基于网络药理学探讨健脾化浊汤精简方治疗血脂异常的作用机制

The action mechanism of the Jianpi Huazhuo decoction on treating dyslipidemia based on network pharmacology

目的:基于网络药理学和分子对接方法探讨健脾化浊汤精简方治疗血脂异常的作用机制。方法:利用中药系统药理学数据库与分析平台(TCMSP)筛选健脾化浊汤精简方的活性成分,利用成分靶点预测数据库(SwissTargetPrediction)、药物数据库(DrugBank)、中药分子机理的生物信息学分析工具(Batman-TCM)筛选复方成分靶点,利用治疗靶点数据库(TTD)等8个数据库和1个基因表达综合数据库(GEO)的Affymetrix基因芯片获得血脂异常的靶点,采用Cytoscape 3.2.1绘制“活性成分-治疗靶点”和“成分靶点-疾病靶点”网络,STRING网站构建蛋白质相互作用网络,使用R语言软件进行靶点基因本体论(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。最后利用iGEMDOCK进行分子对接验证。结果:筛选出健脾化浊汤精简方活性成分70个、治疗靶点109个,核心靶点包括胰岛素、丝氨酸/苏氨酸蛋白激酶1(Serine/Threonine Kinase 1,AKT1)、表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)、前列腺素内过氧化物合酶2(Prostaglandin-Endoperoxide Synthase 2,PTGS2)、淀粉样前体蛋白(Amyloid Precursor Protein,APP)、雌激素受体1(Estrogen Receptor 1,ESR1)等。通过KEGG富集分析预测,健脾化浊汤精简方治疗血脂异常涉及的信号通路主要有磷脂酰肌醇3激酶(Phosphatidylinositol 3-kinase,PI3K)/蛋白激酶B(Akt)信号通路、过氧化物酶体增殖物激活受体(Peroxisome Proliferator-Activated Receptor,PPAR)信号通路、Rap1信号通路、胰岛素抵抗通路、缺氧诱导因子-1(Hypoxia Inducible Factorr 1,HIF-1)信号通路等。分子对接结果表明,健脾化浊汤精简方中主要活性成分与核心作用靶点具有较为稳定的结合活性。结论:通过对健脾化浊汤精简方治疗血脂异常的活性成分、关键靶点和相关通路的研究,认为健脾化浊汤精简方可能主要通过调节胰岛素分泌、改善胰岛素抵抗、调节脂蛋白代谢相关受体和酶、抑制胆固醇吸收等机制发挥调节血脂的作用,为未来药理学及临床研究提供了思路。

Objective:To explore the action mechanism of the Jianpi Huazhuo decoction(健脾化浊汤)on dyslipidemia based on network pharmacology and molecular docking methods.Methods:The active ingredients of the Jianpi Huazhuo decoction were retrieved by TCMSP platform,and the compound ingredient targets were screened out by SwissTargetPrediction,DrugBank,and Batman-TCM.In 8 databases including TTD and 1 comprehensive gene expression databas GEO,the targets of dyslipidemia were obtained from the Affymetrix gene microarray.Cytoscape 3.2.1 was used to draw the active ingredient-therapeutic target network,and the component target-disease target network.STRING database was used to construct a protein interaction network,and R language software was used for GO function enrichment analysis and KEGG pathway enrichment analysis.Finally,iGEMDOCK was used for molecular docking.Results:A total of 70 active ingredients of the Jianpi Huazhuo decoction and 109 therapeutic targets were screened out.The core targets included insulin,AKT1,EGFR,PTGS2,APP,ESR1,etc..Based on KEGG enrichment analysis,it was predicted that the signaling pathways involved in the treatment of dyslipidemia with the Jianpi Huazhuo decoction mainly included PI3K/Akt signaling pathway,PPAR signaling pathway,Rap1 signaling pathway,insulin resistance pathway,and HIF1 signaling pathway.The results of molecular docking showed that the main active components of the Jianpi Huazhuo decoction had relatively stable binding activity with the core targets.Conclusion:Based on the research on the active ingredients,key targets and related pathways of the Jianpi Huazhuo decoction in the treatment of dyslipidemia,it is believed that the Jianpi Huazhuo decoction may mainly play a role in regulating blood lipids by regulating insulin secretion,ameliorating insulin resistance,regulating receptors and enzymes related to lipoprotein metabolism,and inhibiting cholesterol absorption,providing ideas for future pharmacology and clinical research.