peroxynitrous acid

..These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases...

..Redox state is a critical determinant of cell function, and any major imbalances can cause severe damage or death...

..These findings indicate ONOO(-) plays an essential role in the mechanism of proinflammatory cytokine release by monocytes and that Rel/NF-kappaB activation is the obligatory pathway...

..We investigated the influence of experimental hyperlipidemia on the formation of cardiac NO, superoxide, and peroxynitrite (ONOO(-)) in rat hearts...

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The reaction of peroxynitrous acid with monohydroascorbate, over the concentration range of 250 microM to 50 mM of monohydroascorbate at pH 5...

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..Rather, effects seem to be downstream on decreased protein nitration, decreased lipid peroxidation, and decreased PARP activation...

..The aim of the current work was to produce a potent peroxynitrite decomposition catalyst and to test its effects in rodent models of diabetes and its complications...

..The therapeutic effect on animals with active EAE was associated with increased UA, but not inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of inosine and inosinic acid in EAE is via their metabolism to UA...

..Peroxynitrite generation is inhibited by allopurinol, superoxide dismutase and diphenylene iodonium. A role for this enzyme activity can be found in the antibacterial activity of milk and circulating xanthine oxidase activity...

..In view of the wide range of isoform-specific NOS inhibitors, the determination of the most responsible isoform of NOS for the formation of peroxynitrite in AD could be of therapeutic importance in the treatment of Alzheimer's disease...

..The data point to a potential regulation of GS activity by a reversible tyrosine nitration. High levels of oxidative stress may irreversibly damage and predispose the enzyme to proteasomal degradation...

The oxidant peroxynitrite/peroxynitrous acid (ONOO-/ONOOH) is generated at sites of inflammation via reaction of O2.- with .NO...

..Hence, the characteristics of shear stress in the arterial bifurcations influenced the relative production of O2(-.) and .NO with an implication for ONOO(-) formation as evidenced by LDL protein nitration...

..Here we investigated the role of peroxynitrite in apoptosis occurring in astroglial cells incubated with supernatants of HIV-infected human primary macrophages (M/M)...

..Further work is needed to determine whether neutralization of peroxynitrite also represents a promising strategy to treat human inflammatory diseases such as arthritis and colitis...

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..Taken together, we conclude that PKCzeta can regulate AMPK activity by increasing the Ser428 phosphorylation of LKB1, resulting in association of LKB1 with AMPK and consequent AMPK Thr172 phosphorylation by LKB1...

..The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma...

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..Hydrophobic membranes greatly influenced alpha-synuclein aggregation and nitration in these systems. We conclude that both CO3*- and NO2* could play a major role in the nitration/aggregation of alpha-synuclein...

..Taken together, these data indicate that early diabetes causes breakdown of the BRB by a mechanism involving the action of reactive nitrogen species in promoting expression of VEGF and uPAR...

..The findings provide rationale for development of potent peroxynitrite decomposition catalysts for the treatment of diabetic neuropathy...

..5% chain breaks (per peroxynitrite concentration). These conclusions support the proposal that the yield of hydroxyl radicals arising from the isomerization of ONOOH to nitrate ions is relatively low...

..The data indicate that TNF induces an ONOO(-)-dependent barrier dysfunction, which is associated with the generation of NO(2)-beta-actin...

..In conclusion, tolerance to GTN involves enhanced production of O2*- and ONOO- and activation of NO synthase. Furthermore, sustained activation of alpha- and epsilonPKC isozymes in EC by GTN may play a role in development of tolerance...

..Our findings indicate that DAF-2 fluorometric assays are quantitatively difficult to interpret in cells and in solution when oxidants and (*) NO are co-generated...

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..Finally, ONOO(-) enhanced PKCzeta nuclear import and LKB1 nuclear export. We conclude that PKCzeta mediates LKB1-dependent Akt inhibition in response to ONOO(-), resulting in endothelial apoptosis...

..The time course of formation of these radicals is consistent with these species being involved in polymer fragmentation...

..The current study suggests a role for peroxynitrite production and for PARP activation in the pathogenesis of retinal microvascular leukostasis in early diabetes...

