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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possibility that 5,6,7,8-tetrahydrobiopterin (BH4) biosynthesis is stimulated in glial cells by treatment with lipopolysaccharide (LPS) and tumor necrosis factor (TNF-alpha) was examined in the astrocyte-derived C6 glioma cell line. Under basal culture conditions BH4 levels were found to be at the limit of detection. Concurrent treatment with 10 micrograms/ml LPS and 50 ng/ml TNF-alpha caused a time-dependent 13-fold increase in the levels of BH4. This treatment paradigm also induced nitric oxide synthase activity, as evidenced by increased levels of nitrite, an oxidized metabolite of NO, in the culture medium. LPS and TNF-alpha treatment led to a 25-fold increase in GTPCH enzyme activity, the first and rate-limiting enzyme in BH4 synthesis, and a corresponding 23-fold increase in GTPCH protein levels. Northern blot analysis showed that increased levels of GTPCH mRNA preceded changes in GTPCH protein, GTPCH enzyme activity and BH4 levels and reached a maximal of 44-fold that was sustained for at least 48 h. These results demonstrate that LPS and TNF-alpha stimulate de-novo BH4 biosynthesis and suggest that C6 cells offer a model system for studying the molecular events that control the induction of GTPCH gene expression and BH4 synthesis in glial cells.
Brain Res Mol Brain Res 1996 Sep 05
PMID:Tetrahydrobiopterin biosynthesis in C6 glioma cells: induction of GTP cyclohydrolase I gene expression by lipopolysaccharide and cytokine treatment. 888 40

We have already demonstrated the presence of antibodies in the sera of chagasic patients with the ability to interact with neurotransmitter receptors triggering several intracellular pathways of transduction signals. Here we show that, chagasic IgG induced protein kinase C (PKC) translocation to rat cardiac membranes and this effect was inhibited by muscarinic cholinergic blockers atropine and AF-DX 116 pointing to the participation of M2 receptors in this effect. It was also able to stimulate nitric oxide synthase (NOS) activity and this action was blunted by phospholipase C (PLC) and PKC inhibitors indicating that the production of nitric oxide (NO) would be the consequence of the cascade of enzymatic pathways triggered by mAChR activation. PKC and NOS activities were involved in chagasic IgG negative inotropic actions on rat isolated myocardium as its effects were blunted by staurosporine and L-N-monomethyl arginine. Furthermore, low concentrations of chagasic IgG inhibited the cardiac mechanical action of carbachol in a non-competitive manner. These data suggested that PKC activation in myocardium by chagasic IgG would be involved in its physiological actions by modulating NOS activity. The participation of PKC-mediated phosphorylation of mAChR leading to receptor desensitization as one of the causes of dysautonomia is also discussed.
Mol Cell Biochem
PMID:Involvement of nitric oxide synthase and protein kinase C activation on chagasic antibodies action upon cardiac contractility. 890 58

The report deals with the induction of the inducible form of nitric oxide synthase (iNOS) in infarcted heart muscle of rabbit and man. In the rabbit, nitric oxide synthase was significantly increased in the infarcted area beginning on the third day following ligation of a coronary artery. iNOS induction occurred primarily in macrophages. In man, iNOS immunoreactivity was also primarily localized in macrophages on the seventh day following death from myocardial infarction. Of the specific inhibitors of iNOS in infarcted heart muscle, S-methylisothiourea (SMT) was the most potent. Its greatest effect occurred in the normal non-affected area of the heart. Dexamethasone and cyclosporin A failed to inhibit iNOS. Apoptosis of macrophages commenced two days following ligation of a coronary artery.
Mol Cell Biochem
PMID:Myocardial infarction and nitric oxide. 890 87

