基于网络药理学的栀子抗胆汁淤积的作用机制研究

Mechanism of Gardenia jasminoides against cholestasis based on network pharmacology

运用网络数据挖掘技术筛选栀子治疗胆汁淤积活性成分,并对成分作用潜在靶点与机制进行整合与分析,探究栀子抗胆汁淤积作用机制。采用中药系统药理数据库和分析平台(TCMSP)检索21个栀子活性成分,并筛选出作用靶点,利用Cytoscape 3. 2. 1构建成分与靶点网络。通过Dis Ge NET,KEGG,OMIM检索并筛选208个胆汁淤积疾病相关的靶点,整合筛选出栀子成分和胆汁淤积交集关键靶点,利用Cytoscape 3. 2. 1软件构建成分-靶点-疾病网络,以大于平均自由度为筛选条件筛选出核心网络。利用Cytoscape 3. 2. 1软件中Clue GO插件进行栀子抗胆汁淤积调控生物过程和通路富集分析,GO biological process分析得到17条生物过程,显著性筛选P<0. 01富集分析得到参与急性炎症反应、活性氧代谢调节、一氧化氮合成代谢等3条生物过程紧密相关;KEGG-KEEG-305 terms和REACTOME pathways分析得到17条调控通路,显著性筛选P<0. 01富集分析与细胞色素P450对外源化合物代谢、核受体转录、血小板糖蛋白介导激活级联和血小板活化等4条通路有关。通过大鼠实验验证发现,栀子水提物能改善胆汁淤积大鼠的血清生化异常,栀子水提物可以降低肝组织ESR1的蛋白和mRNA水平,升高PPARG,NOS2,F2R,NOS3,NR3C1的蛋白和mRNA水平。综上所述,栀子的抗胆汁淤积作用可能是通过参与急性炎症反应、活性氧代谢正调节、一氧化氮合成代谢生物过程以及细胞色素P450对外源化合物的代谢、核受体转录、血小板糖蛋白激活级联和血小板活化通路来发挥的。

To screen the active ingredients of Gardenia jasminoides and potential targets,and investigate the mechanisms against cholestasis based on network pharmacology technology.Twenty-one active components of G.jasminoides were retrieved and the target sites were screened by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).Cytoscape3.2.1 was used to construct the component-target network.Two hundred and eight targets related to cholestasis were searched and screened through Dis Ge NET,KEGG and OMIM databases.The key targets of G.jasminoides components and cholestasis were integrated and screened,and the component-target-disease network was constructed with Cytoscape 3.2.1 software to screen out the core network whose freedom degree was greater than the average value.The Clue GO plug-in of Cytoscape 3.2.1 software was used to analyze the biological processes and pathway enrichment of G.jasminoides in regulation of cholestasis.GO biological process analysis revealed 17 biological processes,involving 3 signaling biological processes related to cholestasis,i.e.acute inflammatory response,positive regulation of reactive oxygen species metabolic process,and nitric oxide biosynthetic process.KEGG-KEEG-305 terms and REACTOME pathways analysis revealed 17 regulatory pathways,involving 4 signaling pathways related to cholestasis,i.e.metabolism of xenobiotics by cytochrome P450,nuclear receptor transcription pathway,GPVI-mediated activation cascade and platelet activation.It was found that aqueous extract of G.jasminoides could improve serum biochemical abnormalities in ANIT-induced cholestasis rats.Aqueous extract of G.jasminoides could decrease the protein and mRNA expression levels of ESR1 in liver tissues,and increase the protein and mRNA expression levels of PPARG,NOS2,F2 R,NOS3,and NR3 C1.To sum up,the possible mechanisms of G.jasminoides against cholestasis may be related with the above three processes and four pathways.