Local and traditional uses, phytochemistry, and pharmacology of Sophora japonica L.: A review

Journal of Ethnopharmacology 187 (2016) 160–182

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

Review

Local and traditional uses, phytochemistry, and pharmacology of Sophora japonica L.: A review Xirui He a,b, Yajun Bai a, Zefeng Zhao a, Xiaoxiao Wang a, Jiacheng Fang a, Linhong Huang b,n, Min Zeng a, Qiang Zhang a, Yajun Zhang a, Xiaohui Zheng a,n a b

Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi’an 710069, PR China Hong-Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi’an 710054, PR China

art ic l e i nf o

a b s t r a c t

Article history: Received 3 January 2016 Received in revised form 11 April 2016 Accepted 11 April 2016 Available online 13 April 2016

Ethnopharmacological relevance: Sophora japonica (Fabaceae), also known as Huai (Chinese: 槐), is a medium-sized deciduous tree commonly found in China, Japan, Korea, Vietnam, and other countries. The use of this plant has been recorded in classical medicinal treatises of ancient China, and it is currently recorded in both the Chinese Pharmacopoeia and European Pharmacopoeia. The flower buds and fruits of S. japonica, also known as Flos Sophorae Immaturus and Fructus Sophorae in China, are most commonly used in Asia (especially in China) to treat hemorrhoids, hematochezia, hematuria, hematemesis, hemorrhinia, uterine or intestinal hemorrhage, arteriosclerosis, headache, hypertension, dysentery, dizziness, and pyoderma. To discuss feasible trends for further research on S. japonica, this review highlights the botany, ethnopharmacology, phytochemistry, biological activities, and toxicology of S. japonica based on studies published in the last six decades. Materials and methods: Information on the S. japonica was collected from major scientific databases (SciFinder, PubMed, Elsevier, SpringerLink, Web of Science, Google Scholar, Medline Plus, China Knowledge Resource Integrated (CNKI), and “Da Yi Yi Xue Sou Suo (http://www.dayi100.com/login.jsp)” for publications between 1957 and 2015 on S. japonica. Information was also obtained from local classic herbal literature, government reports, conference papers, as well as PhD and MSc dissertations. Results: Approximately 153 chemical compounds, including flavonoids, isoflavonoids, triterpenes, alkaloids, polysaccharides, amino acids, and other compounds, have been isolated from the leaves, branches, flowers, buds, pericarps, and/or fruits of S. japonica. Among these compounds, several flavonoids and isoflavonoids comprise the active constituents of S. japonica, which exhibit a wide range of biological activities in vitro and in vivo such as anti-inflammatory, antibacterial, antiviral, anti-osteoporotic, antioxidant, radical scavenging, antihyperglycemic, antiobesity, antitumor, and hemostatic effects. Furthermore, flavonoids and isoflavonoids can be used as quality control markers for quality identification and evaluation of medicinal materials and their preparations. Information on evaluating the safety of S. japonica is very limited, so further study is required. To enable safer, more effective, and controllable therapeutic preparations, more in-depth information is urgently needed on the quality control, toxicology data, and clinical value of crude extract and active compounds of S. japonica. Conclusions: S. japonica has long been used in traditional Chinese medicine (TCM) due to its wide range of biological activities, and is administered orally. Phytochemical and pharmacological studies of S. japonica have increased in the past few years, and the extract and active components of this plant can be used to develop new drugs based on their traditional application as well as their biological activities.

Keywords: Sophora japonica Ethnopharmacology Flavonoid Isoflavonoid Anti-inflammatory activity Anti-osteoporotic activity Hemostatic activity

Abbreviations: 2-NBDG, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose; 3T3-L1, mouse embryonic fibroblast cell line; A549, human lung carcinoma cell line; ABTS, 2, 2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); ALP, alkaline phosphatase; bFGF, basic fibroblast growth factor; BGC-823, human gastric cancer cells; C3H10T1/2, mesenchymal stem cell lines; CNE2, human nasopharyngeal carcinoma cells; CNKI, China Knowledge Resource Integrated; Com, compound; COX-2, cyclooxygenase-2; DPPH, 1, 1-diphenyl-2-picrylhydrazyl; EC50, concentration for 50% of maximal effect; ED1, monoclonal antibody; ERα, estrogen receptor alpha; EtOAc, ethyl acetate; Ref, reference; HDL-C, high-density lipoprotein-cholesterol; HepG2, liver hepatocellular carcinoma cell line; HIV-1, human immunodeficiency virus type 1; HPLC, high-performance liquid chromatography; IC50, inhibitory concentration for 50% of viability; LDL-C, low-density lipoprotein-cholesterol; IGF-I, insulin-like growth factor I; IPNI, International Plant Nutrition Institute; IκBα/β, inhibitor of NF-κB; IL, interleukin; LPS, lipopolysaccharide; MCF-7, Michigan Cancer Foundation-7; MDA, malondialdehyde; MIC, minimum inhibitory concentration; MMP-9, matrix metalloproteinase-9; NF-κB, nuclear factor kappa B; NO, nitric oxide;
OH, hydroxyl free radical; OVX, ovariectomized; PR, progesterone receptor; PMA, phorbol myristate acetate; PLs, phospholipids; RAW 264.7, murine macrophage cell lines; S180, sarcoma 180; SOD, superoxide dismutase; STZ, streptozotocin; TC, total cholesterol; TCM, traditional Chinese medicine; TG, triglycerides; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor n Corresponding authors. E-mail addresses: [email protected] (L. Huang), [email protected] (X. Zheng). http://dx.doi.org/10.1016/j.jep.2016.04.014 0378-8741/& 2016 Elsevier Ireland Ltd. All rights reserved.

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Therefore, this review on the ethnopharmacology, phytochemistry, biological activities, and toxicity of S. japonica offers promising data for further studies as well as the commercial exploitation of this traditional medicine. & 2016 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botany and ethnopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Ethnopharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Isoflavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Triterpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Other compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Extraction methods for rutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Pharmacology activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Anti-osteoporotic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Antioxidant and radical scavenging activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Antihyperglycemic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Antiobesity activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Antitumor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Whitening activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.1. Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8.2. Isolated compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.9. Hemostatic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.10. Effect on cerebral infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.11. Antiplatelet activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.12. Antifertility activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Future perspectives and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Sophora japonica L. (Fig. 1) – also known as Chinese scholar tree (Chinese: “槐,” “zhong guo huai,” or “huai shu” ), Japanese pagoda tree (in English), Hoe-wha-na-moo (in Korean), Sophora du Japon (in French), Japanischer Schnurbaum (in German), and acacia del Japón (in Spanish) – is a shrub species belonging to the subfamily Faboideae of the pea family Fabaceae (Orwa et al., 2009). It is a shade tree that grows in tropical areas, and it is commonly used for urban landscaping. S. japonica is also used in traditional medicine to cool the blood and stop bleeding (Zheng et al., 1998). More importantly, every part of this plant, including the flowers, buds, leaves, bark, and seeds, is used as medicine in Asia,

161 162 162 162 162 163 163 163 163 163 163 164 164 164 164 165 165 167 168 168 168 168 168 169 170 170 172 173 173 173 173 173 173 173 173 174 174 174 174 174 174 177 180

particularly in China, Japan, and Korea. The dry flowers (Huaihua or Flos Sophorae) and the flower buds (Huaimi or Flos Sophorae Immaturus) are included in both the Chinese Pharmacopoeia and European Pharmacopeia. Both the flower and flower buds have the same medicinal uses, with significant biological activity, in the treatment of bleeding hemorrhoids, hematuria, hematemesis, hemorrhinia, uterine or intestinal hemorrhage, metrorrhagia, leukorrhea, conjunctivitis, pyoderma, arteriosclerosis, hypertension, and dizziness (Ishida et al.,1989; Chinese Medicine Company, 1994; Tang and Eisenbrand, 1992; Han et al., 1996). The principal components of S. japonica include flavonoids, isoflavonoids, triterpene, and its glycosides, alkaloids, phospholipids (PLs), amino acids, microelements, and polysaccharides.

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Among these compounds, kaempferol (1), quercetin (21), rutin (28), isorhamnetin (34), genistein (40), and sophoricoside (52) are the major active constituents of S. japonica. Rutin (28), in particular, is the most important and abundant constituent of S. japonica. Flos Sophorae Immaturus presents a rich and important source of rutin. Rutin can be extracted from Flos Sophorae Immaturus easily and inexpensively. Modern pharmacological studies have shown that the active components and/or crude extracts of S. japonica exhibit a wide range of pharmacological actions, such as cardiovascular effects as well as anti-inflammatory, anti-osteoporotic, antioxidant, antitumor, antibacterial, antiviral, hemostatic, and anti-atherosclerotic effects. Most of these effects are consistent with those observed for S. japonica in popular medicine. Several researchers have reviewed the plant breeding, germplasm resources, chemistry, and biological activities of the Sophora genus (Krishna, et al., 2012; Mao et al., 2015). However, to date, no comprehensive review on S. japonica has been published. In the current review, we provide a better understanding and a comprehensive overview of the ethnopharmacology, phytochemistry, pharmacological activity, and toxicity of S. japonica based on a survey of the scientific literature and book records published between 1957 and 2015, which would promote the development of new drugs and better utilization of this species.

