目的 研究温心方治疗冠心病抑郁症的分子机制,探索温阳益心调神法作用机理.方法 通过TCMSP、ETCM、化源网、PubChem、SwissTarget Prediction、Gene Cards、DrugBank、TTD 等获取中药有效成分、药物和疾病靶点.通过 STRING11.5、Cytoscape3.9.1 获取核心成分和核心靶点,构建蛋白质-蛋白质互相作用(protein-protein interaction,PPI)和"药物-成分-核心靶点"网络.通过Metascape进行富集分析,筛选通路.通过Cytoscape3.9.1 算法分析,获取蛋白受体(关键基因)和小分子配体(逆靶向化合物),由RCSB PDB、TCMSP、PubChem、AutoDockTools1.5.6、pymol等进行分子对接及可视化呈现.结果 温心方有效成分 103个,核心成分5 个,分别为五味子酯乙(gomisin B)、黄芩素(baicalein)、柚皮素(naringenin)、维生素E(vitamin E,VE)、前列腺素B1(prostaglandinB1,PGB1).作用靶点608 个,核心靶点 138 个,主要募集在磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase,PI3K)-蛋白激酶B(protein kinase B,AKT)通路、晚期糖基化终末产物(advanced glycation end product,AGE)-晚期糖基化终产物受体(receptor for advanced glycosylation end products,RAGE)通路、叉头盒转录因子(forkhead box,FOXO)通路、两面神激酶(janus kinase,JAK)-信号转导及转录激活蛋白(signal transducer and activator of transcription,STAT)通路,涉及细胞增殖与凋亡、细胞形态调节与骨架重构、细胞周期调节、轴突运输、血管内皮生长、血管紧张度等细胞功能和生物进程.关键基因和逆靶向化合物对接构象合理,对接结果可行.结论 黄芩素、柚皮素、维生素E等可能是温心方加减治疗冠心病抑郁症的重要成分,通过VEGFA、NFKB1、MAPK1 等靶点调控AGE-RAGE通路、JAK-STAT通路、PI3K-AKT通路、FOXO通路,发挥药理作用.温阳益心调神法通过降低心肌细胞、神经元的氧化应激反应,促进抗氧化机制启动,清除氧化应激物质,抑制炎症过程,从而调节细胞增殖、凋亡的动态平衡,维持机体稳态,保护血管内皮生长、改善神经功能,达到治疗冠心病抑郁症的目的.该研究也间接表明冠心病和抑郁症的共病机制与氧化应激有关.
Exploration of the Mechanism of Warming Yang,Benefiting Heart,and Regulating Shen Therapy in the Treatment of Coronary Heart Disease and Depression Based on Oxidative Stress and Bioinformatics
Objective To study the molecular mechanism of warming heart prescription in the treatment of coronary heart disease with depression,and explore the action mechanism of warming Yang,benefiting heart,and regulating Shen therapy.Methods The active components of TCM were retrieved and screened through TCMSP,ETCM,Chemsrc,PubChem and SwissTarget Prediction databases to obtain drug targets.Gene Cards,DrugBank and TTD databases were used to obtain comorbidity targets.The construction of PPI network and obtaining core targets were carried out by STRING11.5.Cytoscape3.9.1 was used to establish the"drug-active ingredients-core targets"network to obtain the core components.Through Metascape,GO functional enrichment analysis and KEGG pathway enrichment analysis were carried out,and visual charts were made by using microbioinformatics and synthetic analyzing important enrichment pathways.Cytoscape3.9.1 was used to analyze targets recruited to important pathways,obtain key genes,and correlated compounds.The molecular structures of protein receptors(key genes)and molecule ligands(correlated compounds)were obtained by RCSB PDB,TCMSP and PubChem databases.AutoDockTools1.5.6 and pymol,were used for molecular docking and visual presentation.Results There were 103 active components of Wenxin prescription and 5 core components,which were gomisin B,baicalein,naringenin,vitamin E and prostaglandin B1.There were 608 targets and 138 core targets,which were mainly recruited in AGE-RAGE pathway,JAK-STAT pathway,PI3K-AKT pathway and FOXO pathway.It may be involved in cell proliferation and apoptosis,cell morphology regulation and skeletal remodeling,cell cycle regulation,axonal transport,vascular endothelial growth,vascular tension and other cellular functions and biological processes.Between core gene and correlated compounds have reasonable docking conformation and feasible results.Conclusion Baicalein,naringenin and vitamin-E may be important components of Wenxin prescription in the treatment of coronary heart disease with depression.These compounds exert pharmacological effects by regulating AGE-RAGE pathway,JAK-STAT pathway,PI3K-AKT pathway and FOXO pathway through VEGFA,NFKB1,MAPK1 and other gene targets.In conclusion,warming Yang,benefiting heart,and regulating Shen therapy achieves the purpose of treating coronary heart disease with depression by reducing the oxidative stress reaction of myocardial cells and neurons to protect vascular endothelial growth and improve nerve function.It can promote anti-oxidation mechanism and scavenge oxidative stress as well as reduce the production of proinflammatory medium and inhibit inflammatory process by stabling redox reaction processes,thus adjusting the dynamic balance between cell proliferation and apoptosis to maintain homeostasis.At the same time,this study also indirectly indicated that the comorbidity mechanism of coronary heart disease and depression was related to oxidative stress.
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