Alisma Orientale: Ethnopharmacology, Phytochemistry and Pharmacology of an Important Traditional Chinese Medicine

Alisma orientale: Ethnopharmacology, Phytochemistry and Pharmacology of an Important Traditional Chinese Medicine

Zhiheng Shu,*,† Jiang Pu,‡ Ling Chen,* Yuanbin Zhang,† Khalid Rahman,§ Luping Qin* and Chengjian Zheng* *Department of Pharmacognosy, School of Pharmacy Second Military Medical University, Shanghai 200433, P.R. China †School of Pharmacy, Ningxia Medical University Yinchuan 750004, P.R. China ‡Administrative Ofﬁce, Changhai Hospital Second Military Medical University, Shanghai 200433, P.R. China §Faculty of Science, School of Biomolecular Sciences, Liverpool John Moores University, Byrom Street Liverpool L3 3AF, England, UK

Published 1 April 2016

Abstract: Alisma orientale (Sam.) Juzep. (Alismataceae) is a traditional and famous Chinese medicinal herb. Its rhizomes, which possess versatile bioactivities, are commonly used to treat oliguria, edema, gonorrhea with turbid urine, leukorrhea, diarrhea and dizziness. Approxi- mately 120 compounds have been isolated from A. orientale. Terpenoids have been identiﬁed as A. orientale’s characteristic constituents, which include protostane triterpenoids and guaiane sesquiterpenoids. The traditional medical uses of A. orientale in TCM have been evaluated in modern pharmacological studies, which have shown that A. orientale and its active constituents Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com exhibit a wide range of bioactivities, such as diuretic, anti-urolithiatic, antinephritic, anti- by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. atherosclerotic, immunomodulatory, and hepatoprotective activities. The medicinal potential of A. orientale makes it an ideal candidate for new drug development. Further studies are still required to identify its bioactive constituents, and elucidate the structure–activity relationship and detailed mechanisms of action. Additionally, the use of the other medicinal parts of A. orientale may reduce resource waste and afford novel secondary metabolites.

Keywords: Alisma orientale (Sam.) Juzep.; Ethnopharmacology; Phytochemistry; Pharma- cology; Terpenoids; Review.

⁄ Correspondence to: Dr. Chengjian Zheng and Dr. Luping Qin, Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Yangpu District, Shanghai 200433, China. Tel: (þ86) 21-8187-1305, E-mail: [email protected] (C. Zheng); Tel: (þ86) 21-8187-1309, E-mail: [email protected] (L. Qin)

227 228 Z. SHU et al.

Introduction

Alisma orientale (Sam.) Juzep. (Alismataceae) is a traditional, popular Chinese medicinal herb native to several Asian countries, including China, Korea, and Japan (Liu et al., 2010; Han et al., 2013; Lin, 2014). Alismatis rhizoma (AR) (also known as Ze Xie in Chinese and Takusha in Japanese), the dried stem tuber of A. orientale, can remove dampness and promote water metabolism, according to the theory of traditional Chinese medicine (TCM). AR has been used for centuries in China, Korea, and Japan for the treatment of various diseases, including oliguria, edema, gonorrhea with turbid urine, leukorrhea, diarrhea and dizziness (Yoneta et al., 2009; The State Pharmacopoeia Commission of P. R. China, 2010; Han et al., 2013). Recently, it was proven that A. orientale has therapeutic effects on hyperlipidemia (Dan et al., 2011), fatty liver disease (Liu et al., 2013), cancer (Huang et al., 2006), and obesity (Guo et al., 2009). A. orientale has been listed in the Pharmacopoeia of the People’s Republic of China since 1985. The components used in traditional medicine, the rhizomes, are commonly listed as an important ingredient in many TCM formulations, such as Long Dan Xie Gan Wan and Wu Ling San. Modern pharmacological studies have shown that A. orientale and its active compounds possess a wide range of bioactivities, including diuretic activities (Feng et al., 2014), anti-urolithiatic activities (Cao et al., 2003), anti-atherosclerotic activities (Xue et al., 2014), immunomodulatory activities (Matsuda et al., 1998), hepatoprotective activities (Hong et al., 2006), antinephritic activities (Hattori et al., 1998). Most of these actions support the traditional medical uses of A. orientale in TCM. Due to its versatile traditional use and promising pharmacological actions, A. orientale has been the subject of many phytochemical studies. Since 1960, more than 120 compounds have been isolated from A. orientale and identified, including terpenoids, flavonoids, polysaccharides, and other compounds. Terpenoids, including protostane triterpenoids, guaiane sesquiterpenoids and kaurane diterpenoids, are the characteristic constituents of this plant (Liu et al., 2010). Alisol B 23-acetate, a major protostane triterpenoid in A. orientale, exhibits potent bioactivity and is regarded as the official indicator for the quality control of this medicinal herb in the Pharmacopoeia of the People’s

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com Republic of China (The State Pharmacopoeia Commission of P. R. China, 2010). This paper aims to review the advances in the published ethnopharmacological, phy- by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. tochemical, pharmacological and toxicological proﬁles of A. orientale in the past decades so as to facilitate its further study and its use as a resource. Additionally, the potential for future investigations on this plant are also discussed.

Ethnopharmacology

A. orientale plays a very important role in TCM due to its versatile therapeutic properties. Dating back more than 1800 years, “Ming Yi Bie Lu”, a famous monograph of traditional Chinese medicine written in China during the Han dynasty, lists it as a “top grade” medicine. In this book, A. orientale is described as useful for the treatment of abdominal REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 229

