降糖消脂片治疗NAFLD的分子作用机制分析

Molecular Mechanism Analysis of Jiangtang Xiaozhi Tablets in Treatment of NAFLD

目的:运用网络药理学和分子对接方法探讨降糖消脂片治疗非酒精性脂肪性肝病(NAFLD)的分子作用机制。方法:借助中药系统药理学数据库与分析平台(TCMSP),中医药综合数据库(TCMID),中医药百科全书数据库(ETCM)和中药分子机制的生物信息学分析工具(BATMAN-TCM)获取降糖消脂片各药味的化学成分,于SwissTargetPrediction和STITCH数据库预测化学成分的靶点;借助人类基因数据库(GeneCards),在线《人类孟德尔遗传》数据库(OMIM),治疗靶标数据库(TTD)和疾病相关的基因与突变位点数据库(DisGeNET)筛选NAFLD靶点,并与降糖消脂片活性成分的靶点进行交集分析,获得降糖消脂片治疗NAFLD的靶点。借助STRING 11.0构建治疗靶点蛋白质-蛋白质相互作用(PPI)网络,并利用DAVID 6.8对治疗靶点进行富集分析。最后基于分子对接验证降糖消脂片关键成分与核心治疗靶点的作用特征。结果:降糖消脂片治疗NAFLD的关键成分包括槲皮素、木犀草素、山柰酚、小檗碱、异鼠李素、白桦脂酸、齐墩果酸、熊果酸、芒柄花黄素和己糖醇,核心靶点为丝裂原活化蛋白激酶1(MAPK1),Jun原癌基因(JUN),MAPK3,蛋白激酶B1(AKT1或者Akt1),肿瘤蛋白p53(TP53),E1A结合蛋白P300(EP300),Fos原癌基因(FOS),肿瘤坏死因子(TNF),β-淀粉样前体蛋白(APP)和细胞色素P450家族成员2E1(CYP2E1)。富集分析表明降糖消脂片主要通过外源代谢、氧化还原和胆固醇代谢等生物过程,调节磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)信号通路,MAPK信号通路,NAFLD及胰岛素信号通路发挥对NAFLD的治疗作用。分子对接结果显示降糖消脂片关键成分与降糖消脂片治疗NAFLD核心靶点有较好的亲和力。结论:降糖消脂片可通过多种活性成分、多个关键靶点及多种作用途径治疗NAFLD。

Objective:To explore the molecular mechanism of Jiangtang Xiaozhi tablets(JTXZT)in the treatment of non-alcoholic fatty liver disease(NAFLD)by means of network pharmacology and molecular docking. Method: With the help of traditional Chinese medicine(TCM)Systems Pharmacology Database and Analysis Platform(TCMSP),TCMs Integrated Database(TCMID),Encyclopedia of TCM(ETCM)and Bioinformatics Analysis Tool for Molecular Mechanism of TCM(BATMAN-TCM),the chemical compositions of medicinal materials in JTXZT were obtained,the compound targets were predicted in SwissTargetPrediction database and STITCH database. The targets of NAFLD were searched by The Human Gene Database(GeneCards),Online Mendelian Inheritance in Man(OMIM),Therapeutic Target Database(TTD)and DisGeNET,and intersection analysis was performed with the targets of the active ingredients to obtain the targets of JTXZT for treatment of NAFLD. Based on STRING 11.0 database,the protein-protein interaction(PPI)network of therapeutic targets was constructed,and the enrichment analysis of therapeutic targets was carried out by DAVID 6.8. Finally,the interaction characteristics of key components and core therapeutic targets of JTXZT for treatment of NAFLD were verified based on molecular docking. Result: The key components of JTXZT for treatment of NAFLD were quercetin,luteolin,kaempferol,berberine,isorhamnetin,betulinic acid,oleanolic acid,ursolic acid. formononetin and hexitol,and the core targets of JTXZT for treatment of NAFLD were mitogen-activated protein kinase 1(MAPK1), Jun proto-oncogene, activator protein-1(AP-1)transcription factor subunit(JUN),MAPK3,protein kinase B1(AKT1 or Akt1),tumor protein p53(TP53),E1 A binding protein p300(EP300),Fos proto-oncogene,AP-1 transcription factor subunit(FOS),tumor necrosis factor(TNF),amyloid beta precursor protein(APP)and cytochrome P450 family 2 subfamily E member 1(CYP2 E1). Biological function and pathway enrichment analysis showed that JTXZT mainly through xenobiotic metabolic process,oxidation-reduction process,cholesterol metabolic process and other biological processes,regulating phosphatidylinositol 3-kinase/protein kinase B(PI3 K/Akt)signaling pathway,MAPK signaling pathway,NAFLD and insulin signaling pathway to play a role in the treatment of NAFLD. The results of molecular docking showed that the active components of JTXZT had a good affinity with the core targets of JTXZT for the treatment of NAFLD. Conclusion: JTXZT treats NAFLD through multiple active components,multiple key targets and multiple action pathways.