemical constituents 73 ………………………………………………………… ( ) 3． 3 Iridoid glycosides 77 ……………………………………………………………… ( ) 3． 4 Phenylpropanoid glycosides 77 …………………………………………………… ( ) 3． 5 Lignan glycosides 77 ……………………………………………………………… ( ) 3． 6 Flavonoids 78 ……………………………………………………………………… ( ) 3． 7 Alkaloids 78 ……………………………………………………………………… ( ) 3． 8 Othercompounds 78 ……………………………………………………………… ( ) 3． 9 Biological activity 92 ……………………………………………………………… ( ) 3． 10 Anti-tumor activity 92 …………………………………………………………… ( ) 3． 11 Antioxidative activity 93 ………………………………………………………… ( ) Contents vii · ·

3． 12 Antihemolysis activity 94 ……………………………………………………… ( ) 3． 13 Repair effects on DNA damage 94 ……………………………………………… ( ) 3． 14 Hepatoprotective activity 95 …………………………………………………… ( ) 3． 15 Improving the spleen asthenia symptoms 95 …………………………………… ( ) 3． 16 Anti-fatigue activity 95 ………………………………………………………… ( ) 3． 17 Improving learning and memory 95 …………………………………………… ( ) 3． 18 Antibacterial activity 96 ………………………………………………………… ( ) 3． 19 Other activities 96 ……………………………………………………………… ( ) 3． 20 Conclusions 96 …………………………………………………………………… ( ) 3． 21 Acknowledgement 97 …………………………………………………………… ( ) 3． 22 References 97 …………………………………………………………………… ( ) Chapter 4 Ethnopharmacological and phytochemical review of genus Epimedium 102 …………………………………………………………… ( ) 4． 1 Introduction 102 …………………………………………………………………… ( ) 4． 2 Botanical description and distribution 102 ……………………………………… ( ) 4． 3 Ethnopharmacological use 106 …………………………………………………… ( ) 4． 4 Chemical constituents 108 ………………………………………………………… ( ) 4． 4． 1 Flavonoids 120 ……………………………………………………………… ( ) 4． 4． 2 Lignans 121 ………………………………………………………………… ( ) 4． 4． 3 Ionones 121 ………………………………………………………………… ( ) 4． 4． 4 Phenol glycosides 122 ……………………………………………………… ( ) 4． 4． 5 Phenethyl alcohol glycosides 122 …………………………………………… ( ) 4． 4． 6 Sesquiterpenes 122 …………………………………………………………… ( ) 4． 4． 7 Other compounds 122 ……………………………………………………… ( ) 4． 5 Methods of quality control 123 …………………………………………………… ( ) 4． 6 Biological activity 125 …………………………………………………………… ( ) 4． 6． 1 Treatment of sexual dysfunction aphrodisiac kidney tonic 125 ( , ) ……… ( ) 4． 6． 2 Effect on bone metabolism 127 ……………………………………………… ( ) 4． 6． 3 Effect on the immune system 130 …………………………………………… ( ) 4． 6． 4 Effect on the cardiovascular system 132 …………………………………… ( ) 4． 6． 5 Anti-tumor effects 134 ……………………………………………………… ( ) 4． 6． 6 Anti-aging and anti-oxidation effects 135 …………………………………… ( ) 4． 6． 7 Anti-hypoxia and anti-fatigue effects 136 …………………………………… ( ) 4． 6． 8 Anti-inflammatory anti-virus and anti-bacterial activities 136 , …………… ( ) 4． 6． 9 Hepatoprotective 137 ………………………………………………………… ( ) 4． 7 Clinical studies 137 ……………………………………………………………… ( ) 4． 8 Processing 137 …………………………………………………………………… ( ) 4． 9 Side effects and acute toxicity 138 ……………………………………………… ( ) viii Ethnopharmacology Phytochemistry and Pharmacology Review of Traditional Chinese Medicine - · · , Ⅰ

4． 10 Conclusion 138 …………………………………………………………………… ( ) 4． 11 References 139 …………………………………………………………………… ( ) Chapter 5 Ethnopharmacology phytochemistry and pharmacology of , Lonicera japonica Thunb 152 …………………………………………… ( ) 5． 1 Introduction 152 …………………………………………………………………… ( ) 5． 2 Botany and ethnopharmacology 153 ……………………………………………… ( ) 5． 2． 1 Botany 153 …………………………………………………………………… ( ) 5． 2． 2 Ethnopharmacology 154 ……………………………………………………… ( ) 5． 3 Phytochemistry 159 ……………………………………………………………… ( ) 5． 3． 1 Essential oils 173 …………………………………………………………… ( ) 5． 3． 2 Organic acids 175 …………………………………………………………… ( ) 5． 3． 3 Flavones 175 ………………………………………………………………… ( ) 5． 3． 4 Iridoids 176 ………………………………………………………………… ( ) 5． 3． 5 Saponins 177 ………………………………………………………………… ( ) 5． 3． 6 Other compounds 178 ……………………………………………………… ( ) 5． 4 Effects of crude extract 178 ……………………………………………………… ( ) 5． 4． 1 Anti-inflammatory activity 178 ……………………………………………… ( ) 5． 4． 2 Antiviral activity 179 ………………………………………………………… ( ) 5． 4． 3 Antibacterial activity 181 …………………………………………………… ( ) 5． 4． 4 Antioxidant activity 182 ……………………………………………………… ( ) 5． 4． 5 Hepatoprotective 183 ………………………………………………………… ( ) 5． 4． 6 Anti-tumor activity 183 ……………………………………………………… ( ) 5． 4． 7 Insecticidal and acaricidal activities 184 …………………………………… ( ) 5． 4． 8 Anti-pregnant activity 184 …………………………………………………… ( ) 5． 4． 9 Antihyperlipidemic and antithrombotic activities 184 ……………………… ( ) 5． 4． 10 Anti-lipase activity 185 …………………………………………………… ( ) 5． 5 Application on veterinary and agriculture 185 …………………………………… ( ) 5． 5． 1 Application on veterinary 185 ……………………………………………… ( ) 5． 5． 2 Cadmium-hyperaccumulator 185 …………………………………………… ( ) 5． 6 Preparations the qualitative and quantitative analysis 186 , ……………………… ( ) 5． 7 Acute and subacute toxicity 187 ………………………………………………… ( ) 5． 8 Conclusion 188 …………………………………………………………………… ( ) 5． 9 Acknowledgements 189 …………………………………………………………… ( ) 5． 10 Reference 189 …………………………………………………………………… ( ) Chapter 6 Ethnopharmacological and phytochemical review of genus Scutellaria 196 …………………………………………………………… ( ) 6． 1 Introduction 196 …………………………………………………………………… ( ) 6． 2 Biology and ethnopharmacology 196 …………………………………………… ( ) Contents ix · ·

