The Genus Anemarrhena Bunge: a Review on Ethnopharmacology, Phytochemistry and Pharmacology

Journal of Ethnopharmacology 153 (2014) 42–60

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Journal of Ethnopharmacology

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Review The genus Anemarrhena Bunge: A review on ethnopharmacology, phytochemistry and pharmacology

Yingli Wang a,c, Yang Dan b, Dawei Yang c, Yuli Hu c, Le Zhang a,c, Chunhong Zhang c, Hong Zhu c, Zhanhu Cui a,c, Minhui Li a,c,n, Yanze Liu b,nn a Guangxi Botanical Garden of Medicinal Plants, Nanning 530023, China b Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Beijing 100193, China c Baotou Medical College, Baotou, Inner Mongolia 014060, China article info abstract

Article history: Ethnopharmacological relevance: Anemarrhena asphodeloides Bunge. (Asparagaceae) yields Anemarrhenae Received 10 September 2013 Rhizoma, which has a long history to be used as a traditional medicine to treat various ailments, like cold- Received in revised form induced febrile disease with arthralgia, hematochezia, tidal fever and night sweats by Yin deficiency, bone- 9 February 2014 steaming, cough, and hemoptysis. It is also used as an ingredient of healthy food, wine, tea, biological Accepted 9 February 2014 toothpaste. Its importance is demonstrated by large scale to treat kinds of diseases in eastern Asian countries. Available online 17 February 2014 The aim of this review is to provide up-to-date information about phytochemistry, pharmacology, and Keywords: toxicology of Anemarrhena asphodeloides based on scientific literatures. It will build up a new foundation for Anemarrhena asphodeloides further study on mechanism and development of better therapeutic agent and healthy product from Ethnopharmacology Anemarrhena asphodeloides. Phytochemistry Material and methods: All the available information on Anemarrhena asphodeloides was collected via electronic Pharmacology search (using PubMed, SciFinder Scholar, CNKI, TPL (www.theplantlist.org), Google Scholar, Baidu Scholar, and Chemical compounds studied in this article: Web of Science). Mangiferin (Pubchem CID: 5281647) Results: Comprehensive analysis of the literatures searched through sources available above confirmed that the Neomangiferin (Pubchem CID: 6918448) ethnomedical uses of Anemarrhena asphodeloides had been recorded in China, Japan, and Korea for thousands Timosaponin BII (Pubchem CID: 53486384) fl Timosaponin AIII (Pubchem CID: 15953793) of years. The phytochemical investigation revealed the presence of steroidal saponins, avonoids, phenylpro- Sarsasapogenin (Pubchem CID: 92095) panoids, alkaloids, steroids, organic acids, anthraquinones, and others. Crude extracts and pure compounds Nyasol (Pubchem CID: 12310493) from Anemarrhena asphodeloides exhibited significant pharmacological effects on the nervous system and the Broussonin B (Pubchem CID: 5315503) blood system. They also showed valuable bioactivities, such as antitumor, anti-oxidation, anti-microbial, anti- virus, anti-inflammation, anti-osteoporosis, anti-skin aging and damage as well as other activities. Conclusions: In light of long traditional use and modern phytochemical and pharmacological studies summarized, Anemarrhena asphodeloides has demonstrated a strong potential for therapeutic and health- maintaining purposes. Both the extracts and chemical components isolated from the plant showed a wide range of biological activities. Thus more pharmacological mechanisms on main active compounds (TBII, TAIII, mangiferin and other ingredients) are necessary to be explored. In addition, as a good source of the traditional medicine, clinical studies of main therapeutic aspects (e.g. diabetes, Alzheimer's disease, Parkinson's disease, etc.), toxicity and adverse effect of Anemarrhena asphodeloides will also undoubtedly be the focus of future investigation. & 2014 Elsevier Ireland Ltd. All rights reserved.

Abbreviations: Aβ2535, amyloid β-peptide fragments 25–35; AChE, acetylcholinesterase; AP-1, activator protein-1; BDNF, brain derived neurotrophic factor; COX-2, cyclooxygenase-2; DA, dopamine; DAT, dopamine transporter; ECE-1, endothelin-converting enzyme 1; ERK, extracellular signal-regulated kinase; FRAP, ferric reducing antioxidant power; FST, forced swimming test; GDNF, glial cell-derived neurotrophic factor; 5-HT, 5-hydroxytryptamine; IL-6, Interleukin-6; Inos, inducible nitric oxide synthase; JNK, JUN N-terminal kinase; LDH, lactate dehydrogenase; LPO, lipid peroxides; MAPK, mitogen-activated protein kinase; MAO-B, monoamine oxidase B; MEK, mitogen-activated protein kinase kinase1; MIC, minimum inhibitory concentration; MMPs, matrix metalloproteinases; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-kappaB, nuclear factor kappaB; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; SAaB, Saponins from Anemarrhena asphodeloides Bunge; TAIII, timosaponin AIII; TBII, timosaponin BII; TEAC, trolox equivalent antioxidant capacity; TNF-α, tumor necrosis factor-α; TST, tail suspension test n Corresponding author at: Baotou Medical College, Baotou, Inner Mongolia 014060, China. Tel.: þ86 4727 1677 95. nn Corresponding author. Tel.: þ86 10 5783 3035. E-mail addresses: [email protected] (M. Li), [email protected] (Y. Liu). http://dx.doi.org/10.1016/j.jep.2014.02.013 0378-8741 & 2014 Elsevier Ireland Ltd. All rights reserved. Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 43

Contents

1. Introduction ...... 43 2. Botanical characterization and distribution ...... 43 3. Traditional uses and ethnopharmacology...... 44 4. Chemical constituents ...... 44 4.1. Steroidal saponins ...... 44 4.2. Flavonoids ...... 47 4.3. Phenylpropanoids ...... 48 4.4. Alkaloids ...... 48 4.5. Steroids ...... 48 4.6. Organic acids ...... 48 4.7. Anthraquinones ...... 48 4.8. Other compounds ...... 48 5. Pharmacological activities ...... 51 5.1. Nervous system activities ...... 51 5.1.1. Neuroprotective activities ...... 51 5.1.2. Alzheimer's disease ...... 51 5.1.3. Parkinson's disease ...... 52 5.1.4. Anti-depression ...... 52 5.2. Blood system activities ...... 53 5.2.1. Anti-diabetes ...... 53 5.2.2. Anti-coagulated blood ...... 54 5.2.3. Lowering blood pressure ...... 54 5.3. Antitumor ...... 54 5.4. Anti-oxidation ...... 55 5.5. Anti-microbia...... 55 5.6. Anti-virus ...... 55 5.7. Anti-inﬂammation...... 55 5.8. Anti-osteoporosis...... 56 5.9. Anti-skin aging and damage ...... 56 5.10. Other effects ...... 56 6. Toxicity...... 56 7. Conclusion...... 56 Acknowledgment ...... 57 References...... 57

1. Introduction traditional uses and ethnopharmacology, chemical constituents, pharmacological activities and toxicity of Anemarrhena asphode- Anemarrhena asphodeloides Bunge., the only species in genus loides based on scientific literatures in recent years. It will Anemarrhena Bunge. (Asparagaceae) (Chen and Nicholas, 2000), is construct a new foundation for further study on mechanism and mainly distributed in China, Mongolia and other eastern Asian development of better therapeutic agent and healthy product from countries. The rhizomes of Anemarrhena asphodeloides,Anemarrhe- Anemarrhena asphodeloides. nae Rhizoma, is known as Zhimu (Chinese: ), which is called Yanghuzi in vernacular name (Committee for the Pharmacopoeia of PR China, 2010a), Chimo in Japanese Sino-medicine (Nakashima 2. Botanical characterization and distribution et al., 1993)andJimo in Korean medicine (Jigden et al., 2010). Anemarrhena asphodeloides has been commonly used in traditional Anemarrhena asphodeloides is a perennial erect and herbaceous medicine in China, Japan, and Korea for thousands of years (Duke plant with horizontal and thickened rhizomes, which is 1 m tall, et al., 2002). The traditional curative functions of Anemarrhena 0.5 cm–1.5 cm wide and covered by the remained sheaths. The asphodeloides are to treat febrile diseases, fever, cough and diabetes, leaves are grasslike and all basal, up to 60 cm long and 2 cm wide, etc. Based on the phytochemical and pharmacological studies since gradually narrowed into afiliform in the distal part. The scape is 1930s, Anemarrhena asphodeloides is able to treat Alzheimer's erect and longer than leaves, the bract with acuminate elongated disease, Parkinson's disease, and Schizophrenia, etc. The compounds tip is ovate and small and the flower is an elongated raceme and isolated from Anemarrhena asphodeloides so far mainly include bisexual. They are always subsessile and shortly predicellate, and steroidal saponins, flavonoids, norlignans, and polysaccharides, etc. often grow solitary or in clusters of 2 or 3. Perianth is narrowly Modern pharmacological researches have confirmed that the crude funnelform up to 5–10 mm long. The flower has 3 stamens, extracts and pure compounds of Anemarrhena asphodeloides pos- versatile anthers and 3-celled ovary. The color of the flower is sessed beneficial effects on central nervous system, and can regulate pink, purple or white. The fruits are narrowly elliptic capsules with mood (Cui et al., 2007). Meanwhile, Anemarrhena asphodeloides also short beaks at apex (Chen and Nicholas, 2000). The typical displays significant inhibitory bioactivity against gastric cancer photographs of Anemarrhena asphodeloides selected are shown in (Takeda et al., 2001). In addition, Anemarrhena asphodeloides can Fig. 1. improve inflammation and prevent other diseases. Anemarrhena asphodeloides is mainly distributed in China and The aim of this review is to summarize and critically analyze Mongolia, wildly growing on hillsides, dry mountain areas or pastures up-to-date data on the botanical characterization and distribution, nearly 1500 m above sea level (Committee for the Pharmacopoeia of 44 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60

Fig. 1. Anemarrhenae asphodeloides from Compendium of Materia Medica (A), whole plant (B), and ﬂowering stems of Anemarrhenae asphodeloides (C).

