基于网络药理学探讨真武汤治疗特发性膜性肾病的作用机制

Mechanism of action of Zhenwu decoction in treatment of idiopathic membranous nephropathy:A study based on network pharmacology

目的:通过网络药理学及GEO数据库,探讨真武汤治疗特发性膜性肾病(IMN)的作用机制。方法:运用TCMSP检索真武汤有效活性成分及靶点,利用GeneCards等4个数据库获得IMN靶点,采用STRING数据库和Cytoscape软件构建药物-成分-靶点-疾病相互作用网络和蛋白质-蛋白质相互作用(PPI)核心靶点网络,并进行基因本体(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析,最后进行分子模拟对接,并基于GEO进行核心靶点基因差异表达分析及免疫细胞浸润分析验证。结果:真武汤治疗IMN的关键活性成份是豆甾醇、山柰酚、β-谷甾醇等,其中核心靶点为丝氨酸苏氨酸蛋白激酶-1(AKT1)、转录因子AP-1(JUN)、半胱氨酸天冬氨酸蛋白酶-3(CASP3)等,KEGG富集分析发现主要作用在流体剪切应力等117条信号通路;分子对接显示山柰酚、β-谷甾醇与前列腺素G/H合成酶-2(PTGS2)、CASP3、AKT1等靶点具有较强结合力;GSE115857数据集中AKT1、细胞间黏附分子-1(ICAM1)、CASP3为上调基因,JUN为下调基因,这些可能与未活化的CD4记忆性T细胞、未活化的自然杀伤细胞等免疫细胞有关。结论:真武汤通过多成份、多靶点、多通路等方式治疗IMN,可为后续研究提供参考。

Objective:To investigate the mechanism of action of Zhenwu decoction in the treatment of idiopathic membranous nephropathy(IMN)based on network pharmacology and GEO database.Methods:TCMSP database was used to obtain the active components and targets of Zhenwu decoction,and four databases,including GeneCards,were used to obtain the targets of IMN.STRING database and Cytoscape software were used to construct a drug-component-target-disease interaction network and a protein-protein interaction network of core targets,and the gene ontology functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed.Molecular docking was performed,and the analyses of differentially expressed core target genes and immune cell infiltration were performed based on GEO database.Results:The key active components of Zhenwu decoction in the treatment of IMN included stigmasterol,kaempferol,and beta-sitosterol,and the core targets included AKT1,JUN,and CASP3.The KEGG enrichment analysis showed that 117 signaling pathways were involved,including the fluid shear stress pathway.Molecular docking showed that kaempferol and beta-sitosterol showed strong binding activities to the targets such as PTGS2,CASP3,and AKT1.In the GSE115857 dataset,AKT1,intercellular adhesion molecule-1,and CASP3 were upregulated genes,and JUN was a downregulated gene,which might be associated with the immune cells such as unactivated CD4 memory T cells and unactivated natural killer cells.Conclusion:Zhenwu decoction exerts a therapeutic effect on IMN through multiple components,targets,and pathways,which provides a reference for subsequent studies.