6． 3 Phytochemistry 203 ……………………………………………………………… ( ) 6． 3． 1 Flavonoids 216 ……………………………………………………………… ( ) 6． 3． 2 Phenylethanoid glycosides 234 ……………………………………………… ( ) 6． 3． 3 Iridoid glycosides 234 ……………………………………………………… ( ) 6． 3． 4 Diterpenes 235 ……………………………………………………………… ( ) 6． 3． 5 Triterpenoids 235 …………………………………………………………… ( ) 6． 3． 6 Neo-Clerodane diterpenoid alkaloids 235 …………………………………… ( ) 6． 3． 7 Alkaloids 235 ………………………………………………………………… ( ) 6． 3． 8 Essential oils 235 …………………………………………………………… ( ) 6． 3． 9 Other compounds 236 ……………………………………………………… ( ) 6． 4 Qualitative and quantitative analysis 236 ………………………………………… ( ) 6． 5 Effects of crude extract 237 ……………………………………………………… ( ) 6． 5． 1 Antitumor 237 ……………………………………………………………… ( ) 6． 5． 2 Anti-angiogenesis 238 ……………………………………………………… ( ) 6． 5． 3 Hepatoprotective 239 ………………………………………………………… ( ) 6． 5． 4 Antioxidant 239 ……………………………………………………………… ( ) 6． 5． 5 Anticonvulsant 239 …………………………………………………………… ( ) 6． 5． 6 Antibacterial and antiviral 240 ……………………………………………… ( ) 6． 5． 7 Neuroprotective effects and memory improvement 240 …………………… ( ) 6． 6 Conclusion 241 …………………………………………………………………… ( ) 6． 7 References 241 …………………………………………………………………… ( ) Chapter 7 Botany chemistry and pharmacology review of Rehmannia , glutinosa 250 ……………………………………………………………… ( ) 7． 1 Introduction 250 …………………………………………………………………… ( ) 7． 2 Botany of Rehmannia glutinosa 258 ……………………………………………… ( ) 7． 3 Chemical components 259 ………………………………………………………… ( ) 7． 3． 1 Iridoids monoterpenes and glycosides 259 , ………………………………… ( ) 7． 3． 2 Other glycosides 261 ………………………………………………………… ( ) 7． 3． 3 Saccharides 261 ……………………………………………………………… ( ) 7． 3． 4 Amino acids and microelements 261 ………………………………………… ( ) 7． 3． 5 Organic acids 262 …………………………………………………………… ( ) 7． 3． 6 The chemical composition changes before and after the processing 262 … ( ) 7． 4 Pharmacological properties 262 …………………………………………………… ( ) 7． 4． 1 Effects on blood system 262 ………………………………………………… ( ) 7． 4． 2 Anti-tumor effects 264 ……………………………………………………… ( ) 7． 4． 3 Effects on immune system 264 ……………………………………………… ( ) 7． 4． 4 Effects on cardiovascular system 265 ……………………………………… ( ) 7． 4． 5 Effects on center nervous system 265 ……………………………………… ( ) x Ethnopharmacology Phytochemistry and Pharmacology Review of Traditional Chinese Medicine - · · , Ⅰ

7． 4． 6 Effects on bone metabolism 266 …………………………………………… ( ) 7． 4． 7 Effects on endocrine system and glucose metabolism 267 ………………… ( ) 7． 4． 8 Other pharmacological effects 267 ………………………………………… ( ) 7． 5 Conclusion 268 …………………………………………………………………… ( ) 7． 6 Acknowledgements 270 …………………………………………………………… ( ) 7． 7 References 270 …………………………………………………………………… ( ) Chapter 8 Phytochemical and biological studies of plants from the Genus Oxytropis 275 …………………………………………………… ( ) 8． 1 Introduction 275 …………………………………………………………………… ( ) 8． 2 Chemical constituents 284 ………………………………………………………… ( ) 8． 2． 1 Flavones 284 ………………………………………………………………… ( ) 8． 2． 2 Alkaloids 285 ………………………………………………………………… ( ) 8． 2． 3 Triterpenoids 285 …………………………………………………………… ( ) 8． 2． 4 Other compounds 285 ……………………………………………………… ( ) 8． 3 Biological activities 285 …………………………………………………………… ( ) 8． 3． 1 Anti-tumor activity 285 ……………………………………………………… ( ) 8． 3． 2 Clearing and inducing free radicals activities 286 ………………………… ( ) 8． 3． 3 Bacteriostatic activity 286 …………………………………………………… ( ) 8． 3． 4 Eliminating phlegm and anti-inflammatory effect 287 ……………………… ( ) 8． 3． 5 Hemostasis 287 ……………………………………………………………… ( ) 8． 3． 6 Other activities 288 ………………………………………………………… ( ) 8． 4 Toxicity 288 ……………………………………………………………………… ( ) 8． 4． 1 Enzyme inhibition 288 ……………………………………………………… ( ) 8． 4． 2 Effect on embryonic development 288 ……………………………………… ( ) 8． 4． 3 Immune suppression activity 289 …………………………………………… ( ) 8． 4． 4 Effect on tissue and cell 289 ………………………………………………… ( ) 8． 5 Conclusion 289 …………………………………………………………………… ( ) 8． 6 References 289 …………………………………………………………………… ( ) Chapter 9 Phytochemical and biological studies of plants from the Genus Phlomis 295 ……………………………………………………… ( ) 9． 1 Introduction 295 …………………………………………………………………… ( ) 9． 2 Chemical constituents 302 ………………………………………………………… ( ) 9． 2． 1 Terpenoids 302 ……………………………………………………………… ( ) 9． 2． 2 2-Phenylethanoid and benzyl glycosides 302 ……………………………… ( ) 9． 2． 3 Flavonoids 303 ……………………………………………………………… ( ) 9． 2． 4 Lignans 303 ………………………………………………………………… ( ) 9． 2． 5 Essential oil 303 ……………………………………………………………… ( ) 9． 2． 6 Other compounds 303 ……………………………………………………… ( ) Contents xi · ·

