Study On The Molecular Mechanisms Of Cepharanthine In The Treatment Of COVID-19 And Breast Cancer Based On Bioinformatics And Network Pharmacology

Objectives: Patients with Breast Cancer(BRCA)may be susceptible to the coronavirus disease-2019(COVID-19).However,there is currently no specific treatment for these patients.Since cepharanthine is an alkaloid with anti-inflammatory,antiviral and immunomodulatory effects,the present study explored the potential targets and mechanisms of cepharanthine against BRCA and COVID-19 at the molecular level based on bioinformatics,network pharmacology and molecular docking methods,so as to provide reference for experimental design and new drug research.Methods:(1)The transcriptome data of BRCA were downloaded from the Cancer Genome Atlas(TCGA)database.The genes related to COVID-19 were downloaded from the gene database CNBI,KEGG,Gene Card and OMIN,and the gene clusters of these two diseases were intersected to obtain the overlapping genes of BRCA and COVID-19.Subsequently,the differentially expressed genes required for this study were screened using the “Limma” package of R language,and univariate Cox regression analysis was performed on the differentially expressed genes related to BRCA and COVID-19 to screen out genes with significant prognostic value.Finally,multivariate Cox regression analysis was performed on prognostic genes to establish a risk score prognostic model,and clinical correlation analysis was performed based on the risk score value.(2)The targets related to cepharanthine were collected and screened from Batman,Swiss Target Prediction,Target Net and Drugbak databases.The targets of cepharanthine were intersected with the differentially expressed genes of BRCA and COVID-19 to obtain the common drug-disease targets.Gene ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed using R language.The protein-protein interaction network(PPI)was analyzed by STRING database.Cytoscape 3.7.2 software was used to screen the core targets.Auto Dock Tools 1.5.7 and Auto Dock Vina software were used for molecular docking to verify the binding ability of cepharanthine to core target proteins.Results:(1)Differential expression analysis identified 406 differential genes related to BRCA and COVID-19,with 216 up-regulated genes and 190 down-regulated genes.According to the P value of univariate Cox regression analysis,30 prognostic genes related to BRCA and COVID-19 were screened out,and 16 core differentially expressed genes were obtained by multivariate Cox regression analysis.Subsequently,the risk score was calculated based on the regression coefficients of these core differential genes,and a risk score prognostic model with good predictive performance was constructed to evaluate the prognosis of BRCA patients with COVID-19.At the same time,the patients were divided into high and low risk groups according to the median risk score.Survival analysis found that the high and low risk groups associated with these 16 core differential genes had a significant impact on overall survival,and the risk score was analyzed.The results showed that the higher the risk score,the greater the risk value of the patients,and the high-risk patients usually had a shorter survival time.(2)There were 11 intersection targets of cepharanthine with BRCA and COVID-19,which were imported into STRING database for PPI network analysis.Six core targets were screened by Cytoscape 3.7.2 software,including PRKCA,MET,EGFR,MMP3,MMP1 and CYP3A4.GO functional enrichment results showed that the targets were mainly enriched in the positive regulation of protein kinase B signal,the regulation of protein kinase B signal and protein kinase B signal transduction and other related biological processes.The results of KEGG pathway enrichment showed that the targets were mainly concentrated in the Relaxin signaling pathway,Non-small cell lung cancer,Rap1 signaling pathway and Coronavirus disease-2019.Finally,molecular docking results showed that cepharanthine had a high binding ability with the core target.Conclusion: In this study,the clinical characteristics of patients with BRCA and COVID-19 were predicted by the screened differentially expressed genes,including susceptibility genes,survival rate and prognosis.This is the first time to reveal the molecular function and potential pharmacological targets of cepharanthine in the treatment of BRCA and COVID-19,providing a therapeutic option for BRCA patients with COVID-19 infection.