masses based on its good diuretic properties (Tao et al., 1986). Then, in “Ben Cao Gang Mu”, the most famous classical book of Chinese material medicine, this plant was recorded to be used for the treatment of wet-swelling, stranguria and to expel heat (Li, 2007). Due to its long-term traditional use and well known efficacy, A. orientale has been listed in the Chinese Pharmacopoeia since 1985 and its rhizome has been listed as a treatment for oliguria, edema, gonorrhea with turbid urine, leukorrhea, diarrhea, and dizziness (The State Pharmacopoeia Commission of P. R. China, 2010). It is commonly used as the main component of many famous TCM formulations, and it plays a vital role (Table 1). Among TCM prescriptions, “Liu Wei Di Huang Wan”, a very famous formula in TCM, is used to invigorate the kidney and nourish yin. “Long Dan Xie Gan Wan”, another famous pre- scription in TCM, has been applied to clear away liver heat and damp-heat. The rhizome of this plant is used as the effective agent in these formulations, after it is processed by bran, wine, salt, or dried by the fire, all of which may influence its clinical efficacy (Duan et al., 2004). A. orientale also has a long history of use as a folk remedy in Korea, where it is applied to inhibit hypersensitivity reactions (Lee et al., 2012) and to treat acute lung injury (Han et al., 2013). In Japan, A. orientale, also known as Takusha, is prescribed in many preparations in Kampo medicine, such as Hachimi-Jio-Gan, Saiei-to and Chorei-to (Liu et al., 2010). A. orientale is currently popular on the Japanese market and has been use to cure nephritis (Hattori et al., 1998), vertigo, and dizziness (Yoneta et al., 2009). With both medical and edible functions, A. orientale has been applied in many health care products, mixed with other medicines or with food, to treat obesity, reduce edema, and tonify the kidney and spleen. For instance, “Ze Xie Cu (vinegar)”, consists of A. orientale, fructus crataegiand sticky rice, and can be used to reduce phlegm, nourish the liver and reduce blood pressure. Another healthy beverage, “Ze Xie Tea”, which consists of A. orientale, Radix et Rhizoma Rhei and Semen Cassiae, can be used to lower lipids, promote water metabolism, reduce edema, and nourish the kidney and spleen (Yi et al., 2007).

Phytochemistry

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com Since the 1960s, extensive phytochemical studies have been carried out on A. orientale in

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. China, Japan, Korea and other countries. Based on previous reports, terpenoids are considered the main constituents of A. orientale, with protostane triterpenoids and guaiane sesquiterpenoids regarded as the characteristic compounds (Jiang et al., 2006). Protostane- type triterpenoids mainly include alisols A–I and their derivatives, while guaiane-type sesquiterpenoids include alismol, alismoxide, orientalols A–F and orentalols sulphate. A. orientale also contains small amounts of diterpenoids, ﬂavanoids, alkaloids, asparagine, phytosterols, fatty acids and resins. As the rhizome was the component traditionally used in TCM, most investigations have just focused on the chemical constituents of the rhizomes. To date, approximately 122 chemical components have been isolated and identiﬁed (Table 2). The structures of the principal constituents, including triterpenoids, diterpenoids and sesquiterpenoids, are shown in Figs. 1 and 2. Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. 3 .SHU Z. 230

Table 1. The Preparations, in Which A. orientale was the Main Component, used in TCM.

Preparation Name Main Compositions Traditional and Clinical Uses References

Ze Xie Tang Rhizoma Alismatis and Rhizoma Aatractylodis Macrocephalae Curing dizziness “Jin Kui Yao Lue”* Ze Xie Wan Rhizoma Alismatis, Radix Ophiopogonis, Semen Plantaginis, Curing diabetes and dysphoria “Tai Ping Sheng Hui Fang” Rhizoma Coptidis, Concha Ostreae, Ootheca Mantidis Vol. 53* Mu li Ze Xie San Rhizoma Alismatis, Concha Ostreae, Semen Lepidii, Sargassum, Relieving edema through diuresis “Shang Han Lun”* Radix Phytolaccae Fu Ling Ze Xie Tang Rhizoma Alismatis, Poria, Ramulus Cinnamomi, Rhizoma Curing regurgitation and polydipsia “Jin Kui Yao Lue”* Aatractylodis Macrocephalae, Rhizoma Zingiberis Recens Cang Zhu Ze Xie Wan Rhizoma Alismatis, Rhizoma Atractylodis, Fructus Aurantii Curing hemorrhoids “Jie Gu Jia Zhen”* Immaturus, Radix Gentianae Macrophyllae, Radix Sanguisorbae Zhu Ling Tang Rhizoma Alismatis, Polyporus, Poria, Talcum Nourishing Yin, clearing away heat “Chinese Pharmacopoeia”** and relieving edema

San Bai San Rhizoma Alismatis, Rhizoma Aatractylodis Macrocephalae, Tonifying spleen and relieving water “Tai Ping Hui Min He Ji Ju Fang” al. et Poria retention Vol. 2* Ze Xie San Rhizoma Alismatis, Cortex Moutan, Cortex Cinnamomi, Radix Curing consumptive disease and Qi “Tai Ping Sheng Hui Fang” Glycyrrhizae, Rhizoma Aatractylodis Macrocephalae, Poria, depression Vol. 29* Caulis Akebiae Long Dan Xie Gan Wan Rhizoma Alismatis, Radix Gentianae, Radix Bupleuri, Radix Clearing away the dampness-heat of “Chinese Pharmacopoeia”** Scutellariae, Fructus Gardenia, Caulis Akebiae, Semen the liver and gall Plantaginis, Radix Angelicae Sinensis, Radix Rehmanniae, Radix Glycyrrhizae Wu Ling San Rhizoma Alismatis, Poria, Polyporus, Cortex Cinnamomi, Nourishing Yang to transform Qi, “Chinese Pharmacopoeia”** Rhizoma Aatractylodis Macrocephalae Removing dampness and promoting water metabolism *Cited from the Website: http://www.zysj.com.cn. **Cited from (Chinese Pharmacopoeia Commission, 2010). REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 231

Table 2. Chemical Compounds Isolated from A. orientale.