PR China, 2010a). In China, it is mainly distributed in northern areas, to cure the allergic diseases (Saiki, 2002) and clear acute bron- such as Heilongjiang, Jilin, Hebei, Inner Mongolia, Shanxi, Gansu, chitis, chronic bronchitis, upper respiratory inflammation, hoarse- Henan, and Shandong provinces. Among them, Yixian county of Hebei ness, etc. (Sekiya et al., 2006). is the producing area of dao-di herbs of Anemarrhena asphodeloides, In traditional Korean medicine, the rhizomes of Anemarrhena and the medicinal material is called ‘Xilinzhimu’ which possesses high asphodeloides were exploited for the treatments of fever, dire quality (Chen et al., 2005). thirst, cough and diabetes (Seung et al., 2008). In addition, Anemarrhena asphodeloides was often cultivated in Korea for its limited wild distribution (Natural Products Research Institute, 3. Traditional uses and ethnopharmacology Seoul National University, 1998). The same prescriptions processed various usages with different The rhizomes of Anemarrhena asphodeloides have been widely cultural backgrounds in different countries and regions. Jaeum- used in traditional Chinese medicine (TCM) for more than 2000 ganghwa Tang (JGT), an oriental traditional herbal formula, has years with remarkably therapeutic effects for the treatments of been used in China (Ziyin Jianghuo Tang in Chinese), Japan (Jiin febrile diseases with high fever and thirst, heat in the lung with Koka To in Japanese), and Korea for many years (Shin et al., 2012). dry cough, consumptive fever as well as diabetes due to internal As the traditional Chinese herbal medicine, it has been used to heat and constipation. It exerted curative functions by clearing the treat immune thrombocytopenic purpura in children (Huang et al., evil-heat and purging body-fire, generating body-fluids and moist- 2013). As the traditional Japanese herbal medicine, it has been ening dryness in TCM. The earliest record in China appeared in applied in treating bronchial asthma and tuberculosis (Sekiya Shennong Bencao Jing, A.D. 300 and it was considered as a ‘Middle et al., 2003), liver function protecting effect (Kubo et al., 2004), grade’ herb (Editorial Board of China Bencao, 1999). Later, it was diabetes (Fujii et al., 2003) and anti-aging (Fujii et al., 2005). As the documented in many other well-known medicinal works, includ- traditional Korean herbal medicine, Jaeumganghwa Tang has been ing Bencao Jing Jizhu (Liang Dynasty, A.D. 1565), Bencao Gangmu explored for the treatments of chronic bronchitis, nephritis and (Ming Dynasty, A.D. 1590), Bencao Qiuyuan (Qing Dynasty, A.D. diabetes mellitus (Yun, et al., 2012). 1848), etc. Generally, the rhizomes of Anemarrhena asphodeloides are used directly without any processing by its function of clearing body-heat and purging internal fire, generating body-fluids and 4. Chemical constituents moistening dryness in clinic. However, when it was used to drain fire in the kidney, Anemarrhena asphodeloides must be processed Up to now, 108 compounds have been isolated from Anemar- with brine (Health Department and National Chinese Medicine rhena asphodeloides, including steroidal saponins, flavonoids, phe- Management Office, 1999). It was recorded that Anemarrhena nylpropanoids, alkaloids, steroids, organic acids, anthraquinones, asphodeloides had been used for prevention of miscarriage and and others. Their structures were shown in Figs. 2–9. restraint of irritability during pregnancy in Yixue Qiyuan (Song Dynasty, A.D. 1127), the most famous Chinese medicine docu- 4.1. Steroidal saponins ments. According to Bencao Qiuyuan, it was used to treat hema- turia and emission (Qing Dynasty, A.D. 1488). In the Chinese The main compounds isolated from Anemarrhena asphodeloides Pharmacopoeia 2010, it has been described to have the effect are steroidal saponins and the total content in the rhizome is more on treating diabetes due to internal heat and constipation than 6% (Ji and Feng, 2010). To date, 48 steroidal saponins have (Committee for the Pharmacopoeia of PR China, 2010b). It has been isolated. According to the difference of aglycone, the steroidal also been used for the treatment of immune thrombocytopenic saponins, shown in Tables 2 and 3, can be summarized as purpura in children (Huang et al., 2013). In order to increase its spirostanol saponins and furostanol saponins (Yi et al., 1994; Ji clinical effect, Anemarrhena asphodeloides is also used as a key and Feng, 2010). Most of the spirostanol saponins (1–17)havea ingredient in combination with other Chinese herbs, such as sugar chain at C3 position, rarely at C5 or C15. Compounds (18–48) Gypsum Fibrosum, Glycyrrhizae Radix et Rhizoma, and Scutellar- are furostanol saponins, also called bides mosidic steroidal sapo- iae Radix, etc. in a number of prescriptions (Table 1). nins, which typically can bear two sugar chains at C3 and C26 In Japan, the rhizomes of Anemarrhena asphodeloides were positions of the steroidal skeleton (Cong et al., 2010; Ji and Feng, traditionally used in some prescriptions (such as Byakko Kaninjin 2010; Kang et al., 2012; Liu et al., 2013). Among these furostanol To, Biyan Tablet, Jiinshiho To, Dabuyin Pill and Qingfei Yihuo Pill, etc.) saponins, some scholars suggested that timosaponin B I (22) might Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 45

Table 1 Traditional uses of Anemarrhenae asphodeloides in China.

Preparation Compositions crude drug names (Latin names of original plants) Traditional uses References name (family/compounds)

Baihe Zhimu Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing lily disease, clearing heat and relieving ﬁdgetness. Jinkui Yaolue (Dong Tang (Asparagaceae), Lilii Bulbus (Lilium lancifolium Thunb., Lilium han Dynasty, A.D. brownii F.E.Br. ex Miellez, Lilium pumilum Delile) (Liliaceae). 300)

Baihu Tang Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Treating fever of external contraction with high fever and Shang Han Lun

(Asparagaceae), Gypsum Fibrosum (CaSO4 2H2O), Glycyrrhizae thirst. (Dong han Dynasty, Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) (Leguminosae). A.D. 200–205)

Baihu Guizhi Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing temperature abuse, veins ﬂat, scleromere ache and Jinkui Yaolue (Dong Tang (Asparagaceae), Glycyrrhizae Radix et Rhizoma (Glycyrrhiza invariably vomiting. han Dynasty, A.D. uralensis Fisch.) (Leguminosae), Gypsum Fibrosum 300)

(CaSO4 2H2O), Oryzae Fructus Germinatus (Oryza sativa L.) (Poaceae), Cinnamomi Cortex (Cinnamomum cassia (L.) J. Presl) (Lauraceae).

Baihu Renshen Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing thirst with desire for drinks, dry mouth and tongue. Jinkui Yaolue (Dong

Tang (Asparagaceae), Gypsum Fibrosum (CaSO4 2H2O), Ginseng Radix han Dynasty, A.D. et Rhizoma (Panax ginseng C. A. Mey.) (Araliaceae). 300)

Byakko Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing the allergic diseases, xerostomia. Saiki (2002); Kaninjin To (Asparagaceae), Ginseng Radix et Rhizoma (Panax ginseng C. A. Sakaguchi et al. (Baihu Jia Mey.) (Araliaceae), Glycyrrhizae Radix et Rhizoma (Glycyrrhiza (2005) Renshen uralensis Fisch.) (Leguminosae). Tang)

Biyan Tablet Xanthii Fructus (Xanthium sibiricum Patrin ex Widder) Dispel wind and remove toxic heat from the nose. List of kampo herbs (Compositae), Anemarrhenae Rhizoma (Anemarrhena 1976; Chinese asphodeloides Bge.) (Asparagaceae), Phellodendri Chinensis Pharmacopoeia Cortex (Phellodendron chinense C. K. Schneid) (Rutaceae). 2010a

Caoguo Zhimu Tsaoko Fructus (Amomum tsao-ko Crevost et Lemaire) Curing chilly feeling in back, clearing lung. Wenbing Tiaobian Tang (Zingiberaceae), Pinelliae Rhizoma (Pinellia ternata (Thunb.) Ten. (Qing Dynasty, ex Breitenb.) (Araceae), Anemarrhenae Rhizoma (Anemarrhena A.D.1798) asphodeloides Bge.) (Asparagaceae).

Dabuyin Pill Rehmanniae Radix (Rehmannia glutinosa (Gaertn.) DC.) Curing fever from Yin deﬁciency, bone-steaming and tidal List of kampo herbs (Plantaginaceae), Anemarrhenae Rhizoma (Anemarrhena fever, night sweat, cough, hemoptysis. 1976; Chinese asphodeloides Bge.) (Asparagaceae), Phellodendri Chinensis Pharmacopoeia Cortex (Phellodendron chinense C. K. Schneid) (Rutaceae), 2010a Testudinis Carapax et Plastrum (Chinemys reevesii (Gray)) (Geoemydidae)n.