9． 3 Bioligical activity 308 …………………………………………………………… ( ) 9． 3． 1 Antinociceptive and anti-inflammatory activities 308 ……………………… ( ) 9． 3． 2 Cytotoxic and cytostatic activities 308 ……………………………………… ( ) 9． 3． 3 Antidiabetic activiy 309 ……………………………………………………… ( ) 9． 3． 4 Anti-ulcerogenic activity 309 ………………………………………………… ( ) 9． 3． 5 Antioxidant activity 309 ……………………………………………………… ( ) 9． 3． 6 Antiprotozoal activity 309 …………………………………………………… ( ) 9． 3． 7 Antimutagenic activity 310 ………………………………………………… ( ) 9． 3． 8 Antimicrobial and antifungal activitives 310 ………………………………… ( ) 9． 4 Conclusions 310 …………………………………………………………………… ( ) 9． 5 References 311 …………………………………………………………………… ( ) Chapter 10 The genus Patrinia Ethnopharmacology phytochem- : , istry and pharmacology of an important traditional , Chinese medicine 314 ………………………………………………… ( ) 10． 1 Introduction 314 ………………………………………………………………… ( ) 10． 2 Botanical description and ethnopharmacology 315 ……………………………… ( ) 10． 2． 1 Botanical description 315 …………………………………………………… ( ) 10． 2． 2 Ethnopharmacology 316 …………………………………………………… ( ) 10． 3 Phytochemistry 317 ……………………………………………………………… ( ) 10． 3． 1 Triterpenoids and triterpenoids saponins 317 ……………………………… ( ) 10． 3． 2 Iridoids 354 ………………………………………………………………… ( ) 10． 3． 3 Flavonoids 354 ……………………………………………………………… ( ) 10． 3． 4 Essential oils 355 …………………………………………………………… ( ) 10． 3． 5 Organic acids 355 ………………………………………………………… ( ) 10． 3． 6 Lignans 356 ………………………………………………………………… ( ) 10． 3． 7 Anthraquinones 356 ………………………………………………………… ( ) 10． 3． 8 Coumarins 356 ……………………………………………………………… ( ) 10． 3． 9 Steroids 356 ………………………………………………………………… ( ) 10． 3． 10 Others compounds 356 …………………………………………………… ( ) 10． 4 Pharmacology 357 ……………………………………………………………… ( ) 10． 4． 1 Anti-tumor activity 357 …………………………………………………… ( ) 10． 4． 2 Sedative and hypnotic activities 361 ……………………………………… ( ) 10． 4． 3 Anti-inflammatory and anti-nociceptive activities 362 …………………… ( ) 10． 4． 4 Anti-bacterial and anti-viral activities 363 ………………………………… ( ) 10． 4． 5 Anti-oxidant activity 364 …………………………………………………… ( ) 10． 4． 6 Hepatoprotective activity 365 ……………………………………………… ( ) 10． 4． 7 Anti-hypoxia activity 365 ………………………………………………… ( ) 10． 4． 8 Hypolipidemic activity 365 ………………………………………………… ( ) xii Ethnopharmacology Phytochemistry and Pharmacology Review of Traditional Chinese Medicine - · · , Ⅰ

10． 4． 9 Cytotoxic activity 366 ……………………………………………………… ( ) 10． 4． 10 Effect on the immune system 367 ………………………………………… ( ) 10． 4． 11 Effect on the blood system 368 …………………………………………… ( ) 10． 4． 12 Effect on central nervous system 369 …………………………………… ( ) 10． 5 Modern clinical application 369 ………………………………………………… ( ) 10． 5． 1 Treatment of cancers 369 …………………………………………………… ( ) 10． 5． 2 Treatment of neurasthenia 370 …………………………………………… ( ) 10． 5． 3 Treatment of epidemic parotitis 370 ……………………………………… ( ) 10． 5． 4 Treatment of acute bacterial inflammation 370 …………………………… ( ) 10． 5． 5 Treatment of cold 370 ……………………………………………………… ( ) 10． 5． 6 Adverse reactions 370 ……………………………………………………… ( ) 10． 6 Toxicity 371 ……………………………………………………………………… ( ) 10． 7 Future perspectives and conclusion 371 ………………………………………… ( ) 10． 8 Acknowledgements 372 ………………………………………………………… ( ) 10． 9 References 372 …………………………………………………………………… ( ) Chapter 1

Ethnopharmacology phytochemistry and , pharmacology of Leonurus japonicus Houtt

1． 1 Introduction

Leonurus japonicus Houtt． Labiatae commonly called Chinese motherwort is an ( ), , herbaceous flowering plant native to several regions in Asia including China Korea Japan , , , and Cambodia． It has escaped cultivation to become naturalized in other parts of the world , including South and North America as well as Europe and Africa Http / / www． ars- ( : grin． gov / cgi-bin / npgs / html / taxon． pl 407691 ． For thousands of years in China the aerial ? ) , part of Leonurus japonicus has been primarily used to treat menoxenia dysmenorrhea amen- , , orrhea lochia edema of body oliguresis sores ulcerations and other diseases in women , , , , , and was thus named Yi Mu Cao Chinese 益母草 meaning literally beneficial herb “ ” ( : ), “ for mothers． Since 1990 Leonurus japonicus has been listed in the Pharmacopoeia of the ” , People s Republic of China and more than 300 prescriptions containing Leonurus japonicus ’ , have been used to treat various diseases in China especially those specific to women Cai , ( , 2005 ． Modern pharmacological studies show that the active components in Leonurus japoni- ) cus possess wide pharmacological actions such as effects on the uterus as well as cardiopro- , tective anti-oxidative anti-cancer analgesic anti-inflammatory neuroprotective and anti- , , , , , bacterial actions． Most of these actions are consistent with those for Leonurus japonicus in tra- ditional medicine． Because of the marked effects on women s health and diseases researchers began focu- ’ , sing attention on Leonurus japonicus extensively studying its chemical components. Alka- , loids diterpenes flavones spirocyclic nortriterpenoids phenylethanoid glycosides sesquit- , , , , , erpene glycosides essential oils and other compounds were the main components isolated and , studied． Among them stachydrine has been the most studied and shows the best bioactivi- , ty． According to the Pharmacopoeia of China stachydrine is now used as the official , indicator to monitor the quality of the herb and of the preparations with Leonurus japonicus Committee for the pharmacopoeia of P． R． China 2010 ． ( , ) In this review we examine the advances in the ethnopharmacology phytochemistry , , , pharmacology and toxicology of Leonurus japonicus as well the increasing data that support the utilization of Leonurus japonicus as a novel drug． Considering that Leonurus japonicus has many synonyms http / / www． theplantlist． org we use Leonurus japonicus as the name of ( : ), 1 · · 2 Ethnopharmacology, Phytochemistry and Pharmacology Review of Traditional Chinese Medicine-Ⅰ · · the plant throughout this review except in those instances where we indicate a synonym has , been used．

