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)

We have previously shown that rat astrocytes undergo apoptosis upon inflammatory activation. Nitric oxide (NO) produced by activated astrocytes was the major cytotoxic mediator in this type of autoregulatory apoptosis. However, an inhibitor of nitric oxide synthase did not completely block the apoptosis of activated astrocytes, suggesting the presence of other apoptotic pathways. Here, we present evidence that caspase-11 is an essential molecule in NO-independent apoptotic pathway of activated astrocytes. Inflammatory activation (lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha treatment) of rat astrocyte cultures and C6 glioma cells led to the induction of caspase-11 followed by activation of caspases-11, -1, and -3. In contrast, NO donors induced activation of caspase-3 only. Inactivation of caspase-11 by the transfection of dominant negative mutant or treatment with the caspase inhibitors rendered the astrocytes partially resistant to the apoptosis following inflammatory activation, but not NO donor exposure. These results indicate that inflammatory stimuli not only induce the production of cytotoxic NO, but also initiate NO-independent apoptotic pathway through the induction of caspase-11 expression.
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PMID:Essential role of caspase-11 in activation-induced cell death of rat astrocytes. 1190 13

The neurotransmitter norepinephrine (NE) can inhibit inflammatory gene expression in glial cells; however, the mechanisms involved are not clear. In primary astrocytes, NE dose-dependently increased the expression of inhibitory I kappa B alpha protein accompanied by an increase in steady state levels of I kappa B alpha mRNA. Maximal increases were observed at 30-60 min for the mRNA and at 4 h for protein, and these effects were mediated by NE binding to beta-adrenergic receptors. NE activated a 1.3-kilobase I kappa B alpha promoter transfected into astrocytes or C6 glioma cells, and this activation was prevented by a beta-antagonist and by protein kinase A inhibitors but not by an NF kappa B inhibitor. NE increased I kappa B alpha protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of I kappa B alpha. I kappa B alpha was detected in the frontal cortex of normal adult rats, and its levels were reduced if central NE levels were depleted by lesion of the locus ceruleus. The reduction of brain I kappa B alpha levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that I kappa B alpha expression is regulated by NE at both transcriptional and post-transcriptional levels, which could contribute to the observed anti-inflammatory properties of NE in vitro and in vivo.
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PMID:Norepinephrine increases I kappa B alpha expression in astrocytes. 1205 Jan 58

Macrophages play an important role in the regulation of malignant tumors. Although glioma contains abundance of macrophages, their role in apoptosis of glioma is not known. We stimulated macrophages with lipopolysaccharide and culture supernatants of activated macrophages were collected to treat glioma cells. The results showed that molecules released from activated macrophages significantly increased apoptosis of glioma via Fas/FasL and caspase-3 pathways. The level of soluble Fas did not appear to be involved in the mechanism responsible for apoptosis seen in this study, as its level was barely detected in both experimental and control groups. Two cytokines, TNFalpha and IFNgamma, were significantly elevated in the supernatant obtained from the activated macrophages. Considering an important role of these two molecules in the induction of apoptosis mediated by the Fas/FasL system, the present data suggested that TNFalpha and IFNgamma were the main molecules to trigger the cascade of apoptotic reactions in glioma cells. In conclusion, the present study indicates that molecules released from the activated macrophages provide significant signals to stimulate the expression of Fas/FasL and caspase-3, which function to induce apoptosis in glioma cells.
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PMID:Induction of apoptosis in glioma cells by molecules released from activated macrophages. 1212 80

The regulation of matrix metalloproteinase-9 (MMP-9) expression in glioma cells is one of the key processes in tumor invasion through the brain extracellular matrix. Although some studies have demonstrated the implication of classic protein kinase C (PKC) isoforms in the regulation of MMP-9 production by phorbol esters or lipopolysaccharide, the involvement of specific PKC isoforms in the signaling pathways leading to MMP-9 expression by inflammatory cytokines remains unclear. Here we report that the atypical PKC-zeta isoform participates in the induction of MMP-9 expression by interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in rat C6 glioma cells. Indeed, zymography and semi-quantitative reverse transcriptase-PCR analysis showed that pretreatment of C6 cells with PKC-zeta pseudosubstrate abolished MMP-9 activity and gene expression induced by IL-1 or TNF-alpha. Accordingly, IL-1 and TNF-alpha were able to induce PKC-zeta activity, as demonstrated by in vitro kinase assay using immunoprecipitated PKC-zeta. Furthermore, stable C6 clones overexpressing PKC-zeta, but not PKC-epsilon, displayed an up-regulation of MMP-9 constitutive expression as well as an increase of mmp-9 promoter activity. These processes were inhibited by an NF-kappaB-blocking peptide and completely prevented by NF-kappaB-binding site mutation in the mmp-9 promoter. Taken together, these results indicate that PKC-zeta plays a key role in the regulation of MMP-9 expression in C6 glioma cells through NF-kappaB.
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PMID:Protein kinase C-zeta regulates transcription of the matrix metalloproteinase-9 gene induced by IL-1 and TNF-alpha in glioma cells via NF-kappa B. 1213 Jun 32

