基于网络药理学探讨白花蛇舌草-半枝莲抗肝细胞癌的作用机制

Mechanism of Hedyotis Diffusa-Scutellariae Barbatae Herba for Hepatocellular Carcinoma Based on Network Pharmacology

[目的]基于网络药理学探讨白花蛇舌草-半枝莲药对治疗肝细胞癌的潜在靶点及作用机制。[方法]利用中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)检索白花蛇舌草和半枝莲活性成分,导入Drugbank数据库进行蛋白靶点匹配,使用GeneCards数据库、人类在线孟德尔遗传(Online Mendelian Inheritance in Man,OMIM)数据库、治疗目标数据库(Therapeutic Target Database,TTD)、Drugbank、肝细胞癌肿瘤数据库(Oncogenomic Database of Hepatocellular Carcinoma,OncoDB.HCC)和Liverome数据库等获取肝细胞癌相关靶点,运用Cytoscape构建“药物-活性成分-靶点”网络,String数据库构建蛋白相互作用(protein-protein interaction,PPI)网络,并通过网络拓扑分析筛选关键成分及核心靶点,最后利用R语言及Cluego对预测得到的核心靶点进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析。[结果]白花蛇舌草-半枝莲药治疗肝细胞癌的潜在靶点89个,通过网络拓扑分析筛选得到6个核心靶点、5种关键成分。GO功能富集分析显示,白花蛇舌草-半枝莲药对主要参与细胞增殖、细胞凋亡、炎症反应和血管生成等生物学途径。KEGG通路富集分析显示,p53抑癌基因通路、磷脂酰肌醇3-激酶/蛋白激酶B(phosphatidylinositol-3-kinase/protein kinase B,PI3K-Akt)通路、缺氧诱导因子-1(hypoxia inducible factor-1,HIF-1)通路、核因子-κB(nuclear factor-κB,NF-κB)通路、血管内皮生长因子(vascular endothelial growth factor,VEGF)通路等是其关键信号通路。[结论]白花蛇舌草-半枝莲药对中有效成分主要是槲皮素、木犀草素、β-谷甾醇等,通过调节p53、PI3K-Akt、HIF-1、NF-κB和VEGF等信号通路抑制肝癌细胞增殖,并促进细胞凋亡,减少炎症反应,抑制血管生成,从而实现对肝细胞癌的治疗作用。

[Objective]To explore the potential targets and mechanism of Hedyotis diffusa-Scutellariae barbatae Herba in treating hepatocellular carcinoma(HCC)based on network pharmacology.[Methods]The active components of Hedyotis diffusa and Scutellariae barbatae Herba were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),the Drugbank Database were used for protein targets matching.HCC-related targets were obtained from GeneCards,Online Mendelian Inheritance in Man(OMIM),Therapeutic Target Database(TTD),Drugbank,Oncogenomic Database of Hepatocellular Carcinoma(OncoDB.HCC)and Liverome Database.Cytoscape was applied to construct a“drug-component-target”network,String Database was used to construct a protein-protein interaction(PPI)network,screen key-components and key-targets through network topology analysis.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of key-targets were performed by R software and Cluego.[Results]Totally 89 potential targets of Hedyotis diffusa-Scutellariae barbatae Herba were predicted for the treatment of HCC.Totally 6 key-targets and 5 key-components were obtained from the network topology analysis.GO function enrichment showed that biological functions of Hedyotis diffusa-Scutellariae barbatae Herba were concentrated on cell proliferation,apoptosis,inflammation and angiogenesis.KEGG pathway enrichment showed that p53 signaling pathway,phosphatidylinositol-3-kinase/protein kinase B(PI3K-Akt)signaling pathway,hypoxia inducible factor-1(HIF-1)signaling pathway,nuclear factor-κB(NF-κB)signaling pathway,vascular endothelial growth factor(VEGF)signaling pathway were the key signaling pathways.[Conclusion]The effective components of Hedyotis diffusa-Scutellariae barbatae Herba are mainly quercetin,luteolin andβ-sitosterol,which can inhibit cell proliferation,induce cell apoptosis,reduce inflammatory reaction and inhibit angiogenesis through regulating p53,PI3K-Akt,HIF-1,NF-κB and VEGF signaling pathways,so as to achieve the therapeutic effect on HCC.