The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review

Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Contents lists available at ScienceDirect 2 3 4 5 6 journal homepage: www.elsevier.com/locate/jep 7 8 9 Review 10 11 12 13 14 15 De-Gang Kong 1,a, Yu Zhao a,1, Guo-Hui Li b, Bang-Jiao Chen a, Xiao-Ning Wang a, 16 c a a,n Q1 Hong-Lei Zhou , Hong-Xiang Lou , Dong-Mei Ren , Tao Shen a,n 17 a 18 Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China b Department of Pharmacy, Jinan Maternity and Child Care Hospital, Jinan, PR China 19 c School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, PR China 20 21 22 art ic l e i nf o a b s t r a c t 23 24 Article history: Ethnopharmacological relevance: The genus Litsea, mainly distributed in the tropical and subtropical Q8 25 Received 19 October 2014 regions, has been used in traditional and indigenous Chinese medicines for the treatment of diarrhea, 26 Received in revised form stomachache, dyspepsia, gastroenteritis, diabetes, edema, cold, arthritis, asthma, pain, traumatic injury, 27 5 February 2015 etc. for a long history. The present review aims to provide a comprehensive summary on the Accepted 8 February 2015 28 ethnomedical uses, phytochemistry, and pharmacology of the Litsea species used in traditional Chinese 29 medicine (TCM). Based on these data, evidences supporting their ethnopharmacological effectiveness are 30 Keywords: illustrated, and opportunities for the future research and development as well as the therapeutic Litsea 31 potential of this genus are analyzed to highlight the gaps in our knowledge that deserves further Phytochemistry 32 investigation. Pharmacology Material and methods: Information on the Litsea species was collected via electronic search (using 33 Ethnomedical uses Pubmed, SciFinder, Google Scholar, Web of Science and CNKI) and a library search for articles published 34 in peer-reviewed journals. Furthermore, information was also obtained from some local books on 35 ethnopharmacology. 36 Results: Twenty plants of the genus Litsea are found to be important traditional medicines in China, and 37 have a long medicinal application for diarrhea, stomachache, dyspepsia, gastroenteritis, diabetes, edema, 38 cold, arthritis, asthma, pain, traumatic injury, etc. Over 200 ingredients have been identified from these 39 20 Litsea species used in TCM, and flavonoids, terpenoids and alkaloids are considered as the 40 characteristic and bioactive constituents. The crude extracts and the isolated metabolites of these 41 medicinal plants have exhibited some in vitro and in vivo pharmacological effects, including antimicro42 bial, hepatoprotection, anti-inflammatory, antiasthmatic, immunomodulation, anti-diabetic, anticholelithogenic, as well as function on central nervous system, etc. 43 Conclusions: The extensive literature survey reveals Litsea species to be a group of important medicinal 44 plants used for the ethnomedical treatment of gastrointestinal diseases, diabetes, inflammatory 45 disorders, and microbial infection in TCM. Pharmacological investigations have supported the use of 46 some Litsea species in the traditional medicines. In addition, further researches targeting individual 47 ingredients responsible for the pharmacological effects, as well as their mechanisms of action are 48 necessary. The outcome of these studies will further support the therapeutic potential of the genus Litsea, 49 and provide convincing evidences to its future clinical applications in modern medicine. 50 & 2015 Published by Elsevier Ireland Ltd. 51 52 67 53 68 54 69 55 70 Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CCAAT, cytidine–cytidine–adenosine–adenosine–thymidine; 56 CHOP, CCAAT/enhancer binding protein homologous protein; CTGF, connective tissue growth factor; FFA, free fatty acid; GC, gas chromatography; GRP 78, glucose regulated 71 57 protein 78; GSH-PX, glutathione peroxidase; γ-GT, γ-glutamyltransferase; HA, hyaluronic acid; ICR, Institute for Cancer Research; IL-1, interleukin-1; IL-1β, interleukin-1β; 72 LDL-C, low density lipoprotein-cholesterol; LN, laminin; MDA, malondialdehyde; MMP-9, matrix metalloproteinase-9; PGE2, prostaglandin E2; PIIINP, procollagen III 58 73 N-terminal peptide; PPARα, peroxisome proliferator-activated receptor α; SOD, superoxide dismutase; TC, total cholesterol; TCM, traditional Chinese medicine; TFLC, total 59 74 flavonoids of Litsea coreana; TG, triglyceride; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor; TrACP, tartarate resistance phosphatase 60 n 75 Correspondence to: School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, PR China. Tel.: þ 86 531 88382028; 61 fax: þ86 531 88382548. 76 E-mail addresses: [email protected] (D.-M. Ren), [email protected] (T. Shen). 62 77 1 These two authors contributed equally. 63 78 64 79 http://dx.doi.org/10.1016/j.jep.2015.02.020 65 0378-8741/& 2015 Published by Elsevier Ireland Ltd. 80 66