2. Botany and ethnopharmacology 2.1. Botany S. japonica is native to China, mainly distributed in the Liaoning, Shaanxi, Shanxi, Shandong, Hebei, Henan, Jiangsu, Guangdong, and Guangxi provinces. It is also found in Japan, Korea, and Vietnam, and it has been naturalized in the United States, Europe, and other parts of the world. In English, it is known as the Chinese scholar tree, Japanese pagoda tree, umbrella tree, or pagoda tree. According to Flora of China, it is a deciduous, wide-branching, small to medium-sized tree growing up to a height of 15–25 m. The bole with dark-brown bark and longitudinal cracks is generally short and dark greenish brown or dark grey–green in color, with spreading branches and paler lenticels. The leaves are pinnately compound (odd) with a length of 15–25 cm, with leaflets being alternate to subopposite, 9–15, elliptical to ovate-lanceolate, of size 2.5–7.5  1.5–5.0 cm. The plant has terminal flowers and a raceme with calyx campanulate and five denticles of 15–35-cm length. The corolla is creamy white and the calyx is 3–4 mm long, with 10 stamens. The seed pods are indehiscent, glabrous, beaded, dark brown in color, and up to 2.5–5 cm in length. S. japonica flowers between July and August, and its fruit ripens during August and October into a yellowish-brown, globose pod with one to six seeds. It is worth noting that these flowers are often mistaken for the flowers of Dolichos lablab L., Pueraria lobata (Willd.) Ohwi, and Pueraria thomsonii Benth. due to their similarities. It should also be noted that although the name S. japonica is mentioned in Flora of China and is widely accepted by scholars, Styphnolobium japonicum (L.) Schott is the current scientific name according to the plant lists of International Plant Nutrition Institute (IPNI), Tropicos, and ILDIS (http://www.ildis.org/). However, in both professional books and databases, the species is more widely known as S. japonica. 2.2. Ethnopharmacology Due to its wide range of biological and pharmacological effects, S. japonica has long been used therapeutically. Every part of the tree, especially the dried fruits, flowers, and buds, has great medicinal value in indigenous medicine. Briefly, in China, the roots

of S. japonica have been traditionally used as an insecticide in the treatment of ascaridiasis, and it is known to eliminate stasis, thus reducing swelling. Young branches of this plant at an exact dose of 15–30 g are decocted in water and used to treat eye congestion, photophobia, hemorrhoids, scabies, eczema, itchy skin, and leukorrhea (Ran, 1998). In addition, the leaves and barks of S. japonica have “heat”-clearing and toxin-removing effects, and they are mixed with other herbal medicine to treat infantile convulsion, hemuresis, eczema, scall, and ulcerative carbuncle (Han et al., 1996). The dried ripe fruit of S. japonica, also known as Fructus Sophorae or “Huai Jiao” in Chinese, was first listed in the classic Chinese medical text "Shen-Nung′s Pen-Ts′ao" 2000 years ago in the Han Dynasty, ranked as the “highest-grade” medicine. Since then, its use has been recorded in generations of classical Chinese medical texts. The dried flowers and buds of S. japonica were first recorded in “Ri Hua Zi Ben Cao (日华子本草).” In the Ming Dynasty, according to “Ben Cao Pin Hui Jing Yao (本草品汇精要),” the unopened flower is preferred, which implies that the bud of S. japonica (namely Flos Sophorae Immaturus or “Huai mi” in Chinese) was commonly used to treat various diseases. Because of its beneficial biological effects, it is used in traditional Chinese medicine (TCM) to treat conditions such as hemafecia, hemorrhoids, blood flux, dysfunctional uterine bleeding, hematemesis, and diarrhea (Kim and Yun-Choi, 2008; Ha et al., 2010). In particular, long-term consumption of the fruit extract of this plant has been shown to have no adverse effect; instead, it is useful in alleviating postmenopausal symptoms in postmenopausal women (Lee et al., 2010). In Chinese medical practice, Flos Sophorae Immaturus and Fructus Sophorae have been traditionally used either alone or in combination with several other drugs. They are also important raw materials in TCM, the pharmaceutical industry, and food industry. They are bitter in flavor and cold in nature and they have been documented in each edition of the Pharmacopoeia of the People’s Republic of China in the treatment of hemorrhoids, hematochezia, hemoptysis, epistaxis, metrorrhagia, vertigo, and headache (Chinese Pharmacopoeia Commission, 2015). Currently, many drugs (e.g., tablets, capsules, and ointments) containing Flos Sophorae Immaturus, Fructus Sophorae, or their main ingredients are being used to treat hemorrhagic disease, coronary heart disease, hypertension, and cerebral embolism (Table, 1). In particular, Huaijiao pills and Diyu huaijiao pills have been approved by the China Food and Drug Administration for the treatment of anorectal disorders, which is produced by 4120 pharmaceutical companies in China. Furthermore, Flos Sophorae Immaturus and Fructus Sophorae are considered to be nontoxic and healthy due to their well-known effects of “clearing heat and purging fire” and “cooling blood and stopping bleeding”. Due to their high nutritional value, they are macerated in wine, braised with flour, or decocted with water for oral consumption, to help prevent cardiovascular diseases. The flower, buds, and fruits of S. japonica are also used as herbal medicine in Korea and Japan. In traditional Korean medicine, the buds and fruits of S. japonica are considered effective hemostatic agents; flavonoids isolated from the buds have been shown to have hemostatic effects (Ishida et al., 1989). The leaves of this tree are used to staunch blood, decrease blood pressure, and reduce inflammation (Kim et al., 2004). In Traditional Japanese medicine, the dried flowers of the S. japonica exhibit antihemorrhagic, antihemostatic, and analgesic effects (Kitagawa et al., 1988; Ishida et al., 1989). 3. Phytochemistry To date, chemical investigations of S. japonica have led to the isolation and identification of at least 153 constituents, including

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flavonoids, isoflavonoids, triterpenoids, alkaloids, mineral elements, and amino acids. Their names, the corresponding plant part, and references are listed in Table, 2 (the structure of each compound is illustrated in Fig. 2, and the activities of some compounds are shown in Table, 3). Among these secondary metabolites, flavonoids and isoflavonoids are considered the major bioactive components of this popular medicine, which exhibits various pharmacological effects. Interestingly, the major flavonoids are mainly found in the flowers and buds of S. japonica, whereas isoflavonoid glycosides are present in the fruits and seeds (Gevrenova et al., 2007; Kite et al., 2009). It is worth noting that the flavonoid glycoside rutin (28) has been extensively studied and used in China. It is known to exhibit significant pharmacological effects including antioxidant, anti-inflammatory, anticancer, antidiabetic, anti-adipogenic, kidney-protecting, cardioprotective, neuroprotective, antimicrobial, and antiasthma effects. Thus, it is commonly used to treat hemorrhagic disease, coronary heart disease, hypertension, and cerebral embolism (Kamal, 2010; Chua, 2013). The semisynthesized flavonoid troxerutin is also used. Rutin tablets, which contain 20 mg of rutin and 50 mg of vitamin C, have been approved for clinical use by the China Food and Drug Administration. It is mainly used to improve capillary fragility associated with hemorrhagic disease, and as an adjunctive therapy in hypertensive encephalopathy, cerebral hemorrhage, retinal hemorrhage, bleeding purpura, acute hemorrhagic nephritis, recurrent epistaxis, traumatic pulmonary hemorrhage, and postpartum hemorrhage. Another important compound, isoflavonoid glycoside (sophoricoside (52)), exhibits promising biological effects, including anti-inflammatory, estrogenic, osteoblast proliferation stimulatory, antioxidant, and immunosuppressive activities (Min et al., 1999; Kim et al., 2003a; Xu et al., 2009; Izumi et al., 2000; Lee et al., 2013). Therefore, the above two compounds are documented in the Chinese Pharmacopoeia (2015 Version) as the standard for the evaluation and quality control of S. japonica and its preparations (Chinese Pharmacopoeia Commission, 2015). According to this source, the rutin content, analyzed by HPLC in the flowers and buds of S. japonica, should not be less than 6.0% and 15%, respectively. The sophoricoside content, analyzed by HPLC in the fruits of S. japonica, should not be less than 4.0% (Chinese Pharmacopoeia Commission, 2015). Furthermore, the total flavonoid content (rutin as the index component), analyzed by ultraviolet–visible spectrophotometry in the flowers and buds of S. japonica, should not be less than 8.0% and 20%, respectively, according to the 2015 edition of the Chinese Pharmacopoeia. However, it should be noted that a single component or a single class of components does not represent the bioactivities of a herb. Rather, multiple components must be analyzed to validate its quality and various preparations. 3.1. Flavonoids Flavonoids comprise the major family of compounds identified in S. japonica, with 39 flavonoids and related glycosides (1–39). Because of their beneficial biological effects, they have been increasingly studied in recent decades in China. To date, kaempferol, quercetin, and their derivatives, including kaempferol (1), kaempferol 3-O-β-rutinoside (7), kaempferol 3-O-β-D-glucopyranosyl-(12)-β-D-glucopyranoside-7-O-α-L-rhamnopyranoside (9), kaempferol 3-O-α-L-rhamnopyranosyl-(1-6)-β-D-glucopyranosyl-(1-2)-βD-glucopyranoside (12), quercetin (21), tamarixetin (23), rutin (28), isorhamnetin 3-O-β-D-rutinoside (35), and japonicasins A (38) and B (39), are best known for their antioxidant, hemostatic, antitumor, antibacterial, and anti-inflammatory effects.

