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)

1. Ethanol inhibits inducible nitric oxide synthase (iNOS) expression in C6 glioma cells by an unknown mechanism. Because relatively high concentrations are needed for inhibition in drug-naive cells (IC50 approximately = to 150 mM), suppression due to cytotoxicity is one possible mechanism that has not been ruled out. Therefore, the present study examined the effects of ethanol and other alkanols on C6 glioma cell viability and iNOS activity to better understand the mechanism for inhibition. 2. iNOS expression was induced in cell culture with lipopolysaccharide and phorbol ester treatment. Nitrite accumulation in culture medium, the in vitro conversion of [3H]-L-arginine to [3H]-L-citrulline, and immunoblotting were used to quantify iNOS induction and activity. Trypan blue exclusion, extracellular release of lactate dehydrogenase, and quantity of total cell protein were used as measures of viability. 3. Short chain alkanols, methanol through 1-heptanol, concentration-dependently inhibited nitrite accumulation. Longer chain alkanols, 1-octanol and 1-decanol, did not except at cytotoxic concentrations. Experiments indicated short chain alkanol inhibition was not due to direct actions on iNOS catalytic activity, but that it transpires during iNOS induction. Immunoblots showed reduced iNOS protein levels. 4. Correlation analysis ruled out iNOS inhibition as being due to decreased cell number, total cell protein, or cell viability. In contrast, there was significant correlation with physical measures of lipophilicity. 5. In conclusion, inhibition of iNOS expression by ethanol and other short chain alkanols is not due to cytotoxicity. Instead, the strong correlation with lipophilicity suggests the inhibition derives from an interaction with unknown hydrophobic cellular sites.
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PMID:Effects of short chain alkanols on the inducible nitric oxide synthase in a glial cell line. 1020 16

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) modulates production of proinflammatory cytokines in brain tissue and in peripheral inflammatory cells. Transcription of the genes for these proinflammatory cytokines is regulated by the nuclear factor kappaB (NF-kappaB). NF-kappaB is also activated by proinflammatory cytokines. Degradation of the cytoplasmic inhibitor IkappaBalpha protein results in activation of NF-kappaB. Because of increasing evidence that NF-kappaB is involved in brain injury and inflammation and neurodegenerative disease, we examined whether alpha-MSH inhibits activation of NF-kappaB and limits degradation of IkappaBalpha protein induced by lipopolysaccharide (LPS) in human glioma cells (A-172) and in mouse brain. Electrophoretic mobility shift assays of nuclear extracts from A-172 cells and whole mouse brains stimulated with LPS revealed that alpha-MSH does suppress NF-kappaB activation. Western blot analysis demonstrated that alpha-MSH preserved expression of IkappaBalpha protein in vitro (glioma cells) and in vivo (brain tissue). Chloramphenicol acetyltransferase assay indicated that alpha-MSH suppresses NF-kappaB-dependent reporter gene expression induced by LPS in A-172 cells. The findings are consistent with the possibility that the anti-inflammatory action of alpha-MSH in CNS inflammation occurs via modulation of NF-kappaB activation by peptide-induced inhibition of degradation of IkappaBalpha protein.
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PMID:alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaBalpha degradation in human glioma cells and in experimental brain inflammation. 1036 47

1 The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) or tumour necrosis factor-alpha/interleukin-1beta/IFN-gamma (TNF-alpha/IL-1beta/IFN-gamma, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated. 2 Treatment with LPS/IFN-gamma and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 microM abrogated the LPS/IFN-gamma- and mixed cytokines-mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines-induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2-10 microM) was concentration-dependent. 3 The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase-polymerase chain reaction. 4 Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor-kappaB (NF-kappaB). Results showed that nepalolide A diminished the LPS/IFN-gamma-mediated association of NF-kappaB with consensus oligonucleotide in a concentration-dependent manner. The activation of NF-kappaB by mixed cytokines was modulated both in the extent of activation and in its time-course by nepalolide A. 5 The ability of nepalolide A to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB, as measured by immunoblotting. 6 The present study demonstrates that the attenuation of NF-kappaB activation by nepalolide A was mediated by blockade of the degradation of IkappaB, leading to suppression of the expression of iNOS.
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PMID:Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IkappaB-alpha and IkappaB-beta in C6 glioma cells and rat primary astrocytes. 1051 Apr 44

