Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In primary cocultures of neurons and glial cells prepared from the neonatal rat brain, lipopolysaccharide (LPS) reduced the numbers of neuronal cells but the effects were markedly inhibited by NG-monomethyl-L-arginine, indicating the involvement of NO and LPS-induced NO synthase in neuronal death. LPS stimulated the expression of inducible NOS (iNOS) in preparations of primary cultured microglias/astrocytes, but not in primary cultured neurons. In addition, LPS caused DNA fragmentation only in NG108-15 cells but not in primary cultured astrocytes as well as astrocytes in cocultures of the two cell types, suggesting that NOS induces the apoptosis of neurons but not glial cells. We then examined the NO-induced neuronal death in NG108-15 cells using NO donors. SNP, and NO donor, caused NO-2 accumulation in the reaction medium and lactate dehydrogenase (LDH) leakage from NG108-15 cells. Although SNP stimulated guanylyl cyclase and accumulated cGMP, cGMP analogs did not affect LDH leakage. In addition, SNP induced chromosomal condensation and fragmentation of nuclei in NG108-15 cells. Gel electrophoretic analysis of cellular DNA extracted from SNP-treated cells, confirmed the internucleosomal DNA fragmentation typical of apoptosis in this culture. SNP increased the amount of radioisotopic labeled glyceraldehyde-3 phosphate dehydrogenase (GAPDH) in the presence of [32P]NAD and inhibited the enzyme activity. The results suggested that SNP-induced cell death is partly due to the NO-induced inhibition of GAPDH, perhaps by stimulating the binding of NAD to GAPDH.
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PMID:Neuronal apoptosis by glial NO: involvement of inhibition of glyceraldehyde-3-phosphate dehydrogenase. 918 51

The major contribution of this paper is the finding of a glycolytic source of ATP in the isolated postsynaptic density (PSD). The enzymes involved in the generation of ATP are glyceraldehyde-3-phosphate dehydrogenase (G3PD) and phosphoglycerate kinase (PGK). Lactate dehydrogenase (LDH) is available for the regeneration of NAD+, as well as aldolase for the regeneration of glyceraldehyde-3-phosphate (G3P). The ATP was shown to be used by the PSD Ca2+/calmodulin-dependent protein kinase and can probably be used by two other PSD kinases, protein kinase A and protein kinase C. We confirmed by immunocytochemistry the presence of G3PD in the PSD and its binding to actin. Also present in the PSD is NO synthase, the source of NO. NO increases the binding of NAD, a G3PD cofactor, to G3PD and inhibits its activity as also found by others. The increased NAD binding resulted in an increase in G3PD binding to actin. We confirmed the autophosphorylation of G3PD by ATP, and further found that this procedure also increased the binding of G3PD to actin. ATP and NO are connected in that the formation of NO from NOS at the PSD resulted, in the presence of NAD, in a decrease of ATP formation in the PSD. In the discussion, we raise the possible roles of G3PD and of ATP in protein synthesis at the PSD, the regulation by NO, as well as the overall regulatory role of the PSD complex in synaptic transmission.
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PMID:The synthesis of ATP by glycolytic enzymes in the postsynaptic density and the effect of endogenously generated nitric oxide. 937 36

Poly(ADP-ribose) polymerase (PARP) transfers ADP ribose groups from NAD(+) to nuclear proteins after activation by DNA strand breaks. PARP overactivation by massive DNA damage causes cell death via NAD(+) and ATP depletion. Heretofore, PARP has been thought to be inactive under basal physiologic conditions. We now report high basal levels of PARP activity and DNA strand breaks in discrete neuronal populations of the brain, in ventricular ependymal and subependymal cells and in peripheral tissues. In some peripheral tissues, such as skeletal muscle, spleen, heart, and kidney, PARP activity is reduced only partially in mice with PARP-1 gene deletion (PARP-1(-/-)), implicating activity of alternative forms of PARP. Glutamate neurotransmission involving N-methyl-d-aspartate (NMDA) receptors and neuronal nitric oxide synthase (nNOS) activity in part mediates neuronal DNA strand breaks and PARP activity, which are diminished by NMDA antagonists and NOS inhibitors and also diminished in mice with targeted deletion of nNOS gene (nNOS(-/-)). An increase in NAD(+) levels after treatment with NMDA antagonists or NOS inhibitors, as well as in nNOS(-/-) mice, indicates that basal glutamate-PARP activity regulates neuronal energy dynamics.
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PMID:Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission. 1067 44

