Mechanisms of resveratrol against diabetic wound by network pharmacology and experimental validation

Background Resveratrol (RSV) that possesses anti-oxidative, anti-inflammatory, and pro-angiogenic effects is an effective drug for diabetic wound (DW), while its pharmacological mechanism remains to be elucidated. In this study, we apply network pharmacology and experimental validation approach to reveal the potential mechanism of RSV against DW.Methods We obtained potential targets for RSV and DW from the publicly available database. Using interaction networks and conducting GO and KEGG pathway enrichment analyses, we constructed target-pathway networks to explore the relationship between RSV and DW. To validate the pharmacological mechanism of RSV, we induced the DW model.Results Ninety overlapped targets between RSV and DW were obtained, and the hub genes of the PPI network included TNF, IL-6, CASP3, MAPK3, VEGFA, IL-1 beta, AKT1, and JUN. Based on target-pathway networks, the AGE-RAGE signalling pathway was involved in the RSV treatment of DW. Furthermore, in vivo experiments revealed that RSV significantly promoted wound healing in diabetic mice and attenuated the expression of pro-inflammatory cytokines in wound tissue. Meanwhile, RSV could inhibit the AGE-RAGE signalling pathway and thus reduce the activation of NF-kappa B.Conclusion This study initially revealed the biological mechanism of RSV for treating DW through multi-target and multi-pathway. AGE-RAGE, FoxO, MAPK, PI3K-AKT and other signalling pathways may be the main pathways of RSV in treating DW. RSV reduces the inflammatory response by inhibiting the AGE-RAGE signalling pathway, which in turn promotes DW healing.