Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present experiments was to test the possible involvement of nitric oxide (NO) in cytokine-induced enhancement of tumor cell (TC) adhesion to endothelial cells (ECs). Exposure of EA hyb 926 cells to TNF (500 U/ml) plus IFN (100 U/ml) for 24 h significantly enhanced their adhesivity for the 51Cr-labeled GLC1 (small cell lung carcinoma) TCs. Conversely, exposure of TCs to cytokines did not result in an increased adhesion of these cells to ECs. TC-stimulated adhesion to EA hyb 926 was abrogated by the glucocorticoid dexamethasone (Dex, 10(-7) M), the NO synthase inhibitors N omega-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) and NG-monomethyl-L-arginine (L-NMMA, 10(-5) M) and the protein synthesis inhibitor cycloheximide (Cex, 10(-6) M). Furthermore, GLC1-stimulated adhesion to EA hyb 926 was reversed following removal of L-arginine from the medium or pretreatment with the guanylate cyclase inhibitor methylene blue. TC-stimulated adhesion was also prevented when TCs were pretreated with the monoclonal antibody CD15 directed against the endothelial-leukocyte adhesion molecule (ELAM-1) ligand or following exposure of ECs to anti-ELAM-1 monoclonal antibody. Although suppressing TC-stimulated adhesion, L-NMMA failed to modify significantly cytokine-induced ELAM-1 expression in EA hyb 926. These results (a) provide evidence for the NO-inducible pathway contributing to cytokine-induced enhancement of tumor cell adhesion to the vascular endothelium and (b) demonstrate the involvement of the ELAM-1/CD15 adhesion system in tumor cell-stimulated adhesion to ECs.
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PMID:Involvement of nitric oxide in tumor cell adhesion to cytokine-activated endothelial cells. 128 56

Cytokines have been implicated as immunological effector molecules that induce dysfunction and destruction of the pancreatic beta-cell. The mechanisms of cytokine action on the beta-cell are unknown; however, nitric oxide, resulting from cytokine-induced expression of nitric oxide synthase, has been implicated as the cellular effector molecule mediating beta-cell dysfunction. Nitric oxide is a free radical that targets intracellular iron-containing enzymes, which results in the loss of their function. The cytokine IL-1 beta induces the formation of nitric oxide in isolated rat islets and the insulinoma cell line, Rin-m5F. NMMA and NAME, both inhibitors of nitric oxide synthase, completely protect islets from the deleterious effects of IL-1 beta. These inhibitors are competitive in nature and inhibit both the cytokine-inducible and constitutive isoforms of nitric oxide synthase with nearly identical kinetics. This may preclude their use as therapeutic agents because of increases in blood pressure which result from the inhibition of constitutive nitric oxide synthase activity. Aminoguanidine, an inhibitor of nonenzymatic glycosylation of cellular and extracellular constituents associated with diabetic complications, recently has been reported to inhibit nitric oxide synthase. Aminoguanidine is approximately 40-fold more effective in inhibiting the inducible isoform of nitric oxide synthase, suggesting that aminoguanidine or analogues may serve as potential therapeutic agents to block diseases associated with nitric oxide production by the inducible isoform of nitric oxide synthase. In vivo administration of TNF IL-1 has been shown to induce anti-diabetogenic effects in the NOD mouse. This anti-diabetogenic effect of cytokines appears to conflict with evidence suggesting that cytokines mediate beta-cell dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. 137 15

