Traditional uses, phytochemistry, pharmacology, toxicology and quality control of Alisma orientale (Sam.) Juzep: a 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 Ting Tian 1, Hua Chen 1, Ying-Yong Zhao n 16 17 Q1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi’an, Shaanxi 710069, PR China 18 19 20 art ic l e i nf o a b s t r a c t 21 22 Article history: Ethnopharmacological relevance: Rhizoma alismatis (simplified as RA, “Zexie” in Chinese, 泽泻) is a well23 Received 24 June 2014 known natural medicine with long history in Chinese medicine. As a traditional medicine in China, RA is 24 Received in revised form an important part of many prescriptions and has been commonly used for treating a wide range of 25 28 October 2014 ailments related to dysuria, edema, nephropathy, hyperlipidaemia, diabetes, inflammation as well as Accepted 28 October 2014 26 tumor in clinical applications. Based on scientific literatures, the present paper aims to provide Q10 27 comprehensive and up-to date information about the traditional uses, phytochemistry, pharmacology, Keywords: 28 toxicology and quality control of RA as well as critical analysis of the research. The review will provide a Rhizoma alismatis 29 new foundation and direction for the further studies of RA. Phytochemistry Materials and methods: All available information about RA was supplied by library database and 30 Pharmacology electronic search (ScienceDirect, Web of Science, Pubmed, Google Scholar, etc.). The different types of 31 Toxicology useful information were collected and arranged in corresponding part of the paper. 32 Quality control Results: Phytochemical studies showed that the main chemical composition of RA was the terpenoid 33 including sesquiterpene, diterpene and triterpene. The crude extracts and isolated compounds from RA 34 showed diverse pharmacological activities including diuretic, nephroprotective, anti-hyperlipidemic, 35 anti-atherosclerotic, anti-cancer, anti-inflammatory and anti-oxidative activities. However, high-dose 36 or long-term use of RA can lead to water-electrolyte imbalance, bloody urine, acidosis and even 37 hepatotoxicity or nephrotoxicity, which have been proven by several studies. 38 Conclusions: Pharmacological researches show RA possessing various bioactivities including diuresis, 39 nephroprotective effect, anti-hyperlipidemia, etc. However, more bioactive components especially 40 diuretic and nephroprotective compounds need to be isolated and identified, and more rigorous researches on action mechanisms are required. More experiments in vitro or in vivo and clinical studies 41 are encouraged to clarify correlation between traditional uses and modern applications, and the toxicity 42 need to be further and precisely explored. In addition, a standardized fingerprint for RA is indispensable 43 and emergent. These achievements will further expand to therapeutic potential and usage of RA and 44 provide a powerful support for clinical use. 45 & 2014 Published by Elsevier Ireland Ltd. 46 47 67 48 68 49 69 Contents 50 70 51 71 1. Traditional use and ethnopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 52 72 2. Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 53 73 2.1. Triterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 54 2.2. Diterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 74 55 2.3. Sesquiterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 75 56 3. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 76 57 3.1. Diuretic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 77 58 3.2. Hypolipidemic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 78 59 79 60 80 n 61 Corresponding author. Tel.: þ 86 29 88304569; fax: þ 86 29 88304368. 81 E-mail addresses: [email protected], [email protected] (Y.-Y. Zhao). 62 1 82 Ting Tian and Hua Chen are co-first authors. 63 83 64 http://dx.doi.org/10.1016/j.jep.2014.10.061 84 65 0378-8741/& 2014 Published by Elsevier Ireland Ltd. 85 66

Journal of Ethnopharmacology

Traditional uses, phytochemistry, pharmacology, toxicology and quality control of Alisma orientale (Sam.) Juzep: A review

Please cite this article as: Tian, T., et al., Traditional uses, phytochemistry, pharmacology, toxicology and quality control of Alisma orientale (Sam.) Juzep: A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.10.061i

T. Tian et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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3.3. 3.4. 3.5. 3.6. 3.7. 3.8.

Hypoglycemic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Inhibition of renal stone formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Immuno-enhancing activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Anti-tumor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Pharmacology of TCM formulas containing RA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.8.1. Pharmacological activity of Wulingsan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.8.2. Pharmacological activity of Liuwei Dihuang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.8.3. Pharmacological activity of Danggui-Shaoyao-San (DSS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.9. Other bioactivities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 4. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5. Analytical methods for quality control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6. Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. Traditional use and ethnopharmacology Rhizoma alismatis belongs to the Alisma genus, Alismataceae, Alismatineae, Helobiae, Monocotyledoneae of the Angiospermae. In China, six taxa i.e. Alisma canaliculatum A. Braun & C.D.Bouché, Alisma grmineum Lej., Alisma lanceolatum With., Alisma nanum D.F. Cui., Alisma plantago-aquatica L. and its subspecies Alisma plantago-aquatica subsp. orientale (Sam.) Sam. are known (Flora of China, 2011). In addition, the following seven taxa are recognized: Alisma bjoerkqvistii Tzvelev, Alisma gramineum var. graminifolia (Wahlenb.) Hendricks, Alisma juzepczukii Tzvelev, Alisma rhicnocarpum Schotsman, Alisma subcordatum Raf., Alisma triviale Pursh and Alisma wahlenbergii (Holmb.) Juz. (The Plant List, 2013). Chinese medicine Rhizoma Alismatis (RA) is the dried rhizome of the fresh plant Alisma. plantago-aquatica L. subsp. Orientale Sam., Alismataceae, which is mainly distributed in China, Russia, Japan, Mongolia and North India. Alisma orientale (Sam.) is a hard aquatic plant commonly with the habitat in South China, and its underground part is the medicinal part of RA. The fresh plant of RA can be usually found in the swamps or near the river and mainly distributed in China, Russia, Japan, Mongolia and North India. The plants are reproduced by seedling-raising, which has the characteristic of seeding in summer and harvesting in winter. In China, RA was mentioned and recorded as a high-grade drug for the first time in a drug monograph Shen Nong's Herbal Classic (Shen Nong Ben Cao Jing) that dated back to Han dynasty (Gu, 2007). It has been described in lots of Chinese ancient medical books such as Compendium of Materia Medica (Ben Cao Gang Mu in Chinese) written by Li Shizhen dated to Ming dynasty, Treatise on Cold Febrile Diseases (Shang Han Lun in Chinese) written by Zhang Zhongjing in the third century, Chinese Materia Medica (Zhong Hua Ben Cao in Chinese) etc. ( Li, 2007; Zhang, 2013b; State Administration of Traditional Chinese Medicine of the PR China, 1998 ). Chinese Materia Medica recorded that RA was a medicine to treat edema and promote urinary excretion (Chinese Materia Medica, 1998). According to Compendium of Materia Medica, it was used for

excreting dampness and eliminating edema in ancient times (Li, 2007), and used for treating dysuria and promoting water metabolism in Ben Cao Yan Yi (Kou, 1990). RA also has been used to “remove dampness and promote water metabolism” in human body according to Chinese medicinal principles (Zhou et al., 2010). Particularly, RA is widely used as an important ingredient in a number of traditional Chinese medicine (TCM) formulations for thousands of years. Such as Liu Wei Di Huang Wan, Wulingsan, Choreito, etc., these prescriptions that contained RA showed the therapeutic effects on dysuria (Ahn et al., 2012a), cystitis (Kawashima et al., 2012), diabetes (Liu et al., 2013), etc. which are mainly related to kidney and body fluid metabolism. RA was also listed in each version of Chinese Pharmacopoeia and applied for many disease treatments, such as edema, urine negative, etc. (The State Pharmacopoeia Commission of PR China. Pharmacopoeia of PR China, 2010). The historical sources and the traditional uses of RA was listed in the Table 1. Based on its traditional applications, nowadays RA is mainly applied for diuresis as well as some diseases related to renal and body fluid. As a famous TCM, RA has been widely used for treatment for diuretic, nephroprotective, anti-hyperlipidemic, anti-atherosclerotic, anti-diabetic and anti-inflammatory activities in China in recent times. RA is also a well-known medicine in other East Asian countries. Combined with other medicine, its formulations (Oryeongsan, Choreito, Liuwei Dihuang, Danggui-Shaoyao-San) have been commonly applied for the treatment of urological diseases (Ahn et al., 2012a, 2012b, 2012c), diabetes (Liu et al., 2013), hypertension (Imai et al., 1970), senile dementia (Kou et al., 2005), etc., and many other bioactivities (Kawashima et al., 2012; Kori et al., 2013) have been validated in China, Korean, Japan and other Asian countries in recent years. This review summarizes the traditional uses, phytochemistry, pharmacology, toxicology and quality control of RA on basis of the published references. The scientific gaps of RA and the next specific research challenges also have been analyzed, which is expected to

