基于铁死亡角度治疗心力衰竭中药的筛选

Chinese Herbs for Treatment of Heart Failure Based on the Perspective of Iron Death

目的:通过生物信息学从铁死亡角度筛选治疗心力衰竭的中药,为心力衰竭的治疗开辟新途径。方法:在GEO数据库中检索与心力衰竭相关的符合条件的数据集,利用R软件进行limma差异分析获得心力衰竭的差异表达靶点,在FerrDb平台收集与铁死亡相关靶点,将铁死亡靶点与心力衰竭差异表达靶点取交集后构建蛋白互作(PPI)网络,并对该网络进行拓扑学性质分析,利用R软件对共同靶点进行基因本体(GO)及京都基因与基因组百科全书(KEGG)富集分析。借助HERB数据库检索共同靶点对应的天然药物成分和中药,利用AutoDock软件对天然药物成分及其所对应靶点后进行分子对接。结果:GEO数据库筛选出数据集2个,通过limma差异分析后得到14 093个靶点,得到与铁死亡相关靶点214个,铁死亡与心力衰竭差异表达靶点取交集得到共同靶点176个,利用共同靶点构建PPI网络与拓扑学性质分析得到关键靶点抑癌基因(TP53)、原癌基因(JUN)、泛素C(UBC)、腺苷酸活化蛋白激酶(MAPK)14、MAPK3、信号转导与转录激活蛋白3(STAT3)、表皮生长因子受体(EGFR)等。GO及KEGG富集分析显示心力衰竭的发病从铁死亡角度或与细胞对化学应激的反应、对氧化应激的反应、次级溶酶体、黑色素体、自噬体、线粒体外膜、基底质膜核、氧化还原酶活性、铁离子结合、脂质和动脉粥样硬化、叉头转录因子(FoXO)信号通路等相关。检索HERB数据库结果显示,黄连素、醉茄素A、血根碱等近80种天然药物成分以及白鲜皮、半枝莲、苍术、穿心莲、防风等100余种中药或可通过作用于关键靶点治疗心力衰竭。分子对接结果显示JUN与黄连素、MAPK14与醉茄素A、MAPK3与血根碱结合较好。结论:通过生物信息学研究发现,黄连素、醉茄素A、血根碱等天然药物成分以及黄连、防己、黄柏、延胡索、牛膝、吴茱萸、黄芪、丹参等中药或可作用于TP53、MAPK14、MAPK3、JUN、STAT3等靶点治疗心力衰竭。

Objective:To screen traditional Chinese medicine for the treatment of heart failure(HF)based on the perspective of iron death.Methods:HF related eligible datasets in GEO database were retrieved,limma differential analysis were carry out to obtain HF differential expression targets using R software,iron death related targets were collected on FerrDb platform,protein-protein interaction network was constructed after intersection(PPI)of iron death targets and HF differential expression targets,and topological properties of the network were analyzed.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were performed for common targets using R software.The HERB database was used to search the compounds and traditional Chinese medicine corresponding to the common target,and the small molecule compounds and their corresponding targets were used to carry out molecular pairs.Results:Two datasets were screened from GEO database,there were 14093 targets obtained through limma differential analysis,214 targets related to iron death were obtained through collection,176 targets were obtained through intersection of iron death and HF differential expression targets,and key targets TP53,JUN,UBC,MAPK14,MAPK3,STAT3,EGFR,etc.were obtained through PPI network construction and topological property analysis of common targets of iron death and HF differential expression.The enrichment analysis of GO and KEGG showed that HF was related to cell response to chemical stress,oxidative stress,secondary lysosome,melanosome,autophage,outer membrane of mitochondria,nucleus of basement membrane,oxidoreductase activity,iron binding,lipid and atherosclerotic,FoXO signal pathway,etc.from the perspective of iron death.The results of searching HERB database showed that nearly 80 kinds of compounds of natural drugs,such as berberine,withaferin A,sanguinarine,and more than 100 kinds of traditional Chinese medicines,such as cortex dictamni,scutellaria barbata,atractylodes,andrographis paniculata,and fangfeng could be used to treat HF by acting on key targets.Molecular docking results showed that JUN and berberine,MAPK14 and withaferin A,MAPK3 and sanguinarine could well combine.Conclusion:Through bioinformatics research,it is found that with berberine,withaferin A,sanguinarine and other compounds,as well as some traditional Chinese medicines such as Coptis,Radix Stephaniae,Cortex Phellodendri,Rhizoma Corydalis,Radix Achyranthes,Fructus Evodiae,Radix Astragali,Radix Salviae Miltiorrhizae can act on TP53,MAPK14,MAPK3,JUN,STAT3,and other targets to treat HF.