Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conversion of L-[3H]arginine to L-[3H]citrulline in the absence of calcium can be used to assay selectively the activity of inducible nitric oxide synthase (NOS) in rat spleen homogenates 6 h after lipopolysaccharide administration. Using similar assay conditions, changes in inducible NOS activity were measured within ischemic brain tissue between 2 h and 7 days following permanent middle cerebral artery (MCA) occlusion in Sprague-Dawley rats and SV-129 mice. Total (constitutive and inducible) NOS activity was measured in the presence of 0.5 mM CaCl2. Whereas total NOS activity in rat decreased dramatically to 16% and 6% of baseline 6 and 12 h after MCA occlusion, inducible NOS activity remained undetectable before 2 days after occlusion, became maximal at 3 days, and decreased to less than 10% of maximal iNOS activity at 7 days. In the mouse, total NOS activity decreased after MCA occlusion but inducible NOS activity was undetectable from 2 h to 4 days after occlusion. Sustained NO production by inducible NOS activity does not contribute to ischemic injury within 24 h after MCA occlusion, but may contribute to infarct maturation 2-4 days after ischemia in some but not all species.
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PMID:Induction of nitric oxide synthase activity in rodent brain following middle cerebral artery occlusion. 747 41

We have evaluated the role of prostaglandin E2 (PGE2) in the synthesis of nitric oxide (NO) by the activation of the inducible form of nitric oxide synthase (NOS) in the murine macrophage cell line, J774, stimulated with different doses of lipopolysaccharide (LPS). The stimulation of the J774 line with suboptimal doses of LPS (0.1 microgram/mL) caused a production of endogenous PGE2 that was capable of stimulating NOS activity inducing an increase in the NO synthesis, as attested by the fact that cyclooxygenase enzyme inhibitor, indomethacin, significantly reduced NO secretion. On the contrary, a higher dose of LPS (1 microgram/mL) produced high levels of PGE2 that reduced the levels of NOS and, subsequently, NO production. Experiments carried out with exogenous PGE2 indicated that concentrations between 1 and 10 ng/mL are able to stimulate the expression of NOS and the release of NO, while higher concentrations (> 50 ng/mL) are inhibitory. Furthermore, our data indicate that there is a network of interaction which involves NO, PGE2, and tumor necrosis factor. High levels of PGE2 inhibited TNF alpha secretion, which in turn could exert inhibitory effects on NO synthesis.
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PMID:Prostaglandin E2 regulates inducible nitric oxide synthase in the murine macrophage cell line J774. 748 Jul 96

We have previously clarified that sensitization with a sulfated polygalactose, carrageenan (CAR), enhances endotoxin-induced tumor necrosis factor (TNF) production and lethality in mice. The present study was performed to examine the role of nitric oxide (NO) in CAR-sensitized septic mice with two different types of NO synthase (NOS) inhibitors, a non-selective inhibitor to NOS subtypes, N omega-nitro-L-arginine methyl ester (L-NAME), and a selective inhibitor to inducible NOS, aminoguanidine. Seven or eight-week-old male ddY mice were given 5 mg of CAR intraperitoneally as a primer. Then, 5 micrograms of lipopolysaccharide (LPS) was injected into the tail vein 16 hours later the pretreatment. Marked synthesis of NO was induced in CAR-sensitized mice, as indicated by the high plasma levels of the stable endproducts, NO2-/NO3- peaking at 12 hr after the LPS challenge. The peak values at 12 hr after the LPS challenge were dependent on the dose of CAR with 1 to 5 mg, although the injection with 10 mg of CAR was adversely inhibited NO production compared with 5 mg of CAR. The LPS challenge was followed by either L-NAME (0.25, 0.5 or 1 mg) or aminoguanidine (1, 2 or 4 mg) in the septic mice sensitized with 5 mg of CAR. L-NAME reduced the plasma NO2-/NO3- level in a dose-dependent fashion, although it augmented liver injury, as measured by plasma levels of ornithine carbamyltransferase (OCT) and the LPS-induced lethality in a dose-dependent fashion. In contrast, aminoguanidine did not significantly deteriorate either liver injury or lethality in spite of the decrease of NO endproducts in a similar fashion to L-NAME. These findings suggest that the inhibition of constitutive NOS is detrimental and augments LPS-induced liver injury and subsequent lethality.
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PMID:Role of nitric oxide during carrageenan-sensitized endotoxin shock in mice. 749 Oct 89

