基于网络药理学探讨表没食子儿茶素没食子酸酯治疗阿尔茨海默病的作用机制

Mechanism of epigallocatechin gallate in the treatment of Alzheimer′s disease based on network pharmacology

目的基于网络药理学探讨表没食子儿茶素没食子酸酯(EGCG)治疗阿尔茨海默病(AD)的相关作用靶点及主要信号通路,探讨其治疗AD的可能作用机制。方法通过Pubchem数据库筛选EGCG活性成分及作用靶点;通过利用Genecards数据库和人类孟德尔遗传数据库(OMIM)检索AD的基因靶点,将疾病靶点与药物作用靶点融合找出交集靶点。在String平台利用EGCG的靶标基因与AD靶标基因的交集基因构建蛋白相互作用(PPI),运用Cytoscape 3.7.2软件构建“EGCG-成分-靶点”网络,通过Metascape等数据库进行基因本体(GO)功能富集分析和京都基因与基因组百科全书(KEGG)通路富集分析,最后采用AutoDock Vina软件进行分子对接。结果获得EGCG有效成分和作用靶点有171个,其中与AD相关的靶点95个。EGCG改善AD病理变化的核心靶点主要集中在AKT1、肿瘤坏死因子(TNF)、白细胞介素(IL)-6等蛋白上。这些靶点涉及信号通路169条,包括磷脂酰肌醇3-羟激酶(PI3K)/Akt信号通路、低氧诱导因子(HIF)-1信号通路、促分裂原活化的蛋白激酶(MAPK)信号通路、Ras信号通路等。分子对接结果显示:核心成分与关键靶点具有良好的结合力。结论EGCG治疗AD的潜在生物学作用机制可能是通过调控TNF等信号通路的活性,改善海马神经元细胞的损伤,减轻Aβ沉积,Tau蛋白过度磷酸化从而延缓AD的发生。

Objective To investigate the related targets and main signaling pathways of epigallocatechin gallate(EGCG)in the treatment of Alzheimer's disease(AD)based on network pharmacology,and to explore its possible mechanism of action in the treatment of AD.Methods The active components and targets of EGCG were screened by Pubchem database.By using the Genecards database and the On-line Mendelian Inheritance in Man(OMIM)to search the gene targets of AD,the disease targets and drug targets were fused to find out the intersection targets.The protein-protein interaction(PPI)was constructed using the intersection gene of EGCG target gene and AD target gene on String platform,and the"EGCG—component—target"network was constructed using Cytoscape 3.7.2 software.Gene ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed by Metascape and other databases.Finally,AutoDock Vina software was used for molecular docking.Results A total of 171 active components and targets of EGCG were obtained,including 95 targets related to AD.The core targets of EGCG in improving the pathological changes of AD are mainly AKT1,tumor necrosis factor(TNF),interleukin(IL)-6 and other proteins.These targets involved 169 signaling pathways,including phosphatidylinositol 3-hydroxykinase(PI3K)/Akt signaling pathway,hypoxia-inducible factor(HIF)-1 signaling pathway,mitogen-activated protein kinase(MAPK)signaling pathway,Ras signaling pathway,etc.Molecular docking results showed that the core components had good binding to the key targets.Conclusion The potential biological mechanism of EGCG in the treatment of AD may be to regulate the activity of TNF signaling pathway,improve the damage of hippocampal neurons,reduce the deposition of Aβ,and hyperphosphorylation of Tau protein to delay the occurrence of AD.