Belamcanda chinensis (L.) DC-An ethnopharmacological, phytochemical and pharmacological review

Belamcanda chinensis (L.) DC-An ethnopharmacological, phytochemical and pharmacological review

Journal of Ethnopharmacology 186 (2016) 1–13 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.c...

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Journal of Ethnopharmacology 186 (2016) 1–13

Contents lists available at ScienceDirect

Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep

Review

Belamcanda chinensis (L.) DC-An ethnopharmacological, phytochemical and pharmacological review Le Zhang a,b, Kunhua Wei b, Jianping Xu a,b, Dawei Yang a, Chunhong Zhang a, Zhipeng Wang d, Minhui Li a,b,c,n a

Baotou Medical College, Inner Mongolia, Baotou 014060, China Guangxi key Laboratory of Medicinal Resources Protection and Genetic Improvement, Guangxi Botanical Garden of Medicinal Plants, Nanning 530023, China c Inner Mongolia Research Center of Characteristic Medicinal Plants Cultivation and Protection Engineering Technology, Inner Mongolia, Baotou 014060, China d Department of Chemistry, Texas A&M University, College Station, TX 77840, USA b

art ic l e i nf o

a b s t r a c t

Article history: Received 3 August 2015 Received in revised form 15 March 2016 Accepted 18 March 2016 Available online 23 March 2016

Ethnopharmacological relevance: Belamcanda chinensis (L.) DC is the sole species in the genus Belamcanda Adans. (Iridaceae), found mainly in Northeast Asia. Bombus chinensis has long been used in traditional Chinese medicine for its multiple therapeutic uses in the form of antipyretic agents, antidote, expectorant, antiphlogistic and analgesic. Aim of the review: This manuscript comprehensively summarizes the various studies published in recent years on the botany, ethnopharmacology, phytochemistry, biological activity and toxicology of B. chinensis. We hope to provide a foundation for future studies on the mechanism of action and development of better therapeutic agents based on B. chinensis. Material and methods: All information available on B. chinensis was collected using electronic search engines, such as PubMed, SciFinder Scholar, CNKI, TPL (www.theplantlist.org), Google Scholar and Web of Science. Results: The analysis shown that ethno-medical uses of B. chinensis have been recorded in China, Japan and Korea since a long time. Based on a phytochemical investigation, this plant contains flavonoids, terpenoids, quinones, phenolic compounds, ketones, organic acids, etc. Crude extracts and pure compounds isolated from B. chinensis exhibited various biological effects. Conclusions: In light of its long traditional use and the modern phytochemical and pharmacological studies summarized here, B. chinensis is known to be a promising medicinal plant with the isolated extracts and chemical components showing a wide range of biological activities. Thus, it is imperative that the necessary programs and value assessment of B. chinensis be established for further studies. It is also important that the synergistic or antagonistic effects of this traditional herbal medicine are investigated in depth to identify more bioactive components by bioactivity-guided isolation strategies, and to illustrate the mechanisms of action targeting on ethnomedical uses. Future clinical studies can also focus on the main therapeutic aspects, toxicity and adverse effects of B. chinensis. & 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Belamcanda Chinensis Ethnopharmacology Phytochemistry Pharmacology Chemical compounds studied in this article: irigenin (PubChem CID: 5464170) iridin (PubChem CID: 5281777) iristectogenin A (PubChem CID: 5488781) iristectorigenin B (PubChem CID: 5491637) iristectorin A (PubChem CID: 11968629) iristectorin B (PubChem CID: 5318487) irilin D (PubChem CID: 10495590) tectorigenin (PubChem CID: 5281811) tectoridin (PubChem CID: 5281810) genistein (PubChem CID: 5280961) psi-tectorigenin (PubChem CID: 5353911) belamcandin (PubChem CID: 15290942) irilone (PubChem CID: 5281779) irisflorentin (PubChem CID: 170569) dichotomitin (PubChem CID: 5316653) hispidulin (PubChem CID: 5281628) apigenin (PubChem CID: 5280443) isorhamnetin (PubChem CID: 5281654)

Abbreviations: AMPK, Adenosine 5′-Monophosphate-Activated Protein Kinase; COX-1, Cyclooxygenase-1; COX-2, Cyclooxygenase-2; Ca2 þ -ATPase, Calcium Pump; CPAE, Calf Pulmonary Arterial Endothelial; CCl4, Carbon Tetrachloride; DPPH, 1,1-Diphenyl-2-Picrylhydrazyl; ETOH, Ethanol; EMSA, Electrophoretic Mobility Shift Assay; ELISA, Enzyme-Linked Immunosorbent Assay; ERα, Estrogen Receptor Alpha; ERβ, Estrogen Receptor β; GSH, Glutathione; GSH-px, Glutathione Peroxidase; hTERT, Human Telomerase Reverse Transcriptase; IC50, Half Maximal Inhibitory Concentration; ICR, Institute of Cancer Research; iNOS, Inducible Nitric Oxide Synthase; ISOR, Isorhapontigenin; IGF-1, Insulin-like Growth Factors-1; LXR, Liver X Receptor; LPS, Lipopolysaccharide; LLC, Lewis Lung Carcinoma; MDA, Malondialdehyde; MIC, the Minimum Inhibitory Concentration; NO, Nitric Oxide; NF-κB, Nuclear Factor Kappa B; Ovx, Ovariectomized; PPARα, Peroxisome Proliferator-Activated Receptor α; PGE2, Prostaglandin E2; RT-PCR, Reverse Transcription-Polymerase Chain Reaction; SOD, Superoxide Dismutase; TLm, Tolerance Limit; TBA, Thiobarbituric Acid; TPA, 12-O-Tetradecanoylphorbol 13-Acetate; TIMP-3, Tissue Inhibitor of Metalloproteinases-3; WAF1, Wild-Type P53-Activated Fragment-1 n Corresponding author at: Baotou Medical College, Inner Mongolia, Baotou 014060, China. E-mail address: [email protected] (M. Li). http://dx.doi.org/10.1016/j.jep.2016.03.046 0378-8741/& 2016 Elsevier Ireland Ltd. All rights reserved.

