Progress on pharmacological activities and hepatotoxicity of bavachinin

ZHOU Rongrui; WEI Yanping; CHEN Wei; DING Qianqian; WANG Jinxin; ZU Xianpeng

doi:10.12206/j.issn.2097-2024.202204031

Volume 41 Issue 8

Aug. 2023

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2023 > 41(8): 465-471

ZHOU Rongrui, WEI Yanping, CHEN Wei, DING Qianqian, WANG Jinxin, ZU Xianpeng. Progress on pharmacological activities and hepatotoxicity of bavachinin[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(8): 465-471. doi: 10.12206/j.issn.2097-2024.202204031

Citation:

ZHOU Rongrui, WEI Yanping, CHEN Wei, DING Qianqian, WANG Jinxin, ZU Xianpeng. Progress on pharmacological activities and hepatotoxicity of bavachinin[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(8): 465-471. doi: 10.12206/j.issn.2097-2024.202204031

Progress on pharmacological activities and hepatotoxicity of bavachinin

doi: 10.12206/j.issn.2097-2024.202204031

ZHOU Rongrui^{1a
,},
WEI Yanping²,
CHEN Wei^1b,
DING Qianqian³,
WANG Jinxin^{1a
,
,},
ZU Xianpeng^{1b
,
,}

1a.
Basic Medicine School, b. School of Pharmacy, Naval Medical University, Shanghai 200433, China
1b.
Basic Medicine School, b. School of Pharmacy, Naval Medical University, Shanghai 200433, China
2.
School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
3.
School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China

Received Date: 2022-04-08
Rev Recd Date: 2022-08-23
Publish Date: 2023-08-25

Abstract

Bavachinin is a dihydroflavone isolated from dried ripe fruits of Psoralea corylifolia L., which has various pharmacological activities, such as anti-tumor, anti-virus, anti-diabetes, anti-inflammatory and neuroprotective, and good potential in clinical applications. With the increasing concern about the safety of P. corylifolia applications in clinical, the bavachinin has been found to be one of the main components causing liver injury. In this paper, the pharmacological activities and hepatotoxicity of bavachinin in the recent 20 years were reviewed, in order to provide reference for the further study and clinical application.
- bavachinin,
- pharmacological activity,
- anti-tumor,
- anti-virus,
- anti-diabetes,
- neuroprotective,
- anti-inflammatory,
- liver toxicity