No. Chemical Component Reference

Protostane triterpenes 1 Alisol A (Murata et al., 1968) 2 Alisol B (Murata et al., 1968) 3 Alisol C (Nakajima et al., 1994) 4 Alisol D (13β,17β-Epoxy-alisol B 23-acetate) (Nakajima et al., 1994) 5 Alisol E (epi-alisol A) (Murata et al., 1968) 6 Alisol F (Matsuda et al., 1999) 7 Alisol G ( 25-Anhydro-alisol A) (Matsuda et al., 1999) 8 Alisol H (Matsuda et al., 1999) 9 Alisol I (Matsuda et al., 1999) 10 Alisol O (Zhao et al., 2008) 11 Alisol P (Zhao et al., 2008) 12 Alisol X (Xu et al., 2012) 13 Alisol A 23-acetate (Makabel et al., 2008) 14 Alisol B 23-acetate (Murata et al., 1968) 15 Alisol C 23-acetate (Murata et al., 1970) 16 Alisol E 23-acetate (Yoshikawa et al., 1993a) 17 Alisol J 23-acetate (Yoshikawa et al., 1999) 18 Alisol K 23-acetate (Matsuda et al., 1999) 19 Alisol L 23-acetate (Matsuda et al., 1999) 20 Alisol M 23-acetate (Matsuda et al., 1999) 21 Alisol N 23-acetate (Matsuda et al., 1999) 22 Alisol Q 23-acetate (Jin et al., 2012) 23 Alisol A 24-acetate (Murata et al., 1968) 24 Alisol E 24-acetate (Peng and Lou, 2001b) 25 Alizexol A (Alisol F 24-acetate) (Jiang et al., 2006) 26 Alismaketone A 23-acetate (Yoshikawa et al., 1997) 27 Alismaketone B 23-acetate (Matsuda et al., 1999) 28 Alismaketone C 23-acetate (Matsuda et al., 1999) 29 Alismalactone 23-acetate (Matsuda et al., 1999) 30 3-Methylalismalactone 23-acetate (Matsuda et al., 1999) 31 Alisolide (Zhao et al., 2008) 32 11-Deoxy-alisol A (Nakajima et al., 1994) Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com 33 11-Deoxy-alisol B (Yoshikawa et al., 1993b) by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. 34 11-Deoxy-alisol C (Yoshiyasu et al., 1988) 35 11-Deoxy-alisol B 23-acetate (Yoshikawa et al., 1993b) 36 11-Deoxy-alisol C 23-acetate (Nakajima et al., 1994) 37 13β,17β-Epoxy-alisol A (Yoshikawa et al., 1993a) 38 13β,17β-Epoxy-alisol B (Nakajima et al., 1994) 39 11-Deoxy-13β,17β-epoxy-alisol A (Nakajima et al., 1994) 40 13β,17β-Epoxy-alisol A 24-acetate 41 11-Deoxy-13β,17β-epoxy-alisol B 23-acetate (Nakajima et al., 1994) 42 24-Deacetyl-alisol-O-(11-Anhydro-alisol F) (Hu et al., 2008b) 43 25-Anhydro-alisol A 11-acetate (Peng et al., 2002b) 44 25-Dehydroxy-alisol A 24-acetate (Peng et al., 2002b) 45 25-Anhydro-alisol F (Hu et al., 2008b) 46 11, 25-Anhydro-alisol F (Hu et al., 2008a) 232 Z. SHU et al.

Table 2. (Continued)

No. Chemical Component Reference 47 11,24-Dihydroxy-alisol H (Li, 2012) 48 16-Oxo-alisol A (Nakajima et al., 1994) 49 16,23-Oxido-alisol B (Nakajima et al., 1994) 50 16-Oxo-11-anhydro-alisol A (Kato et al., 1994) 51 16-Oxo-23-deoxy-alisol A (Kato et al., 1994) 52 25-O-methyl-alisol A (Nakajima et al., 1994) 53 16β-Methoxy-alisol B 23-acetate (Jin et al., 2012) 54 16β-Hydroxy-alisol B 23-acetate (Jin et al., 2012) 55 Neoalisol A (Peng et al., 2002b) Guaiane-type sesquiterpenoids 56 Orientalol A (Matsuda et al., 1999) 57 Orientalol B (Yoshikawa et al., 1994) 58 Orientalol C (Matsuda et al., 1999) 59 Orientalol D (Peng and Lou, 2001a) 60 Orientalol E (Peng et al., 2002a) 61 Orientalol F (Peng et al., 2003) 62 Orientalol E 6-acetate (Peng et al., 2003) 63 Orientanone (Peng et al., 2002c) 64 Sulfoorientalol A (Yoshikawa et al., 1993c) 65 Sulfoorientalol B (Yoshikawa et al., 1993c) 66 Sulfoorientalol C (Yoshikawa et al., 1993c) 67 Sulfoorientalol D (Yoshikawa et al., 1993c) 68 Sulfoorientalol D monoacetate (Peng et al., 2003) 69 Alismorientol A (Jiang et al., 2007) 70 Alismorientol B (Jiang et al., 2007) 71 Alismol (Peng et al., 2003) 72 Alismoxide (Peng et al., 2003) 73 10-O-Ethyl-alismoxide (Xu, 2000) 74 10-O-Methoxyl-alismoxide (Nakajima et al., 1994) 75 1(S),5(S)-Guaia-6,7en-4,10 diol (Xu, 2000) 76 1(R),5(S)-Guaia-6,7en-4,10diol (Xu, 2000) 77 Guaia-7,10epoxide-4,6-diol (Xu, 2000)

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com 78 Guaia-4,7epoxide-6ol (Xu, 2000) α α

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. 79 4 ,10 -Dihydroxy-5b-H-guaj-6-en (Zhang, 2009) 80 4β,1,2-Dihydroxyguaian-6,10-diene (Jin et al., 2012) 81 Clovandiol (Zhang, 2009) Germacrane-type sesquiterpenoids 82 Germacrene D (Matsuda et al., 1999) 83 Germacrene C (Peng et al., 2003) Eudesmane-type sesquiterpenoid 84 Eudesma-4(14)-en-1,6-diol (Nakajima et al., 1994) Oplopanane-type sesquiterpenoid 85 Oplopanone (Peng and Lou, 2001c) Diterpenes 86 16(R)-(-)Kaurane-2,12-dione (Peng and Lou, 2001b) REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 233

Table 2. (Continued)