Table 1 The historical sources and the uses of Rhizoma alismatis. Historical sources

Traditional uses

References

Shen Nong's Herbal Classic Compendium of Materia Medica Treatise on Cold Febrile Diseases Chinese Materia Medica Ben Cao Yan Yi Chinese Pharmacopoeia

Promoting water metabolism Excreting dampness and eliminating edema Promoting water metabolism Treating edema and promoting urinary excretion Treating dysuria and promoting water metabolism Treating edema and urine negative

Gu, (2007) Li, (2007) Zhang, (2013b) Chinese Materia Medica, (1998) Kou, (1990) Chinese Pharmacopoeia, (2010)


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provide some references and new directions for future investigations. This review aims to highlight the utilization and the exploitation of RA as well as the opportunities for further development of its medicinal properties at local and international levels.

2. Phytochemistry From the previous researches, terpenoid was considered as the main chemical component of RA. Phytochemical studies revealed that protostane-type triterpenes and sesquiterpenes are the principal terpenes in RA (Jiang et al., 2006). Most bioactive effects of RA are attributed to its terpenoids (Hur et al., 2007). The terpenoids of RA include protostane-type triterpenes, guaiane-type sesquiterpenes and kauranetype diterpenes (Murata et al., 1970; Fukuyama et al., 1988; Yoshikawa et al., 1994c; Peng et al., 2003; Liu et al., 2010). Besides triterpenes and sesquiterpenes, diterpenes and other minor compounds were also found. Currently, 54 triterpenes, 36 sesquiterpenes, 3 diterpenes and 35 alisol have been isolated from RA (Zhu and Peng 2006; Xiao et al., 2009). Many other compounds were also discovered including polysaccharide (Tomoda et al., 1994), phenolic compounds (Zhao et al., 2012), daucosterol, uridine (Peng et al., 1999), novel lectin (Shao et al., 2011), carbohydrates (Zhang et al., 2009), protein, amino acids and some metal elements. However, current researches on phytochemistry of the RA mainly focused on the terpenoid. Studies on the other chemical components of RA such as polysaccharide or metal elements need to be more investigated. And detailed reports about extraction,

3

separation and quantitation methods of bioactive components in the RA are less. Fig. 1 2.1. Triterpenes At present, triterpenes isolated from RA are found to mainly contain protostane-type tetracyclic triterpenoids, including alisol A, alisol B, alisol C, alisol D, alisol E, alisol F, alisol G, alisol H, alisol I, alisol J, alisol K, alisol L, alisol M, alisol N, alisol O, alisol P and their derivatives. Their biosynthesis pathways in plants are shown in Fig. 2 and these triterpenes are all derived from the alisol B 23acetate which is highly content in the fresh plants (Zhu and Peng, 2006). Among these triterpenes, alisol A and its acetate, alisol B and its acetate as well as alisol C 23-acetate are initially isolated from RA in 1970 (Murata et al., 1970). Many bioactive triterpenes of RA such as alisol A and alisol A monoacetate were formed during the drying process (Yoshikawa et al., 1994a). Nucleuses of the triterpenes are shown in Fig. 3 and the individual triterpenes in RA are described in Table 2. 2.2. Diterpenes Currently, three kaurane diterpenoids including 16(R)-entkaurane-2,12-dione, oriditerpenol and oriediterpenoside have been isolated from RA. In the mid 1990s, kaurane tetracyclic diterpenoid 16(R)-ent-kaurane-2,12-dione was firstly isolated from fresh plants of RA (Nakajima et al., 1994). Then, Peng et al. isolated two new kaurane tetracyclic diterpenoids including oriditerpenol and oriediterpenoside (Peng and Lou, 2002a). The structures of these diterpenoids are shown in Fig. 4.

Fig. 1. The plant and medicinal materials (overground part (a), fresh tuber (b) and decoction pieces (c)) of Rhizoma alismatis.

OH O H

OH

OH

HO

OAc

OAc H O

H O

O O

H H O

O HO

H O

C

H O

O

O O

HO

OH

HO

O

OH

H O

O

H

Fig. 2. The pathway of biology synthesis of triterpenoids.


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Fig. 3. The nucleus of the triterpenes in Rhizoma alismatis.

2.3. Sesquiterpenes According to the previous published literatures, 36 sesquiterpenes including guaiane-type, germaerane, eudesmane and Oplopanane have been obtained from RA. Alismol and alismoxide were isolated as two kinds of guaiane-type sesquiterpenes in the early 1980s (Yoshiteru et al., 1983). In the early 1990 s, Yoshikawa et al. isolated two germaerane sesquiterpenes (germacrene C and germacrene D) and derivatives of alismol (orientalol A, B, C and sulfoorientalol A, B, C, D) for the first time (Yoshikawa et al., 1992; Yoshikawa et al., 1993a; Yoshikawa et al., 1994b). Two sesquiterpenes 10-O-methoxylalismoxide and eudesma-4(14)-en-1,6-diol from RA were isolated and identified, which were transformed from germacrene C when RA was processed (Nakajima et al., 1994). Orientalol E, orientalol F and oplopanane were considered the first group of oplopanane-skeleton isolated from RA (Peng et al., 2001). The nucleuses of the sesquiterpenes are shown in Fig. 5 and the sesquiterpenes in RA are presented in Table 3.

3. Pharmacology Recently, more and more pharmacological studies revealed RA exhibited diverse bioactivities including diuretic, hypolipidemic, hepatoprotective, hypoglycemic, anti-inflammatory and anti-tumor effects. The bioactivities of different extracts or isolated compounds from RA are summarized in Table 4. An

overview of the modern pharmacological evaluations on RA has been described in details as follows. 3.1. Diuretic activity RA, a significant diuretic agent, is commonly used to “remove dampness and promote water metabolism” according to Chinese medicinal principles (Zhou et al., 2010). Wang et al. investigated the diuretic effects of aqueous extract, ethanol extract and alisol A 24-acetate using saline-loaded rats. The results showed that the ethanol extract and alisol A 24-acetate at the dose of 20 mL/kg increased urine output significantly, but its diuretic activity was lower than hydrochlorothiazide. Both alisol A 24-acetate and hydrochlorothiazide increased the excretion of Na þ and K þ in rat (Wang et al., 2008). Further research on the diuretic activity of RA was evaluated on Sprague–Dawley rats (Wu et al., 2010). Aqueous extract of different doses (100 mg/kg, 500 mg/kg, 1000 mg/kg) were administrated to rats, then the urine was collected to record urine volume and determine concentrations of Na þ , K þ and Cl . It indicated urinary output and concentrations of Na þ , K þ and Cl were significantly increased and relative expression of kidney medulla aquaporin-2 mRNA was down-regulated by the extract. However, recent study revealed both diuretic activities and anti-diuretic effects of RA (Feng et al., 2014). Firstly, the research of the ethanol and aqueous extracts of RA were conducted on the male Sprague–Dawley rats. It showed a notable dual bioactivity