Dangnyoh Pill Trichosanthis Radix (Trichosanthes kirilowii Maxim., Curing diabetes mellitus. Seung et al. (2008) Trichosanthes rosthornii Harms) (Cucurbitaceae), Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) (Asparagaceae), Ginseng Radix et Rhizoma (Panax ginseng C. A. Mey.) (Araliaceae), Puerariae Lobatae Radix (Pueraria lobata (Willd.) Ohwi) (Leguminosae), Corni Fructus (Cornus ofﬁcinalis Sieb.et Zucc.) (Cornaceae), etc.

Er Mu San Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing lung-heat. Jijiu Xianfang (Song (Asparagaceae), Fritillariae Thunbergii Bulbus (Fritillaria Dynasty, A.D. thunbergii Miq.) (Liliaceae). 960–1127)

Guizhi Shaoyao Cinnamomi Ramulus (Cinnamomum cassia (L.) J. Presl) Clearing heat and promote blood circulation to remove Jinkui Yaolue (Dong Zhimu Tang (Lauraceae), Anemarrhenae Rhizoma (Anemarrhena meridian obstruction; Expeling wind and dampness, han Dynasty, A.D. asphodeloides Bge.) (Asparagaceae), Paeoniae Radix Alba (Paeonia dizziness and shortness of breath; Curing arthralgia. 300) lactiﬂora Pall.) (Paeoniaceae), etc.

Jiinshiho To Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Clearing acute bronchitis, chronic bronchitis, upper Sekiya et al. (2006) (Ziyin Zhiba (Asparagaceae), Fritillariae Thunbergii Bulbus (Fritillaria respiratory inﬂammation, hoarseness. Tang) thunbergii Miq.) (Liliaceae), Citri Reticulatae Pericarpium (Citrus Reticulata Blanco) (Rutaceae), etc.

Jaeumganghwa Phellodendri Amurensis Cortex (Phellodendron amurence Rupr.) Curing the chronic bronchitis, antiaging and immune Shin et al. (2012) Tang (Ziyin (Rutaceae), Anemarrhenae Rhizoma (Anemarrhena asphodeloides thrombocytopenic purpura, etc. Jianghuo Bge.) (Asparagaceae), etc. Tang)

Kan Li Pill Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Nourishing kidney, reinforcing qi, eliminating Guoyi Zongzhi (Ming (Asparagaceae), Phellodendri Chinensis Cortex (Phellodendron heat in urinary bladder. Dynasty, A.D.1607) chinense C. K. Schneid.) (Rutaceae), Astragali Radix (Asrtragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, Astragalus membranaceus (Fisch.) Bge.) (Leguminosae)n.

Qingfei Yihuo Scutellariae Radix (Scutellaria baicalensis Georgi) (Lamiaceae), Removing heat from the lungs, relieving cough, resolving List of kampo herbs Pill Gardeniae Fructus (Gardenia jasminoides J. Ellis) (Rubiaceae), phlegm and relaxing the bowels. 1976; Chinese Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Pharmacopoeia (Asparagaceae), Fritillariae Thunbergii Bulbus (Fritillaria 2010a thunbergii Miq.) (Liliaceae), Phellodendri Chinensis Cortex 46 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60

Table 1 (continued )

Preparation Compositions crude drug names (Latin names of original plants) Traditional uses References name (family/compounds)

(Phellodendron chinense C. K. Schneid.) (Rutaceae), Sophorae Flavescentis Radix (Sophora flavescens Ait.) (Leguminosae), Platycodonis Radix (Platycodon grandiflorum (Jacq.) A. DC.) (Campanulaceae), Peucedani Radix (Peucedanum praeruptorum Dunn) (Apiaceae)n, Trichosanthis Radix (Trichosanthes kirilowii Maxim., Trichosanthes rosthornii Harms) (Cucurbitaceae), Rhei Radix et Rhizoma (Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., Rheum officinale Baill.) (Polygonaceae).

Sansonin To Ziziphi Spinosae Semen (Ziziphus jujuba Mill. var. Spinosa Curing asthenia of viscera, restlessness along Ushiroyama (2013) (Bunge) Hu ex H. F. Chou) (Rhamnaceae), Glycyrrhizae Radix et with chronic consumptive disease Rhimzoma (Glycyrrhiza uralensis Fisch.) (Leguminosae), Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) (Asparagaceae).

Shigao Xiebai Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing lung impairment due to dry ﬁre, aphonia, dyspnea. Sheng Hui Fang San (Asparagaceae), Mori Cortex (Morus alba L.) (Moraceae), Lycii (Song Dynasty, A.D. Cortex (Lycium chinense Mill) (Solanaceae), Glycyrrhizae Radix 992) et Rhimzoma (Glycyrrhiza uralensis Fisch.) (Leguminosae),

Gypsum Fibrosum (CaSO4 2H2O). Tong Guan Pill Phellodendri Chinensis Cortex (Phellodendron chinense C. K. Nourishing kidney, warming yang for dieresis. Pu Ji Fang (Ming Schneid.) (Rutaceae), Anemarrhenae Rhizoma (Anemarrhena Dynasty, A.D. 1390) asphodeloides Bge.) (Asparagaceae), Cinnamomi Cortex (Cinnamomum cassia (L.) J. Presl) (Lauraceae).

Yu Ye Tang Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing diabetes, intestinal dryness and constipation. Yixue Zhongzhong (Asparagaceae), Dioscoreae Rhizoma (Dioscorea opposite Thunb.) Canxi Lu (Qing (Dioscoreaceae), Puerariae Lobatae Radix (Pueraria lobata (Wild.) Dynasty, A.D. 1909) Ohwi) (Leguminosae), Astragali Radix (Asrtragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, Astragalus membranaceus (Fisch.) Bge.) (Leguminosae)n, Trichosanthis Radix (Trichosanthies kirilowii Mxim., Trichosanthies rosthornii Harms) (Cucurbitaceae).

Zhimu Tang Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing cold-induced febrile disease with arthralgia, headache, Waitai Miyao (Tang

(Asparagaceae), Gypsum Fibrosum (CaSO4 2H2O), Scutellariae eye pain and cough. Dynasty, A.D. 752) Radix (Scutellaria baicalensis Georgi) (Lamiaceae), Glycyrrhizae Radix et Rhimzoma (Glycyrrhiza uralensis Fisch.) (Leguminosae).

Zhimu Biejia Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing malaria with fever ﬁrst, chill second, anorexia. Waitai Miyao (Tang Tang (Asparagaceae), Trionycis Carapax (Trionyx sinensis Wiegmann) Dynasty, A.D. 752) (Trionychidae)n, Lycii Cortex (Lycium chinense Mill) (Solanaceae), Dichroae Radix (Dichroa febrifuga Lour.) (Hydrangeaceae), Lophatheri Herba (Lophatherum gracile Brongn.) (Poaceae),

Gypsum Fibrosum (CaSO4 2H2O). Zhimu Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing cold stomach but hot, upset, hematochezia. Bian Que Xinshu Huangqin (Asparagaceae), Scutellariae Radix (Scutellaria baicalensis Georgi) (Song Dynasty, A.D. Tang (Lamiaceae), Glycyrrhizae Radix et Rhimzoma (Glycyrrhiza 1146) uralensis Fisch.) (Leguminosae).

Zhibai Dihuang Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing bone-steaming, tidal fever and night sweats by yin Yizong Jinjian (Qing Pill (Asparagaceae), Phellodendri Chinensis Cortex (Phellodendron deﬁciency. Dynasty, A.D. 1742) chinense C. K. Schneid.) (Rutaceae), Schisandrae Chinensis Fructus (Schisandra Chinensis (Turcz.) Baill.) (Schisandraceae), Corni Fructus (Cornus ofﬁcinalis Siebold & Zucc.) (Cornaceae), Moutan Cortex (Paeonia suffruticosa Andr.) (Paeoniaceae), Poriae Cutis (Poria cocos (Schw.) Wolf) (Fomitopsidaceae)n, Alismatis Rhizoma (Alisma orientalis (Sam.) Juz.) (Alismataceae), Dioscoreae Rhizoma (Dioscorea opposita Thumb.) (Dioscoreaceae).

Zhimu Pill Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Treatment of pregnancy months not enough, like production, Lanshi Micang (Yuan (Asparagaceae). abdominal pain. Dynasty, A.D. 1279–1368)

Zhimu San Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing eyes drooping. Yifang Jijie (Qing (Asparagaceae), Cimicifugae Rhizoma (Cimicifuga heracleifolia Dynasty, A.D.1682) Kom., Cimicifuga dahurica (Turcz.) Maxim., Cimicifuga foetida L.) (Ranunculaceae), Rhei Radix et Rhizoma (Rheum palmatum L., Rheum tanguticum Maxim. ex Balf., Rheum ofﬁcinale Baill.) (Polygonaceae), Glycyrrhizae Radix et Rhimzoma (Glycyrrhiza uralensis Fisch.) (Leguminosae), Isatidis Radix (Isatis indigotica Fortune ex Lindl.) (Brassicaceae).

Zhibai Dihuang Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing flaming of fire from Yin deficiency, tidal fever and Zhengyin Maizhi Tablet (Asparagaceae), Phellodendri Chinensis Cortex (Phellodendron night sweat, tinnitus and seminal emission, concentrated (Qing Dynasty, chinense C. K. Schneid) (Rutaceae), Rehmanniae Radix urine. A.D.1706) (Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & C. A. Mey.) Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 47

Table 1 (continued )

Preparation Compositions crude drug names (Latin names of original plants) Traditional uses References name (family/compounds)

(Plantaginaceae), Poriae Cutis (Poria cocos (Schw.) Wolf) (Fomitopsidaceae)n, Corni Fructus (Cornus ofﬁcinalis Siebold & Zucc.) (Cornaceae), Alismatis Rhizoma (Alisma orientalis (Sam.) Juz.) (Alismataceae).