1． 2 Botany and ethnopharmacology

1． 2． 1 Botany

The Leonurus japonicus plants are either annual or biennial growing from taproots with , dense and fibrous rootlets． The stems are upright growing to a height from 30 to 120 cm and , are approximately 5 mm in diameter． The main stem filled with marrow and the 4 prismatic , , stems are covered in fine hair-like filaments． The flowers are sessile and are produced in ver- ticillasters． The calyx is tubular-campanulate shaped and 6-8 mm long with broad triangular- shaped teeth． The corolla is white or reddish to purplish-red． The flowering period is from June to September and the plants bloom from July and October Fig． 1-1 http / / , ( ) ( : frps． eflora． cn Cai 2005 ． , , ) In China Leonurus japonicus mainly grows along the roadsides hillsides and in fields , , in most regions with an altitude of 0-3000 m． Different regions have provided various names for Leonurus japonicus such as Kuncao or Yimuhao in the Jilin and Liaoning provinces , ( ), Yema or Tianzhima Jiangsu Sanjiaohuma Zhejiang Qinghao Sichuan province ( ), ( ), ( ), Qiancengta Qinghai and Tougucao Yunnan province ． In addition Leonurus artemisia ( ) ( ) , Lour． S． Y． Hu Leonurus heterophyllus Sweet and Leonurus sibiricus auct． pl． and ( ) , Stachys artemisia Lour． were thought to be synonyms of this species． Now Leonurus japoni- , cus has become distributed in other regions including Cambodia Japan Korea Laos Ma- , , , , , laysia Myanmar Thailand and Vietnam as well as in some countries of Africa North A- , , , , merica and South America http / / frps． eflora． cn ． Because of its beauty and long flowering ( : ) period Leonurus japonicus also has been used as an ornamental plant in some regions． , 1． 2． 2 Ethnopharmacology

Due to its marked effect in treating blood diseases and diseases stemming from multi- parity Leonurus japonicus played an important role in traditional Chinese medicine , TCM and was considered for thousands of years a superior medicine for treating ( ) women s diseases． In Sheng Nong Ben Cao Jing the oldest classical medicinal book Le- ’ , , onurus japonicus was listed as Top grade． In Ben Cao Gang Mu the most famous me- “ ” , dicinal book in China Leonurus japonicus was thought to be innocuous and useful for the , treatment of vaginal bleeding during pregnancy dystocia retained fetal membranes brui- , , , sing metrorrhagia metrostaxis hemuresis and other diseases． Since its listing in Ben Cao , , , Gang Mu Leonurus japonicus has been recorded in virtually all classical medicinal books , in China Cai 2005 ． ( , ) The aerial part of Leonurus japonicus has been listed in the Pharmacopoeia of the Peo- Chapter 1 Ethnopharmacology, phytochemistry and pharmacology of Leonurus japonicus Houtt 3 · · ple s Republic of China since 1990． It is now listed in China as one of the 50 fundamental ’ herbs used in traditional Chinese medicine． More than 15 preparations in which Leonurus ja- , ponicus was the main and active component were listed in the Chinese Pharmacopoeia and , approved by the State Administration of Traditional Chinese Medicine of the People s ’ Republic of China such as Yi Mu Cao Gao and Ba Zhen Yi Mu Wan which were wide- , “ ” “ ”, ly used as therapies in women to promote blood circulation and restore menstrual flow induce , dieresis and reduce edema and clear the heat-evil and expel superficial evils Table 1-1 , ( ) Committee for the pharmacopoeia of P． R． China 2010 http / / www． satcm． gov． cn . Chen ( , , : ) et al． 2010 reviewed the records of women who had received Chinese herbal medicine ther- ( ) apies for menopausal symptoms at the Traditional Medicine Center of Veterans General Hos- pital in Taipei between January 2003 and December 2006． Their results showed that the most frequently prescribed single Chinese herb was Yi-Mu-Tsao L． japonicus . However at the ( ) , same time it was forbidden in the clinics of China to treat diseases in pregnant women be- , cause of the potential effect on the uterus． Leonurus japonicus has also been employed in health care products with other medicines or food to improve the body and prevent illness in the women of China． For ex- ample after decocting 1 h the herb Leonuri 30-60 g with rhizoma Corydalis Yanhusuo , , ( ) 20 g and two eggs could be used to prevent and treat menalgia． Another concoction with ( ) the herb Leonuri rhizoma Zingberis Recens fructus Jujubae and brown sugar could be , , used to treat postpartum abdominal pain etc． In addition Leonurus japonicus has an excel- , , lent effect in cosmetology and halts the progression of caducity． In the Tang dynasty Zetian , Wu the only woman emperor in the history of China commonly used a cosmetic made , , from L． japonicus to maintain her skin and to provide rejuvenation． Currently the plant is , used in cosmetics and other beauty products such as facial masks or ointments as well as , , in food products along with other materials to activate blood circulation and to treat skin dis- eases Deng 2010 ． ( )