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5

1 Table 2 Triterpenes in the Rhizoma alismatis. 2 3 No. Chemical name Nucleus R R1 R2 R3 R4 R5 Reference(s) 4 5 1 Alisol B 23-acetate A O H OH H H OAc Yoshikawa et al. (1993c) 6 2 Alisol B A O H OH H H OH Murata et al., (1970) 3 Alisol C 23-acetate A O H OH H O OAc Murata et al., (1970),Zhan et al., (2008) 7 4 Alisol C A O H OH H O OH Murata et al., (1970) 8 5 11-Deoxy-alisol B A O H H H H OH Yoshikawa et al. 1993c 9 6 11-Deoxy-alisol B 23-acetate A O H H H H OAc Nakajima et al. 1994 10 7 11-Deoxy-alisol C A O H H H O OH Fukuyama et al. (1988) 8 11-Deoxy-alisol C 23-acetate A O H H H O OAc Nakajima et al. (1994) 11 16-Methyoxy-alisol 23-acetate A O H H H OCH3 OAc Peng et al. (1988) 12 Q7 9 10 16-Hethyoxy-alisol 23-acetate A O H OH H OH OAc Peng et al. (1988) 13 11 Alisol M 23-acetate A O H OH OH O OAc Yoshikawa et al. (1999) 14 12 Alisol N 23-acetate A O H OH OH H OAc Yoshikawa et al. (1999) 15 13 16β-Methoxyalisol B diacetate A O H OAc H OMe OAc Nakajima et al. (1994) 14 16β-Hydroxyalisol B-triacetate A O H OAc H OAc OAc Nakajima et al. (1994) 16 15 Alisol B diacetate A O H OAc H H OAc Murata et al., (1970) 17 16 Alismakectone A 23-acetate A OH O OH OH O Ac Yoshikawa et al. (1997) 18 17 Alisol A B OH OH OH OH H O Murata et al., (1970) 19 18 Alisol A B OH OH OAc OH H O Murata et al., (1970) 19 Alisol A 24-acetate B OH OH OH OH O O Nakajima et al. (1994); Makabel et al., (2008) 20 20 16-Oxo-alisol A B OH OH OH OMe H O Nakajima et al. (1994) 21 21 25-O-methoxy-alisol A B H O H OH O O Yoshikawa et al. (1999) 22 22 Alisol H B H OH OH OH H O Peng et al. (2002c) 23 23 11-deoxyalisol A B OH OH OH OH H O Nakajima et al. (1994) 24 24 23-O-Methylalisol A B OH OMe OH OH H O Nakajima et al. (1994) 25 11,23,25-Tri-O-alisol A B OCH2-OCH3 OCH2-OCH3 OH Nakajima et al. (1994) 25 26 Alisol A 23,24-diacetate B OH OAc OAc OH H O Nakajima et al. (1994) 26 27 Alisol E B OH OH OH OH H O Yoshikawa et al. (1993b) 27 28 Alisol E 23-acetate B OH OAc OH OH H O Yoshikawa et al. (1993b) 28 29 Alisol E 24-acetate B OH OH OAc OH H O Peng et al. (2002a) 30 13β,17β-epoxy-alisol B C H CH3 OH Fukuyama et al., (1988) 29 31 Alisol D C Ac CH3 OH Nakajima et al. (1994) 30 32 11-Deoxy-13,17-epoxy-alisol B 23-acetate C Ac CH3 H Yoshikawa et al. (1999) 31 33 11-deoxyalisol D C H CH3 H Yoshikawa et al. (1999) 32 34 Alisol D acetate C Ac CH3 OAc Fukuyama et al., (1988) 33 35 Alisol L 23-acetate D Nakajima et al. (1994) 36 13,17-Epoxy-alisol A E OH H H Nakajima et al. (1994) 34 37 11-Deoxy-13,17-epoxy-alisol A E H H H Peng et al. (2002c) 35 38 13,17-Epoxy-alisol A 24-acetate E OH H Ac Nakajima et al. (1994) 36 39 16,23-Oxido-alisol B F OH Nakajima et al. (1994) 37 40 Alisol I F H Yoshikawa et al. (1999) 41 Alisol K 23-acetate G Yoshikawa et al. (1999) 38 42 Alismalactone 23-acetate H Yoshikawa et al. (1997) 39 43 Neoalisol I H H Peng et al. (2002d) 40 44 Neoalisol 11,24-diacetate I Ac Ac Peng et al. (2002d) 41 45 Alisol F J H H Yoshikawa et al. (1993b) 42 46 Alisol F 24-acetate J Ac H Peng and Lou (2001a) Q8 47 Alisol F diacetate J Ac Ac Peng and Lou (2001b) 43 48 25-Anhydro-alisol A(Alisol G) K H H Yoshikawa et al. (1993b) 44 49 25-Anhydro-alisol A 11-acetate K Ac H Peng et al. (2002d) 45 50 25-Dehydroxy-alisol A 24-acetate K H Ac Peng et al. (2002d) 46 51 Alisol J 23-acetate L Yoshikawa et al. (1999) 52 24-deacetyl alisol O M H Zhou et al. (2008) 47 53 alisol O M Ac Zhou et al. (2008) Zhao et al. (2008) 48 54 11,25-anhydro-alisol F N Hu et al. (2008a, 2008b) 49 50 51 O O O 52 H H H 53 54 55 H HO O H O 56 H H H 57 H H 58 HO O H H H H 59 OH 60 61 16(R)-ent-kaurane-2,12-dione Oriediterpenol Oriediterpenoside 62 Fig. 4. The structures of the diterpenoids in Rhizoma alismatis. 63 64 with diuretic and anti-diuretic effects of the ethanol extract for the 2.5 mg/kg, 5 mg/kg and 10 mg/kg doses while decrease the urine 65 first time. The results showed that ethanol extract could increase output and Na þ and Cl excretion at 20 mg/kg, 40 mg/kg and þ þ 66 the urinary output and electrolyte excretion (Na , K and Cl ) at 80 mg/kg doses compared with the control group. Then, different Please cite this article as: Tian, T., et al., Traditional uses, phytochemistry, pharmacology, toxicology and quality control of Alisma orientale (Sam.) Juzep: A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.10.061i

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

CH2

H

OR

H

H

i-Pr

Me

HO

H O H

HO

Me

H

i-Pr

OH

H

i-Pr

HO

H

Me

i-Pr

H

i-Pr

i-Pr

H OR

OH

i-Pr

Me

Me

i-Pr

H

H

O

H

OR

SO2 HO

H O

H

H O

i-Pr

i-Pr

O2S

H O

H

H

H

R1 R2

CinnO

i-Pr

H O

OR Me

OH

H

i-Pr

HO

H

H

H

H

HO

HO

R

i-Pr

H

HO

i-Pr

H O

i-Pr

OR

i-Pr

H

OH OH

H

H O

i-Pr

O

H

HH OH

SO3H

O

R

HH

CH3

O

OH

OH

i-Pr

OH H O

i-Pr

H O

i-Pr

HO Me

OH

H H

i-Pr

HO

i-Pr

H OH

Fig. 5. The nucleuses of the sesquiterpenes in Rhizoma alismatis.

