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)

Glutathione (GSH) is a major antioxidant in the brain and ammonia neurotoxicity is associated with oxidative stress. In this study, we show that intracerebral administration of ammonium chloride ("ammonia", final concentration 5mM) via a microdialysis probe, increases by 80% the glutathione content in cerebral cortical microdialysates, and tends to increase its content in striatal microdialysates. Treatment with ammonia in vitro dose-dependently increased the glutathione content in cultured cerebral cortical astrocytes and a C6 glioma cell line. Significant effects have been observed after 1h (astrocytes) or 3h (C6 cells) of exposure and were sustained up to 72 h of incubation. A gradual decrease of the GSH/GSSG ratio noted during 3 h (astrocytes) or 24 h (C6 cells) of exposure, was followed by an partial recovery after 24 h of incubation, the latter phase possibly reflecting increased availability of de novo synthesized glutathione. In our hands, cystine, the precursor for astrocytic glutathione synthesis, was transported to astrocytes almost exclusively by system X(AG)-, while in C6 cells the transport engaged both system x(c)- (approximately 60% of uptake) and X(AG)- (approximately 40% of uptake). Ammonia in either cell type stimulated cystine uptake without changing the relative contribution of the uptake systems. The results are consistent with the concept of increased astrocytic glutathione synthesis as an adaptive response of the brain to ammonia challenge, and emphasize upregulation of cystine uptake as a factor contributing to this response.
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PMID:Upregulation of cerebral cortical glutathione synthesis by ammonia in vivo and in cultured glial cells: the role of cystine uptake. 1723 89

1H MRS signals of glutathione and of free glutamate were examined in samples from cultured tumour cells, namely MCF-7 from mammary carcinoma and TG98 from malignant glioma, with the aim of relating signal intensities to aspects of GSH metabolism. Spectra of cells harvested at different cell densities suggest that GSH and glu signal intensities are related to cell density and proliferation and their ratio is dependent on the activity of the gamma-glutamyl cysteine synthetase. The hypothesis is confirmed by experiments performed on cells treated with buthionine sulfoximine that inhibits the enzyme activity.
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PMID:Metabolism of glutathione in tumour cells as evidenced by 1H MRS. 1725 97

In the present study, we investigated the effects of the branched-chain amino acids (BCAA) leucine (Leu), isoleucine (Ile) and valine (Val), which accumulate in maple syrup urine disease (MSUD), on C6 glioma cell morphology and cytoskeletal reorganization by exposing the cultured cells to 1 and 5 mM BCAA. We observed that cells showed a fusiform shape with processes after 3 h treatment. Cell death was also observed when cells were incubated in the presence of the BCAA for 3 and 24 h. Val-treated cells presented the most dramatic morphological alterations. Immunocytochemistry with anti-actin and anti-GFAP antibodies revealed that all BCAA induced reorganization of actin and GFAP cytoskeleton. Although phosphorylation regulates intermediate filament (IF) assembly/disassembly, we verified that the BCAA did not change the in vitro phosphorylation of IF proteins either in C6 cells or in slices of cerebral cortex of rats during development (9-, 12-, 17- and 21-day-old). Furthermore, we observed that 3 h cell exposure to 5 mM of each BCAA resulted in a marked reduction of reduced glutathione (GSH) levels and significantly increased nitric oxide production. Finally, we observed that the morphological features caused by the BCAA on C6 cells were prevented by the use of the antioxidants GSH (1 mM) and N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.5 mM). On the basis of the present results, we conclude that free radical attack might be involved in the cell morphological alterations, as well as, in the cytoskeletal reorganization elicited by the BCAA. It is therefore presumed that these findings could be involved in the neuropathological features observed in patients affected by MSUD.
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PMID:Branched-chain amino acids accumulating in maple syrup urine disease induce morphological alterations in C6 glioma cells probably through reactive species. 1731 75