Zhishen Tablet Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing BPH, prostatitis or frequent urination (Yuan Dynasty, (Asparagaceae), Phellodendri Chinensis Cortex (Phellodendron by the kidney-toniﬁng. A.D.1279) chinense C. K. Schneid.) (Rutaceae), Cinnamomi Cortex (Cinnamomi cassia Presl) (Lauraceae)n.

Zhibai Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.) Curing emaciation with shallow complexion, action burnout. Sheng Hui Fang Shendong (Asparagaceae), Phellodendri Chinensis Cortex (Phellodendron (Song Dynasty, Yin chinense C. K. Schneid.) (Rutaceae), Ginseng Radix et Rhizoma A.D.992) (Panax ginseng C. A. Mey.) (Araliaceae), Ophiopogonis Radix (Ophiopogon japonicus (Thunb.) Ker Gawl.) (Asparagaceae), Citri Reticulatae Pericarpium (Citrus reticulate Blanco) (Rutaceae), Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) (Leguminosae).

All the crude drug names in column 2 were identified properly according to Chinese Pharmacopoeia 2010, and most Latin names and families of original plants were identified in TPL (www.theplantlist.org), except the plants signed with ‘n’ which were identified according to Flora of China (2000).

H O O H O H O O H H O R2 H H H H HH R2 HH R2 R HH 3 R 1 R1 R H 3

Fig. 2. The skelectal structures of spirostanol saponin from Anemarrhenae asphodeloides. be an artifact product in the extraction procedure (Ji et al., 2005). (50), neomangiferin (51), and 1,4,5,6,-tetrahydroxyxanthone (52)(Li And compounds 42–48 were the steroidal saponins isolated from et al., 2010; Jo et al., 2013). Baohuoside-I (53) and icariside-I (54)are Anemarrhena asphodeloides recently. In addition, it was suggested two flavonols identified from the EtOH extracts of Anemarrhena that furostanol steroidal saponins were parent glycosides from asphodeloides (Bian et al., 1996). There are three homoisoflavanones, which spirostanol steroidal saponins were yielded enzymatically 7,40-dihydroxyhomoisoflavanone (55), (E)-40-demethyl-6-methyleuco- in plants during processing and storage (Kawasaki et al., 1974; min (56), and (E)-5,7-dihydroxy-3-(40-hydroxybenzylidene)chroman- Zhang et al., 2000). 4-one (57) isolated from the EtOAc-soluble fraction of the MeOH Steroidal saponins are the main active components of the extracts from the rhizomes of Anemarrhena asphodeloides (Youn et al., Anemarrhena asphodeloides, with extremely diverse structures and 2009a, 2009b). Three chalcones 20-O-methylisoliquiritigenin (58), broad spectrum of biological and pharmacological activities, such as 20,40,4-trihydroxychalcone (59), 4,40-dihydroxychalcone (60), a chal- improving senile dementia, anti-coagulated blood, anti-oxidant, cone derivative anemarchalconyn (61), and a dihydrochalcone 20-O- anti-tumor, anti-osteoporosis, anti-inflammation, lowering blood methylphlorethin (62)wereobtainedfromAnemarrhena asphodeloides pressure and blood sugar, etc. (Nakashima et al., 1993; Kaname (Bianetal.,1996;Younetal.,2009a,2009b). In addition, two et al., 2000; Li et al., 2003; Nian et al., 2006; Ni et al., 2008; Lee et al., flavanones, (2S)-7,40-dihydroxy-5-methoxyflavanone (63)andisosa- 2009; Lu et al., 2009). Among these steroidal saponins, the contents kuranetin (64) and a chroman 7-hydroxy-3-(4-hydroxylbenzyl) chro- of timosaponin E1, BII, BIII, and AII are higher than other compo- man (65)wereobtainedfromAnemarrhena asphodeloides (Tsukamoto nents in Anemarrhenaasphodeloides, and they possess definite phar- et al., 2005; Youn et al., 2009b; Jo et al., 2013). macological actions (Hu et al., 2005; Nian et al., 2006; Xiao et al., Among them, xanthones were reported as its main chemical 2006; Li et al., 2007a; Miura et al., 2001a). Therefore, to some extent, constituents in previous phytochemical investigations (Hong these components can reflect the quality of this crude drug. and Han, 1985). Mangiferin and noemangiferin are the major Timosaponin BII has been used as a quality control marker of xanthones in Anemarrhena asphodeloides in which the content of Anemarrhena asphodeloides in Pharmacopoeia of P.R. China mangiferin is more than 0.7%, and the content of neomangiferin is (Committee for the Pharmacopoeia of PR China, 2010a). relatively higher (Chen et al., 2012). Studies have confirmed that mangiferin is the major active compound of Anemarrhena asphodeloides which acted as an antioxidant, antiviral and antidiabetic 4.2. Flavonoids agents, had effects on Alzheimer’s disease, and showed anti- inflammation and antitumor activities, etc. (Miura et al., 2001a; There are 16 flavonoid compounds isolated from Anemarrhena Deng et al., 2002; Jiang and Xiang, 2004; Peng et al., 2004; Jung asphodeloides, including four xanthones, mangiferin (49), ismangiferin et al., 2009; Chae et al., 2011). 48 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60

R O 3 R O Glc 3 R1 O H Glc Glc O H H O O H H R1 H H H H R1 HH HH HH OH R2 H R R 2 H 2

R1 R1 O O H Glc Glc O H H O O H H H H H H R R1 HH 3 HH H H R2 R R2 2 H

O O O O OH O O R Glc 1 R1 O O O H H H H H R1 HH HH HH R R2 2 R2 H H H

Fig. 3. The skelectal structures of furostanol saponins from Anemarrhenae asphodeloides.

4.3. Phenylpropanoids asphodeloides (Chi, 1988; Bian et al., 1996; Zhu et al., 2012).

Timopregnane A is a ﬁrst C21 steroidal saponin reported in The main phenylpropanoid compounds isolated from Anemar- Anemarrhena asphodeloides (Zhu et al., 2012). rhena asphodeloides include six norlignans (-)-(R)-40-O-methylnyasol (66), nyasol (67), oxy-hinokiresinol (68)(Bian and Xu, 1993), 4.6. Organic acids broussonin A (69)(Bae et al., 2007), broussonin B (70)(Tsukamoto et al., 2005), and 1,3-di-P-hydroxyphenyl-4-penten-1-one (71) To date, six organic acids have been reported in the genus, (Jeong et al., 1999), one lignans (Z)-40,400-(3-nethenyl-1-propene- including pantothenic acid (88), palmitic acid (89), stearic acid 1,3-diyl) bisphenol (72)(Matsuoka et al., 1999), and one coumarin (90), 4-hydroxybenzoic acid (91), vanillic acid (92), and benzoic anemarcoumarin A (73)(Youn et al., 2009a, 2009b). acid (93)(Nian and Qin, 2005; Youn et al., 2010).

4.4. Alkaloids 4.7. Anthraquinones

Seven alkaloids (74–80) were isolated and identified from Chrysophanol (94) and emodin (95) were identified from a 70% water extracts of Anemarrhena asphodeloides, including aurantia- EtOH extract of Anemarrhena asphodeloides (Liu et al., 2011a, mide acetate (74), aurantiamide (75), cyclo (Tyr-Leu) (76), N-p- 2011b), which were isolated from this genus for the first time. coumaroyltyramine (77), N-trans-feruloyltyramine (78), N-cis- feruloyltyramine (79), nicotinicacid (80), 3-pyridylcarbinol (81) 4.8. Other compounds and nicotinamide (82)(Hikino, 1992; Bae et al., 2007; Shen et al., 2007; Youn et al., 2010). A range of other compounds were also isolated from Anemar- rhena asphodeloides. Six benzophenones, zimoside A (96), iriflo- 4.5. Steroids phenone (97), 2,40,6-trihydroxy-4-methoxybenzophenone (98), foliamangiferoside A (99), (2,3-dihydroxy-4-methoxyphenyl) Five Steroids (83–87) including β-sitosterol (83), β-stigmasterol (4-hydroxyphenyl)-methanone (100), and 2,40-dihydroxy-4-methox- (84), β-sitosterol-3-O-β-D-glucopyranoside (daucosterol) (85), ybenzophenone (101)wereidentified from Anemarrhena asphode- β-stigmasterol-3-O-β-D-glucopyranoside (86), and timopregnane loides (Youn et al., 2009a, 2009b; Jo et al., 2013). Compound 96 is a A(87) were isolated and determined from Anemarrhena benzophenone glycoside isolated from Anemarrhena asphodeloides in Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 49

O R3 R4 H HO R R2 O OH R2 O 2 OCH3

R1 R5 R1 OH O OH O R1 O

49 R1 =GlcR2 =OH R3 =H R4 =H R5 =OH 53 R1 =ORha R2 =OH 58 R1 =OMe R2 =H 59 R =OH R =H 50 R1 =H R2 =OHR3=Glc R4 =H R5 =OH 54 R1 =OH R2 =OGlc 1 2 60 R =H R =H 51 R1 =GlcR2 =OH R3 =H R4 =H R5 = OGlc 1 2

52 R1 =H R2 =H R3 =OHR4 =OHR5 =H O H HO O OH HO O OH HO C C R O OH O O

55 56 R = CH3 61 57 R = H

R2 O OMe HO O O HO O H

HO HO OH

R1 O

62 63 R1 =OMe R2 =OH 65

64 R1 =OH R2 =OMe

Fig. 4. The structures of compounds 49–65 from Anemarrhenae asphodeloides.