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L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

rhamnazin (PubChem CID: 5320945) rhamnocitrin (PubChem CID: 5320946) luteolin (PubChem CID: 5280445) 5,4′-dihydroxy-6, 7-methylenedioxy-3′-methoxyflavone (PubChem CID: 91573736) dichotomitin (PubChem CID: 5316653) kanzakiflavone-2 (PubChem CID: 44258472) shikimic acid (PubChem CID: 8742) gallic acid (PubChem CID: 3700) isoferulic acid (PubChem CID: 736186) vanillic acid (PubChem CID: 8468) p-hydroxybenzoic acid (PubChem CID: 135) apocynin (PubChem CID: 9804654) 4-hydroxy-acetophenone (PubChem CID: 7469) ardisianone A (PubChem CID: 6443649) 28-deacetylbelamcandal (PubChem CID: 6440311) anhydrobelachinal (PubChem CID: 10742927) epianhydrobelachinal (PubChem CID: 10790466) belachinal (PubChem CID: 10838654) ursolic acid (PubChem CID: 64945) betulin (PubChem CID: 72326) betulonic acid (PubChem CID: 9933683) betulone (PubChem CID: 24852171) cycloartanol (PubChem CID: 313075) stigmasterol (PubChem CID: 5280794) β-sitosterol (PubChem CID: 842222) daucosterol (PubChem CID: 296119)

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Botanical characterization and distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Traditional uses, preparations, and ethnopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Chemical constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.1. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.2. Terpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.3. Quinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.4. Organic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4.5. Other compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5. Pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.1. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.2. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.3. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.4. Antitumor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 5.5. Estrogen-like effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.6. Hepatoprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.7. Antidiabetic activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.8. Other activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6. Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. Introduction The genus Belamcanda Adans. (Iridaceae) comprises only one species, namely Belamcanda chinensis (L.) DC, which mainly distributed in Northeast Asia. Bombus chinensis, also known as Shegan (射干) or Jiaojiancao in China, widely used as a traditional herbal medicine in the form of antipyretic agents, expectorants, antiphlogistics, and analgesics, among other uses (Committee for the Pharmacopoeia of PR China, 2015). Studies on B. chinensis focused

on its biological activities, including antidiabetic, hepatoprotective, estrogen-like, antitumor, antioxidant, anti-inflammatory and antibacterial activities. The aim of this review is to summarize the recent findings on the botanical characterization, distribution, ethnopharmacology, phytochemistry, pharmacology and toxicity of B. chinensis from the recent literature in this field. This review will provide the groundwork for further studies on the development of better therapeutic agents and health products from B. chinensis.

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2. Botanical characterization and distribution

4. Chemical constituents

B. chinensis is a perennial herb with a pale-brown rhizome, growing up to a height of 20–120 cm. The stem is simple and typically 1–1.5 m in length, and the leaves are usually 20–60  2–4 cm in size, with an obscure midvein and an acuminate apex. The flowers are reddish orange with dark spots, 3–4 cm diameter, a slender pedicel, ovate or elliptic perianth segments on the outside (approximately 2.5  1 cm), a cuneate base, and an obtuse apex. The perianth segments contain lobes spreading with a capsule of about 2.5–3  1.5–2.5 cm, but the apex is not beaked; the stamens are approximately 1.8–2 cm in length. The male catkins of the flower are slender, 5–7 cm in length, and about 5 mm in diameter. Its flowering period lasts from June to August, with mature fruits being found from August to September. Typically, B. chinensis grows at altitudes of 2200 m from sea level, found abundantly across China (ranging from Heilongjiang province to Guangxi province and from the Inner Mongolia plateau to the coastal regions of Zhejiang) (Bhutan, India, Japan, Korea, Myanmar, Nepal, Philippines, Russia, Vietnam, and probably elsewhere). (Flora of China).

It is rich in different classes of natural products with different structural patterns in B. chinensis. In the past few decades, more than 100 chemical constituents have been isolated, including flavonoids, terpenoids, quinones, organic acids and other compounds from B. chinensis (Table 2). 4.1. Flavonoids Flavonoids are the primary active components of B. chinensis. They have highly diverse structures and a broad spectrum of biological and pharmacological activities, such as antimutagenic and antioxidant (Wozniak et al., 2006), antibacterial (Oh et al., 2001), hypoglycemic (Wu et al., 2011) and anticancer effects. At present, isoflavonoids are known to be major components among the studied chemicals. To date, 58 flavonoids were been isolated. Based on the different of substituents, they can be divided into six types of skeletons (A–F) (Ito et al.,1999; Ji et al., 2001; Jin et al., 2007a, 2007b, 2008; Liu et al., 2012; Monthakantirat et al., 2005; Qiu et al., 2006a, 2006b; Zhang et al., 2010, 2011; Zhou et al., 1996; Zhi et al., 2007).

3. Traditional uses, preparations, and ethnopharmacology 4.2. Terpenoids The rhizomes of B. chinensis have been widely used in traditional Chinese medicine as antipyretic agents, antidotes, expectorants, antiphlogistics, and analgesics (The Committee for the Pharmacopoeia of PR China, 2015). The rhizomes of B. chinensis are collected in early spring or autumn after cultivation for 2–3 years. The root was washed by immersion in water for 2–3 h, filleted and dried. The dried forms are suitable for preparing prescriptions and extracting the medicinal components. So far, there is no specific standardized method for the preparation of folk medicines. Preparation technique is based upon the plant utilized and sometimes depends on the pathogenic condition. The parts or whole plants are administered as in liquid, solid, semi-solid or gas states (Mafimisebi and Oguntade, 2010). The common preparation techniques include decoction (boiled teas), infusion (soaked teas in water), powders (crushed dried plant parts), tinctures (alcohol and water extracts), macerations (cold-soaking) and smokes or volatile oils therapy (Mohagheghzadeh et al., 2006; Ningthoujam et al., 2013). The therapeutic use of this plant was first recorded in Shennong Bencao Jing which is a monograph of traditional Chinese medicine written in A. D. 300. It described B. chinensis as an antipyretic agent, antidote, expectorant, antiphlogistic, analgesic and so on. Later, its use was documented in many other well-known medicinal works, including Shengji Zonglu (Song Dynasty, A. D. 1117), Bencao Yanyi (Song Dynasty, A. D. 1116), Bencao Jing Jizhu (Liang Dynasty, A. D. 1565) and Bencao Gangmu (Ming Dynasty, A. D. 1590). The use of B. chinensis was proposed to treat stroke, hyperhidrosis and laryngeal dryness in Shang Han Lun (Han Dynasty, A. D. 219), which is one of the earliest Chinese medical documents. According to Waitai Miyao (Tang Dynasty, A. D. 752), this plant was used as antiphlogistic and analgesic. It was also reported B. chinensis is used as an antipyretic agent, antidote, expectorant, antiphlogistic analgesic in Shiyi Dexiao Fang (Yuan Dynasty, A. D. 1345). In general, B. chinensis is used with other herbs, for example, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.), Asari Radix et Rhizoma (Asarum sieboldii Miq), Ephedrae Herba (Ephedra sinica Stapf), Asteris Radix et Rhizoma (Aster tataricus L.f), Farfarae Flos (Tussilago farfara L.) and other Chinese crude drugs in Table 1. The names of these crude drugs were established by the Committee for the Pharmacopoeia of PR China (2015). In addition, the rhizomes of B. chinensis have been traditionally used (such as Dongyi Baojian Decoction) to treat carbuncle abscesses in North Korea.