No. Chemical Component Reference 87 Oriediterpenol (Peng and Lou, 2001b) 88 Oriediterpenoside (Peng and Lou, 2001b) Flavonoids 89 Robustaflavone (Hu et al., 2008a) 90 Amentoflavone (Hu et al., 2008a) 91 2,20,40-Trihydroxychalcone (Hu et al., 2008a) 92 Daidzein (Qiu, 2009) 93 Calycosin (Qiu, 2009) 94 7-Hydroxy-coumarin (Qiu, 2009) 95 Apigene (Qiu, 2009) 96 Luteolin (Qiu, 2009) 97 Emodin (Cai et al., 1996) Polysaccharides 98 Alisman SI (Shimizu et al., 1994) 99 Alisman PII (Tomoda et al., 1994) 100 Alisman PIIIF (Tomoda et al., 1993) Other compounds 101 β-Sitosterol (Hu et al., 2008a) 102 Falcalindiol (Xu, 2000) 103 Isoimperatorin (Xu, 2000) 104 Seselin (Xu, 2000) 105 Dulcitol (Xian et al., 1999) 106 Daucostero (Zhang, 2009) 107 Alismin (Shao et al., 2011) 108 Glycerol (Zhang, 2009) 109 Adenosine (Zhang, 2009) 110 Uridine (Zhang, 2009) 111 Adenine (Zhang, 2009) 112 α-D-Fructofuranose (Zhang, 2009) 113 β-D-Fructofuranose (Zhang, 2009) 114 Ethyl α-D-Fructofuranoside (Zhang, 2009) 115 Ethyl β-D-Fructofuranoside (Zhang, 2009) Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com 116 5-Hydroxymethyl-furaldehyde (Zhang, 2009) by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. 117 Sucrose (Zhang, 2009) 118 Raffinose (Zhang, 2009) 119 Stachyose (Zhang, 2009) 120 Verbascose (Zhang, 2009) 121 Manninotriose (Zhang, 2009) 122 Verbascotetraose (Zhang, 2009)

Triterpenoids

Triterpenoids are regarded as the principal and bioactive components of A. orientale.To date, 55 triterpenoids (1–55) have been isolated and identiﬁed, all of which belong to the protostane-type, a stereoisomer of the tetracyclic dammarane triterpenoid. Protostane 234 Z. SHU et al. Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only.

(A)

Figure 1. Chemical structures of protostane triterpenoids. REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 235 Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only.

(B)

Figure 1. (Continued) 236 Z. SHU et al. Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only.

Figure 2. Chemical structures of sesquiterpenoids and diterpenoids.

triterpenoids display many biological activities in vitro and in vivo, such as hypolipidemic (Imai et al., 1970), immunomodulatory (Kubo et al., 1997), anticancer (Huang et al., 2006), anti-HBV (Jiang et al., 2006), and antibacterial activities (Jin et al., 2012). As early as 1968, Murata et al., ﬁrst reported the isolation of alisol A (1), alisol A 24-acetate (23), alisol B (2), alisol B 23-acetate (14) and alisol E (5) from the rhizome of A. orientale (Murata et al., 1968). Later, four known compounds (1, 2, 14, and 23) and a REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 237

new compound, alisol C 24-acetate (7), were isolated from the methanol extract (ME) of rhizomes. Further biological tests revealed that these isolated compounds possessed hypocholesterolemic activities (Murata et al., 1970). Then in 1993, the ﬁrst investigation on the fresh rhizome of A. orientale led to the isolation of 11-deoxyalisol B (33) and its 23-acetate derivative (35) (Yoshikawa et al., 1993b). Alisolide (31), alisol O (10), and alisol P (11) were isolated from the rhizome in 2008 (Zhao et al., 2008). Recently, alisol Q 23-acetate (22) was isolated from the ME of A. orientale rhizomes (Jin et al., 2012). In addition, a new protostane triterpenoid, 11, 24-dihydroxy-alsol H (46), was isolated and identiﬁed from the 70% ethanol extract (EE) (Li, 2012). Of these triterpenoids, alisol B 23-acetate (14) is the most popular and it shows excellent bioactivities (Kubo et al., 1997; Matsuda et al., 1998, 1999; Huang et al., 2006). It used to characterize the quality of the A.orientale plant and its decoction pieces, with a minimum content of 0.050% and 0.040%, respectively, in the Pharmacopoeia of the People’s Republic of China (The State Pharmacopoeia Commission of P. R. China, 2010).

Sesquiterpenoids

Another main group of components of A. orientale are sesquiterpenoids, a class of terpenoids that consists of three isoprene units. A total of 30 sesquiterpenoids have been isolated from A. orientale and identiﬁed, which can be classiﬁed into four types: the guaiane-type (56–81), the germacrane-type (82–83), the eudesmane-type (84), and the oplopanane-type sesquiterpenoids (85) (Table 2).

Diterpenoids

So far, only three diterpenoids have been purified from A. orientale and identified. In 1994, kaurane-2,12-dione (86) was isolated from the rhizome of A. orientale (Nakajima et al., 1994). Then, Peng et al.(Peng and Lou, 2001b) isolated and identified two new diterpenoids, oriediterpenol (87) and oriediterpenoside (88), from the rhizome of A. orientale.

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com Flavonoids by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. 9 flavonoids have currently been purified from A. orientale and identified, including robustaflavone (89), amentoflavone (90), 2, 20, 4-Trihydroxychalcone (91), daidzein (92), calycosin (93), 7-hydroxy-coumarin (94), apigene (95), luteolin (96), emodin (97) (Cai et al., 1996; Hu et al., 2008a; Qiu, 2009).

Polysaccharides

Three polysaccharides with potential immunological properties were isolated from A. orientale. In 1993, a polysaccharide was puriﬁed from the tuber of A. orientale, namely, alisman PIIIF (100) (Tomoda et al., 1993). Then, alisman PII (99) and alisman SI (98) were isolated from A. orientale (Shimizu et al., 1994; Tomoda et al., 1994). 238 Z. SHU et al.

Other Compounds

Dulcitol (105) and daucosterol (106) were isolated from this plant in several groups (Xian et al., 1999; Zhang, 2009). Xu reported the presence of falcalindiol (102), isoimperatorin (103), and seselin (104) from this plant for the ﬁrst time (Xu, 2000). In addition, Zhang obtained eleven carbohydrates (112–122) and three nucleotides (109–111) from an aqueous extract (AE) of the rhizome of A. orientale (Zhang, 2009). A novel lectin, alismin (107), which possesses antitumor activities, was isolated from fresh A. orientale rhizome in 2011 (Shao et al., 2011).