Fig． 1-1 The flower of Leonurus japonicus and chemical structure of stachydrine． 4 Ethnopharmacology, Phytochemistry and Pharmacology Review of Traditional Chinese Medicine-Ⅰ · · Table 1-1 The preparations in which L． japonicus was the main compositions listed in , , Chinese Pharmacopoeia and approved by goverment∗

Preparation name Main compositions Usage

Yi Mu Cao Gao Herb Leonuri． Promoting blood circulation to restore menstrual flow． Treating menoxenia induced by blood stasis and few menstruations．

Yi Mu Cao Kou Herb Leonuri． Promoting blood circulation to restore menstrual Fu Ye flow． Treating menoxenia induced by blood stasis and few menstruations．

Yi Mu Cao Zhu Herb Leonuri． Uterotonic． Regulating menstruation and hemosta- She Ye sis． Yi Mu Cao Pian Herb Leonuri． Promoting blood circulation to restore menstrual flow． Treating the few menstruations． Yi Mu Wan Herb Leonuri Radix Angelicae Sinensis Rhi- Regulating menstruation and nourishing , , zoma Chuanxiong Radix Aucklandiae． blood． Treating Qi regurgitating and blood sta- , sis menstrual abdominal pain leucorrhea , , , sore waist and tired dizzy and tinnitus induced , by cold in blood and blood -deficiency． Ba Zhen Yi Herb Leonuri Radix Paeoniae Alba Rhizoma Invigorating vital energy and regulating menstruc- , , Mu Wan Atractylodis Macroce phalae Rhizoma tion． Treating Qi and blood deficiency of , Chuanxiong Radix Angelicae Sinensis women physically weak and few menstrua- , , , Radix Codonopsis Pilosulae Poria Radix tions． , , Glycyrrhizae Radix Rehmanniae , , Fu Fang Yi Mu Herb Leonuri Radix Angelicae Sinensis Rhi- Regulating menstruation and nourishing , , Cao Gao zoma Chuanxiong Radix Paeoniae Alba blood． Treating menoxenia abdominal pain in , , , Radix Rehmanniae Radix Aucklandiae． the period of menorrhea induced by stagnation , of Qi and blood．

Jia Wei Yi Mu Herb Leonuri Radix Angelicae Sinensis Regulating menstruation and nourishing , , Cao Gao Radix Rehmanniae Radix Paeoniae Alba blood． Treating menoxenia and few menstrua- , , Rhizoma Chuanxiong tions． , Fu Fang Yi Mu Herb Leonuri Radix Rehmanniae Radix An- Regulating menstruation and nourishing blood , , , Cao Liu Qin Gao gelicae Sinensis． removing blood stasis． Treating menoxenia in- , sufficiency of uterus resetting after childbirth , lochia．

Fu Kang Ning Pian Herb Leonuri Radix Paeoniae Alba Rhizoma Nourishing blood and regulating vital energy , , , Cyperi Radix Angelicae Sinensis Radix promoting blood circulation to restore , , Notoginseng Folium Artemisiae Argyi menstrual flow． Treating menoxenia induced , , Radix ophiopogonis Radix Codonopsis Pi- blood-deficiency few menstructions abdom- , , losulae inal pain in menstrual period． , Kang Gong Yan Pi- Herb Leonuri Herba Callicarpa Radix Lin- Expelling dampness． Treating leucorrhea． , , an derae Chapter 1 Ethnopharmacology, phytochemistry and pharmacology of Leonurus japonicus Houtt 5 · · Continued

Preparation name Main compositions Usage

Tong Jing Wan Herb Leonuri Radix Angelicae Sinensis Radix Warming meridians and activating blood circula- , , Paeoniae Alba Rhizoma Chuanxiong Radix tion regulating menstruation and analgesi- , , , Rehmanniae Rhizoma Cyperi Fructus Peri- a． Treating dysmenorrheal menoxeni induced , , , carpium Fructus Crataegi Rhizoma Coryda- by blood stasis． etc． , , , lis Rhizoma Zingiberis Cortex Cinnamomi , , , Radix Salviae Miltiorrhizae Fructus , Leonuri Flos Carthami Faeces , , Trogopterorl Radix Aucklandiae． , Kun Ning Ke Li Herb Leonuri Radix Angelicae Sinensis Activating blood circulation and promoting Qi , , , Radix Paeoniae Alba Radix Salviae Miltior- hemostasis andregulating menstruction. Tre- , rhizae Radix Curcumae Radix Achyranthis ating menorrhagia and menostaxis induced by , , Bidentatae Fructus Aurantii Herba Schi- Qi-stagnancy and blood stasis． , , zonepetae Rhizoma Zingiberis Radix Ru- , , biae Radix Aucklandiae． , Jia Wei Ba Zhen Yi Herb Leonuri Radix Ginseng Poria Invigorating vital energy and regulating menstruc- , , , Mu Gao Rhizoma Atractylodis Macroce phalae tion removing blood stasis and regulating , , Radix Angelicae Sinensis Radix Paeoniae menstruation． Treating insufficiency of vital en- , Alba Rhizoma Chuanxiong Radix Reh- ergy and blood menoxenia menstruction ret- , , , , manniae Flos Carthami Radix Salviae rocession etc． , , , Miltiorrhizae Herba Lycopi Radix Glycyr- , , rhizae etc． , Fu Fang Yi Mu Herb Leonuri Radix Rehmanniae Radix An- Nourishing liver and kidney nourishing blood , , , Yang Shen Kou gelicae Sinensis Radix Paeoniae Alba Rhi- and regulating vital energy． Treating burn sen- , , Fu Ye zoma Chuanxiong Fructus Corni sation of five centres soreness and weakness , , , Mudanpi Radix Morindae Officinalis of waist and knees dizzy amnesia and in- , , , , Herba Epimedii Radix Salviae somnia in female change of life． , Miltiorrhizae Radix Ginseng Rhizoma , , Anemarrhenae etc． , Xian Yi Mu Cao FreshHerb Leonuri． Uterotonic regulating menstruction． Treating , Jiao Nang menoxenia postpartum metrorrhagia uterus , , meromorphosis．

Qian Lie Tai Herb Leonuri Herba Polygonum Flos Cartha- Clearing away heat evil and promoting dieresis , , , Jiao Nang mi Bee pollen Rhizoma Anemarrhenae activating blood circulation and eliminating , , , Cortex phellodendri． stagnation． Treating chronic prostatitis．

