The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.

Uncontrolled accumulation of methylglyoxal (MG) and reactive oxygen species (ROS) occurs in hyperglycemia-induced endothelial dysfunction associated with diabetes. Resveratrol (RSV) protects the endothelium upon high glucose (HG); however, the mechanisms underlying such protective effects are still debated. Here we identified key molecular players involved in the glycative/oxidative perturbations occurring in endothelial cells exposed to HG. In addition, we determined whether RSV essentially required SIRT1 to trigger adaptive responses in HG-challenged endothelial cells. We used primary human umbilical vein endothelial cells (HUVECs) undergoing a 24-h treatment with HG, with or without RSV and EX527 (i.e., SIRT1 inhibitor). We found that HG-induced glycative stress (GS) and oxidative stress (OS), by reducing SIRT1 activity, as well as by diminishing the efficiency of MG- and ROS-targeting protection. RSV totally abolished the HG-dependent cytotoxicity, and this was associated with SIRT1 upregulation, together with increased expression of GLO1, improved ROS-scavenging efficiency, and total suppression of HG-related GS and OS. Interestingly, RSV failed to induce effective response to HG cytotoxicity when EX527 was present, thus suggesting that the upregulation of SIRT1 is essential for RSV to activate the major antiglycative and antioxidative defense and avoid MG- and ROS-dependent molecular damages in HG environment.