OH HO OMe OH

R1 HO HO R2 OMe

66 R1 = OMe R2 = H 69 70

67 R1 = OH R2 = H

68 R1 = OH R2 = OH OH

CH2 HO HO O O OH

O HO OH

71 72 73

Fig. 5. The structures of compounds 66–73 from Anemarrhenae asphodeloides. 50 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60

OH O O O O O CH3 N H H N O NH NH N H HN O HO O

74 75 76

OH OH O O

N N H H HO HO OMe 77 78

O O OH N OH NH2 HO O N OH H N N OMe 79 80 81 82

Fig. 6. The structures of compounds 74–82 from Anemarrhenae asphodeloides.

HO HO GlcO 83 84 85

Gla-(2 1)GlcO GlcO H 86 87

Fig. 7. The structures of compounds 83–87 from Anemarrhenae asphodeloides.

recent years. One furan, 5-hydroxymethyl-2-furaldehyde (102)was and 2,3-dihydroxypropyl heptadecoa (108)wereisolatedfromAne- obtained from Anemarrhena asphodeloides (Jo et al., 2013). Other marrhena asphodeloides (Bian et al., 1996; Nian and Qin, 2005; Youn compounds including tannic acid (103), pentaeosyl vinyl ester (104), et al., 2010; Liuetal.,2011a,2011b; Jo et al., 2013. Additionally, four tyrosol (105), and nonacosanol (106), 4-hydroxyacetophenone (107) polysaccharides were obtained from Anemarrhena asphodeloides,and Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 51

CH OH 3 H N OH HO H3C OH CH3 O O O 88 89 O

R2 R1 HO CH3

R3 O

90 91 R1 = OH R2 = OH R3 = H

92 R1 = OH R2 = OMe R3 = OH

O OH O OH OH O OH

Me Me OH O O

93 94 95

Fig. 8. The structures of compounds 88–95 from Anemarrhenae asphodeloides.

24 volatile compounds were identiﬁed by GC–MS from the herbs as compounds, neurotrophic activity of compound 67 was less active well (Chen et al., 2005). than 65, 70 and 98 (Tsukamoto et al., 2005). The mechanisms of neuroprotective activities for these four compounds were related to their proteasome inhibitory activity, and it was suggested that 5. Pharmacological activities 65 and 70 could be used as a proteasome inhibitor and a neurite outgrowth-inducer as lactacystin did (Fenteany et al., 1994). 5.1. Nervous system activities

Anemarrhena asphodeloides is one of the most frequently used herbs with neuroprotective activities on central nervous system. It 5.1.2. Alzheimer's disease has already showed beneficial effects on many central nervous The decrease of cholinergic M receptor’s density in brain tissue system diseases, such as Alzheimer's and Parkinson's disease is closely related to Alzheimer's disease. SAaB could prevent the caused by neuronal cell death, Schizophrenia, and depression. progressive deterioration of the cholinergic system in Alzheimer's Systematic activities of Anemarrhena asphodeloides and mechan- disease through increasing the muscarinic receptor density of isms were reviewed as follows. dementia model mouse caused by AlCl3 (Ma et al., 2005), Aβ25–35 (Chen et al., 2002, 2003, 2004a), and L-glutamic acid (Cheng et al., 5.1.1. Neuroprotective activities 2008). Extracts and some compounds from Anemarrhena asphode- Alzheimer's disease is also caused by neuronal cell death. loides showed obvious neuroprotective activity to prevent cell Apoptosis, oxidative stress, and inflammation were discussed to death of neurons. Methanolic extracts of Anemarrhena asphode- contribute to neuronal cell death. Lee et al. (2009) found that loides at the doses of 50 and 100 μg/mL showed significantly timosaponin AIII (TAIII) and timosaponin BII (TBII) could improve neuroprotective activity in the glutamate-induced neurotoxicity of memory and learning dysfunction via anti-inflammatory proper- primary cultures in rat cortical cells (Won and Ma, 2009). Saponins ties (Li et al., 2007a; Lee et al., 2009). Daily oral administration of from Anemarrhena asphodeloides Bunge. (SAaB) could prevent TBII to rat vascular dementia at 100 and 200 mg/kg resulted in a neuronal damage. SAaB could significantly inhibit Aβ25–35-induced significant improvement of the deficit in the learning of the water phospho-ERK1/2 and phospho-p38 MAPK protein increment at maze task. Meanwhile, the expression of interleukin-10, an the doses of 30 and 100 μmol/L, while it could decrease the levels anti-inflammatory cytokine and its receptor were significantly of TNF-α and NO in supernatants of cultured macrophage, and increased in treating vascular dementia rats with TBII (Li et al., inhibit Aβ25–35-induced increase of iNOS protein expression in 2007a). TAIII was able to inhibit the increase of proinflammatory macrophages at 10, 30 and 100 μmol/L (Liu et al., 2006). SAaB also cytokines in scopolamine-treated mice, while NF-κB (pp65) acti- exerted protective effects on nigral dopaminergic neurons in vation in scopolamine or TNF-α stimulated BV-2 microglia and SK- chronic MPTP-lesioned mice model through increasing the levels H-SH neuroblastoma cells. These results indicated that TAIII might of striatal BDNF and GDNF, the number of nigral TH immunor- weaken the inflammation in scopolamine-stimulated mice by eactive cells, and locomotor ability (Xie et al., 2009). In addition, inhibiting NF-κB (pp65) activity (Lee et al., 2009). TBII and 7-hydroxy-3-(4-hydroxybenzyl) chroman (65), nyasol (67), brous- timosaponin E1 obviously enhanced the learning and memory sonin B (70), and 2,6,40-trihydroxy-4-methoxybenzophenone (98) capacities presumably related to promoting the scavenging of the from Anemarrhena asphodeloides induced neurite outgrowth in rat free radicals. SAaB at three different doses (50, 100, 200 mg/kg) pheochromocytoma (PC-12) cells at 50 μg/mL. Among the four could remarkably enhance the leaming and memory capacities in 52 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60

R2 O HO R R 1 3 O OH H3C(CH2)23 C O C CH H H O 2 R4

O R5 102 104 O OH MeO 96 R1 = OGlc R2 =OH R3 =OMe R4 =H R5 =H Me 97 R1 = OH R =H R =OH R =H R=OH 2 3 4 5 HO HO 98 R1 = OH R =H R =OMe R =H R=OH 2 3 4 5 105 O 107 99 R1 = OH R =H R =OMe R =OGlcR=OH 2 3 4 5 O (CH2)15 CH3

100 R1 = OH R2 =H R3 =OMe R4 =OH R5 =OH OH 101 R1 = OH R =H R =OMe R =H R=H OH 2 3 4 5 108 OH OH OH O HO OH OH OH HO O

O O OH HO OH O O O O O OH OH HO O HO O O O O OH O O O OH HO O O HO OH O OH HO OH O

HO OH 103

H3C OH 106

Fig. 9. The structures of compounds 96–108 from Anemarrhenae asphodeloide.

rats with Aβ25–35-induced dementia presumably through promot- pathway. Xiong et al. (2009) studied the effect of SAaB on the ing the scavenging of the free radicals (Ouyang et al., 2005). dopaminergic system in a chronic model of Parkinson's disease. In addition, Wang and Xu (2001) found that SAaB could enhance They found that SAaB-10 (10 mg/kg of SAaB) and SAaB-26 (26 mg/kg the learning and memory abilities of aged rats by increasing of SAaB) could increase striatal DA levels in chronic MPTP-model cerebral nicotinic receptors. Ouyang et al. (2006) reported that mice, which was closely related to the eleation of striatal DAT, but SAaB ameliorated memory deficit and resisted Alzheimer's disease not related to catabolism of DA and MAO-B activity. As a traditional by inhibiting AChE after absorption and transformation in vivo. prescription, DaBuyin Pill also could treat Parkinson's disease (Zhang Mangiferin also could improve long-term cholinergic memory et al., 2013). deficits by AChE inhibition or cholinergic receptor stimulation and inhibition of NF-kappaB activation (Jung et al., 2009). 5.1.4. Anti-depression It is reported that sarsasapogenin, total saponins, and TBII from 5.1.3. Parkinson's disease Anemarrhena asphodeloides possessed antidepressant bioactivity. The significant neuropathol features of Parkinson's disease The bioassay showed that sarsasapogenin at 50 mg/kg could sharply include extreme decrease of striatal dopamine (DA) and down increase noradrenaline and serotonin levels in hypothalamus and regulation of striatal dopamine transporter (DAT) in the nigrostriatal hippocampus (Ren et al., 2006, 2007a). Different doses of SAaB Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 53

Table 2 Spirostanol saponins isolated from Anemarrhena asphodeloides (1–17).

