[Perspectives on pharmacological and clinical benefits from sirtuin 1 activators in oxidative damage]. / Perspektivy farmakologického a klinického prínosu aktivátoru sirtuinu 1 pri oxidativním poskození.

Sirtuins, named after their homology to the Saccharomyces cerevisiae Silent Information Regulator Two, constitute a family of highly conserved nicotinamide adenine dinucleotide-dependent enzymes that deacetylate histones and residues of acetylated lysine. The main aim of this article is to put forward the pharmacological importance of major sirtuin 1 activators of natural or synthetic origin tested in last years in cases of oxidative tissue damage. The related bioactivity of these activators as "leading" compounds in the search for new drugs and remedies is also described. With the recent development of our knowledge on the cross talks between sirtuin 1 and its modulators (e.g. resveratrol), pharmacological and clinical research on this topic is getting a new horizon.

Inhibition of endotoxemia-induced nitric oxide synthase expression by cyclosporin A enhances hepatocyte injury in rats: amelioration by NO donors.

The goals of the present study were to provide information into the controversy about nitric oxide (NO) status of the liver during endotoxemia and to assess the role of the phosphatase inhibitor cyclosporin A (CsA) during the insult. Rats were injected with saline, lipopolysaccharide (LPS, 10 mg/kg i.p.) or cyclosporin A (CsA, 5 mg/kg. i.p.) + LPS, S-nitroso-N-acetyl penicillamine (SNAP, 0.1 mMikg) + CsA + LPS or molsidomine (molsid, 0.2 mg/kg) + CsA + LPS. Rat hepatocytes were isolated and tested for metabolic competence by the rate of urea synthesis and for lipid peroxidation. Hepatocytes were cultured under various treatments as LPS or cytokine mixture (CM, TNF-alpha 500 U/ml, INF-gamma 100 U/ml, IL-1beta 200 U/ ml) with or without CsA and iNOS expression was evaluated by NO productivity and by RT-PCR. Twenty-four hours after LPS dosing in vivo, the mortality rate was 15%, while CsA pretreatment increased mortality rate to 30% and reduced hepatocyte viability, increased ALT leakage and reduced urea synthesis. SNAP and Molsid resulted in complete survival of rats, increased urea synthesis, increased cell viability and reduced alanine aminotransferase leakage. LPS or CM increased iNOS expression while CsA pretreatment reduced iNOS expression. There was no correlation between lipid peroxide levels in hepatocytes and functional status of hepatocytes under various treatments. This study demonstrates that NO produced during endotoxemia and under the present conditions is protective to the liver and may function as an adaptive mechanism and that the inhibition of iNOS by compounds like CsA produce unfavorable effects.