Glutamate induced glutathione (GSH) depletion in C6 rat glioma cells, which resulted in cell death. This cell death seemed to be apoptosis through accumulation of reactive oxygen species (ROS) or hydroperoxides representing cytochrome c release from mitochondria and internucleosomal DNA fragmentation. A significant increase of 12-lipoxygenase enzyme activity was observed in the presence of arachidonic acid (AA) under GSH depletion induced by glutamate. AA promoted the glutamate-induced cell death, which reduced caspase-3 activity and diminished internucleosomal DNA fragmentation. Furthermore, AA reduced intracellular NAD, ATP and membrane potentials, which indicated dysfunction of the mitochondrial membrane. Protease inhibitors such as N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and 3, 4-dichloroisocumarin (DCI) but no Ac-DEVD, a caspase inhibitor, suppressed the glutamate-induced cell death. AA reduced the inhibitory effect of TPCK and DCI on the glutamate-induced cell death. These results suggest that AA promotes cell death by inducing necrosis from caspase-3-independent apoptosis. This might occur through lipid peroxidation initiated by ROS or lipid hydroperoxides generated during GSH depletion in C6 cells.
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PMID:Arachidonic acid promotes glutamate-induced cell death associated with necrosis by 12- lipoxygenase activation in glioma cells. 1740 Feb 55

Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV) and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) occurs in tissues and biological fluids of patients affected by the neurometabolic disorder maple syrup urine disease (MSUD). The objective of this study was to verify the effect of the BCKA on S100B release from C6 glioma cells. The cells were exposed to 1, 5 or 10 mM BCKA for different periods and the S100B release was measured afterwards. The results indicated that KIC and KIV, but not KMV, significantly enhanced S100B liberation after 6 h of exposure. Furthermore, the stimulatory effect of the BCKA on S100B release was prevented by coincubation with the energetic substrate creatine and with the N-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, indicating that energy deficit and nitric oxide (NO) were probably involved in this effect. Furthermore, the increase of S100B release was prevented by preincubation with the protein kinase inhibitors KN-93 and H-89, indicating that KIC and KIV altered Ca2+/calmodulin (PKCaMII)- and cAMP (PKA)-dependent protein kinases activities, respectively. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble vitamin E) were not able to prevent KIC- and KIV-induced increase of S100B liberation, suggesting that the alteration of S100B release caused by the BCKA is not mediated by oxidation of sulfydryl or other essential groups of the enzyme as well as by lipid peroxyl radicals. Considering the importance of S100B for brain regulation, it is conceivable that enhanced liberation of this protein by increased levels of BCKA may contribute to the neurodegeneration characteristic of MSUD patients.
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PMID:Effect of the branched-chain alpha-keto acids accumulating in maple syrup urine disease on S100B release from glial cells. 1749 67

Changes in cellular energy and redox states were studied in the C6 glioma cells following exposure to chemicals that affect glutathione metabolism. It was demonstrated that treatment with sublethal concentrations (25, 50 and 100 microM) of buthionine sulfoxamine (BSO) did not affect cellular energy state as measured by total adenosine nucleotides (TAN=ATP+ADP+ AMP), ATP:ADP:AMP and energy charge potential (ECP=[ATP + 0.5 (ADP)]/TAN). However, there was a significantly decrease in cellular GSH/GSSG and total glutathione (TG=[GSH+GSSG]/ TAN). The change was due to a significant decrease in intracellular GSH level without significant change in [GSSG]. Cells exposed to BSO for 24 hr were much more sensitive to subsequent injuries caused by Cd (0.6 mM for 3 hr). The results indicated that while a significant reduction of intracellular redox state did not affect cell viability, it could increase the susceptibility of cells to subsequent chemical stress. N-acetylcysteine (NAC), on the other hand, caused a dose (1, 5 and 10 mM)-dependent increase in GSH/GSSG without significant changes in intracellular energy state. Improvement of intracellular GSH/GSSG offered no protection against subsequent Cd induced cell death unless NAC was present at the time Cd was added. The pattern of cell death also correlated with the increase in intracellular free radial generation as measured by the fluorescence labeling with 27- dichlorofluorescin. Results of the present study demonstrated that intracellular redox states could be manipulated by addition of chemicals that affect glutathione metabolism. While the redox state may not be the sufficient condition to cause cell death, it could modulate the response of cells to subsequent Cd treatment. Furthermore, the action of NAC against Cd cytotoxicity may not be related to intracellular redox status.
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PMID:Manipulation of energy and redox states in the C6 glioma cells by buthionine sulfoxamine and N-acetylcysteine and the effect on cell survival to cadmium toxicity. 1751 12

