基于网络药理学和分子对接探讨四妙散调控铁死亡治疗痛风性肾病的作用机制  

A study on the mechanism of Simiao San regulating ferroptosis in the treatment of gouty nephropathy based on network pharmacology and molecular docking

作　　者：王蓉 石芹芹 施华 谢菲菲 WANG Rong

机构地区：[1]浙江中医药大学附属杭州市中医院,浙江杭州310000 [2]浙江中医药大学,浙江杭州310000

出　　处：《中医临床研究》2024年第34期13-22,共10页Clinical Journal Of Chinese Medicine

基　　金：国家中医药管理局第六批全国老中医药专家学术经验继承工作项目(国中医药人教发[2017]29号);朱彩凤全国老中医药专家传承工作室建设项目(国中医人教函[2022]75号);国家中医药管理局科技司-浙江省中医药管理局共建科技计划项目(GZX-ZJ-KJ-23033)。

摘　　要：目的:基于网络药理学和分子对接探讨四妙散调控铁死亡治疗痛风性肾病(Gouty Nephropathy,GN)的作用机制。方法:通过中药系统药理学数据库与分析平台(TCMSP)获取四妙散活性成分并预测相关作用靶点,构建有效成分-靶点数据库。在人类基因数据库(GeneCards)和疾病基因数据库(DisGeNET)获取GN相关靶点。利用微生信网站获取四妙散和GN的交集靶点。利用Cytoscape 3.10.0软件绘制药物-成分-疾病-靶点网络图。通过STRING数据库分析蛋白质-蛋白质相互作用关系并绘制网络图。利用DAVID数据库对交集靶点进行基因本体论(GO)富集分析和京都基因与基因组百科全书(KEGG)富集分析。在FerrDB数据库获取铁死亡相关靶点,综合分析四妙散、GN和铁死亡之间的关系,并将度值居前5位的活性成分和核心靶点进行分子对接验证。结果:共得到四妙散72种活性成分、对应靶点757个,GN靶点181个,铁死亡靶点511个,取三者的交集,共获得14个靶点。由蛋白质-蛋白质相互作用网络分析发现,丝裂原活化蛋白激酶(Mitogen-Activated Protein Kinase,MAPK)1、信号转导和转录激活因子(Signal Transducer and Activator of Transcription,STAT)3、V-rel网状内皮细胞病毒癌基因同源物A(Recombinant V-Rel Reticuloendotheliosis Viral Oncogene Homolog A,RELA)、过氧化物酶体增殖物激活受体γ(Peroxisome Proliferator Activated Receptor γ,PPARγ)、Toll样受体(Toll-like Receptor,TLR)4及非受体酪氨酸激酶(Non-Receptor Tyrosine Kinase,SRC)为调控铁死亡的核心靶点。KEGG富集分析显示,四妙散调控铁死亡治疗GN主要通过介导肿瘤坏死因子(Tumor Necrosis Factor,TNF)、核因子-κB(Nuclear Factor kappa B,NF-κB)及MAPK信号通路实现。分子对接结果表明,四妙散主要活性成分与核心靶点有较好的结合能力。结论:四妙散治疗GN主要通过多成分、多靶点、多通路,推测调控铁死亡通路可能为重要的作用机制。Objective:To explore the mechanism of Simiao San(四妙散)regulating ferroptosis in the treatment of gouty nephropathy(GN)based on network pharmacology and molecular docking.Methods:The active ingredients of Simiao San were obtained from TCMSP database,the related targets were predicted,and the active ingredient-target database was constructed.The GN related targets were obtained in GeneCards and DisGeNET database.The intersection targets of Simiao San and GN were obtained by bioinformatics wibsite.The drug-component-disease-target map was drawn by Cytoscape 3.10.0 software.Protein protein interaction(PPI)was analyzed in the String database,and the network diagram was drawn.DAVID database was used to conduct gene ontology(GO)enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis for intersection targets.The ferroptosis related targets were obtained in the FerrDB database,and the relationship between Simiao San,GN and ferroptosis was comprehensively analyzed.The top five active ingredients and core targets were verified by molecular docking.Results:A total of 72 active components of Simiao San were obtained,including 757 corresponding targets,and there were 181 GN targets and 511 ferroptosis targets.A total of 14 targets were obtained by taking the intersection of the three.MAPK1,STAT3,RELA,PPARγ,TLR 4 and SRC were the core targets for regulating ferroptosis.KEGG enrichment analysis showed that Simiao San regulated ferroptosis by mediating TNF,NF-κB and MAPK signaling pathways to treat GN.The results of molecular docking showed that the main active components of Simiao San had good binding ability with the core target.Conclusion:Simiao San mainly treats GN through multi-component,multi-target and multi-channel.It is speculated that ferroptosis pathway may be the important mechanism.

关 键 词：痛风性肾病 铁死亡 四妙散 网络药理学 分子对接 

分 类 号：R256.5[医药卫生—中医内科学]