Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH(4)), a required cofactor for inducible nitric-oxide synthase (iNOS) activity, is usually coordinately regulated with iNOS expression. In C6 glioma cells, tumor necrosis factor-alpha (TNF-alpha) concomitantly potentiated the stimulation of nitric oxide (NO) and BH(4) production induced by IFN-gamma and interleukin-1beta. Expression of both iNOS and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the BH(4) biosynthetic pathway, was also markedly increased, as were their activities and protein levels. Ceramide, a sphingolipid metabolite, may mediate some of the actions of TNF-alpha. Indeed, we found that bacterial sphingomyelinase, which hydrolyzes sphingomyelin and increases endogenous ceramide, or the cell permeable ceramide analogue, C(2)-ceramide, but not C(2)-dihydroceramide (N-acetylsphinganine), significantly mimicked the effects of TNF-alpha on NO production and iNOS expression and activity in C6 cells. Surprisingly, although TNF-alpha increased BH(4) synthesis and GTPCH activity, neither BH(4) nor GTPCH expression was affected by C(2)-ceramide or sphingomyelinase in IFN-gamma- and interleukin-1beta-stimulated cells. It is likely that increased BH(4) levels results from increased GTPCH protein and activity in vivo rather than from reduced turnover of BH(4), because the GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, blocked cytokine-stimulated BH(4) accumulation. Moreover, expression of the GTPCH feedback regulatory protein, which if decreased might increase GTPCH activity, was not affected by TNF-alpha or ceramide. Treatment with the antioxidant pyrrolidine dithiocarbamate, which is known to inhibit NF-kappaB and sphingomyelinase in C6 cells, or with the peptide SN-50, which blocks translocation of NF-kappaB to the nucleus, inhibited TNF-alpha-dependent iNOS mRNA expression without affecting GTPCH mRNA levels. This is the first demonstration that cytokine-stimulated iNOS and GTPCH expression, and therefore NO and BH(4) biosynthesis, may be regulated by discrete pathways. As BH(4) is also a cofactor for the aromatic amino acid hydroxylases, discovery of distinct mechanisms for regulation of BH(4) and NO has important implications for its specific functions.
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PMID:Divergence in regulation of nitric-oxide synthase and its cofactor tetrahydrobiopterin by tumor necrosis factor-alpha. Ceramide potentiates nitric oxide synthesis without affecting GTP cyclohydrolase I activity. 1078 33

The action of copper on the nitric oxide (NO) pathway was investigated in rat C6 glioma cells expressing both inducible and constitutive NO synthase (NOS) isoforms. The inducible NOS-II-mediated NO synthesis (i.e., nitrite production induced by LPS plus IFNgamma) was found to be increased upon copper uptake by cells, this effect being attributable to NOS-II mRNA transcriptional over-expression. On the other hand, the constitutive neuronal isoform (NOS-I) was inhibited after copper uptake, as revealed by the decrease of basal intracellular cGMP levels in C6 cells. Consistently, in vitro experiments showed that copper selectively blocked the catalytic activity of NOS-I, but not of NOS-II. The observed modulation of NOS isoforms by copper in C6 cells is in line with the previous hypothesis that selective inhibition of NOS-I leads to enhanced NO production through transcriptional activation of NOS-II.
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PMID:Modulation of the nitric oxide pathway by copper in glial cells. 1097 98

The present study was aimed at elucidating the effect of cyclosporine on phenylephrine-evoked nitric oxide (NO) production in C6 glioma cells using direct electrochemical NO monitoring. Phenylephrine (0.1-10 microM) dose-dependently stimulated NO production (0.8-12.9 microM) and this was blocked by NO synthase inhibitor, prazosin, Ca2+-depletion and Xestospongin C (a blocker of the inositol 1,4,5-trisphosphate (IP3) receptor), suggesting that the alpha1-adrenoceptor signaling pathway mediates NO production in C6 cells. Cyclosporine (approximately 10 microM) failed to evoke NO production but increased phenylephrine-evoked NO production by 20-120% of phenylephrine alone in a dose-dependent manner (1-5 microM). Xestospongin C, at a concentration which showed no effect on phenylephrine-induced NO production, significantly inhibited the cyclosporine-enhanced phenylephrine response. This finding suggests that cyclosporine may increase phenylephrine-induced NO production by accelerating IP3 receptor function in the alpha1-adrenoceptor signaling pathway in C6 cells. This enhanced NO production in glial cells may be operative for the occurrence of cyclosporine neurotoxicity including convulsions and encephalopathy.
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PMID:Cyclosporine enhances alpha1-adrenoceptor-mediated nitric oxide production in C6 glioma cells. 1106 17