Journal of Ethnopharmacology

The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

D.-G. Kong et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnomedical uses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Terpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Butanolides and butenolactones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Lignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Miscellaneous constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Hepatoprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Antiasthmatic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Immunomodulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Anti-diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Function on central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Anticholelithogenic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9. Miscellaneous bioactivities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The genus Litsea, belonging to the family Lauraceae, contains approximately 200 plant species, which are mainly distributed in the tropical and subtropical regions around the world (Richter, 1981). It is documented that 74 plant species of this genus have been found in China, most of which are growing in the regions between 181 and 341 north latitude of Southern and Southwest China, including Anhui, Zhejiang, Fujian, Yunnan, Sichuan and Tibet provinces (Flora of China Editorial Committee, 1994). In the aspect of ethnomedicine,20 plants in Litsea species have a long history of use in traditional and indigenous Chinese medicines (Xie and Yu, 1996). Fruit of the plant is the commonly prescribed medicinal part for the treatment of gastrointestinal diseases, pain, asthma, and traumatic injury. Meanwhile, the leaves, stems, velamina, roots and barks have also been adopted to treat people suffering from stomachache, cold, pain, arthritis, diarrhea, traumatic injury, etc. (Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration, 1999; Xie and Yu, 1996; Xie and Liang, 1996). A great deal of studies concerning the phytochemical and pharmacological aspects of the genus Litsea have been carried out. More than 200 chemical ingredients, covering flavonoids, terpenoids, alkaloids, butanolides and butenolactones, lignans, amides, steroids, fatty acids, megastigmanes, etc., have hitherto been isolated from these 20 plants medicinally used in traditional Chinese medicine (TCM). Of these chemical ingredients, flavonoids and terpenoids are regarded as the two groups of bioactive substances that are responsible for the observed pharmacological effects of Litsea species (Chen et al., 2004; Tang et al., 2013; Wan et al., 2006; Wang and Liu, 2010; Wang et al., 2009; Ye et al., 2006). Extracts of plants from this genus, as well as the purified molecules, demonstrate a wide spectrum of pharmacological functions, involving in antifungal (Yang et al., 2010), antibacterial (Chen and Xu, 2013), antidiarrheal (Mandal et al., 2000), antiinflammatory (Tang et al., 2013), anti-arthritic (Zhou et al., 2010), anti-HIV (H. Zhang et al., 2003), anti-asthma (Yin et al., 2006), hepatoprotective (Wang et al., 2009), immunomodulatory (Hu et al.,

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2007), and anti-diabetic properties (Sun et al., 2010), confirmed by experiments in vivo and in vitro. Several reviews dealing with the phytochemistry and pharmacology of the genus Litsea have been reported. Two reviews focusing on terpenoids and alkaloids from Litsea species and their biological activities have been published (Xie and Zhang, 1999; Zhao, 2006). Recently, Agrawal et al. (2011) comprehensively summarized the chemical ingredients isolated from the genus Litsea before the year of 2009, and also briefly introduced their biological activities. Different from writing objectives of above literatures, the present review focuses on the research progress targeting the Litsea species used in TCM, to provide a comprehensive summary on the ethnomedical uses, phytochemistry and pharmacology of these plants. Besides, correlations of ethnomedical uses, phytochemistry and pharmacology have been discussed based on the research findings of these fields (Arora and Kaur, 2007; Mandal et al., 2000; Chen and Xu, 2013; Wang and Liu, 2010; Devib and Meera, 2010; Chen et al., 2004; Zhong et al., 2013; Zhang and Di, 2008; Zhou et al., 2007; Wang et al., 1999, 2006; Tu et al., 1985; Fang et al., 2002; Qian et al., 1980; Yin et al., 2006; Lv et al., 2008).

2. Ethnomedical uses Common names, ethnomedical uses and medicinal parts of the Litsea species used in TCM are listed in Table 1. On the basis of our investigations, 20 Litsea species are used in a Chinese ethnomedical system (Xie and Yu, 1996). Fruits, roots, leaves and barks of these plant species are adopted for the therapy of diseases in the different approaches including (i) pharmaceutics (e.g. decoction, pill, pulvis, etc.) of signal medicine, or compound preparations with other traditional Chinese medicines; (ii) drunk as tea; (iii) eaten as spices. The Litsea plants in TCM are mainly used for the therapies of diarrhea, stomachache, dyspepsia, gastroenteritis, diabetes, edema, cold, arthritis, asthma, pain, traumatic injury, etc. (Editorial Committee of Zhonghua Bencao National Traditional

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

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Table 1 Medicinal plants of the genus Litsea used in TCM. Species

Common/vernacular names

L. auriculata S.S. Chien Bajiaoyang and W.C. Cheng L. coreana var. sinensis Bopifeng, (C.K. Allen) Yen C. HuakechaiBaopizhang Yang and P.H. Huang Baicha, Hawk tea L. coreana var. lanuginosa (Migo) Yen C. Yang and P. H. Huang L. cubeba (Lour.) Pers. Bichengqie, Shancangzishu, Changzimu, Manshanxiang, Gangouzhang, Dongpizhuang

Medicinal parts

Ethnomedical uses

References

Fruits and velamina Leaves Barks

Expelling parasite, treating teniasis and enterobiasis Relieving pain, treating traumatic injury Treating stomach distension

The Health Department of Zhejiang Province (1965)

Roots Leaves

Treating edema Treating stomach distension, diarrhea, lowering Wang et al. (2010) and blood fat, and sunstroke Xiang and Lu (1998)

Fruits

Relieving pain, promoting blood circulation, as well as treating stomach distension, asthma, emesia, diarrhea, turbid urine and traumatic injury Treating cold, stomachache, headache, dermatophytosis and arthralgia Promoting blood circulation, treating mammitis, as well as externally used for hemostasis, sores furuncle, insect and snake bites Tonifying spleen, treating dyspepsia and sore

Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration (1999), Xie and Yu (1996), and Xie and Liang (1996)

Barks and leaves

Treating furuncle and traumatic injury

Nanning City Institute of Traditional Chinese Medicine (1960), Huang et al. (1980), and Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration (1999).