..Mitochondrial O(2)(.-) formation in hyperglycemic conditions was associated with increased glucose metabolization in the Krebs cycle and hyperpolarization of the mitochondrial membrane...

..However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurodegeneration and NGF survival signaling have not been elucidated...

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..Early inhibition of tyrosine nitration with use of epicatechin or NAC can represent safe and effective vascular-protective agents in ischemic retinopathy...

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..Hyperglycemia increases NO production in retinal cells, and aminoguanidine can inhibit this abnormality. Inhibition of diabetic retinopathy by aminoguanidine might be mediated in part by inhibition of sequelae of NO production...

..Thus, nitrated HDL might represent a previously unsuspected link between nitrosative stress, atherosclerosis, and inflammation...

..Better understanding of the molecular mechanisms by which NO is protective may ultimately identify new potential therapeutic targets...

..We conclude that ONOO(-) inhibits Akt and increases AMPK-dependent Ser(1179) phosphorylation of eNOS resulting in enhanced O(2)() release...

..In conclusion, peroxynitrite is critically involved in transducing VEGF's angiogenic signal via nitration-independent and oxidation-mediated tyrosine phosphorylation...

..53+/-0.1 protein/actin vs. virgins: 1.0+/-0.14 protein/actin). These data suggest that multiparity induces endothelial dysfunction through decreased NO bioavailability and increased reactive oxygen species formation...

..Our results suggest that peroxynitrite reduces the IRS-1 protein level and decreases phosphorylation of IRS-1 concurrent with nitration of its tyrosine residues...

..Stimulation of peroxynitrite catalysis attenuates HFD-induced insulin resistance in mice by restoring insulin signalling and insulin-stimulated glucose uptake in skeletal muscle tissue...

..Moreover, post-treatment with insulin inhibited caspase-3 activation and loss of cell viability in NONOate- but not in SIN-1-exposed cells. These findings suggest that NO is a potent toxin independent of peroxynitrite formation...

..This provides the rationale for development of agents counteracting peroxynitrite formation and promoting peroxynitrite decomposition, and their evaluation in DN...

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..Peroxynitrite/peroxynitrous acid, which is generated at elevated levels at sites of inflammation, is believed to play a role in ECM damage; ..

..The preferential protein targets of peroxynitrite and the role of proteins in peroxynitrite detoxifying pathways are discussed...

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..These findings indicate that both superoxide and nitric oxide radicals contribute to islet beta-cell destruction in autoimmune diabetes via peroxynitrite formation in the beta-cells...

..Modeling studies suggest that Tyr 190 may play a structural role in maintaining the integrity of the protein for maximal activity through hydrogen bonding with Glu 149...

..The activity was shown to be specific for Histone H1.2, to differ from proteasome activity, and to require no additional cofactors...

..In the presence of SeLA, the inactivation was reversible under the action of thiols, allowing us to conclude that the observed action of SeLA may be considered as protective...

..Thus, inhibition of NO production may be another means whereby melatonin reduces oxidative damage under conditions, such as ischemia-reperfusion, sepsis, etc, where NO seems to be important in terms of the resulting damage...

..Peroxynitrite might be the main marker of brain damage and neurological impairment in acute ischemic stroke...

..On the contrary, lack of NO disrupts pathways like S-nitrosylation or H(2)O(2) production and likewise is a gateway to disease in amyotrophic lateral sclerosis with superoxide dismutase 1 mutations or to cancer proliferation...

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..Scavengers of PON, or its derived free radical species, may provide an improved antioxidant neuroprotective approach for the treatment of post-traumatic oxidative damage in the injured spinal cord...

..Mitochondrial dysfunction may be an understudied component of the endothelial dysfunction associated with various cardiovascular disease states...

..We believe alaternin can be developed as an effective ONOO- scavenger for the prevention of ONOO- -associated diseases...

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..Our data explain the mechanism of enhanced vulnerability of sublethally injured neurons to secondary excitotoxic insults and highlight the importance of secondary mechanisms to the ultimate outcome of neurons in mild neurotrauma...

..The present study was designed to determine the mechanism by which adiponectin exerts its protective effects against myocardial ischemia/reperfusion...