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3.2. Isoflavonoids Isoflavonoids comprise a class of flavonoid phenolic compounds, many of which are biologically active, abundantly present in plants. The literature review indicates that isoflavonoids are the major and widely studied group of secondary metabolites found in S. japonica. To date, 41 isoflavonoids (40–90) have been isolated from the flowers, buds, pericarps, and other parts of S. japonica. It is worth noting that these isoflavonoids, and especially genistein and its analogues, have been identified as the bioactive components contributing to the wide range of biological properties of S. japonica including its anti-inflammatory, anti-osteoporotic, antihyperglycemic, and antiplatelet activities. In fact, the therapeutic effects of genistein (40) on syndromes associated with female postmenopause, malignant cancers, and cardiovascular diseases have been confirmed by modern research. 3.3. Triterpenoids Phytochemical investigations have shown that triterpenoids and their derivatives, especially the characterized olean-12-ene3β, 22β-diol, are generally present in the flowers, buds, and seeds of S. japonica. Before 2015, 17 compounds (91–107) were isolated and identified from S. japonica. However, few bioactive triterpenoids have been reported recently. 3.4. Alkaloids Although alkaloids are the characteristic components of the genus Sophora, only four (108–111) kinds of alkaloids have been purified and characterized from S. japonica. They are matrine (108), sophocarpine (109), N-methylcytisine (110), and cytisine (111) (Abdusalamov et al., 1972). 3.5. Other compounds To date, only few compounds other than those mentioned above have been reported. Briefly, 14 kinds of amino acids have been identified from the fruits of S. japonica, including lysine, asparagine, arginine, serine, aspartic acid, glutamic acid, threonine, alanine, proline, tryptophan, valine, phenylalanine, leucine, and isoleucine. In addition, the fruits of S. japonica are known to be rich in PLs, with neutral lipid (NL) and PL content of 7% and 1.1%, respectively. Briefly, nine kinds of PL compounds have been isolated from fruits of S. japonica: lysophosphatidylcholine (Lyso-PCs), phosphatidylinositols (PIs), phospholipid acid ethanol ester (PES), N-acyl phosphatidylethanolamines (N-acyl-PEs), hemolytic N-acyl phosphatidyl- ethanolamines (N-acyl-lyso-PEs), phosphatidic acid (PA), phosphatidic acid glycerates (PGs), phosphatidylcholines (PCs), and diphosphoglycerates (DPGs). In addition, the flowers of S. japonica contain nine mineral elements: Mg (346.6 mg/g), Fe (247.2 mg/g), Ca (132.3 mg/g), Mn (14.75 mg/g), Zn (23.94 mg/g), Cu (12.56 mg/g), Cr (0.06 mg/g), Se (0.61 mg/g), and Sr (3.83 mg/g) (Jing et al., 2012). Furthermore, a range of infrequently occurring compounds (112–153), including a few phenols, phenolic acids, and glycosides, have also been isolated from different parts of S. japonica trees (as shown in Table, 2).

4. Extraction methods for rutin Rutin, a citrus flavonoid glycoside, is the most important and abundant component of S. japonica. This section presents an overview of the extraction of rutin from Flos Sophorae Immaturus. A literature search in this field revealed various isolated methodologies for the extraction of rutin from Flos Sophorae

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Fig. 1. Sophora japonica L. (1) Chinese scholar tree, (2) Flos Sophorae, (3) Flos Sophorae Immaturus, (4) Fructus Sophorae, and (5) Honey-processed Fructus Sophorae.

Immaturus, such as alkali dissolution–acid deposition (including cold alkali extraction and hot alkali extraction), heat reflux extraction, ultrasound-assisted extraction, and microwave-assisted extraction. Therefore, the general process of isolating rutin from Flos Sophorae Immaturus is depicted in Fig. 3, and these isolated methods are compared in detail in Table, 4.

5. Pharmacology activities Flos Sophorae Immaturus and Fructus Sophorae, used in TCM, are the dried flower buds and ripe fruits of the leguminous plant S. japonica (Chinese Pharmacopoeia Commission, 2015). They are known to eliminate “heat” and purge “fire”, cool the blood, and stop bleeding, and they have been used to treat a variety of diseases in ancient China (Tian, 2002). The varied popular uses of different plant parts of S. japonica have led to many modern pharmacological investigations and clinical studies. Their anti-inflammatory, antibacterial, antiviral, anti-osteoporotic (Shim et al., 2005), antioxidant (Han et al., 2009), hemostatic, anti-angiogenic (Miura et al., 2002), and anti-atherosclerotic properties (Si and Liu, 2007) can support the wide-range use of this plant in several traditional medicine systems. Among the activities under study, the anti-inflammatory and anti-osteoporotic activities are the most commonly reported. The effects of the extract or active ingredients of S. japonica have been demonstrated in some animal models, as well as in vitro studies. However, no large clinical study has demonstrated the significant, positive effects of S. japonica. 5.1. Anti-inflammatory activity 5.1.1. Crude extracts In vitro, the ethanol extracts of Flos Sophorae exhibit significant anti- inflammatory activity by inhibiting the production of both NO and tumor necrosis factor alpha (TNF-α) in a RAW 264.7 macrophage model with IC50 values of 0.06 and 0.18 mg/mL, respectively (Zhang et al., 2011). The effects exerted by the ethanol extracts can be attributed to the high content of phenolics and flavonoids.

5.1.2. Isolated compounds To date, several papers have been published on the anti-inflammatory properties of the compounds isolated from the Chinese herb S. japonica in vitro and in vivo. Many isoflavonoids including genistein (40), genistin (41), sophoricoside (52), and orobol (78) have demonstrated strong anti-inflammatory activity by inhibiting chemical modulators (cytokines, inflammatory factors, and mediators) formed during inflammatory response. Briefly, in vitro, the isoflavonoids genistein, orobol, sophoricoside, and genistin, isolated from Fructus Sophorae, have been shown to have the most potent activity against interleukin (IL)-5 (main pro-inflammatory mediators), with the IC50 values (inhibitory potency) in the IL-5 bioassay being in the order sophoricoside (1.5 mM) 4 orobol (9.8 mM) approximately equal to genistin (10.6 mM) 4 oxyphenylbutazone (positive control, 31.7 mM) 4 genistein (51.9 mM) (Min et al., 1999). In particular, sophoricoside exhibits a significant and dose-dependent inhibitory effect in the IL-5 bioassay, with 89.0% inhibition at 12.5 mM, 82.0% at 6.3 mM, 72.0% at 3.1 mM, 59.0% at 1.6 mM, and 24.0% at 0.8 mM (Min et al., 1999). Structure–function relationship studies have shown that the planarity of the chromen-4-one ring, the presence of phenolic hydroxyl at the 4-position of the B ring, and the introduction of benzyloxy at the 5-position are structural requirements of isoflavonones for the inhibitory activity of IL-5 (Jung et al., 2003). Furthermore, sophoricoside has shown a favorable inhibitory effect on chemical mediators involved in inflammatory response in vitro. It has also shown a dose-dependent inhibitory effect on the bioactivity of members of the cytokine receptor superfamily type I including IL-3 and IL-6, but it does not affect the production of IL1β and TNF-α in RAW264.7 macrophage cell lines. It also does not affect the production of reactive oxygen species including superoxide anions in unopsonized zymosan- or phorbol myristate acetate (PMA)-stimulated human monocytes, nitric oxide in lipopolysaccharide (LPS)-stimulated murine macrophages of RAW264.7, and MPO activity from rat neutrophils. In addition, sophoricoside has been identified as a selective inhibitor of cyclooxygenase (COX)-2 activity with an IC50 value of 4.4 mM, although it does not show any inhibitory effect on the synthesis of COX-2 (Kim et al., 2003a; Yun et al., 2000).

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Fig. 2. The chemical structure of compounds from Sophora japonica.

In vivo, sophoricoside (administered orally at 4100 mg/kg or injected intravenously at 410 mg/kg) significantly suppresses carrageenin- or croton oil-induced paw edema in mice (Kim et al., 2003b). At doses of 3 and 10 mg/kg, sophoricoside ameliorates 2, 4-dinitrochlorobenzene-induced acute and chronic contact dermatitis by 50–70%. Recent studies have shown that sophoricoside improves contact dermatitis mainly by inhibiting the phosphorylation and degradation of IκBα/β as well as the nuclear

translocation of nuclear factor kappa B (NF-κB) p65 in B cells (Lee et al., 2013). 5.2. Antibacterial activity 5.2.1. Crude extracts In vitro, the ethanol extract from flower buds of S. japonica exhibits a significant antibacterial activity against Staphylococcus

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Fig. 2. (continued)

aureus, Propionibacterium avidum, and Propionibacterium acnes under weak acidic conditions (Kimura and Yamada, 1984). The ethyl acetate (EtOAc)-soluble fraction is effective in inhibiting Escherichia coli and Klebsiella pneumoniae with a minimum inhibitory concentration (MIC) value of 125 and 125 mg/mL, respectively (Park et al., 2009). Furthermore, the essential oil extracted

from Flos Sophorae Immaturus is active against S. aureus with a minimal lethal concentration of 0.39 μL/mL for the spread-plate method. This essential oil also exhibits an antibacterial effect on S. aureus ATCC 6538, Salmonella typhi CMCC 50,013, Shigella dysenteriae CMCC 51,334, and E. coli ATCC 8099 with MIC50 values of 0.39, 0.78, 1.56, and 425 μL/mL (Chen et al., 2008). Thus, the

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Fig. 2. (continued)

essential oil can be used as a natural food preservative (Yao et al., 2011). 5.2.2. Isolated compounds Yang et al. (2015) isolated two maltol derivatives such as maltol 3-O-(4′-O-p-coumaroyl-6′-O-(3-hydroxy-3-methylglutaroyl))-βglucopyranoside (119), maltol-3-O-(4′-O-cis-p-coumaroyl-6′-O-(3-

hydroxy-3-methylglutaroyl))-β-glucopyranoside (120), together with kaempferol-3-rutinoside (7), and isorhamnetin 3-O-β-D-rutinoside (35) from the dried flowers of S. japonica, which significantly inhibited the action of sortase A (SrtA) from Streptococcus mutans. Among them, the compound 120 showed the strongest inhibitory effect on saliva-induced aggregation in S. mutans with an IC50 value of 58.6 mM (Yang et al., 2015).

