Effects of betel nut on oral submucosal fibrosis based on network toxicology and experimental verification
Objective To investigate the effects of betel nut on oral submucosal fibrosis(OSF)and its mechanism of action based on network toxicology and in vivo experimental verification.Methods Targets corresponding to the potential active ingredients of betel nut were screened through TCSMP and Swiss databases,and OSF-related targets were obtained using GeneCards and Disgenet databases.The intersection targets were uploaded to the String data platform to construct a protein-protein interaction(PPI)network,and then the Metascape data platform was used to perform gene ontology(GO)function and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analyses.The oral mucosa of rats was treated with the aqueous extract of betel nut at low,medium,and high concentrations respectively,and the results of network toxicology were verified by the measurement of mouth opening degree,pathomorphological examination,and immunohistochemical analysis in the rats..Results The network toxicology analysis showed that there were 587 related targets in the 52 ingredients of betel nut and 761 OSF-related targets,of which there were 72 intersection targets.PPI network analysis indicated that interleukin-6(IL-6),tumor necrosis factor(TNF),matrix metalloproteinase-9(MMP-9),apoptosis regulator Bcl-2(BCL2),epidermal growth factor receptor(EGFR),and cellular tumor antigen p53(TP53)may be the key targets of betel nut affecting OSF.PI3K-Akt,AGE-RAGE,and relaxin signaling pathways,EGFR tyrosine kinase inhibitor resistance and other signaling pathways were obtained by KEGG pathway enrichment analysis.The animal experiments showed that the mouth opening degrees of the medium-and high-dose groups were significantly different from those of the control group and low-dose group(P<0.05).HE staining and Masson staining showed that the medium-and high-dose groups had different degrees of fibrotic lesions.Immunohistochemical analysis suggested that the aqueous extract of betel nut upregulated the levels of inflammatory factors such as IL-6 and TNF-α,and this upregulation exhibited a certain dose-dependent relationship.Conclusion Betel nut may induce OSF by upregulating key inflammatory factors such as IL-6 and TNF-α,thereby mediating the inflammatory response.
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