Nitric oxide (NO) is an endogenous protectant against reperfusion-induced ventricular fibrillation (VF) in the rat isolated heart. Here, the following were investigated: (1) the tissue source of cardioprotective NO using a novel inhibitor (7-nitro indazole; 7-NI) of the neuronal form of NO synthase (NOS) and direct detection of coronary effluent NO by chemiluminescence; and (2) the species dependence by comparing rat and rabbit hearts. Perfusion with modified Krebs solution was followed by 60 min left regional ischemia and 10 min reperfusion. 7-NI (1 microM) increased the incidence of VF from 0% to 60% in rat hearts (n = 10; P < 0.05). Co-perfusion with L-arginine (1 mM) reduced VF incidence to 20% (P:N.S. v controls). The inactive analog of 7-NI (6-amino indazole: 6-AI) had no pro-fibrillatory activity. Neither 7-NI nor 6-AI affected coronary flow or recovery of flow during reperfusion. 7-NI reduced basal coronary effluent NO levels to below the limit of detection (< 1 pmol), but a massive increase in NO levels occurred when L-arginine was co-perfused with 7-NI. Although 7-NI had no effect on basal coronary flow and, by implication, resting NO release, it was found, in separate studies, to antagonise substance P-induced vasodilatation and NO release, suggesting that its neuronal selectivity is lost in the presence of an exogenously administered activator of endothelial NOS in rat hearts. In rabbit hearts, in contrast, 7-NI had no effect on VF or NO levels. However, in rabbit hearts the isozyme non-selective NO synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), increased VF incidence from 0 to 50% (P < 0.05) and, during the first minute of reperfusion, reduced NO levels from 4929 +/- 893 to 2505 +/- 483 pmol/min/g (P < 0.05) and recovery of coronary flow by 22% (P < 0.05). Each of these effects were prevented by L-arginine co-perfusion. These data indicate a role for basally released NO as an endogenous antifibrillatory cardioprotectant in rat and rabbit isolated heart and indicate that the tissue source (neuronal in rat but not in rabbit heart) is species-dependent.
J Mol Cell Cardiol 1996 Oct
PMID:Endogenous protection against reperfusion-induced ventricular fibrillation: role of neuronal versus non-neuronal sources of nitric oxide and species dependence in the rat versus rabbit isolated heart. 893 Aug 5

Nitric oxide (NO), the free radical that accounts for the biological activity of endothelium-derived relaxing factor, is synthesized from L-arginine by NO synthase (NOS). There is evidence that NO availability is reduced in the peripheral vasculature of patients with congestive heart failure (CHF). The aim of this study was to investigate the expression of NOS in the descending aorta and in the skeletal muscles of rats subjected to heart failure. The alkaloid, monocrotaline, was used to induce pulmonary hypertension and cardiac failure in rats. The expression of both the constitutive (ecNOS) and the inducible (iNOS) isoforms of the enzyme was assessed by Western blot analysis. In CHF animals, the ecNOS location in the aorta is altered: the endothelial protein expression is substantially reduced (from 0.083 +/- 0.012 to 0.003 +/- 0.004 OD/microgram total proteins, P < 0.001) whereas the expression of ecNOS in the smooth muscle is increased (from 0.024 +/- 0.004 to 0.059 +/- 0.009 OD/ microgram total proteins, P < 0.01). The total aortic ecNOS is diminished in CHF respect to control animals (0.062 +/- 0.009 v 0.107 +/- 0.013 OD/microgram total proteins, P < 0.01). On the contrary, no difference in ecNOS protein expression was observed in the extensor digitorum longus and soleus muscles. Furthermore, iNOS was not detected in any of the tissues considered. In conclusion, experimental CHF causes a re-setting of the ecNOS protein expression in the descending aorta but not in skeletal muscles. The reduced abundance of ecNOS in the aortic endothelium is consistent with the impairment of the vasodilating function reported in patients with CHF.
J Mol Cell Cardiol 1996 Nov
PMID:Aorta and skeletal muscle NO synthase expression in experimental heart failure. 893 77