Roots

Treating diarrhea, traumatic injury, mumps, diabetes, acute or chronic gastritis and rheumatalgia Reducing swelling, and treating sore

Xie and Yu (1996)

Roots Leaves

L. euosma W.W. Sm.

Bichengqie, Jiguxiang, Daliwang, Quwenshu, Shuicang L. glutinosa (Lour.) C.B. Chuanshu, Shanjiaomu, Rob. Chunguishu, Shangaozi, Changaomu, Yanggushu

L. glutinosa var. brideliifolia (Hayata) Merr. L. hupehana Hemsl. L. ichangensis Gamble L. mollis Hemsl.

L. monopetala (Roxb.) Pers. L. moupinensis var. szechuanica (C.K. Allen) Yen C. Yang and P.H. Huang L. populifolia (Hemsl.) Gamble L. pungens Hemsl.

Fruits

Xie and Yu (1996)

Houyezhang, Yegaoshu, Yuanweigao, Qingyegaomu

Barks and roots

Baichuncha, Laoyingcha Goujiangzishu, Yehujiaozishu Shanhujiao, Mujiangzi, Shancangzi, Yemujiangzi, Bichengqie

Leaves Fruits and roots Fruits

Treating diarrhea Treating dyspepsia and diarrhea

Xie and Yu (1996) Xie and Yu (1996)

Treating chronic eczema

Xie and Yu (1996)

Roots Leaves

Treating traumatic injury Treating fracture and dislocation

Xie and Yu (1996)

Fruits

Relieving pain, treating stomachache and emesia

Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration (1999)

Roots

Treating dyspepsia, relieving pain, nausea and emesia Strengthening spleen, treating dyspepsia, diarrhea, and sunstroke, as well as externally used for sore Treating stomach distension. Relieving the pain, treating stomachache and arthralgia Treating rheumatic pain Relieving pain, treating rheumatic arthritis, traumatic injury, dysmenorrheal, stomachache and diarrhea Treating enterogastritis, stomachache and dyspepsia

Xie and Yu (1996)

Jiashali, Jiashishu, Nagao, Muzhugao, Shanboluoshu Bichengqie, Chengqiezi

Laoyapi, Chengqiezi, Laoyapimimi, Muxiangzi Shanhujiao, Lajiangzi, Huanghuazi, Baidamu, Muzhangzi

Fruits and leaves Stems Roots

L. rotundifolia Hemsl. L. rotundifolia var. oblongifolia (Nees) C.K. Allen L. rubescens Lecomte

Yuanyechaipizhang Baichai, Xiangyezi, Shanhujiao, Guoshanxiang, Shanrougui Shanhujiao, Mujiangzi, Hongmujiangzi, Muwuyu, Yeqilazi

L. sericea (Wall. ex Nees) Hook. f. L. veitchiana Gamble

Mujiangzi, Bichengqie, Shanhujiao, Tuguizhi Muxiangzi, Mujiangzi, Chengqiezi, Huashuye, Shanhujiao Niulali, Diedalao, Gaoshu, Jiawujia, Yingxiongjian

L. verticillata Hance

Xie and Yu, (1996)

Roots Roots and barks Fruits

Roots Fruits Fruits

Roots, leaves and barks

Treating traumatic injury and cold Preventing corrosion, eliminating phlegm, and improving digestion Treating dyspepsia

Xie and Yu (1996)

Xie and Yu (1996) Xie and Yu (1996)

The Tibet Autonomous Regional Revolutionary Committees Health Bureau (1973) and Xie and Yu (1996) The Botany Institute of Jiangsu Province (1990) Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration (1999)

Promoting blood circulation, relieving pain and Xie and Yu (1996) treating traumatic injury

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

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Chinese Herb Administration, 1999; The Health Department of Zhejiang Province, 1965; Xie and Yu, 1996; Xie and Liang, 1996). These ethnomedical uses of the Litsea species might originate from their antimicrobial, anti-inflammatory, anti-diabetic, and antiasthmatic activities as evaluated by the modern pharmacological investigations. As can be seen from Table 1, stomach diseases, traumatic injury, pain and diarrhea are the diseases most frequently treated by the Litsea species. Regarding the quantity of plants used for the therapy of each disease, it is concluded that 12 plants are adopted for the treatment of stomach diseases, seven plants for traumatic injury, seven plants for pain, and seven plants for diarrhea. The fruit of Litsea cubeba, named as ‘Bi-Cheng-Qie’(荜澄茄), is the most important and widely used medicine of this genus. It has been used for the treatment of cold and pain in TCM since the Tang Dynasty in 600 AD, which was recorded in the Chinese medical document Ben Cao Shi Yi (本草拾遗). Some prescriptions created by the ancient famous doctors are adopted for the treatment of stomach diseases and pain, such as ‘Bi-Cheng-Qie-Wan’ [pill recorded in Sheng Ji Zong Lu (圣济总录)], ‘Bi-Cheng-Qie-San’ [pulvis recorded in Bian Que Xin Shu (扁鹊心书)], ‘Bi-Cheng-QieYin’ [decoction recorded in Pu Ji Fang (普济方)], etc. In the modern monograph of TCM, it is described as a medicine for treating traumatic injury, dermatophytosis, stomachache, toothache, etc. (Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration, 1999; Enshi in Hubei Province of Chinese Herbal Medicine Research Group, 1970; Jiangxi Province Health Bureau Revolutionary Committee, 1970; The Medicine Institute of Fujian Province, 1970). The tender leaves of Litsea coreana var. lanuginosa were initially acted as tea for drinking by the local residents of Dalou mountain of Guizhou province, and was named as ‘hawk-tea’ because hawk was accustomed to establish nest on the tree (Xiang and Lu, 1998). Since its special flavor and functions of treating stomach distension, fever, diarrhea and sunstroke, hawk-tea spread out in the southwest of China, such as Guizhou, Sichuan, Chongqing, etc. (Xu et al., 2012). Hawktea can be further processed using larvae of Aglossa dimidiata to furnish it with the favorable taste and beneficial functions on human health. Larvae of A. dimidiate are fed with hawk-tea to produce feces, and the feces are collected and named as ‘sandytea’ for drinking (Wang et al., 2010; Xiang and Lu, 1998). Sandy-tea bears similar functions on human health to hawk-tea. The fruits and roots of some Litsea plants are important and characteristic spices in south and southwest regions of China, exemplified by Guizhou, Hunan, Hubei, and Taiwan. The ethnomedical values and applications of these Litsea species are intimately known by the local residents, and have been recorded in the regional medical monographs, covering Hu Nan Yao Wu Zhi (湖南药物志), Gui Zhou Min Jian Yao Wu (贵州民间药物), Chong Qing Cao Yao (重庆草药), Dian Nan Ben Cao (滇南本草), etc. (Xie and Yu, 1996; Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration, 1999).