Quality of Herbal Materials and Extracts

During the long history of TCM utilization, our ancestors found that many factors have effects on the quality, and the clinical efﬁcacy of medicinal material. Generally, the plant habitat, harvest time, extraction methods and processing conditions, are factors that affect the content of the bioactive components in A. orientale.

Different Habitats

A. orientale is mainly distributed and cultivated in the Chinese provinces of Fujian, Jiangxi, Guangxi and Sichuan. According to a quality analysis report, the A. orientale that is planted in the Guangxi province has the highest content of alisol A 24-acetate (23) (0.1040%). However, the content of alisol B 23-acetate (14) in the A. orientale planted in the Sichuan province was the highest (0.2182%), whereas that of the plants in Guangxi province was the lowest (0.0162%). This indicates that differences in habitats may alter the proportion of the chemical compounds in A. orientale (Wu et al., 2010).

Harvest Time

Wen et al investigated the dynamic content variation of alisol B 23-acetate (14) in

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com A. orientale plants from January to April (Wen et al., 1998). The results showed that the

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. rhizomes harvested in April had more alisol B 23-acetate than those collected in the other three months, which suggests that different harvest times result in different contents of the bioactive constituents in A. orientale.

Processing Conditions

The most commonly used form of A. orientale in TCM is the cut crude drug. The Chinese Pharmacopoeia (2010 edition) records two kinds of A. orientale rhizome cut crude drugs: raw slices and stir-baked slices with salt solutions (The State Pharmacopoeia Commission of P. R. China, 2010). The latter is clinically used more often and the optimum processing procedure is set as follows: mix 2 g of salt in four times the quantity of water per 100 g slices, moisten for 10 min, and then roast at 7080C for 10 min (Zhang, 2007). REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 239

Extraction Methods

In 2007, Yang et al. analyzed the content of alisol B 23-acetate (14) in A. orientale that was extracted by four different methods (water extraction, ethanol reflux, methanol ultrasonic extraction and supercritical fluid extraction (SFE)) (Yang et al., 2007). They showed that alisol B 23-acetate was absent in the extract of the water extraction, whereas the content of alisol B 23-acetate in the extracts of ethanol reflux, methanol ultrasonic extraction and SFE were 0.26%, 0.88% and 3.44%, respectively. The optimal extracting conditions for SFE were determined as follows: a pressure of 25 Megapascal (Mpa), a temperature of 40C, a segregation pressure of 3.5 Mpa, and a segregation temperature of 35C.

Pharmacology

A. orientale has attracted widespread attention due to its promising pharmacological activities. A. orientale has traditionally been used for the treatment of oliguria, edema, gonorrhea with turbid urine, leukorrhea, diarrhea and dizziness, while modern pharmacological studies mainly focus on its diuretic, anti-urolithiatic, anti-atherosclerotic, antinephritic, immunomodulatory and hepatoprotective activities (Table 3). The diuretic activity is the principal bioactivity of A. orientale as a traditional medicine, which is supported by modern pharmacological research. An overview of its biological properties has been described in detail in the following sections.

Diuretic Activity

According to the theory of traditional Chinese medicine (TCM), A. orientale possesses an ability to remove dampness and promote water metabolism, which has been validated by its widely reported diuretic activity. A series of modern studies have conﬁrmed that A. orientale has diuretic effects (Cai et al., 1988; Wang et al., 2008; Zeng et al., 2012; Feng et al., 2014). The diuretic effects of orally administrated EE and AE of A. orientale rhizomes were evaluated in a saline-loaded rat model (Feng et al., 2014). The results indicated that EE, but not

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com AE, produced a remarkable diuretic effect. EE, at doses of 2.5, 5 and 10 mg/kg, increased the þ þ by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. urinary output and the electrolyte excretion (Na ,K and Cl ) in 6 h in a dose-dependent manner, with the urinary excretion volumes of 9%, 24%, and 27%, respectively. And the urinary excretion volume of 10 mg/kg EE in 6 h was equivalent to that of the positive drug, furosemide, at dose of 20 mg/kg. Furthermore, the diuretic effects of EE lasted longer (6 h after oral administration) than that of furosemide (3 h after oral administration). In contrast, at higher doses of 20, 40 and 80 mg/kg, EE signiﬁcantly decreased the urinary output and electrolyte excretion (Naþ and Cl) in 6 h compared to the control group (1 mL/100 g body weight of water). These results suggest that EE has a dual effect on renal function, including the promotion of diuretic activity at lower doses (2.5, 5, and 10 mg/kg) and the inhibition of diuretic activity at higher doses (20, 40, and 80 mg/kg). The mechanism for the diuretic and antidiuretic activities may be related to the inhibition and promotion of the sodium–chloride co-transporter in the renal distal tubule (Feng et al., 2014). 240 Z. SHU et al.

Table 3. The Main Bioactivities of the Extracts and Compounds from A. orientale.

Pharmacological Effective Fraction/ Possible Mechanisms Reference Actions Effective Compounds

Diuretic activity Ethanol extract Inhibit and promote the sodium– (Feng et al., 2014) chloride co-transporter in the renal distal tubule Aqueous extract Competitively bind the receptor site (Cai et al., 1988) where aldosterone inﬂuences sodium, potassium exchange and the acid absorption in the collecting tube Anti-urolithiatic A. orientale extract Inhibit OPN expression (Yasui et al., 1999) activity Active constituents of Down-regulate the bikunin mRNA (Cao et al., 2004) A. orientale expression Anti-atherosclerotic Alisma decoction Alleviate lipid deposition and decrease (Xue et al., 2014) activity the ox-LDL-induced expression of inﬂammatory cytokines through the activation of the liver X receptor alpha pathway Aqueous extracts Damage vascular endothelial cells by (Zhang, 2007)

H2O2 and ox-LDL Aqueous extracts Reduce the oxidative damage of (Xi et al., 2012) endothelial cells to improve the cell survival Antinephritic MeOH-100% MeOH Inhibit endothelin-1 synthesis in the (Hattori et al., 1998) activity fraction glomeruli Immunomodulatory Methanol extract Inhibit hemolysis associated with (Matsuda et al., 1998) activity complement activation via an antigen–antibody mediated process and antibody independent process. Hepatoprotective Methanol extract Improve antioxidation enzyme activities (Hur et al., 2007) activity and suppress lipid peroxidation Aqueous extract Improve antioxidation enzyme activities (Han et al., 2012) and suppress lipid peroxidation Alisol A and its Inhibit the secretion of HBV surface (Zhang, 2009) Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com derivatives antigen and HBV e antigen by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only.