1． 3 Phytochemistry

Currently approximately 140 chemical components have been isolated and identified , from Leonurus japonicus including alkaloids diterpenes flavones phenylethanoid glyco- , , , , sides and essential oils Table 1-2 ． The chemical structures of the primary compounds are , ( ) 6 Ethnopharmacology, Phytochemistry and Pharmacology Review of Traditional Chinese Medicine-Ⅰ · · shown in Fig． 1-2． 1． 3． 1 Alkaloids

Although alkaloids are the main chemical compounds and active components inLeonurus japonicus to date only four alkaloids have been identified and studied leonuridine 1 , , : ( ), leonurine 2 leonurinine 3 and stachydrine 4 ． Of these leonurine 2 and ( ), ( ) ( ) , ( ) stachydrine 4 are the most studied have the best bioactivities and have been used to moni- ( ) , tor the quality of the herb and preparations of Leonurus japonicus in the Pharmacopoeia of China． 1． 3． 2 Diterpenes

Since 1982 four diterpene compounds ballatenol 5 leosibirin 6 isoleosibirin , ( ( ), ( ), 7 and leosibiricin 8 have been isolated from Leonurus sibiricus Savona et al． ( ) ( )) ( , 1982 . Currently more than 50 diterpene compounds have been isolated and identified from ) , Leonurus japonicus and all are labdane diterpenoids． These compounds can be sorted to five , types based on the pentacyclic ring on C12 a furan ring dihydrofuran ring lactone ring : , , , -undersaturated lactone ring and tetrahydrofuran ring． Many of these chemical α, β compounds have shown marked bioactivities in vivo or in vitro． In 2004 seven new labdane diterpenes sibiricinones A-E 21-25 and 15-epi-sibirici- , , ( ) nones D 26 and E 27 were isolated from the aerial part of Leonurus sibiricus Boalino ( ) ( ), ( et al． 2004 ． Then in 2010 six new bis-spirolabdane-type diterpenoids were isolated from , ) , , the aerial part of Leonurus sibiricus leosibrinone A 28 leosibrinone B 29 3 -acetox- : ( ), ( ), α yleoheteronone A 34 3 -acetoxyleoheteronone C 35 3 -acetoxyleoheteronone E ( ), α ( ), α 36 and 3 -acetoxy-15-epileoheteronone E 37 Moon et al． 2010b ． Khan et al． ( ) α ( ) ( , ) 2012 isolated and identified 15 16-epoxy-3 -hydroxylabda-8 13 16 14-trien-7-one ( ) , α , ( ), 15 from Leonurus japonicus． ( ) Narukawa et al． 2014 isolated twelve diterpenoid compounds from the acetone extract ( ) of the aerial part of Leonurus sibircus and studied the estrogen sulfotransferase inhibitory ac- , tivity of these compounds． Their results demonstrated that the IC of 15 16-epoxy-8 17-di- 50 , , nor-9-oxo-7 9-seco-13 16 14-labdadien-7-oic acid 54 6 9 15 16-diepoxy-6- , ( ), ( ), , : , hydroxy-6 7-seco-13 16 14-labdadien-7-oic acid 55 + -6 - hydroxy-15 16-epoxy- , ( ), ( ), [ ] β , labda-8 13 16 14-trien-7-one 50 + -hispanone 49 and - -6 9 15 16- , ( ), ( ), [ ] ( ) [ ] , : , diepoxy-9 -hydroxy-8 9-seco-13 16 14-labdadiene-7-one 51 were 2． 9 23． 2 31． 3 α , ( ), ( ) , , , 19． 8 and 40． 5 m respectively． Satoh et al． 2003 studied and isolated six μ , ( ) furanoditerpene-lactones from Leonurus sibiricus LS-1 57 LS-2 58 leonotinin 59 : ( ), ( ), ( ), leonotin 60 dubiin 61 and nepetaefuran 62 ． Their results demonstrated that these ( ), ( ) ( ) compounds exhibited moderate cytotoxic activity IC = 50-60 g / ml against leukemia ( 50 μ ) cells L1210 in tissue culture． ( ) Chapter 1 Ethnopharmacology, phytochemistry and pharmacology of Leonurus japonicus Houtt 7 · ·

1． 3． 3 Flavones

To date approximately 30 flavones from Leonurus japonicus have been isolated and , identified． Cai 2005 isolated four compounds rutin 63 wogonin 64 5 7 3′ 4′ ( ) : ( ), ( ), , , , , 5′-pentamethoxy-flavone 65 and apigenin-7-O- -D-glucopyranoside 66 ． Then Deng et ( ) β ( ) , al． 2013 isolated and identified quercetin-3-neohesperidoside 70 quercetin-3-O- ( ) ( ), rutinoside 71 kaempferol-3-O- -D-glucopyranoside 72 kaempferol-3-O- -D-galacto- ( ), β ( ), β pyranoside 73 kaempferol-3-O- -D-robinobinoside 74 and kaempferol-3-neohesperido- ( ), β ( ) side 75 ． Cong et al． 2009 isolated eight chemical constituents from Leonurus heterophyl- ( ) ( ) lus and studied their antitumor activity against the leukemia K562 cell line． Their results using an MTT viability assay indicated that the IC for quercetin-3-O-robinobioside 79 rutin 50 ( ), 63 isoquercitrin 80 hyperoside 81 quercetin 68 apigenin 82 and benzoic ( ), ( ), ( ), ( ), ( ) acid 120 against K562 cells was 17． 29 21． 56 21． 67 24． 12 6． 3 10． 4 and 116． 5 ( ) , , , , , mg / l respectively whereas the IC for the positive control drug adriamycin was 1． 48 mg / l. , , 50 Zhang et al． 2013 isolated five new syringyl acylated flavonol glycosides from the aerial ( ) part of Leonurus japonicus leonurusoides A 87 B 88 C 89 D 90 and E 91 , ( ), ( ), ( ), ( ) ( ), and suggested that these compounds inhibited triglyceride accumulation in free fatty acid-in- duced HepG2 cells． 1． 3． 4 Spirocyclic nortriterpenoids