Cell membrane dielectric properties of five different cultivated cell lines and human peripheral blood mononuclear cells (PBMC) were determined from dielectrophoretic crossover frequency measurements on a 5 x 5 microelectronic chip array. Based on distinct dielectric property differences between individual cell types, efficient cell separations were achieved by dielectrophoresis on this 5 x 5 array, which included separation of monocytic cells (U937) or human T cell leukemia virus type 1 (HTLV-1) tax-transformed cells (Ind-2) from PBMC, as well as separation of neuroblastoma cells (SH-SY5Y) from glioma cells (HTB). The purity of dielectrophoretically separated cells can be greater than 95%. Expression profiles of IL-1, TNF-alpha, and TGF-beta genes for U937 cells mixed with PBMC before and after the separation were determined by a means of electric field-facilitated hybridization on a 10 x 10 microelectronic chip array. By using the expression levels of pure U937 cells as a control, it was shown that the gene expression profiles of the postseparation cells were significantly different from those of the preseparation cell mixtures. The increase in gene expression levels for U937 cells upon lipopolysaccharide induction could be accurately determined only in the postseparation cells, while the preseparation samples masked these changes. Furthermore, by cultivating the separated HTB and SH-SY5Y cells and measuring expression of the stress-related gene c-fos, dielectrophoretic forces were shown to have little effect on cell survival and stress. The presented approach of using microelectronic chip arrays for both cell separation and gene expression profiling provides a great potential for accurate genetic analysis of specific cell subpopulations in heterogeneous samples.
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PMID:Dielectrophoretic cell separation and gene expression profiling on microelectronic chip arrays. 1213 41

We investigated whether glioma cells affected the maturation of dendritic cells (DCs). First, DCs phenotypes were analyzed using FACScan. Incubation of both human and mouse immature DCs with glioma cells altered their expression of cell surface molecules, whereas expression of cell surface molecules by mature mouse and human DCs was not affected by exposure to glioma cells. Subsequently, phagositosis was assessed by uptake of FITC-dextran. Coculture with glioma cells did not inhibit phagositosis of either mature or immature DCs relative to the controls. We also analyzed the concentration of IL-12 secreted by mature DCs using enzyme-linked immunoabsorbent assay (ELISA). IL- 12 production by DCs was inhibited by coculture with glioma cells. However, stimulation with lipopolysaccharide restored the production of IL- 12 by both human and mouse DCs. These data suggest that glioma cells suppress the maturation of DCs.
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PMID:Effects of glioma cells on maturation of dendritic cells. 1216 83

Neurological injury and Parkinson disease (PD) are often associated with the increase of nitric oxide (NO) and free radicals from resident glial cells in the brain. In vitro, exposure to L-3-4-dihydroxyphenylalanine (L-DOPA), one of the main therapeutic agents for the treatment of PD, can lead to neurotoxicity. In this study, lipopolysaccharide (LPS) and interferon-gamma (IFN-g) were used to stimulate C6 glioma cells in the presence of varying concentrations of L-DOPA (1 microM-1 mM). The results indicated a slight augmentation of NO(2)(-) production at low concentrations of L-DOPA (<100 microM) and complete inhibition of NO(2)(-) at higher concentrations (500 microM, 1 mM), (p < 0.001). Western blot analysis corroborated that L-DOPA effects on iNOS was at the level of its protein expression. Total reactive oxygen species (ROS) were detected using 2', 7'-dichlorofluorescein diacetate fluorescence dye (2', 7'-DCFC) and there was an increase of intensity with the increasing concentrations of L-DOPA. Furthermore, large amounts of superoxide (O(2)(-)) and hydrogen peroxide (H(2)O(2)) were generated from the autoxidation of L-DOPA. C6 cells contain high levels of catalase, with inadequate levels of superoxide dismutase (SOD); therefore, there was an accumulation of O(2)(-), tantamount to elevation in 2'7'-DCFC intensity. Simultaneous accumulation of O(2)(-) and NO(2)(-) would propel formation of peroxynitrite (ONOO-). SOD completely attenuated the autoxidation of L-DOPA and significantly reversed the inhibitory effects on iNOS at high concentrations. The data obtained confirmed that the observed effects on iNOS were not due to the activation of the D(1) or beta1 adrenergic receptors by L-DOPA. It was concluded from this study that L-DOPA contributed to the modulation of iNOS and to the increase of O(2)(-) production in the stimulated glioma cells in vitro.
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PMID:Levodopa modulating effects of inducible nitric oxide synthase and reactive oxygen species in glioma cells. 1241 52

