Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking

doi:10.3724/zdxbyxb-2021-0230

J Zhejiang Univ (Med Sci)

2022, Vol. 51

Issue (1): 62-72 DOI: 10.3724/zdxbyxb-2021-0230

Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking

WANG Zhiqiang^1,²,GONG Caixia³,LI Zhenbin^1,^2,*(

)

1. Department of Rheumatology and Clinical Immunology, the 980th Hospital of the Joint Logistic Support Force of the People’s Liberation Army, Shijiazhuang 050082, China;
2. First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China;
3. Department of Nephrology, Shijiazhuang Ping’an Hospital, Shijiazhuang 050012, China

Download:

HTML( 2 )

PDF(6936KB)
Export: BibTeX | EndNote (RIS)

Abstract

Objective: To explore the mechanism of ovarian toxicity of Tripterygium wilfordii Hook. F. (TwHF) by network pharmacology and molecular docking. Methods: The candidate toxic compounds and targets of TwHF were collected by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Comparative Toxicogenomics Database (CTD). Then, the potential ovarian toxic targets were obtained from CTD, and the target genes of ovarian toxicity of TwHF were analyzed using the STRING database. The protein-protein interaction (PPI) network was established by Cytoscape and analyzed by the cytoHubba plug-in to identify hub genes. Additionally, the target genes of ovarian toxicity of TwHF were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses by using the R software. Finally, Discovery Studio software was used for molecular docking verification of the core toxic compounds and the hub genes. Results: Nine candidate toxic compounds of TwHF and 56 potential ovarian toxic targets were identified in this study. Further network analysis showed that the core ovarian toxic compounds of TwHF were triptolide, kaempferol and tripterine, and the hub ovarian toxic genes included TP53, MYC, PTEN, MAPK3, MTOR, STAT3, EGFR, KRAS, CDH1 and AKT1. Besides, the GO and KEGG analysis indicated that TwHF caused ovarian toxicity through oxidative stress, reproductive system development and function, regulation of cell cycle, response to endogenous hormones and exogenous stimuli, apoptosis regulation and aging. The docking studies suggested that 3 core ovarian toxic compounds of TwHF were able to fit in the binding pocket of the 10 hub genes. Conclusion: TwHF may cause ovarian toxicity by acting on 10 hub genes and 140 signaling pathways.

Key words： Tripterygium wilfordii Hook.F. Ovarian toxicity Network pharmacology Target Pathway

Received: 08 August 2021 Published: 17 May 2022

CLC:

R285.5

Corresponding Authors: LI Zhenbin E-mail: lizb1962@126.com

	Service
	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	WANG Zhiqiang
	GONG Caixia
	LI Zhenbin

Cite this article:

WANG Zhiqiang,GONG Caixia,LI Zhenbin. Molecular mechanism of ovarian toxicity of Tripterygium wilfordii Hook.F.: a study based on network pharmacology and molecular docking. J Zhejiang Univ (Med Sci), 2022, 51(1): 62-72.

URL:

https://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0230 OR https://www.zjujournals.com/med/Y2022/V51/I1/62