fractions of the ethanol extract of RA including petroleum ether, ethyl acetate, n-buthanol, and the remaining fractions were further investigated (Chen et al., 2014). The data showed that the 100 mg/kg and 400 mg/kg doses of the ethyl acetate fraction and the 12.5, 25 and 50 mg/kg doses of the n-buthanol fraction significantly increased the urinary output and K þ excretion, while the 800 mg/kg dose of ethyl acetate fraction and the 75 mg/kg and 100 mg/kg doses of n-buthanol fraction produced a remarkable decrease the excretion of urinary as well as the change of the electrolyte excretion. It indicated that the ethyl acetate fraction and the n-butanol fraction presented notable diuretic effects as well as the dual effect on renal function. It was inferred that dual effect of RA might be related to the sodium-chloride co-transporter in the renal distal convoluting tubule which was different from the positive control furosemide. The results firstly verified that RA did possess diuretic activity related to the increase of the urinary output and electrolyte excretion. However, its diuretic activity weakened with the increase of the dose, even appeared the opposite effect when the dose is large enough, which needed to be especially noticed when applied for clinic uses. However, it reminded to be explored the mechanism of this special diuretic activity of RA. 3.2. Hypolipidemic activity Several studies have revealed that RA is efficacious to treat hyperlipidaemia in animal models. Dated to 1970, experiments on

the male Sprague–Dawley JCL rats discovered the hypocholesterolemic activity of RA. The levels of the plasma and liver cholesterol in the rats were obviously lowered when oral administration alisol A-24 monoacetate at the dose of 425 mg/kg. Since the absorption of cholesterol in the rat with a thoracic duct-fistula was markedly depressed by the oral administration of alisol A-24 monoacetate, it was inferred that RA could interfere with the absorptive mechanism of cholesterol to reduce the cholesterol in rats (Imai et al., 1970). Recently, Dan and co-workers investigated the hypolipidemic effects of RA by evaluating serum lipids, liver lipids and reverse transcriptase polymerase chain reaction on mice, meanwhile serum aminotransferases and histopathological changes were also measured (Dan et al., 2011). The results showed 2.26 g/kg/d of RA decreased cholesterol and triglyceride in serum and liver, however, serum high-density lipoprotein cholesterol was elevated in hyperlipidemic mice. The histopathological results showed that adipose vacuoles in RA-treated mice liver were almost identical to those of normal control mice. Serum alanine transaminase, aspartate aminotransferase and the relative liver weight were significantly decreased in the RA-treated mice. And RA substantially decreased mRNA expressions of 3-hydroxy-3methylglutaryl coenzyme A reductase (Hmgcr), while expressions of sterol regulatory element binding factor 2 (Srebf2) and cholesterol 7α-hydroxylase (Cyp7A1) were marginally affected. It was inferred that RA might exert the effect by decreasing cholesterol synthesis in liver rather than increasing cholesterol catabolism. Another report showed that alisol monoacetate A and B could


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1 Table 3 Sesquiterpenes in the Rhizoma alismatis. 2 3 Number Chemical name Nucleus 4 5 1 Gemanacren D A 2 Alismoxide B 6 3 10-O-Methyl-alismoxide B 7 4 Alismol C 8 5 Orientalol E D 9 6 Orientalol E 6-acetate D 7 Germacrene C E 10 8 Orientalol F F 11 9 Orientalol C G 12 10 Orientalol A H 13 11 Orientalol B I 14 12 Sulfoorientalol A J 13 Sulfoorientalol B J 15 14 Sulfoorientalol C J 16 15 10-Methoxyl-alismoxide J 17 16 Orientanone K 18 17 Oplopanane L 19 18 Oplopanane acetate L 19 Anhydrooplopanone M 20 20 9β-Hydroxyanhydrooplopannone M 21 21 9α-Hydroxyanhydrooplopannone N 22 22 8α-Hydroxyanhydrooplopannone N 23 23 15-Cinnamoyloxy-oplopanone O 24 3β-Hydroxy-oplopanone P 24 3β-Acetoxy-oplopanone P 25 Q9 25 26 27 28 29 26 3α-Acetoxyoplopanone P 30 31 27 9α-Hydroxyoplopanone Q 32 28 9α-Hydroxy-oplop2112enone Q 29 Oplopanane R 33 30 α-Oplopenone S 34 31 Ent-oplopanone T 35 32 Sulfoorientalol D U 36 33 Sulfoorientalol D monoacetate U 37 34 Alismorientol A V 35 Alismorientol B W 38 36 Eudesma-4(14)-en-1,6-diol X 39 40 41 42 enhance the metabolic activity of mitochondria and increase the 43 synthesis of cholesterol at the minimum concentration of 3 μM in 44 HepG2 cell line with concentration–response relationship (Wu et 45 al., 2007). A further study was conducted on mice to explore the 46 effect of RA on anti-atherosclerosis. The result showed the RA 47 group and simvastitin group at the dose of 10-fold to human dose 48 significantly reduced total cholesterol and low-density lipopro49 tein–cholesterol in apoE gene knock-out mice and up-regulated 50 the expression of liver heparan sulfate proteoglycan compared 51 with the model group (Qin et al., 2007). Overall, RA could decrease 52 the cholesterol in mice to anti hyperlipidaemia, but studies on the 53 hypolipidemic activity were too limited to reveal the way for 54 treatment hyperlipidaemia of RA. 55 56 3.3. Hypoglycemic activity 57 58 RA has been used in therapy of diabetes in traditional folk 59 medicine of China for a long time. The hypoglycemic activity has 60 been revealed in vitro. The ethanol extract and eight isolated 61 compounds from the ethanol extract of RA were incubated with 62 3T3-L1 preadipocytes. Glucose and lipid levels in the 3T3-L1 63 adipocytes culture medium were measured to analyze α64 glucosidase inhibition. As a result, compared with the anti65 diabetic drug thiazolidinediones, the ethanol extract of RA at 66 0.5 g/kg increased glucose uptake instead of adipogenesis in 3T3-

R

7

R1

H CH3

H Ac

CH3; OH CH2SO3H; OH CHSO3H CH3; OCH3

SO3H OH H OH

H Ac H OH OH H

H OH

—OH

Reference(s) Peng et al. (2003) Oshima et al. (1983) Oshima et al. (1983) Oshima et al. (1983) Peng and Lou (2001a, 2001b) Peng and Lou (2001a) Peng et al. (2003) Peng et al. (2002b) Yoshikawa et al. (1992) Yoshikawa et al. (1992) Yoshikawa et al. (1992) Peng et al. (2003) Peng et al. (2003) Peng et al. (2003) Nakajima et al. (1994) Peng et al. (2002b) Bohlmann et al. (1982) De Bruyn et al. (1990) Bohlmann et al. (1982) Alberto Marco et al. (1993) Matsuura et al. (1992) Alberto Marco et al. (1993) Tamayo-Castillo et al. (1988) Ahmed et al. (1990) Appendino et al. (1997)

Dupre et al. (1991) —CH3 ¼ CH2

H Ac

Alberto Marco et al. (1993) Kijjoa et al. (1999) Pascual-T et al. (1983) Pascual-T et al. (1983) Kitagawa et al. (1987) Peng et al. (2003) Peng et al. (2003) Jiang et al. (2007) Jiang et al. (2007) Nakajima et al. (1994)

L1 adipocyte model, meanwhile, α-glucosidase activity was inhibited at the does of 25 μg/mL (Li and Qu, 2012). Another study reported that alisol M 23-acetate and alisol A 23-acetate of RA exerted anti-hyperglycemic effect by acting as Farnesoid X receptor (FXR) agonists. In the mammalian one-hybrid and transient transfection reporter assays, both triterpenes at 10 μM transactivated FXR to modulate promoter action including GAL4, small heterodimer partner, cholesterol 7α-hydroxylase (CYP7A1) and phospholipid transfer protein promoters in the dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid did, an endogenous FXR agonist (Lin, 2012). From the previous reports, researches on the hypoglycemic activity of RA were all conducted in vitro and it should be more and further investigated in vivo or clinically. 3.4. Inhibition of renal stone formation Inhibitory effect on renal stone formation of RA has been demonstrated by some modern pharmacological studies on rats. Mi et al. studied the effects of several active fractions of RA on urinary calcium oxalate stone formation and osteopontin expression in urolithiasis model rats, and explored the mechanism of RA on preventing urinary calculi formation (Mi et al., 2005). The rats with renal calcium oxalate stone formation were induced by oral administration of ethylene glycol and 1α-hydroxyvitamin D3 for


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Table 4 The bioactivities of extracts and compounds from Rhizoma alismatis.