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Fig. 2. (continued)

5.3. Anti-osteoporotic activity 5.3.1. Crude extracts Osteoporosis is a disease caused by hormonal deficiency, especially in menopausal women. In vivo, hot water extract of Fructus Sophorae, at oral dosage of 0.556 g/kg/day for 9 weeks, has been shown to increase trabecular bone area in the tibia and lumbar of ovariectomized (OVX) rats. It is also known to significantly decrease deoxypyridinoline (Dpd: bone resorption marker) and elevate calcium (Ca: bone formation marker) levels in OVX rat serum (Shim et al., 2005). In vitro, the dichloromethane fractionated extracts from the mature fruit of S. japonica stimulates alkaline phosphatase (ALP) activity and matrix mineralization of C3H10T1/2 clone 8 cells in a dose-dependent manner. These extracts also induce the expression of osteoblast markers such as ALP, osterix, and osteocalcin in C3H10T1/2 and primary bone marrow cells in a dose-dependent manner. In addition, the dichloromethane fractions also induce ALP expression in freshly isolated mouse embryonic fibroblasts. Further studies show that genistein is the most abundant compound (8.0 7 0.08 g/kg) in the dichloromethane fractions, which points to genistein as the key phytoestrogen and critical pro-osteogenic compound in dichloromethane extracts (Yoon et al., 2013). 5.3.2. Isolated compounds The isoflavones extracted from Fructus Sophorae has been shown to exert potential anti-osteoporotic effects in in vitro and in vivo models (Joo et al., 2003; Joo et al., 2005). Genistin, genistein, kaempferol, rutin, and quercetin are important phytoestrogens and pro-osteogenic constituents of S. japonica. In particular, isoflavonoids represented by genistein showed therapeutic effects in the case of osteoporosis. Isoflavonoids have been the focus of studies on the natural phytoestrogens and glucosidic isoflavone complex extracted from Fructus Sophorae. They have been found to

upregulate insulin-like growth factor I (IGF-I) and transforming growth factor beta (TGF-β) and to inhibit osteoclastogenesis in rat bone marrow cells (Joo et al., 2004). Wang et al. (2006a) indicated that treatment with 4.5 or 9 mg/kg of genistein prevented osteoporosis in OVX rats significantly after 4 weeks (Wang et al., 2006a). In 2014, Abdallah et al. showed that sophoricoside isolated from S. japonica seeds exhibited potential anti-osteoporotic effect. In OVX rats, oral administration of 15 and 30 mg/kg for 45 days increased the level of ALP and osteocalcin, decreased the level of serum acid phosphatase, and ameliorated ovariectomy-induced osteoporosis in a dose-dependent manner. Furthermore, with sophoricoside treatment at a dose of 30 mg/kg, the original mechanical bone hardness was regained in osteoporotic rats compared with normal non-osteoporotic rats (Abdallah et al., 2014). 5.4. Antioxidant and radical scavenging activities 5.4.1. Crude extracts Many studies have provided data on the antioxidant and radical scavenging activities of S. japonica extracts. Park et al. (2009) studied the antioxidant activity of n-hexane, EtOAc, n-butanol, and water fractions partitioned from the methanolic extract of Flos Sophorae, with the EtOAc-soluble fraction exhibiting the highest antioxidant activity (RC50 ¼3.13 μg/mL) (Park et al., 2009). The ethanol extracts of S. japonica also displayed potent antioxidant effects in a yeast model (Saccharomyces cerevisiae). Wang et al. (2006b) demonstrated the in vitro antioxidant activities of the ethanol extracts of S. japonica in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radical scavenging assay, with IC50 values of 14.46 and 1.95 mM/mL, respectively. Zhang et al. (2011) suggested the role of total phenolics and flavonoids in the observed antioxidant activity of the extracts. In addition, flavonoids extracted from S. japonica leaves can be used as a natural antioxidant in both the medical and food

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Fig. 2. (continued)

industries. The antioxidant activity of flavonoids from S. japonica leaves has been investigated using an 2, 2′- azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) removal system, DPPH removal system, H2O2/Fe2 þ salicylic system, nitroso removal system, Prussian blue method, and pyrogalla autoxidation system. The results show that, at a concentration of 50 μg/mL, the scavenging rates of S. japonica leaves on ABTS, DPPH,
OH, NO2  , and O
2  are

62.09%, 47.70%, 43.28%, 22.11%, and 21.83%, respectively (Li et al., 2013). 5.4.2. Isolated compounds Kim et al. (2004) showed that the compounds kaempferol 3-Oα-Lrhamnopyranosyl-(1-6)-β-D-glucopyranosyl-(1-2)-β-Dglucopyranoside (12),kaempferol 3-O-[α-L-rhamnopyranosyl-(1-

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Fig. 2. (continued)

6)]-[β-D-glucopyranosyl-(1-2)]-β-D- glucopyranoside (13), and kaempferol 3-O-β-D-glucopyranosyl-(1-2)-β-D- glucopyranoside-7-O-α-L-rhamnopyranoside (15) exhibited antioxidant activities in DPPH and cytochrome-c assay with IC50 values of 25.5, 25.3, 26.6, 25.8, 25.7, and 27.1 mM, respectively (Tang et al., 2002b). Moreover, gallic acid 4-O-β-D-(6′-O- galloyl)-glucopyranoside (146) isolated from Fructus Sophorae showed potent antioxidant

activity against radical scavenging of DPPH with an IC50 value of 17.1 mg/mL (Kim et al., 2004). 5.5. Antihyperglycemic activity 5.5.1. Crude extracts S. japonica extracts exhibit potent antihyperglycemic activity

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Fig. 2. (continued)

in vivo. Jung et al. (2006) found that the oral administration of S. japonica extracts for 4 weeks significantly reduced the blood glucose levels and significantly decreased the levels of thiobarbituric

acid-reactive substance in rats with streptozotocin (STZ)-induced diabetes (Jung et al., 2006). Oral administration of total flavonoids of Flos Sophorae (150, 300, and 600 mg/kg) to these rats once daily

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Fig. 2. (continued)

for 30 days significantly decreased the level of blood sugar and leptin, and increased the level of insulin and C-peptide, indicating a favorable hypoglycemic effect (Miao et al., 2011).

5.5.2. Isolated compounds In vitro studies have shown that the isolated flavonoids rutin, tamarixetin (23), and kaempferol and the isoflavonoids cajanin

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173

Fig. 3. The general process of isolating rutin from Flos Sophorae Immaturus.

(76), pratensein (77), and orobol (78) from the EtOAc-soluble fraction of Flos Sophorae significantly improve basal glucose uptake in HepG2 cells in a concentration-dependent manner. Interestingly, the effects of compounds such as tamarixetin, kaempferol, cajanin, and pratensein are stronger than those of rosiglitazone, which is used in combination to treat diabetes. Furthermore, quercetin 3-O-β-D-glucopyranosyl-(1-3)-O-α-L-rhamnopyranosyl- (1-6)-O-β-D-glucopyranoside (33) from Flos Sophorae at 10 mM has been shown to increase glucose uptake in differentiated adipocyte 3T3-L1 cells (Ha et al., 2010). These results highlight the potential of these compounds as hypoglycemic drugs and/or functional natural food additives (Chen et al., 2010). 5.6. Antiobesity activity 5.6.1. Crude extracts Obesity is a noticeable risk factor for metabolic disorders, coronary heart disease, diabetes, hypertension, and certain forms of cancer (Hajer et al., 2008). Thus, it may reduce life expectancy and/ or increase health problems. In vivo, S. japonica can be used to control body weight and obesity-related metabolic diseases. Oral administration of total flavonoids from Fructus Sophorae at doses of 40, 80, and 120 mg/kg once daily for 6 weeks can decrease the total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) levels, and increase the high- density lipoprotein-cholesterol (HDL-C) level in the blood in lipid metabolite of high-lipid rats (Wang et al., 2009). Diets containing mature fruits of S. japonica prevent body weight gain in high-fat diet-induced obesity. S. japonica (5%) in combination with a 30% high-fat diet for 4 weeks significantly decreases body weight gain, reduces serum and hepatic TG levels, and reduces the serum TC and HDL-C levels in C57BL/6 mice. In addition, S. japonica decreases the number of large adipocytes while also increasing the number of small adipocytes, and lowering the glucose level and fat mass in high-fat diet-induced obese mice (El-Halawany et al., 2009). In vitro, at a concentration of 50 mg/mL, the EtOAc extracts of mature fruit of S. japonica inhibit morphological differentiation and lipid accumulation in C3H10T1/2 and 3T3-L1 preadipocytes. Molecular studies indicate that the EtOAc fraction extracts also reduce the expression of peroxisome proliferator-activated receptor γ and other adipocyte markers. Furthermore, the EtOAc fraction extracts have the highest total phenolic contents, with genistein probably mediating the anti-adipogenic effects of the EtOAc fractions (Jung et al., 2011). 5.6.2. Isolated compounds In 2010, Ha et al. showed that quercetin (21) and quercein 3-O[β-D- glucopyranosyl-(1-3)-O-α-L-rhamnopyranosyl-(1-6)-O-βD-glucopyranoside (33) from Flos Sophorae are endogenous adipogenesis inhibitors, exhibiting significant inhibitory effects on lipid accumulation and adipocyte differentiation in a dose- dependent manner by regulating the adenosine monophosphate-

activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling pathways (Ha et al., 2010). 5.7. Antitumor activity 5.7.1. Crude extracts Several in vivo and in vitro studies have demonstrated the significant inhibitory effect of S. japonica on cancer. Oral administration of ethanol extracts of Flos Sophorae (50, 100, and 200 mg/ kg) to sarcoma 180 (S180) tumor-bearing mice once a day for 21 days significantly increases thymus and spleen coefficients as well as body weight, with a tumor inhibition rate of 29%. These extracts also increase the levels of superoxide dismutase (SOD) and IL-2, and decrease the levels of malondialdehyde (MDA), TNF-α, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and matrix metalloproteinase (MMP-9) in the serum of tumor-bearing mice. In vitro, at doses ranging from 31.25 to 500 μg/mL, Flos Sophorae could inhibit the proliferation of S180 cells in a dose-dependent manner (Chen et al., 2014). Phytochemicals such as flavonoids and isoflavonoids may be responsible for these inhibitory effects. 5.7.2. Isolated compounds Quercetin isolated from Flos Sophorae can significantly inhibit the growth of Michigan Cancer Foundation-7 (MCF-7) and human nasopharyngeal carcinoma cells (CNE2) in a dose- and time-dependent manner (Gu et al., 2012; Zhang et al., 2012). In addition, three isoflavonoids, namely genistein, sophoricoside, and genistin, isolated from fruits of S. japonica at 100 mg/mL, show positive antitumor activity with inhibitory rates of 82.01%, 38.87%, and 32.97% for A549, and 91.25%, 23.26%, and 13.98% for BGC-823, respectively (Ma and Lou, 2006). 5.8. Whitening activity 5.8.1. Crude extracts Plant-based skin-care products have become increasingly popular. In 1997, with the aim of developing whitening products, Lee et al. (1997) evaluated the in vitro inhibition of tyrosinase and DOPA autooxidation activity of 100 plant extracts. They concluded that S. japonica significantly inhibits mushroom tyrosinase activity (Lee et al., 1997). In addition, S. japonica extracts exhibit potent inhibitory effects on melanin; thus, they may be considered for use in cosmetic skin-whitening applications and as tyrosinase and melanogenesis inhibitors (Wang et al., 2006b). Lai et al. (2014) further indicated that, at a concentration of 0.1%, the weak acidtreated flavonoid complex from S. japonica shows a marked tyrosinase inhibitory activity equivalent to that of 1% ascorbic acid or hydroquinone. These data suggest that S. japonica may be used as a functional agent in medicine, food products, and cosmetics for its significant anti- tyrosinase activity (Lai et al., 2014).

174

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Table 1 The prescriptions and traditional uses of Sophora japonica in China. Preparation name

Main composition

Traditional use

Reference

Curing hematochezia, hemorrhoids, and Chinese Pharmacopoeia ComFructus Sophorae (Sophora japonica L.), Sanguisorba officinalis L., Anmission (2015) gelica sinensis (Oliv.) Diels, Saposhnikovia divaricata (Turcz.) Schischk., sore pain Curing hypertension Dong and Wang (2001) Scutellaria baicalensis Georgi, Citrus aurantium L. Curing toothache Ma (1995) Curing acne Xie and Dai (1999) Diyu huaijiao pills Sanguisorba officinalis L., Fructus Sophorae, Flos Sophorae, Scutellaria Curing hematochezia, hemorrhoids, and Chinese Pharmacopoeia Commission (2015) baicalensis Georgi, Rheum palmatum L., Rehmannia glutinosa (Gaert.) constipation Libosch. ex Fisch. et Mey., Angelica sinensis (Oliv.) Diels, Paeonia lactiflora Pall., Saposhnikovia divaricata (Turcz.) Schischk., Nepeta cataria L., Citrus aurantium L. Huaijiao tea Fructus Sophorae Curing hemorrhoids and vertigo Cao (1983) Huaizi pills Fructus Sophorae Curing hernia “Shengji Zonglu” (Song Dynasty) Mingmu Huaizi pills Fructus Sophorae, Coptis chinensis Franch. Improving eyesight “Taiping Royal Prescriptions” (Song Dynasty) Huaizi Fang Ox gallbladder, Fructus Sophorae Curing malnutritional dampness “Prescriptions for Universal Relief” (Ming Dynasty) Huaizi San Fructus Sophorae, Fructus Aurantii Submaturus (Citrus aurantium L.) Curing bloody stranguria, and uterine “Liang peng Huiji” (Qing Dynasty) bleeding Huihua San (i) Flos Sophorae (Sophora japonica L.), Platycladus orientalis (L.) Franco, Curing hemorrhoidal hemorrhage, dys- “Puji Benshi Fang” (Song Dynasty Nepeta cataria L., Fructus Aurantii Submaturus entery, and hematochezia ) Huihua San (ii) Flos Sophorae, Gardenia jasminoides Ellis Curing gastric distention, dysentery, and “Jingyan Liangfang” (Qing hematochezia Dynasty) Huihua wine Flos Sophorae Curing sore and gangrene “Waike Fahui” (Ming Dynasty) Huihua soup Flos Sophorae, Vigna umbellata (Thunb.) Ohwi et Ohashi, Moschus Curing ecthyma “Zhidou Quanshu” (Ming Dynasty) Huihua pills Flos Sophorae, Typha angustifolia L. Sanguisorba officinalis L., SelagiCuring hematochezia “Jifeng Puji Fang” (Song Dynasty ) nella tamariscina (P. Beauv.) Spring, Zingiber officinale Roscoe Huihua Jinyin wine Flos Sophorae, Flos Lonicerae (Lonicera japonica Thunb.) Curing sores and ulceration “Yixue Qimeng” (Qing Dynasty) Huihua zhiqiao San Flos Sophorae, Coptis chinensis Franch., Fructus Aurantii Submaturus Curing hemorrhoids and hematochezia “Puji Fang” (Song Dynasty ) Huaixiang San Flos Sophorae, Moschus Curing hematemesis “Shengji Zonglu” (Song Dynasty) Huaihuang pills Coptis chinensis Franch., Flos Sophorae Curing hemorrhoidal hemorrhage “Gujin Yijian” (Ming Dynasty) Curing headache, vertigo, conjunctival Chinese Pharmacopoeia ComJiangya pills Concha Margaritifera Usta, Gentiana scabra Bunge, Flos Sophorae mission (2015) Immaturus, Prunella vulgaris L., Rehmannia glutinosa (Gaert.) Libosch. congestion, tinnitus, and hypertension ex Fisch. et Mey., Achyranthes bidentata Blume Huaijiao pills

5.8.2. Isolated compounds N-feruloyl-N′-cis-feruloyl-putrescine (151) isolated from S. japonica is known to inhibit tyrosinase activity in human epidermal melanocytes with minimal cytotoxic effects (cell viability 490% at 100 mM) and an IC50 value of 85.0 μM (Lo et al., 2009), thus finding application in skin-care and whitening products.

ischemia–reperfusion cerebral infarction (Lao et al., 2005). Based on these findings, S. japonica is known to reduce cerebral infarction partly due to its antiplatelet, antioxidant, and anti-inflammatory activities.

5.9. Hemostatic activity

Genistein (40), biochanin A (64), tectoridin (72), and irisolidone (73) isolated from methanol extracts of S. japonica exhibit superior inhibitory effects on platelet aggregation induced by arachidonic acid and U46619 (a thromboxane A2 mimetic agent) with IC50 values of 20.3 and 53.8 μM, 19.9 and 99.8 μM, 25.9 and 123.4 μM, and 1.6 and 15.6 μM, respectively, compared to drugs such as aspirin (IC50: 63.0 and 350.0 μM) (Kim and Yun-Choi, 2008). Thus, these antiplatelet compounds may have wide therapeutic potential for various circulatory diseases such as cerebral infarction.

Fructus Sophorae has been traditionally used in China and Korea as an antihemorrhagic agent, for the purpose of clearing “heat,” purging pathogenic “fire,” and cooling the blood. Modern pharmacological studies have shown that Fructus Sophorae can promote blood coagulation and reduce the permeability of blood vessel walls because of the presence of glucosides (Wang et al., 2002). Flos Sophorae extracts, which are rich in quercetin (21), isorhamnetin (34), isorhamnetin-3-O- rutinoside (35), kaikasaponin I (96), and rutin, can significantly shorten the bleeding time and recalcification time in mice, indicating a favorable antihemorrhagic effect (Ishida et al., 1989; Zhao et al., 2010). 5.10. Effect on cerebral infarction A cerebral infarction is a type of ischemic stroke due to a blockage in the blood vessels supplying blood to the brain. The aqueous extract of S. japonica shows a positive effect against myocardial infarction. Pretreatment with 100 or 200 mg/kg of S. japonica and posttreatment with 200 mg/kg of S. japonica lead to a significant reduction in the area of cerebral infarction and the grade of neurological deficit. Pretreatment with 200 mg/kg of S. japonica also significantly reduces microglial activation, ED1 and IL-1β release, and the number of apoptotic cells in rats with

5.11. Antiplatelet activity

5.12. Antifertility activity Kaempferol, genistein, and sophoricoside isolated from fruits of S. japonica show antifertility effects in laboratory animals (Ho et al., 1982, 1984). Further study shows that sophoricoside could impair embryo implantation by modulating the expression levels of estrogen receptor alpha (ERα) and progesterone receptor (PR) in the uterus, affecting the formation of pinopodes and reducing mouse endometrial receptivity (Qu et al., 2014).

6. Toxicity Information on the side effects and safety evaluations for S. japonica is limited, although this plant is frequently used in TCM.

X. He et al. / Journal of Ethnopharmacology 187 (2016) 160–182

175

Table 2 The compounds isolated from Sophora japonica (Structure of each compound illustrated in Fig. 2 and the activities of some compounds are shown in Table, 3). NO. Compounds

Resource

Ref.