Common vascular disease states including diabetes, hypertension and atherosclerosis are associated with endothelial dysfunction, characterised by reduced bioactivity of nitric oxide (NO). Loss of the vasculoprotective effects of NO contributes to disease progression, but the mechanisms underlying endothelial dysfunction remain unclear. Increased superoxide production in animal models of vascular disease contributes to reduced NO bioavailability, endothelial dysfunction and oxidative stress. In human blood vessels, the NAD(P)H oxidase system is the principal source of superoxide, and is functionally related to clinical risk factors and systemic endothelial dysfunction. Furthermore, the C242T polymorphism in the NAD(P)H oxidase p22phox subunit is associated with significantly reduced superoxide production in patients carrying the 242T allele, suggesting a role for genetic variation in modulating vascular superoxide production. In vessels from patients with diabetes mellitus, endothelial dysfunction, NAD(P)H oxidase activity and protein subunits are significantly increased compared with matched non-diabetic vessels. Furthermore, the vascular endothelium in diabetic vessels is a net source of superoxide rather than NO production, due to dysfunction of endothelial NO synthase (eNOS). This deficit is dependent on the eNOS cofactor, tetrahydrobiopterin, and is in part mediated by protein kinase C signalling. These studies suggest an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production and endothelial dysfunction in human vascular disease states.
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PMID:Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. 1251 89

Pharmacological agents currently in use to treat interstitial lung fibrosis are either ineffective or too toxic in humans. This review addresses mechanistically based novel approaches that have the potential to minimize the accumulation of collagen in the lung, a hallmark of lung fibrosis. These approaches include maintaining the intracellular levels of NAD(+) and ATP, blocking the biological activities of TGF-beta and integrins, evaluating the effectiveness of PAF-receptor antagonists and NOS inhibitors, and developing a new generation of cysteine pro-drugs with an adequate degree of bioavailability. A critical analysis of each approach as it relates to management of IPF in humans is presented.
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PMID:Novel pharmacological approaches to manage interstitial lung fibrosis in the twenty-first century. 1254 Jul 41

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive "causal" antioxidant therapy. New low-molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase beta isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.
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PMID:New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. 1271 23

Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney by inducing pro-inflammatory mechanisms and disrupting tissue remodeling. Oxidative stress is increased in RVD, but its direct contribution to renal injury has not been fully established. The authors hypothesized that chronic antioxidant intervention in RVD would improve renal function and attenuate tissue injury. Single-kidney hemodynamics and function at baseline and during vasoactive challenge were quantified using electron-beam computed tomography in pigs after 12 wk of experimental RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7), RVD daily supplemented with antioxidant vitamins C (1 g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal tissue was studied ex vivo using Western blot analysis and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly decreased in the stenotic kidney of both RVD groups. RBF and GFR response to acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P < 0.05 versus RVD). RVD+Vitamins also showed increased renal expression of endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H-oxidase, nitrotyrosine, inducible-NOS, and NF-kappaB, suggesting decreased superoxide abundance and inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVD+Vitamins was accompanied by augmented expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems, resulting in significantly attenuated glomerulosclerosis and renal fibrosis. In conclusion, chronic antioxidant intervention in early experimental RVD improved renal functional responses, enhanced tissue remodeling, and decreased structural injury. This study supports critical pathogenic contribution of increased oxidative stress to renal injury and scarring in RVD and suggests a role for antioxidant strategies in preserving the atherosclerotic and ischemic kidney.
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PMID:Antioxidant intervention blunts renal injury in experimental renovascular disease. 1503 98