This study has demonstrated the mechanism of protein kinase A (PKA)-dependent inhibition of astrocytic nitric oxide production and inducible NO synthase mRNA expression induced by lipopolysaccharide. In C6 glioma cells, the stimulation with lipopolysaccharide (LPS; 1 microg/ml) evoked increases of nitric oxide (NO) production, NO synthase (iNOS) mRNA expression, phosphorylation of p38 mitogen activated protein kinase (p-p38), and the activation of NF kappa B. LPS-induced NO production and iNOS mRNA expression were inhibited by the pretreatment with forskolin (FSK; 5 microM) in a dose-dependent manner, and which were reversed by PKA inhibition by compound H89. Furthermore, LPS-induced increases of p-p38, but not activation of NF kappa B, were also reduced by FSK and H89 reversed the FSK-induced inhibition response. The dose-dependent inhibition of NO production and iNOS mRNA expression by compound SB203580 (p38 inhibitor) suggests the participation of p38 in PKA-dependent inhibition of LPS-induced NO production and iNOS mRNA expression. However, the activation of NF kappa B by LPS also not affected by SB203580. Therefore, our results suggest that, in C6 glioma cells, LPS-induced NO production and iNOS gene expression may be regulated by PKA pathway through the reduction of activity of p38 kinase. This inhibitory role of PKA may not involve the activation of NF kappa B.
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PMID:Forskolin inhibits expression of inducible nitric oxide synthase mRNA via inhibiting the mitogen activated protein kinase in C6 cells. 1131 70

The biological activities of nitric oxide (NO) include vasodilatation, inhibition of platelet aggregation, neurotransmission, neural plasticity, and modulation of inflammatory and immunological functions. NO synthase (NOS), which is the enzyme that produces NO, has been detected in resected human glioma specimens, and both human and rodent glioma cell lines. NO production in gliomas can alter several important pathophysiological processes, such as local host immune response, tumour cell apoptosis, tumour invasion/metastasis, free radical injury to tumour cells and adjacent normal brain tissues, tonic vasodilatation of tumour vessels, vascular permeability and neovascularization. Recently, some therapeutic strategies for gliomas using NO manipulation have been proposed, and evaluated both experimentally and indirectly in preliminary clinical trials. These include NO manipulation designed to modify tumour cell oncogenesis, tumour blood flow and disposition of anti-cancer drugs in tumour tissue. This review will discuss the biological role of NO in the central nervous system and gliomas and its current and future possibilities in neuro-oncology.
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PMID:Nitric oxide and glioma: a target for novel therapy? 1147 55

The mitogen-activated protein kinase (MAPK) pathway is believed to function as an important mediator of inducible nitric oxide synthase (iNOS) expression. In the present study, we investigated the role of the p38 MAPK signaling pathway in advanced glycosylation end products (AGEs)-induced iNOS expression in C6 glioma cells. AGEs caused a dose-dependent increase of nitrite accumulation in C6 glioma cells. The AGEs-stimulated nitrite production from C6 glioma cells was inhibited by actinomycin D, cyclohexamide, and the NO synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), suggesting that the increase of AGEs-induced nitrite release is due to iNOS up-regulation. Consistently, treatment of C6 glioma cells with AGEs induced iNOS protein expression. AGEs-stimulated nitrite production was inhibited by pretreatment of C6 glioma cells with anti-AGEs antibodies (1:100 or 1:50). The tyrosine kinase inhibitor (genistein and tyrphostin), the Ras-farnesyl transferase inhibitor (FPT inhibitor-II), or the p38 MAPK inhibitor (SB203580) suppressed AGEs-induced iNOS expression and nitrite release from C6 glioma cells. AGEs activated p38 MAPK in C6 glioma cells, and this effect was blocked by genistein (20 microM), tyrphostin (30 microM), FPT inhibitor-II (20 microM), and SB203580 (10 microM). Taken together, our data suggest that AGEs may activate the pathways of tyrosine kinase and Ras to induce p38 MAPK activation, which in turn induces iNOS expression and NO production in C6 glioma cells.
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PMID:Advanced glycosylation end products induce nitric oxide synthase expression in C6 glioma cells: involvement of a p38 MAP kinase-dependent mechanism. 1169 58

In C6 glioma cells, the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase (iNOS) induced by tumor necrosis factor alpha (TNF-alpha) without affecting GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the biosynthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH(4)), a cofactor required for iNOS activity. TNF-alpha also stimulates sphingosine kinase, the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (SPP), a further metabolite of ceramide. Several clones of C6 cells, expressing widely varying levels of sphingosine kinase, were used to examine the role of SPP in regulation of GTPCH and BH(4) biosynthesis. Overexpression of sphingosine kinase, with concomitant increased endogenous SPP levels, potentiated the effect of TNF-alpha on GTPCH expression and activity and BH(4) biosynthesis. In contrast, enforced expression of sphingosine kinase had no effect on iNOS expression or NO formation. Furthermore, N,N-dimethylsphingosine, a potent sphingosine kinase inhibitor, completely eliminated the increased GTPCH activity and expression induced by TNF-alpha. Surprisingly, we found that, although C6 cells can secrete SPP, which is enhanced by TNF-alpha, treatment of C6 cells with exogenous SPP or dihydro-SPP had no affect on BH(4) biosynthesis. However, both SPP and dihydro-SPP markedly stimulated ERK 1/2 in C6 cells, which express cell surface SPP receptors. Interestingly, although this ERK activation was blocked by PD98059, which also reduced cellular proliferation induced by enforced expression of sphingosine kinase, PD98059 had no effect on GTPCH activity. Collectively, these results suggest that only intracellularly generated SPP plays a role in regulation of GTPCH and BH(4) levels.
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PMID:Involvement of sphingosine kinase in TNF-alpha-stimulated tetrahydrobiopterin biosynthesis in C6 glioma cells. 1181 3