基于网络药理学和分子对接技术探讨雷公藤卵巢毒性的机制

目的：通过网络药理学和分子对接技术探讨雷公藤卵巢毒性的作用机制。方法：通过中药系统药理数据库及分析平台（TCMSP）和比较毒理基因组学数据库（CTD）收集雷公藤的候选毒性化合物和靶点，从CTD中获得雷公藤潜在的卵巢毒性靶点，并利用STRING数据库对雷公藤卵巢毒性的靶点基因进行分析。用Cytoscape软件构建蛋白质-蛋白质相互作用（PPI）网络，用cytoHubba插件鉴定核心基因。此外，利用R软件对雷公藤卵巢毒性的靶点基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。最后，使用Discovery Studio软件对核心毒性化合物和核心基因进行分子对接验证。结果：共获得9个雷公藤候选毒性化合物和56个潜在的卵巢毒性靶点。网络分析结果，雷公藤甲素、山柰酚和雷公藤红素是雷公藤的关键卵巢毒性化合物，核心卵巢毒性基因包括TP53、MYC、PTEN、MAPK3、MTOR、STAT3、EGFR、KRAS、CDH1和AKT1。GO和KEGG分析显示，雷公藤通过氧化应激、生殖系统发育和功能、细胞周期调节、对内源性激素和外源性刺激的反应、细胞凋亡调节、衰老等途径引起卵巢毒性。分子对接研究显示，雷公藤的3个关键卵巢毒性化合物可与10个核心基因的对接口袋相匹配。结论：雷公藤可能通过作用于10个核心基因和140条信号通路而导致卵巢毒性。

关键词： 雷公藤, 卵巢毒性, 网络药理学, 靶点, 通路

Table 1 The candidate toxic compounds and the corresponding targets of Hook.F.

Figure 1 The toxic compound-ovarian toxic target network of Hook.F.

Figure 2 Protein-protein interaction network of ovarian toxicity targets of Hook.F.

Table 2 Details of the hub genes in protein-protein interaction networks of ovarian toxicity targets of Hook.F.

Figure 3 The top 20 of Gene Ontology（GO） enrichment analysis of ovarian toxicity targets of Hook.F.

Figure 4 The top 20 of KEGG enrichment analysis of ovarian toxicity targets of Hook.F.

Figure 5 Molecular docking pattern diagram of triptolide with hub genes of ovarian toxicity

Table 3 The CDOCKER interaction energy between core toxic compounds and hub ovarian toxicity target genes of Hook.F.in molecular docking


[1]	赵　莉, 周学平. 中药配伍减轻雷公藤生殖毒性的研究进展[J]. 中华中医药杂志, 2015, 30(2): 482-484 ZHAO Li, ZHOU Xueping. Research advance of reducing reproduction toxicity of Tripterygium wilfordii with compatibility of Chinese medicine[J]. China Journal of Traditional Chinese Medicine and Pharmacy, 2015, 30(2): 482-484. (in Chinese)

[2]	徐　颖, 樊媛芳, 赵　元, 等. 近40年雷公藤生殖毒性研究概述[J]. 中国中药杂志, 2019, 44(16): 3406-3414 XU Ying, FAN Yuanfang, ZHAO Yuan, et al. Overview of reproductive toxicity studies on Tripterygium wilfordii in recent 40 years[J]. China Journal of Chinese Materia Medica, 2019, 44(16): 3406-3414. (in Chinese)

[3]	李逸群, 胡瑞学, 贾可欣, 等. 雷公藤多苷(甙)片治疗类风湿关节炎的安全性系统评价[J]. 中国中药杂志, 2020, 45(4): 775-790 LI Yiqun, HU Ruixue, JIA Kexin, et al. Meta-analysis on safety of Tripterygium glycosides ablets in treatment of rheumatoid arthritis[J]. China Journal of Chinese Materia Medica, 2020, 45(4): 775-790. (in Chinese)

[4]	LIUL, JIANGZ, LIUJ, et al.Sex differences in subacute toxicity and hepatic microsomal metabolism of triptolide in rats[J]Toxicology, 2010, 271( 1-2): 57-63. doi: 10.1016/j.tox.2010.03.004

[5]	LI S, ZHANG B. Traditional Chinese medicine network pharmacology: theory, methodology and application[J]. Chin J Nat Med, 2013, 11(2): 110-120

[6]	RUJ, LIP, WANGJ, et al.TCMSP: a database of systems pharmacology for drug discovery from herbal medicines[J]J Cheminform, 2014, 6( 1): 13. doi: 10.1186/1758-2946-6-13