References

[1]	鲁亚奇, 张晓, 王金金, 等. 补骨脂化学成分及药理作用研究进展[J]. 中国实验方剂学杂志, 2019, 25(3): 180-189. doi: 10.13422/j.cnki.syfjx.20182022
[2]	ALAM F, KHAN G N, BIN ASAD M H H. Psoralea corylifolia L: Ethnobotanical, biological, and chemical aspects: a review[J]. Phytother Res, 2018, 32(4): 597-615. doi: 10.1002/ptr.6006
[3]	BHALLA V K, NAYAK U R, DEV S. Some new flavonoids from[J]. Tetrahedron Lett, 1968, 9(20): 2401-2406. doi: 10.1016/S0040-4039(00)76141-7
[4]	ZAFAR S K, IQBAL S, MUMTAZ M, et al. Inhibitory mechanism exhibited by phenol-based natural products against DNA polymerase α from Psoralea corylifolia by molecular docking[J]. J Chem Soc Pak, 2018, 40(6): 1093-1102.
[5]	ZHAO H Y, CHEN Z L. Screening of aromatase inhibitors in traditional Chinese medicines by electrophoretically mediated microanalysis in a partially filled capillary[J]. J Sep Sci, 2013, 36(16): 2691-2697. doi: 10.1002/jssc.201300474
[6]	LEE S W, YUN B R, KIM M H, et al. Phenolic compounds isolated from Psoralea corylifolia inhibit IL-6-induced STAT3 activation[J]. Planta Med, 2012, 78(9): 903-906. doi: 10.1055/s-0031-1298482
[7]	KUNTZ S, WENZEL U, DANIEL H. Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines[J]. Eur J Nutr, 1999, 38(3): 133-142. doi: 10.1007/s003940050054
[8]	NEPAL M, ChOI H J, ChOI B Y, et al. Anti-angiogenic and anti-tumor activity of Bavachinin by targeting hypoxia-inducible factor-1α[J]. Eur J Pharmacol, 2012, 691(1-3): 28-37. doi: 10.1016/j.ejphar.2012.06.028
[9]	JEONG D, WATARI K, SHIROUZU T, et al. Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs[J]. Biol Pharm Bull, 2013, 36(1): 152-157. doi: 10.1248/bpb.b12-00871
[10]	HUNG S Y, LIN S C, WANG S Z, et al. Bavachinin induces G2/M cell cycle arrest and apoptosis via the ATM/ATR signaling pathway in human small cell lung cancer and shows an antitumor effect in the xenograft model[J]. J Agric Food Chem, 2021, 69(22): 6260-6270. doi: 10.1021/acs.jafc.1c01657
[11]	PAI J T, HSU M W, LEU Y L, et al. Induction of G2/M cell cycle arrest via p38/p21^Waf1/Cip1-dependent signaling pathway activation by bavachinin in non-small-cell lung cancer cells[J]. Molecules, 2021, 26(17): 5161. doi: 10.3390/molecules26175161
[12]	FARAJZADEH M, Dehkordi. Deciphering the DNA-binding affinity, cytotoxicity and apoptosis induce as the anticancer mechanism of Bavachinin: an experimental and computational investigation[J]. J Mol Liq, 2021, 341: 117373. doi: 10.1016/j.molliq.2021.117373
[13]	GE L N, YAN L, LI C, et al. Bavachinin exhibits antitumor activity against non-small cell lung cancer by targeting PPARγ[J]. Mol Med Rep, 2019, 20(3): 2805-2811.
[14]	ZHAO C, GHOSH B, CHAKRABORTY T, et al. Bavachinin mitigates DMH induced colon cancer in rats by altering p53/Bcl2/BAX signaling associated with apoptosis[J]. Biotech Histochem, 2021, 96(3): 179-190. doi: 10.1080/10520295.2020.1778087
[15]	DARZI S, MIRZAEI S A, ELAHIAN F, et al. Improvement of cytotoxicity of mitoxantrone and daunorubicin by candidone, tephrosin, and bavachinin[J]. Mol Biol Rep, 2021, 48(11): 7105-7111. doi: 10.1007/s11033-021-06700-7
[16]	DARZI S, MIRZAEI S A, ELAHIAN F, et al. Enhancing the therapeutic efficacy of daunorubicin and mitoxantrone with bavachinin, candidone, and tephrosin[J]. Evid Based Complement Alternat Med, 2019, 2019: 3291737.
[17]	丁钦, 吴克俭, 郑璐, 等. 补骨脂二氢黄酮甲醚调控Gamma delta T细胞消减胃癌SGC-7901研究[J]. 世界中医药, 2020, 15(20): 3040-3045. doi: 10.3969/j.issn.1673-7202.2020.20.007
[18]	BILEŞIKLER K, BAKıŞ O. An overview on flavonoids as potential antiviral strategies against coronavirus infections[J]. Gazi Med J, 2020, 31(3A): 478-484. doi: 10.12996/gmj.2020.117
[19]	YOON J H, LEE J, LEE J Y, et al. Study on the 2-phenylchroman-4-one derivatives and their anti-MERS-CoV activities[J]. Bull Korean Chem Soc, 2019, 40(9): 906-909. doi: 10.1002/bkcs.11832
[20]	ZHAO H, CHEN Z. Screening of neuraminidase inhibitors from traditional Chinese medicines by integrating capillary electrophoresis with immobilized enzyme microreactor[J]. J Chromatogr A, 2014, 1340: 139-145. doi: 10.1016/j.chroma.2014.03.028
[21]	Yin S , Fan C Q , Wang Y , et al. Antibacterial prenylflavone derivatives from Psoralea corylifolia, and their structure-activity relationship study[J]. Bioorg Med Chem, 2004, 12(16): 4387-4392. doi: 10.1016/j.bmc.2004.06.014
[22]	王天晓, 尹震花, 张伟, 等. 补骨脂抗氧化、抑制α-葡萄糖苷酶和抗菌活性成分研究[J]. 中国中药杂志, 2013, 38(14): 2328-2333.
[23]	CUI Y M, TANIGUCHI S, KURODA T, et al. Constituents of Psoralea corylifolia fruits and their effects on methicillin-resistant Staphylococcus aureus[J]. Molecules, 2015, 20(7): 12500-12511. doi: 10.3390/molecules200712500
[24]	MA S, HUANG Y, ZHAO Y, et al. Prenylflavone derivatives from the seeds of Psoralea corylifolia exhibited PPAR-γ agonist activity[J]. Phytochem Lett, 2016, 16: 213-218. doi: 10.1016/j.phytol.2016.04.016
[25]	FENG L, LUO H, XU Z J, et al. Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice[J]. Diabetologia, 2016, 59(6): 1276-1286. doi: 10.1007/s00125-016-3912-9
[26]	FENG L , LU S , ZHENG Z ,et al. Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects[J]. Sci Bull, 2021, 66(15): 1559-1570. doi: 10.1016/j.scib.2021.01.023
[27]	DU G, FENG L, YANG Z, et al. Separation and peroxisome proliferator-activated receptor-γ agonist activity evaluation of synthetic racemic bavachinin enantiomers[J]. Bioorg Med Chem Lett, 2015, 25(12): 2579-2583. doi: 10.1016/j.bmcl.2015.04.029
[28]	DU D G, ZHAO D Y, FENG D L, et al. Design synthesis and structure-activity relationships of bavachinin analogues as peroxisome proliferator-activated receptor γ agonists[J]. ChemMedChem, 2017, 12(2): 183-193. doi: 10.1002/cmdc.201600554
[29]	LYMAN M, LLOYD D G, JI X M, et al. Neuroinflammation: the role and consequences[J]. Neurosci Res, 2014, 79: 1-12. doi: 10.1016/j.neures.2013.10.004
[30]	KIM Y J, LIM H S, LEE J, et al. Quantitative analysis of Psoralea corylifolia linne and its neuroprotective and anti-neuroinflammatory effects in HT22 hippocampal cells and BV-2 microglia[J]. Molecules, 2016, 21(8): 1076. doi: 10.3390/molecules21081076
[31]	SORIA LOPEZ J A, GONZÁLEZ H M, LÉGER G C. Alzheimer’s disease[J]. Handb Clin Neurol, 2019, 167: 231-255.
