基于网络药理学预测芹菜素治疗系统性红斑狼疮的机制

Network pharmacology analysis of apigenin action in treatment of systemic lupus erythematosus

目的通过网络药理学预测芹菜素治疗系统性红斑狼疮(SLE)的潜在靶点以及涉及的信号通路。方法通过SwissTargetPrediction及PharmMapper数据库预测芹菜素的潜在靶点,用OMIM、GeneCards、DrugBank和PharmGKB等数据库收集SLE疾病相关靶点。从STRING数据库获取蛋白质-蛋白质相互作用关系(PPI),并运用Cytoscape 3.8.2软件绘制芹菜素-SLE的PPI图,并筛选核心靶点。基于DAVID数据库和Bioconductor生物信息软件包对共同靶点进行基因功能(GO)分析和京都基因与基因组百科全书(KEGG)通路富集分析。通过双荧光素酶报告基因实验验证芹菜素对所筛选通路的调控作用。结果共筛选出芹菜素潜在靶点77个,SLE相关靶点1016个,芹菜素-SLE共同靶点21个,其中核心靶点3个:ALB、HSP90AA1、ESR1;GO分析结果包括37条生物学功能、12条细胞组成过程和26条分子功能过程;KEGG通路分析显示与12条通路相关,主要涉及雌激素信号通路、NF-κB信号通路、精氨酸和脯氨酸代谢通路等经典通路。双荧光素酶报告基因实验结果显示芹菜素可抑制ERα、ERβ和NF-κB的转录。结论网络药理学的研究结果提示,芹菜素治疗SLE有多靶点、多途径的特点,可以通过调控雌激素信号通路和NF-κB信号通路,从而抑制下游基因及炎症因子的表达,改善SLE。

Objective To assess the key target genes and then explore the potential mechanism of apigenin in treatment of systemic lupus erythematosus(SLE)using the network pharmacology analysis.Methods The SwissTargetPrediction and PharmMapper databases were applied to predict the apigenin-related targeting genes,while the SLE disease-related genes were identified after screening the OMIM,GeneCards,DrugBank,and PharmGKB databases.The protein-protein interaction(PPI)network was then constructed using of the STRING database and plotted using the Cytoscape 3.8.2 software.The gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed to assess these targeting genes using the DAVID database and Bioconductor bioinformatics software package for R.The dual luciferase gene reporter assay was used to verify the regulatory effect of apigenin on the selected genes.Results There were a total of 77 apigenin potential target genes and 1016 SLE-related target genes identified,while there were 21 ingredients-disease proteins revealed.The top three key molecules were ALB,HSP90AA1,and ESR1.The GO analysis identified 37 biological functions,12 cell composition processes,and 26 molecular functional processes,while the KEGG pathway analysis obtained 12 signaling pathways,such as the estrogen and NF-κB signaling pathways and arginine and proline metabolism pathways.The dual luciferase gene reporter assay revealed that apigenin was able to inhibit the transcriptional activity of ERα,ERβ,and NF-κB.Conclusion Apigenin was able to target multiple genes in treatment of SLE through the estrogen and NF-κB signaling pathways,thereby attenuating expression of downstream genes and inflammatory factors.