SIRT1, an ubiquitous NAD(?)-dependent deacetylase that plays a role in biological processes such as longevity and stress response, is significantly activated in response to reactive oxygen species (ROS) production. Resveratrol (Resv), an important activator of SIRT1, has been shown to exert major health benefits in diseases associated with oxidative stress. In ischemia-reperfusion (IR) injury, a major role has been attributed to the mitogenactivated protein kinase (MAPK) pathway, which is upregulated in response to a variety of stress stimuli, including oxidative stress. In neonatal rat ventricular cardiomyocytes subjected to simulated IR, the effect of Resv-induced SIRT1 activation and the relationships with the MAPK pathway were investigated. Resv-induced SIRT1 overexpression protected cardiomyocytes from oxidative injury, mitochondrial dysfunction, and cell death induced by IR. For the first time, we demonstrate that SIRT1 overexpression positively affects the MAPK pathway-via Akt/ASK1 signaling-by reducing p38 and JNK phosphorylation and increasing ERK phosphorylation. These results reveal a new protective mechanism elicited by Resv-induced SIRT1 activation in IR tissues and suggest novel potential therapeutic targets to manage IR-induced cardiac dysfunction.

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In pathological conditions, the balance between reactive oxygen species (ROS) and antioxidants may shift toward a relative increase of ROS, resulting in oxidative stress. Conflicting data are available on antioxidant defenses in human failing heart and they are limited to the left ventricle. Thus, we aimed to investigate and compare the source of oxidant and antioxidant enzyme activities in the right (RV) and left (LV) ventricles of human failing hearts. We found a significant increase in superoxide production only by NADPH oxidase in both failing ventricles, more marked in RV. Despite unchanged mRNA or protein expression, catalase (CAT) and glutathione peroxidase (GPx) activities were increased, and their increases reflected the levels of Tyr phosphorylation of the respective enzyme. Manganese superoxide dismutase (Mn-SOD) activity appeared unchanged. The increase in NADPH oxidase-dependent superoxide production positively correlated with the activation of both CAT and GPx. However, the slope of the linear correlation (m) was steeper in LV than in RV for GPx (LV: m=2.416; RV: m=1.485) and CAT (LV: m=1.007; RV: m=0.354). Accordingly, malondialdehyde levels, an indirect index of oxidative stress, were significantly higher in the RV than LV. We conclude that in human failing RV and LV, oxidative stress is associated with activation of antioxidant enzyme activity. This activation is likely due to post-translational modifications and more evident in LV. Overall, these findings suggest a reduced protection of RV against oxidative stress and its potential contribution to the progression toward overt heart failure.

Background: Psoriasis is a chronic hyperproliferative inflammatory skin disease, characterized by a generalized redox imbalance. Anti-tumor necrosis factor (TNF)-α therapy is widely used for the treatment of this disease, but its effect on blood redox status hasn't been explored. Objective: To investigate the effects of anti-TNF-α therapy on blood redox status in psoriatic patients. Methods: Twenty-nine psoriatic patients (PSO) were divided into two groups: one remained untreated (NRT) and to another the anti-TNF-α therapy was prescribed (TR). The levels of main oxidative stress markers and total antioxidant capacity (TAC) in plasma, levels of total reactive oxygen species (ROS) production, lipoperoxidation, TAC, glutathione content, and activity of NADPH oxidase in white blood cells (WBC) were evaluated in PSO, in NTR and TR after 6 months of the study. Results: Plasma levels of malondialdehyde (MDA) and protein carbonyl content (PCO), ROS production, lipoperoxidation, and glutathione content in WBC were increased, while TAC in both plasma and WBC was decreased in PSO with respect to controls. In the plasma of TR, levels of MDA and PCO were significantly lower with respect to PSO and NTR. The activity of NADPH oxidase was significantly increased in WBC of PSO and NTR but not in TR versus controls. Discussion: Our results represent novel data about the redox status of WBC in psoriatic patients. A significant redox-balancing effect of anti-TNF-α therapy, probably associated with the normalization of NADPH oxidase activity in WBC, was demonstrated.

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