No. Name Skeletons R1 R2 R3

4 3-xyl 1 Degalactotigonin I H H O-gal -glc2-glc 2 Isoarsasapogenin I H H OH 3 Markogenin I H OH OH 4 Neogitogenin I H OH OH 5 Sarsasapogenin I H H OH 6 Timosaponin A I I H H O-gal 7 Timosaponin A II I H OH O-gal2-glc 8 Timosaponin A III I H H O-gal2-glc 9 Timosaponin A IV I H H O-glc2-mano 4 3-xyl 10 Timosaponin F I H OH O-gal -glc2-glc 11 Xilingsaponin B I H H O-glc2-gal3-glc 12 Anemarrhenasaponin III II O-gal2-glc OH H 13 Timosaponin F II O-gal2-glc OH OH 14 Timosaponin G II O-gal2-glc H OH 15 (3β,5β,25s)-Spirostan-3-ol III OH OH H 16 Diosgenin III H OH 4 3-xyl 17 Timosaponin G (C50) III OH O-gal -glc2-glc

Table 3 Furostanol saponins isolated from Anemarrhena asphodeloides (18–48).

No. Name Skeletons R1 R2 R3

4 3-xyl 18 Timosaponin D1 IV H O-gal -glc2-glc OH 4 3-xyl 19 Timosaponin F IV OH O-gal -glc2-glc OH 4 3-xyl 20 Timosaponin D2 IV H O-gal -glc2-glc OMe 21 Timosaponin B I V H O-gal2-glc OMe 22 Timosaponin B II V H O-gal2-glc OH 4 3-xyl 23 Timosaponin B V(C57) V H O-gal -glc2-glc OH 24 Timosaponin B V(C46) V H O-gal2-glc OMe 4 3-xyl 25 Timosaponin B VI V H O-gal -glc2-glc OMe 26 Timosaponin N V OH O-gal2-glc OH 27 Timosaponin O V OH O-gal2-glc OMe 28 Timosaponin E1 VI OH O-gal2-glc 29 Timosaponin E2 VI OMe O-gal2-glc 30 Anemarrhenasaponin I VII OH O-gal2-glc OH 31 Anemarrhenasaponin Ia VII OMe O-gal2-glc OH 32 Anemarrhenasaponin II VII OH O-gal2-glc H 4 3-xyl 33 Timosaponin C1 VIII OH O-gal -glc2-glc 4 3-xyl 34 Timosaponin C2 VIII OMe O-gal -glc2-glc 4 3-xyl 35 Timosaponin H1 VIII OH O-gal -glc2-glc Timosaponin B III IX (Anemarrhenasaponin IV, 36 Timosaponin B, H O-gal2-glc Pseudoprototimosaponin A III) 37 Timosaponin C IX H O-glc2-glc 38 Timosaponin D IX OH O-gal2-glc 4 3-xyl 39 Timosaponin B IV (C57) IX H O-gal -glc2-glc 40 Timosaponin B IV (C51) IX H O-gal2-glc4-glc 41 Macrostemonoside F IX H O-glc2-glc 42 Timosaponin J X H O-gal2-glc 43 Timosaponin K X OH O-gal2-glc 4 3-xyl 44 (25S)-Karatavioside C V OH O-gal -glc2-glc OH 45 Timosaponin L V H O-gal2-glc OH 46 (25S)-Ofﬁcinalisnin-I V H O-glc2-glc OH 47 Anemarnoside A XI O-glc O-gal2-glc 48 Anemarnoside B XII O-glc O-gal2-glc

(0.05 mg/kg, 0.50 mg/kg, and 5.00 mg/kg) could improve the mor- (Lu et al., 2010). Besides, SAaB was also found evidently effective in phol level induced by corticosterone in PC12 cell, increase the treating anxiety (Cui et al., 2007). survival rate (Po0.01), and decrease the activity of LDH (Po0.01) (Ren et al., 2007b). TBII at 100 and 150 mg/kg could effectively 5.2. Blood system activities shorten the immobility time in tail suspension test (TST) and force swimming test (FST). It had significant antidepressant bioactivity 5.2.1. Anti-diabetes that might be related to the potential function of 5-HT (5-hydro- The ethanol extracts of Anemarrhena asphodeloides were found xytryptamine) nerve system and the DA nerve system in the brain to stimulate insulin secretion in Wistar rat islets which were 54 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 incubated both at 3.3 and 16.7 μM glucose, in which exocytotic manner in vitro, and TAIII did not affect intrinsic and extrinsic machinery of the B-cell, mediation of pertussis toxin sensitive Gi- coagulation factors and thrombin activity in vivo. (or Ge-) proteins were involved (Hoa et al., 2004). Total flavones In vitro experiments showed that TBII could inhibit ADP- from Anemarrhena asphodeloides can be used as a potential drug to induced platelet aggregation with dose-dependently in effect at treat type II diabetes. After administration of total flavones, the the doses of 20, 40 and 80 mg/mL. TBII could prolong activated blood sugar and serum insulin levels in diabetes mice significantly partial thromboplastin time by 9.29%, 16.86% and 25.50% at 1, decreased and the insulin sensitivity increased in BCG vaccine- 3 and 6 mg/kg, respectively, and significantly reduced the wet induced insulin resistance mice (Chen et al., 2004b). In addition, weight, dry weight and length of the thrombi. Studies showed that total polyphenols from Anemarrhen asphodeloides could markedly TBII was also able to decrease the plasminogen levels at doses of 1, decrease the level of fasting serum glucose of the alloxan 3 and 6 mg/kg (i.v.) in arteriovenous shunt rabbit by 14.4%, 18.3% orstreptozotocin-induced diabetic animals (Huang et al., 2005). and 29.0%, respectively. It demonstrated that TBII had significant Mangiferin and mangiferin-7-O-β-glucoside from Anemarrhena antiplatelet and anticoagulation bioactivities which could contri- asphodeloides could also be useful in treating type II diabetes at bute to neuroprotective effect against damage following cerebral 90 mg/kg (oral administration) in KK-Ay diabetes mice, and the blood ischemia damage (Lu et al., 2011). glucose levels could be markedly reduced from 5.2170.17 mg/mL to Cong et al. (2010) determined the inhibitory effect on anti- 2.9070.36 mg/mL and from 5.6570.19 mg/mL to 3.1270.44 mg/ platelet aggregation of steroidal saponins, based on groups situ- mL, respectively (Po0.001). The antidiabetic mechanism might be ated at C3,C15 and C22 of their structures. Furostanol saponins had caused by the decrease of insulin resistance and the increase of no inhibitory effect on platelet aggregation, and spirostanol insulin sensitivity (Ichiki et al., 1998; Miura et al., 2001a, 2001b). saponins inhibited platelet aggregation in varying degree with

Mangiferin could improve the renal function of diabetic nephropathy various monosaccharide chains at C3 aglycon. Glycosylation of rats, which was related to inhibitory effect of mangiferin on over- sarsasapogenin with glucopyranosyl donors completely inhibited expression of TGF-β1, AGE and ECM accumulation, polyol pathway the platelet aggregation, however, other sugar moieties, such as activation, ROS generation and MCs proliferation (Li et al., 2010). -Gal, -Ara, -Rib as well as -Rha or -Man (timosaponin AI and Intraperitoneal injection pseudoprototimosaponin AIII at 64 mg/kg timosaponin III, etc.), showed attenuated inhibitory bioactivities in isolated from Anemarrhena asphodeloides could decrease the blood varying degrees. sugar level of diabetic mice by 68.2% (Kimura et al., 1992). It exhibited hypoglycemic bioactivity in a dose-dependently manner in strep- 5.2.3. Lowering blood pressure tozotocin-diabetic mice, and the hypoglycemic mechanism might be Li et al. (2003) found that angiotensinogen gene, α -adreno- related to inhibition of hepatic gluconeogenesis and/or glycogenolysis 2A ceptor gene, and endothelin-converting enzyme 1 (ECE-1) gene (Nakashima et al., 1993). Seishin Kanro To (1700 mg/kg) could reduce were downregulated 2.8, 1.9 and 3.1 folds respectively after human the blood glucose of KK-Ay mice from 5.57 to 3.83 mg/mL 7 h after a umbilical vein endothelial cells were incubated with SAaB of single oral administration and decrease the blood glucose and improve 80 mg/L. These results suggested that SAaB might affect cardio- glucose tolerance after 5 weeks' repeated administration in KK-Ay vascular diseases, especially on lowering blood pressure, by mice. These results confirmed that Seishin Kanro To could act as a modulating the function of vein endothelial cells. traditional medicine with the treatment of diabetes. And further study has shown that the active plants of Seishin Kanro To were identified as Anemarrhena asphodeloides and Rehmannia glutinosa Libosch. (Miura 5.3. Antitumor et al., 1997). Anemarans A, B, C, and D from Anemarrhena asphodeloides Water-soluble ingredients of Anemarrhena asphodeloides dis- displayed significant hypoglycemic bioactitvities in normal and played significant inhibitory bioactivity against gastric cancer cell alloxan-produced hyperglycemic mice (Takahashi et al., 1985). lines, MKN-45, and KATO-III in a dose-dependently manner. Anemarans at 2 mg/kg and 20 mg/kg (ig) could significantly Apoptosis in MKN-45 and KATO-III cells appeared to be initiated reduce the blood glucose of the alloxan-induced diabetes rabbits, by the release of cytochrome c into the cytosol from the mito- while Anemarans at the dose of 200 mg/kg (ig) could reduce blood chondria followed by the activation of caspase 3 or caspase 3-like glucose of normal rabbits (Huang et al., 2004). Ig or ip adminis- activity (Takeda et al., 2001). The EtOAc extracts were evaluated tration of 50, 100, 300 mg/kg of the polysaccharide to mice could for cytotoxicity against five kinds of human tumor cell lines, significantly decrease the blood glucose and liver tissue glycogen A-549, SK-OV-3, SK-MEL-2, XF-498 and HCT-15 (Lee et al., 1995). without the alteration of the blood lipid. Ig administration in Chloroform extracts showed cytotoxic activity against P-388 cell alloxan diabetic mice also exhibited marked hypoglycemic activity line, and the compounds nyasol and TAIII isolated from Anemar- (Wang et al., 1996). And the traditional medicine, Dangnyoh Pill rhena asphodeloides showed cytotoxicity against eight tumor cell also has been applied to treat diabetes mellitus (Seung et al., lines such as A-549, HCT-15, DLD-1, MCF-7, SKOV-3, HL-60, K-562 2008). and P-388 (Park and Kim, 1994). Diosgenin from Anemarrhena asphodeloides exhibited antitumor activity. In vivo, both ig and ip, diosgenin inhibited S-180, 5.2.2. Anti-coagulated blood Hep-A, U-14 mice transplanted tumor growth with the inhibiting Some researchers believed that anemarrhenasaponin Ia, timo- rates of 30–50%, however, it had no effect on the EAC mice saponin I, Ia, BI, BII, BIII, E1, E2 and anemarsaponin B from transplant tumor. In vitro, diosgenin inhibited L-929, HeLa, MCF