[32]	CHEN Z J, YANG Y F, ZHANG Y T, et al. Dietary total prenylflavonoids from the fruits of Psoralea corylifolia L. prevents age-related cognitive deficits and down-regulates alzheimer’s markers in SAMP8 mice[J]. Molecules, 2018, 23(1): 196. doi: 10.3390/molecules23010196
[33]	杨柳, 李爽, 王业秋, 等. 补骨脂二氢黄酮甲醚对Aβ诱导PC12细胞损伤的保护作用及机制研究[J]. 中药新药与临床药理, 2021, 32(1): 68-72.
[34]	CHEN X, YANG Y, ZHANG Y. Isobavachalcone and bavachinin from Psoraleae Fructus modulate Aβ42 aggregation process through different mechanisms in vitro[J]. FEBS Lett, 2013, 587(18): 2930-2935. doi: 10.1016/j.febslet.2013.07.037
[35]	CHOI Y H, YON G H, HONG K S, et al. In vitro BACE-1 inhibitory phenolic components from the seeds of Psoralea corylifolia[J]. Planta Med, 2008, 74(11): 1405-1408. doi: 10.1055/s-2008-1081301
[36]	Thomas T. Monoamine oxidase-B inhibitors in the treatment of Alzheimers disease[J]. Neurobiol Aging, 2000, 21(2): 343-348. doi: 10.1016/S0197-4580(00)00100-7
[37]	ZARMOUH N O, MAZZIO E A, ELSHAMI F M, et al. Evaluation of the inhibitory effects of bavachinin and bavachin on human monoamine oxidases A and B[J]. Evid Based Complement Alternat Med, 2015, 2015: 852194.
[38]	SIROTKIN A V, HARRATH A H. Phytoestrogens and their effects[J]. Eur J Pharmacol, 2014, 741: 230-236. doi: 10.1016/j.ejphar.2014.07.057
[39]	LIM S H, HA TY, AHN J, et al. Estrogenic activities of Psoralea corylifolia L. seed extracts and main constituents[J]. Phytomedicine, 2011, 18(5): 425-430. doi: 10.1016/j.phymed.2011.02.002
[40]	蔡心银, 张紫佳. 植物雌激素药理作用及相关中药的研究进展[J]. 现代中药研究与实践, 2020, 34(2): 75-78, 86.
[41]	刘国良, 李建民, 姚远, 等. 补骨脂二氢黄酮甲醚对A375细胞黑素合成的影响[J]. 中医药学报, 2015, 43(6): 9-12. doi: 10.19664/j.cnki.1002-2392.2015.06.004
[42]	刘国良, 于英君, 姚远, 等. 补骨脂二氢黄酮甲醚对A375细胞黑素合成及ER/MAPK信号通路的影响[J]. 中国医药导报, 2015, 12(36): 4-8, 20.
[43]	HILLMER E J, ZHANG H Y, LI H S, et al. STAT3 signaling in immunity[J]. Cytokine Growth Factor Rev, 2016, 31: 1-15. doi: 10.1016/j.cytogfr.2016.05.001
[44]	MATSUDA H, KIYOHARA S, SUGIMOTO S, et al. Bioactive constituents from Chinese natural medicines XXXIII Inhibitors from the seeds of Psoralea corylifolia on production of nitric oxide in lipopolysaccharide-activated macrophages[J]. Biol Pharm Bull, 2009, 32(1): 147-149. doi: 10.1248/bpb.32.147
[45]	SHARMA M L, SINGH B, CHANDAN B K, et al. Actions of some flavonoids on specific and non-specific immune mechanisms[J]. Phytomedicine, 1996, 3(2): 191-195. doi: 10.1016/S0944-7113(96)80035-3
[46]	PAWANKAR R, CANONICA G W, HOLGATE S T, et al. Allergic diseases and asthma: a major global health concern[J]. Curr Opin Allergy Clin Immunol, 2012, 12(1): 39-41. doi: 10.1097/ACI.0b013e32834ec13b
[47]	CHEN X, WEN T, WEI J, et al. Treatment of allergic inflammation and hyperresponsiveness by a simple compound, Bavachinin, isolated from Chinese herbs[J]. Cell Mol Immunol, 2013, 10(6): 497-505. doi: 10.1038/cmi.2013.27
[48]	TINDEMANS I, SERAFINI N, DI SANTO J P, et al. GATA-3 function in innate and adaptive immunity[J]. Immunity, 2014, 41(2): 191-206. doi: 10.1016/j.immuni.2014.06.006
[49]	WANG K, FENG Y P, LI S, et al. Oral delivery of bavachinin-loaded PEG-PLGA nanoparticles for asthma treatment in a murine model[J]. J Biomed Nanotechnol, 2018, 14(10): 1806-1815. doi: 10.1166/jbn.2018.2618
[50]	SATOH T, HOSOKAWA M. Structure function and regulation of carboxylesterases[J]. Chem Biol Interact, 2006, 162(3): 195-211. doi: 10.1016/j.cbi.2006.07.001
[51]	SUN D X, GE G B, DONG P P, et al. Inhibition behavior of fructus psoraleae’s ingredients towards human carboxylesterase 1 (hCES1)[J]. Xenobiotica, 2016, 46(6): 503-510. doi: 10.3109/00498254.2015.1091521
[52]	ZHU X H. Species difference for herb-drug interaction between Fructus psoralea and cardiovascular drug clopidogrel[J]. Lat Am J Pharm, 2016, 35(6): 1473-1475.
[53]	LI Y G, HOU J, LI S Y, et al. Fructus Psoraleae contains natural compounds with potent inhibitory effects towards human carboxylesterase 2[J]. Fitoterapia, 2015, 101: 99-106. doi: 10.1016/j.fitote.2015.01.004
[54]	LALE A, HERBERT J M, AUGEREAU J M, et al. Ability of different flavonoids to inhibit the procoagulant activity of adherent human monocytes[J]. J Nat Prod, 1996, 59(3): 273-276. doi: 10.1021/np960057s
[55]	陈瑞战, 杨思敏, 刘志强, 等. HPLC-ESI-MS快速筛选并鉴定补骨脂甲醇提取物中的抗氧化活性成分[J]. 分子科学学报, 2014, 30(2): 142-146.
[56]	KASSAHUN GEBREMESKEL A, DARSHANA WIJERATHNE T, KIM J H, et al. Psoralea corylifolia extract induces vasodilation in rat arteries through both endothelium-dependent and-independent mechanisms involving inhibition of TRPC3 channel activity and elaboration of prostaglandin[J]. Pharm Biol, 2017, 55(1): 2136-2144. doi: 10.1080/13880209.2017.1383484
[57]	DONG X, ZHU Y, WANG S, et al. Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway[J]. Int Immunopharmacol, 2020, 88: 106865. doi: 10.1016/j.intimp.2020.106865
[58]	DRAGOVIC S, VERMEULEN N P E, GERETS H H, et al. Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man[J]. Arch Toxicol, 2016, 90(12): 2979-3003. doi: 10.1007/s00204-016-1845-1
[59]	季宇彬, 王敏, 王姗, 等. 补骨脂二氢黄酮甲醚诱导HepaRG细胞损伤机制探讨[J]. 中国药理学通报, 2018, 34(4): 544-550. doi: 10.3969/j.issn.1001-1978.2018.04.021
[60]	WANG S, WANG M, WANG M, et al. Bavachinin induces oxidative damage in HepaRG cells through p38/JNK MAPK pathways[J]. Toxins, 2018, 10(4): 154. doi: 10.3390/toxins10040154
[61]	GUO Z J, LI P, WANG C G, et al. Five constituents contributed to the Psoraleae Fructus-induced hepatotoxicity via mitochondrial dysfunction and apoptosis[J]. Front Pharmacol, 2021, 12: 682823. doi: 10.3389/fphar.2021.682823
[62]	朱月, 王姗, 徐丽娇, 等. 基于Label-free技术分析补骨脂二氢黄酮甲醚的肝毒性作用机制[J]. 大理大学学报, 2020, 5(4): 1-6. doi: 10.3969/j.issn.2096-2266.2020.04.001
[63]	WANG X X, LV X, LI S Y, et al. Identification and characterization of naturally occurring inhibitors against UDP-glucuronosyltransferase 1A1 in Fructus Psoraleae (Bu-gu-Zhi)[J]. Toxicol Appl Pharmacol, 2015, 289(1): 70-78. doi: 10.1016/j.taap.2015.09.003
[64]	ZECCA E, DE LUCA D, BARONI S, et al. Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study[J]. Pediatrics, 2008, 121(1): e146-e149. doi: 10.1542/peds.2007-1220
[65]	秦子飞, 王培乐, 邢晗, 等. 补骨脂富含的异戊烯基成分对CYP1A1活性的影响及分子对接验证[J]. 南京中医药大学学报, 2021, 37(5): 750-759. doi: 10.14148/j.issn.1672-0482.2021.0750
[66]	LI A, GAO M H, ZHAO N, et al. Acute liver failure associated with Fructus Psoraleae: a case report and literature review[J]. BMC Complement Altern Med, 2019, 19(1): 84. doi: 10.1186/s12906-019-2493-9

