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.Biomolecules 2020, 10, 420 2 of 16 focus on the p53-dependent senescence signaling pathways involved with different stages of senescence and with a consideration for the associated key biomarkers. We also provide an overview on the regulation of p53-mediated cellular senescence in the context of different pathophysiological conditions. Senescence as Cellular Response to StressCellular senescence is defined as a cell state characterized by prolonged and generally irreversible cell-cycle arrest [14] and the acquisition of different phenotypic alterations, including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of pro-inflammatory factors or SASP (senescence associated secretory phenotypes). These latter count cytokines, growth factors, proteases, and non-soluble extracellular matrix proteins [15]. All these features ultimately limit the replication of both old and damaged cells. Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19]. Regardless of their origin, the stress factors trigger DNA damage responses (DDR) in the affected cells, which can result in different outcomes, depending on the cell type and the extent of the damage [20]. Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of th...

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Modern technologies relying on wireless communication systems have brought increasing levels of electromagnetic field (EMF) exposure. This increased research interest in the effects of these radiations on human health. There is compelling evidence that EMFs affect cell physiology by altering redox-related processes. Considering the importance of redox milieu in the biological competence of oocyte and sperm, we reviewed the existing literature regarding the effects of EMFs on reproductive systems. Given the role of mitochondria as the main source of reactive oxygen species (ROS), we focused on the hypothesis of a mitochondrial basis of EMF-induced reproductive toxicity. MEDLINE, Web of Science, and Scopus database were examined for peer-reviewed original articles by searching for the following keywords: “extremely low frequency electromagnetic fields (ELF-EMFs),” “radiofrequency (RF),” “microwaves,” “Wi-Fi,” “mobile phone,” “oxidative stress,” “mitochondria,” “fertility,” “sperm,” “testis,” “oocyte,” “ovarian follicle,” and “embryo.” These keywords were combined with other search phrases relevant to the topic. Although we reported contradictory data due to lack of uniformity in the experimental designs, a growing body of evidence suggests that EMF exposure during spermatogenesis induces increased ROS production associated with decreased ROS scavenging activity. Numerous studies revealed the detrimental effects of EMFs from mobile phones, laptops, and other electric devices on sperm quality and provide evidence for extensive electron leakage from the mitochondrial electron transport chain as the main cause of EMF damage. In female reproductive systems, the contribution of oxidative stress to EMF-induced damages and the evidence of mitochondrial origin of ROS overproduction are reported, as well. In conclusion, mitochondria seem to play an important role as source of ROS in both male and female reproductive systems under EMF exposure. Future and more standardized studies are required for a better understanding of molecular mechanisms underlying EMF potential challenge to our reproductive system in order to improve preventive strategies.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a poor response to current treatment regimens. The multifunctional DNA repair-redox signaling protein Ref-1 has a redox signaling function that activates several transcriptional factors (TFs) including NF-κB (RelA), STAT3, AP-1. These have been implicated in signaling in PDAC and associated with cancer progression and therapy resistance. Numerous studies have shown a role for RelA in PDAC inflammatory responses and therapy resistance, little is known as to how these inflammatory responses are modulated through Ref-1 redox signaling pathways during pancreatic pathogenesis. RelA and STAT3 are two major targets of Ref-1 and are important in PDAC pathogenesis. To decipher the mechanistic role of RelA in response to Ref-1 inhibition, we used PDAC cells (KC3590) from a genetically engineered KrasG12D-driven mouse model that also is functionally deficient for RelA (Parent/Vector) or KC3590 cells with fully functional RelA added back (clone 13; C13). We demonstrated that RelA deficient cells are more resistant to Ref-1 redox inhibitors APX3330, APX2009, and APX2014, and their sensitivity is restored in the RelA proficient cells. Knockdown of STAT3 did not change cellular sensitivity to Ref-1 redox inhibitors in either cell type. Gene expression analysis demonstrated that Ref-1 inhibitors significantly decreased IL-8, FOSB, and c-Jun when functional RelA is present. We also demonstrated that PRDX1, a known Ref-1 redox modulator, contributes to Ref-1 inhibitor cellular response. Knockdown of PRDX1 when functional RelA is present resulted in dramatically increased PDAC killing in response to Ref-1 inhibitors. The enhanced cell killing was not due to increased intracellular ROS production. Although Ref-1 inhibition decreased the NADP/NADPH ratio in the cells, the addition of PRDX1 knockdown did not further this redox imbalance. This data suggests that the mechanism of cell killing following Ref-1 inhibition is at least partially mediated through RelA and not STAT3. Further imbalancing of the redox signaling through disruption of the PRDX1-Ref-1 interaction may have therapeutic implications. Our data further support a pivotal role of RelA in mediating Ref-1 redox signaling in PDAC cells with the KrasG12D genotype and provide novel therapeutic strategies to combat PDAC drug resistance.