Involvement of environmentally relevant toxic metal mixture in Alzheimer's disease pathway alteration and protective role of berberine: Bioinformatics analysis and toxicogenomic screening.

We aimed to examine the molecular basis of the positive effect of berberine against environmentally relevant toxic metal-linked Alzheimer's disease (AD). The Comparative Toxicogenomic Database (CTD) retrieved a set of genes common to lead, cadmium, methylmercury and arsenic linked to AD development and a set of genes through which berberine exerts a therapeutic mode of action in AD. GeneMania prediction server revealed detailed gene interactions, while Metascape highlighted protein-protein interaction enrichment (PPIE). SwissADME evaluated physicochemical properties of berberine. Berberine had an antagonistic effect for the majority of genes mutual for AD and toxic metal mixture: ACHE, APP, BAX, BCL2, CASP3, HMOX1, IL1B, MAPT, SOD2, TNF. Gene network analysis revealed interactions predicted by the server (45.29%) and physical interactions (18.39%) as the most important. Enriched biological processes analysis showed apoptotic signaling pathway, positive regulation of organelle organization and response to oxidative stress as dominant pathways involved in berberine protective effects against toxic metal mixture, while PPIE analysis showed regulation of apoptotic signaling pathway as the main gene ontology process targeted by berberine. Physicochemical properties and pharmacokinetics of berberine are in concordance with its beneficial properties in AD due to the high gastrointestinal absorption and capability to pass the blood-brain barrier.