3. Phytochemistry Agrawal et al. (2011) have reviewed the chemical ingredients isolated from the genus Litsea before the year 2009. With respect to these 20 medicinal plant species in China, more than 200 chemical ingredients, covering flavonoids, terpenoids, alkaloids, butanolides and butenolactones, lignans, amides, steroids, fatty acids and megastigmanes, have been reported. Their structures and resources have been comprehensively summarized, and given in Supplementary data. Based on these results, we conclude that flavonoids and terpenoids, especially the monoterpenes and

sesquiterpenes, are both abundant and bioactive constituents in this genus. 3.1. Flavonoids The traditionally used Litsea species are rich sources of flavonoids. Currently, 26 flavonoids have been isolated from these 20 Litsea species (Table S1 and Fig. S1). Flavonoids mainly occur in the plants of L. coreana, Litsea glutinosa and L. cubeba, and are classified to be flavones, flavonols, flavanones, flavanonols, anthocyanidins, chalcones, and flavan-3-ols. Flavones, flavonols, and flavanones mainly exist in the form of glycosides, consisted of glucose, galactose and rhamnose. Flavonoids are regarded to be ingredients responsible for the therapeutic action of Litsea species. For instance, the flavonoids (1 11) from L. coreana demonstrate anti-inflammatory, antioxidant and hepatoprotective activities (Chen et al., 2004; Tang et al., 2013; Wang et al., 2009; Ye et al., 2006). Some new flavonoids have been reported from these plants. Two new flavanocoumarins, isophyllocoumarin (8) and isoepiphyllocoumarin (9), together with phyllocoumarin (10) and epiphyllocoumarin (11), were isolated from the leaves of L. coreana. These four flavanocoumarins possessed a similar catechin core and a pyran-2-one ring in each molecule (Tang et al., 2013). 3.2. Terpenoids There are approximately 60 terpenoids, covering monoterpenes and sesquiterpenes, isolated from these 20 Litsea species (Tables S2, S3 and Figs. S2, S3). Monoterpenes mainly occur in volatile oil, and are identified by GC-based techniques. Many papers have described the GC analysis of volatile oil from different Litsea species, including L. cubeba (Cheng and Cheng, 1983; Jiang et al., 2009; Yang et al., 2010; Zhan et al., 1985), Litsea euosma (Thang et al., 2006), L. glutinosa (Choudhury et al., 1996), Litsea mollis (Wang et al., 2002) and Litsea pungens (Jiang et al., 2009; Zhang et al., 1992). There are 20 monoterpenes isolated from the essential oil of L. cubeba which have attracted the attention of researchers since their diverse biological activities, exemplified by antioxidative, antifungal, antiasthmatic, anti-anaphylactic properties, as well as function on the central nervous system (Chen et al., 2012; Chen, 2005; Gogoi et al., 1997; Lu et al., 1988; Qian et al., 1980). Litsea verticillata is the plant species containing the largest number of sesquiterpenes in this genus. So far, 31 sesquiterpenes, exemplified by 12–26, have been isolated from L. verticillata (Hoang et al., 2002; H.J. Zhang et al., 2003; H. Zhang et al., 2003; Zhang et al., 2005). 3.3. Alkaloids About 30 alkaloids have been isolated from these 20 Litsea species, covering aporphine, proaporphine, 1-benzylisoquinoline, morphinane, phenanthrene, and dibenzopyrrocoline (Table S4 and Fig. S4). Alkaloids mainly exist in L. cubeba, and hitherto 23 alkaloids have been isolated from this species. In addition, L. glutinosa, Litsea rotundifolia, L. rotundifolia var. oblongifolia and L. euosma are reported to be the sources of alkaloids (Xiao et al., 2006a; Yan et al., 2000; Yang et al., 2005). The aporphine alkaloids constitute the biggest group of Litsea alkaloids, and 22 aporphine alkaloids have been found in this genus. A aporphine-type alkaloid, oxonantenine (27), was recently isolated from L. cubeba (Yang et al., 2010). 3.4. Butanolides and butenolactones Fifteen butanolides and butenolactones have been found in three Litsea species (Table S5 and Fig. S5), including L. glutinosa (Agrawal et al., 2013), L. rotundifolia var. oblongifolia (Zhao et al., 2005) and L. verticillata (Zhang et al., 2005). Hydroxydihydrobovolide (28),