Another human study on the diuretic activity of the AE of A. orientale (100, 500, and 1000 mg/kg) showed that it has remarkable diuretic effects on normal individuals (Wu et al., 2010). In addition, the diuretic effects of the AE of A. orientale in rabbits were investigated. The results showed that the AE of A. orientale did not show diuretic effects after oral administration, whereas it did show signiﬁcant diuretic effects after intraperito- neal injection (Xu, 2000). The above-mentioned studies suggest that different experimental subjects and different routes of administration affect the diuretic activity of A. orientale. An early diuretic mechanism study indicated that the crude extract of A. orientale acts directly on collecting renal tubular cells and has the same mechanism as that of REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 241

spironolactone: competitive binding on the receptor site where aldosterone inﬂuences the sodium, potassium exchange, and acid absorption in the collecting tube (Cai et al., 1988). A bioassay-guided isolation of the EE of A. orientale revealed that alisol A 24-monoacetate is the active component responsible for the diuretic activity of this plant (Wang et al., 2008). The results show that alisol A 24-monoacetate has a similar diuretic effect to that of EE, which promotes EE (Naþ and Kþ) to increase urinary output.

Anti-Urolithiatic Activity

Nephrolithiasis is a common clinical problem, with a lifetime prevalence of 10% in men and 5% in women (Hall, 2009). Over 80% of renal stones are caused by Calcium oxalate (CaOx) calculi (Prien and Prien, 1968). Phytotherapy has long been applied in Traditional Chinese Medicine as a treatment for kidney stones. A. orientale,an important traditional medicine, is commonly used to cure urolithiasis and has been used to prevent CaOx stone formation in China folk medicine for thousands of years. In 1995, Koide et al. selected 16 kinds of Kampou extracts that have been used to treat stone disease in both China and Japan, and tested their inhibitory activity on CaOx crystallization in vitro using western methods (Koide et al., 1995). They found that the A. orientale extracts (even at 5 μg/ml) exhibited potent inhibitory activities on CaOx crystallization in vitro, compared to the vehicle control. Then, in anin vivo study, Yasui et al. investigated the effects of takusha (Japanese name of A. orientale) on osteopontin (OPN) expression, an important stone matrix protein, and stone formation (Yasui et al., 1999). Takusha treatments signiﬁcantly decreased the formation of CaOx deposits and the OPN expression in the takusha group was rather weak (p < 0:05), compared to the stone group. The mechanism underlying this effect might lie in the inhibition of OPN expression, which has also been conﬁrmed by other groups (Mi et al., 2005). In 2004, Cao et al. evaluated the anti-urolithiatic effects of an active fraction (rich in tetracyclic triterpenoids) of A. orientale using a rat urolithiasis model, and explored the mechanism of this traditional Chinese medicine in the prevention of urinary calculi (Cao et al., 2004). In the group treated with the active constituents of A. orientale, calcium oxalate deposits in the kidney

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com and the bikunin mRNA expression levels were both signiﬁcantly lower than those in the

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. model group (p < 0:05). The inhibitory effects on renal stone formation might be related to the down-regulation of the bikunin mRNA expression. In 2003, three different extracts of A. orientale, the AE, 50% methanolic extract and 100% methanolic extract, were tested for their ability to inhibit urinary calcium oxalate stone formations. Among these three different extracts, the 50% methanolic extract showed the strongest anti-urolithiatic activity (Li et al., 2003). Further, the anti-urolithiatic activities of the three fractions (ethyl acetate, n-butanol and water fractions) of the 50% methanolic extract were investigated. The results showed that the ethyl acetate fraction had the strongest ability to inhibit urinary calcium oxalate stones formation (Cao et al., 2003). Moreover, three compounds, alisol F 24- acetate, alisol A 24-acetate and alismoxide were isolated from the ethyl acetate fraction by bioactivity-guided isolation strategies and the compounds exhibited signiﬁcant anti-urolithiatic activities (Zhou et al., 2005). 242 Z. SHU et al.

Anti-Atherosclerotic Activity

A series of studies have indicated that A. orientale exerts anti-atherosclerotic activities by regulating lipid levels, suppressing inflammatory responses, and inhibiting endothelial cell injuries (Zhang et al., 2005; Zhang, 2007; Xi et al., 2012; Xue et al., 2014). Hyperlipidemia and inflammation are dominant risk factors that can lead to atherosclerosis (Hegele, 1996). It was reported that A. orientale has lipid lowering and anti- inflammatory effects. In macrophage-derived foam cells, an alisma decoction significantly alleviated lipid deposition and decreased the oxidized low-density lipoprotein (ox-LDL) induced expression of inflammatory cytokines through the activation of the liver X receptor alpha pathway (Xue et al., 2014). In addition, an in vivo study revealed that the oral administration of the AE and alcohol extract (6 g/kg/day) of A. orientale for 10 days significantly lowered the total cholesterol and triglyceride concentrations and enhanced the high-density lipoprotein cholesterol of animals fed a high-fat diet (10% of lard oil, 2% of cholesterol, wt/wt) (Zhang et al., 2005). Vascular endothelial dysfunction plays a vital role in the pathogenesis of atherosclerosis in the early stages (Zeiher et al., 1991; Yao et al., 2015). A. orientale also exhibits

promising potential to prevent endothelial cell injuries induced by H2O2 and ox-LDL. A serum pharmacological study revealed that orally administered rat serum containing different concentrations of AE of A. orientale to Sprague–Dawley rats (at doses of 3.6 and 7.2 g/kg for 5 days), strongly elevated the cell’s viability, SOD activity and NO secretion of

vascular endothelial cells (VEC304) damaged by H2O2 or ox-LDL. A. orientale may serve as a new therapeutic agent for the treatment of vascular endothelial dysfunction and the underlying mechanisms may be related to the reduction of the oxidative damage of endothelial cells to improve the cell’s survival (Zhang, 2007; Xi et al., 2012).

