Showing papers by "Pál Gergely published in 2011"

Ecto-5′-nucleotidase (CD73) decreases mortality and organ injury in sepsis

Abstract: The extracellular concentrations of adenosine are increased during sepsis, and adenosine receptors regulate the host's response to sepsis. In this study, we investigated the role of the adenosine-generating ectoenzyme, ecto-5'-nucleotidase (CD73), in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture. CD73 KO mice showed increased mortality in comparison with WT mice, which was associated with increased bacterial counts and elevated inflammatory cytokine and chemokine concentrations in the blood and peritoneum. CD73 deficiency promoted lung injury, as indicated by increased myeloperoxidase activity and neutrophil infiltration, and elevated pulmonary cytokine levels. CD73 KO mice had increased apoptosis in the thymus, as evidenced by increased cleavage of caspase-3 and poly(ADP-ribose) polymerase and increased activation of NF-κB. Septic CD73 KO mice had higher blood urea nitrogen levels and increased cytokine levels in the kidney, indicating increased renal dysfunction. The increased kidney injury of CD73 KO mice was associated with augmented activation of p38 MAPK and decreased phosphorylation of Akt. Pharmacological inactivation of CD73 in WT mice using α, β-methylene ADP augmented cytokine levels in the blood and peritoneal lavage fluid. These findings suggest that CD73-derived adenosine may be beneficial in sepsis.

Poly(ADP-ribose) polymerase-2 depletion reduces doxorubicin-induced damage through SIRT1 induction

Abstract: Aims Doxorubicin (DOX) is widely used in cytostatic treatments, although it may cause cardiovascular dysfunction as a side effect. DOX treatment leads to enhanced free radical production that in turn causes DNA strand breakage culminating in poly(ADP-ribose) polymerase (PARP) activation and mitochondrial and cellular dysfunction. DNA nicks can activate numerous enzymes, such as PARP-2. Depletion of PARP-2 has been shown to result in a protective phenotype against free radical-mediated diseases, suggesting similar properties in the case of DOX-induced vascular damage. Methods and results PARP-2+/+ and PARP-2−/− mice and aortic smooth muscle (MOVAS) cells were treated with DOX (25 mg/kg or 3 μM, respectively). Aortas were harvested 2-day post-treatment while MOVAS cells were treated with DOX for 7 hours. Aortas from PARP-2−/− mice displayed partial protection against DOX toxicity, and the protection depended on the conservation of smooth muscle but not on the conservation of endothelial function. DOX treatment evoked free radical production, DNA breakage and PARP activation. Importantly, depletion of PARP-2 did not quench any of these phenomena, suggesting an alternative mechanism. Depletion of PARP-2 prevented DOX-induced mitochondrial dysfunction through SIRT1 activation. Genetic deletion of PARP-2 resulted in the induction of the SIRT1 promoter and consequently increased SIRT1 expression both in aortas and in MOVAS cells. SIRT1 activation enhanced mitochondrial biogenesis, which provided protection against DOX-induced mitochondrial damage. Conclusion Our data identify PARP-2 as a mediator of DOX toxicity by regulating vascular SIRT1 activity and mitochondrial biogenesis. Moreover, to the best of our knowledge, this is the first report of SIRT1 as a protective factor in the vasculature upon oxidative stress.

Effect of glucopyranosylidene-spiro-thiohydantoin on glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats.

Abstract: The major role of liver glycogen is to supply glucose to the circulation in order to maintain normal blood glucose levels. In the muscle and liver, the accumulation and breakdown of glycogen are regulated by the reciprocal activities of glycogen phosphorylase and glycogen synthase. Glycogen phosphorylase catalyses the key step of glycogen degradation and its activity is inhibited by glucose and its analogues. Thus, any readily accessible inhibitor of glycogen phosphorylase may serve as a potential therapy for non-insulin-dependent or type 2 diabetes. Hepatic glycogen phosphorylase has been identified as a novel target for drugs that control blood glucose concentration. Glucopyranosylidene-spiro-thiohydantoin (TH) was found to be one of the most potent glucose derivates, inhibiting the catalytic activity of both muscle and liver glycogen phosphorylase. Here, we demonstrated the co-ordinated regulation of glycogen phosphorylase and synthase by 50 µM TH in liver extracts of Wistar rats, resulting in the activation of synthase by a shortening of the latency compared to control animals. TH was also effective in lowering blood glucose levels and restoring hepatic glycogen content in streptozotocin-induced diabetic rats. Furthermore, intravenous administration of TH to Zucker diabetic fatty rats significantly decreased hepatic glycogen phosphorylase a levels, and the activation of synthase was initiated without any delay.