Seventeen terpenoids were isolated from the rhizomes of B. chinensis. Among them, 12 iridal-type triterpenes were isolated from the rhizomes of B. chinensis, including iridobelamal A (59), 16-O-acetyl-isoiridogermanal (60), isoiridogermanal (61), 28-deacetylbelamcandal (62), (6R,10S,11R)  26-hydroxy-(13R)-oxaspiroirid-16-enal (63), (6R,10S,11S,14S,26R)  26-hydroxy-15-methylidene-spiroirid-16-enal (64), anhydrobelachinal (65), epianhydrobelachinal (66), isoanhydrobelachinal (67), iristectorene B (68), 3-O-tetradecanoyl-16-O-acetylisoiridogermanal (69), and 3-O-decanoyl-16-O-acetylisoiridogermanal (70). Four pentacyclic triterpenoids were isolated from the ethyl acetate extract of the roots, including ursolic acid (71), betulin (72), betulonic acid (73) and betulone (74) (Liu et al., 2012). Another pentacyclic triterpenoids, cycloartanol (75), was isolated from the ethanol extracts of the rhizomes of B. chinensis (Wu et al., 2008). 4.3. Quinones To date, nine quinones were isolated from the seed of B. chinensis, including belamcandones A–D (76–79) (Swki et al., 1995), belamcand aquinone A–B (80–81), ardisianone A (82) and belamcandols A–B (83–84) (Fukuyama et al., 1993). 4.4. Organic acids Thirteen organic acid compounds were purified from ethyl acetate extracts of B. chinensis rhizomes, including five phenolic compounds were isolated from the rhizomes of B. chinensis, such as resveratrol (85), iriflophenone (86), belalloside A (87), belalloside B (88) and belamphenone (89) (Monthakantirat et al., 2005). Acetovanillone (90) was isolated from the 80% ethanol extract of B. chinensis rhizomes. In addition, two compounds were purified from the ethyl acetate extract of the rhizomes of B. chinensis, including shikimic acid (91) and gallic acid (92). In addition, isoferulic acid (93) and vanillic acid (94) were isolated from the ethanolic extract of B. chinensis (Qiu et al., 2006a, 2006b; Zhang et al., 2011). Four sterol compounds were isolated from B. chinensis, including stigmasterol (95), β-sitosterol (96), daucosterol (97), and vittadinoside (98) (Qin et al., 2004; Zhou et al., 1996).

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L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

Table 1 Traditional uses of B. chinensis. Preparation name

Shegan Mahuang Decoction

Compositiona crude drug names (Latin names of origi- Traditional uses nal plants)

Belamcandae Rhizoma (Belamcanda chinensis L.) is 9 g, Asari Radix Et Rhizoma (Asarum sieboldii Miq) is 12 g, Ephedrae Herba (Ephedra sinica Stapf) is 12 g, Asteris Radix et Rhizoma (Aster tataricus L. f) is 9 g, Farfarae Flos (Tussilago farfara L.) is 9 g, Zingiberis Rhizoma (Zingiber officinale Rosc.) is 9 g, Schisanderae Chinensis Fructus (Schisandra chinensis (Turcz.) Baill.) is 3 g Shegan Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 3 g, Angelicae Sinensis Radix (Angelica sinensis (Oliv.) Diels) is 6 g, Cimicifugae Rhizoma (Cimicifuga foetida L). is 9 g, Angelicae Dahuricae Radix (Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f.) is 3 g Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 3 g Armeniacae Semen Amarum (Prunus armeniaca L.) is 3 g. Huangqi Shegan Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 6 g Scutellaria (Scutellaria baicalensis Georgi) is 3 g Pinellia Rhizoma (Pinellia ternata (Thunb.) Breit) is 3 g Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 3 g Cimicifugae Rhizoma (Cimicifuga foetida L) is 3 g Cinnamomi Cortex (Cinnamomum Cassia) is 3 g. Luoshi Shegan Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 30 g Trachelospermi Caulis et Folium (Trachelospermum jasminoides (Lindl.) Lem) is 3 g Paeoniae Radix Alba (Paeonia lactiflora Pall) is 30 g Cimicifugae Rhizoma (Cimicifuga foetida L) is 30 g Tribuli Fructus (Tribulus terrestris L) is 30 g. Shegan Decoction (2) Belamcandae Rhizoma (Belamcanda chinensis L.) is 3 g, Fructus Arctii (Arctium lappa L.) is 1.5 g, Platycodonis Radix (Platycodon grandiflorum (Jacq.) A. DC.) is 1.5 g, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 1.5 g, Belamcandae Rhizoma (Belamcanda chinensis L.) is 3 g, Shegan Shunianzi Decoction Fructus Arctii (Arctium lappa L.) is 1.5 g, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 3 g, Cimicifugae Rhizoma (Cimicifuga foetida L) is 1.5 g, Shegan Lianqiao Belamcandae Rhizoma (Belamcanda chinensis L.) is 90 g, Decoction Forsythiae Fructus (Forsythia suspensa (Thunb.) Vahl) is 90 g, Scrophulariae Radix (Scrophularia ningpoensis Hemsl) is 90 g, Prunellae Spica (Prunella vulgaris L) is 60 g, Shegan Douling Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 40 g, Aristolochiae Fructus (Aristolochia debilis Sieb. et Zucc) is 30 g, Scutellaria (Scutellaria baicalensis Georgi) is 40 g, Mori Cortex (Morus alba L.) is 40 g, Ganzhe Shegang Belamcandae Rhizoma (Belamcanda chinensis L.) is 40 g Decoction Platycodonis Radix (Platycodon grandiflorums (Jacq.) A. DC.) is 30 g, Forsythiae Fructus (Forsythia suspensa (Thunb.) Vahl) is 40 g, Schizonepetae Herba (Schizonepeta tenuifolia Briq) is 40 g, Sophorae Tonkinensis Radix et Rhizoma (Sophora tonkinensis Gagnep) is 40 g, Arctii Fructus (Arctium lappa L.) is 40 g, Saposhnikoviae Radix (Saposhnikovia divaricata (Trucz.) Schischk.) is 30 g, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 40 g, Shegan Xiaodu Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 60 g, Scrophulariae Radix (Scrophularia ningpoensis Hemsl.) is 60 g, Forsythiae Fructus (Forsythia suspensa (Thunb.) Vahl) is 60 g, Schizonepetae Herba (Schizonepeta tenuifolia Briq) is 60 g,