Antinephritic Activity

Sairei-to, a formula composed of twelve herbal medicines (A. orientale, Polyporus umbellatus Fries, etc.), has long been used for the treatment of nephritis diseases. The anti-

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com nephritic activity of Sairei-to in rats with antiglomerular basement membrane (GBM)

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. nephritis was investigated. Sairei-to exhibited a promising antinephritic effect on nephritic rats, partially by inhibiting endothelin-1 synthesis in the glomeruli (Hattori et al., 1997). Furthermore, A. orientale (Takusha in Japanese), a principal component of the 12 herbs composing Sairei-to, was regarded as principally responsible for the inhibitory action. Additional studies have shown that oral administration of the methanol fraction (30 mg/kg) of A. orientale inhibits endothelin-1 production both in nephritic rats and in vitro and the alisols are supposed to be the antinephritic constituents (Hattori et al., 1998).

Immunomodulatory Activity

The complement system acts as the primary effector of humoral immunity and the complement system’s components can lead to immune cytolysis and immune haemolysis, REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 243

which results in a number of immune diseases, including rheumatoid arthritis, atopic dermatitis, lung fluid inflammation and atherosclerotic lesion (Abbas et al., 1994). The complement-inhibiting property of the methanol extract from the dried rhizome of A. orientale was investigated in vitro. The results showed that the methanol extract (at a concentration range of 50–200 μg/mL) exhibited a strong inhibitory activity on the hemolysis associated with complement activation via an antigen–antibody mediated process (classical pathway) and an antibody independent process (alternative pathway). Addi- tionally, six terpenoids from the methanol extract were isolated. Four triterpenoids (alisol A, alisol A monoacetate, alisol B, and alisol B monoacetate) inhibited the complement- induced hemolysis through the classical pathway, while the two sesquiterpenes (alismol and alismoxide) were ineffective, suggesting that the triterpenoids may be responsible for the anticomplementary effect (Matsuda et al., 1998). Moreover, another structure–activity relationship (SAR) study on the anticomplementary activity of the protostane-type triterpenoids revealed that the 23-hydroxyl group of those protostane-type triterpenoids may primarily contribute to their anticomplementary activity (Lee et al., 2003). Apart from the triterpenoids mentioned above, three polysaccharides (alisman PII, alisman PIII, alisman SI) isolated from A. orientale also exhibited anticomplementary activity (Shimizu et al., 1994; Matsuda et al., 1998). In vivo carbon clearance tests revealed that these three polysaccharides also exhibited significant reticuloendothelial system-potentiating activities and potent anticomplementary activities, thereby regulating the immune response (Shimizu et al., 1994; Tomoda et al., 1994). Treatment with the methanolic extract of A. orientale also inhibited nitrite (NO 2 ,a product of nitric oxide) accumulation in lipopolysaccharide (LPS) activated macrophages. The two guaiane-type sesquiterpenoids and eleven protostane-type triterpenoids isolated from the active fraction exhibited inhibition of nitric oxide (NO) production (IC50 ¼ 8:468 μM) without cytotoxic effects. Additionally, alismol and alisol F were found to suppress the inducible nitric oxide synthase (iNOS) expression, indicating that the active constituents might inhibit NO production by suppressing the up-stream signaling pathway of iNOS induction (Matsuda et al., 1999). The anti-allergic effect of A. orientale against type III hypersensitivity to methanol and

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com aqueous extracts was investigated in 1997. The results showed that the methanol extract

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. (50 and 200 mg/kg) signiﬁcantly inhibited paw swelling in the direct passive arthus re- action in rats, while the aqueous extract was ineffective. Furthermore, four triterpenoids (alisol A, alisol A acetate, alisol B and alisol B acetate) were proven to be the active ingredients. Additionally, the methanol extract of A. orientale also exhibited an inhibitory effect on type I, II, IV hypersensitivity (Kubo et al., 1997).

Hepatoprotective Activity

The hepatoprotective effect of the crude extracts from A. orientale was investigated using different animal models. The ME of A. orientale rhizome was shown to protect the rat hepatocytes against bromobenzene (BB)-induced damage in vivo. ME, at a oral dose of 500 mg/kg, mildly reduces hepatic lipid peroxide levels and partially recovers the hepatic 244 Z. SHU et al.

antioxidant enzymes, such as the hepatic epoxide hydrolase (EH) activity and glutathione S-transferase (GST) activity. Further investigation revealed that alisol B 23-acetate also prevents lipid peroxidation and regulates enzyme activities with effects similar to ME, suggesting it might be responsible for the hepatoprotective activity of ME (Hur et al., 2007). In addition, ME also exhibited a potent efficacy on the experimental nonalcoholic fatty liver disease induced by a high-fat diet (Hong et al., 2006). After ME was orally administered (150, 300 and 600 mg/kg), the serum and liver lipids markedly decreased, the oxidative stress was prevented by a lessening of lipid peroxidation and antioxidant enzymes were activated, compared to those of the model animals. The high fasting serum glucose level was reduced and insulin resistance improved. The ME treatment also markedly reduced the aminotransferase abnormalities, and morphological changes, such as liver steatosis, mixed inflammation and collagen deposition, and improved hepatomegaly. A recent systematic review on herbal medicine for fatty liver disease also indicated that A. orientale was one of the most commonly used herbs in traditional Chinese medicine for the treatment of fatty liver disease (Liu et al., 2013). An in vitro study showed that the aqueous extract of A. orientale could prevent hepatocellular injuries induced by long-chain saturated fatty acids, which may be related to the inhibition of the reactive oxygen species (ROS) generation and the suppression of the mitogen-activated protein kinases (MAPK) family protein Jun N-terminal kinase (JNK) (Han et al., 2012). In diethylene glycol-induced acute liver injury model, A. orientale also showed an obvious protective effect against liver injury (Zhu et al., 2009). A total of 41 derivatives of alisol A were synthesized and assayed for their in vitro anti- hepatitis B virus (HBV) activities and cytotoxicities in 2009. Chemical modifications were performed on the hydroxyl groups at C-11, 23, 24, 25 positions and the C-13(17) double bond of alisol A, in the structure–activity relationship study (Zhang, 2009). The results showed that 14 compounds were active against the HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion in HepG 2.2.15 cells. The most promising tetra- methoxyacetyl derivative of alisol A exhibited potent activities against the secretion of HBsAg, HBeAg and exhibited remarkable selective indices. The investigation indicates that the double bond at C-25(26) of alisol A analogues is crucial for the potent anti-HBV

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com activity. As for the dehydrated derivatives, the anti-HBV activity largely depends on the

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. size and character of the substituents on the 11, 23, 24-ester moieties. These results suggest that A. orientale and its alisols may be potential clinical candidates for the treatment of liver diseases.