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

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3-epilitsenolide D2 (29), 4-hydroxy-2-methylbut-2-enolide (30), litseabutenolide (31) were isolated from the leaves and twigs of L. verticillata (Zhang et al., 2005). Recently, four butanolides (32–35) were purified from methanolic extract of L. glutinosa (Agrawal et al., 2013). 3.5. Lignans A total of 20 lignans have been discovered in four Litsea species, including L. cubeba, L. euosma, L. glutinosa and L. verticillata (Table S6 and Fig. S6). ( þ)-Epiexcelsin (36) and (þ)-50 -demethoxyepiexcelsin (37) were isolated from L. verticillata (Hoang et al., 2002). Recently, a series of lignans were obtained from L. glutinosa (Pan et al., 2010; Wang et al., 2011). 3.6. Amides Zhu and Yang (2007) firstly reported two amides N-feruloyltyramine (38) and cis-N-feruloyl-3-methoxytyramine (39) from L. cubeba. Subsequent investigations led to the isolation of five additional amides (4044) (Chen et al., 2010; Tanaka et al., 2009). Amides only occur in the plants of Litsea auriculata and L. cubeba (Table S7 and Fig. S7). 3.7. Miscellaneous constituents Many other constituents have been obtained (Tables S8  S11 and Figs. S8  S11), such as phenyl esters (45 47) (Agrawal et al., 2013; Xiao et al., 2006b), stilbenes (48  50) (Sun and Guo, 2006), megastigamanes (Wang et al., 2011, 2012), etc. A water soluble polysaccharide, arabinoxylan (51), was isolated from green leaves of L. glutinosa (Das et al., 2013).

4. Pharmacology 4.1. Antimicrobial activity The EtOH extract of the L. glutinosa leaves was evaluated for its antibacterial effect in vitro against urinary tract infection causing pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus mirabilis, Enterococcus faecalis and Escherichia coli using the disc diffusion assay method. The extract at the concentration of 250 μg/disc displayed good inhibition against these tested pathogens with the zones of inhibition ranging from 8.1 mm to 11.8 mm (Arora and Kaur, 2007). Mandal et al. (2000) have investigated antibacterial effect of MeOH extract from the bark of L. glutinosa against 16 bacteria using the agar diffusion method. This MeOH extract inhibited both Gram-positive and Gram-negative bacteria, with the zones of inhibition in the range of 6.5–13.5 mm, which was comparable to the positive control chloramphenicol. The EtOH extract of stem and bark of Litsea populifolia demonstrated antibacterial activities against nine pathogenic bacteria with the MIC values between 8 and 125 mg/mL. The antibacterial effect of L. populifolia was further confirmed by its protective effect on the mice infected with S. aureus and E. coli in vivo (Chen and Xu, 2013). The essential oils from different parts of L. cubeba, including roots, stems, leaves, flower buds, flowers, and fruits, were tested for their antibacterial activities against six bacteria using disc diffusion and micro-broth dilution assays. The zones of inhibition and MIC values for the tested strains were in the range of 10.1– 35.0 mm and 100–1000 mg/mL (Wang and Liu, 2010). These data supported the traditional use of Litsea species for the therapy of bacterial infection related diseases, such as diarrhea, gastritis and turbid urine (Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration, 1999; Xie and Yu, 1996).

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The essential oils from the L. cubeba fruits or leaves have been evaluated for their antifungal properties in vitro. The L. cubeba leaves oil demonstrated potent inhibitory effects against eight skin pathogens, including Crytococcus neoformans, Sporothrix schenckii, Microsporum lanosum, Microsporum gypseum, Aspergillus niger, Aspergillus flavus, Rhizopus nigricans, and Chaetomium globosum, with MIC values ranging 0.03–1.0 μg/mL (Wang et al., 1999). Tu et al. (1985) reported that 60% L. cubeba fruits oil emulsion completely inhibited growth of nine fungi. The L. cubeba fruits oil was tested for antifungal effects against five Candida strains with MIC values of 14.2–76.2 μg/mL in the broth microdilution method (Fang et al., 2002). The antifungal effect in vivo of the L. cubeba fruit oil has been studied using the mice infected with Candida albican. The result revealed that treatment with 40 mg/kg L. cubeba oil prolonged median survival time of infected mice and reduced the colony count in the kidney of mouse (Wan et al., 2006). A series of compounds, including litseachromolaevane B (15-epieudesm-4(15)-ene-1β,6β-diol (13), litseagermacrane (14), litseaverticillols A–H (16–23), isolitseane B (24), 1,2,3,4-tetrahydro-2,5-dimethyl-8(1-methylethy)-l,2-naphthalenediol (25), oxyphyllenodiol B (26), verticillatol (15), hydroxydihydrobovolide (28), 3-epilitsenolide D2 (29), 4-hydroxy-2-methylbut-2-enolide (30), litseabutenolide (31), (þ )-epiexcelsin (36), and (þ)-50 -demethoxyepiexcelsin (37), were isolated from the leaves and twigs of L. verticillata, and subjected to the evaluation for their anti-HIV effects. These compounds inhibited the replication of HIV in HOG.R5 cells with IC50 values from 2.0 to 34.5 μg/mL (Hoang et al., 2002; Zhang et al., 2001; H.J. Zhang et al., 2003; H. Zhang et al., 2003; Zhang et al., 2005). Of these, litseaverticillol B (17) is the most active compound (H. Zhang et al., 2003). These findings provided potential leads for discovering new anti-HIV agents.