Administration of bacterial lipopolysaccharide (LPS) to rats stimulates synthesis of nitric oxide (NO), a free radical molecule that activates soluble guanylate cyclase, thereby increasing intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration and inducing systemic vasodilatation. To investigate the effect of endotoxemia on the pulmonary NO/cGMP signal transduction system, we measured the release of cGMP by isolated-perfused lungs of rats that received an intraperitoneal injection of LPS (1 mg/kg) or saline 2 days earlier. Over 90 min, 1.4 +/- 0.78 and 0.079 +/- 0.016 nmol cGMP accumulated in pulmonary perfusates of saline- and LPS-treated rats, respectively (P < 0.05). Despite addition to the perfusate of Zaprinast, superoxide dismutase, or A23187, markedly less cGMP was released from the lungs of rats exposed to LPS than from the lungs of control rats. In contrast, after ventilation with 100 parts per million NO gas, cGMP accumulating in the perfusate of the lungs of both groups of rats was markedly increased, and the quantity of cGMP released from the lungs of LPS-treated rats was similar to that released by control rat lungs (2.8 +/- 0.57 vs. 3.3 +/- 0.88 nmol, P = NS). With the use of immunoblot techniques, equal concentrations of constitutive endothelial NO synthase were detected in the lungs of rats treated with saline or LPS. These results demonstrate that the NO/cGMP signal transduction system is abnormal in the lungs of rats exposed to LPS, at least in part, at the level of endothelial NO synthase activation.
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PMID:In vivo lipopolysaccharide pretreatment inhibits cGMP release from the isolated-perfused rat lung. 749 80

Administration of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (5 mg/kg s.c.) provoked acute microvascular injury (assessed by the leakage of radiolabelled human serum albumin) in the rat colon within 1 h, when administered concurrently with endotoxin (Escherichia coli lipopolysaccharide, 3 mg/kg i.v.). Pretreatment with the selective inhibitor of 5-lipoxygenase, BW A137C (N-[4-benzyloxybenzyl] acetohydroxamic acid; 1-20 mg/kg s.c., 15 min before endotoxin) attenuated such damage in a dose-dependent manner. These findings suggest a balance between protective constitutive nitric oxide and the detrimental actions of 5-lipoxygenase products in the maintenance of vascular integrity in the early stage of sepsis.
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PMID:Colonic microvascular integrity in acute endotoxaemia: interactions between constitutive nitric oxide and 5-lipoxygenase products. 749 98

The isolated perfused kidney of the rat was used to examine the hypothesis that lipopolysaccharide-induced nitric oxide (NO) production inhibits cytochrome P450-dependent vasodilation. The vasodilator responses to arachidonic acid and bradykinin were examined as the response to arachidonic acid is wholly dependent, and that to bradykinin partly dependent on cytochrome P450 metabolism. In endotoxin-treated rats, the vasodilator response to arachidonic acid was inhibited, and those to bradykinin and acetylcholine were enhanced. Following treatment with phenobarbitone, the inducer of certain isoforms of cytochrome P450 enzymes, the vasodilator effects of all three agonists, especially that of arachidonic acid, were amplified. Lipopolysaccharide inhibited the effect of phenobarbitone on the vasodilator effect of arachidonic acid and bradykinin but enhanced that of acetylcholine. The effect of lipopolysaccharide was antagonized by haemoglobin, a NO antagonist, and N omega-nitro-L-arginine, an inhibitor of NO synthase, suggesting that the inhibitory effect of lipopolysaccharide on arachidonic acid- and bradykinin-induced vasodilation was mediated by NO/NO synthase. N omega-Nitro-L-arginine enhanced vasodilation induced by arachidonic acid while that induced by bradykinin or acetylcholine was reduced, implying that endogenous NO inhibits vasodilator cytochrome P450 metabolites in the rat kidney. Pretreatment with dexamethasone, an inhibitor of inducible NO synthase, resulted in inhibition of the lipopolysaccharide modulation of arachidonic acid-induced vasodilation, suggesting that the inducible NO synthase is the target of the inhibitory effect of lipopolysaccharide. The inhibitory effect of lipopolysaccharide was mimicked by nitroprusside, the L-arginine-independent NO donor, and by L-arginine, the biosynthetic precursor of NO. The effect of L-arginine, but not of nitroprusside, was antagonized by N omega-nitro-L-arginine, suggesting a specific role for NO synthase in the inhibitory effect of lipopolysaccharide in the inhibition of cytochrome P450-dependent vasodilation in the rat kidney.
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PMID:The suppression by lipopolysaccharide of cytochrome P450-dependent renal vasodilation in the rat is mediated by nitric oxide. 749 99

Endotoxin (Escherichia coli lipopolysaccharide 0111:B4, 3 mg/kg i.v.) induced the expression of a calcium-independent nitric oxide (NO) synthase, determined after 5 h in cardiac, hepatic, pulmonary and renal tissues, as assessed by the conversion of radiolabelled L-arginine to L-citrulline. This widespread induction of NO synthase in these conscious rats was associated with microvascular injury, as assessed by the vascular leakage of radiolabelled human serum albumin. Concurrent administration of the NO synthase inhibitor. NG-nitro-L-arginine methyl ester (L-NAME, 1-5 mg/kg s.c.) with endotoxin, provoked acute vascular leakage within 2 h in the various organs. By contrast, the delayed injection of L-NAME (1-5 mg/kg s.c.) or NG-monomethyl-L-arginine (12.5-50 mg/kg s.c.) until 3 h after endotoxin challenge inhibited the subsequent microvascular leakage in these organs. These effects of NO synthase inhibitors were reversed by L-arginine (300 mg/kg s.c.) pretreatment. These results support a protective role of constitutive NO synthase in the early phase of endotoxin shock. Such actions contrast with the aggressive actions of the products of inducible NO synthase in the development of widespread microvascular injury in endotoxemic states.
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PMID:Association of microvascular leakage with induction of nitric oxide synthase: effects of nitric oxide synthase inhibitors in various organs. 749 20

