基于网络药理学葵花护肝片“多成分-多靶点-多通路”的作用机制研究

"Multi-component-multi-target-multi-pathway" mechanism of Kuihua Hugan Tablets based on network pharmacology

该研究通过网络药理学的方法,对葵花护肝片活性成分作用靶点预测,探讨其多成分-多靶点-多通路肝脏保护作用模式。首先,采用中药系统药理学技术平台(TCMSP)及TCM Database@Taiwan资料库,以口服利用度(OB),类药性(DL)和药物半衰期(HL)筛选葵花护肝片中活性成分。然后,依据反向药效团匹配(PharmMapper)方法预测葵花护肝片活性成分靶点;通过CooLGeN数据库文本挖掘及GeneCards数据库中与慢性肝炎及早期肝硬化相关靶基因比对筛选,借助生物信息学注释数据库(Metascape)分析靶点基因功能及信号通路,采用Cytoscape软件构建葵花护肝片化合物-靶点,化合物-靶点-通路。通过STRING数据库结合Cytoscape软件绘制蛋白相互作用(PPI)网络并进行网络拓扑学分析;最后,通过Systems Dock Web Site软件将葵花护肝片活性成分与枢纽靶点进行分子对接验证。实验筛选得到护肝片26个化合物和509个靶点;通过核心靶点蛋白互作网络分析确定了葵花护肝片活性成分与白蛋白(ALB)、胰岛素样生长因子1(IGF1)、基质金属蛋白酶-9 (MMP-9)、基质金属蛋白酶-2 (MMP-2)、非受体酪氨酸激酶原癌基因(SRC)及雌激素受体1(ESR1)等6个靶点及肿瘤-信号转导-炎症-药物代谢等相关生物过程和代谢通路紧密相关。结果表明,护肝片改善慢性肝炎及早期肝硬化作用体现了中药多成分-多靶点-多途径的作用特点,该研究为深入阐释葵花护肝片临床研究及进一步开发提供了思路。

To predict the targets of active ingredients of Kuihua Hugan Tablets by network pharmacology, and explore the "multi-component-multi-target-multi-pathway" hepatoprotective mechanism of action. First, through traditional Chinese medicine systems pharmacology(TCMSP) and TCM Database@Taiwan Database, main active ingredients of Kuihua Hugan Tablets were screened out based on oral bioavailability(OB), drug-likeness(DL) and effective half-lives(HL). The targets of active ingredients of Kuihua Hugan Tablets were predicted based on the PharmMapper method. Then, the prediction was conducted by screening the target genes associated with chronic hepatitis and early cirrhosis through CooLGeN and GeneCards databases. Target gene functions and signal pathways were analyzed by bioinformatics annotation database Metascape. Cytoscape software was used to construct the Kuihua Hugan Tablets ingredient-target and ingredient-target-pathway network. String database combined with Cytoscape software was used to construct the networks of component-target and component-target-pathway. STRING database was combined with Cytoscape software to draw protein-protein interaction(PPI) network and conduct network topology analysis. Finally, Systems Dock Web Site software was applied in verifying the molecular docking between active ingredients and potential protein targets. A total of 26 compounds and 509 potential targets were screened out from Kuihua Hugan Tablets in the experiment. The results of PPI network analysis indicated that albumin(ALB), insulin-like growth factor 1(IGF1), matrix metalloproteinase-9(MMP9), matrix metalloproteinase-2(MMP2), non-receptor tyrosine kinase proto-oncogene(SRC), estrogen receptor 1(ESR1) and cancer-signal transduction-inflammation-drugs metabolism-related biological processes and metabolic pathways were closely associated with the active ingredients in Kuihua Hugan Tablets. The effects of Kuihua Hugan Tablets in alleviating chronic hepatitis and early cirrhosis indicated the multi-component, multi-target, and multi-pathway characteristics of traditional Chinese medicines, providing new ideas for further research and development of Kuihua Hugan Tablets.