[7]	DAVISA P, GRONDINC J, JOHNSONR J, et al.Comparative Toxicogenomics Database (CTD): update 2021[J]Nucleic Acids Res, 2021, 49( D1): D1138-D1143. doi: 10.1093/nar/gkaa891

[8]	OTASEKD, MORRISJ H, BOUÇASJ, et al.Cytoscape automation: empowering workflow-based network analysis[J]Genome Biol, 2019, 20( 1): 185. doi: 10.1186/s13059-019-1758-4

[9]	SZKLARCZYKD, GABLEA L, LYOND, et al.STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets[J]Nucleic Acids Res, 2019, 47( D1): D607-D613. doi: 10.1093/nar/gky1131

[10]	YUG, WANGL G, HANY, et al.ClusterProfiler: an R package for comparing biological themes among gene clusters[J]OMICS-J Integrative Biol, 2012, 16( 5): 284-287. doi: 10.1089/omi.2011.0118

[11]	KIMS, CHENJ, CHENGT, et al.PubChem 2019 update: improved access to chemical data[J]Nucleic Acids Res, 2019, 47( D1): D1102-D1109. doi: 10.1093/nar/gky1033

[12]	GOODSELLD S, ZARDECKIC, DI COSTANZOL, et al.RCSB Protein Data Bank: enabling biomedical research and drug discovery[J]Protein Sci, 2020, 29( 1): 52-65. doi: 10.1002/pro.3730

[13]	ZHANGB, ZHAOJ, WANGZ, et al.Identification of multi-target anti-AD chemical constituents from traditional Chinese medicine formulae by integrating virtual screening and in vitro validation[J]Front Pharmacol, 2021, 709607. doi: 10.3389/fphar.2021.709607

[14]	FAND, GUOQ, SHENJ, et al.The effect of triptolide in rheumatoid arthritis: from basic research towards clinical translation[J]Int J Mol Sci, 2018, 19( 2): 376. doi: 10.3390/ijms19020376

[15]	曾又佳, 孙惠力, 徐缘钊, 等. 颗粒细胞凋亡在雷公藤甲素诱导卵巢损伤中的作用[J]. 广东医学, 2014, 35(7): 969-973 ZENG Youjia, SUN Huili, XU Yuanzhao, et al. The role of granulose cell apoptosis in Triptolide-induced ovary injury in NIH mice[J]. Guangdong Medical Journal, 2014, 35(7): 969-973. (in Chinese)

[16]	周　雪, 赵光锋, 陈士雯, 等. MSCs上清可减轻雷公藤甲素对KGN细胞的损伤作用[J]. 中国免疫学杂志, 2014, 30(12): 1641-1646 ZHOU Xue, ZHAO Guangfeng, CHEN Shiwen, et al. Mesenchymal stem cell-conditioned medium could ameliorated triptolide induced damage in KGN cells[J]. Chinese Journal of Immunology, 2014, 30(12): 1641-1646. (in Chinese)

[17]	FRANCISA R, SHETTYT K, BHATTACHARYAR K. Modulating effect of plant flavonoids onthe mutagenicity of N-methyl-N’-nitro-N-nitrosoguanidine[J]Carcinogenesis, 1989, 10( 10): 1953-1955. doi: 10.1093/carcin/10.10.1953

[18]	NIERINGP, MICHELSG, WÄTJENW, et al.Protective and detrimental effects of kaempferol in rat H4IIE cells: implication of oxidative stress and apoptosis[J]Toxicol Appl Pharmacol, 2005, 209( 2): 114-122. doi: 10.1016/j.taap.2005.04.004

[19]	ALAMW, KHANH, SHAHM A, et al.Kaempferol as a dietary anti-inflammatory agent: current therapeuticstanding[J]Molecules, 2020, 25( 18): 4073. doi: 10.3390/molecules25184073

[20]	CASCÃOR, FONSECAJ E, MOITAL F. Celastrol: a spectrum of treatment opportunities in chronic diseases[J]Front Med, 2017, 69. doi: 10.3389/fmed.2017.00069