Pharmacological activities

Extract/compound

Test living system

Routes of administration/ Reference(s) dose

Diuretic effect

Ethanol and aqueous extracts Alisol A 24-acetate Aqueous extract of RA The extract of RA Alisol Monoacetate A and B Terpeniod of RA Alisol A 24 monoacetate and its related compounds Ethanol extract and 8 compounds Alisol M 23-acetate and alisol A 23-acetate The extract of RA The extract of RA The extract of RA Methanol and aqueous extracts of RA 70% ethanol extract of RA

Male SD rats Male SD rats Male SD rats Male Kunming mice HepG2 cell line C 57 /BL mice

p.o. multidoses p.o. 20 mL/kg p.o. multidoses p.o. 2.26 g/kg/d 0, 3, 10, 20 μM p.o. 10-fold to human

Feng et al. (2014) Wang et al. (2008) Wu et al. (2010) Dan et al. (2011) Wu et al. (2007) Qin et al. (2007)

Male Sprague–Dawley-JCL rats

p.o. multidoses

Imai et al. (1970)

3T3-L1 adipocytes and Male SD rats HepG2 cell line Adult male Wistar rats Adult male Wistar rats in vitro rats mice and NC/Nga mice

p.o. 0.5 g/kg 10 μM p.o. 5.0 mL/kg p.o. 1 mL/d 1 g/mL p.o. multidoses i.e. and p.o. multidoses

Li et al. (2012) Lin et al. (2012) Mi et al. (2005) Cao et al. (2006) Cao et al. (2005) Kubo et al. (1997) Lee et al. (2012) Shimizu et al. (1994) Han et al. (2013) Dai et al. (1991)

Hypolipidemic activity

Hyperglycemic activity Nephroprotective effect

Immuno-enhancing activity

alisman SI

ICR-SPF male mice

i.p. 20 mg/kg

Anti-inflammatory activity

80% ethanol extract Aqueous extract

RAW 264.7 cells and C57BL/6 mice Mice and rats

Ethanol extract

Mice and C57BL/6 mice

Anti-tumor activity

95% ethanol extract Alisol B acetate Alisol B 23-acetate Four prostane-type triterpenes Alisol B Alisol B acetate

p.o. 0.3 or 1.2 g/kg/d p.o. 10 and 20 g/kg Intratracheal spraying multidoses 25 mg/mL 30 μM

MDR HepG2-DR and K562-DR cells Human prostate cancer PC-3 cells HepG2-DR and K562-DR cell lines SK-OV3, B16-F10 and HT1080 cancer cells Multidoses C666-1 cells and PC3 cells etc. 30 μmol/L human gastric cancer cell line SGC7901 30 μmol/L

Fong et al. (2007) Huang et al. (2006) Wang et al. (2004) Lee et al. (2001) Law et al., (2010) Xu et al. (2009)

Aqueous extract

RAW 264.7 cells

Kim et al. (1999)

Inhibition the production of NO

Anti-complement activity Anti-oxidative activity

Four protostane-type triterpenes Aqueous extract

Peritoneal exudate cells collected from male ddY mice in vitro HepG2 cells

Antiviral effect

Terpene derivative V-54

Infected KMB17 cells

Inhibition on angiotensin II

Aqueous extract

Antiplasmodial effect

Ethyl acetate extract and compounds

Sesquiterpenes and triterpenes from RA

Anti-hepatitis B virus activity Alisol A 24-acetate, 25-anhydroalisl A etc. Alisol B 23-acetate, alisol C 23-acetate, alisol Antibacterial activity A 24-acetate Osteoclastogenesis inhibition Alisol-B Hepatoprotective effect Methanolic extract Regulation the 5-HT3A Protostane-type triterpenoid receptors Inhibition the adipocyte Ethanol extract differentiation

Multidoses Multidoses i.p.100 μM 100 mg/mL 1 μg/mL V-54 i.e. multidoses

Plasmodium falciparum K1 strain Hep G2.2.15 cell line

Multidoses

Kim et al. (2013)

Matsuda et al., (1999) Lee et al. (2003) Han et al. (2012) Wang et al. (2010b) Makino et al., (2002) Adams et al. (2010, 2011) Jiang et al. (2006)

Eight antibiotic resistant strains

5–10 μg/mL

Jin et al. (2012)

DdY mice and C57BL/6J (B6) mice Male SD rat

i.p. 100 μM p.o. multidoses

Lee et al. (2010b) Hong et al. (2006)

Xenopus laevis frogs

Injection multidoses

Lee et al. (2010a)

OP9 cells

40 μg/mL

Park et al., (2014) Matsuda et al., (1988) Wang et al., (2010a)

Adrenergic mechanism

A sesquiterpenoid alismol

Male albino rabbits in vitro

10 4 M

Hypouricemic effect

Ethanol extract

Mice

p.o. multidoses

four weeks. Some biochemical indexes as renal tissue calcium content, 24 h urinary oxalic acid excretion, and physiological change in renal tissue were assessed. Protein as well as mRNA expression of osteopontin in renal tissues were also observed. One group of rats was treated by 4 weeks' oral administration of 5.0 mL/kg active fractions which were identified as tetracyclic triterpenoid components. After treatment, serum creatinine and blood urea nitrogen levels, renal tissue calcium content, 24 h urinary calcium excretion, crystal deposition, and the osteopontin expression in the treated rats were significantly decreased than the model group. It indicated that the active fractions of RA might prevent formation of renal calcium oxalate stone in rats by inhibiting osteopontin expression and deposition of calcium oxalate in renal tissue. Another study elucidated that the administration of 1 mL/day the active components of RA for 28 days could down-regulate the bikunin mRNA expression to reduce the

calcium oxalate formation in rat kidneys and inhibit renal stone formation in urolithiasis rat model (Cao et al., 2006). Further, an isolated tetracyclic triterpenoid exhibited a powerful inhibition of the formation of calcium oxalate calculus at the concentration of 1 g/mL with the inhibitory index of 89.43% in vitro (Cao et al., 2005). 3.5. Immuno-enhancing activity The immune-system protective activity of RA has been widely assessed on rats (Kubo et al., 1997). Methanol and aqueous extracts from RA have been screened to evaluate the inhibitory activity of type I–IV allergies. The results showed that methanol extract at 50 mg/kg, 200 mg/kg doses and six terpenes from methanol extract of RA (alisol A, alisol B, alisol A monoacetate, alisol B monoacetate, alismol and alismoxide) at


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

0.05 mmol/kg, 0.20 mmol/kg had an inhibitory effect on the direct passive Arthus reaction (a typical type III allergic in rats), where the aqoeous extract did not have. Methanol extract of RA at 200 mg/kg also could inhibited 48 h homologous passive cutaneous anaphylaxis in the type I allergic model as well as reversed cutaneous anaphylaxis in the type II allergic model. Furthermore, in the type IV allergic model, methanol extract at 200 mg/kg had an inhibitory effect on the induction phase in picryl chloride-induced contact dermatitis compared with prednisolone at 10 mg/kg. These results indicated that RA had effects on various anti-allergic reactions especially on the type III allergic reaction, and it did influence antibody-mediated allergic reactions as well as cell reaction. The 70% ethanol extract was found to significantly inhibit 5lipoxygenase-catalyzed leukotriene production from basophilic leukemia-1 cells in rat and β-hexosaminidase release by antigenstimulated RBL-2H3 cells. It also attenuated delayed-type hypersensitivity reaction in mice (Lee et al., 2012). Alisol B and its 23acetate significantly inhibited leukotriene production and βhexosaminidase release in 1–10 mM. Considering other investigations, alisol B, alisol B 23-acetate and alisol C 23-acetate significantly inhibited delayed-type hypersensitivity response after oral administration. RA showed an activity of inhibition on immediatetype as well as delayed-type hypersensitivity reactions. In addition, the ethanol extract of RA (200 mg/kg/d) was found for the first time to alleviate hapten-induced dermatitis symptoms in NC/ Nga mice. Earlier studies have isolated two polysaccharides with potential immunological activities alisman SI and alisman PII. The phagocytic index of Alisman SI, a glucan composed of D-glucose, was significantly increased when intraperitoneally injecting to male mice of the carbon clearance test at the 20 mg/kg body weight, compared with the positive control zymosan (Shimizu et al., 1994, Tomoda et al., 1994).

