Vanadyl Acetylacetonate and Berberine Synergistically Ameliorate Diabetes-induced Vascular Dysfunction and Reduce Endothelial Toxicity through ERK and Akt Regulation.

Vanadyl acetylacetonate (VO) and berberine (BBR) have both demonstrated anti-diabetic effects. Previous studies in type 1 diabetic rats suggest that their co-administration of VO and BBR is safer and more effective than either compound alone. However, the precise vascular effects and underlying molecular mechanisms remain unclear. Diabetic rats received VO, BBR, or both. Blood glucose and body weight were monitored. Alizarin Red staining detected vascular calcification. Vascular morphology, intercellular junctions (E-Cadherin/β-catenin staining), cytoskeleton (Phalloidin), and permeability (FITC-BSA) were assessed. Cell viability was evaluated via MTT assay, apoptosis kit, and flow cytometry. Western blotting analyzed Bax, Bcl-2, and related pathway proteins. NOS activity including tNOS and iNOS were measured. GO and KEGG pathway enrichment identified potential mechanisms. Co-administration of VO and BBR reduced blood glucose without affecting weight. It attenuated vascular calcification, preserved intercellular junctions, and improved endothelial barrier function. BBR reversed VO-induced E-Cadherin/β-catenin disruption, cytoskeletal damage, and permeability increase. Cell apoptosis reduced with BBR, associated with downregulation of Bax, upregulation of Bcl-2, and normalized tNOS and iNOS activity. Mechanistically, ERK and PI3K-Akt pathways were implicated. BBR suppressed VO-induced overactivation of p-ERK and p-Akt. VO and BBR synergistically improve glucose control and provide enhanced vascular protection more effectively than either compound alone in diabetic rats. Furthermore, BBR prevents the over-activation of ERK and Akt induced by VO, thereby reducing iNOS and tNOS production, subsequent apoptosis, intercellular junction damage, and increased permeability in HUVECs. These preliminary findings lay the groundwork for future research aimed at developing novel therapeutic strategies and safer anti-diabetic treatments with improved efficacy and reduced toxicity.