基于网络药理学和实验验证探讨八宝丹胶囊治疗肝细胞癌的作用机制

Study on the mechanism of Babaodan Capsules in the treatment of hepatocellular carcinoma based on network pharmacology and experimental validation

关键词:  网络药理学  八宝丹胶囊  肝细胞癌  分子对接  STAT3

Key words:  network pharmacology  Babaodan Capsule  hepatocellular carcinoma  molecular docking  STAT3

摘要:

[目的] 采用网络药理学方法探究八宝丹胶囊治疗肝细胞癌的作用机制。[方法] 使用多数据库及文献收集八宝丹胶囊化学成分、药物靶点和肝细胞癌疾病靶点。Cytoscape 3.9.0软件构建“药物-成分-靶点”网络。选取药物靶点与疾病靶点交集基因构建蛋白质相互作用（PPI）网络。选取网络高Degree值基因完成基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路富集分析，运用Autodock tools和Pymol对八宝丹胶囊的核心成分与核心靶点进行分子对接验证；最后结合细胞实验验证八宝丹胶囊的作用靶点与作用途径。[结果] 从八宝丹胶囊中获取115个潜在活性化合物，393个作用靶点，其中与肝细胞癌疾病交集靶点共346个。通过构建并分析网络图，确定八宝丹胶囊主要活性成分有雌二醇、槲皮素、鹅去氧胆酸、三七皂苷、熊果酸等，核心靶点为信号转导和转录激活因子3（STAT3）、肿瘤蛋白p53（TP53）、连环蛋白1（CTNNB1）等10个。通过富集分析得到GO生物过程2 781条、细胞组分119条、分子功能275条，得到KEGG通路187条。分子对接结果表明八宝丹胶囊中雌二醇、槲皮素、熊果酸等核心成分与STAT3、TP53、CTNNB1等核心靶点均有良好的结合活性。细胞实验确证八宝丹胶囊通过调控STAT3、TP53等靶点诱导肝脏癌细胞凋亡。[结论] 八宝丹胶囊治疗肝细胞癌的主要药效物质包括皂苷类、胆酸类、黄酮类等，具体作用机制与调控STAT3等靶点及肿瘤坏死因子-α/核因子-κB（TNF-α/NF-κB）等信号通路有关。

Abstract:

[Objective] To explore the mechanism of Babaodan Capsules in the treatment of hepatocellular carcinoma（HCC） by network pharmacology methods. [Method] Multiple huge databases and literature were used to collect the chemical components，drug targets，and HCC disease targets of Babaodan Capsules. Constructed a “drug-component-target” network by Cytoscape 3.9.0. Constructed a protein-protein-interaction（PPI） network by selecting genes that intersect drug and disease targets. Selected genes with higher degree values in the network to complete gene oncology（GO） and kyoto encyclopedia of genes and genomes（KEGG） pathway enrichment analysis. Molecular docking verification of the core components and core targets of Babaodan Capsules was carried out by Autodock tools and Pymol. Finally，the target and pathway of action of Babaodan Capsules were verified through cell experiments. [Results] 115 potential active compounds and 393 targets were obtained from Babaodan capsules，among which a total of 346 targets intersected with HCC. By constructing and analyzing a network diagram，it was determined that the main active ingredients of Babaodan Capsules include estradiol，quercetin，chenodeoxycholic acid，notoginsenoside，ursolic acid，etc. There are 10 core targets including signal transducer and activator of transcription 3（STAT3），tumor protein p53（TP53），catenin beta 1（CTNNB1），etc. Through enrichment analysis，2 781 GO biological processes，119 cell components，and 275 molecular functions were obtained，resulting in 187 KEGG pathways. The molecular docking results indicated that the core components of Babaodan Capsules such as estradiol，quercetin，and ursolic acid had a good binding activity with core targets such as STAT3，TP53，and CTNNB1. Cell experiments confirmed that Babaodan Capsules induced apoptosis in liver cancer cells by regulating targets such as STAT3 and TP53 significantly. [Conclusion] The main pharmacodynamic substances of Babaodan Capsules in the treatment of HCC include saponins，cholic acids，flavonoids，etc. The specific mechanism is related to the regulation of STAT3 and other targets and TNF-α / NF-κB signaling pathways.