3.6. Anti-inflammatory activity Anti-inflammatory activity of RA was discovered in recent years. Han et al. revealed a potential anti-inflammatory function and mechanism of RA by using a lipopolysaccharide-induced acute lung injury mouse model and a murine macrophage RAW 264.7 cell line. It showed that RA ameliorated acute lung injury by suppressing neutrophil infiltration which was associated with activation of nuclear factor-erythroid-2-related factor 2 (Nrf2) activity and reduction of nuclear factor-kappa B (NF-κB) activity. Prior to inducing acute lung injury by an intranasal administration of lipopolysaccharide (0.01 g/kg), C57BL/6 mice were fed with the RA extract at the dose of 0.3 g/kg or 1.2 g/kg once a day for 14 days. The extract pre-treatment of RAW 264.7 cell suppressed NF-κB activity and the expression of its related genes including cyclooxygenase-2, interleukin-1B and inducible nitric oxide synthase. Analysis of the lungs revealed that the ethanol extract of RA pretreatment induced expression of Nrf2-regulated genes, with down-regulated expression of inflammatory gene (Han et al., 2013). Acute lung injury mice were induced via intraperitoneal injection of lipopolysaccharide to explore the anti-inflammatory effect of RA. Mice received an intratracheal spraying of different doses (3 mg/kg, 30 mg/kg and 300 mg/kg) of the RA extract to the lung 2 h after lipopolysaccharide injection. Bioluminescence imaging of transgenic NF-κB/luciferase reporter mice showed that intratracheal spraying of the extract of RA post-treatment suppressed lung inflammation. Experiments on C57BL/6 mice illustrated that posttreatment of the extract significantly improved lung inflammation. Furthermore, the extract of RA post-treatment enhanced the survival rates of mice with a lethal dose of lipopolysaccharide

9

(Kim et al., 2013). The therapeutic effect of RA on acute lung injury was ascertained. 3.7. Anti-tumor activity Nowadays the study of anti-tumor and anti-cancer drugs has already become a hot point of the field. A long-term chemotherapy may lead to the selective proliferation of multidrug resistant cancer cells. Herbal drugs were good choices for reversing multidrug resistant. In multidrug resistant HepG2-DR and K562-DR cells characterized by over-expressed P-glycoprotein, the extract of RA 25 mg/mL showed an elevated synergistic inhibitory effect when coupled with anti-cancer drugs including actinomycin D, puromycin, paclitaxel, vinblastine and doxorubicin. The RA extract showed different levels of synergism when added with different drugs, from a 10-fold increase of drug sensitivity to a compete reversal of resistance. At the same toxicity levels, the RA extract was more effective than verapamil, a P-glycoprotein inhibitor, in enhancing cellular doxorubicin accumulation and preventing the efflux of rhodamin-123 from multidrug resistant cells. It suggested that RA may contain components that are effective inhibitors of P-glycoprotein and anti-tumor (Fong et al., 2007). A recent study was conducted with alisol B 23-acetate through bio-assay guided fractionation. Alisol B 23-acetate restored the sensitivity of multidrug resistant cell lines HepG2-DR and K562DR to anti-tumor agents which took actions as multidrug resistant substrates in different ways. In multidrug resistant cells, Alisol B 23-acetate could not only restore the activity of vinblastine in causing G2/M arrest but inhibit P-glycoprotein by way of a partial non-competition when verapamil was used as a substrate. It suggested that alisol B 23-acetate could be taken as a candidate for potential multidrug resistant reversal agent (Wang et al., 2004). The 30 μmol/L dose of Alisol B could activate the autophagy by inducing calcium mobilization from internal stores through the CaMKK-AMPK-mTOR pathway. It further led to apoptotic cell death by endoplasmic reticulum stress and unfolded protein responses (Law et al., 2010). Another compound, Alisol B acetate, induced apoptotic cell death in human hormone-resistant prostate cancer PC-3 cells in a time- and concentration-dependent manner. Alisol B acetate (30 μM) could increase of sub-G1 hypodiploid cells indicating that it induced apoptotic cell death through a mechanism independence of cell cycle regulation (Huang et al., 2006). The correlation between loss of mitochondrial membrane potential and apoptotic cell death indicated mitochondria-related mechanism participated in this process. Alisol B acetate induced Bax upregulation and nuclear translocation as well as the activation of initiator caspase-8, caspase-9 and executor caspase-3, which suggested the involvement of both extrinsic and intrinsic apoptosis pathways. Alisol B acetate at a concentration of 30 μmol/L also induced apoptosis of human gastric cancer cell line SGC7901 via mitocondrial and phosphatidylinositol 3-kinases/Akt signal pathways after 24 h, 48 h and 72 h incubation, with occurrence rates of apoptotic cells of 4.36%, 14.42% and 21.16%, respectively (Xu et al., 2009). 3.8. Pharmacology of TCM formulas containing RA 3.8.1. Pharmacological activity of Wulingsan Wulingsan (WLS), consisted of Rhizoma alismatis, Poria cocos, Polyporus umbellatus and the other two drugs that dated to Song Dynasty, is used as a formula to regulate body fluid homeostasis with the activity of diuresis and nephroprotection (Chen et al., 2007; Zhao, 2013). The diuretic effects of WLS were examined in rats (Ahn et al., 2012a). The findings showed that WLS at the 100 mg/kg dose had different effects on balance of water and electrolyte through various routes of drug administration. Oral


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administration of aqueous extract of WLS (0.1 mg/kg, 1 mg/kg, 10 mg/kg) was applied to examine its diuretic effects and the results indicated that WLS induced diuresis and natriuresis via inhibiting the renin-angiotensin-aldosterone system in rats (Ahn et al., 2012b). The nephroprotective activity of WLS was evaluated on diabetic nephropathy rats (Liu et al., 2009). The researches showed WLS (2.5 g/kg/d) decreased the high level of plasma glucose in diabetic rats. It further attenuated the expression of NF-κB as well as transforming growth factor-β1 (TGF-β1) and the progressive accumulation of fibronectin in kidney of diabetic rats. In addition, WLS showed an anti-diabetic effect by reducing hyperglycemia to downregulate angiotensin receptor blocker–receptor for angiotensin receptor blocker pathway and attenuate TGF-β1 expression in diabetic glomeruli, consequently lessens extracellular matrix deposition in renal tissue. Furthermore, the effects of WLS on nucleation, growth and aggregation of calcium oxalate were studied in vitro. The results showed WLS extract at concentrations of 6.25 mg/mL, 12.5 mg/mL, 25 mg/mL, and 50 mg/mL inhibited nucleation of calcium oxalate crystallization, however, calcium oxalate aggregation could be markedly inhibited at the concentration of 50 mg/mL (Chen et al., 2007). It was reported WLS possessed effectiveness in suppressing the development of nephrocalcinosis (Liu et al., 2001). Oral administration of WLS and its individual compound (0.5 g/kg) can suppress nephrocalcinosis in rats induced by high phosphorus diet. The suppression might simple through its diuretic action. It was also indicated that WLS could effectively inhibit the formation of calcium oxalate crystal and lower the incidence of stones in rats. Oral administration of WLS at 375 mg/kg once a day for four weeks significantly reduced the severity of calcium oxalate crystal deposits in rat kidneys (Tasai et al., 2008).