In heart muscle, the cytokine-inducible isoform of nitric oxide synthase (NOS2) is expressed in both cardiac myocytes and microvascular endothelial cells (CMEC). mRNA levels for both NOS2 and for osteopontin, a multifunctional extracellular matrix phosphoprotein containing and RGD integrin binding domain, are increased in cardiac muscle following intraperitoneal injection of adult rats with lipopolysaccharide. In vitro, interleukin-1 beta and interferon-gamma increased osteopontin mRNA levels in CMEC as well as NOS2 expression in both CMEC and cardiac myocytes. However, osteopontin mRNA levels in heart muscle in vivo, and in cardiac myocytes and CMEC in vitro, also are increased 10-30-fold by the synthetic glucocorticoid dexamethasone, an agent that suppresses cytokine induction of NOS2 in both cell types. The hexapeptide GRGDSP, which interrupts binding of RGD-containing proteins to cell surface integrins, increased NOS2 mRNA, while a synthetic osteopontin peptide analogue decreased NOS2 mRNA and protein levels in both cytokine-pretreated cardiac myocytes and CMEC cultures. Also, transfection with a full-length antisense-osteopontin cDNA in cytokine-pretreated CMEC decreased endogenous osteopontin mRNA and increased NOS2 mRNA levels. These results suggest that osteopontin could regulate the location and extent of NOS2 induction in the heart. Increased expression of osteopontin also may be one mechanism by which glucocorticoids suppress NOS2 activity in cardiac myocytes and microvascular endothelial cells.
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PMID:Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. 749 54

The purpose of these studies was to identify phosphatase activities required for the production of nitric oxide in murine macrophages exposed to lipopolysaccharide (LPS), synthetic lipopeptide (LPP), and mouse interferon-gamma (IFN-gamma). The in vitro treatment of macrophages with IFN-gamma and LPS or IFN-gamma and LPP resulted in production of NO, which was inhibited by addition of the specific phosphatase 1 and 2A (PP1/2A) inhibitors okadaic acid (OA), calyculin A, and cantharidin (but not the nonactive analogues okadaic acid tetraacetate and 1,4-dimethylendothall). OA suppressed the accumulation of steady-state inducible NO synthase (iNOS) mRNA and iNOS protein (without alteration of their stability). The cytosol and nuclei of control macrophages contained large amounts of PP1/2A activities that were inhibited by OA in a dose-dependent manner. Taken together, these data indicate that PP1/2A activities are involved in the regulation of iNOS gene expression in murine macrophages.
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PMID:Activation of inducible nitric oxide synthase gene in murine macrophages requires protein phosphatases 1 and 2A activities. 749 72

Classically, osteoarthritis (OA) has been considered a noninflammatory disease. However, the detection of selected inflammatory mediators in osteoarthritic fluid, in the absence of significant inflammatory cell infiltrate, is increasingly appreciated. We sought to identify the inflammatory component in human OA-affected cartilage that may be involved in cartilage damage/destruction. Using Western blot analysis and an antibody to the conserved region of nitric oxide synthase (NOS), we have observed up-regulation of NOS, one of the "key players" of inflammation, in chondrocytes of OA-affected patients. Remarkably, none of the cartilage samples examined from normal joints demonstrated detectable amounts of this NOS. Western blot analysis using the same alpha-NOS antibody indicated that this NOS from OA-affected cartilage (OA-NOS) was larger in size than (and distinct from) transfected human hepatocyte or murine inducible NOS (iNOS) (150 versus 133 kD) and similar in size to neuronal constitutive NOS (ncNOS). Antibodies specific for iNOS showed binding to murine and human iNOS but not to OA-NOS, endothelial constitutive NOS, or ncNOS. Antibodies specific for ncNOS bound to ncNOS and also to OA-NOS, but not to murine or human iNOS or endothelial constitutive NOS. Incubation of OA cartilage in serum-free medium resulted in spontaneous release, for up to 72 h, of substantial amounts of nitrite (up to approximately 80 microM/100 mg wet tissue), which could be inhibited by at least 80% with various inhibitors of iNOS, including inhibitors of protein synthesis and transcription factor NF-kappa B, but which (unlike murine macrophage iNOS) was not sensitive to hydrocortisone or TGF-beta. Exposure of OA-affected cartilage to interleukin 1 beta, tumor necrosis factor-alpha, and lipopolysaccharide resulted in approximately 20-50% augmentation of nitrite accumulation, which was also sensitive to cycloheximide and pyrrolidine dithiocarbamate. Hence, our data indicate that OA-NOS (based on immunoreactivity and molecular weight) is similar to ncNOS and that it releases nitric oxide, which may contribute to the inflammation and pathogenesis of cartilage destruction in OA.
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PMID:The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. 750 55


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