References

Treating stroke, hyperhidrosis and laryngeal dryness

Shanghan Lun (Han Dynasty, A. D. 219)

Treating throat-swelling diseases

Waitai Miyao (Tang Dynasty, A. D. 752)

Treating throat-swelling diseases

Shengji Zonglu (Song Dynasty, A. D. 1117)

Treating throat-swelling diseases

Shengji Zonglu (Song Dynasty, A. D. 1117)

Treating flatulence, and for heat dissipation, detumescence, and detoxification

Shiyi Dexiao Fang (Yuan Dynasty, A. D. 1345)

Treating measles fever, mouth and tongue sores, Xiaoer Douzheng Fanglun (Song throat-swelling diseases Dynasty, A. D. 1254)

Treating hyperfunction of liver–gallbladder fire, stagnation of phlegm and gas.

Zhengzhi Zhunsheng (Ming Dynasty, A. D. 1602)

To ventilate the lung and dissipate phlegm, and clear heat from and detoxify the body.

Shazhang Yuheng (Qing Dynasty, A. D. 1675)

Treating flatulence and clearing heat, detoxifying, Songya Zunsheng (Qing Dynasty, and relieving sore throat. A. D. 1695)

Curing throat-swelling diseases

Zhangshi Yitong (Qing Dynasty, A. D. 1695)

L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

5

Table 1 (continued ) Preparation name

Compositiona crude drug names (Latin names of origi- Traditional uses nal plants)

Fructus Arctii (Arctium lappa L.) is 60 g, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 30 g, Qingwei Shegan Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 7.5 g, Ophiopogonis Radix (Ophiopogon japonicus (L. f) Ker Gawl) is 7.5 g, Cimicifugae Rhizoma (Cimicifuga foetida L) is 5 g, Rhei Radix et Rhizoma (Rheum palmatum L.) is 3.5 g, Scutellaria (Scutellaria baicalensis Georgi) is 3.5 g, Gardeniae Fructus Praeparatus (Gardenia jasminoides Ellis) is 3.5 g, Gancao Jiegeng Shegan Belamcandae Rhizoma (Belamcanda chinensis L.) is 15 g, Decoction Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 10 g, Platycodonis Radix (Platycodon grandiflorum (Jacq.) A. DC.) is 15 g, Pinellia Rhizoma (Pinellia ternata (Thunb.) Breit) is 15 g, Jiawei Shegan Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 5 g, Rehmanniae Radix (Rehmannia glutinosa Libosch) is 5 g, Platycodonis Radix (Platycodon grandiflorum (Jacq.) A. DC.) is 3.5 g, Forsythiae Fructus (Forsythia suspensa (Thunb.) Vahl) is 3.5 g, Scutellaria (Scutellaria baicalensis Georgi) is 3.5 g, Scrophulariae Radix (Scrophularia ningpoensis Hemsl.) is 3.5 g, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 3.5 g, Schizonepetae Herba (Schizonepeta tenuifolia Briq) is 3.5 g, Fructus Arctii (Arctium lappa L.) is 2.5 g, Neixiao Woxue Decoction Belamcandae Rhizoma (Belamcanda chinensis L.) is 5 g, Angelicae Sinensis Radix (Angelica sinensis (Oliv.) Diels) is 5 g, Paeoniae Radix Alba (Paeonia lactiflora Pall.) is 5 g, Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch.) is 3.5 g, Lonicerae Japonicae Flos (Lonicera japonica Thunb.) is 5 g, Forsythiae Fructus (Forsythia suspensa (Thunb.) Vahl) et al. is 5 g.

References

Curing epigastralgia

Yizong Jinjian (Qing Dynasty, A. D. 1742)

Treating throat-swelling diseases

Sisheng Xinyuan (Qing Dynasty, A. D. 1753)

Treating throat-swelling diseases

Nangmi Houshu (Qing Dynasty, A. D. 1902)

Treating carbuncle abscesses

Dongyi Baojian (North Korea Seonjo, A. D. 1596)

a All the crude drug names in column 2 were identified in line with the Chinese Pharmacopoeia (2015) and the Latin names of the original plants were identified with TPL (www.theplantlist.org).

4.5. Other compounds A range of other compounds were isolated from B. chinensis such as isorhapontigenin (ISOR), bisisorhapontigenin, apocynin, testosterone 5-α-reductase, and paraben. Three compounds iridotectorals A, B and iridobelamal A, were isolated from B. chinensis by gas chromatography–mass spectrometry (GC–MS) (Takahashi et al., 2000). To date, four ketones were isolated from B. chinensis including belamcandaphenol (99) (Wu et al., 2008), 4-hydroxy-acetophenone (100), sheganone (101) (Yu et al., 1983) and apocynin (102) (Figs. 1–5).

5. Pharmacological activities 5.1. Antibacterial activity Oh et al. (2001) evaluated the antifungal activity of B. chinensis by a single-cell bioassay method. The rhizomes of B.chinensis were collected in the vicinity of Seoul in Korea. The air-dried powders of rhizomes were soaked in 60% aqueous acetone at room temperature for 5 days. The organic solvent was removed

wad evaporated and the aqueous fraction was sequentially extracted with several organic solvents. The ethyl acetate (EtOAc) faction shown the most marked inhibiting effect and was further purified by column chromatography. Finally, tectorigenin was identified as the most active principle and its antimicrobial activity was tested against 17 strains of fungi and six strains of bacteria. Significant antifungal activity was found against dermatophytes of the genus Trichophyton with a minimum inhibitory concentration (MIC) of 3.12–6.25 mg/ml. In vivo, the bacteriostatic effect of the B. chinensis extract was determined in mice which received peritoneal injection of Staphylococcus aureus. Qin et al. (2011) found that Streptococcus pneumoniae and Pseudomonas aeruginosa were more sensitive to the B. chinensis extract than S. aureus, Bacillus coli, Streptococcus agalactiae, Micrococcus scarlatinae and Shigella dysenteriae. Among them, the MIC of S. aureus, S. pneumoniae, B. coli and P. aeruginosa was 0.0625, 0.0156, 0.2500 and 0.0312 mg/ml, respectively. Whereas the MIC values of S. agalactiae, M. scarlatinae and S. dysenteriae were 0.0156, 0.0156, and 0.0625 mg/ml, respectively. After intragastric administration of different dose (0.46, 0.92 and 1.82 g/kg) of the B. chinensis extract for 7 days, the mortality rates for mice which were injected with S. aureus suspension were 45%,

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L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

Table 2 Flavonoids from B. chinensis. No.

