Nitrosative stress and pharmacological modulation of heart failure

Dysregulation of nitric oxide (NO) and increased oxidative and nitrosative stress are implicated in the pathogenesis of heart failure. Peroxynitrite is a reactive oxidant that is produced from the reaction of nitric oxide with superoxide anion and impairs cardiovascular function through multiple mechanisms, including activation of matrix metalloproteinases (MMPs) and nuclear enzyme poly(ADP-ribose) polymerase (PARP). Recent studies suggest that the neutralization of peroxynitrite or pharmacological inhibition of MMPs and PARP are promising new approaches in the experimental therapy of various forms of myocardial injury. In this article, the role of nitrosative stress and downstream mechanisms, including activation of MMPs and PARP, in various forms of heart failure are discussed and novel emerging therapeutic strategies offered by neutralization of peroxynitrite and inhibition of MMPs and PARP in these pathophysiological conditions are reviewed

Pulsed laser ablation and incubation of nickel, iron and tungsten in liquids and air

Incubation effects in the nanosecond laser ablation of metals exhibit a strong dependence on the thermal and mechanical properties of both the target material and the background gas or liquid. The incubation in air is controlled mainly by thermal properties such as the heat of vaporization. In liquid, the correlation of the incubation and the ultimate tensile stress of the metals suggests that incubation may be related to the mechanical impact on the solid material by the cavitation bubble collapse, causing accumulation of voids and cracks in the subsurface region of the ablation craters. At high ultimate tensile stress, however, the low sensitivity to the environment suggests that the mechanical impact is likely to play a negligible role in the incubation. Finally, the correlation between the incubation and the carbon content of alcoholic liquids may be explained by an absorptivity increase of the cavity surfaces due to carbonaceous deposits generated by laser-induced pyrolysis, or by the mechanical impact of long-living bubbles at higher dynamic viscosity of liquids

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl4 or bile duct ligation, the hybrid CB1R/iNOS antagonist surpassed the antifibrotic efficacy of the CB1R antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CB1R occupancy in the CNS. The hybrid inhibitor also targeted CB1R-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin alphavbeta6 signaling, as judged by its ability to inhibit these pathways in cnr1-/- but not in nos2-/- mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis