栀子调控铁死亡治疗脑缺血再灌注损伤的网络药理学研究

Network pharmacology study of Gardeniae Fructus in regulating ferroptosis for the treatment of cerebral ischemia-reperfusion injury

目的采用网络药理学方法探究栀子调控铁死亡治疗脑缺血再灌注损伤(CIRI)的分子机制。方法采用中药系统药理数据库及分析平台(TCMSP)获取栀子有效活性成分及其预测靶点,利用基因卡(GeneCards)数据库收集获取CIRI的基因靶点,通过韦恩图工具获得栀子有效活性成分和CIRI的交集基因。利用Cytoscape 3.9.1软件构建栀子、活性成分以及预测靶点间的相互关系网络图。应用R语言软件对“栀子-CIRI”交集基因进行基因本体(GO)富集和京都基因和基因组百科全书(KEGG)分析。使用铁死亡FerrDb数据库,收集铁死亡的相关基因,对栀子活性成分、CIRI、铁死亡三者间的公共靶点进行综合分析并预测栀子调控铁死亡干预CIRI的有效成分及靶点。结果从栀子中筛选出有对应基因靶点的65个有效活性成分进行相关预测,得到缺氧诱导因子RE-1亚基α(HIF-1α)、肿瘤蛋白P53(TP53)、丝裂原活化蛋白激酶8(MAPK8)、血红素加氧酶1(HMOX1)、一氧化氮合酶2(NOS2)、核因子κB(NF-κB)亚基-RELA原癌基因(RELA)、白细胞介素-6(IL-6)等24个栀子调控铁死亡干预CIRI的可能作用靶标,介导HIF-1、肿瘤坏死因子(TNF)、MAPK和Toll样受体信号通路等途径调控铁死亡过程,从而对CIRI损伤产生治疗作用。结论栀子可能通过调控铁死亡途径治疗CIRI。

Objective To investigate the molecular mechanism of Gardeniae Fructus regulating ferroptosis in the treatment of cerebral ischemia-reperfusion injury(CIRI)by network pharmacology methods.Methods The effective active ingredients of Gardeniae Fructus and their predicted targets were obtained from the TCMSP database.Cerebral ischemia-reperfusion injury were collected and obtained from the GeneCards database.The active ingredients of Gardeniae Fructus and the intersection genes of CIRI injury were obtained through Venny.The Cytoscape 3.9.1 software was utilized to construct a relationship network among Gardeniae Fructus,its active components and predicted targets.The gene ontology(GO)enrichment and the Kyoto encyclopedia of genes and genomes(KEGG)analyses of the"gardenia-CIRI"intersection genes were performed using R software.The ferroptosis-related genes were obtained from the FerrDb database,and the common targets among the active components of Gardeniae Fructus,CIRI and ferroptosis were comprehensively analyzed to predict the effective components and targets involved in the regulation of ferroptosis in the context of CIRI.Results Sixty-five active components with corresponding gene targets were identified from Gardeniae Fructus,and the correlating prediction was conducted.HIF 1α,TP53,MAPK8,HMOX1,NOS2,RELA and IL-6 were identified as potential targets of Gardeniae Fructus in regulating ferroptosis and preventing cerebral ischemia-reperfusion injury.KEGG analysis suggested that Gardeniae Fructus may mediate HIF-1,TNF,MAPK and Toll-like receptor signaling pathways to regulate the ferroptosis process,thus exerting therapeutic effects on CIRI.Conclusion Gardeniae Fructus may treat cerebral ischemia-reperfusion injury by regulating the ferroptosis pathway.