Name

Skeletons

R1

R2

R3

R4

R5

R6

R7

R8

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

Irigenin Iridin Iristectogenin A Iristectorigenin A Iristectorigenin B Iristectorin A Iristectorin B Irilin A Irilin D Isoirigenin Tectorigenin Tectoridin Tectorigenin-4′-glucoside Genistein Dimethyl tectorigenin Psi-tectorigenin Belamcandin 2,3-dihydroegnin 3′,4′,5,7-tetrahydroxy-4′-methoxyisoflavone 3′-hydroxy tectoridin 4′-methoxy-5,6-dihydroxyisoflavone-7-O-β-D-glucopyranoside 5,6,7,3′-tetrahydroxy-4′-methoxyisoflavone 5,6,7,3′-tetrahydroxy-8,4′, 5′-trimethoxyisoflavone 5,6,7,3′-tetrahydroxy-8-methoxyisoflavone 6-methoxy-5,7,8,4′-tetrahydryoxyisoflavone 5,7,3′-trihydroxy-8,4′-dimethoxyisoflavone 5,7,3′-trihydroxy-6,2′,5′-trimethoxyisoflavone 5,7,4′-trihydroxy-6,3′,5′-trimethoxyisoflavone 5,7-dihydroxy-6,3′,4′,5′-tetramethoxyisoflavone 4′,5,6-trihydroxy-7-methoxyisoflavone Isoirigenin 7-O-β-D-glucoside 3′,5′-dimethoxy irisolone-4′-O-β-D-glucoside Irilone Irisflorentin Nonirisflorentin Dichotomitin Irisolone Hispidulin Apigenin Isorhamnetin Rhamnazin Rhamnocitrin Luteolin 5,3′-dihydroxy-7,4′,5′-trimethoxyflavonol 3,5,3′, -trihydroxyl-7,4′,5′-trimethoxyflavone 5,7,4′-trihydroxyflavanones 5,7,4′-trihydroxyl-3′,5′-dimethoxyflavone 5,4′-dihydroxy-6,7-methylenedioxy-3′-methoxyflavone Irisflorentin Nonirisflorentin Dichotomitin Kanzakiflavone-2 2″ -O-rhamnosylisovitexin Isovitexin Swertisin 2″-O-rhamnosylswertisin 6″-O-vanilloyliridin 6″-O-p-hydroxybenzoyliridin

A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A B B B B B B C C C C C C C C C C D D D D D E E E E F F

OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH H OH OH OH OH OH OH OH OH OH OH OH OH OH OCH3 OH OCH3 OH OH OCH3 H H OH OH OH H H OH H H OH OCH3 OH OH OH Rha Rha H H H OCH3

OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 OCH3 H OCH3 OCH3 OCH3 H OCH3 H OCH3 OCH3 H OCH3 OH OH OH OH OCH3 H OCH3 OCH3 OCH3 OH H OCH3 H OCH3 OCH3 OH H OH OH OH OH OH OH OH OH OH OH OCH3 OCH3 OCH3 H H H H H H – –

OH OGlc OH OH OH OGlc OGlc OCH3 OH OH OH OGlc OH OH OH OH OCH3 OH OH OGlc OGlc OH OH OH OH OH OH OH OH OCH3 OGlc OGlc OH OCH3 OCH3 OCH3 OH OCH3 H H H H H H H H H OH OCH3 OCH3 OCH3 OH H CH3 H CH3 – –

H H H H H H H H H OCH3 H H H H H OCH3 H H OCH3 H H H OCH3 OCH3 OH OCH3 H H H H OCH3 OCH3 H OCH3 OCH3 OCH3 H OH OH OH OCH3 OCH3 OH OCH3 OCH3 OH OH H OCH3 OCH3 OCH3 H – – – – – –

H H H H H H H OH H H H H H H H H H H H H H H H H H H OCH3 H H H H – – – – – – H H OCH3 OCH3 H OH OH OH H OCH3 – – – – – – – – – – –

OH OH H OH H H H H H OH H H H H H H H OH OH OH H OH OH OH H OH OH OCH3 OCH3 H OH – – – – – – OH OH OH OH OH OH OCH3 OCH3 OH OH – – – – – – – – – – –

OCH3 OCH3 OCH3 OCH3 OH OCH3 OH H OH OCH3 OH OH OGlc OH OCH3 OH OCH3 OCH3 OH OH OCH3 OCH3 OCH3 H OH OCH3 H OH OCH3 OH OCH3 – – – – – – H H H H H H OCH3 OCH3 H OCH3 – – – – – – – – – – –

OCH3 OCH3 OH H OCH3 OH OCH3 H OH OCH3 H H H H H H OCH3 OCH3 H H H H OCH3 H H H OCH3 OCH3 OCH3 H OCH3 – – – – – – – – – – – – – – – – – – – – – – – – – – –

(Glc: β-D-glucopyranose; Rha: α-L-rhamnopyranose).

35% and 30%, respectively, compared with the control group (P o0.05 or P o0.01). 5.2. Anti-inflammatory activity Tectorigenin and tectoridin were isolated from the rhizomes of B. chinensis which are used to treat inflammation in traditional Chinese medicine. One of the anti-inflammatory mechanisms of B. chinensis rhizomes was to inhibit the induction of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) by tectorigenin and tectoridin in the inflammatory cells. To test this

hypothesis, they suppressed PGE2 production which stimulated by 12-O-tetradecanoylphorbol 13-acetate (TPA), or thapsigargin in the rat peritoneal macrophages. Tectorigenin inhibited PGE2 production more powerful than tectoridin. Neither compounds inhibited the release of radioactivity from arachidonic acid-labeled macrophages stimulated by TPA or thapsigargin. In addition, these two compounds not inhibited the activities of cyclooxygenase-1 (COX-1) and COX-2 in vitro. Western blot analysis revealed that the induction of COX-2 by TPA or thapsigargin was inhibited by the two compounds in parallel with the inhibition of PGE2 production (Kim et al., 1999).

L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

7

Fig. 1. Images of B. chinensis from Bencao Gangmu (A), flowering B. chinensis (B), and sliced roots of B. chinensis (C).

R4 R3

O

O

R5

O

R6

R2

R2

O R1

O

R1

R7

O R3

R8

R4

R4 R3

O

O

R6

R2 R1

O

R5 R2

O R1

O

O

R3

R7 R4

R8 OH

OH OH R 3O

OR 2

O

C

OR 1

OH

O

R1 O OH

H3CO OH

OH

OH

O

HO O

O

HO

HO

O

O

OCH3 OCH3

Fig. 2. The skeletal structures of flavonoids from B. chinensis.