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补骨脂是豆科补骨脂属植物补骨脂Psoralea corylifolia L.的干燥成熟果实，呈扁椭圆形，主要产地包括西双版纳、四川等地，印度、缅甸也有分布。其性味苦、辛、温，归肾、脾经，具有温肾助阳，温脾止泻等功效^[1]，外用可消风祛斑，民间常用于治疗白癜风^[2]。补骨脂还是经典方剂四神丸、二神丸等的主要组成。目前从补骨脂中分离出化合物为香豆素类、黄酮类及单萜酚类三大类^{[1- 2]}。补骨脂二氢黄酮甲醚是二氢黄酮类化合物，具有抗肿瘤、抗病毒、抗哮喘、神经保护等药理活性^[3]。近年来，中药用药的安全性越来越受到人们关注，补骨脂二氢黄酮甲醚已被证实长期使用会引起严重肝损伤。本文主要从补骨脂二氢黄酮甲醚的药理作用和肝毒性方面进行总结，以期为补骨脂二氢黄酮甲醚的进一步研究和临床合理使用提供参考。

1. 药理作用

1.1. 抗肿瘤

补骨脂二氢黄酮甲醚通过抑制肿瘤细胞增殖、抗淋巴管生成、诱导肿瘤细胞凋亡、逆转多药耐药等多个作用环节抑制乳腺癌、肺癌、胃癌等肿瘤细胞。DNA聚合酶在有丝分裂过程中参与DNA复制、转录及重组，是癌症化疗药物的重要靶点，而补骨脂二氢黄酮甲醚对DNA聚合酶具有明显的抑制作用^[4]。普遍认为，雌激素及其受体在乳腺癌的发生发展中发挥了重要作用，而芳香化酶(AR)作为一种限速酶在雄激素转化为雌激素过程中也有重要作用，它在卵巢、胎盘、乳腺组织中高水平表达，特别是在肿瘤部位和周围的区域高表达。补骨脂二氢黄酮甲醚可以抑制AR活性从而减少雌激素依赖性肿瘤生长^[5]。此外，体外抗增殖实验表明，补骨脂二氢黄酮甲醚对于人肝癌细胞HepG2、Hep3B、人结肠腺癌细胞Caco-2、人结肠癌细胞HT-29均有抗增殖作用，IC₅₀分别为11.32±0.69 μmol/L、3.02±0.53 μmol/L、55.94±4.9 μmol/L、39.7±2.3 μmol/L^[6-7]。补骨脂二氢黄酮甲醚的抗肿瘤作用及机制见表1。

药理作用	作用机制	模型	文献
抑制肿瘤血管生成	促进缺氧诱导因子-la(HIF-1a)的降解作用，抑制肿瘤血管生成	KB癌细胞（HeLa细胞衍生物） HOS人骨肉瘤细胞	[8]
抗淋巴管生成	抑制TR-LE细胞增殖和毛细血管样管形成	TR-LE细胞	[9]
抑制肿瘤细胞增殖	通过激活ATM/ATR-CHK2/CHK1信号通路，诱导DNA损伤和细胞周期阻滞于G2/M期	SCLC细胞株(H1688)	[10]
	通p38-MAPK介导的p21Waf1/cip1信号通路诱导细胞周期阻滞G2/M期	NSCLS细胞系(A549、H23、HCC827)	[11]
	抑制IL-6和STAT3通路	Hep3B细胞	[6]
诱导肿瘤细胞凋亡	剂量相关性上调Fas、FasL、caspase-8和 caspase-3表达	SCLC细胞株(H1688)	[10]
	上调促凋亡基因p53、caspase-3、caspase -8和caspase -9表达	MCF-7细胞	[12]
	激活PPARγ，ROS水平升高	NSCLC细胞系(A549)	[13]
	激活细胞凋亡相关p53、Bcl2、BAX信号通路	DMH+DSS诱导的大鼠结肠癌模型	[14]
逆转多药耐药	下调MDR1和ABCG2基因表达，减少药物外排	胃癌耐药细胞系(EPG85.257RDB) 乳腺癌耐药细胞系(MCF7/MX)	[15] [16]
免疫作用	诱导γδT细胞增殖	胃癌细胞(SGCA99)	[17]
注：SCLC：小细胞肺癌；NSCLC：非小细胞肺癌；DMH：二甲肼；DSS：葡聚糖硫酸钠

1.2. 抗菌、抗病毒

木瓜蛋白酶(PLpro)是冠状病毒成熟和复制环节不可或缺的蛋白酶。补骨脂二氢黄酮甲醚通过结合PLpro上关键氨基酸残基抑制冠状病毒的木瓜蛋白酶样蛋白酶活性，从而阻止病毒复制、逃避宿主先天免疫反应，可能成为治疗冠状病毒的候选药物^[18]。Yoon等^[19]发现，在vero细胞中，天然补骨脂二氢黄酮甲醚和人工合成的外消旋体均有良好的抗MERS-COV活性，IC₅₀为6.6 μmol/L。此外，Zhao等^[20]通过一种新型神经氨酸酶固定化毛细管微反应器发现补骨脂二氢黄酮甲醚具有剂量依赖性地抑制神经氨酸酶的作用。

补骨脂二氢黄酮甲醚对金黄色葡萄球菌(Staphylococcus aureus ATCC 25923)和表皮葡萄球菌(S. epidermidis ATCC 12228)具有较强的抑菌活性^[21]。在浓度为10 μg/ml，补骨脂二氢黄酮甲醚对金黄色葡萄球菌有抑菌圈(8 mm)，但对耐甲氧西林的金黄色葡萄球菌(MRSA)和β-内酰胺酶阳性的金黄色葡萄球菌(Beta lactamase positive S. aureus)无抑制作用^[22]。Cui等^[23]研究也发现，补骨脂二氢黄酮甲醚在浓度为32 μg/ml时对MRSA(OM481、OM584)仍无抑制活性，这提示补骨脂二氢黄酮甲醚可能对耐药性菌不敏感。

1.3. 抗糖尿病

过氧化物酶体增殖物激活受体(PPARs)是核受体超家族的一种，作为配体诱导的转录因子，控制多个靶基因的表达。PPAR共有α、β/δ和γ三种亚型。PPAR γ是脂肪细胞分化的主要调节因子，在糖脂代谢中发挥重要作用。体外实验证明，补骨脂二氢黄酮甲醚通过激活PPAR γ，调节糖代谢^[24]。同时补骨脂二氢黄酮甲醚作为一种天然的泛过氧化物酶体增殖物受体激活剂，通过调节PPAR等相关基因表达增强了葡萄糖的转运和利用，降低血糖水平，减轻药物肝毒性，提高胰岛素敏感性，调节脂质代谢^[25]。与噻唑烷二酮类降糖药物和贝特类调血脂药物合用，可以放大胰岛素增敏作用，降低肝毒性并在不影响食物摄入量的条件下减轻药物引起的体质量增加，这种联合用药可以作为代谢综合征和2型糖尿病的辅助治疗药物提高疗效和降低毒性^[26]。天然的补骨脂二氢黄酮甲醚是R/S构型的混合物，通过超临界流体色谱法分离得到R、S两种对映体，并且发现它们具有相似的PPAR γ激动剂活性^[27]。Du等^[28]还对补骨脂二氢黄酮甲醚的构效关系进行了研究，总结了补骨脂二氢黄酮甲醚的活性必需结构。

1.4. 神经保护作用

神经炎症会导致并加速成人及儿童的许多神经退行性疾病，主要是造成中枢神经系统细胞内的稳态紊乱，比如铁的积累通过增强小胶质细胞的促炎活性、改变线粒体功能和诱导活性氧的产生而促进疾病进展，这在阿尔茨海默病（AD）和帕金森病（PD）等中枢神经系统疾病中得到证实^[29]。补骨脂二氢黄酮甲醚抑制BV-2小胶质细胞中脂多糖（LPS）诱导的NO、TNF-α、IL-6生成，对H₂O₂诱导的神经细胞（HT-22小鼠海马细胞）损伤起到保护作用，可以作为退行性神经疾病的潜在药物^[30]。