..We conclude that sGC/cGMP/PKG cascade and peroxynitrite formation may participate in Mev-induced phasic cardiovascular responses as signals downstream to NO generated respectively by NOS I and II in the RVLM...

..Therefore, variations of combination of cell membrane receptor blockers, antioxidants, nitric oxide synthase inhibitors, ONOO(-) scavengers, and PARP inhibitors should be investigated...

..These bands were also recognized in INF1-treated BY-2 cells and were found to be slightly suppressed by urate. Our study is the first to report ONOO(-) detection and tyrosine nitration in defense responses in plants...

..The observation that 3-nitrotyrosine-containing proteins colocalize with markers of ER stress within early atherosclerotic lesions suggests that peroxynitrite contributes to atherogenesis through a mechanism involving ER stress...

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..The results suggest that hydroquinone may potently modulate reactivity of ONOO(-) and may therefore be a useful agent against ONOO(-) mediated diseases...

..Thioredoxin (Trx) is an oxidoreductase that prevents free radical-induced cell death in cultured cells. Here we assessed the mechanism(s) underlying the cardioprotective effects of Trx in vivo...

..The present study suggests that Glycyrrhizae Radix extract could protect the kidneys against ONOO- through scavenging ONOO- and/or its precursor NO, inhibiting protein nitration and improving renal dysfunction caused by ONOO-...

..We tested the hypothesis that AngII-derived superoxide reacts with nitric oxide (NO) to form peroxynitrite, which, in turn, contributes to the vascular dysfunction...

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..Thus, peroxynitrite, in addition to its well-established deleterious role in ischemic brain injury and neurodegeneration, can also be beneficial by inducing tolerance to excitotoxicity...

..We sought to define the intracellular effects and signaling mechanisms of nitric oxide and peroxynitrite in smooth muscle cells...

..We conclude that 7,8-dihydroneopterin while being a weak scavenger of superoxide acts as a very efficient inhibitor of tyrosine nitration induced by peroxynitrite...

..These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess...

..In conclusion, these results suggest that nitration of tyrosine residues of cytochrome c and procaspase 3 is induced by chemoradiotherapy but their nitration does not suppress cancer cell apoptosis...

..Thus, EC-SOD promotes NO* vasodilation by scavenging *O2- while hyperoxia opposes NO* and promotes constriction by enhancing endogenous *O2- generation and decreasing basal vasodilator effects of NO*...

..These results argue against an essential role of peroxynitrite in protein tyrosine nitration in vivo...

..AA also potentiated lipid peroxidation in vivo and in vitro. In conclusion, the superior protective properties of UA in EAE may be related to its ability to neutralize the oxidative properties of ONOO- in the presence of free iron ions...

..These results suggest that PQQ scavenges superoxide without forming toxic levels of H2O2. Therefore, the protective effect of PQQ on stroke might be due, at least in part, to the suppression of peroxynitrite formation...

..The present study suggests that sinapic acid has an efficient ONOO(-) scavenging ability, which may well be a potent ONOO(-) oxidant scavenger for the protection of the cellular defense activity against the ONOO(-)-involved diseases...

..The present results indicate that ciclopirox protects astrocytes from peroxynitrite cytotoxicity by attenuating peroxynitrite-induced mitochondrial dysfunction...

..CONCLUSIONS: Impaired PDNO bioactivity and augmented platelet aggregability may be caused by an imbalance of the intraplatelet redox state through increased oxidative stress in smokers...

..Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats...

..These data suggest that tyrosine nitration of cytoskeletal proteins has a physiological role in vivo, which depends on the protein involved and is differentially regulated...

..CONCLUSION: NO contributes to free radical generation and nitrosative injury after epicardial shocks; NOS inhibitors decrease radical generation by inhibiting the production of O = NOO-...

..The data indicate that DHEA prevents the glucose deprivation-evoked augmented death by inhibiting the production of superoxide anion in immunostimulated C6 glioma cells...

..Among the substances under investigation in this study, glutathione and the synthetic compound ebselen had a major effect on preventing peroxynitrite formation, whereas ascorbate failed to decrease peroxynitrite levels...