In another study, the anti-inflammatory effects of six flavonoids isolated from the rhizomes of B. chinensis were investigated in RAW 264.7 macrophages. The results indicated that irigenin inhibited lipopolysaccharide (LPS)-induced production of nitric

oxide (NO) and PGE2 in a concentration-dependent manner. Furthermore, irigenin inhibited the expression of inducible nitric oxide synthase (iNOS) as well as COX-2 proteins and messenger RNAs (mRNAs) without any cytotoxic effect. The treatment of the

8

L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13 OR

HO HO

HO

OH

R

OH

OHC

R 59 R1=CH3 R2=CHO R3=H 60 R1=CHO R2=CH3 R3=Ac 61 R1=CHO R2=CH3 R3=H

62

O

HO

HO HO

HO

OH

OHC

OH

OHC

63

O

64

O

OR

RO

OH

OHC OH

R1 R

65 R1=CHO R2=CH3 C-13:S 66 R1=CHO R2=CH3 C-13:R 67 R1=CH3 R2=CHO C-13:S

68 R1=CO(CH2)12CH3 R2=G 69 R1=CO(CH2)12CH3 R2=Ac 70 R1= CO(CH2) 8 CH3 R2=Ac

OH

OH

OH

O HO

71

O HO

O

72

73

Fig. 3. The structures of compounds 59–73 from B. chinensis.

RAW 264.7 cells with irigenin reduced the levels of nuclear factor kappa B (NF-κB) activity and also effectively lowered NF-κB binding, as measured by the electrophoretic mobility shift assay (EMSA), which was associated with decreased p65 protein levels in the nucleus. According to the data, it suggested that irigenin decreased LPS-induced NO and PGE2 synthesis by decreasing the mRNA and protein expression of iNOS and COX-2, respectively, as well as by suppressing NF-κB activation (Ahn et al., 2006). 5.3. Antioxidant activity Wang et al. (2001) demonstrated the potent antioxidant effect of ISOR, which isolated from B. chinensis. They investigated the antioxidant activity of ISOR in vitro. Oxidative damage of rat liver microsomes, brain mitochondria and synaptosomes was induced by Fe2 þ –Cys, VitC–ADP–Fe2 þ and H2O2, respectively. They

determined the formation of malondialdehyde (MDA), the decrease of reduced glutathione (GSH) and the increase of ultraweak chemiluminescence during the lipid peroxidation process. Meanwhile, the characteristic of oxidative DNA damage induced by the CuSO4–Phen–VitC–H2O2 system was studied. The results shown that ISOR inhibited MDA formation significantly, which induced in liver microsomes, brain mitochondria and synaptosomes by Fe2 þ –Cys. In addition, ISOR significantly prevented the decrease of GSH in the mitochondria and synaptosomes induced by H2O2 and the increase of ultra-weak chemiluminescence during lipid peroxidation induced by VitC–ADP–Fe2 þ as well as oxidative DNA damage induced by CuSO4–Phen–VitC–H2O2. The effects of 10  5 to 10  6 mol/l of ISOR on the MDA formation and decrease of GSH were similar to the classical antioxidant vitamin E (10  4 mol/l). Kang et al. (2005) compared tectoridin with tectorigenin for the radical scavenging effect of intracellular reactive oxygen species

L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

9

OH O OH HO

OH

O

OH 74

75

86 O

R O O

O

OR

CH2(CH2)8CH=CH(CH2)3CH3 OR

R O O

O OH

RO

R

O 76 77 78 79

R1=R2=(CH2)9CH=CH(CH2)3CH3 R1=(CH2)9CH=CH(CH2)3CH3 R1=(CH2)9CH=CH(CH2)3CH3 R1=(CH2)11CH=CH(CH2)3CH3

R3=H R2=(CH2)9CH=CH(CH2)3CH3 R3=H R2=(CH2)16CH3 R3=H R2=(CH2)16CH3 R3=H

O

80 R1=H R2=CH2(CH2)8CH=CH(CH2)3CH3 R3=CH3 81 R1=CH2(CH2)8CH=CH(CH2)3CH3 R3=CH3

OH

R

O O

(CH2)9CH=CH(CH2)3CH3

HO

OH

OR

O 82

83 R1=OH, R2=CH3 84 R1=H , R2=H

85

O

O

O O

O

O

HO

O

O

HO

O

O O

O HO

HO

OH

O

OH OH

OH 87

88 OH

OH COCH3

HO

OH

HO

OH

OH HO

OCH

OH OH

89

90

O

HO 91

Fig. 4. The structures of compounds 74–92 from B. chinensis.

O

HO 92

10

L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13 OCH3 OH

O

O

OH CH3

O

O

O HO

O

CH3

HO OH

OH 93

94

99

100

CH3

CH3

CH3

HO

95

96

OH

OH HO

OH

HO

O

OH

O

O

O

OH

OH 97

98 O

OH

H3CO O

OH H3CO H3CO

H3CO OCH3

OCH3 101

102

Fig. 5. The structures of compounds 93–102 from B. chinensis.

(iROS) and 1-diphenyl-2-picrylhydrazyl (DPPH) free radical. They used the DCFH-DA (2′,7′-dichlorofluorescin diacetate) method to detect the levels of iROS (Rosenkranz et al., 1992) and they found that the iros scavenging activity of tectoridin was 12.1 72.3% at 0.1 μg/ml, 25.1 71.7% at 1.0 μg/ml, and 36.2 71.3% at 10 μg/ml (n ¼3/group). In the case of tectorigenin, the scavenging activity was 22.9 73.3% at 0.1 μg/ml, 42.3 72.5% at 1.0 μg/ml, and 63.2 72.3% at 10 μg/ml (n ¼3/group). N-acetylcysteine was used as a positive control, which showed 83% inhibition of iROS at 2 mM. The iROS scavenging activity of both compounds was consistent with DPPH radical scavenging activity. The DPPH radical scavenging activity of tectoridin was found to be 8.1 70.8% at 0.1 μg/ml, 17.371.1% at 1.0 μg/ml, and 39.3 71.3% at 10 μg/ml (n ¼ 3/group). In the case of tectorigenin, the scavenging activity was 9.0 7 1.2% at 0.1 μg/ml, 31.573.4% at 1 μg/ml, and 54.3 72.3% at 10 μg/ml (n ¼3/group), when compared with 90% of N-acetylcysteine. The lipid peroxidation inhibition of tectorigenin was also investigated in H2O2-treated V79-4 cells. Tectorigenin was also found to inhibit the generation of malondialdehyde and related substances that