AD的发病机制尚不明确，目前认为与β-淀粉样堆积有关，称为“淀粉样蛋白联级假说”，即淀粉样前体蛋白APP经β-分泌酶等切割产生β-淀粉样蛋白（Aβ），Aβ聚集形成淀粉样斑块，同时诱发下级事件，如蛋白Tau过度磷酸化、氧化应激，进而导致细胞损伤及神经递质缺失^[31]。有研究表明，膳食中添加补骨脂果实中提取的总异戊二烯基黄酮可有效预防与年龄相关的AD小鼠的认知缺陷，其中补骨脂二氢黄酮甲醚和补骨脂乙素通过抑制Aβ聚集减少神经损伤^[32]。杨柳等^[33]研究表明补骨脂二氢黄酮甲醚提高超氧化物歧化酶和谷胱甘肽过氧化物酶活性，降低丙二醛水平，减少由于氧化应激引起的神经元损害，降低炎症因子IL-1β、IL-6、TNF-α含量，减少白细胞聚集引起炎症反应，能有效抑制Aβ诱导的PC12细胞损伤，发挥对神经细胞的保护作用。此外，补骨脂二氢黄酮甲醚能够抑制Aβ纤维化，高浓度下使Aβ42生成大的“非途径”聚集体，显著降低Aβ42诱导的SH-SY5Y人神经母细胞瘤细胞毒性，其机制可能与药物直接结合Aβ淀粉样变区，诱导Aβ构象变化，抑制“通路”聚集有关^[34]。BACE-1是导致Aβ聚集的关键酶，体外研究证明补骨脂二氢黄酮甲醚能抑制杆状病毒中BACE-1的表达，IC₅₀为3.8±0.2 μmol/L ^[35]。

PD的主要病理特征为在SNpc神经元中，多巴胺水平减少、多巴胺能神经元损失和神经元胞质内包涵体“路易小体”的产生。单胺氧化酶-B（MAO-B)是调节多巴胺重要代谢酶，有临床试验证明，单胺氧化酶-B抑制剂作为早期PD的单一治疗和晚期PD左旋多巴的辅助治疗都是有效的^[36]。补骨脂二氢黄酮甲醚可竞争抑制人单胺氧化酶-B，分子对接结果显示7位C上的甲氧基在特异性抑制中起到关键作用，可用于PD的治疗^[37]。

1.5. 雌激素样作用

植物雌激素的化学结构与哺乳动物雌激素类似，可以结合雌激素受体，影响特定基因表达^[38]。雌激素经典的核受体分为ER-α和ER-β两类，ER-α主要促进细胞增殖而ER-β使细胞凋亡。补骨脂二氢黄酮甲醚对ER-α有微弱的抑制作用，IC₅₀为1.11×10⁻⁴ mol/L，而对ER-β没有抑制活性^[39]。绝经后骨质疏松症(PMOP)指绝经后女性雌激素水平下降、骨稳态改变的一种代谢性疾病。有研究发现植物雌激素可用于改善围绝经期的女性骨质疏松，减少PMOP患者的雌激素用量，提高生活质量^[40]。这提示补骨脂二氢黄酮甲醚作为一种植物雌激素，可用于治疗ER异常表达引起的骨质疏松。

1.6. 抗色素沉着

黄褐斑是一种色素沉着病，与黑素细胞合成过量黑素蓄积于皮肤有关，机体内雌激素参与黑素形成，可影响黑素细胞增殖、黑素合成中限速酶酪氨酸酶(TYR)活性，从而影响黑素合成，导致色素沉着。补骨脂二氢黄酮甲醚能够下调人黑素瘤细胞（A375细胞）中TYR、TRP-1、TRP-2的mRNA表达，进而抑制黑素形成^[41]。与雌激素受体结合，通过第二信使激活ERK、JNK信号通路，而减少相关mRNA的表达，抑制TYR活性，减少细胞中黑素含量，用于治疗色素沉着^[42]。

1.7. 抗炎

白细胞介素-6(IL-6)是一种多功能的细胞因子，通过不同的信号传导通路激活各种生化功能。IL-6的失调在慢性炎症和自身免疫发挥病理作用。STAT-3被发现是IL-6激活的急性期反应因子(APRF)复合物的组成部分，共同参与炎症反应^[43]。在Hep3B细胞中，补骨脂二氢黄酮甲醚抑制IL-6诱导的STAT3依赖的启动子活性并且抑制其磷酸化，已知STAT3通过两个单体之间的SH2结构域磷酸化相互作用形成同型二聚体是功能激活的关键^[6]。Matsuda等^[44]发现，补骨脂二氢黄酮甲醚在26 μmol/L 浓度下能够抑制LPS诱导的小鼠巨噬细胞中NO的生成，这些发现提示补骨脂二氢黄酮甲醚可作为先导化合物用于开发治疗炎症性疾病的药物。

1.8. 抗哮喘

补骨脂二氢黄酮甲醚有免疫调节活性，在具有正常免疫功能的小鼠体内，可增强绵羊红细胞(SRBC)诱导的初次和二次体液免疫，轻微降低SRBC诱导的迟发型超敏反应^[45]。哮喘是一种慢性气道炎症性疾病，常与气道高反应性、可变气流阻塞有关。根据世界卫生组织的数据，现有患哮喘患者的数量为3亿，预计到2025年将增加到4亿^[46]。研究发现，哮喘与2型辅助T细胞(Th2)的免疫反应有关，Th2细胞产生的细胞因子包括白介素IL-4、IL-5、IL-9、IL-13和IL-33，这些细胞因子驱动嗜酸性炎症和组织损伤，导致气道高反应性和气道浸润^[47]。因此，阻断Th2细胞因子已成为治疗哮喘的新策略。补骨脂二氢黄酮甲醚能显著抑制细胞因子IL-4、IL-5、IL-13的产生，阻断卵清蛋白致敏的动物哮喘模型中的炎症反应^[47]。锌指转录因子GATA-3不仅是Th2细胞分化的主调控因子控制相关白介素的表达，还是过敏性炎症的关键转录因子，因此它成为一个对抗炎症的抑制靶点^[48]。最近研究发现，补骨脂二氢黄酮甲醚通过降低GATA-3 mRNA的稳定性，选择性抑制GATA-3的表达^[47]。然而，补骨脂二氢黄酮甲醚的水溶性极低（<30 ng/ml），限制了其临床应用。Wang等^[49]制备了一种装载补骨脂二氢黄酮甲醚的纳米颗粒(PEG5000-PLGA NPs)，这些纳米颗粒的生物相容性好，并对有炎症的肺组织表现出特异性的靶向能力，在小鼠过敏性哮喘模型中表现出非常好的抗哮喘治疗效果。

