摘要
背景:炎症是脑卒中病理生理过程的关键组成部分,然而脑卒中与炎症之间的因果关系仍不清楚。目的:采用孟德尔随机化及分子对接技术探索91种靶向炎症细胞因子的脑卒中治疗机制。方法:从开放全基因组关联研究数据库(IEU Open GWAS,https://gwas.mrcieu.ac.uk/,由英国布里斯托大学医学研究委员会综合流行病学单位主办)中获得炎症细胞因子及脑卒中的数据,使用逆方差加权法作为主要研究方法进行两样本孟德尔随机化分析,评估91种炎症细胞因子与脑卒中之间的因果关系。随后基于孟德尔随机化研究结果进行了基因本体分析和京都基因与基因组通路分析,并构建了蛋白质-蛋白质相互作用网络。使用美国西奈山伊坎医学院建立的Enrichr数据库(http://amp.pharm.mssm.edu/Enrichr)和美国科罗拉多大学丹佛分校建立的药物特征数据库(http://tanlab.ucdenver.edu/dsigdb)进行脑卒中治疗药物预测,并使用AutoDock软件进行分子对接,通过Discovery Studio2019对结果进行可视化。结果与结论:(1)发现11种炎症细胞因子与全因脑卒中风险之间存在显著的因果关联;9种炎症细胞因子与缺血性脑卒中风险呈强相关;6种细胞因子与大动脉脑卒中风险显著相关;7种炎症细胞因子与心源性栓塞性脑卒中风险呈显著因果关系;12种细胞因子与小血管脑卒中风险显著相关;3种炎症细胞因子与脑内出血风险具有显著的因果关联;(2)基因本体分析和京都基因与基因组通路分析揭示,炎症细胞因子在代谢、炎症及免疫反应等方面对脑卒中具有重要影响;(3)通过蛋白质-蛋白质相互作用网络分析,筛选出与脑卒中密切相关的10种炎症细胞因子;(4)药物预测和分子对接结果表明,阿托伐他汀和氟氢可的松与关键核心靶点白细胞介素18和CCL3的结合力较高;(5)此次研究的数据来源于国际数据库中的欧洲人群,所获得的结果可为中国脑卒中的遗传流行病学研究提供参考;(6)此次研究阐明了炎症细胞因子与脑卒中之间的因果关系,揭示了炎症细胞因子治疗脑卒中的机制,为脑卒中的治疗提供了新思路。
BACKGROUND:Inflammation is a crucial component of the pathophysiological process in stroke;however,the causal relationship between stroke and inflammation remains unclear.OBJECTIVE:To explore the mechanisms of stroke treatments targeting 91 inflammatory cytokines using Mendelian randomization and molecular docking techniques.METHODS:Data on inflammatory cytokines and stroke were obtained from the IEU Open GWAS database(https://gwas.mrcieu.ac.uk/)hosted by the Medical Research Council Comprehensive Epidemiology Unit at the University of Bristol in the United Kingdom.Two-sample Mendelian randomization analysis was performed using the inverse variance weighting method to assess the causal relationship between 91 inflammatory cytokines and stroke.Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were then conducted based on the results of Mendelian randomization,and protein-protein interaction networks were constructed.Stroke drug prediction was performed using the Enrichr database(http://amp.pharm.mssm.edu/Enrichr)established by the Icahn School of Medicine at Mount Sinai and the Drug Repurposing Hub database(http://tanlab.ucdenver.edu/dsigdb)established by the University of Colorado Denver.Molecular docking was performed with AutoDock software,and the results were visualized using Discovery Studio 2019.RESULTS AND CONCLUSION:(1)We identified 11 inflammatory cytokines with significant causal associations with the overall stroke risk;9 cytokines were strongly associated with ischemic stroke risk;6 cytokines were significantly related to large artery stroke risk;7 cytokines exhibited a significant causal relationship with cardioembolic stroke risk;12 cytokines were significantly related to small vessel stroke risk;and 3 cytokines were significantly associated with the risk of intracerebral hemorrhage.(2)Gene Ontology and Kyoto Gene and Genome Pathway analyses revealed that inflammatory cytokines play significant roles in metabolism,inflammation,and immune responses in stroke.(3)Protein-protein interaction network analysis identified 10 inflammatory cytokines closely linked to stroke.(4)Drug prediction and molecular docking results indicated that atorvastatin and fludrocortisone had high binding affinity to key core targets interleukin-18 and CCL3.(5)The data for this study were sourced from the European population in international databases,and the findings provide valuable insights for genetic epidemiological research on stroke in China.(6)This study clarifies the causal relationship between inflammatory cytokines and stroke,unveiling the mechanisms of inflammatory cytokine therapy in stroke treatment and offering novel therapeutic strategies for stroke.
作者
程乐
朱才丰
周冰原
高大红
崔晓雅
李静
王雪伟
杨高尚
陈希阳
Cheng Le;Zhu Caifeng;Zhou Bingyuan;Gao Dahong;Cui Xiaoya;Li Jing;Wang Xuewei;Yang Gaoshang;Chen Xiyang(Anhui University of Chinese Medicine,Hefei 230000,Anhui Province,China;Geriatrics Department III,Second Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230000,Anhui Province,China;Medical Affairs Department,Second Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230000,Anhui Province,China;Neurology Department IV,Second Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230000,Anhui Province,China)
出处
《中国组织工程研究》
北大核心
2026年第12期3198-3216,共19页
Chinese Journal of Tissue Engineering Research
基金
安徽省中医药传承创新科研项目(2024CCCX004):基于周楣声“灸感病理感传”规律的经穴感传灸疗体系构建,项目负责人:朱才丰
安徽省华佗中医药研究院科技重大专项“揭榜挂帅”项目(BZKZ2402):艾灸督脉组穴调控EC-CA1区神经环路突触可塑性机制研究,项目负责人:朱才丰
安徽省自然科学基金项目(2208085MH273):LncRNA RP4调控自噬促进艾灸督脉清除APP/PS1双转基因小鼠Aβ蛋白的机制研究,项目负责人:朱才丰
国家级重点专科项目-老年病优势专科建设项目,项目负责人:朱才丰。
关键词
脑卒中
炎症细胞因子
孟德尔随机化
因果关系
药物预测
分子对接
逆方差加权法
stroke
inflammatory cytokines
Mendelian randomization
causality
drug prediction
molecular docking
inverse variance weighting method