reacted with thiobarbituric acid (TBA) with estimated activities of 28.97 1.2% at 0.1 μg/ml, 32.9 72.1% at 1.0 μg/ml, and 34.97 3.4% at 10 μg/ml, as compared to 21.7 70.3% in the untreated group (n ¼3/ group). 5.4. Antitumor activity Yamaki et al. (2002) reported the inhibitory effects of the isoflavones tectorigenin and tectoridin (a glycosylated tectorigenin) which were isolated from B. chinensis rhizomes on PGE2 production in TPA-stimulated rat peritoneal macrophages. The inhibitory effect of tectorigenin was stronger than tectoridin. They investigated the structure–activity relationship of various isoflavones in the inhibition of PGE2 production in TPA-stimulated rat peritoneal macrophages. The isoflavones investigated were isolated from the rhizomes of B. chinensis. The order of potency to inhibit PGE2 production was as follows: irisolidone, tectorigenin4genistein4tectoridin (tectorigenin 7-glucoside), glycitein4daidzein. It was not shown a significant inhibitory effect including Kakkalide (irisolidone

L. Zhang et al. / Journal of Ethnopharmacology 186 (2016) 1–13

7-xylosylglucoside), glycitin (glycitein 7-glucoside), daidzin (daidzein 7-glucoside), puerarin (daidzein 8-glucoside) and genistin (genistein 7-glucoside). These findings indicated that 6-methoxylation and 5-hydroxylation could increase the potency to inhibit PGE2 production and that 7-O-glycosylation decreases the inhibitory activity. In in vitro and in vivo, Jung et al. (2003) investigated whether tectorigenin and tectoridin isolated from B. chinensis rhizomes had an inhibitory effect on angiogenesis. Tectorigenin and tectoridin decreased the angiogenesis of both chick embryos in the chorioallantoic membrane assay and basic fibroblast growth factor-induced vessel formation in the mouse Matrigel plug assay. Both compounds also reduced the proliferation of calf pulmonary arterial endothelial (CPAE) cells and shown relatively weak gelatinase/collagenase inhibitory activity in vitro. Tectorigenin significantly reduced the tumor volume by 30.8%. When administered subcutaneously at a dose of 30 mg/kg for 20 days to mice implanted with murine Lewis lung carcinoma (LLC). Tectorigenin and tectoridin treated ICR mice bearing sarcoma 180 with the same dose for 10 days, significantly reduced the tumor weight by 44.2% and 24.8%, respectively. 5.5. Estrogen-like effect Phytoestrogens, were nonsteroidal plant-derived compounds with estrogenic activity. It could protect against the progression of prostate cancer. Morrissey et al. (2004) hypothesized that two purified phytoestrogens derived from B. chinensis extract (irigenin and tectorigenin) and the antiandrogen bicalutamide altered the cell number and enhanced antiandrogen-induced cell death in prostate cancer cells. Phytoestrogens (50–100 μM) or bicalutamide (10–50 μM) alone decreased the cell number in RWPE-1, LNCaP and PC-3 cell lines. Compared to the alone treat group, phytoestrogens (50 μM) in combination with bicalutamide (10 μM) could further decrease the number of RWPE-1 and PC-3 cells, Tectorigenin and irigenin, inhibited the proliferation of RWPE-1, LNCaP and PC-3 cells, which induced the expression of p21 (WAF1) or p27kip1 protein, whereas bicalutamide was shown to induce apoptosis in a dose-dependent manner in all three cell lines. On the contrary, phytoestrogens did not exhibit any antiandrogenic activity. These pioneering in vitro studies demonstrated the role of tectorigenin and irigenin was to regulate the cell number in prostate cancer by inhibiting proliferation through cell cycle regulation. SeidlovaWuttke et al. (Seidlova-Wuttke et al., 2004) conducted binding studies with recombinant human estrogen receptor alpha (ERα) and estrogen receptor β (ERβ) to demonstrate the ability of tectorigenin to bind to both receptor subtypes. Tectorigenin caused transactivation in ERα-expressing MCF7 and ERβ-expressing MDA-MB231 reporter gene-transfected cells. Conversely, they intravenously administered tectorigenin to ovariectomized (ovx) rats, which inhibited pulsatile pituitary luteinizing hormone (LH) secretion. In postmenopausal women, estrogen-unopposed LH pulses are correlated with hot flushes. Therefore, suppression of pulsatile LH secretion may be beneficial in women suffering from hot flushes. In ovx rats, chronic administration of 5% B. chinensis extract at a daily dose of 33 mg or 130 mg had no effect on uterine weight or on estrogen-regulated uterine gene expression. Moreover, this had no effect on the estrogenic bone and the bone mineral density of the metaphysis of the tibia established. Tectorigenin exhibited a strong hypothalamotropic and osteotropic effect, but no effect in the uterus or the mammary gland. Therefore, in future studies, tectorigenin could be established as a clinically useful estrogen receptor modulator with high selectivity. In addition, Thelen et al. (2005) found that isoflavones produced antiproliferative effects on cancer cells by disrupting steroid receptor signaling. They demonstrated the potential of compounds extracted from B. chinensis as anticancer agents, which regulated the aberrant expression of genes involved in proliferation, invasion, immortalization and apoptosis. LNCaP cells were treated with tectorigenin or