1.9. 抑制人羧酸酯酶

羧酸酯酶(CEs)是α/β水解酶折叠酶的一个保守的多基因家族，广泛分布于哺乳动物多种组织中。CEs负责多种内源性和外源性物质的水解，包括脂肪酸酯、环境毒素和含酯药物等，是哺乳动物重要的Ⅰ相代谢酶^[50]。人体内CEs主要分为两类，人羧酸酯酶1(hCE1)和人羧酸酯酶2(hCE2)。hCE1主要在肝脏中表达，参与肝内物质代谢如药物的生物转化、调节脂质代谢、参与体内胆固醇的转运代谢等。研究表明，补骨脂二氢黄酮甲醚竞争性抑制hCE1活性^[51]，减少了心血管药物氯吡格雷水解，提高氯吡格雷的疗效，这提示补骨脂二氢黄酮甲醚可作为辅助药物，降低治疗药物副作用^[52]。hCE2主要在胃肠道和肿瘤组织中表达，在肝脏中表达相对较低，因此对口服药物的生物利用以及酯类抗癌药物的治疗起着重要作用。Li等^[53]发现，补骨脂二氢黄酮甲醚是hCE2的天然抑制剂，通过非竞争性抑制hCE2活性，IC₅₀为4.31 μmol/L，在缓解化疗药物所致的胃肠道副作用方面具有良好的应用前景。

1.10. 其他作用

研究发现，补骨脂二氢黄酮甲醚通过抑制人单核细胞中IL-1诱导的组织因子的表达从而减缓血液凝固，减少血栓形成^[54]。陈瑞战等^[55]通过二苯基三硝基苯肼法发现，补骨脂二氢黄酮甲醚具有抗氧化活性，但活性较弱。补骨脂提取物（PCE）主要通过NO/cGMP通路介导的内皮依赖性发挥血管舒张作用，补骨脂二氢黄酮甲醚可能与PCE中的补骨脂酚产生协同作用，增强PCE的血管平滑肌放松作用^[56]。此外，Dong等^[57]报道，补骨脂二氢黄酮甲醚未来可能成为代替他汀类药物治疗非酒精性脂肪性肝病的潜在药物，通过抑制Akt/mTOR/SPEBP通路抑制FDFT1的转录及翻译，抑制胆固醇合成的关键因子角鲨烯合成酶，进而抑制胆固醇合成。

2. 肝毒性机制

肝脏是机体的物质代谢中枢，不仅是糖、脂肪、蛋白质的代谢中心，还具有生物转化功能，进入体内的非营养物质比如药物经生物转化可增加水溶性，使其易于从胆汁或者尿液中排出。药物性肝损伤(DILI)是指在药物使用过程中，由于药物或其代谢产物所导致的肝细胞损害或特殊体质对药物及其代谢产物超敏感性或耐受性降低所致的疾病。现已发现补骨脂二氢黄酮甲醚具有肝细胞毒性，不利于新药的开发，因此明确其肝毒性机制非常重要。

DILI能改变肝重要细胞器——线粒体的功能和能量状态，因此线粒体被认为是介导肝细胞损伤和凋亡的中心环节，介导肝细胞死亡的多种途径^[58]。补骨脂二氢黄酮甲醚作用于HepaRG细胞，Bax/Bcl2蛋白比值、caspase-3活性增强，线粒体膜通道开放孔打开，伴随线粒体膜电位、ATP水平下降、细胞色素C活性增强，诱导细胞凋亡和坏死^[59]。Wang等^[60]发现，补骨脂二氢黄酮甲醚通过激活p38/JNK MAPK信号通路，在不同时间段内刺激ROS生成，包括早期p38的激活刺激ROS产生以及后期JNK激活维持生成ROS，进而诱导HepaRG细胞死亡。最新研究发现，补骨脂二氢黄酮甲醚提高ROS水平，会伴随线粒体膜电位降低，推测ROS异常增加引起的线粒体损伤可以诱导肝细胞凋亡和坏死，同时通过破坏L02和HepG2细胞中脂质合成和代谢之间的平衡，造成肝细胞中脂质积累^[61]。Label-free高通量蛋白质组学分析技术发现，补骨脂二氢黄酮甲醚可诱导HepaRG细胞蛋白表达差异化，表达差异的蛋白涉及30条信号通路，多数差异蛋白与氨基酸降解途径相关，推测补骨脂二氢黄酮甲醚通过影响细胞代谢通路的基因表达而诱导肝毒性^[62]。

人尿苷5’-二磷酸-葡萄糖醛酸转移酶1A1（UGT1A1）负责胆红素的代谢消除，补骨脂二氢黄酮甲醚是UGT1A1的天然抑制剂（IC₅₀为1.27 μmol/L），可能会造成胆红素升高，诱发急性肝损伤^[63]。CYP1A1是一种只要分布于肝脏的细胞色素P450酶，它通过结构中血红素的铁离子传递电子，在维持雌激素的稳态中发挥重要作用，雌激素过多在肝脏内蓄积后常引起胆汁淤积^[64]。研究表明，补骨脂二氢黄酮甲醚对CYP1A1表现也出较强的抑制活性，IC₅₀为4.07±0.85 μmol/L ^[65]。

3. 结语

补骨脂二氢黄酮甲醚具有抗肿瘤、抗菌抗病毒、抗糖尿病及抗哮喘等药理活性。同时，补骨脂二氢黄酮甲醚因其药理活性的多样性可以多靶点、多条通路相互关联、共同发挥治疗作用。因此，需要加强对补骨脂二氢黄酮甲醚药理作用机制的探索，以便更好的服务于临床。

补骨脂及其制剂的用药安全性越来越受到关注。补骨脂作为驱白巴布期片的主要成分被报道具有潜在的肝毒性，并且已引起一例患者死亡^[66]。研究发现，补骨脂中补骨脂素、异补骨脂素、补骨脂酚和补骨脂二氢黄酮甲醚均具有肝毒性。补骨脂二氢黄酮甲醚通过影响线粒体功能、脂质积累等途径造成肝损伤。建议在使用药物时注意平衡药效和不良反应，尽量在最大程度地发挥其药理作用的同时又减少不良反应的发生。

此外，目前对于补骨脂二氢黄酮甲醚的研究多是体内和体外的研究，临床试验少。因此，应该加强对补骨脂二氢黄酮甲醚临床药理学和用药安全性研究，进一步阐明其作用机制，更好地服务于临床。

Reference (66)