Flavonoids 1 Kaempferol

A; D; E; G; J

2 3 4 5

B; C; D; J F E D; E; F

Ho et al. (1982); Tulaganov and Gaibnazarava (2001); Tang et al. (2002a); Wang et al. (2008); Chen et al. (2010); Diao et al. (2011) Tang et al. (2001a, 2008a); Ha et al. (2010) Wang et al. (2001) Akhmedkhodzhaeva and Svechnikova (1983) Ho et al. (1982); Tulaganov and Gaibnazarava (2001); Wang et al. (2003a)

G

Kite et al. (2007)

B; E

Tang et al. (2001a); Yang et al. (2015)

D D

Tang et al. (2001b) Tang et al. (2001b, 2002b)

G

Kite et al. (2007)

G

Kite et al. (2007)

D; F

Ho et al. (1984); Tang et al. (2002b); Abdallah et al. (2014)

D

Tang et al. (2002b)

E

Kim et al. (2004)

E; F

Kite et al. (2009)

F

Wang et al. (2003a)

G

Kite et al. (2007)

E; F

Kite et al. (2009)

E; F

Kite et al. (2009)

E; F

Kite et al. (2009)

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

Kaempferol 3-O-β-D-glucopyranoside Kaempferol 7-O-α-L-rhamnopyranoside Kaempferol 3,7-diglucoside Sophoroflavonoloside (Kaempferol-3-diglycoside; Kaempferol 3-Oβ-Glc(1-2)-β-Glc; Kaempferol-3-O-β-D- sophoroside) Kaempferol 3-O-α-rhamnopyranosyl (1-6)- β-galactopyranoside (Kaempferol 3-O- robinobioside) Kaempferol 3-O-α-rhamnopyranosyl(1-6)- β-glucopyranoside (Kaempferol 3-O-β- rutinoside) Kaempferol 3-O-(2′-O-β-D-glucosy1)-β- D-rutinoside Kaempferol 3-O-β-D-glucopyranosyl-(1- 2)-β-D-glucopyranoside7-O-α-L- rhamnopyranoside Kaempferol 3-O-α-rhamnopyranosyl(1- 2)[α-rhamnopyranosyl (1-6)]-β- glucopyranosides Kaempferol 3-O-α-rhamnopyranosyl(1- 2) [α-rhamnopyranosyl (1-6)]-β- galactopyranoside Kaempferol 3-O-α-L-rhamnopyranosyl- (1-6)-β-D-glucopyranosyl-(1-2)-β-D- glucopyranoside Kaempferol 3-O-[α-L-rhamnopyranosyl- (1-6)]-[β-D-glucopyranosyl-(1-2)]-β-D- glucopyranoside Kaempferol-3-O-β-D-glucopyranosyl-(1- 2)-α-L-rhamnopyranosyl-(1-6)-β- glucopyranoside Kaempferol 3-O-β-glucopyranosyl(1-2)-β- galactopyranoside-7O-α-rhamnopyranoside Kaempferol 3-O-α-L-rhamnopyranosyl (1- 6)-β-D-glucopyranosyl (1-2)-β-D- glucopyranoside-7-O-α-L-rhamnopyranoside Kaempferol 3-O-α-rhamnopyranosyl (1-2) [α-rhamnopyranosyl (1-6)]-β- galactopyranoside-7-O-α-rhamnopyranoside Kaempferol 3-O-β-xylopyranosyl(1-3)-α- rhamnopyranosyl (16) [β-glucopyranosyl (1-2)]-β-glucopyranoside Kaempferol 3-O-β-glucopyranosyl(1- 2)[α-rhamnopyranosyl(16)]-β- glucopyranoside-7-O-α-rhamnopyranoside Kaempferol 3-O-β-glucopyranosyl(1- 2)[α-rhamnopyranosyl (16)]-β- galactopyranoside-7-O-α-rhamnopyranoside Quercetin

Kimura and Yamada (1984); Ishida et al. (1987); Tulaganov and Gaibnazarava (2001); Tang et al. (2002b); Wang et al. (2008); Diao et al. (2011) 3′-methylquercetin A; B Lo et al. (2009) Tamarixetin (4′-O-methyl quercetin) G; B Chen et al. (2010); Mohamed et al. (2015) Isoquercitrin (Quercetin 3-O-β- glucopyranoside) A; B; C; D; J Li et al. (2010); Tang et al. (2001a, 2008a); Ha et al. (2010) Quercitrin (Quercetin3-O-L-rhamnoside) E; G; I Kim and Yun-Choi (2008) Quercetin-3-O-β-L-rhamnopyranosyl-(1-6)- β-D-glucopyranoside D Liu et al. (2007a) Quercetin 5-O-β-D-glucopyranoside B; C Ha et al. (2010) Rutin (Quercetin 3-O-α-rhamnopyranosyl (1-6)-βA; D; E; F; G; J Ho et al. (1982); Kimura and Yamada (1984); Tulaganov and Gaibnazarava glucopyranoside) (2001); Tang et al. (2001a); Wang et al. (2001); Kim et al. (2004); Kim and Yun-Choi (2008); Tang et al. (2008a); Abdallah et al. (2014) Rutin-7-O-rhamnoside A; B Kite et al. (2009) Quercetin 3-O-α-rhamnopyranosyl(1- 2)[α-rhamnopyranosyl(1- G Kite et al. (2007) 6)]-β- glucopyranosides Quercetin 3-O-α-rhamnopyranosyl (1-2) [α-rhamnopyranosyl G Kite et al. (2007) (1-6)]-β- galactopyranoside-7-O-α-rhamnopyranoside B; C Ha et al. (2010) Camellianoside (Quercein 3-O-β-D- xylopyranosyl-(1-3)-O-α-Lrhamnopyranosyl-(1-6)-O-β-D-glucopyranoside) Quercein 3-O-β-D-glucopyranosyl-(1-3)- O-α-L-rhamnopyrB; C Ha et al. (2010) anosyl-(1-6)-O-β-D- glucopyranoside Isorhamnetin A; D; G Ishida et al. (1989); Tang et al. (2002b); Diao et al. (2011) Narcissin (Isorhamnetin-3-rutinoside) A Kimura and Yamada (1984); Yang et al. (2015) Apigenin E; G; I Kim and Yun-Choi (2008) Isoscutellarein F Wang et al. (2001) Japonicasins A G Zhang et al. (2013) Japonicasins B G Zhang et al. (2013)

Isoflavonoids 40 Genistein

41

Genistin (Genistein 7-glucoside)

42 43

Genistein 7-O-β-D-cellobioside Genistein 7-O-β-D-glucopyranoside-4′-O- β-D-glucopyranosiderhamnopyranoside Genistein 7-O-β-D-glucopyranoside- 4′-O- [(β-D-glucopyranosyl)(1-2)-β-D- glucopyranoside]

44

A; D; E; G; J

A; D; E; F; G; I; Ho et al. (1982); Tulaganov and Gaibnazarava (2001); Wang et al. (2001, J 2008); Tang et al. (2002b); Kim et al. (2004); Ma and Lou (2006); Kim and Yun-Choi (2008); Chen et al. (2010); Diao et al. (2011) D; E; G; I; F; J Tang et al. (2001c, 2008a); Ma and Lou (2006); Kim and Yun-Choi, (2008); Abdallah et al. (2014) D Ho et al. (1984) D; F Ho et al. (1984); Tang et al. (2001a) D

Tang et al. (2001a)

176

X. He et al. / Journal of Ethnopharmacology 187 (2016) 160–182

Table 2 (continued ) NO. Compounds

Resource

Ref.

45

D

Tang et al. (2001a)

D

Tang et al. (2001a)

D

Tang et al. (2001a)

G

Tang et al. (2008b)

G

Tang et al. (2008b)

50

Genistein 7-O-α-L-rhamnopyranoside-4′- O-[(β-D-glucopyranosyl)(1-2)-β-D- glucopyranoside] Genistein 7-O-α-L-rhamnopyranoside- 4-O- [(α-L-rhamnopyranosyl)-(1-2)-β-D- glucopyranoside] Genistein 7-O-β-D-glucopyranoside-4′-O- [(α-L-rhamnopyranosyl)(1-2)-β-D- glucopyranoside] Genistein 7-O-β-D-glucopyranoside-4′-O- (6′-O-α-L-rhamnopyranosyl)-β-sophoroside Genistein 7-O-α-L-rhamnopyranoside-4′-O- (6′-O-α-L-rhamnopyranosyl)-β-sophoroside Genistein-7, 4′-di-O-β-D-glucopyranoside

D; E; F; J

51 52

Genistein-4′-O-L-rhamnopyranoside Sophoricoside (Genistein-4′-glycoside)

E D; E; F; J

53

Sophorabioside

D; E; F; G; J; I

54 55 56 57 58 59 60 61 62 63 64 65 66 67

Genistein-4′-O-α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranoside Genistein-4′-β-L-rhamnopyranosyl-(1-2)-α- D-glucopyranoside Sophorobioside (Genisteine-4′-diglycoside) Genistein 4′-O-(6′-O-α-L-rhamnopyranosyl)- β-sophoroside Genistein 4′-O-(6′-O-α-L-rhamnopyranosyl) -β-sophoroside Prunetin Prunetin 4′-O-β-D-glucopyranoside Daidzin Daidzein Di-O-methyldaidzein Biochanin A Sissotrin (BiochaninA 7-O-β-D- glucopyranoside) Biochanin A-7-O-β-D-xylopyranosyl-(1-6)- β-D-glucopyranoside Biochanin A 7-O-β-D-glucopyranosyl (1-6)- β-D-glucopyranosyl (Biochanin A 7-O-β-D- gentiobioside) Formononetin Afrormosin Ononin Glycitin Tectoridin Irisolidone Pseudobaptigenin Calycosin Cajanin Pratensein Orobol 7, 3′-di-O-methylorobol Orobol-7-β-D-glucoside 7-O-methylpseudobaptigenin 5-hydroxypseudobaptigenin-7-O-glucoside calycosin-7-O-glucoside 5,6',7-trihydroxy-3′,4′-methylenedioxy- isoflavone 6′-O-β-Dglycoside 5,7-dihydroxy-3′,4′-methylenedioxy- isoflavone Sophorophenolone Paratensein-7-O-glucoside Glycitein-4′-O-β-D-glucoside Dihydroformononetin Sophorol

