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: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(6R)-5,6,7,8-Tetrahydrobiopterin (BH4), which is synthesized intracellularly from GTP, caused a concentration-dependent increase in rat pheochromocytoma (PC12) cell proliferation when added exogenously. Incubation with sepiapterin, which is converted enzymatically to BH4 within cells, also increased PC12 cell proliferation and BH4 levels concomitantly. These sepiapterin effects were mediated by BH4 as inhibition of sepiapterin conversion to BH4 by a sepiapterin reductase inhibitor, N-acetyl-serotonin, blocked the increase in proliferation and the elevation of BH4 levels. 7,8-Dihydrobiopterin (BH2) also increased BH4 levels and PC12 cell proliferation, both of which were reversed by methotrexate, which blocks the conversion of BH2 to BH4 by dihydrofolate reductase. The BH4-induced increase in PC12 cell proliferation was not related to elevated catecholamine or nitric oxide synthesis as inhibitors of tyrosine hydroxylase or nitric oxide synthase did not reduce the BH4 effect. BH4 and its precursors did not alter intracellular cAMP levels, suggesting that this second messenger is not involved in the enhancement of PC12 cell proliferation by BH4. Sepiapterin and BH4 also enhanced the proliferation of SV40-transformed human fibroblasts and rat C6 glioma cells, indicating that the stimulatory effect of BH4 on cell proliferation is not restricted to PC12 cells.
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PMID:Mitogenic effects of tetrahydrobiopterin in PC12 cells. 856

NBXFO hybridoma cells produced both the membrane and secreted isoforms of macrophage colony-stimulating factor (M-CSF). Murine bone marrow cells stimulated by the secreted form of M-CSF (sM-CSF) became Mac1+, Mac2+, Mac3+, and F4/80+ macrophages that inhibited the growth of NBXFO cells, but not L1210 or P815 tumor cells. In cytotoxicity studies, M-CSF activated macrophages and freshly isolated macrophages killed NBXFO cells in the presence of polymyxin B, eliminating the possibility that contaminating lipopolysaccharide (LPS) was responsible for the delivery of the cytotoxic signal. Retroviral-mediated transfection of T9 glioma cells with the gene for the membrane isoform of M-CSF (mM-CSF), but not for the secreted isoform of M-CSF, transferred the ability of macrophages to kill these transfected T9 cells in a mM-CSF dose-dependent manner. Macrophage-mediated killing of the mM-CSF transfected clone was blocked by using a 100-fold excess of recombinant M-CSF. Catalase, superoxide dismutase, and the nitric oxide inhibitor, N-omega-nitro-arginine methyl ester (NAME), did not effect macrophage cytotoxicity against the mM-CSF transfectant T9 clones. T9 parental cells when cultured in the presence of an equal number of the mM-CSF transfectant cells were not killed, indicating specific target cell cytotoxicity by the macrophages. Electron microscopy showed that macrophages were capable of phagocytosizing mM-CSF bearing T9 tumor cells and NBXFO hybridoma cells; this suggested a possible mechanism of this cytotoxicity. This study indicates that mM-CSF provides the necessary binding and triggering molecules through which macrophages can initiate direct tumor cell cytotoxicity.
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PMID:Macrophages can recognize and kill tumor cells bearing the membrane isoform of macrophage colony-stimulating factor. 865 38

The actions of an intracellular nitric oxide generator compound on the properties of a co-culture model of the blood-brain barrier are described. Addition of the iron-sulphur cluster nitrosyl Roussin's black salt (RBS, heptanitrosyl-tri-mu3-thioxotetraferrate (1-)) resulted in a rapid and dose-dependent (50-250 microM) decline in the electrical resistance displayed by co-cultures of vascular endothelial cells and C6 glioma cells. The breach in barrier integrity elicited by RBS (250 microM) could be prevented by either haemoglobin (100 microM), methylene blue (200 microM), or by photon-induced inactivation of RBS. In contrast, the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (250 microM) caused no inhibition in the decline in resistance of RBS-exposed cultures. Addition of 8-bromo-guanosine-cyclic monophosphate (500 microM) did not mimic the actions of RBS. Exposure to intense light of co-cultures manifesting a high transcellular electrical resistance resulted in a reduction in tissue resistance which could be prevented by the presence of haemoglobin (100 microM). We conclude that nitric oxide liberated from RBS results in a reversible diminution in the integrity of the endothelial cell barrier in the co-culture system, and we suggest that light-sensitive endogenous nitric oxide generator compounds may be present in intact cells. Possible roles of nitric oxide in blood-brain-barrier function are considered.
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PMID:Nitric oxide-induced perturbations in a cell culture model of the blood-brain barrier. 869 45

