摘要
目的基于生物信息学技术筛选缺血性脑卒中(IS)相关转录因子(TF)及中药活性成分。方法在基因表达综合数据库(GEO)中选择GSE16561、GSE58294、GSE162955芯片数据集,使用R 4.0.5软件对GSE16561、GSE58294数据集进行预处理并筛选差异表达基因(DEGs),然后进行基因集富集分析(GSEA)。通过STRING平台构建DEG的蛋白质-蛋白质相互作用(PPI)网络并筛选关键DEG,通过GSE162955数据集绘制ROC曲线,以评估关键DEG对IS的诊断价值;然后通过TRRUST平台构建TF-miRNA-核心DEG调控网络,筛选枢纽TF、主要miRNA及核心DEG。通过Coremine Medical及Uniprot平台预测并筛选IS相关中药活性成分。结果韦恩图结果显示,GSE16561数据集和GSE58294数据集的交集DGEs共220个,包括130个上调DGEs和90个下调DEGs。GSEA结果显示,KEGG通路主要富集在MAPK信号通路、神经营养因子信号通路和趋化因子信号通路;GO功能生物过程主要富集在中心粒细胞外渗,细胞成分主要富集在细胞器内膜,分子功能主要富集在电子传递活动。通过PPI网络共筛选出10个关键DEG,其中Janus激酶(JAK)2〔AUC=0.944,95%CI(0.816,1.000)〕、Toll样受体(TLR)4〔AUC=0.833,95%CI(0.580,1.000)〕、CD247〔AUC=0.667,95%CI(0.309,1.000)〕、CC趋化因子受体(CCR)7〔AUC=0.639,95%CI(0.273,1.000)〕、基质金属蛋白酶(MMP)9〔AUC=0.861,95%CI(0.641,1.000)〕、FCGR2A〔AUC=0.722,95%CI(0.361,1.000)〕对IS具有一定诊断价值。TF-miRNA-核心DEG调控网络分析结果显示,枢纽TF为SPI1、信号转导因子和转录激活因子(STAT)3、缺氧诱导因子(HIF)1A、RELA,主要miRNA为hsa-miR-8085、hsamiR-183、hsa-miR-324-3p,核心DEG为JAK2、TLR4、CCR7、MMP9。通过Coremine Medical及Uniprot平台筛选出的IS相关主要中药活性成分为槲皮素、山柰酚、β-谷甾醇、豆甾醇、黄芩苷、人参皂甙rh2。结论IS相关的枢纽TF为RELA、SPI1、HIF1A和STAT3,主要miRNA为hsa-miR-8085、hsa-miR-183-5p和hsa-miR-324-3p,核心DEG为JAK2、TLR4、CCR7、MMP9,中药活性成分为槲皮素、山柰酚、β-谷甾醇、豆甾醇、黄芩苷、人参皂甙rh2。
Objective To screen ischemic stroke(IS)-related transcription factors(TF)and active ingredients of Chinese medicine based on bioinformatics technology.Methods The GSE16561,GSE58294 and GSE162955 datasets were selected in the Gene Expression Omnibus(GEO)database,and the GSE16561 and GSE58294 datasets were preprocessed and screened for differentially expressed genes(DEGs)using R 4.0.5 software,followed by gene set enrichment analysis(GSEA).The protein-protein interactions(PPI)network of DEG was constructed by the STRING platform and screened for key DEG,and ROC curve was drawn by the GSE162955 dataset to evaluate the diagnostic value of key DEG for IS;and then the TF-miRNAhub DEG network was constructed through TRRUST platform to screen the key TF,primary miRNAs and hub DEG.The active ingredients of IS-related Chinese medicines were predicted and filtered by Coremine Medical and Uniprot platforms.Results Venn diagram results showed that there were 220 intersecting DGEs between the GSE16561 dataset and the GSE58294 dataset,including 130 upregulated DGEs and 90 downregulated DEGs.GSEA results showed that KEGG pathway was mainly enriched in MAPK signaling pathway,neurotrophic factor signaling pathway and chemokine signaling pathway;GO functional biological processes was mainly enriched in central granulocyte extravasation,cell components was mainly enriched in the inner membrane of organelles,and molecular functions was mainly enriched in electron transport activities.A total of 10 key DEGs were screened by the PPI network,among them,Janus kinase(JAK)2[AUC=0.944,95%CI(0.816,1.000)],Toll-like receptor(TLR)4[AUC=0.833,95%CI(0.580,1.000)],CD247[AUC=0.667,95%CI(0.309,1.000)],CC chemokine receptor(CCR)7[AUC=0.639,95%CI(0.273,1.000)],matrix metallopeptidase(MMP)9[AUC=0.861,95%CI(0.641,1.000)],FCGR2A[AUC=0.722,95%CI(0.361,1.000)]had some diagnostic value for IS.TF-miRNA-hub DEG network analysis showed that the hub TF was SPI1,signal transducer and activator of transcription(STAT)3,hypoxia inducible factor(HIF)1A and RELA,the primary miRNAs were hsa-miR-8085,hsa-miR-183 and hsa-miR-324-3p,and the key DEGs were JAK2,TLR4,CCR7 and MMP9.The main active ingredients of IS-related Chinese medicines screened through Coremine Medical and Uniprot platform were quercetin,kaempferol,β-sitosterol,dousterol,baicalin,and ginsenoside rh2.Conclusion IS-related key TFs are RELA,SPI1,HIF1A and STAT3,primary miRNAs are hsa-miR-8085,hsa-miR-183 and hsa-miR-324-3p,hub DEG are JAK2,TLR4,CCR7,and MMP9,and the active ingredients of Chinese medicine are quercetin,kaempferol,β-sitosterol,dousterol baicalin and ginsenoside rh2.
作者
魏汝恒
苗珠月
戴瑶瑶
刘可心
韩光远
张海飞
宋丽娟
马东
马存根
WEI Ruheng;MIAO Zhuyue;DAI Yaoyao;LIU Kexin;HAN Guangyuan;ZHANG Haifei;SONG Lijuan;MA Dong;MA Cungen(The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology,Shanxi University of Chinese Medicine,Jinzhong 030619,China;Shanxi Datong University Institute of Brain Science/Department of Neurology,Datong Fifth People's Hospital/the First Affiliated Clinical Hospital of Datong University,Datong 037009,China;Depatment of Neurosurgery,General Hospital of Sinopharm Tongliang Group/Shanxi Provincial Health Commission Key Laboratory of Neurological Disease Control,Datong 037003,China;Ministry of Education Key Laboratory of Cell Physiology,Shanxi Medical University,Taiyuan 030001,China)
出处
《实用心脑肺血管病杂志》
2023年第3期74-80,86,共8页
Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease
基金
国家自然科学基金资助项目(81473577,82004028)
中国博士后科学基金面上资助项目(2020M680912)
山西省应用基础研究计划项目(201901D211538)
山西中医药大学学科建设经费、山西省卫健委医学科技领军团队(2020TD05)
中枢神经炎症变性疾病新药创制省市共建山西省重点实验室培育基地立项建设项目(201805D111009)
山西省教育厅高等学校科技创新项目(2019L0734)
2021年山西中医药大学附属医院国家区域中医医疗中心心血管专项基金项目(XGZX202115)
山西中医药大学青年科学家培育项目(2021PY-QN-09)
山西省研究生创新项目(2021Y733,2021Y732)
山西中医药大学2021年研究生创新创业项目(2021CX036,2021CX037)。
关键词
卒中
缺血性脑卒中
生物信息学
转录因子
中药
Stroke
Ischemic stroke
Bioinformatics
Transcription factors
Traditional Chinese drugs