Cannabinoids modulate nitric oxide (NO) levels in cells of the central nervous system. Here we studied the effect of cannabinoid CB(1) and CB(2) receptor agonists on the release of NO and cell toxicity induced by the human immuno-deficiency virus-1 Tat protein (HIV-1 Tat) in rat glioma C6 cells. The CB(1) and CB(2) agonist WIN 55,212-2 inhibited the expression of inducible NO synthase (iNOS) and NO release caused by treatment of C6 cells with HIV-1 Tat and interferon-gamma (IFN-gamma). The effect of WIN 55,212-2 was uniquely due to CB(1) receptors, as shown by experiments carried out with selective CB(1) and CB(2) receptor agonists and antagonists. CB(1) receptor stimulation also inhibited HIV-1 Tat + IFN-gamma-induced and NO-mediated cell toxicity. Moreover, cell treatment with HIV-1 Tat + IFN-gamma induced a significant inhibition of CB(1), but not CB(2), receptor expression. This effect was mimicked by the NO donor GSNO, suggesting that the inhibition of CB(1) expression was due to HIV-1 Tat + IFN-gamma-induced NO overexpression. HIV-1 Tat + IFN-gamma treatment also induced a significant inhibition of the uptake of the endocannabinoid anandamide by C6 cells with no effect on anandamide hydrolysis. These findings show that the endocannabinoid system, through the modulation of the l-arginine/NO pathway, reduces HIV-1 Tat-induced cytotoxicity, and is itself regulated by HIV-1 Tat.
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PMID:The endocannabinoid system protects rat glioma cells against HIV-1 Tat protein-induced cytotoxicity. Mechanism and regulation. 1238 47

Nitric oxide (NO) is thought to be a mediator in many of the processes of malignant brain tumor progression. We examined NO production in the brain of normal conscious, freely moving rats with or without implanted C6 glioma. Both nitrite (NO(2)(-)) and nitrate (NO(3)(-)) in the dialysates of the two groups were measured using an in vivo microdialysis technique. The mean concentration of NO(2)(-) in the glioma group was two-times higher than that in the control group (P<0.01). Concentrations of both NO(2)(-) and NO(3)(-) in the glioma and control groups decreased following intraperitoneal injection of N(G)-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NO synthase (NOS). NO production was also significantly suppressed in the glioma group, but not the control group, by intraperitoneal injection of 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a selective inhibitor of inducible NOS (iNOS). On immunohistochemical examination, diffuse iNOS-positive cells were located within glioma tissue. ED1-positive cells (microglia/macrophages) were intermingled between glioma cells on double immunostaining. These results indicate that the basal level of NO production in the glioma group is higher than that in the control group and that the increased NO production was continuously induced by iNOS-expressing cells in glioma.
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PMID:Pathodynamics of nitric oxide production within implanted glioma studied with an in vivo microdialysis technique and immunohistochemistry. 1268 26

Malignant gliomas, most of which show an elevated level of vascular endothelial cell growth factor (VEGF) expression, are well known for their hyper-vascularity. One of the possible inducers of VEGF in tumor cells is nitric oxide (NO), which is synthesized by NO synthase and stimulates soluble guanylate cyclase (GC) in tumor cells. Here, we report that 2 of 9 human glioma cell lines, CCF-STTG1 and U-87MG, overproduced cyclic GMP (cGMP) and showed increased expression of both or either subunits of soluble GC1, GUCY1A3 and GUCY1B3. Transfection of antisense GUCY1A3 or GUCY1B3 into these two glioma cell lines markedly reduced the content of cGMP and expression of VEGF. The angiogenic activity in vitro was subsequently inhibited, which was determined by induction of HUVEC cell growth. Furthermore, subcutaneous tumor formation by U-87MG cells in nude mice was dramatically suppressed to less than 0.05% in volume by transfection of either antisense GUCY1A3 or antisense GUCY1B3, which was accompanied by the significant decrease in vascular index to about 10%. These findings demonstrate that cGMP is an upstream mediator of VEGF expression in glioma cells and that soluble guanylate cyclases could be the target molecules for controlling neo-vascularization in a subset of human malignant gliomas.
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PMID:Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3. 1520 57


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