[21]	HOUW, LIUB, XUH. Celastrol: progresses in structure-modifications, structure-activity relationships, pharmacology and toxicology[J]Eur J Medicinal Chem, 2020, 112081. doi: 10.1016/j.ejmech.2020.112081

[22]	BERGAMASCHID, SAMUELSY, O’NEILN J, et al.iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human[J]Nat Genet, 2003, 33( 2): 162-167. doi: 10.1038/ng1070

[23]	LIUT E, ZHANGL, WANGS, et al.Tripterygium glycosides induce premature ovarian failure in rats by promoting p53 phosphorylation and activating the serine/threonine kinase 11-p53-p21 signaling pathway[J]Exp Therapeutic Med, 2015, 10( 1): 12-18. doi: 10.3892/etm.2015.2498

[24]	SEYYED ANVARI S, DEHGAN G H, RAZI M. Preliminary findings of platelet-rich plasma-induced ameliorative effect on polycystic ovarian syndrome[J]. Cell J, 2019, 21(3): 243-252

[25]	JIANG B H, LIU L Z. PI3K/PTEN signaling in angiogenesis and tumorigenesis[J]. Adv Cancer Res, 2009, 102: 19-65

[26]	KUANGH, ZHANGL, PENGJ, et al.Premature ovarian failure, menopause and ovarian cancer, three nodes on the same string: Pten and other potential genes on the GO[J]Med Hypotheses, 2009, 73( 6): 961-962. doi: 10.1016/j.mehy.2009.06.023

[27]	GRATAOA A, DAHLHOFFM, SINOWATZF, et al.Betacellulin overexpression in the mouse ovary leads to MAPK3/MAPK1 hyperactivation and reduces litter size by impairing fertilization[J]Biol Reprod, 2008, 78( 1): 43-52. doi: 10.1095/biolreprod.107.062588

[28]	GROSBOISJ, DEMEESTEREI. Dynamics of PI3K and Hippo signaling pathways during in vitro human follicle activation[J]Hum Reprod, 2018, 33( 9): 1705-1714. doi: 10.1093/humrep/dey250

[29]	CECCONIS, MAUROA, CELLINIV, et al.The role of Akt signalling in the mammalian ovary[J]Int J Dev Biol, 2012, 56( 10-11-12): 809-817. doi: 10.1387/ijdb.120146sc

[30]	TSCHERNERA, BROWNA C, STALKERL, et al.STAT3 signaling stimulates miR-21 expression in bovine cumulus cells during in vitro oocyte maturation[J]Sci Rep, 2018, 8( 1): 11527. doi: 10.1038/s41598-018-29874-w

[31]	ZHENGQ, LIY, ZHANGD, et al.ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats[J/OL]Cell Death Dis, 2017, 8( 10): e3145. doi: 10.1038/cddis.2017.494

[32]	TEASLEYH E, BEESLEYA, KIMT H, et al.Differential expression of KRAS and SIRT1 in ovarian cancers with and without endometriosis[J]Reprod Sci, 2020, 27( 1): 145-151. doi: 10.1007/s43032-019-00017-4

[33]	LINC, XUX, YANGQ, et al.Circular RNA ITCH suppresses proliferation, invasion, and glycolysis of ovarian cancer cells by up-regulating CDH1 via sponging miR-106a[J]Cancer Cell Int, 2020, 20( 1): 336. doi: 10.1186/s12935-020-01420-7

[34]	TESARIKJ, GALÁN-LÁZAROM, MENDOZA-TESARIKR. Ovarian aging: molecular mechanisms and medical management[J]Int J Mol Sci, 2021, 22( 3): 1371. doi: 10.3390/ijms22031371

[35]	DE FELICIM, KLINGERF G. PI3K/PTEN/AKT signaling pathways in germ cell development and their involvement in germ cell tumors and ovarian dysfunctions[J]Int J Mol Sci, 2021, 22( 18): 9838. doi: 10.3390/ijms22189838