D D; E E J J D; G D; J E D; G; H D K; L; E; G; I G; F; I K K

Tang et al., (2001a); Wang et al. (2003a, 2003b, 2008); Ma and Lou (2006); Qi et al. (2007); Sun et al. (2007) Kim et al. (2004) Ho et al. (1982); Tang et al. (2001b); Wang et al. (2001, 2003a, 2003b, 2008); Kim et al. (2004) Ho et al. (1982); Wang et al. (2001); Tang et al. (2001c, 2008a); Ma and Lou (2006); Kim and Yun-Choi (2008); Abdallah et al. (2014) Kim et al. (2004) Qi et al. (2007); Sun et al. (2007) Tulaganov and Gaibnazarava (2001) Tang et al. (2008a) Tang et al. (2008a) Tang et al. (2002b); Diao et al. (2011) Wang et al. (2008); Tang et al. (2001a) Ma and Lou (2006) Tang et al. (2002b); Park et al. (2010); Diao et al. (2011) Tang et al. (2002b) Komatsu et al. (1976); Park et al. (2004); Kim and Yun-Choi (2008) Wang et al. (2001); Kim and Yun-Choi (2008); Mohamed et al. (2015) Tadahiro et al. (1997); Park et al. (2004) Tadahiro et al. (1997)

D; E; K E E; H H F; E; G; I K; L; E; G; I D H; G A A A; B D C D H H K

Tang et al. (2002a); Park et al. (2004); Ma and Lou (2006) Ma and Lou (2006) Ma and Lou (2006); Park et al. (2010) Park et al. (2010) Wang et al. (2003a); Kim and Yun-Choi (2008) Komatsu et al. (1976); Park et al. (2004); Kim and Yun-Choi (2008) Tang et al. (2002a) Park et al. (2010); Diao et al. (2011) Chen et al. (2010) Chen et al. (2010) Lo et al. (2009); Chen et al. (2010) Tang et al. (2002a) Li et al. (2010) Tang et al. (2002a) Park et al. (2010) Park et al. (2010) Park et al. (2004)

L D H H K K

Komatsu et al. (1976) Tang et al. (2002a) Park et al. (2010) Park et al. (2010) Park et al. (2004) Hiroshi (1959)

A A; E C

Xu (1957) Kitagawa et al. (1988); Zhou et al. (2006) Li (2005)

46 47 48 49

68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90

Triterpenoids 91 Betulin 92 Sophoradiol 93 3-O-(β-D-galactopyranosyl-(1-2)-β-D- glucuronopyranosyl-sophoradiol methyl ester 94 3-O-(β-D-galactopyranosyl-(1-2)-β-D- glucuronopyranosyl-sophoradiol ethyl ester 95 Kakkasaponin II 96 Kaikasaponin I 97 Kaikasaponin III 98 Soyasaponin I

C

Li (2005)

A A A A; F

99 100 101 102 103 104 105

A A A; F A A; F A; F A

Zhang et al. Kitagawa et Kitagawa et Kitagawa et (2015) Zhang et al. Zhang et al. Kitagawa et Kitagawa et Kitagawa et Kitagawa et Kitagawa et

Dehydrosoyasaponin I Phaseoside IV Soyasaponin III Azukisaponin I Azukisaponin II Azukisaponin V Kaikasaponin II

(2015) al. (1988); Zhang et al. (2015) al. (1988); Zhang et al. (2015) al. (1988); Grishkovets and Gorbacheva (1995); Zhang et al. (2015) (2015) al. (1988); Grishkovets and Gorbacheva (1995) al. (1988) al. (1988); Grishkovets and Gorbacheva (1995) al. (1988); Grishkovets and Gorbacheva (1995) al. (1988)

X. He et al. / Journal of Ethnopharmacology 187 (2016) 160–182

177

Table 2 (continued ) NO. Compounds

Resource

Ref.

106 Soyasapogenol B 107 Soyasapogenol B 3-(O-β-D-glucopy- ranuronoside)

C F

Li et al. (2010) Grishkovets and Gorbacheva (1995)

Alkaloids 108 Matrine 109 Sophocarpine 110 N-methylcytisine 111 Cytisine

F; G; I F F F

Abdusalamov Abdusalamov Abdusalamov Abdusalamov

H; K; L L L L L C; E A B; G

Shirataki et al. (1987a); Park et al., (2004, 2010) Shirataki et al. (1987a) Shirataki et al. (1987a) Shirataki et al. (1987b) Shirataki et al. (1987b) Li (2005); Zhou et al. (2006) Zhang et al. (2015) Kite et al. (2007); Yang et al. (2015)

B

Yang et al. (2015)

et et et et

al. al. al. al.

(1972) (1972) (1972) (1972)

Other compounds 112 Puerol A 113 Puerol B 114 Sophoraside A 115 Sophoraside B 116 Sophoraol A 117 Maltol 118 Maltol 3-O-(β-D-apiofuranosyl-(1-2)-β-D- glucopyranosyl) 119 Maltol 3-O-(4′-O-p-coumaroyl-6′-O-(3- hydroxy-3-methylglutaroyl))-β- glucopyranoside 120 Maltol-3-O-(4′-O-cis-p-coumaroyl-6′-O-(3-hydroxy-3-methylglutaroyl))-β-glucopyranoside 121 Maltol-3-O-(6′-O-4′-hydroxy-trans- cinnamoyl-β-glucopyranoside 122 Soyamalosides A 123 Soyamalosides B (Maltol 3-O-(3′-O-trans-p-coumaroyl-6′-O-(3-hydroxy-3-methylglutaroyl))-β-D-glucopyranoside) 124 Soyamalosides C 125 Maackiain

C A A

Li (2005) Zhang et al. (2015) Zhang et al. (2015)

A D; G; K; L

126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153

L H L L D G E; G; L G G E E G E G G E G C G G; F E F A; B A; B A; B A; B A G

Zhang et al. (2015) Shibata and Nishikawa (1963); Vanejten et al. (1983); Komatsu et al. (1976); Tang et al. (2002a); Park et al. (2004) Shibata and Nishikawa (1963) Park et al. (2010) Komatsu et al. (1976) Shibata and Nishikawa (1963) Tang et al. (2002a) VanEtten et al. (1983) Komatsu et al. (1976); Zhou et al. (2006); Diao et al. (2011) Diao et al. (2011) Diao et al. (2011) Zhou et al. (2006) Zhou et al. (2006) Diao et al. (2011) Zhou et al. (2006) Diao et al. (2011) Diao et al. (2011) Zhou et al. (2006) Diao et al. (2011) Li et al. (2010) Diao et al. (2011) Wang et al. (2001); Mohamed et al. (2015); Kim et al. (2004) Wang et al. (2003a) Lo et al. (2009) Lo et al. (2009) Lo et al. (2009) Lo et al. (2009) Zhang et al. (2015) Mohamed et al. (2015)

Sophojaponicin (d-maackiain-mono-β-D- glucoside) Trifolirhizin Anhydropisatin (Flemichapparin B) l-pterocarpin Medicagol Medicarpin β-sitosterol Stigmasterol Daucosterol Cerylalcohol Octacosanol Eicosanol Hexacosanic acid Behenic acid Eicosyl behenate Glycerol-α-monohexacosanate Pyrocatechol 2-O-methyl-inositol Protocatechuic acid Gallic acid Gallic acid 4-O-β-D-(6′-O-galloyl)- glucopyranoside 1,6-di-O-galloyl-β-D-glucose N, N′-diferuloyl-putrescine N,N′-dicoumaroyl-putrescine N-p-coumaroyl-N′-feruloylputrescine N-(E)-feruloyl-N′-(Z)-feruloyl-putrescine N, N’-dicoumaroylputrescine Ellagic acid 4-O-α-L-arabinofuranoside

Note: A: flower buds; B: flowers; C: Flos Sophorae carbonisatus; D: pericarps; E: fruits; F: seeds; G: leaves; H: stem bark; I: stem; J: branches; K: woods; L: roots.

To prevent toxic effects, the 2015 edition of the Chinese Pharmacopoeia recommends an exact dose of the root of 5–10 g for Flos Sophorae Immaturus and 6–9 g for Fructus Sophorae (Chinese Pharmacopoeia Commission, 2015). The Chinese Food and Drug Administration caution against the use of this herb in pregnant women or people with spleen-Yang insufficiency. In China, package inserts for such formulations warn that the oral administration of Fructus Sophorae pills (Huaijiao Wan in Chinese) may result in mild diarrhea in some patients. Other significant side effects are yet to be established. Hence, comprehensive well-controlled, and double-blind clinical trials on systemic toxicity are urgently needed to reevaluate the efficacy and safety of this herb.

7. Future perspectives and conclusions This review presents an up-to-date and comprehensive summary of the various uses and recent findings of research into the phytochemistry, traditional use, pharmacology, and toxicity of S. japonica. Flos Sophorae Immaturus and Fructus Sophorae, the two medicinal forms of S. japonica, have been used in TCM since the beginning of the Han Dynasty, which is supported by most of the current in vitro and in vivo studies. During the last four decades, several compounds have been isolated from Flos Sophorae Immaturus and Fructus Sophorae. Flavonoids and isoflavonoids are the two major groups of plant derivatives, which may contribute either directly or indirectly to the biological effects of Flos

178

Table 3 The activities of some compounds isolated from Sophora japonica. Effect Com. In vivo

In vitro

IC50 (lM) Dosage

A A A A A

40 41 52 52 52

Y16 cell line (IL-5 bioassay) Y16 cell line (IL-5 bioassay)

51.9 10.6

A A A A A

52 52 52 52 52

BAF/BO3B cells (IL-3 bioassay) Y16 cell line (IL-5 bioassay) Hybridoma MH60/BSF-2 (IL-6 bioassay) RAW264.7 cells (IL-6 bioassay) RAW264.7 cells (COX-2 activity)

6.9 1.5 6.0 6.1 4.4

A A B

78 78 7

Strepto-

9.8 18 60.7

B

35

Strepto-

62.1

Yang et al. (2015)

B

119

Strepto-

94.3

Yang et al. (2015)

B

120

Y16 cell line (IL-5 bioassay) GM-CSF bioassay Saliva-induced aggregation in coccus mutans Saliva-induced aggregation in coccus mutans Saliva-induced aggregation in coccus mutans Saliva-induced aggregation in coccus mutans