4.2. Hepatoprotection Total flavonoids of L. coreana (TFLC) mainly consist of seven flavonoids, including kaempferol (1), kaempferol-3-O-β-D-galactoside (2), kaempferol-3-O-β-D-glucoside (3), quercetin-3-O-β-D-galactoside (4), quercetin-3-O-β-D-glucoside (5), (2R,3S)-catechin (6) and (2R,3R)epicatechin (7) (Wang et al., 2009; Ye et al., 2006). TFLC was evaluated for its prevention on steatohepatitis in rats fed with high fat diet (Wang et al., 2009). Oral administration of TFLC for 4 weeks dosedependently suppressed the levels of TG, TC, FFA and LDL-C, in serum and/or liver. Noteworthily, treatment with 400 mg/kg TFLC almost blocked the formation of steatosis. Meanwhile, expression of PPARα, which was a protein associated with increased SOD and decreased MDA levels, up-regulated in TFLC-treated rat liver. Ni et al. (2006) reported that TFLC attenuated the increased level of MDA, and elevated SOD level in the fat emulsion-induced nonalcoholic steatohepatitis rat model. TFLC was also active in preventing alcoholic steatohepatitis. After treatment with TFLC for 200 and 400 mg/kg, the levels of ALT, AST, ALP, γ-GT, TG, TC, and MDA in serum and/or liver, significantly reduced, while the activities of SOD and GSH-PX were enhanced in EtOH and the fat emulsion-induced alcoholic steatohepatitis rat model (Y.Y. Wang et al., 2007). TFLC protected liver against acute alcoholic hepatic injury in mice (Lv et al., 2010). In CCl4-induced hepatic fibrosis rat model, oral administration of TFLC at doses of 200 and 400 mg/kg, reduced the levels of ALT, AST, HA, LN, CIV and PIIINP, and inhibited mRNA expression of TGF-β1 and CTGF in liver tissue (Zhu et al., 2009). Cumulative evidences confirmed that TFLC exerted hepatoprotection against nonalcoholic and alcoholic steatohepatitis, hepatic fibrosis and acute alcoholic hepatic injury. The levels of TG, TC, FFA and LDL-C in rat serum and/or liver significantly decreased by TFLC treatment (Y.Y. Wang et al., 2007, 2009). All of these data supported the traditional use of L. coreana as a hypolipidemic drug in southern China.

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

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4.3. Anti-inflammatory activity Devib and Meera (2010) have investigated anti-inflammatory activity of L. glutinosa using the rat paw edema model. The aqueous extract of L. glutinosa leaves inhibited edematous response with inhibition rates of 46%, 35%, and 43%, respectively, at a dose of 500 mg/kg body weight in carrageenan, histamine and dextrin induced rat paw edema assay. TFLC, prepared from the diethyl ether partition of L. coreana leaves, has been evaluated for its anti-inflammatory properties (Chen et al., 2004). Oral administration of TFLC at a dose of 100 mg/kg, inhibited 17% xylene-induced ear edema response in rat. TFLC was able to inhibit carrageenan-induced paw swelling and cotton ballinduced granuloma in rat at doses of 133 and 266 mg/kg. A further study indicated that TFLC suppressed the expression of inflammatory markers and mediators, such as MDA, NO, PGE2 and TNF-α, and inhibited protein levels of CHOP and GRP 78 in carrageenan-induced rat paw edema model (Zhong et al., 2013). In adjuvant-induced arthritis rat model, administration of TFLC, recovered secretory function of synoviocyte, suppressed IL-1β activity (Zhou et al., 2007), and inhibited the expression of protein MMP-9 (T.Y. Wang et al., 2007). These data supported that TFLC had a potential to be developed as an anti-inflammatory agent. Roots of L. cubeba were used to cure humans suffering from arthritis in traditional medicine (Liu, 1994; Zhang and Zhang, 1998). Oral administration of L. cubeba roots decoction relieved the swelling of ankle joint, and down-regulated TNF-α and IL-1β levels in collagen induced rat rheumatoid arthritis model (Zhang and Di, 2008). Four flavanocoumarins, isophyllocoumarin (8), isoepiphyllocoumarin (9), phyllocoumarin (10) and epiphyllocoumarin (11), were obtained from the leaves of L. coreana. Tang et al. (2013) have studied their anti-inflammatory activity. These compounds (8–11) inhibited TNF-α and IL-1 production in lipopolysaccharides activated primary mouse peritoneal macrophages at the doses of 0.2 and 0.02 mM. 4.4. Antiasthmatic activity Therapeutic effect of L. cubeba on asthma has been intimately known by local residents in many regions of China, and was confirmed by guinea-pig models in vitro and in vivo. The essential oil of L. cubeba at a concentration of 90 μg/mL inhibited histamine and/or acetylcholine induced guinea-pig tracheal smooth muscle contraction in vitro (Qian et al., 1980). A further in vivo study indicated that oral administration, intraperitoneal injection and inhalation of the essential oil of L. cubeba alleviated bronchial asthma caused by histamine and/or acetylcholine in conscious guinea-pigs (Qian et al., 1980). Yin et al. (2006) have identified citral to be the dominant component of the L. cubeba essential oil, and investigated its anti-asthma effect using two different guinea pig asthma models induced by acetylcholine and ammonia, respectively. The results demonstrated that citral was able to prolong incubation period and inhibit smooth muscle constriction induced by acetylcholine, as well as prolong the coughing incubation period and reduce coughing frequency caused by ammonia. Above data displayed therapeutic values of citral and the L. cubeba essential oil as anti-asthma agents. 4.5. Immunomodulation Arabinoxylan (51), a polysaccharide from the leaves of L. glutinosa stimulated the proliferations of splenocyte and thymocyte, and promoted NO production in macrophages at tested concentration ranging from 25 to 100 μg/mL (Das et al., 2013). Ni and Hong (2001) have studied immunomodulatory activity of polysaccharides from the roots of L. pungens using cyclophosphamide-induced immunosuppressive mice models. Polysaccharides evidently enhanced immunomodulatory functions through increase of phagocytosis for macrophages, augment