11

other isoflavones isolated from the total B. chinensis extract, and the mRNA expression was quantified using real-time reverse transcription-polymerase chain reaction (RT-PCR). In addition, enzyme-linked immunosorbent assay (ELISA), telomeric repeat amplification protocol (TRAP) assays and Western blots were used to measure the protein expression or activity. Male nude mice (n¼18) were injected subcutaneously with LNCaP cells and were fed B. chinensis extracts. Their tumor development was monitored against a control animal group (n¼ 18). As a result, PSA secretion and insulin-like growth factor-1 (IGF-1) receptor protein expression were decreased, and human telomerase reverse transcriptase (hTERT) mRNA expression and telomerase activity were decreased after treatment with tectorigenin. However, the tissue inhibitor of metalloproteinase-3 (TIMP-3) mRNA was upregulated on treatment with tectorigenin. In nude mice fed B. chinensis extracts, the growth of subcutaneous tumors was delayed and diminished. The downregulation of PDEF, PSA, hTERT, and IGF-1 receptor gene expression by tectorigenin demonstrated the antiproliferative potential of these agents. The upregulation of TIMP-3 gene expression indicated the pro-apoptotic effect of the drug and a reduction in the invasiveness of tumors. The animal experiments demonstrated that B. chinensis significantly inhibited the development of tumors in vivo. Thus, these compounds can be used to prevent or treat human prostate cancer. 5.6. Hepatoprotective activity In another important study, Jung et al. (2004) investigated whether tectorigenin and tectoridin isolated from B. chinensis rhizomes inhibited hepatic damage which induced by carbon tetrachloride (CCl4) intoxication in rats in vitro and in vivo. Tectorigenin and tectoridin significantly decreased the serum transaminase activities elevated by hepatic damage induced by CCl4 intoxication in rats, as well as inhibiting lipid peroxidation, leading to a significant decrease in MDA production by a TBA-reactant assay. Both compounds were also shown a marked increasing in the level of antioxidant enzymes, such as hepatic cytosolic superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-px). These results show that tectorigenin and tectoridin isolated exhibited not only antioxidant but also hepatoprotective effects on CCl4-intoxicated rats. 5.7. Antidiabetic activity Aldose reductase, which was the key enzyme of the polyol pathway, play key roles in diabetic complications. Therefore, the inhibitors of aldose reductase were potential agents for the prevention of diabetic complications. Jung et al. (2004) isolated 12 phenolic compounds from B. chinensis rhizomes. It investigated the effects of these compounds on rat lens aldose reductase. They found that isoflavones such as tectorigenin, irigenin and their glucosides shown a strong inhibitory effect on aldose reductase. Tectoridin and tectorigenin exhibited the highest aldose reductase inhibitory, based on the IC50 values, at a concentration of 1.08  10  6 and 1.12  10  6 M, respectively, whereas DL-glyceraldehyde was used as a substrate in both cases. When administered orally at 100 mg/kg for 10 consecutive days to rats with streptozotocin-induced diabetes, both compound significantly inhibited sorbitol accumulation in tissues such as lens, sciatic nerves, and red blood cells, and tectorigenin showed a stronger inhibitory effect than tectoridin. Overall, tectorigenin is indicated as a promising agent for the prevention and/or treatment of diabetic complications. 5.8. Other activities Irisflorentin derived from B. chinensis roots might exert its action by promoting rpn-3 expression to enhance the activity of

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proteasomes and by downregulating egl-1 expression to block apoptosis pathways. Thus, further studies of irisflorentin are guarantee for the treatment of Parkinson's disease (PD) (Chen et al., 2015). B. chinensis also exhibited hypocholesterolemic effects. Jun et al. (2012) found that iristectorigenin B reduced the macrophage cholesterol levels in vitro by activating liver X receptor (LXR) target genes, without inducing hepatic steatosis. In addition, the leaf extract of B. chinensis exhibited an antihyperlidemic effect by upregulating adenosine 5′-monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα) in the ICR mice (Zhao et al., 2014). Tectoridin could transform into the active agent to act as a potential antiallergic agent (Park et al., 2004) and reduced allergic contact hypersensitivity responses (Fu et al., 2015). Bhatia et al. (2008) shown that the modulation of microglial activation might contribute to the mechanism of cerebral protection. In addition, B. chinensis acted as an antitussive and expectorant in a mice cough model induced by ammonia and phenol red (Li et al., 2008). Jun et al. (2012) demonstrated that iristectorigenin B isolated from B. chinensis exhibited hypocholesterolemic effects by activating liver X receptor, which in turn induce the transactivation of LXR-a and LXR-b and might stimulate cholesterol efflux in macrophages without inducing hepatic steatosis. Thus, this agent can be used to develop pharmaceutical agents in the treatment of hypercholesterol.

the biological activities of this plant. Therefore, further investigations are needed to study the pharmacokinetics and features of B. chinensis and its active constituents. Furthermore, clinical studies should be established to evaluate the possible therapeutic effects to investigate side effects and toxicity of B. chinensis and its constituents to the target organs. Finally, the toxicity of B. chinensis could not describe and analyze the underlying mechanism in depth. The literature on the toxicity of B. chinensis dates back to as recently as 1999, whereas systematic toxicity and safety evaluations of the plant are lacking, and no major side effects have been discovered yet. Therefore, it needed to provide further useful physiological data. The toxicity of B. chinensis should be consider in tandem with its pharmacological effects, which will undoubtedly be one of the core topics of further research. In the present paper, we systematically reviewed the traditional uses, botany, phytochemistry, pharmacology and toxicology of B. chinensis, and hoped to provide the groundwork for further research on its mechanism of action and the development of better therapeutic agents using B. chinensis in the future. We hope this review highlights the importance of B. chinensis and provides some directions for the future development of this medicinal herb.

Acknowledgments 6. Toxicity Ito et al. (1999) investigated iridal-type the ichthyotoxic activity of triterpenoids. These compounds were extracted with hexane from the rhizomes of B. chinensis than extracted with methyl alcohol, after concentrated and partitioned with ether. The extract exhibited a toxic effect on killifish with median tolerance limit (TLm) values of 4.6 and 4.2 mg/l. In the present study, 16-O-acetylos-poro dogermanal, belachinal, and spiroirdal were found to be highly toxic to killifish with median TLm values of 1.6–3.5 mg/ml after 24 h. The TLm values of the active iridals are comparable to those of buddledin B, which was isolated as an ichthyotoxic constituent from Buddleja davidii roots and later proved to be cytotoxic against P-388 lymphocytic cells.

7. Conclusions B. chinensis widely used with various other herbal ingredients as antipyretic agents, antidotes, expectorants, antiphlogistics and analgesics. Although there were great progress in the phytochemistry and pharmacology of B. chinensis, some research areas remained to be explored for deeper insight into B. chinensis. The primary goal, for example, is to find other active molecules from B. chinensis. Apart from these bioactive compounds, B. chinensis also consisted of a significant proportion of similar compounds, including a number of flavonoids and other types of compounds, which might contain several biologically active substances. Despite many active component of B. chinensis were conducted comparatively deep research, but several aspects of these substances also remained to be elucidated. Thus, it is necessary to establish useful programs and value assessment of B. chinensis in further studies. Second, Shegan Decoction has been traditionally used with other medicinal herbs in the treatment of diseases, such as Shegan Mahuang Decoction, Huangqi Shegan Decoction, and Qingwei Shegan Decoction. Therefore, Third, system data is limited on the pharmacokinetics and clinical research of B. chinensis and only few studies of target organ toxicity had been documented. In addition, the evidence is insufficient to interpret the specific chemical mechanisms underlying

This work was financially supported by grants (81060372) (81460582) from the National Natural Science Foundation of China, Guangxi Natural Science Foundation of China (2013GXNSFBA019086) and the National “Twelfth Five-year Plan” of China Program supported by the Ministry of Science and Technology (2012BAI28B02).

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