The survival of mast cells are dependent on two kinds of growth factors, one derived from T cells (IL-3) and another derived from fibroblasts (stem cell factor [SCF]). The 3T3 fibroblast cell line derived from WCB6F(1-)+/+ mouse embryos (+/+ 3T3 fibroblasts) supported the proliferation of bone marrow-derived cultured mast cells (BMCMC) in the PWM-stimulated spleen cell conditioned medium (PWM-SCM), whereas the 3T3 fibroblast cell line from WCB6F1-Sl/Sld mouse embryos (Sl/Sld 3T3 fibroblasts) did not. To study the role of nitric oxide (NO) on the growth of mast cells in BMCMC-fibroblast coculture, we used a NO synthase inhibitor, NG-monomethyl-L-arginine (NGMMA). NGMMA recovered survival and maintained proliferation of mast cells in BMCMC-Sl/Sld 3T3 fibroblasts coculture. Sl/Sld 3T3 fibroblasts as well as 3T3 fibroblasts from NIH(-)+/+, BALB(-)+/+ or Swiss(-)+/+ mouse embryos secreted NO in PWM-SCM, but not in alpha-MEM. SCF protected BMCMC from cytotoxicity of exogenous NO in IL-3-supplemented alpha-MEM. We concluded that SCF might protect BMCMC from cytocidal effect of NO in BMCMC-fibroblasts coculture.
Biochem Mol Biol Int 1996 Nov
PMID:Stem cell factor protects bone marrow-derived cultured mast cells (BMCMC) from cytocidal effect of nitric oxide secreted by fibroblasts in murine BMCMC-fibroblast coculture. 895 30

The effect of cycloheximide (CHX) on the gene expression for inducible NO synthase (iNOS), interferon (IFN)-beta, and IFN regulatory factor (IRF)-1 was examined in LPS-stimulated J774 macrophages. LPS caused increased expression of mRNAs specific for iNOS, IFN-beta, and IRF-1 with different kinetics. Addition of CHX resulted in inhibition of the LPS-induced iNOS gene expression and parallel decrease in NO production. In contrast, expression of IFN-beta and IRF-1 genes in response to LPS was potentiated in the presence of CHX. These results indicate that de novo protein synthesis is not required for IFN-beta and IRF-1 gene expression and that ongoing protein synthesis including IFN-beta and IRF-1 may be involved in the induction process of iNOS in mouse macrophages.
Biochem Mol Biol Int 1996 Nov
PMID:Effect of cycloheximide on the expression of LPS-inducible iNOS, IFN-beta, and IRF-1 genes in J774 macrophages. 895 77

Human peripheral blood monocytes are permissive for the growth of Mycobacterium bovis (BCG), but the fate of nonpathogenic Mycobacterium bovis in these cells is not clearly known. Both oxidative and nonoxidative pathways have been implicated in killing of intracellular mycobacteria. Since human monocytes are not so far confirmed to release Reaction Nitrogen Intermediates (RNI), we tried indirect approach to inhibit the production of NO by the addition of NG-monomethyl-L-arginine (LNMMA)-an NO synthase blocker, in the infected cell cultures. In our studies adherent human peripheral blood monocytes were found to be permissive for the growth of Mycobacterium bovis, as measured by [3H] uridine uptake and confirmed by Colony Forming Unit (CFU) estimate. The killing of Mycobacterium bovis was not blocked by LNMMA, suggesting that it was not due to the production of Reactive Nitrogen Intermediates. Culture of the monocyte-derived macrophages for 1 to 14 days before infection had no effect on the fate of Mycobacterium bovis, and no nitric oxide was detected in the culture supernatants of these infected cell cultures. Graded doses of sodium nitrite at physiological concentrations however failed to affect cell free cultures of Mycobacterium bovis. These findings suggest that the addition of NG-monomethyl-L-arginine (LNMMA), an antagonist of L-arginine oxidation and inhibitor of NO production, had no effect on the fate of Mycobacterium bovis in human monocytes and macrophages.
Biochem Mol Biol Int 1996 Nov
PMID:The effect of NG-monomethyl-L-arginine(LNMMA), an NO-synthase blocker on the survival of intracellular BCG within human monocyte-derived macrophages. 895 94