of the immune organ weights, and promotion of the lymphocyte transformation rate. TFLC demonstrated similar function on enhancement of immunity in cyclophosphamide-induced mice model (Hu et al., 2007). Furthermore, productions of immunoglobulin M and immunoglobulin G, T lymphocyte cell CD4 þ and CD8 þ , as well as the interleukin-2, a key modulator for T lymphocyte cell proliferation, were activated after oral administration with TFLC. 4.6. Anti-diabetes The aqueous extract of L. coreana apparently reduced blood glucose levels in adrenaline- and alloxan-induced rat diabetic models, with the optimal doses of 100 and 300 mg/kg, respectively (Lv et al., 2005). Later, Lv et al. (2008) investigated the hypoglycemic activity of TFLC, the active ingredients of L. coreana. TFLC decreased blood glucose levels in diabetic mice models induced by adrenaline and alloxan. Diabetic patients are commonly complicated with hyperlipoidemia. Administration of TFLC evidently reduced the serum levels of TC, TG, and LDL-C, in the streptozotocin-induced rat diabetic model (Lv et al., 2008; Sun et al., 2010), which was constituent with the finding in hepatic injury (Lv et al., 2008; Y.Y. Wang et al., 2007, 2009). A further study using insulin resistance rat with hyperlipemia indicated that TFLC increased insulin sensitivity and improved the insulin resistance (Lv et al., 2009). 4.7. Function on central nervous system The essential oil of the L. cubeba fruits, used as spice in Taiwan, demonstrated neuropharmacological effect in ICR mice (Chen et al., 2012). Treatment with this essential oil at doses of 100, 300 and 500 mg/kg extended pentobarbitone-induced mouse sleeping time by 20%, 110%, and 159%, respectively compared with the control group. Furthermore, oral administration of 500 mg/kg L. cubeba fruit oil significantly prolonged the reaction time of mice in the tail-flick test, and its analgetic effect was comparable to that of the positive control acetaminophen at a dose of 90 mg/kg. This result is consistent with the use of L. cubeba fruits for relieving pain in traditional medicines (Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration, 1999). TFLC has been evaluated for its neuroprotective effect using a focal ischemia/reperfusion injury rat model. Oral administration of TFLC (25, 50 and 100 mg/kg) evidently alleviated cerebral ischemia-induced neurological deficits and reduced infarct volume. Specially, TFLC diminished the increased levels of nitrates plus nitrites, MDA and lactate dehydrogenase, and up-regulated the reduced levels of glutathione, superoxide dismutase and catalase activity in cerebral ischemia/reperfusion injury model. The potency of TFLC at 100 mg/kg for intragastric administration was similar with that of positive control edaravone at 3 mg/kg for intraperitoneal injection (Dong et al., 2013). These findings suggested that TFLC had a potential on neuroprotection, which might be associated with its antioxidant activity (Ye et al., 2006). 4.8. Anticholelithogenic activity The essential oil of L. cubeba fruits at the concentration of 10% (w/w) demonstrated potent potency on dissolving both pigment calculus and cholesterol calculus in vitro, with the calculus dissolution ratios of 76% and 88%, respectively (Lu et al., 1988). Its anticholelithogenic activity was further confirmed by experiment using rcabbit implanted with gallstone in the gallbladder (Lu et al., 1989). Rabbits implanted with gallstone were treated with 2 mL/kg 10% (w/w) the essential oil emulsion or 0.9% NaCl solution one time a day for consecutive 14 days. It was observed that the dissolution ratios were 73% for pigment calculus, and 69% for cholesterol calculus, which were 7% and 2% in NaCl-treated group. These data

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

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indicated that the essential oil of L. cubeba fruits had a potential as anticholelithogenic agent. 4.9. Miscellaneous bioactivities L. glutinosa was evaluated for its osteoprotective effect using ovariectomized rat model (Parikh et al., 2009). ALP and TrACP have been identified to be biomarkers for osteoporosis. Oral administration of food containing 5% the bark of L. glutinosa significantly inhibited ALP and TrACP in rat, and notably improved the quality and micro-architecture of bone, which were benefit for bone remodeling. These results suggested L. glutinosa as a promising phytomedicine for the therapy of osteoporosis. The leaves of L. glutinosa were adopted for the treatment of traumatic injury in traditional medicine (Editorial Committee of Zhonghua Bencao National Traditional Chinese Herb Administration, 1999). Devib and Meera (2010) have evaluated its action on wound healing using excision and incision wound models in rat. Ointment with 4% EtOH extract of L. glutinosa leaves significantly promoted wound healing by expediting wound contracting and increasing tensile strength. This effect was even comparable with that of the positive control 0.2% w/w nitrofurazone ointment. Using ceftriaxone sodium induced intestinal dysbiosis mice model, the extracts of L. coreana were tested for their actions on ameliorating intestinal microbe dysbiosis (Wu et al., 2012). The results indicated that both aqueous and EtOH extracts were capable of regulating and improving dysbiosis of intestinal flora. However, they bore different targets: the aqueous extract regulated the aerobes on the surface of intestinal canals, while the EtOH extract coordinated the anaerobes in the depth of intestinal canal. Its function on improvement of intestinal microbe dysbiosis might be related with its traditional use for the therapy of diarrhea. Citral, the dominant constituent of the L. cubeba oil, possessed antiarrhythmic function in vivo. Oral administration of 0.2 mL/kg citral relieved BaCl2- and aconitine-induced rat arrhythmia, and inhibited CaCl2 and digoxin induced cardiac toxicity in rat (Cha et al., 1985). Hu et al. (1988) have verified citral as a cardioprotective agent because of its capacity of inhibiting platelet aggregation. This effect supported the traditional use of some Litsea plants on cardiovascular system.