Malignant rat T9 glioma cells retrovirally transduced with the membrane form of macrophage colony stimulating factor (mM-CSF) were killed by bone marrow derived macrophages in 24 h cytotoxicity assays. Prostaglandin E2 (PGE) and interleukin-10 (IL10) were tested for their ability to block this tumoricidal reaction. Only at very high nonphysiological concentrations of PGE (10(-5) and 10(-6) M) was this cytotoxicity inhibited. Use of high doses of theophylline, a phosphodiesterase inhibitor, also prevented macrophages from killing the mM-CSF transduced target cells. IL10 did not alter the killing potential of the mM-CSF tumoricidal macrophages, even though IL10 reduced the production of nitric oxide by macrophages in response to tumor necrosis factor and lipopolysaccharide. IL10 enhanced the growth of bone marrow macrophages suggesting that IL10 has a complex role in the regulation of tumoricidal macrophages. Thus, the mM-CSF may be an ideal agent to treat tumors that utilize either of these two immunosuppressive defense mechanisms that may block other forms of treatment.
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PMID:Macrophages that kill glioma cells expressing the membrane form of macrophage colony stimulating factor are resistant to prostaglandin E2 and interleukin-10. 1054 Oct 53

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) modulates inflammation by inhibiting production of proinflammatory cytokines. Using a plasmid vector encoding alpha-MSH, we examined whether autocrine alpha-MSH inhibits activation of the nuclear transcription factor NF-kappaB, a factor that is essential to expression of proinflammatory cytokines, in human glioma cells (A-172). Electrophoretic mobility shift assays of nuclear extracts demonstrated that NF-kappaB activation induced by lipopolysaccharide was inhibited in glioma cells transfected with alpha-MSH vector. Western blot analysis revealed that this inhibition was linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase assay indicated that NF-kappaB-dependent reporter gene expression was suppressed in A-172 cells transfected with alpha-MSH vector. Finally, fluorescence staining confirmed that A-172 cells bear alpha-MSH receptors. The findings are consistent with the idea that, in central nervous system (CNS) inflammation, autocrine alpha-MSH exerts anti-inflammatory actions via modulation of NF-kappaB activation by preservation of IkappaBalpha protein. Based on this action of the peptide, it should be possible to treat neurodegenerative disease, stroke, encephalitis, trauma, and other CNS disorders that have an inflammatory component through gene therapy with alpha-MSH vector.
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PMID:Autocrine alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation in human glioma. 1056 96

P11 cells, derived from the transplantahle rat pituitary tumor 7315a, have been used previously ias a model system to study the regulation of serotonin2A (5-HT2A) receptor expression. As our laboratory has been interested in characterizing the interactions between the 5-HT2A receptor and inducible nitric oxide synthase (iNOS), we have analyzed the Pl I cell line for iNOS expression. Treatment of P ll cells with interferon-gamma and lipopolysaccharide resulted in a 23-fold increase in nitrite production and induced expression of iNOS protein. The increase in nitrite levels was attenuated by the non-selective nitric oxide synthase (NOS) inhibitor N i-nitro-L-arginine methyl ester, hut not the neuronal NOS inhibitor 7-nitroindazole. Typically, Pl 11 cells have been grown in either charcoal-stripped or dialyzed serum-containing medium. We have observed that Pl 1 cells grown under these culture conditions express basal iNOS activity, as evidenced by a 5-fold increase in nitrite accumulation over a 48-hr period, compared with that in cells grown in non-modified serum, which was inhibited by the selective iNOS inhibitor L.N6-(1-iminoethyl)-lysine. Conditioned medium from Pll cells was ahle to stimulate nitrite accumulation in C6 glioma cells, suggesting that the Pl I cells may produce a pro-inflammatory-like factor. As pro-inflammatory cytokines have been shown to modify hormone secretion from the anterior pituitary, the P11 cell line may be a useful in vitro model by which to characterize the function of cells from this organ. In addition, our data suggest that alteration of the microenvironment of the anterior pituitary may result in iNOS expression, possibly altering the function of the hypothalamic-pituitary-adrenal axis.
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PMID:Inducible nitric oxide synthase in P11 cells: expression in the presence of interferon-gamma, lipopolysaccharide, and modified serum. 1066 Jan 17

Sodium valproate (VPA) is frequently used to treat epilepsy and convulsive disorders. Several reports have indicated that anti-epileptic drugs (AED) affect the immune system, but the mechanism has not been clear. We examined whether the commonly used AEDs, diazepam (DZP), carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and VPA, can inhibit activation of the nuclear transcription factor kappa B (NF-kappaB), in human monocytic leukemia cells (THP-1) and in human glioma cells (A-172). NF-kappaB is essential to the expression of the kappa light chain of immunoglobulin and proinflammatory cytokines. Electrophoretic mobility shift assays (EMSA) of nuclear extracts demonstrated that VPA inhibits NF-kappaB activation induced by lipopolysaccharide (LPS), but the other AEDs do not. Western blot analysis revealed that this inhibition is not linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase (CAT) assay indicated that NF-kappaB-dependent reporter gene expression is suppressed in glioma cells pretreated with VPA. VPA significantly inhibited LPS-induced production of TNF-alpha and IL-6 by THP-1 cells, whereas other AEDs did not. The findings are consistent with the idea that VPA suppresses TNF-alpha and IL-6 production via inhibition of NF-kappaB activation. Our results suggest that VPA can modulate immune responses in vitro. These findings raise the possibility that such modulation might occur with clinical use of VPA.
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PMID:Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. 1070 May 73