..enzyme, myeloperoxidase, and the microbicidal competence of the putative macrophage-generated toxin, peroxynitrous acid (ONOOH)...

..Researchers must consider and assess the effects of reactive molecules on abundant brain proteins because it is very likely that many proteins are damaged as we age. ..

..Estimated worldwide revenues after market entry and maturation (ca. 4 years after FDA approval)=$750 million (annual). ..

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..Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage. ..

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..A novel A3 receptor agonist may represent a useful anti-inflammatory adjunct to current therapeutic regimens; funding of the current SBIR Phase II will allow for starting human safety trials in 2 years. ..

..If these studies confirm that Inotek's PARP inhibitor is effective in improving erectile function in diabetes, a Phase II component will be triggered, which will focus on formal preclinical safety testing. ..

..Further, based on exciting preliminary data, the final, fifth aim is focusing in establishing the role of PARS in myocardial preconditioning. ..

..Kuhn will remain extensively engaged in scientific mentoring activities. ..

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..These studies will test novel hypotheses relating to the identification of reactive species that mediate METH and MDMA effects on monoamine nerve endings. ..

..The final aim of the study is to investigate the activation of PARP in human microvasculature, and to correlate the degree of PARP activation with the degree of endothelial dysfunction in humans. ..

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..4 To establish the role of Bel family proteins in the regulation of calcium homeostasis during peroxynitrite-induced cell death. The studies proposed here have broad pathophysiological relevance. ..

..The current project will enable the applicants to move forward in two years, near to the level of the beginning of Phase II efficacy trial in septic patients. PROPOSED COMMERCIAL APPLICATION: Not Available ..

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..Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage. ..

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..The principal investigator will also investigate the changes in endothelial function during myocardial reperfusion injury, and the role of PARS in these changes. ..

..Increases in brain levels of BH4 will test the hypothesis that the TPH cofactor can modulate the in vivo inactivation of TPH caused by MDMA as it does in vitro with NO/ROS. ..

..4 To establish the role of Bel family proteins in the regulation of calcium homeostasis during peroxynitrite-induced cell death. The studies proposed here have broad pathophysiological relevance. ..

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..A better understanding of the mechanisms by which METH causes persistent damage to the DA neuronal system could lead to more targeted therapies and would open newer lines of investigation into this and other neurotoxic drugs of abuse. ..

..Microarray-based scanning of the human genome has the potential to establish those genes or gene clusters that define the addictive phenotype, leading the way to proteomic-based studies of the bases of addiction. ..

..PROPOSED COMMERCIAL APPLICATIONS: The annual anticipated revenues for an effective therapeutic to prevent anti-cancer-drug induced cardiodepression is over $100 million in the US alone. ..

..Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage. ..

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..The studies are of direct relevance to the pathogenesis of PDN and may provide the rationale for development of PARS inhibitors for its prevention and treatment. ..

..The results may suggest new therapeutic approaches for the treatment of microvascular dysfunction in patients with diabetes. ..

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..A better understanding of the fundamental nature of the reactive species formed in the enzymes and the mechanisms of their reactions is expected to lead to lead ultimately to health-related advances in disease treatment and drug design. ..

..Project Description Page 6 ..

..We will also examine following LPS-induced vascular injury the ultrastructural defects and the cellular nature of the leaks and repair failure of the pulmonary vasculature in mice with endothelial cell- restricted deficiency of FoxM1. ..

..We will also examine following LPS-induced vascular injury the ultrastructural defects and the cellular nature of the leaks and repair failure of the pulmonary vasculature in mice with endothelial cell- restricted deficiency of FoxM1. ..

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..They should also yield insights into how endothelium attempts to protect itself against these stresses and whether AMPK is a potential target for therapy for diabetes. ..

..The findings will generate new information on the role for 12/15-LO in PDN of Type 1 and Type 2 diabetes, and may provide rationale for development of 12/15-LO inhibitors for its prevention and treatment. ..

..Additional derivatives will be examined in vivo. Finally, we will compare the metabolism and pharmacokinetics of NalBzoH following both oral and intravenous administration...

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