Nitric oxide (NO) has been proposed as a neuronal messenger molecule in hypoxic/ischemic cell injury (Nowicki et al., 1991; Trifiletti, 1992). We conducted studies in a model of combined glucose-oxygen deprivation using cultured rat cerebellar granule cells. Experiments were designed to test the hypothesis that sustained elevation of cytosolic calcium ([Ca2+]i) and NO generation act in concert to trigger neuronal injury after anoxic insult. A hypoxic state was achieved by perfusing the cells with medium pre-equilibrated with argon gas. [Ca2+]i was monitored using digital-imaging fluorescence microscopy in cells loaded with fura-2 AM. Under short-term hypoxic conditions, cells displayed a progressive and sustained, moderate increase of [Ca2+]i, which returned to near basal levels on restoration of O2-containing medium. Prolonged hypoxic conditions (> 60 min) caused irreversible elevation of [Ca2+]i followed by disruption of cell membrane integrity, as indicated by severe swelling, loss of regular cell shape and processes, leakage of dye fura-2, and propidium iodide uptake ("point of no return"). Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), a specific NO synthase inhibitor, markedly delayed the onset of intensity of the rise of [Ca2+]i. The hypoxia-induced elevation of [Ca2+]i was also greatly attenuated if L-NAME (100 microM) was added to the argon-perfused medium before the cells demonstrated signs of irreversible injury. Prolonged or repeated hypoxic conditions, however, caused a rapid and intense increase of [Ca2+]i, which could not be blocked by inhibition of NO synthase (NOS). In addition, reoxygenation after the "point of no return," as characterized above, greatly potentiated [Ca2+]i overload and facilitated the process of cell injury. The potentiation and facilitation of cell damage, as demonstrated by rapid massive increase of [Ca2+]i and subsequent cell death, was not blocked by NOS inhibitor, L-NAME.
Mol Chem Neuropathol 1996 Feb
PMID:Involvement of nitric oxide in the deregulation of cytosolic calcium in cerebellar neurons during combined glucose-oxygen deprivation. 896

To evaluate the effects of the in vivo endotoxin treatment of the rat on (1) the contractile responses in the subsequently isolated papillary muscle to adrenergic and cholinergic agonists and (2) the biochemical parameters (cyclic GMP, nitric oxide synthesis, protein phosphorylation and ADP-ribosyslation) in the subsequently isolated cardiomyocytes. Following the in vivo endotoxin treatment (4 mg/kg i.p., 18 h), contractile responses to increasing amounts of isoprenaline or to increasing amounts of oxotremorine in the presence of a fixed amount of isoprenaline were determined in isolated papillary strips. Activities of nitric oxide synthase, guanylyl cyclase, as well as phosphorylation of phospholamban and troponin-inhibitory subunit, and pertussis toxin-catalyzed and endogenous ADP-ribosylations were determined in the intact cardiomyocytes and subcellular fractions. The increase in the force of contraction by isoprenaline was reduced, while its inhibition by oxotremorine was greater in the endotoxin-treated papillary strips. The activities of both nitric oxide synthase, primarily of the inducible form of the enzyme, and cytosolic guanylyl cyclase were higher while the phosphorylations of both phospholamban and troponin-inhibitory subunit were of lesser magnitude in the cardiomyocytes following the in vivo endotoxin treatment. Pertussis toxin-catalyzed ADP-ribosylation of the 41 kDa polypeptide, which is the alpha subunit of Gi, was also decreased. The results of the present study support the postulate that alterations in both the cyclic AMP and cyclic GMP signalling cascade contribute to the myocardial dysfunction caused by endotoxin and cytokines.
Mol Cell Biochem
PMID:Alterations in inotropy, nitric oxide and cyclic GMP synthesis, protein phosphorylation and ADP-ribosylation in the endotoxin-treated rat myocardium and cardiomyocytes. 897 70


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