[1]	鲁亚奇, 张晓, 王金金, 等. 补骨脂化学成分及药理作用研究进展[J]. 中国实验方剂学杂志, 2019, 25(3): 180-189.
[2]	ALAM F, KHAN G N, BIN ASAD M H H. Psoralea corylifolia L: Ethnobotanical, biological, and chemical aspects: a review[J]. Phytother Res, 2018, 32(4): 597-615.
[3]	BHALLA V K, NAYAK U R, DEV S. Some new flavonoids from[J]. Tetrahedron Lett, 1968, 9(20): 2401-2406.
[4]	ZAFAR S K, IQBAL S, MUMTAZ M, et al. Inhibitory mechanism exhibited by phenol-based natural products against DNA polymerase α from Psoralea corylifolia by molecular docking[J]. J Chem Soc Pak, 2018, 40(6): 1093-1102.
[5]	ZHAO H Y, CHEN Z L. Screening of aromatase inhibitors in traditional Chinese medicines by electrophoretically mediated microanalysis in a partially filled capillary[J]. J Sep Sci, 2013, 36(16): 2691-2697.
[6]	LEE S W, YUN B R, KIM M H, et al. Phenolic compounds isolated from Psoralea corylifolia inhibit IL-6-induced STAT3 activation[J]. Planta Med, 2012, 78(9): 903-906.
[7]	KUNTZ S, WENZEL U, DANIEL H. Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines[J]. Eur J Nutr, 1999, 38(3): 133-142.
[8]	NEPAL M, ChOI H J, ChOI B Y, et al. Anti-angiogenic and anti-tumor activity of Bavachinin by targeting hypoxia-inducible factor-1α[J]. Eur J Pharmacol, 2012, 691(1-3): 28-37.
[9]	JEONG D, WATARI K, SHIROUZU T, et al. Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs[J]. Biol Pharm Bull, 2013, 36(1): 152-157.
[10]	HUNG S Y, LIN S C, WANG S Z, et al. Bavachinin induces G2/M cell cycle arrest and apoptosis via the ATM/ATR signaling pathway in human small cell lung cancer and shows an antitumor effect in the xenograft model[J]. J Agric Food Chem, 2021, 69(22): 6260-6270.
[11]	PAI J T, HSU M W, LEU Y L, et al. Induction of G2/M cell cycle arrest via p38/p21^Waf1/Cip1-dependent signaling pathway activation by bavachinin in non-small-cell lung cancer cells[J]. Molecules, 2021, 26(17): 5161.
[12]	FARAJZADEH M, Dehkordi. Deciphering the DNA-binding affinity, cytotoxicity and apoptosis induce as the anticancer mechanism of Bavachinin: an experimental and computational investigation[J]. J Mol Liq, 2021, 341: 117373.
[13]	GE L N, YAN L, LI C, et al. Bavachinin exhibits antitumor activity against non-small cell lung cancer by targeting PPARγ[J]. Mol Med Rep, 2019, 20(3): 2805-2811.
[14]	ZHAO C, GHOSH B, CHAKRABORTY T, et al. Bavachinin mitigates DMH induced colon cancer in rats by altering p53/Bcl2/BAX signaling associated with apoptosis[J]. Biotech Histochem, 2021, 96(3): 179-190.
[15]	DARZI S, MIRZAEI S A, ELAHIAN F, et al. Improvement of cytotoxicity of mitoxantrone and daunorubicin by candidone, tephrosin, and bavachinin[J]. Mol Biol Rep, 2021, 48(11): 7105-7111.
[16]	DARZI S, MIRZAEI S A, ELAHIAN F, et al. Enhancing the therapeutic efficacy of daunorubicin and mitoxantrone with bavachinin, candidone, and tephrosin[J]. Evid Based Complement Alternat Med, 2019, 2019: 3291737.
[17]	丁钦, 吴克俭, 郑璐, 等. 补骨脂二氢黄酮甲醚调控Gamma delta T细胞消减胃癌SGC-7901研究[J]. 世界中医药, 2020, 15(20): 3040-3045.
[18]	BILEŞIKLER K, BAKıŞ O. An overview on flavonoids as potential antiviral strategies against coronavirus infections[J]. Gazi Med J, 2020, 31(3A): 478-484.
[19]	YOON J H, LEE J, LEE J Y, et al. Study on the 2-phenylchroman-4-one derivatives and their anti-MERS-CoV activities[J]. Bull Korean Chem Soc, 2019, 40(9): 906-909.
[20]	ZHAO H, CHEN Z. Screening of neuraminidase inhibitors from traditional Chinese medicines by integrating capillary electrophoresis with immobilized enzyme microreactor[J]. J Chromatogr A, 2014, 1340: 139-145.
[21]	Yin S , Fan C Q , Wang Y , et al. Antibacterial prenylflavone derivatives from Psoralea corylifolia, and their structure-activity relationship study[J]. Bioorg Med Chem, 2004, 12(16): 4387-4392.
[22]	王天晓, 尹震花, 张伟, 等. 补骨脂抗氧化、抑制α-葡萄糖苷酶和抗菌活性成分研究[J]. 中国中药杂志, 2013, 38(14): 2328-2333.
[23]	CUI Y M, TANIGUCHI S, KURODA T, et al. Constituents of Psoralea corylifolia fruits and their effects on methicillin-resistant Staphylococcus aureus[J]. Molecules, 2015, 20(7): 12500-12511.
[24]	MA S, HUANG Y, ZHAO Y, et al. Prenylflavone derivatives from the seeds of Psoralea corylifolia exhibited PPAR-γ agonist activity[J]. Phytochem Lett, 2016, 16: 213-218.
[25]	FENG L, LUO H, XU Z J, et al. Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice[J]. Diabetologia, 2016, 59(6): 1276-1286.
[26]	FENG L , LU S , ZHENG Z ,et al. Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects[J]. Sci Bull, 2021, 66(15): 1559-1570.
[27]	DU G, FENG L, YANG Z, et al. Separation and peroxisome proliferator-activated receptor-γ agonist activity evaluation of synthetic racemic bavachinin enantiomers[J]. Bioorg Med Chem Lett, 2015, 25(12): 2579-2583.
[28]	DU D G, ZHAO D Y, FENG D L, et al. Design synthesis and structure-activity relationships of bavachinin analogues as peroxisome proliferator-activated receptor γ agonists[J]. ChemMedChem, 2017, 12(2): 183-193.
[29]	LYMAN M, LLOYD D G, JI X M, et al. Neuroinflammation: the role and consequences[J]. Neurosci Res, 2014, 79: 1-12.
[30]	KIM Y J, LIM H S, LEE J, et al. Quantitative analysis of Psoralea corylifolia linne and its neuroprotective and anti-neuroinflammatory effects in HT22 hippocampal cells and BV-2 microglia[J]. Molecules, 2016, 21(8): 1076.
[31]	SORIA LOPEZ J A, GONZÁLEZ H M, LÉGER G C. Alzheimer’s disease[J]. Handb Clin Neurol, 2019, 167: 231-255.