1. We have investigated whether glibenclamide, an inhibitor of ATP-sensitive potassium channels, influences the induction of the calcium-independent isoform of nitric oxide synthase (iNOS) in cultured J774.2 macrophages activated by bacterial endotoxin (E.coli lipopolysaccharide; LPS), as well as in the lung and aorta of rats with endotoxic shock. 2. Pretreatment of J774.2 macrophages with glibenclamide (10(-7) to 10(-5) M for 30 min) dose-dependently inhibited the accumulation of nitrite caused by LPS (1 microgram ml-1). In contrast, pretreatment of macrophages with tetraethylammonium (10(-4) to 10(-2) M for 30 min), a non-selective inhibitor of potassium channels, did not affect the rise in nitrite caused by LPS. At the highest concentration (10(-5) M) used, cromakalim, an opener of ATP-sensitive potassium channels, caused a small, but significant inhibition of nitrite formation in macrophages activated with LPS, while lower concentrations (10(-7) to 3 x 10(-6) M) were without effect. 3. The inhibition by glibenclamide (3 microM) of the increase in nitrite induced by LPS in J774.2 macrophages was weaker when glibenclamide was given several hours after LPS, indicating that glibenclamide inhibits the induction, but not the activity, of iNOS. In contrast, the degree of inhibition of nitrite formation caused by the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was similar when this agent was given up to 10 h after LPS. 4.In anaesthetized rats, LPS caused a fall in mean arterial blood pressure (MAP) from 120 +/-(time 0)to 98 +/- mmHg at 180 min (P<0.05, n = 6). Treatment of LPS-rats with glibenclamide (1 mg kg-1, i.v.at 60 min after LPS) caused a rapid and sustained rise in MAP (e.g. MAP at 180 min after LPS:122 +/-4 mmHg; n =6, P <0.05 when compared to LPS-rats). The maximum of the rise in MAP produced by glibenclamide (1 mg kg-1 , i.v.) was similar when the drug was given either at 60 or 180 min after LPS. However, the duration of the pressor response was significantly longer when glibenclamide was given at 60 min, rather than at 180 min after LPS.5. LPS-treatment caused a significant reduction of the pressor responses elicited by noradrenaline (NA,1 microg kg-1, i.v.) from 35 +/- 2 to 19 +/- 1 mmHg at 60 min and 20 +/- 2 mmHg at 180 min (P<0.05).Treatment of LPS-rats with glibenclamide (1 mg kg-1, i.v. at 60 min) caused a significant restoration of the pressor responses elicited by NA from 19 +/- 1 mmHg at 60 min (prior to glibenclamide injection) to 29 +/- 3 mmHg at 180 min (P<0.05).6. Endotoxaemia for 180 min resulted in a significant increase in a calcium-independent NOS activity(which was taken to represent iNOS activity) in the lung from 0.17 +/- 0.1 (control, n =4) to 6.21 +/- 0.48 pmol mg-1 min-1 (n =6, P<0.05). Injection of glibenclamide (1 mg kg-1, i.v.) at 60 min after LPS attenuated the increase in iNOS activity caused by endotoxaemia in the lung by 43 +/- 7%(n = 6, P <0.05). In contrast, injection of glibenclamide at 180 min after LPS did not result in a significant inhibition of iNOS activity (n = 6, P <0.05. 7. Thoracic aortae obtained from rats at 180 min after LPS showed a significant reduction in the contractions elicited by noradrenaline (NA, 10-9 to 10-6 M). Treatment of LPS-rats with glibenclamide(1 mg kg-1, i.v. at 60 min after LPS) significantly alleviated this LPS-induced hyporeactivity to NA ex vivo. In contrast, when aortic rings from LPS-rats were incubated in vitro with glibenclamide (10 microM for 20 min), glibenclamide did not reverse the vascular hyporeactivity to NA. However, L-NAME (300 microM for 20 min) significantly enhanced the contractile response to NA in aortic rings obtained from LPS-rats(P<0.05, n=6).8. No significant amounts of tumour necrosis factor-alpha (TNF alpha) were detectable in the plasma before the injection of LPS. Endotoxaemia for 90 min resulted in a significant rise in plasma TNFalpha levels(0.05 +/- 0.05 ng ml-1 at time 0, 3.78 +/- 0.24 ng ml-1 at 90 min, n = 6, P < 0.05). Treatment of LPS-rats with glibenclamide (1 mg kg-1, i.v. at 15 min prior to LPS, n = 5) did not significantly reduce the rise in plasma TNF alpha levels caused by endotoxin.9. Thus, glibenclamide inhibits the induction, but not the activity, of iNOS in vitro and in vivo. This inhibition of iNOS induction may contribute to the beneficial haemodynamic effects of glibenclamide in endotoxic shock.
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PMID:Glibenclamide-induced inhibition of the expression of inducible nitric oxide synthase in cultured macrophages and in the anaesthetized rat. 754 32

The regulatory signals required to induce the production of IL-8, an important neutrophil chemoattractant and activator, have yet to be clearly defined. We examined the role of nitric oxide (NO) in IL-8 regulation. The NO synthase inhibitor, (L)-NG-nitroarginine methyl ester (L-NAME), inhibited the TNF-stimulated IL-8 production in the human endothelial cell line, ECV304, in a dose-dependent manner without affecting cellular viability (TNF alone, 5.5 +/- 0.9 ng/ml; TNF + 5 mM L-NAME, 2.4 +/- 0.5 ng/ml). Moreover, exogenously added NO produced by the spontaneous NO generating compounds, S-Nitroso-N-acetyl-D,L-pennicillamine (SNAP) and Ethanamine, 2,2'-(hydroxynitrosohydrazono)bis- (DETA NONOate), induced a dose-dependent release of IL-8 from these cells. Maximal stimulation of IL-8 was found to be 1.2 +/- 0.1 ng/ml with the 1 mM concentration of SNAP and 1.6 +/- 0.1 ng/ml with the 2 mM concentration of DETA NONOate. These results provide key evidence substantiating a regulatory role of NO in IL-8 expression.
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PMID:Nitric oxide regulation of IL-8 expression in human endothelial cells. 779 82

Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism and that some of these changes occur via the nitric oxide pathway.
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PMID:Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. 788 56

1. Drinking was induced in rats by 24 h of water deprivation. Water intake (ml) was evaluated for a 1 h period. 2. NG-nitro-L-arginine methyl ester (L-NAME, 5-10 micrograms, i.c.v., 50-100 ng into the preoptic area (POA)), an inhibitor of nitric oxide (NO) synthase, and methylene blue (50-100 ng into POA), an inhibitor of guanylate cyclase activation, antagonized the inhibition of drinking induced by E. coli endotoxin (LPS, 640 micrograms kg-1, i.v.) and tumour necrosis factor (TNF alpha, 40 ng, i.c.v.) in 24 h water-deprived rats. 3. L-Arginine (25, 50 and 100 ng), the precursor amino acid of NO, but not the stereoisomer D-arginine (100 ng), inhibited drinking induced by water deprivation when injected into the POA 30 min before water presentation (74.4% of inhibition with the highest dose). A dose of 12.5 ng L-arginine into the POA did not exhibit antidipsogenic effects. 4. TNF alpha (20 and 40 ng, i.c.v.; 1.25, 2.5 and 5 ng into the POA) showed a dose-dependent and powerful inhibition of drinking behaviour in water-deprived rats (70.4% and 80.8%, i.c.v. and into POA, with the highest doses, respectively). A dose of 10 ng of TNF alpha given i.c.v. had no effect on the intake of water. 5. LPS and TNF alpha, given at doses (160 micrograms kg-1, i.v. and 10 ng, i.c.v., respectively) that did not influence drinking in water-deprived rats, exhibited a strong antidipsogenic effect in water-deprived rats treated with a dose of L-arginine (12.5 ng, into the POA) which did not modify drinking by itself. (LPS + L-arginine:53.6% of inhibition; TNFalpha + L-arginine: 52.0% of inhibition).6. These results suggest that NO into the POA: (1) acts as an inhibitory mechanism on thirst and (2)plays a role in the antidipsogenic effect of LPS and TNFalpha.
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PMID:Mediation by nitric oxide formation in the preoptic area of endotoxin and tumour necrosis factor-induced inhibition of water intake in the rat. 803 19

This study shows that human ramified microglial cells derived from fetal brain primary cultures, are able to produce nitric oxide (NO). In fact, stimulation with Escherichia coli lipopolysaccharide (LPS) (1 microgram ml-1) or tumor necrosis factor alpha (TNF alpha) (500 U ml-1) enhances nitrite release in cell supernatants, as determined by the Griess reaction. A synergistic effect is achieved following treatment with LPS plus TNF alpha, this effect being inhibited by pretreating cells with NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Using reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis, we also found that LPS/TNF alpha produce an increase of inducible NO synthase (iNOS) mRNA expression.
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PMID:Human ramified microglial cells produce nitric oxide upon Escherichia coli lipopolysaccharide and tumor necrosis factor alpha stimulation. 861 65

Nitric oxide synthase (NOS) isoenzymes generate nitric oxide (NO), a sensitive multifunctional intercellular signal molecule. High NO levels are produced by an inducible NOS (iNOS) in activated macrophages in response to proinflammatory agents, many of which also regulate local bone metabolism. NO is a potent inhibitor of osteoclast bone resorption, whereas inhibitors of NOS promote bone resorption both in vitro and in vivo. The possibility that osteoclasts, like macrophages, express a regulated iNOS and produce NO as a potential autocrine signal following inflammatory stimulation was investigated in well-characterized avian marrow-derived osteoclast-like cells. NO production (reflected by medium nitrite levels) was markedly elevated in these cells by the proinflammatory agents lipopolysaccharide (LPS) and the synergistic action of IL-1 alpha, TNF alpha, and IFN gama. inhibitors of NOS activity (aminoguanidine, L-NAME) or iNOS induction (dexamethasone, TGF beta) reduced LPS-stimulated nitrite production. LPS also increased the NOS-associated diaphorase activity of these cells and their reactivity with anti-iNOS antibodies. RT-PCR cloning, using avian osteoclast-like cell RNA and human iNOS primers, yielded a novel 900 bp cDNA with high sequence homology (76%) to human, rat, and mouse iNOS genes. In probing osteoclast-like cell RNA with the PCR-derived iNOS cDNA, a 4.8 kb mRNA species was detected whose levels were greatly increased by LPS. Induction of iNOS mRNA by LPS, or by proinflammatory cytokines, occurred prior to the rise of medium nitrite in time course studies and was diminished by dexamethasone. Moreover, osteoclast-like cells demonstrated an upregulation of NO production and iNOS mRNA by IL-8 and IL-10, regulatory mechanism's not previously described. It is concluded that osteoclast-like cells express a novel iNOS that is upregulated by inflammatory mediators, leading to NO production. Therefore, NO may serve as both a paracrine and autocrine signal for modulating osteoclast bone resorption.
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PMID:Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells. 870 87

