Modulation of Akt-p38-MAPK/Nrf2/SIRT1 and NF-κB pathways by wine pomace product in hyperglycemic endothelial cell line

[Display omitted] •Hyperglycemic-induced oxidative stress upregulates NF-κB and downregulate Nrf2 pathways.•NF-κB/SOD2 participates in an early adaptive response to oxidative stress.•rWPP reduce endothelial oxidative stress through Nrf2, SIRT1 and NF-κB.•rWPP increases antioxidant and antiinflamatory cell response. Wine by-products show great potential as source of bioactive compounds that protect the vascular endothelial function by the modulation of both Nrf2 and Nf-κB pathways. This study investigates the pathways involved in the effects of a red wine pomace product (rWPP) against inflammatory and oxidative damage in hyperglycemic EA.hy926 endothelial cells.rWPP-digested fractions showed an inhibitory effect on IKK/IκBα/NF-κB pathway and a stimulatory effect on Akt-p38-MAPK/Nrf2 pathway with an impact on their antioxidant and anti-inflammatory downstream targets. In addition, the pathways regulation was also accompanied by downregulation of the gene expression of superoxide dismutase 2, cyclooxygenase 2 and NADPH oxidase 4. These results suggest the expression of SOD2 as an early adaptive response to the inflammatory effect mediated by NF-κB in hyperglycemic cells, and the treatment with the rWPP-digested fractions regulate this inflammatory process by Nrf2 pathway increased expression of antioxidant enzymes.