In 2012 four new spirocyclic nortriterpenoids leonurusoleanolide A 92 B 93 C , , ( ), ( ), 94 and D 95 were isolated from the methanol extract of the fruit of Leonurus hetero- ( ) ( ), phyllus and they were found to exist as equilibrium mixtures of trans and cis isomers． The , results of pharmacological tests demonstrated that a mixture of 92 and 93 and a mixture of 94 and 95 at concentrations of 1 10 and 30 M promoted neurite outgrowth in NGF-treated , , μ PC12 cells Liu et al． 2012 ． Meanwhile two new C-28 nortriterpenoids leonujaponin A ( , ) , 96 and phlomistetraol B 97 were isolated and identified from the fruit of Leonurus ja- ( ) ( ) ponicus Zheng et al． 2012 ． ( , ) 1． 3． 5 Sesquiterpene glycosides

In 2012 a new sesquiterpene glycoside from the aerial part of Leonurus japonicus was i- , solated namely 7 H -eudesmane-4 11 12 -diene-3-one-2 -hydroxy-13- -D- gluco- , , α ( ) , ( ) β β pyranoside 98 Li et al． 2012 ． At the same time - - 1S 2S 3R -3- ( ) ( , ) , ( ) ( ∗, ∗, ∗) ethoxycupar-5-ene-1 2-diol 99 - - 1S 4S 9S -1 9-epoxybisabola-2 10- , ( ), ( ) ( ∗, ∗, ∗) , , diene- 4-ol 100 and arteannuin B 101 were isolated from Leonurus japonicus Xiong et ( ) ( ) ( al． 2013b ． , ) 1． 3． 6 Megastigma

To date four megastigma compounds have been isolated from Leonurus japonicus 9- , : 8 Ethnopharmacology, Phytochemistry and Pharmacology Review of Traditional Chinese Medicine-Ⅰ · · hydroxy-megastigma-4 7-dien-3-one-9-O-glucopyranoside 102 staphylionoside E , ( ), 103 megastigmane 104 and citroside A 105 Cong et al． 2003 Li et al． 2012 ． ( ), ( ) ( ) ( , ; , ) 1． 3． 7 Phenylethanoid glycosides

Li et al． 2012 isolated two new phenylethanoid glycosides from the aerial part of Le- ( ) onurus japonicus leonoside E 107 and leonoside F 108 These compounds exhibited , ( ) ( ), potent hepatoprotective activity against D-galactosamine-induced toxicity in HL-7702 cells at a concentration of 1 ×10 -5 M． At the same time verbascoside 109 2- 3 4-dihydroxy- , ( ), ( , phenethy -O- -arabinopyranosyl- 1 2 - -L-rhamnopyranosyl- 1 3 -6- O- -D-glucopy- ) α ( → ) α ( → ) β ranoside 110 cistanoside E 111 and lavandulifolioside 112 were also isolated and i- ( ), ( ) ( ) dentified． 1． 3． 8 Nonapeptides

In 1997 cycloleonuripeptides A B C D 114-117 four new proline-rich cyclic de- , , , , ( ), capeptides were isolated from Leonurus heterophyllus Morita et al． 1997 ． Then in , ( , ) , 2006 cycloleonuripeptides E 118 and F 119 as cyclic nonapeptides were isolated and , ( ) ( ), , identified from Leonurus heterophyllus Morita et al． 2006 ． ( , ) 1． 3． 9 Essential oils

Xiong 2013a analyzed and studied the chemical composition of the essential oils from ( ) the herb Yimucao and the fruit Chongweizi of Leonurus japonicus with GC-MS and its ( ) ( ) antibacterial activity with micro-dilution assays． The results of GC-MS demonstrated that Yimucao oil was mainly composed of diterpenes 32． 77% and sesquiterpenes “ ” ( ) 45． 37% with phytone 19． 02% phytol 13． 75% caryophyllene oxide 11． 49% ( ), ( ), ( ), ( ) and β-caryophyllene 9． 89% being the most significant constituents． Other sesquiterpenes ( ) present in appreciable amounts were spathulenol 5． 31% α-caryophyllene 3． 38% and ( ), ( ) isocaryophyllene 3． 00% ． The primary structures belonged to the caryophyllane aroma- ( ) , dendrane and cadinane classes． Additionally monoterpene compounds were present． Chong- , “ weizi oil was characterized by large amounts of aliphatic compounds 43． 04% including ” ( ), 12 aliphatic hydrocarbons two aldehydes and five esters． Among them aliphatic hydrocar- , , bons constituted 32． 7% followed by n-hexadecane 9． 65% n-tridecane 7． 72% and , ( ), ( ) n-pentadecane 4． 36% most of which were not detected in Yimucao oil． In the ali- ( ), “ ” phatic compounds the monoterpene fraction was noteworthy 15． 11% with bornyl , ( ), acetate 7． 33% and bornyl acrylate 1． 81% as the main constituents which were also ( ) ( ) , absent in Yimucao oil． With regard to the sesquiterpenes and diterpenes in Chongweizi “ ” “ oil the fractions were relatively small when compared to Yimucao oil accounting for , ” “ , ” only 10． 45% and 8． 45% respectively． The results of a micro-dilution assay indicated that , Yimucao oil had antibacterial activity against various Gram-positive bacteria． In particular “ ” , Chapter 1 Ethnopharmacology, phytochemistry and pharmacology of Leonurus japonicus Houtt 9 · · β-caryophyllene had wide-spectrum activity against Gram-positive bacteria with minimum in- hibitory concentrations MICs from 0． 032 to 0． 256 mg / ml and minimum bactericidal con- ( ) centrations MBCs from 0． 064 to 0． 256 mg / ml． By contrast the oil of Chongweizi was ( ) , “ ” inactive in the antibacterial assay． 1． 3． 10 Others