[36]	REGANS L P, KNIGHTP G, YOVICHJ L, et al.Granulosa cell apoptosis in the ovarian follicle——a changing view[J]Front Endocrinol, 2018, 61. doi: 10.3389/fendo.2018.00061

[37]	WUY, ZHANGZ, LIAOX, et al.Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary[J]Mol Med Rep, 2016, 14( 4): 3894-3900. doi: 10.3892/mmr.2016.5671

[38]	陈燕霞, 袁　苑, 马　堃, 等. 定坤丹对雷公藤多苷诱导卵巢储备功能低下小鼠性激素和卵泡计数的影响[J]. 中国实验方剂学杂志, 2020, 26(14): 78-84 CHEN Yanxia, YUAN Yuan, MA Kun, et al. Effect of Dingkundan on sex hormone and follicle count in mice of Tripterygium Wilfordii Polyglycosides induced diminished ovarian reserve[J]. Journal of Experimental Traditional Medical Formulae, 2020, 26(14): 78-84. (in Chinese)

[39]	徐文君, 高　慧, 李　杨. 补肾调冲方对卵巢早衰大鼠性激素水平及TNF-α、IFN-γ蛋白表达的影响[J]. 药物评价研究, 2016, 39(6):953-957 XU Wenjun, GAO Hui, LI Yang. Effect of Bushen Tiaochong Prescription on sex hormone level and TNF-α and IFN-γ protein expression in rats with premature ovarian failure[J].Drug Evaluation Research, 2016, 39(6): 953-957. (in Chinese)

[40]	SUJ, CHENGJ, SUNH X, et al.Tripterygium glycosides impairs the proliferation of granulosa cells and decreases the reproductive outcomes in female rats[J]Birth Defects Res B, 2014, 101( 3): 283-291. doi: 10.1002/bdrb.21111

[41]	马蔚蓉, 谈　勇. 金丝桃苷改善雷公藤诱导的POI小鼠卵巢储备的作用及机制[J]. 四川大学学报(医学版), 2021, 52(3): 458-466 MA Weirong, TAN Yong. The effect and mechanism of hyperin on ovarian reserve of tripterygium glycosides-induced POI mice[J]. Journal of Sichuan University (Medical Science Edition), 2021, 52(3): 458-466. (in Chinese)

[42]	白　俊, 吴也可, 吴克明, 等. 雷公藤甲素通过PI3K/AKT/mTOR通路诱导卵巢颗粒细胞自噬的实验研究[J]. 中国中药杂志, 2019, 44(16): 3429-3434 BAI Jun, WU Yeke, WU Keming, et al. Triptolide induces autophagy of ovarian granulosa cells via PI3K/AKT/mTOR pathway[J]. China Journal Chinese Materia Medica, 2019, 44(16): 3429-3434. (in Chinese)

[43]	BURIANIA, FORTINGUERRAS, SORRENTIV, et al.Essential oil phytocomplex activity, a review with a focus on multivariate analysis for a network pharmacology-informed phytogenomic approach[J]Molecules, 2020, 25( 8): 1833. doi: 10.3390/molecules25081833

[44]	李芳琼, 赵东晓, 王娟, 等. 基于iTRAQ技术分析不同浓度的雷公藤甲素作用肺癌细胞后的差异蛋白表达[J]. 中国新药杂志, 2018, 27(11): 1321-1328 LI Fangqiong, ZHAO Dongxiao, WANG Juan, et al. Identification of differential expression proteins in lung cancer cells treated with triptolide by iTRAQ[J]. Chinese Journal of New Drugs, 2018, 27(11): 1321-1328. (in Chinese)

[1]	ZHANG Yiwen,SHENG Kongsheng,SONG Feifeng,PAN Zongfu,ZOU Xiaozhou,LIU Yujia,HUANG Ping. Efficacy of Qingfei oral liquid for idiopathic pulmonary fibrosis in rats and related network pharmacology study[J]. J Zhejiang Univ (Med Sci), 2022, 51(1): 53-61.