Strepto-

58.6

Yang et al. (2015)

C C D D D D D D D D D E

40 52 12 12 13 13 15 15 38 39 146 23

E E E E

33 62 75 76

E

77

E

78

E E E E F F G G G G

87 88 112 127 21 33 40 40 21 41

Carrageenin- or croton oil-induced paw edema in ICR mice Carrageenin- or croton oil-induced paw edema in ICR mice 2, 4-dinitrochlorobenzene-induced acute and chronic contact dermatitis

50 mM 49% 50 mM 79% 4100 mg /kg, op. 410 mg /kg, iv. 3 and 10 mg/kg 50–70%

50 mM

92.0%

0.8 mM

75.7%

50 mM

92% 95%

4.5, 9 mg/kg 15, 30 mg/kg DPPH assay Cytochrome-c reduction assay DPPH assay Cytochrome-c reduction assay DPPH assay Cytochrome-c reduction assay DPPH assay DPPH assay DPPH assay Stimulating 2-NBDG uptake in HepG2 cells Glucose uptake in 3T3-L1 cells Aldose reductase inhibitory assay Aldose reductase inhibitory assay Stimulating 2-NBDG uptake in HepG2 cells Stimulating 2-NBDG uptake in HepG2 cells Stimulating 2-NBDG uptake in HepG2 cells Aldose reductase inhibitory assay Aldose reductase inhibitory assay Aldose reductase inhibitory assay Aldose reductase inhibitory assay Adipocyte differentiation inhibition in 3T3-L1 cells A549 BGC-823 MCF-7 A549

Ref.

Min et al. (1999) Min et al. (1999) Kim et al. (2003b) Kim et al. (2003b) Lee et al. (2013) Yun et al. (2000) Min et al. (1999) Yun et al. (2000) Kim et al. (2003a) Yun et al. (2000); Kim et al. (2003a) Min et al. (1999) Yun et al. (2000) Yang et al. (2015)

Wang et al. (2006a) Abdallah et al. (2014) Tang et al. (2002b) Tang et al. (2002b) Tang et al. (2002b) Tang et al. (2002b) Tang et al. (2002b) Tang et al. (2002b) Zhang et al. (2013) Zhang et al. (2013) Kim et al. (2004) Chen et al. (2010)

25.5 25.8 25.3 25.7 26.6. 27.1 35.1 88.7 17.1 1, 10, 100 μg/mL 10 mM

1, 10, 100 μg/mL

Ha et al. (2010) Park et al. (2010) Park et al. (2010) Chen et al. (2010)

1, 10, 100 μg/mL

Chen et al. (2010)

1, 10, 100 μg/mL

Chen et al. (2010)

5, 10, 20 mM 5, 10, 20 mM 100 mg/mL 100 mg/mL 10.0 mM, 72 h 100 mg/mL

Park et al. (2010) Park et al. (2010) Park et al. (2010) Park et al. (2010) Ha et al. (2010) Ha et al. (2010) Ma and Lou (2006) Ma and Lou (2006) Zhang et al. (2012) Ma and Lou (2006)

3.2 29.2

1.9 19.3 6.4 15.4

82.01% 91.25% 60% 32.97%

X. He et al. / Journal of Ethnopharmacology 187 (2016) 160–182

OVX female SD rats OVX female SD rats

Inhibition rate Cell survival rate

41 52 52 40 40

H H H H H H I

64 64 72 72 73 73 151

J J J J J J J J J J J

95 96 97 98 99 100 118 122 123 124 152

100 mg/mL 100 mg/mL 100 mg/mL

BGC-823 A549 BGC-823 Arachidonic acid-induced platelet aggregation in rat blood U46619 (a thromboxane A2 mimetic agent)-induced platelet aggregation in rat blood Arachidonic acid-induced platelet aggregation in rat blood U46619-induced platelet aggregation in rat blood Arachidonic acid-induced platelet aggregation in rat blood U46619-induced platelet aggregation in rat blood Arachidonic acid-induced platelet aggregation in rat blood U46619-induced platelet aggregation in rat blood Tyrosinase activity in human epidermal melanocytes L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A L6 cells treated with antimycin A

20.3 53.8

Ma and Lou (2006) Ma and Lou (2006) Ma and Lou (2006) Kim and Yun-Choi (2008) Kim and Yun-Choi (2008)

19.9 99.8 25.9 123.4 1.6 15.6 85.0

Kim and Yun-Choi Kim and Yun-Choi Kim and Yun-Choi Kim and Yun-Choi Kim and Yun-Choi Kim and Yun-Choi Lo et al. (2009) 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L 10 μM/L

13.98% 38.87% 23.26%

67.7% 70.2% 79.5% 73.8% 82.0% 73.1% 67.4% 77.4% 80.4% 88.6% 75.3%

Zhang Zhang Zhang Zhang Zhang Zhang Zhang Zhang Zhang Zhang Zhang

et et et et et et et et et et et

al. al. al. al. al. al. al. al. al. al. al.

(2008) (2008) (2008) (2008) (2008) (2008)

(2015) (2015) (2015) (2015) (2015) (2015) (2015) (2015) (2015) (2015) (2015)

Note: A, anti-inflammatory activity; B, antibacterial activity; C, antiosteoporotic activity; D, antioxidant activity; E, antihyperglycemic activity; F, antiobesity activity; G, antitumor activity; H, antiplatelet activity; J, whitening effect; J, cell protection.

X. He et al. / Journal of Ethnopharmacology 187 (2016) 160–182

G G G H H

179

180

X. He et al. / Journal of Ethnopharmacology 187 (2016) 160–182

Table 4 Detailed comparison of various methods of isolating rutin from Flos Sophorae Immaturus. Method Extraction solvent

Temperature/ time

Sonication Microwave condition

Inactivation of rue enzyme

Additives

Purity Yield

Ref.

A

Ca(OH)2/H2O

55–60 ºC/50 min

–

–

60

495% 85%

Cao (1993)

A

Ca(OH)2/acetone/( NH4)2SO4/H2O Ca(OH)2/H2O Ca(OH)2/H2O Ca(OH)2/H2O Ca(OH)2/NaOH/H2O Ca(OH)2/H2O

60 ºC/60 min

2 min

–

heating

Na2B4O7/ Na2S2O5 –

100 ºC/40 min r.t. 100 ºC/30 min r.t./12 h r.t.

– 40 min 30 min – –

– – – –

heating – heating – –

23 ºC 3h

30 min –

27 W –

– – 20 ºC 90 ºC/30 min

– – 15 min –

450 W/16 min 296 W/10 min 150 W 210 W/5 min

A AþC AþC B B B B D D D Dþ A

Methanol Ca(OH)2/NaHCO3/ H2O H2O Ca(OH)2/H2O 70% ethanol Ca(OH)2/H2O

Co, 32  104 Gy

95.9%

–

Luo et al. (2014)

– – – – Na2B4O7/ Na2S2O5

– – – – 100%

13.19% 22.18% 17.83% 18% 10.99%

Guo. (1997) Guo. (1997) Guo and Yang (2009) Ji (1991) Yan et al. (2011)

–

Na2B4O7

98.2%

12% 22%

Paniwnyk et al. (2001) Zhai et al. (2003)

– – – heating

– Na2B4O7 – Na2B4O7

– 94.1% – 61.1%

21.97% 17.1% 18.23% 22.4%

Liu et al. (2007b) Gong et al. (2003) Liao et al. (2015) Wang et al. (2003b)

Note: A, Hot alkali extraction; B, Cold alkali extraction; C, Ultrasound-assisted extraction; D, Microwave-assisted extraction.

Sophorae Immaturus and Fructus Sophorae. In particular, rutin and sophoricoside have been used to control the quality of medicinal products due to their high medicinal value. TCM has been a key form of primary health care in China. It has been adopted by Western countries as well, because of its wide uses, extensive biological activities, and reliable clinical efficacy (Chen et al., 2013). Throughout the course of history, medicinal plants have been identified and used. At present, traditional medicine has served as a rich source of novel lead compounds for modern drug discovery (Salminen et al., 2008). S. japonica extract was frequently used in ancient China. It is still widely used in the pharmaceutical, health, and food industries. Many active compounds such as kaempferol, quercetin, rutin, genistein, and sophoricoside in S. japonica exhibit various pharmacological effects such as antioxidant, anticancer, anti-inflammatory, antibacterial, and antiviral activities. They have been developed as novel agents to prevent cancer, hemorrhoids, varicosis, microangiopathy, heart disease, allergies/inflammations, prostatitis, skin disease, and respiratory diseases such as bronchitis and asthma. They have also been used as an ingredient in supplements, beverages, and food products. However, several other properties also need to be investigated further. To date, approximately 153 chemical compounds have been isolated from Flos Sophorae Immaturus and Fructus Sophorae. However, the names of some compounds are confusing because the same compounds are present in various forms, such as sophoroflavonoloside (also named as kaempferol-3-diglycoside, kaempferol 3-O-β- D-Glc(1-2)-β-D-Glc, or kaempferol-3-O-β-Dsophoroside) (Ho et al., 1982; Tulaganov and Gaibnazarava, 2001; Wang et al., 2003). The pharmacological effects of only a few components, such as kaempferol, quercetin, rutin, sophoricoside, and genistein, have been studied. Precise investigations of the chemical composition of popular drugs are needed, as well as studies on more effective compounds and the structure–function relationship. Although the S. japonica extract was recorded in ancient texts such as the Shen Nong Ben Cao Jing (Divine Farmer's Classic of Materia Medica) for the treatment of hemafecia and hemorrhoids, only few modern studies have substantiated the hemostatic effect of the extract. Thus, this aspect can be explored further. Toxicity and clinical studies are urgently needed to confirm the safety of S. japonica extracts for clinical use and to meet the Western standards of evidence-based medicine.

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