The production of superoxide and nitric oxide induced in U87 glioma treated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was examined by electron spin resonance (ESR) spectroscopy using a newly designed flow-type quartz cuvette without detaching cells from the culture plate. ESR spectra of 2,2,6, 6-tetramethyl-4-hydroxy-1-piperidinyloxy (TEMPOL) with U87 cells on a quartz culture plate were measured at 15 min intervals. The signal intensity of TEMPOL decreased in the presence of U87 cells at the pseudo-first order rate. The signal decay was accelerated in the U87 cells treated with LPS/IFN-gamma for 24 h, and was suppressed in the presence of superoxide dismutase and catalase. By the spin-trapping method, nitric oxide from U87 cells pretreated with LPS/IFN-gamma for 24 h was measured by the ESR, but only a weak signal of nitric oxide adducts was detected. Further, the nitrite and nitrate levels in the medium did not increase for 24 h. By the ESR measurement of cells on culture plates without detachment stress, it was found that the production of superoxide was induced by LPS/IFN-gamma, but that of nitric oxide was not, in U87 glioma cells.
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PMID:Induction of superoxide in glioma cell line U87 stimulated with lipopolysaccharide and interferon-gamma: ESR using a new flow-type quartz cell. 1076 20

Clonidine, clinically used in the treatment of hypertension, is a central alpha(2)-adrenergic agonist that reduces blood pressure and slows heart rate by reducing sympathetic stimulation. Considering the structural similarity between clonidine and hydrophobic heterocyclic nitric oxide synthase (NOS) inhibitors, the effect of clonidine on the nitric oxide (NO) pathway was investigated. This was verified by determination of NOS activity in vitro and by analysis of inducible Ca(2+)-independent NOS (NOS-II) mRNA expression and measurement of nitrite levels in rat C6 glioma cells, taken as a cellular model. Clonidine inactivated neuronal Ca(2+)-dependent NOS (NOS-I) competitively without affecting NOS-II and endothelial Ca(2+)-dependent NOS (NOS-III) activity. However, the value of K(i) for clonidine binding to NOS-I depended on tetrahydrobiopterin (BH(4)) concentration, as reported for NOS inhibition by other nitrogen heterocyclic compounds. In particular, the value of K(i) for clonidine binding to NOS-I increased (from [7. 9 +/- 0.4] x 10(-5) M to [8.0 +/- 0.4] x 10(-3) M) as BH(4) concentration was increased (between 3.0 x 10(-7) M and 1.0 x 10(-3) M), at pH 7.5 and 37.0 degrees. In addition, clonidine (1.0 x 10(-4) M) enhanced NOS-II mRNA expression in rat C6 glioma cells, as induced by Escherichia coli lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). Finally, clonidine (1.0 x 10(-4) M to 1.0 x 10(-3) M) dose dependently increased the levels of LPS/IFN-gamma-induced nitrites, the breakdown product of NO, in supernatants of rat C6 glioma cells. As reported for other NOS inhibitors, clonidine was also able to regulate NOS-I and NOS-II inversely.
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PMID:Selective inhibition of nitric oxide synthase type I by clonidine, an anti-hypertensive drug. 1087 28

The effect of lipopolysaccharide (LPS) on the expression of immediate early genes, such as c-fos and c-jun, was examined in C6 rat glioma cells. LPS (1 microg/ml) alone did not affect c-fos mRNA level. LPS, however, transiently increased c-jun mRNA level. Cycloheximide (CHX, 20 microM), a protein synthesis inhibitor, alone caused increases of c-fos and c-jun mRNA levels. LPS showed a potentiating effect in the regulation of c-fos mRNA level, whereas LPS showed an additive action for the regulation of CHX-induced c-jun mRNA expression. To determine if CREB and mitogen-activated protein kinases (MAPKs) are involved in the regulation of c-fos mRNA expression by LPS and CHX, Western blot was carried out using the phosphorylated form of antibodies against ERK, JNK, p38, and CREB. LPS transiently increased the phosphorylation of p38-MAPK and CREB. In addition, LPS alone elevated phosphorylation of ERK (p44/p42) MAPK in a time-dependent manner. Furthermore, LPS plus CHX enhanced phosphorylation of ERK, p38, and CREB in a synergistic manner. Our results suggest that the phosphorylation of ERK, p38, and CREB may be involved in the regulation of synergistic c-fos mRNA expression induced by LPS plus CHX in C6 rat glioma cells.
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PMID:Regulation of c-fos gene expression by lipopolysaccharide and cycloheximide in C6 rat glioma cells. 1092 99


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