5. Toxicology The oil of L. cubeba has been evaluated for its acute toxicity using mice by different research groups. Zhou et al. (1984) reported that the 50% of lethal dose (LD50) for intragastric administration was 3.25 mL/kg. Later, the LD50 for intraperitoneal injection was determined to be 381 mg/kg (Wan et al., 2006). The oil of L. cubeba is pungent for skin, leading to the skin inflammatory response of guinea pig (Tu and Zhang, 1995). Intraperitoneal administration of the essential oil of L. glauca was poisonous to mice, with a LD50 value of 0. 62 mL/kg (Zhang et al., 1985).

6. Conclusions The present review summarizes ethnomedical uses of the Litsea species in TCM, and analyzes phytochemical and pharmacological aspects of 20 medicinal plants from the genus Litsea in China. The phytochemical results indicate a significant variety of structural types of chemical constituents. Pharmacological studies indicated that these plants and ingredients possessed various biological activities, especially in the areas of antimicrobial, hepatoprotection, anti-inflammatory,

Fig. 1. Chemical structures of typical constituents isolated from the plants of Litsea species used in TCM.

Please cite this article as: Kong, D.-G., et al., The genus Litsea in traditional Chinese medicine: An ethnomedical, phytochemical and pharmacological review. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.02.020i

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antiasthmatic and anti-diabetes. To a certain extent, these data validated the application of Litsea species in TCM, and provided the evidences for the correlations between ethnomedical uses and bioscientific evaluations: ethnomedical uses for gastroenteritis, diarrhea and expelling parasite were related to antimicrobial effect; edema, arthritis, enterogastritis, and mammitis to anti-inflammatory activity; trauma and traumatic injury to antimicrobial and anti-inflammatory activities. In addition, their traditional uses for the therapies of asthma, diabetes and pain have also been verified by bioassay in vivo. Regarding the constituents contributed to therapeutic values, the findings are inadequate for survey. Significantly, TFLC has received more attention since its biological functions on anti-inflammatory, anti-diabetic, neuroprotective, and hepatoprotective aspects, and correspondingly is regarded to be substances responsible for its ethnomedical uses for diabetes and inflammation-related diseases. The toxicity of Litsea species is limited according to the reported data, and commonly possessed LD50 values higher than 300 mg/kg (or 0.6 mL/kg for essential oil) for mice in the acute toxic test. And comprehensive toxicological investigations of these plants are required in the future. Because of the limited distribution of the Litsea plants in the Southern and Southwest China, the so far ethnomedical uses of these plants are restricted, and have not been widely recognized by the residents in the north region of China. Even the representative, ‘BiCheng-Qie’, a traditional medicine record in Chinese Pharmacopoeia (2010 edition), is not extensively prescribed by the TCM doctors. Although great progresses on the phytochemistry and pharmacology of the genus Litsea have been made, there are still some areas needed to be explored to gain a better understanding of this genus. (i) Most of the pharmacological studies are conducted using crude and poorly characterized extracts of Litsea species; however, the pharmacological researches of identified compounds would be of particular significance. Hence, more bioactive components should be identified using bioactivity-guided isolation strategies, and then their possible mechanisms of action targeting on ethnomedical uses need to be illustrated. (ii) Some traditional uses of the Litsea species have been validated by modern pharmacological investigations; however, plenty of ethnomedical applications were only confirmed by cellbased bioassay in vitro, and thus further investigations in vivo using laboratory animals are required to certify their therapeutic effects. For instance, seven Litsea species were adopted for the therapy of pain (Table 1); however, this antalgic effect was not comprehensively evaluated by pharmacological methods, and the antalgic substances have not been verified. (iii) Validating the correlations of the ethnomedical uses, bioactive substances and pharmacological effects are of special importance, and is still the primary task for future research. (iv) In TCM, Bi-Cheng-Qi is commonly prescribed with multiple medical materials as compound preparations, such as Bi-Cheng-Qie-San, and Bi-Cheng-Qie-Wan, for the treatment of diseases. Thus, their synergistic or antagonistic effects still need to be explored and interpreted using pharmacological and phytochemical techniques. (v) Based on traditional application and pharmacological functions of Litsea species, research and development on crude extracts and purified compounds as dietary supplements and drugs is significant work. In conclusion, phytochemical and pharmacological data supplied some evidences for the ethnomedical uses of these Litsea species in TCM. The effectiveness provides possibilities of discovering new molecules for drug research and development, and supports the future clinical use of Litsea species in modern medicine (Fig. 1).

Acknowledgments We wish to acknowledge our funding from the NNSF of China (Nos. 31470419, 21472113, 81102319, and 81173528) and NSF of Shandong (No. ZR2014HM019).

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