The inducible nitric oxide synthase (iNOS) plays an important role in endotoxic shock. However,little is known about the involvment of constitutive isoform(s) of NOS (cNOS). The aim of this study was to determine the role of cNOS in the mouse brain after lipopolysaccharide (LPS) injection. Concentrations of nicotinamide adenine dinucleotide (NAD(+)), carbonyl group and thiobarbituric acid reactive substances were determined spectrophotometrically, cNOS mRNA was evaluated by RT-PCR. Our data showed that LPS significantly decreased NAD(+) level, and enhanced protein and lipid oxidation, but had no effect on cNOS mRNA expression. Inhibitors of cNOS protected the cells against alterations evoked by LPS, suggesting involvement of cNOS isoforms in pathology.
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PMID:Inhibition of nitric oxide synthase prevents energy failure and oxidative damage evoked in the brain by lipopolysaccharide. 1559 55

It is tempting to speculate that increased vasoconstriction and loss of endothelium-dependent vasodilation might be etiological factors of elevated blood pressure in the insulin-resistant state. Vascular contraction induced by angiotensin II and the expression of NAD(P)H oxidase were increased in the aorta of insulin-resistant mice. In addition, both angiotensin II type 1 receptor expression and superoxide anion production were up-regulated in these mice. Another mechanism for imparing endothelial function is the uncoupling of endothelial nitric oxide synthase (eNOS). It has become clear from studies on the aorta of insulin-resistant rat that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO (nitric oxide) due to an enhanced formation of superoxide anion (NO/superoxide anion imbalance), which are caused by relative deficiency of tetrahydrobiopterin, a cofactor of NOS, in vascular endothelial cells. Supplementation of tetrahydrobiopterin restored endothelial function and relieved oxidative tissue damage through activation of eNOS in those rats. These results indicate that generation of superoxide anion from NAD(P)H oxidases and an uncoupled eNOS may be pathogenic factors for impaired endothelial function and hypertension in the insulin-resistant state.
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PMID:Malfunction of vascular control in lifestyle-related diseases: mechanisms underlying endothelial dysfunction in the insulin-resistant state. 1559 93

Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) contributes to regulation of cerebral circulation, whereas that produced by neuronal NOS (nNOS) participates in the regulation of brain function. In particular, NO plays an important role in modulation of sympathetic activity and hence central regulation of arterial pressure. Superoxide derived from NAD(P)H oxidase avidly reacts with and inactivates NO and, thereby, modulates its bioavailability. Calmodulin (CM) is required for activation of NOS and soluble guanylate cyclase (sGC) serves as a NO receptor. Superoxide is dismutated to H2O2 by superoxide dismutase (SOD) and H2O2 is converted to H2O by catalase or glutathione peroxidase (GPX). Given the importance of NO in the regulation of brain perfusion and function, we undertook the present study to determine the relative expressions of immunodetectable nNOS, eNOS, CM, sGC, NAD(P)H oxidase and SOD by Western analysis in different regions of the normal rat brain. nNOS was abundantly expressed in the pons cerebellum and hypothalamus and less so in the cortex and medulla. sGC abundance was highest in the hypothalamus and pons, and lowest in the cerebellum and medulla. eNOS and calmodulin were equally abundant in all regions. NAD(P)H oxide was most abundant in the pons compared to other regions. Cytoplasmic SOD was equally distributed among different regions but catalase and GPX were more abundant in pons, hypothalamus and medulla and less so in the cortex and cerebellum. Thus, the study documented regional distributions of NOS, NAD(P)H oxidase, antioxidant enzymes, sGC and calmodulin which collectively regulate production and biological activities of NO and superoxide, the two important small molecular size signaling molecules.
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PMID:Regional expression of NO synthase, NAD(P)H oxidase and superoxide dismutase in the rat brain. 1719 79


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