3.8.2. Pharmacological activity of Liuwei Dihuang Liuwei Dihuang (LWDH), a well-known TCM prescription, comprised of Rhizoma alismatis, Rehmannia glutinosa, Poria cocos and other three crude drugs. It was first recorded in the book of “Xiaoer YaoZheng ZhiJue” in Song Dynasty. LWDH has been used in clinical treatment of various syndromes with “Kidney-Yin” deficiency for more than 1000 years. Recent studies found that LWDH had an underlying benefit for diabetic complications and had important effects on canonical Wnt/beta-catenin signaling pathway in osteoporosis as well as other bioactive effects (Chen et al., 2010; Guo et al., 2013; Liu et al., 2013; Xia et al., 2014). Liu et al. investigated the neuroprotective effect of LWDH on memory and cognition deficits in streptozotocin-induced diabetic encephalopathy rats (Liu et al., 2013). With administration of LWDH (1 g/kg, 2 g/kg, once daily, 30 days), the level of fasting blood glucose and activities of acetylcholinesterase and inducible nitric oxide synthase in hippocampus were significantly decreased, while the level of glutathione and activities of Na þ –K þ –ATP enzyme and choline acetyltransferase were increased. Meanwhile, the expressions of insulin-like growth factor 1 and brain derived neurophic factor were significantly increased, but the neural apoptosis, overexpression of caspase-3 and β-amyloid deposition in the hippocampus as well as cerebral cortex of streptozotocininduced diabetic encephalopathy were attenuated in rats. Xia et al. found that LWDH could influence canonical Wnt/betacatenin signaling pathway in osteoporosis (Xia et al., 2014). Aqueous extract of LWDH were concentrated to 2 g/mL and 20 mL/kg dose was administered to female Sprague–Dawley rats. The results showed that LWDH significantly decreased serum levels of alkaline phosphatase and osteocalcin, increased bone mineral density of femurs, and improved biomechanical capability of vertebral body in maximum loading and elastic modulus. LWDH alleviated osteoporosis induced by ovariectomy through up-

regulation of canonical Wnt/beta-catenin signaling pathway of osteoblast. The effect and mechanism of LWDH against metabolic syndrome were explored by a high-energy-diet induced mice model (Guo et al., 2013). This investigation indicated that LWDH improved metabolic syndrome by increasing insulin sensitivity and alleviating dyslipidemia, hyperglycemia and pathologic damage of fatty liver. The possible mechanism might be partly related to suppressing the appetite and decreasing the levels of inflammatory cytokines.

3.8.3. Pharmacological activity of Danggui-Shaoyao-San (DSS) Danggui-Shaoyao-San (simplified as DSS), Toki-Shakuyaku-San in Japanese and Tangkuei and Peony powder in English, was a traditional Chinese medicinal prescription that widely used in treatment of various diseases in China and Japan (Hagino 1994; Shang and Qiao, 2006). It was originally described in a medical treatise Jin Kui Yao Lue by Zhongjing Zhang in the Eastern Han Dynasty (Zhang 2013a). DDS once has been used for treating some ailments associated with gynaecopathia, Recently, several studies revealed new pharmacological activities including neuroprotective effect, hormones system regulation and senile dementia inhibition (Liu, 1993; Kou et al., 2005; Shang and Qiao, 2006). The aqueous extract of DDS was examined on the naturally aged mice for its neuroprotective effect (Kou et al., 2005). The female ICR aged mice were randomly divided into five groups and treated by oral administration with DDS at doses of 125 mg/kg, 250 mg/kg and 500 mg/kg, vitamin E 100 mg/kg and distilled water respectively. After three months' treatment, DDS at doses of 250 mg/kg and 500 mg/kg and Vitamin E significantly prolonged the step-through latency and increased the brain index to improve impaired cognitive function of the aged mice. Pretreatment with DDS at doses of 250 mg/kg and 500 mg/kg for three months increased dopamine, 5-hydroxytryptamine and norepinephrine in brains of the aged mice to modulate metabolism of monoamine neurotransmitters changing by aging while Vitamin E did not. DSS at doses of 500 mg/kg and Vitamin E 100 mg/kg exhibited obvious protection of ultra-structure of cortex damaged by aging dose-dependently. The results showed that DDS could be applied for treating senile dementia, especially Alzheimer's disease. Another study was conducted on the male ICR mice to investigate the underlying molecular mechanisms of the neuroprotective effect of DDS (Lan et al., 2012). The control group received daily subcutaneous injection of saline, while the other groups of mice received daily subcutaneous injection of D-gal at a dose of 100 mg/kg for six weeks. Meanwhile, the negative control group also as model group received distilled water orally and the positive control group while the experimental group was treated with oral administration of vitamin E of 100 mg/kg and ethanol extract of DDS at doses of 1.8 g/kg, 3.6 g/kg and 7.2 g/kg for six weeks, respectively. Compared with the control group, treatment with DDS at the doses of 3.6 g/kg, 7.2 g/kg and vitamin E significantly prolonged the latency (37.75%, 54.47% and 41.18% of d-gal-treated values, respectively) and decreased the number of errors. DDS at 3.6 g/kg and 7.2 g/kg and vitamin E significantly increased the enzyme activity in D-gal-treated mice by 14.44%, 19.01% and 16.36%, respectively. DDS (3.6 g/kg and 7.2 g/kg) and vitamin E could reverse increased malondialdehyde, carbonyl protein and glutathione in the hippocampus of D-gal-treated mice. DDS at the doses of 3.6 g/kg and 7.2 g/kg and vitamin E also could significant decrease nitric oxide level and nitric oxide synthase activity, these doses of DDS and vitamin E also could significantly increased the mean density of Bcl-2 and reduced the mean densities of Bax and caspase-3. Both DDS and vitamin E treatments


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significantly attenuated neuron apoptosis in D-gal treated mice. The results indicated that DDS could ameliorate oxidative stress induced neuronal apoptosis in the brain of the D-gal-induced senescent mice to exhibit the neuroprotective effects. A bioactive fraction JD-30 was isolated from DDS and found that intragastric infusion of DDS and JD-30 0.1 mL/10 g body weight on mice could ameliorate deterioration of cognition by blocking and disrupting the aggregation of β-amyloid to improve synaptic plasticity (Hu et al., 2010). Recent pharmacological activities have revealed DDS possessed many other bioactivities. For example, it could improve the hypertension and intrauterine growth retardation in preeclampsia rats induced by Nω-nitro-Larginine methyl ester. It affected the choline acetyltransferase activity and mitogenic activity of splenic lymphocytes in ovariectomized mice (Toriizuka et al., 2000; Takei et al., 2004). 3.9. Other bioactivities Besides above-mentioned bioactivities, recent studies revealed some new bioactivities different from traditional uses. To observe other bioactivities, many studies were conducted with crude extracts or isolated compounds from RA. The relevant biological activities of the crude extracts and compounds from RA are listed in Table 4. Based on various bioactivities, RA is commonly applied for some diseases clinically and performing beneficial effects in China. However, the correlation between traditional uses and modern clinical applications needs to be clarified properly and currently. More clinical investigations on clinical applications are required so that RA can better serve for human health. Meanwhile, the action mechanisms of RA, especially related to diuretic activity and the treatment of renal disease, should be further explored and precisely explained.