In 2005 and 2009 benzoic acid 120 salicylic acid 121 syringic acid 122 a- , ( ), ( ), ( ), denosine 123 and stigmasterol 124 were isolated from Leonurus heterophyllus and Le- ( ) ( ) onurus japonicus Cai 2005 Zhang et al． 2009 ． Also identified from Leonurus hetero- ( , , , ) phyllus were 2 6-dimethyl-2E 7-octadiene-1 6-diol 125 -sitosterol 126 and dau- , , , ( ), β ( ) costerol 127 Cong 2004 ． Xiong et al． 2013b isolated five compounds from ( ) ( , ) ( ) Leonurus japonicus 2S 5S -2-hydroxy-2 6 10 10-tetramethyl -1-oxaspiro 4 5 dec-6- : ( , ) , , , [ , ] en-8-one 128 3-oxo- -ionone 129 + -dehydrovomifoliol 130 + -3-hydroxy- ( ), α ( ), ( ) ( ), ( ) -ionone 131 and chamigrenal 132 ． At the same time Kuchta et al． 2012a β ( ) ( ) , ( ) determined the phenolic compounds of Leonurus japonicus using HPLC and HPTLC methods chlorogenic acid 137 caffeic acid 138 ferulic acid 139 cichoric acid : ( ), ( ), ( ), 140 hyperoside 81 rutoside 63 and apigenin-7-O-D-glucoside 66 ． ( ), ( ), ( ) ( ) Table 1-2 The compounds isolated from L． japonicus The structure of main compounds illustrated in Fig． 1-2 ( ) No． Compounds Synonym References

Alkaloids

1 Leonuridine Leonurus heterophyllus Luo et al． 1985 ( ) 2 Leonurine Leonurus Artemisia Yeung et al． 1977 ( ) Leonurus sibiricus Hayashi et al． 1962 ( ) 3 Leonurinine Leonurus artemisia Yeung et al． 1977 ( ) 4 Stachydrine Leonurus heterophyllus Luo et al． 1985 ( ) Diterpenes

5 Ballatenol Leonurus sibiricus Savona et al． 1982 ( ) 6 Leosibirin Leonurus sibiricus Savona et al． 1982 ( ) 7 Isoleosibirin Leonurus sibiricus Savona et al． 1982 ( ) 8 Leosibiricin Leonurus sibiricus Savona et al． 1982 ( ) 9 Galeopsin Leonurus sibiricus Narukawa et al． 2013 ( ) 10 Hispanolone Leonurus heterophyllus Hon et al． 1993 ( ) 11 Leoheterin Leonurus heterophyllus Hon et al． 1993 ( ) 12 Prehispanolone Leonurus heterophyllus Ming et al． 1991 ( ) Leonurus japonicus Xu et al． 1992 ( ) 13 Preleoheterin Leonurus heterophyllus Hon et al． 1993 ( ) Leonurus japonicus Xu et al． 1992 ( ) 10 Ethnopharmacology, Phytochemistry and Pharmacology Review of Traditional Chinese Medicine-Ⅰ · · Continued

No． Compounds Synonym References

14 Leopersin G Leonurus heterophyllus Hung et al． 2011 ( ) 15 15 16-Epoxy-3 -hydroxyllabda- 8 13 16 Leonurus japonicus Khanet al． 2012 , α , ( ), ( ) 14-trien-7-one 16 Leojaponin Leonurus japonicus Moon 2010a ( ) 17 13-Epi-preleoheterin Leonurus japonicus Romero-González et al． 2006 , ( ) 18 Iso-preleoheterin Leonurus japonicus Romero-González et al． 2006 , ( ) Moon 2010 ( ) 19 15 16-Epoxy-3 6 9 -trihydroxylabda-13 Leonurus japonicus Fuchino et al． 2013 , α, β, α ( ) 16 14-dien-7-one ( ), 20 Heteronone A Leonurus heterophyllus Zhang et al． 2004 ( ) Leonurus japonicus Cai 2005 ( ) 21 Sibiricinone A Leonurus sibiricus Boalino et al． 2004 ( ) 22 Sibiricinone B Leonurus sibiricus Boalino et al． 2004 ( ) 23 Sibiricinone C Leonurus sibiricus Boalino et al． 2004 ( ) 24 Sibiricinone D Leonurus sibiricus Boalino et al． 2004 ( ) 25 Sibiricinone E Leonurus sibiricus Boalino et al． 2004 ( ) 26 15-Epi-sibircinone D Leonurus sibiricus Boalino et al． 2004 ( ) 27 15-Epi-sibircinone E Leonurus sibiricus Boalino et al． 2004 ( ) 28 Leosibrinone A Leonurus japonicus Seo et al． 2010 ( ) 29 Leosibirinone B Leonurus sibiricus Moon et al． 2010 ( ) 30 Preleosibirone A Leonurus sibiricus Wu et al． 2011 , ( ) 31 13-Epi-preleosibirone A Leonurus sibiricus Wu et al． 2011 , ( ) 32 Isopreleosibirone A Leonurus sibiricus Wu et al． 2011 , ( ) 33 15-Epi-leosibirone B Leonurus sibiricus Wu et al． 2011 , ( ) 34 3 -Acetoxyleoheteronone A Leonurus sibiricus Moon et al． 2010 α ( ) 35 3 -Acetoxyleoheteronone C Leonurus sibiricus Moon et al． 2010 α ( ) 36 3 -Acetoxyleoheteronone E Leonurus sibiricus Moon et al． 2010 α ( ) 37 3 -Acetoxy-15-epileoheteronone E Leonurus sibiricus Moon et al． 2010 α ( ) 38 7 -Hydroxy-3 -acetyl-9 13 15 16-bicyclice- Leonurus heterophyllus Gong 2011 β α α, ; , ( ) poxy -15 - ethoxylabdane-6-ketone α 39 7 -Hydroxy-3 -acetyl-9 13 15 16-diepoxy- Leonurus heterophyllus Gong 2011 β α α, ; , ( ) 15 -methoxylabdane-6-ketone α 40 6 13-Dihydroxy-15 16-epoxy-15 -ethoxy-8 Leonurus heterophyllus Gong 2011 β, , α , ( ) 9-enelabdane-6-ketone 41 3 7 -Hydroxy-9 13 15 16- bicyclicepoxy- Leonurus heterophyllus Gong 2011 α, β α, ; , ( ) 15 - ethoxylabdane-6-ketone α 42 3 7 -Hydroxy-9 13 15 16- bicyclicepoxy- Leonurus heterophyllus Gong 2011 α, β α, ; , ( ) 15 -ethoxylabdane-6-ketone β