Anemarrhena asphodeloides possessed inhibitory effect on platelet cell growth with IC50 values of 1.2, 18.2, 19.8 μg/mL, respectively aggregation and hemolysis in human blood (Dong and Han, 1992; (Wang et al., 2002a). The inhibitory rate of human 1547 osteosar- Zhang et al., 1999a; Kaname et al., 2000; Lu et al., 2011). coma cells was 86% for 24 h, but it did not signiﬁcantly affect Niwa et al. (1988) reported that TAIII and markogenin from A375-S2 cells (Trouillas et al., 2005). The mechanism of action was Anemarrhena asphodeloides showed the activity of anti-platelet caspase-3 dependent which caused a nuclear localization of aggregation. Li et al. (2006a) conﬁrmed the effect of TAIII on apoptosis inducing factor with a fall of mitochondrial membrane platelet aggregation and thrombus formation of rats in vitro and potential (Corbiere et al., 2004). Furthermore, diosgenin was the in vivo. They found that TAIII could inhibit rat platelet aggregation most effective cell death inductor (Corbiere et al., 2003). The induced by ADP, collagen or thrombin in a dose-dependently biological activity of diosgenin that exhibited strong apoptosis and Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 55 arrested cell cycle was attributed in part to the presence of the In addition, anemaran from Anemarrhena asphodeloides pos- hetero-sugar moiety and the 5,6-double bond in the human sessed an antioxidant activity and had a protective effect on the osteosarcoma 1547 cell line (Trouillas et al., 2005). membranes of erythrocytes through inhibiting the hemolysis of

Sarsasapogenin showed antitumor activity (Bao et al., 2007; Ni red blood cells by itself and H2O2 induced hemolys (Po0.01) et al., 2008) which induced a distinct dose- and time-dependently (Wang et al., 2008). As a protein tyrosine phosphatase 1B inhibitor, d 2 diminution of HepG-2 cell viability with IC50 value of it scavenged OH free radicals and O with the IC50 valuses of 42.471.0 μg/mL for 48 h. Sarsasapogenin induced HepG-2 cell 0.063 mg/mL and 1.16 mg/mL, respectively (Chen et al., 2013). apoptosis and led inhibition of tumor cell growth through cell cycle arrest on G2/M (Bao et al., 2007). The structure-activity 5.5. Anti-microbia relationship of sarsasapogenin was related to hetero-sugar moiety and the 5,6-double bond with a 5β conformation (Trouillas et al., Li et al. (2006b) reported that SAaB could be used for preparing 2005). antifungal drugs, and the ﬁnal product was ointment, cream, TAIII from Anemarrhen asphodeloides induced autophagy pre- tincture, paste, emulsion, and gel. ceding mitochondria-mediated apoptosis in HeLa cancer cells with Steroidal saponins isolated from leaves of Anemarrhena aspho-

IC50 values ranged from 8.5–10.1 μmol/L after 48 h incubation by deloides could prevent anthracnose disease caused by Colletotri- MTT assay (Sy et al., 2008). TAIII could potentially inhibit the chum gloeosporioides (Park et al., 2006). Nyasol (67) was evaluated growth of several human colorectal cancer cells (HCT-15, 6.1 μM; for antimicrobial activity against 43 strains of fungi and ﬁve strains HCT-116, 5.5 μM; HT-29, 10.3 μM; SW-480, 13.1 μM; SW-620, of bacteria with the minimum inhibitory concentration (MIC)

11.1 μM) with IC50 values less than 15 μM(Kang et al., 2011) ranging from 1 to 200 μg/mL (Iida et al. 1999a, 2000; Park et al., through inhibition of mTOR and induction of ER stress (King et al., 2003). Broussonin A (69) was formerly reported as a phytoalexin 2009). of Broussonetia papyrifera Vent (Iida et al., 1999b). (Z)-40,400-(3- SAaB could inhibit alpha-fetoprotein gene expression when nethenyl-1-propene-1,3-diyl) bisphenol (72) from Anemarrhena injected into new born rats, and Li et al. (1989) hypothesized that asphodeloides also showed antimicrobial activity (Matsuoka et al., Anemarrhena asphodeloides might act on AFP gene expression 1999). through glucocorticoid receptor mediated action. Mangiferin from Anemarrhena asphodeloides was studied for its 5.6. Anti-virus antiproliferative activity against K-562 leukemia cells using MTT assay and the inhibition activity was in a dose-dependently and (-)-(R)-40-O-methylnyasol (66), nyasol (67), and broussonin A time-dependently manner (Peng et al., 2004). Different concen- (69) from Anemarrhena asphodeloides exhibited potent antiviral trations of mangiferin could inhibit the MDA-MB-231 cells pro- activities against the RSV-A2 strain propagation in HEp-2 cells liferation with the inhibition of 20.55%, 22.26%, and 22.94% at 1, 5, with IC50 values of 0.85, 0.39, and 0.62 μM, respectively, slightly and 10 μmol/L, respectively, after 24 h treatment (Wu et al., 2007). more active than the positive control ribavirin (IC50 ¼1.15 μM). In In addition, it was indicated that mangiferin might protect the order to develop more potent antiviral drugs, further studies were heart against doxorubicin-incuced cardiotoxocity without interfer- required to optimize these ‘new’ lead compounds in detail (Bae ing with its antitumor activity (Wang et al., 2000). et al., 2007). TAIII from Anemarrhena asphodeloides also exhibited potent inhibitory activity on the respiratory syncytial virus (RSV)

with an IC50 value of 1.00 μM and 1.15 μM for the positive control 5.4. Anti-oxidation ribavirin (Youn et al., 2011). Mangiferin from Anemarrhena asphodeloides was confirmed to have remarkable direct inhibition Previous studies showed that total phenols from Anemarrhena against HSV-I, the maximal tolerant concentration and the median asphodeloides were major contributors of antioxidant activity. The toxic concentration was 0.29 and 3.66 mg/mL, respectively. The antioxidant capacities were evaluated by using ferric reducing antiviral effective rate was 76.42%, and the positive control antioxidant power (FRAP) and trolox equivalent antioxidant capa- acyclovir was 2.54 mg/mL (Jiang and Xiang, 2004). Mangiferin city (TEAC) assays, respectively. In the FRAP assay, the antioxidant was also confirmed to have remarkable direct inhibition against capacity was 83.80770.75 (μmol Fe(II)/g), while the TEAC assay HSV-II at Z2.08 mg/mL, its maximal ER% reached 95% and the was 10.45770.06 (μmol Trolox/g). However, further advanced positive control acyclovir was 1 μg/mL (Li et al., 2005). Mangiferin experiments were required to determine specific bioactive com- showed an obvious inhibition on human influenza virus A, and the pound and illustrate the mechanism (Li et al., 2008). EC50 of inhibition and proliferation after adsorption were 0.70 and The effect on scavenging dOH and O2 free radicals of mangiferin 0.76 mg/mL (Li and Zheng, 2005). It also could restrain the from Anemarrhena asphodeloides displayed more obviously than VE. secretion of HBeAg in HepG-2.2.15 cells at the dose of 4 mg/mL d Moreover, it could significantly scavenge OH (EC50¼26 μmol/L), in vitro (Gao et al., 2007). inhibit the generation rate of OH (IC50¼10.5 μmol/L), and scavenge 2 O free radicals (IC50 ¼45.6 μmol/L) with the positive control 5.7. Anti-inflammation mannitol (EC50 ¼20.5 μmol/L) (Li and Li, 1996; Zhang et al., 1997). And mangiferin at 0.35 mg/d could reduce contents of LPO by MeOH extracts of Anemarrhena asphodeloides showed activity of 39.43%, 47.00%, and 26.40% by γ-irradiation induction in the liver, Leukotriene B4 on intact human polymorphonuclear neutrophils. spleen, and kidney of mice, respectively (Wang et al., 1999). Nyasol from Anemarrhena asphodeloides (67) showed moderate

