No abstract

Objective-In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM. Methods and Results-In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 mol/L (0.4 mg/dL) to 64 mol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (PϽ0.001) and endothelium-dependent vasodilation (Pϭ0.036) and a decrease in plasma von Willebrand factor (Pϭ0.052) were observed. Conclusion-Experimental

Increased levels of reactive oxygen species (ROS) by hyperglycemia can induce apoptosis of renal cells and diabetic nephropathy. The redox balance in the renal cell seems, therefore, of the utmost importance. ROS-mediated apoptosis may be further aggravated by an inadequate cytoprotective response against ROS. When there are insufficient cytoprotective and ROS scavenging molecules, ROS lead to considerable cellular damage and to a point of no return in apoptosis. Induction of cytoprotective proteins may prevent or attenuate apoptosis, renal cell injury, and finally diabetic nephropathy. Here, we discuss some mechanisms of apoptosis and several strategies that have been probed to ameliorate, or to prevent apoptosis in the diabetic kidney.

Dermaseptins are a group of α-helical shaped polycationic peptides isolated from the Hylid frogs, with antimicrobial effects against bacteria, parasites, protozoa, viruses in vitro. Besides, anti-tumor effects have been demonstrated. However, few animal experiments and no clinical trials have been conducted thus far. This review summarizes the current knowledge on the pharmacology, ethno pharmacology, effectivity against infectious pathogens and tumors cells and the mechanism of action of the Dermaseptins. Future research should focus on further clarification of the mechanisms of action, the effectivity of Dermaseptins against several cancer cell lines and their applicability in humans.

Objective-Statins may increase extracellular adenosine formation from adenosine monophosphate by enhancing ecto-5Ј-nucleotidase activity. This theory was tested in humans using dipyridamole-induced vasodilation as a read-out for local adenosine formation. Dipyridamole inhibits the transport of extracellular adenosine into the cytosol resulting in increased extracellular adenosine and subsequent vasodilation. In addition, we studied the effect of statin therapy in a forearm model of ischemia-reperfusion injury. Methods and Results-Volunteers randomly received rosuvastatin or placebo in a double-blind parallel design (nϭ21).The forearm vasodilator response to intraarterial dipyridamole was determined in the absence and presence of the adenosine antagonist caffeine. During a separate visit the vasodilator response to nitroprusside and adenosine was established. In addition, healthy men were randomly divided in 3 groups to receive either placebo (nϭ10), rosuvastatin (nϭ22), or rosuvastatin combined with intravenous caffeine (nϭ12). Subsequently, volunteers performed forearm ischemic exercise. At reperfusion, Tc-99m-labeled annexin A5 was infused intravenously and scintigraphic images were acquired, providing an early marker of cell injury. Rosuvastatin treatment significantly increased the vasodilator response to dipyridamole, which was prevented by caffeine. Rosuvastatin did not influence the response to either sodium nitroprusside or adenosine indicating a specific interaction between rosuvastatin and dipyridamole, which does not result from an effect of rosuvastatin on adenosine clearance nor adenosine-receptor affinity or efficacy. Rosuvastatin increased tolerance to ischemia-reperfusion injury, which was attenuated by caffeine. Conclusions-Rosuvastatin increases extracellular adenosine formation, which provides protection against ischemiareperfusion injury in humans in vivo. [1][2][3] This benefit of statins has been attributed to the lowering of plasma cholesterol. However, preclinical research indicates that HMG-CoA reductase inhibition has additional effects, including the activation of ecto-5Ј-nucleotidase which converses extracellular adenosine monophosphate into adenosine. 4 -6 Increased adenosine formation favorably influences cardiovascular disease by reducing platelet aggregation, 7 atherosclerosis formation, 8 and ischemia-reperfusion injury. 9 As statins possess similar properties, adenosine is a possible candidate to mediate these effects. 3,10 -12 To our knowledge, the role of extracellular adenosine formation in the benefit of statins has not been explored in humans.Here, we report on the results of 3 studies which addressed the effect of rosuvastatin on adenosine formation and its potential relevance in humans in vivo. For this purpose, we used the adenosine receptor antagonist caffeine and the nucleoside transport inhibitor dipyridamole, as pharmacological tools to assess the involvement of endogenous adenosine in statin-induced effects. Dipyridamole reduces clearance of extracellular adenosi...