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mass spectrometry (LC–MS). Three highest toxic compounds, alisol C, 16,23-oxido-alisol B and alisol O, were detected and characterized by multi-stage mass spectrometry. Metabolomics, presenting a description of the quantitative measurement of dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification, has been widely employed to identify biomarkers that are specific indicators of damage to a particular organ (Nicholson et al., 1999). Metabolomics has been applied to evaluate drug toxicity including hepatotoxicity and nephrotoxicity (Beger et al., 2010; Zhang et al., 2012; Zhao, 2013; Zhao and Lin, 2014). A metabolomic approach was used to study the nephrotoxicity of RA in rats (Yu et al., 2011b). Urine samples were collected from control and RA-treated rats at various stages and analyzed by ultra-performance LC–MS in positive ion mode. Potential biomarkers of RA-related nephrotoxicity were identified and its toxicological mechanism was discussed. The variance of metabolic profiles between control rats and treated rats were clearly distinguished by principal components analysis, and significant changes of 13 metabolites were observed in the urine. Potential biomarkers of RA-induced nephrotoxicity were hippuric acid, creatinine, 2,8-dihydroxyquinoline, 2,8-dihydroxyquinoline-β-D-glucuronide, phenylacetylglycine, hexadecasphinganine, dihydrosphingosine, 7-methylguanin, cholic acid and ketonic bile acid. The results indicated that metabolomic analysis of urine samples can be used to predict the chronic nephrotoxicity induced by RA. It concluded that a certain compound as mentioned above did have toxicity on kidney in animals, but the 1440 mg/kg/d extract of RA showed no obvious toxicity to rats. As inferred, a Chinese medicine contains numerous different chemical components, one compound showed toxicity but plenty of compounds in the extract might be not. Synthetic action of several components might lead to a new activity. The toxicity of RA should be given enough attention, and further relevant investigations need to be performed.

4. Toxicology RA once has been commonly considered to be a traditional medicine with little toxicity in some degree. High-dose or longterm use of RA can lead to water-electrolyte imbalance, hematuria and even acidosis (Ding, 1992). However, overdose or long-term usage of RA may result in hepatotoxicity or nephrotoxicity (Xie et al., 2012). It was confirmed that the aqueous extract of RA both at the doses of 20 g/kg/d and 50 g/kg/d had no significant renal toxicity on normal rats, but could lead to the tubular and interstitial injury in rats with nephrectomy (Zhu et al., 2007). The research on the subchronic oral toxicity of the aqueous extract of RA indicated that high dose 33.3 g/kg of the extract can affect some renal function parameters, but have no effect on histopathological changes (Duan et al., 2004). The chronic toxicity research of triterpene-enriched extract of RA was conducted with Sprague– Dawley rats by oral administration. The rats were randomly divided into four groups (10 rats/sex/group) and received the doses of 0 mg/kg/d, 360 mg/kg/d, 720 mg/kg/d, and 1440 mg/kg/ d of the extract for 90 days respectively. No mortality and obvious treatment-related clinical signs as hematology, urinalysis parameters etc. were observed. Differences between treated group and control group in weight gain, food consumption, biochemistry, and relative organ weight were not considered as treatment-relation. The findings showed the extract did not produce chronic toxicity at the dose of 1440 mg/kg/d in both sexes on rats (Huang et al., 2013). However, a recent study found the components of RA possessed nephrotoxicity (Zhao et al., 2011). The nephrotoxicity of RA was shifted using MTT assay and LLC-PK1 in pigs labeled with fluorescein diacetate compared with aristolochic acid as a positive control. The compounds derived from the fraction with obvious nephrotoxicity were identified by liquid chromatography–

5. Analytical methods for quality control The chemical contents of RA vary in different areas and different times (Wen et al., 1998; Chen et al., 2013). In Chinese Pharmacopoeia, the content of alisol B 23-acetate in RA should be not less than 0.050%. With the development of modern separation and identify techniques, the determination of multiple chemical components have been widely applied for quality control of TCM (Zhao et al., 2009; Zhao et al., 2010). Several researches have been conducted using different technologies quantitatively and qualitatively to establish the fingerprint of RA with good reproducibility (Gong et al., 2007; Luo et al., 2010; Wu et al., 2011). These studies mainly focused on determination of alisol F, alisol A 24-acetate and alisol B 23-acetate instead of the determination of only alisol B 23acetate. In addition, a pharmacokinetic study was conducted to determine the alisol A and alisol A 24-acetate in rat plasma after oral administration of the extract of RA successfully (Yu et al., 2011a). However, there is still no unified method for quality control and fingerprint of RA.

6. Discussion and conclusions RA has been extensively used in China, Japan and many other countries for several centuries. It has been used as a diuretic drug for treating some diseases like edema, scanty urine and kidney stones that associated with renal and body fluid in traditional uses, and shown significant diuretic activity and potential efficiency when combined with other natural medicines such as Poria cocos, Polyporus umbellatus, etc. Pharmacological studies have demonstrated that RA


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possessed diuretic, nephroprotective, anti-tumor, immuno-enhancing, hepatoprotective, anti-inflammatory, anti-tumor and other bioactivities. Terpenes are the main chemical components of RA, and the different pharmacological activities of RA can be related to the terpenes. With long history and using experience, RA especially prescriptions containing it have been widely used on clinical applications. Overall, RA is a latent diuretic medicine with great medicinal and scientific value as well as good potential of developing new drugs. Currently, RA has become a prevalent drug for research, especially in phytochemistry, pharmacological and toxicological effects, and relevant studies have achieved great progress. However, some further issues still need to be explored. Firstly and particularly, it is noteworthy that traditional uses and ancient experience of RA showed obvious treatment of diuresis, but the relevant pharmacological studies and literatures are inadequate. Related studies are lacked to further clarify the diuretic compounds and its diuretic mechanism. Thus, more bioactive components especially diuretic compounds should be identified using bioactivity-guided isolation strategies and the possible mechanisms of action were evaluated urgently, so that the relationship between traditional uses and modern diuretic effects could be clarified properly. Secondly, current investigations primarily focused on its liposoluble components especially terpenes, but rarely involving its water-soluble components and other compositions. Studies on its water-soluble components and other compositions need to be conducted widely and deeply. Thirdly, most present pharmacological studies have been performed in animals or in vitro and current studies mainly focus on the validation of traditional uses rather than the discovery of the mechanisms. More researches in vivo and about clinical applications are required to establish the relationship between traditional uses and modern pharmacological effects. Fourthly, to ensure a full utilization of the medicinal resource, researchers can turn to the investigations on the leaves, fruit and other part of the RA, as no reports on this aspect presented. And then, more importance to the detailed investigations of the toxicity of RA should be attached, as literatures on the toxicity are rare. Lastly and importantly, because of the complex composition of Chinese medicine, it needs an unified identification of the RA in China and internationally for quality control and identification of the authenticity from different areas of the herbs. Thus, research to establish a standardized fingerprint of RA is indispensable and emergent. This paper has reviewed RA systematically and provided a comprehensive and detailed evidence for the use of this herb as the information presented in the review on the phytochemistry, pharmacology, toxicity and quality control of RA. Based on the review, besides the rich background of biological activities of RA, it still exists a large number of unaccomplished investigations as above-mentioned. We hope that this review will highlight the importance of RA and can provide new directions for researchers in the future.

Uncited references (Geng et al. (1988); Keun and Athersuch (2007); Xu et al. (2013); Matsuda et al. (1998))

Acknowledgments This study was supported by the Program for New Century Excellent Talents in University, China (No. NCET-13-0954) and Chang jiang Scholars and Innovative Research Team in University, China (No. IRT1174), National Natural Science Foundation of China, China (Nos. J1210063, 81202909, 81274025, 81001622), As a Major New Drug to

Create a Major National Science and Technology Special, China (No. 2014ZX09304-307-02), China Postdoctoral Science Foundation, China (No. 2012M521831), Key Program for the International S&T Cooperation Projects of Shaanxi Province, China (No. 2013KW31-01), Natural Science Foundation of Shaanxi Provincial Education Department, China (No. 2013JK0811) and Administration of Traditional Chinese Medicine of Shaanxi, China (No. 13-ZY006).

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