Serotonin (5-HT)-2 receptor-mediated cGMP generation was investigated in comparison with calcium (Ca2+) mobilization in C6 glioma cells. 5-HT enhanced cGMP generation, and risperidone and ketanserin potently blocked the response. These results indicate that 5-HT-2 receptors are responsible for the cGMP generation. 5-HT-induced cGMP production was completely abolished by BAPTA, an intracellular Ca2+ chelating agent, or NG-mono-methyl-L-arginine(NMMA), a nitric oxide synthase (NOS) inhibitor, suggesting that 5-HT-induced cGMP generation was through nitric oxide (NO)-dependent pathway. 5-HT (10 microM)-elicited Ca2+ mobilization and cGMP generation were reduced to 40 and 15% after pretreatment with 10 microM 5-HT for 4 hours. NMMA did not modify 5-HT-induced desensitization of either Ca2+ mobilization or cGMP generation, suggesting that NO pathway is independent of the desensitization. The present study has demonstrated the nature of 5-HT-2 receptor-mediated cGMP generation in C6 glioma cells.
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PMID:Cyclic GMP generation mediated by 5-HT-2 receptors via nitric oxide-dependent pathway and its effect on the desensitization of 5-HT-2 receptors in C6 glioma cells. 874 61

Nitric oxide (NO), a free radical gas implicated in a wide variety of biological reactions, is a novel signaling molecule that may regulate vasodilation, cerebral blood flow, and vascular permeability. This study was performed to determine whether NO mediates the selective increase in brain tumor microvessel permeability after intracarotid infusion of bradykinin in the RG2 rat glioma model. Intracarotid infusion of bradykinin selectively increased the transport of radiolabeled alpha-aminoisobutyric acid and dextran into brain tumors. Transport into normal brain was not increased. The administration of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester, significantly inhibited the increased transport into tumors for both tracers. The inhibitory effect of NG-nitro-L-arginine methyl ester on the response to bradykinin was reversed by L-arginine. The expression of two NO synthase (NOS) isoforms in cultured RG2 glioma cell lines and intracerebral RG2 glioma was examined by immunohistochemistry and Western blot analysis. High levels of expression of neuronal NOS were detected in cultured and intracerebral RG2 cells but not in normal brain tissue, except in rare neuronal cells. The endothelial form of NOS was also expressed in cultured RG2 cells, but not as strongly as neuronal NOS expression. In intracerebral RG2 gliomas, expression of endothelial NOS in the tumor was detected at higher levels than in normal brain. These findings indicate that RG2 rat gliomas express high levels of NOS, which regulate the production of NO, compared with normal brain. We suggest that the selective permeability increase in brain tumor microvessels after bradykinin infusion is mediated by NO. Furthermore, the absence of high levels of NOS in normal brain may account for the attenuated permeability response to bradykinin in normal brain microvessels.
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PMID:Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide. 875 74

Type III nitric oxide synthase (type III NOS), also known as endothelial cell nitric oxide synthase (eNOS or ecNOS or NOS-3), is a constitutively expressed, calcium- and calmodulin-dependent, isoform of NOS. Its expression has been localized to endothelial cells and a subset of neurons in the brain. We report here that resident astrocytes of the central nervous system (CNS) of mice express type III NOS. Following an experimental neurotropic viral infection, the expression of type III NOS on reactive astrocytes increases substantially, predominantly in virally infected regions of the brain. This upregulation of type III NOS expression is also evident following cytokine treatment in vitro. The intraperitoneal (i.p.) administration of IL-12, a potent activator of IFN-gamma and TNF-alpha production, results in a substantial increase in type III NOS immunoreactivity in astrocytes. Cytokine-mediated activation of type III NOS is observed in vitro following exposure of a C6 glioma cells, which constitutively express type III NOS, to IL-12, IFN-gamma, and TNF-alpha treatment. We conclude that astrocytes of the murine CNS express type III NOS, which may be positively regulated by a number of cytokines following viral infection. Type III NOS expression by astrocytes represents a novel source of nitric oxide in the brain. It may be important in regulating perfusion and maintaining the blood-brain barrier. Given the intimate association of astrocytes with endothelial cells and neurons, increased activity of type III NOS following viral infection may be beneficial in inhibition of viral infection in neighboring cells.
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PMID:Activation of type III nitric oxide synthase in astrocytes following a neurotropic viral infection. 880 68

The presence and the possibility of induction of argininosuccinate synthetase in a glial cell line were investigated. For this purpose, antisera were produced against peptides representing partial sequences 196-222 and 337-349, respectively, of the mouse liver enzyme. Both antisera were shown to be monospecific for argininosuccinate synthetase. In Western blot experiments, immunoreactivity was found in mouse liver and brain homogenates. Only weak immunoreactivity was detectable in homogenates of cultured glioma cells, C6-BU-1. However, when the glioma cells were treated with either bacterial lipopolysaccharide, interferon-gamma, or a combination of both, argininosuccinate synthetase immunoreactivity was increased. The findings demonstrate that this enzyme is present in glial cells and is induced under conditions which stimulate persistent production of nitric oxide. The antisera will be a valuable tool for further investigations on arginine synthesis in brain as well as peripheral cells.
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PMID:Presence of argininosuccinate synthetase in glial cells as revealed by peptide-specific antisera. 904 64

In C6 glioma cells, the nitric oxide (NO) donor 3-morpholinosynonimine hydrochloride (SIN-1) (0.5 mM) produced a significant decrease in the stimulatory G-protein alpha subunit (G alpha(s)) levels. Northern hydridization did not detect any differences in G alpha(s) mRNA levels after SIN-1 treatment. Furthermore SIN-1 increased endogenous and cholera toxin-catalyzed ADP-ribosylation of G alpha(s). 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) (0.5mM), a NO scavenger, had no effect on endogenous or cholera toxin-catalyzed ADP-ribosylation of G alpha(s), but reversed the increase in endogenous and cholera toxin-catalyzed ADP-ribosylation of G alpha(s) induced by SIN-1. These results suggest that increasing ADP-ribosylation may be involved in SIN-1 mediated G alpha(s) down-regulation.
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PMID:Nitric oxide donor SIN-1 mediated down-regulation of the G-protein alpha-subunit in C6 glioma cells. 909 45

The N-methyl-D-aspartate (NMDA) receptor has been reported to be important in synaptic plasticity, neuronal development, normal brain function and neurologic disease. We have recently shown that PC12W cells, a subclone of rat pheochromocytoma PC12 cell line, release nitric oxide (NO), as measured by in vitro spin-trapping combined with electron paramagnetic resonance (EPR) spectroscopy, when challenged with NMDA [Norby, S.W., Weyhenmeyer, J.A. and Clarkson, R.B., Stimulation and inhibition of NO production in macrophages and neuronal cells as observed by spin trapping, Free Rad. Biol. Med., 22 (1997) 1-9]. In the present study, we provide immunochemical evidence for the expression of both the NMDAR1 and NMDAR2A/B receptor subunits in PC12W cells, that express only the angiotensin type-2 (AT2) receptor subtype, and in NG108-15 (NG108) cells, a murine neuroblastoma x glioma hybrid that expresses both the angiotensin type-1 (AT1) and AT2 receptor subtypes. We also show that treatment of PC12W cells with angiotensin (Ang II) decreases NMDA-induced NO release by 28.0 +/- 4.2%, and that this response can be attenuated by pre-treating the cells with the isoform-specific AT2 antagonist, PD 123319. Interestingly, there was no effect on cGMP accumulation in PC12W cells treated with NMDA. Similar experiments were carried out using NG108 cells since the binding properties and functional characteristics of their NMDA receptors have been previously described [Ohkuma, S., Katsura, M., Chen, D., Chen, S. and Kuriyama, K., Presence of N-methyl-D-aspartate (NMDA) receptors in neuroblastoma x glioma hybrid NG 108-15 cells-analysis using 45Ca2+ influx and [3H]MK-801 binding as functional measures, Mol. Brain Res. 22 (1994) 166-172]. Our results show that NG108 cells significantly increase cGMP levels when challenged with NMDA (21.2 +/- 5.0% over control levels), and that this response can be attenuated by the addition of angiotensin (57.1 +/- 6.2% of stimulated levels). The effect of angiotensin on NMDA-mediated changes in cGMP levels was blocked by the AT2 antagonist, PD 123319, but was not significantly changed by the addition of the AT1 antagonist, losartan. Further, Ang II action on NMDA signalling in NG108 cells was completely inhibited by the addition of both the AT1 and AT2 antagonists. Taken together, these results suggest that AngII inhibits NMDA-mediated NO and cGMP production through a mechanism involving the AT2 receptor subtype.
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PMID:Angiotensin II type-2 (AT2) receptor-mediated inhibition of NMDA receptor signalling in neuronal cells. 933 16

C6-glioma cells endogenously express both 5HT2A receptors and inducible nitric oxide synthase (iNOS). iNOS can be induced by transcriptional activation to produce nitric oxide (NO) in response to a challenge with lipopolysaccharide (LPS). Experiments were conducted to determine whether 5HT2A receptor activation could modify the production of NO in response to LPS. Incubation of 10 microg/ml LPS with C6-glioma cells for a period of 24 hours resulted in a 2.6 fold increase in nitrite levels, as a measure of NO levels, over vehicle treated controls. Co-incubation with the selective 5HT2A receptor partial agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) produced a dose-dependent inhibition of the LPS-induced nitrite levels of 22% with an IC50 of 16 nM. The full agonists serotonin (5HT) and alpha-methyl-5HT produced an inhibition of approximately 30% at a concentration of 1 microM. The inhibitory effect of 1 microM DOI was blocked by the 5HT2A receptor antagonists spiperone and ritanserin (10 nM). Inhibition of protein kinase C (PKC) using 100 nM chelerythrine prevented the DOI-mediated decrease in LPS-induced nitrite levels. Addition of DOI to the cells after 1 hr following the LPS addition did not produce a decrease in nitrite levels indicating iNOS was not modified post-translationally. The data demonstrate that iNOS activity can be modulated by serotonin 5HT2A receptor activation, most likely at the initiation of the induction process, via PKC. We therefore suggest that there may be a link between the serotonergic system and NO-mediated immune responses in the brain.
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PMID:Serotonin 5HT2A receptor activation inhibits inducible nitric oxide synthase activity in C6 glioma cells. 936 29


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