[2]	QIAN Chenhong,JIANG Liehao,XU Shiying,WANG Jiafeng,TAN Zhuo,XIN Ying,GE Minghua. Advances in targeted therapy for anaplastic thyroid carcinoma[J]. J Zhejiang Univ (Med Sci), 2021, 50(6): 685-693.

[3]	CAO Qiuli,LI Xiaowei,XUAN Xiuping,HUANG Song,XIE Xuemei. Changes of LRP6/β-catenin pathway in adipose tissue of rats with intrauterine growth restriction with catch-up growth[J]. J Zhejiang Univ (Med Sci), 2021, 50(6): 755-761.

[4]	REN Yuan,CUI Gedan,GAO Yongxiang. Research progress on inflammatory mechanism of primary Sj?gren syndrome[J]. J Zhejiang Univ (Med Sci), 2021, 50(6): 783-794.

[5]	SHI Jianhong,LI Ruizhi,YANG Yuanxiao,JI Liting,LI Changyu. Protective effect of α-asarone and β-asarone on Aβ _25-35-induced inflammatory response in PC12 cells and its mechanism[J]. J Zhejiang Univ (Med Sci), 2021, 50(5): 591-600.

[6]	JIN Hualiang,ZHOU Yan,WANG Limin. The mechanism of rapamycin in promoting asthmatic regulatory T cell differentiation and function in vitro[J]. J Zhejiang Univ (Med Sci), 2021, 50(5): 621-626.

[7]	MAO Hongmei,SUN Yi. Primary cilium and its role in tumorigenesis[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 245-260.

[8]	SHEN Yeqi,WANG Zhongxiu,TAN Jingyi,ZHONG Jiahui,CHEN Lili. TRAF6/ERK/p38 pathway is involved in interleukin-17-mediated autophagy to promote osteoclast precursor cell differentiation[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 162-170.

[9]	ZHANG Diya,LU Kexin,LI Shenglai,WU Yanmin. Ca²⁺ mobilization and signaling pathways induced by Porphyromonas gingivalis rRgpB in human gingival fibroblast[J]. J Zhejiang Univ (Med Sci), 2021, 50(2): 171-178.

[10]	WANG Yanan,YAN Xiaoming,ZHANG Qingyu,SONG Aihua,HAN Fei. Study on the mechanism of Flos Puerariae and Semen Hoveniae in treatment of alcoholic liver injury based on network pharmacology and molecular docking[J]. J Zhejiang Univ (Med Sci), 2020, 49(6): 714-724.

[11]	YU Qing, XIONG Xiufang, SUN Yi. Targeting Cullin-RING E3 ligases for anti-cancer therapy: efforts on drug discovery[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 1-19.

[12]	LI Ai,ZHANG Tianyuan,GAO Jianqing. Progress on utilizing mesenchymal stem cells as cellular delivery system for targeting delivery of as drug/gene for anti-tumor therapy[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 20-34.

[13]	HUANG Yaoping,YANG Feng,ZHOU Tianhua,XIE Shanshan. Emerging roles of Hippo signaling pathway in gastrointestinal cancers and its molecular mechanisms[J]. J Zhejiang Univ (Med Sci), 2020, 49(1): 35-43.

[14]	SHAO Ying,WANG Jiadan,ZHU Danyan. Rictor regulates mitochondrial calcium signaling in mouse embryo stem cell-derived cardiomyocytes[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 65-74.

[15]	LAI Chong, TENG Xiaodong. Molecular biological foundation of targeted therapy for metastatic renal cell carcinoma[J]. J Zhejiang Univ (Med Sci), 2016, 45(1): 91-97.

Viewed

Full text

Abstract

Cited

Shared

Discussed