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    基于代谢组学与网络药理学的白花蛇舌草抑制胃癌作用机制研究

    Study on the Mechanism of Hedyotis Diffusa Willd. in Inhibiting Gastric Cancer Based on Metabolomics and Network Pharmacology

      摘要
    • 摘要:
      目的  通过代谢组学和网络药理学探讨白花蛇舌草(Hedyotis diffusa Willd.，HDW)抗胃癌的活性成分及机制。
      方法 利用TCMSP数据库并结合已发表文献收集HDW的化学成分，同时基于SwissTarget Prediction数据库获取其靶基因，并使用GeneCards数据库获取胃癌靶点基因；通过Cytoscape软件绘制HDW-胃癌共有靶点网络，在STRING数据库构建共有靶点的蛋白-蛋白相互作用(protein-protein interaction，PPI)网络，在DAVID数据库进行基因本体论(GO)分析和京都基因与基因组百科全书(KEGG)通路富集分析，筛选HDW对胃癌的活性成分及靶点。同时，使用AGS胃癌细胞进行体外试验，测试HDW对AGS细胞的增殖、迁移及侵袭的抑制作用，确定HDW抗胃癌的半数有效浓度(IC50)；基于核磁共振代谢组学方法分析细胞代谢物，探讨HDW的作用机制。
      结果 HDW能明显抑制AGS细胞划痕伤口的愈合率及侵袭能力，其对AGS细胞的IC50为4.495 mg·mL−1。通过细胞代谢物代谢组学分析，筛选到15个潜在生物标志物与HDW的抑制作用有关，主要涉及与能量代谢有关的6条代谢通路。此外，网络药理学结果显示，HDW与胃癌共有靶点175个，结合PPI交互网络筛选到5个核心靶点。
      结论 HDW可能通过反式咖啡酸、反式阿魏酸、山柰酚、异麦芽酮糖、槲皮素和香豆酸等潜在活性成分，TNF、EGFR、STAT3、MMP9和PTGS2等靶点，调节能量代谢、活性氧产生与炎症反应等通路治疗胃癌。

       

      Abstract:
      OBJECTIVE To investigate the active components and mechanism of Hedyotis diffusa Willd.(HDW) against gastric cancer by metabolomics and network pharmacology.
      METHODS The TCMSP database and published documents were used to obtain the chemical components of HDW, while SwissTarget Prediction database was used to obtain the target genes of HDW and target genes of gastric cancer were obtained using GeneCards database. Then, the common targets network of HDW and gastric cancer was visualized by Cytoscape, and the protein-protein interaction(PPI) network of common targets was constructed via STRING database. Gene ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment were analyzed in the DAVID database to screen the active components and corresponding targets of HDW against gastric cancer. Meanwhile, the in vitro experiments were conducted using AGS human gastric adenocarcinoma cells to test the inhibitory effects of HDW on the proliferation, migration and invasion of AGS cells, and to determine the half effective concentration(IC50) of HDW against gastric cancer. In addition, metabolomics analysis of cellular metabolites was performed using NMR technology to explore the mechanism of HDW.
      RESULTS HDW significantly suppressed the wound healing rate and invasive capacity of AGS cells, with an IC50 of 4.495 mg·mL−1 against AGS cells. The 15 potential biomarkers were screened that associated with the inhibition effect of HDW and involved in 6 metabolic pathways related to energy metabolism. In addition, the results of network pharmacology showed that there were 175 common targets between HDW and gastric cancer, and 5 core targets were recognized combining the result of PPI interaction network.
      CONCLUSION Trans-caffeic acid, trans-ferulic acid, kaempferol, isomaltulose, quercetin and coumalic acid may be the potential active components of HDW against gastric cancer, acting through the core targets including TNF, EGFR, STAT3, MMP9 and PTGS2, and regulating pathways such as energy metabolism, reactive oxygen species production and inflammation response.

       

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