Explore the mechanism of ursolic acid acting on atherosclerosis through network pharmacological and bioinformatics methods.

Abstract

To explore the deep mechanisms of ursolic acid (UA) for treating atherosclerosis based on network pharmacology and bioinformatics. UA target genes were derived from traditional Chinese medicine system pharmacology, BATMAN-TCM, and SwissTargetPrediction databases. Atherosclerosis-related genes were derived from genecards, NCBI genes, and OMIM databases. The protein interaction network was constructed through the STRING database, and the hub network was extracted by using the Cytoscape software MCODE app. The enrichment analysis of gene ontology and Kyoto encyclopedia of genes and genomes was performed by the R software clusterProfiler package, and the expression and prognostic value of the hub genes were verified on the data set. Screen the genes for expression and prognosis conclusions, conduct methylation analysis, and ceRNA construction. UA had 145 targets in the treatment of atherosclerosis. The top 7 gene ontology (biological process, molecular function, and cellular component) and pathways related to atherosclerosis were screened out. It is principally involved in biological processes, including response to lipopolysaccharide and regulation of inflammatory response. The main signaling pathways incorporated the TNF signaling pathway and the AGE-RAGE signaling pathway. Androgen receptor (AR) and interleukin-1 beta gene (IL1B) were further screened as core target genes. Methylation analysis demonstrated that the AR methylation level was elevated in the atherosclerotic group. On the contrary, the IL1B methylation level was lower in the atherosclerotic group. The results of the ceRNA analysis indicated that there were 43 targeted miRNAs in AR and 3 miRNAs in IL1B. We speculate that the target genes of UA regulating atherosclerosis are AR and IL1B. The mechanism may be that UA regulates the expression of target genes by regulating the methylation of target genes.