Figure 10. Schematic representation of antcin M-mediated protection against HG-accelarated stress-induced premature senescence in HNDFs and HUVECs.

Hyperglycemia induces intracellular ROS, which triggers p38 MAPK and JNK/SAMP activation. The activated p38 MAPK and JNK/SAPK promotes transcriptional activation of p53 and FoxO1 by acetylation. P53 and FoxO1-mediated up-regulation of p16^INK4A and p21^CIP1 distrubs cyclins and CDKs, which increase protein stability of pRB and allow to G₀/G₁ cell-cycle arrest and senescence. Conversely, activated p38 MAPK and JNK/SAPK reduce SIRT-1 level by phosphorylating Ser47, eventually losing deacetylation activity. However, treatment with antcin M activates Nrf2-dependent anti-oxidant genes such as HO-1 and NQO-1 followed by activation of PI3K/AKT and ER1/2 kinases, which facilitates ROS inhibition and upregulates SIRT-1 expression in HNDFs and HUVECs. Results expressed as mean ± SEM of three indipendent expriments. Statistical significance at ^ФP < 0.05 compared to NG vs. HG and *P < 0.05 compared to HG vs. samples.