Hyperglycemia is considered to induce diabetic nephropathy through nonenzymatic glycation of proteins. Since hyperfiltration is likely to be the mechanism initiating the glomerular lesions, we investigated the effects of Amadori glucose adducts in serum albumin on the production of vasoactive mediators, including nitric oxide (NO) and eicosanoids, by endothelial cells (EC). Amadori adducts of glycated albumin induced a dose-response increase in NO synthase activity of murine endothelioma cells, up to 16.4 +/- 2.1-fold increase of basal values (P < 0.0001) at concentrations of 35 mg/ml mimicking physiological serum albumin concentration, and 4.6 +/- 0.8-fold increase at 17 mg/ml (P < 0.001). The effect was still detectable with glycated albumin 1.7 mg/ml, which approaches its estimated concentration in diabetic serum (1.6 +/- 0.3-fold increase, P < 0.05) The phenomenon was reproducible in human umbilical vein endothelial cells, though to a lesser extent, and further studies on murine EC were employed. The mRNA encoding for inducible NO synthase was overexpressed in EC incubated with Amadori adducts of glycated albumin in comparison to native albumin. Glycated albumin induced increased mRNA expression and synthesis of TNF-alpha. The stimulatory effect induced by glycated albumin on NO synthase activity was almost completely inhibited by anti TNF alpha antibodies. 3H-thymidine incorporation by EC was significantly inhibited when cells were grown in presence of glycated albumin (P < 0.001), and the phenomenon was abolished by the coincubation of the NO competitive inhibitor L-NAME. The early glycosylation products increased thromboxane production (P < 0.001), while prostaglandin E2 synthesis was unaffected. These data indicate that Amadori products of glycated albumin modulate NO synthase activity and eicosanoid balance in EC. These effects may be relevant to the hemodynamic changes in the early phases of diabetic nephropathy and in the lasting progression to sclerosis.
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PMID:Nonenzymatically glycated albumin (Amadori adducts) enhances nitric oxide synthase activity and gene expression in endothelial cells. 899 14

Gonadal function is known to be controlled by many factors, including locally acting cytokines like tumor necrosis factor alpha (TNF alpha). One of the ways this cytokine acts is via the nitric oxide (NO)-cGMP pathway. Since we have shown that in the ovary theca cells are a target of TNF alpha's action, it was of interest to determine whether TNF alpha stimulates the NO-cGMP pathway in these cells and whether such a mechanism can be implicated in the observed TNF alpha-mediated inhibition of LH-stimulated prorenin synthesis and secretion. Treatment of isolated theca cells with TNF alpha resulted in a dose- and time-dependent increase in cGMP production. This increase was not detectable until 6 h after the addition of TNF alpha and was totally abolished by the protein synthesis inhibitor cycloheximide. Addition of either L-N6-nitroarginine methyl ester (L-NAME), an inhibitor of all three NO synthase (NOS) isoforms or 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of the inducible isoform of the enzyme, likewise reversed the action of TNF alpha on cGMP formation. Finally, addition of 1H-[1,2,4]oxadiazolo [4,3-a] quinoxalin 1-one (ODQ), an inhibitor of NO-sensitive soluble guanylate cyclase, resulted in a concentration-dependent reduction of TNF alpha-stimulated cGMP formation. In contrast, the TNF alpha-mediated inhibition of LH-stimulated prorenin secretion was not affected by either L-NAME, AMT, or ODQ. Also the addition of stimulators of soluble guanylate cyclase, sodium nitroprusside, and S-nitroso-N-acetylpenicillamine, or 8 bromo-cGMP had no effect on the action of LH on theca cells. We conclude that although TNF alpha is able to stimulate cGMP formation in theca cells by inducing the expression of inducible NOS, the mechanism underlying the TNF alpha-mediated inhibition of LH-stimulated prorenin production is independent of its ability to induce cGMP formation.
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PMID:Stimulation of nitric oxide-cyclic guanosine monophosphate pathway in bovine ovarian theca cells by tumor necrosis factor alpha (TNF alpha). Is this pathway implicated in the TNF alpha-induced inhibition of luteinizing hormone-stimulated prorenin production? 931 69


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