Steroidal saponins of Anemarrhena asphodeloides were also binding affinity to the receptors on human PMNs (IC50¼5.24 μM) good antioxidants. SAaB at 100 μg/mL were tested for their (Lee and Ryu, 1999). TBII and anemarsaponin B from Anemarrhena antioxidant activities, and IC50 values of lipid peroxidation of rat asphodeloides significantly and dose-dependently attenuated the liver microsomes were 18.67 μg/mL, 15.73 μg/mL, and 16.11 μg/mL, increase of these cytokines on both mRNA and protein levels, respectively (Xi et al., 2008). The corresponding compounds were including inhibiting the expressions of IL-1β,TNF-α, and IL-6, sarsasapogenin, TAIII, TBI, TBII, TBIII, TBV, timosaponin C, timosapo- possibly via the p38 MAP kinase pathway and NF-kappaB signal nin F, anemarrhenasaponin-I, macrostemonoside F, and anemarrhe- pathway (Kim et al., 2009; Lu et al., 2009). SAaB could significantly nasaponin Ia (Ma et al., 1996; Meng et al., 1999; Zhang et al., 1999b; inhibit the over-release of inflammatory mediators induced by

Yang et al., 2007). Aβ25–35 in culturing macrophages, a process when the down 56 Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 regulation of Akt/PKB signal transduction pathway took part in asphodeloides have been confirmed to possess hyaluronidase inhi- without affecting total protein levels and the production of TNF-α bitory activity and moderate inhibitory activities against a and NO in cultured macrophages (Liu et al., 2011a, 2011b). Mangi- chymotrypsin-like activity of the proteasome (Jeong et al., 1999; ferin from Anemarrhena asphodeloides prolonged obviously the Oh et al., 2007), testosterone 5 alpha-reductase inhibitory activity incubation period of asthma and cough, decreased cough times, (Matsuda et al., 2001), which might be useful to develop a novel inhibited the permeation of capillary vessel caused by acetic acid, angiogenesis inhibitor (Jeong et al., 2003). In addition, Chinese and increased the emission of phenol red (Deng et al., 2002). herbal mixture with the function of nourishing Yin-removing Fire Studies in RAW 264.7 macrophages suggested that the anti- had been linked to the effect on hypothalamic kisspeptin expression inflammatory mechanism of mangiferin was partly because of in female precocious rats (Sun et al., 2010). down-regulating iNOS, COX-2, TNF-α, and IL-6 levels due to NF- κB inhibition (Shin et al., 2008). And the traditional medicine, Sanshui Baihu Tang had the effect of anti-inflammation (Yang et al., 6. Toxicity 2010). Lee Mo Tang was well-known medicine used in oriental medicine for the treatment of asthma and bronchial inflammation Some toxicity studies on Anemarrhena asphodeloides as a tradi- (Yeum et al., 2007). Zi Shen Pill containing Anemarrhena asphode- tional Chinese herbal medicine has been carried out. The genetic loides had effect on benign prostatic hyperplasia, and the xanthone toxicology test for antifungal constituents in rhizomes of Anemarrhena glycosides, timosaponins, and alkaloids were thought to be its asphodeloides was carried out based on the observation of acute active constituents (Sun et al., 2007, 2008; Cai et al., 2010). toxicity test and bone marrow micronucleus test along with sperm aberration test. Acute toxicity test was based on the observation of 5.8. Anti-osteoporosis Horn's and Korbor's methods. Horn's method: the dosage of oral administration was 21.5, 10.0, 4.6, and 2.15 g/kg, respectively. The drug Sasapogenin from Anemarrhena asphodeloides could prevent was oral administered for a week, and the examination was found to the retinoic acid from inducing osteoporosis, and the possible be normal in mice and the LD50 was over 21.5 g/kg. Korbor's method: mechanism was that sasapogenin improved the level of estrogenic theoraladministrationwas10.0,8.0,6.4,5.12,and4.1g/kg,respec- hormone and inhibited the high bone turnover (Yang et al., 2006). tively. The drug was oral administered in mice for a week, then the A further study (Yang et al., 2009) demonstrated that the sarsa- examination found that the mice were normal, without exceptional sapogenin could effectively promote the proliferation, differentia- reflection, freedom of movement and no deaths, and LD50 was over tion, and mineralization of osteoblasts cultured in vitro. Besides, 10 g/kg. There was no significant difference by comparing experi- sarsasapogenin could inhibit the generation of osteoclasts in mental group with blank group on micronucleus and sperm defor- marrow cells. Qin et al. (2008) found that anemarsaponin BII mity (P40.05), and no dose-effect relationship, but had significant increased bone formation. In addition, Er Xian Tang has long been difference with positive control group (Po0.01), which indicated that used for the treatment of oteoporosisnd menopausal syndrome in the drug had no teratogenicity on sperm cells and mouse bone China (Nian et al., 2006). marrow. Taken together, these results indicated that the antifungal constituents of Anemarrhena asphodeloides had no acute toxicity and 5.9. Anti-skin aging and damage genetic teratogenicity (Li et al., 2007b). To evaluate the toxicity and adverse effects of Anemarrhena Mangiferin derived from Anemarrhena asphodeloides has pro- asphodeloides, the extraction from AnemarrhenaAnemarrhena tective influence on skin aging, which is related to the synthesis of asphodeloides was applied to treat superficial cutaneous mycosis matrix metalloproteinases (MMPs). The mechanism was linked to of guinea pig by the method of the skin acute toxicity, skin allergy, that mangiferin attenuated H2O2-induced MMP-1 activation via and skin irritation test. The results showed no skin irritative inhibition of extracellular signal-regulated kinase (ERK) and JUN reaction of papular, erythema, edema, and no death, etc. The N-terminal kinase (JNK) pathway and activator protein-1(AP-1) preliminary test confirmed the antifungal effects of the extraction (Chae et al., 2011). made from Anemarrhena asphodeloides and this experiment could Mangiferin is also a potential photoprotective agent against provide scientific basis for treating cutaneous fungus with tradi- UVB-induced skin damage (photoaging) from UVB-induced skin tional Chinese herbal medicine clinically (Ju et al., 2009). thickness, wrinkle formation, and collagen fiber loss. The result in vitro showed that mangiferin reduced UVB-induced MMP-9 protein expression, enzyme activity, subsequent attenuation of 7. Conclusion UVB-induced phosphorylation of mitogen-activated protein kinase kinase1 (MEK) and ERK. In vivo studies showed that mangiferin Anemarrhena asphodeloides, as one of the most important and could inhibit UVB-induced mean length and mean depth of skin frequently used traditional Chinese herbal medicines with excel- wrinkle based on skin replica, epidermal thickening, and damage lent safety record, has been effectively used for febrile diseases in to collagen fiber (Kim et al., 2012). oriental clinical practices. It also has been used in combinations with various other herbal ingredients for the purpose of preven- 5.10. Other effects tion and management of acute lung infection, sterility, and climacteric syndrome, etc. (Bai and Liu, 2007). As an ingredient, The pharmaceutical prescription comprising ethanol, methanol, Anemarrhena asphodeloidess has also been used in many health- isopropanol, acetone and dioxane extracts of Anemarrhena aspho- related products (You et al., 2003; Jang et al., 2008; Tian and Tian, deloides possess immunosuppressive activity and can be used as 2009; Yang, 2009; Cheng and Cheng, 2010; Lai, 2011; Liu, 2011; immunosuppressants (Lee and Lee, 1998). SAaB could be used for Ma et al., 2011). preparing medicaments to treat myocardial ischemia (Lou and The following three aspects are important for future research Chen, 2005), hyperlipemia, and arteriosclerosis (Li et al., 2006b). into Anemarrhena asphodeloides and highlight the current gaps in TAIII from Anemarrhena asphodeloides induced relaxation of the scientific literatures. The first one is to ensure the communica- phenylephrine-induced vascular contraction (Wang et al., 2002b). tion and sharing of existing traditional knowledge with different Mangiferin could reduce cholesterol (Po0.05) and triglyceride cultural backgrounds in different countries and regions from which (Po0.01) (Miura et al., 2001a). Norlignans from Anemarrhena the plant originates. Frequent international communication can also Y. Wang et al. / Journal of Ethnopharmacology 153 (2014) 42–60 57 be helpful to improve herbal medicine availability and ensure the Chen, Q.L., Ma, C.H., Wang, W.Q., Yu, M.M., 2005. Analysis of volatile constituents safe medication. The second one is to look for chemical and/or from Anemarrhena asphodeloides by GC–MS. China J. Chin. Mater. Med. 30, 1657–1659. biological markers from Anemarrhena asphodeloides for mechanism Chen, Q.L., Shi, Z.Y., Ma, N.N., Wang, W.Q., Wei, S.L., Sun, W.J., 2012. Determination studies, new drug discovery, and quality ensurance. The third one of two major xanthone glycosides in rhizome of Anemarrhena asphodeloides emphasized is the germplasm resources protection and sustainable using high performance capillary electrophoresis. J. Med. Plants Res. 9, – use of Anemarrhena asphodeloides.Scientific and reasonable culture 1585 1589. Chen, X.Q., Nicholas, J.T., 2000. Lamiaceae. In: Wu, Z.Y. (Ed.), Flora of China, vol. 24. and harvest will be the key for the sustainable use and conservation Science Press, Beijing (pp. 136). of this plant. Hence, it is urgent to establish the necessary programs Cheng, J.X., Cheng, G., 2010. Health Care Nano Fiber–Fabric Product Carrying for medicinal resource utilization and conservation in further Traditional Chinese Medicine and Selenium, Germanium and Zinc Capable of Releasing Anion. CN 101703317A 20100512. studies. Cheng, Z.F., Wang, Y.H., Zhang, G.Y., Xu, L.i., 2008. 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