[32]	CHEN Z J, YANG Y F, ZHANG Y T, et al. Dietary total prenylflavonoids from the fruits of Psoralea corylifolia L. prevents age-related cognitive deficits and down-regulates alzheimer’s markers in SAMP8 mice[J]. Molecules, 2018, 23(1): 196.
[33]	杨柳, 李爽, 王业秋, 等. 补骨脂二氢黄酮甲醚对Aβ诱导PC12细胞损伤的保护作用及机制研究[J]. 中药新药与临床药理, 2021, 32(1): 68-72.
[34]	CHEN X, YANG Y, ZHANG Y. Isobavachalcone and bavachinin from Psoraleae Fructus modulate Aβ42 aggregation process through different mechanisms in vitro[J]. FEBS Lett, 2013, 587(18): 2930-2935.
[35]	CHOI Y H, YON G H, HONG K S, et al. In vitro BACE-1 inhibitory phenolic components from the seeds of Psoralea corylifolia[J]. Planta Med, 2008, 74(11): 1405-1408.
[36]	Thomas T. Monoamine oxidase-B inhibitors in the treatment of Alzheimers disease[J]. Neurobiol Aging, 2000, 21(2): 343-348.
[37]	ZARMOUH N O, MAZZIO E A, ELSHAMI F M, et al. Evaluation of the inhibitory effects of bavachinin and bavachin on human monoamine oxidases A and B[J]. Evid Based Complement Alternat Med, 2015, 2015: 852194.
[38]	SIROTKIN A V, HARRATH A H. Phytoestrogens and their effects[J]. Eur J Pharmacol, 2014, 741: 230-236.
[39]	LIM S H, HA TY, AHN J, et al. Estrogenic activities of Psoralea corylifolia L. seed extracts and main constituents[J]. Phytomedicine, 2011, 18(5): 425-430.
[40]	蔡心银, 张紫佳. 植物雌激素药理作用及相关中药的研究进展[J]. 现代中药研究与实践, 2020, 34(2): 75-78, 86.
[41]	刘国良, 李建民, 姚远, 等. 补骨脂二氢黄酮甲醚对A375细胞黑素合成的影响[J]. 中医药学报, 2015, 43(6): 9-12.
[42]	刘国良, 于英君, 姚远, 等. 补骨脂二氢黄酮甲醚对A375细胞黑素合成及ER/MAPK信号通路的影响[J]. 中国医药导报, 2015, 12(36): 4-8, 20.
[43]	HILLMER E J, ZHANG H Y, LI H S, et al. STAT3 signaling in immunity[J]. Cytokine Growth Factor Rev, 2016, 31: 1-15.
[44]	MATSUDA H, KIYOHARA S, SUGIMOTO S, et al. Bioactive constituents from Chinese natural medicines XXXIII Inhibitors from the seeds of Psoralea corylifolia on production of nitric oxide in lipopolysaccharide-activated macrophages[J]. Biol Pharm Bull, 2009, 32(1): 147-149.
[45]	SHARMA M L, SINGH B, CHANDAN B K, et al. Actions of some flavonoids on specific and non-specific immune mechanisms[J]. Phytomedicine, 1996, 3(2): 191-195.
[46]	PAWANKAR R, CANONICA G W, HOLGATE S T, et al. Allergic diseases and asthma: a major global health concern[J]. Curr Opin Allergy Clin Immunol, 2012, 12(1): 39-41.
[47]	CHEN X, WEN T, WEI J, et al. Treatment of allergic inflammation and hyperresponsiveness by a simple compound, Bavachinin, isolated from Chinese herbs[J]. Cell Mol Immunol, 2013, 10(6): 497-505.
[48]	TINDEMANS I, SERAFINI N, DI SANTO J P, et al. GATA-3 function in innate and adaptive immunity[J]. Immunity, 2014, 41(2): 191-206.
[49]	WANG K, FENG Y P, LI S, et al. Oral delivery of bavachinin-loaded PEG-PLGA nanoparticles for asthma treatment in a murine model[J]. J Biomed Nanotechnol, 2018, 14(10): 1806-1815.
[50]	SATOH T, HOSOKAWA M. Structure function and regulation of carboxylesterases[J]. Chem Biol Interact, 2006, 162(3): 195-211.
[51]	SUN D X, GE G B, DONG P P, et al. Inhibition behavior of fructus psoraleae’s ingredients towards human carboxylesterase 1 (hCES1)[J]. Xenobiotica, 2016, 46(6): 503-510.
[52]	ZHU X H. Species difference for herb-drug interaction between Fructus psoralea and cardiovascular drug clopidogrel[J]. Lat Am J Pharm, 2016, 35(6): 1473-1475.
[53]	LI Y G, HOU J, LI S Y, et al. Fructus Psoraleae contains natural compounds with potent inhibitory effects towards human carboxylesterase 2[J]. Fitoterapia, 2015, 101: 99-106.
[54]	LALE A, HERBERT J M, AUGEREAU J M, et al. Ability of different flavonoids to inhibit the procoagulant activity of adherent human monocytes[J]. J Nat Prod, 1996, 59(3): 273-276.
[55]	陈瑞战, 杨思敏, 刘志强, 等. HPLC-ESI-MS快速筛选并鉴定补骨脂甲醇提取物中的抗氧化活性成分[J]. 分子科学学报, 2014, 30(2): 142-146.
[56]	KASSAHUN GEBREMESKEL A, DARSHANA WIJERATHNE T, KIM J H, et al. Psoralea corylifolia extract induces vasodilation in rat arteries through both endothelium-dependent and-independent mechanisms involving inhibition of TRPC3 channel activity and elaboration of prostaglandin[J]. Pharm Biol, 2017, 55(1): 2136-2144.
[57]	DONG X, ZHU Y, WANG S, et al. Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway[J]. Int Immunopharmacol, 2020, 88: 106865.
[58]	DRAGOVIC S, VERMEULEN N P E, GERETS H H, et al. Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man[J]. Arch Toxicol, 2016, 90(12): 2979-3003.
[59]	季宇彬, 王敏, 王姗, 等. 补骨脂二氢黄酮甲醚诱导HepaRG细胞损伤机制探讨[J]. 中国药理学通报, 2018, 34(4): 544-550.
[60]	WANG S, WANG M, WANG M, et al. Bavachinin induces oxidative damage in HepaRG cells through p38/JNK MAPK pathways[J]. Toxins, 2018, 10(4): 154.
[61]	GUO Z J, LI P, WANG C G, et al. Five constituents contributed to the Psoraleae Fructus-induced hepatotoxicity via mitochondrial dysfunction and apoptosis[J]. Front Pharmacol, 2021, 12: 682823.
[62]	朱月, 王姗, 徐丽娇, 等. 基于Label-free技术分析补骨脂二氢黄酮甲醚的肝毒性作用机制[J]. 大理大学学报, 2020, 5(4): 1-6.
[63]	WANG X X, LV X, LI S Y, et al. Identification and characterization of naturally occurring inhibitors against UDP-glucuronosyltransferase 1A1 in Fructus Psoraleae (Bu-gu-Zhi)[J]. Toxicol Appl Pharmacol, 2015, 289(1): 70-78.
[64]	ZECCA E, DE LUCA D, BARONI S, et al. Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study[J]. Pediatrics, 2008, 121(1): e146-e149.
[65]	秦子飞, 王培乐, 邢晗, 等. 补骨脂富含的异戊烯基成分对CYP1A1活性的影响及分子对接验证[J]. 南京中医药大学学报, 2021, 37(5): 750-759.
[66]	LI A, GAO M H, ZHAO N, et al. Acute liver failure associated with Fructus Psoraleae: a case report and literature review[J]. BMC Complement Altern Med, 2019, 19(1): 84.

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