Inducible nitric oxide synthase (iNOS) plays a significant role in the pathology of central nervous system diseases. Inducible NOS expression is regulated by intracellular adenosine 3',5'-cyclic monophosphate (cAMP) signaling, and astrocytes contain both iNOS and adenylate cyclase-coupled neurotransmitter receptors. The data obtained from the present study indicated that acetylcholine, lambda-amino-n-butyric acid, glutamate, quinolinic acid, N-methyl-D-aspartate and aspartate have no effect on NO(2)(-) production in C6 glioma cells stimulated by lipopolysaccharide and interferon-gamma. However, dopamine (DA) caused inhibition of NO(2)(-) production and iNOS transcription. The effects of DA were not due to homovanillic acid/3,4-dihydroxyphenylacetic acid, the autoxidative products superoxide (O(2)(-))/hydrogen peroxide (H(2)O(2)) or direct reactions with NO(2)(-). Forskolin, adenylate cyclase activator, dose-dependently reduced NO(2)(-). Meanwhile, (+/-) SKF-38393 D(1) receptor agonist attenuated iNOS in a similar fashion to DA. In addition, the results indicated that DA attenuation of iNOS was significantly impeded by the adenylate cyclase inhibitor MDL-12,330A, the D(1) antagonist SCH-23390, the beta2 adrenergic receptor antagonist ICI-118,551 and the beta1 adrenergic receptor antagonist atenolol. In conclusion, it appears that DA attenuates iNOS through a D(1), beta1 and beta2 adrenergic receptor-linked adenylate cyclase-mediated cAMP cascade.
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PMID:Characterization of neurotransmitters and dopamine attenuation of inducible nitric oxide synthase in glioma cells. 1245 38

The synthetic glucocorticoid dexamethasone is routinely used to stabilize patients with malignant gliomas. One putative target for glucocorticoid action is inducible nitric oxide synthase (iNOS), which is produced by the tumor cells as well as the host immune cells. In this study, we characterize the stimulatory effects of lipopolysaccharide (LPS) and the cytokine, tumor necrosis factor-alpha (TNFalpha), as well as the inhibitory effect of glucocorticoids, on iNOS gene expression and activity in C6 glioma cells cultured in vitro. LPS significantly increased iNOS mRNA expression, peaking at 6 h, while nitrite formation increased with time up to 72 h. Although TNFalpha alone induced neither iNOS mRNA expression nor nitrite formation, it significantly potentiated the effect of LPS on both. iNOS activity induced by LPS with or without TNFalpha was dose-dependently inhibited by dexamethasone, reaching a maximum of approximately 83% inhibition. This was completely reversed by the addition of RU38486, an antagonist of glucocorticoid receptors (GR). Dexamethasone inhibited iNOS mRNA expression; however, the maximum inhibition obtained was only 10%. These results suggest that as for induction of iNOS activity in C6 cells in vitro, the stimulatory effect of LPS is mainly due to an action at the transcriptional level. TNFalpha does not have intrinsic inducing activity, but has potentiating effects at the transcriptional and possibly at the posttranscriptional levels in the presence of LPS. The inhibitory effect of dexamethasone is GR-mediated and is mainly due to action at the posttranscriptional level.
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PMID:Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and activity in C6 glioma cells. 1259 38

Heightened monoamine oxidase (MAO) and inducible nitric oxide synthase (iNOS) activity can contribute to oxidative stress, the formation of active neurotoxins, and associated neurodegenerative diseases of the brain. Although these enzymes co-exist within astrocytes, there has been little research examining the correlation between the two during inflammation. In this study, C6 glioma cells were stimulated with lipopolysaccharide (LPS):Escherichia coli 0111:B4 (6 micro g/mL):rat interferon-gamma (IFN-gamma) (100U/mL). In LPS/IFN-gamma-treated cells, the MAO substrates dopamine (DA) and tyramine caused a concentration-dependent attenuation of NO(2)(-) and NO(3)(-). In contrast, treatment with an MAO-A inhibitor (clorgyline) or an MAO-B inhibitor ((-)-deprenyl) did not reverse these effects. MAO activity was inhibited effectively by clorgyline and deprenyl; however, neither MAO inhibitor had an effect on NO(2)(-) in stimulated cells. Inversely, increasing concentrations of LPS/IFN-gamma resulted in heightened iNOS protein expression and NO(2)(-); however, these events did not correlate with any distinctive change in MAO enzyme activity. Moreover, a selective iNOS inhibitor, N(6)-(1-iminoethyl)-L-lysine, in LPS/IFN-gamma-stimulated cells caused a concentration-dependent attenuation of NO(2)(-) with no effects on MAO activity or iNOS protein expression. The attenuating effects of DA on iNOS were blocked completely by ICI 118-551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride], indicating a role for the beta(2)-adrenergic receptor. In conclusion, these data indicate that activity or expression of iNOS does not influence MAO activity in activated rat glioma cells. Moreover, DA exerts an inhibitory effect on glial iNOS through a receptor-mediated cascade.
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PMID:Inflammation and inducible nitric oxide synthase have no effect on monoamine oxidase activity in glioma cells. 1275 8


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