Toxicity

AlthoughA. orientale has long been used as medicine and food, the systematic and comprehensive toxicity and safety investigation related to this traditional Chinese medicine are lacking. A. orientale has been generally considered safe in classical monographs of materia medica, such as “Shen Nong Ben Cao Jing”, “Ben Cao Gang Mu”, “Ming Yi Bie Lu,” etc. However, modern toxicological studies have indicated that it may cause nephrotoxicity and hepatotoxicity. Duan et al. evaluated the subchronic toxicity of the aqueous extract of REVIEW ON ALISMA ORIENTALE (SAM.) JUZEP. 245

A. orientale (Duan et al., 2004). In the study, after oral administration of A. orientale to rats for 60 days (8.3, 16.7, 33.3 g/kg bw), the content of blood urea nitrogen in the serum and the renal enzyme Y-glutamyl transpeptidase were significantly increased in the high dose group (p < 0:05). In addition, the terminal organ/body weight ratios showed that, compared to the control group, liver/body weight ratio and kidney/body weight ratio both significantly increased (p < 0:05), but no gross damage was observed in histopathological analysis. In 2013, the subchronic toxicity of the triterpenoid-enriched extract from A. orientale rhizome was investigated in Sprague–Dawley rats after it was orally administered for 90 days (Huang et al., 2013). The results indicate that the oral administration of triterpenoid-enriched extract (360, 720, and 1440 mg/kg/d) does not produce any test substance-related general organ or systemic toxicity, which was contradictory with the previously reported results in vitro (Zhao et al., 2011). Zhao et al. thought that the most nephrotoxic fraction were of small polarity, mainly containing triterpenoids, such as, alisol C, 16, 23-oxido-alisol B, and alisol O. Due to the lack of clinical trials, there are very few published studies on the clinical efficacy, toxicity or side effects of A. orientale and its constituents. Comprehensive well- controlled and double-blind clinical trials are therefore urgently needed to validate its efficacy and safety.

Conclusion

A. orientale is widely used as an herbal remedy in clinical practice in China, Korea and Japan. In traditional Chinese medicine, A. orientale has long been used for the treatment of oliguria, edema, gonorrhea with turbid urine, leukorrhea, diarrhea, dizziness, atherosclerosis and urological diseases, etc. We have documented the existing phytochemical and pharmacological research on A. orientale. The importance of collecting this information on A. orientale lies in the fact that this herb possesses versatile and potent pharmacological properties that can form a practical base for further scientiﬁc research. Several traditional uses of A. orientale have been validated by modern pharmacological studies, which focus primarily on its diuretic, anti-urolithiatic, antinephritic, antiatherosclerotic, immunomod-

Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com ulatory, and hepatoprotective activities.

by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. According to the TCM theory, A. orientale possesses the ability to promote water metabolism. The regulation of water metabolism can led to the alternation of fluid volume, osmolality and acidbase balance, while the disturbance of water metabolism can result in endocrine and metabolic disorders. The homeostasis of body fluids is preserved primarily by the kidneys. Therefore, the diuretic activity of A. orientale is consistent with the TCM theory and its traditional use. Furthermore, changes in water metabolism also affect lipid metabolism (Boyd and Binhammer, 1957; Sulakyelidze, 1965), which can affect numerous cellular processes, including cell growth, proliferation, differentiation and motility. There is increasing evidence that liver and cancer cells show specific alterations in different aspects of lipid metabolism (Santos and Schulze, 2012). This evidence could explain why a medicinal herb with the function of water metabolism can also have therapeutic effects on liver disease, hyperlipidemia, and cancer. 246 Z. SHU et al.

Due to its versatile pharmacological properties, A. orientale’s chemical profile has been the subject of a large number of studies. A total of 120 compounds, including terpenoids, flavonoids, and polysaccharides from A. orientale, have been isolated and identified. As the literature demonstrated, protostane triterpenoids and guaiane sesquiterpenoids, are the characteristic constituents of A. orientale and are responsible for most of the activities shown by A. orientale. Many compounds have been evaluated for their biological activities, and some chemicals responsible for the pharmacological properties have also been determined. Especially, a principal triterpenoid, alisol B 23-acetate, was regarded as the major bioactive constituent and used to control the quality of A. orientale, with a minimum content of 0.050% according to the Pharmacopoeia of China. However, the efficacy of this herb was mainly achieved by the synergistic effect of multiple chemical components and the quality measured by mono-content was scientifically lacking. Alisol A 24-monoacetate, another representative terpenoid, also presented notable bioactivities, specifically, diuretic activities. The determination of multiple chemical components for the quality control of this plant should be established. In traditional Chinese medicine, A. orientale is regarded to be of superior quality, with high efficacy and low toxicity, and has been used for thousands of years. However, modern toxicological studies have demonstrated that the plant may possess mild renal toxicity and hepatotoxicity following chronic administration, which remains controversial due to the inconsistencies in different studies. Detailed in vitro, in vivo and clinical studies should be encouraged to confirm and explore the possible toxicity of the ingredients and to elucidate their mechanism. In addition, the structure–activity relationship and the possible synergistic action between the bioactive compounds of the plant need to be fully elucidated before their use in clinical practice.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Nos. 81303285 and 81473328), Outstanding Youth Program of Shanghai Medical System (XYQ2013100) and “Chen Guang” project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (13CG40). Am. J. Chin. Med. 2016.44:227-251. Downloaded from www.worldscientific.com by UNIVERSITY OF CALIFORNIA @ SAN DIEGO on 04/17/16. For personal use only. References

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