The vast majority of primary brain tumors derive from glial cells and are collectively called gliomas. While, they share some genetic mutations with other cancers, they do present with a unique biology and have developed adaptations to meet specific biological needs. Notably, glioma growth is physically restricted by the skull, and, unless normal brain cells are destroyed, tumors cannot expand. To overcome this challenge, glioma cells release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. The released glutamate also explains peritumoral seizures which are a common symptom early in the disease. Glutamate release occurs via system X(c), a cystine-glutamate exchanger that releases glutamate in exchange for cystine being imported for the synthesis of the cellular antioxidant GSH. It protects tumor cells from endogenously produced reactive oxygen and nitrogen species but also endows tumors with an enhanced resistance to radiation- and chemotherapy. Pre-clinical data demonstrates that pharmacological inhibition of system X(c) causes GSH depletion which slows tumor growth and curtails tumor invasion in vivo. An Food and Drug Administration approved drug candidate is currently being introduced into clinical trials for the treatment of malignant glioma.
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PMID:A role for glutamate in growth and invasion of primary brain tumors. 1828 16

Oxidative stress is implicated in a variety of disorders including neurodegenerative diseases, and H(2)O(2) is important in the generation of reactive oxygen and oxidative stress. In this study, we have examined the rate of extracellular H(2)O(2) elimination and relevant enzyme activities in cultured astrocytes and C6 glioma cells and have analyzed the results based on a mathematical model. As compared with other types of cultured cells, astrocytes showed higher activity of glutathione peroxidase (GPx) but lower activities for GSH recycling. C6 cells showed relatively low GPx activity, and treatment of C6 cells with dibutyryl-cAMP, which induces astrocytic differentiation, increased catalase activity and H(2)O(2) permeation rate but exerted little effect on other enzyme activities. A mathematical model [N. Makino, K. Sasaki, N. Hashida, Y. Sakakura, A metabolic model describing the H(2)O(2) elimination by mammalian cells including H(2)O(2) permeation through cytoplasmic and peroxisomal membranes: comparison with experimental data, Biochim. Biophys. Acta 1673 (2004) 149-159.], which includes relevant enzymes and H(2)O(2) permeation through membranes, was found to be fitted well to the H(2)O(2) concentration dependences of removal reaction with the permeation rate constants as variable parameters. As compared with PC12 cells as a culture model for neuron, H(2)O(2) removal activity of astrocytes was considerably higher at physiological H(2)O(2) concentrations. The details of the mathematical model are presented in Appendix.
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PMID:Kinetics of hydrogen peroxide elimination by astrocytes and C6 glioma cells analysis based on a mathematical model. 1840 82

Cadmium is a toxic heavy metal and an environmental pollutant. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of the family of MAPK. In this study, we investigated the effect of heavy metals on MKP-1 expression in C6 rat glioma cells. Cadmium treatment induced MKP-1 at both protein and mRNA levels while cobalt or manganese treatment did not, suggesting the specificity. Cadmium treatment also depleted intracellular GSH and activated p38 MAPK, JNKs, and AKT. Profoundly, pretreatment with thiol-containing compounds NAC or GSH, but not vitamin E, blocked GSH depletion, 38 MAPK activation and MKP-1 expression by cadmium. Moreover, pharmacological inhibition of p38 MAPK by SB203580 suppressed the cadmium-induced MKP-1. Collectively, these results demonstrate that cadmium specifically induces MKP-1 by transcriptional up-regulation in C6 cells in a mechanism associated with the glutathione depletion-dependent p38 MAPK activation.
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PMID:Cadmium specifically induces MKP-1 expression via the glutathione depletion-mediated p38 MAPK activation in C6 glioma cells. 1857 14

Elimination of hydrogen sulfide from glutathione (GSH) converts a well known cellular nucleophile to an electrophilic species, gamma-glutamyldehydroalanylglycine (EdAG). We have found that a sulfonium metabolite formed from GSH and busulfan undergoes a facile beta-elimination reaction to give EdAG, which is an alpha,beta-unsaturated dehydroalanyl analog of GSH. EdAG was identified as a metabolite of busulfan in a human liver cytosol fraction. EdAG condenses with GSH in a Michael addition reaction to produce a lanthionine thioether [(2-amino-5-[[3-[2-[[4-amino-5-hydroxy-5-oxopentanoyl]amino]-3-(carboxymethylamino)-3-oxopropyl]sulfanyl-1-(carboxymethylamino)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid); GSG], which is a nonreducible analog of glutathione disulfide. EdAG was less cytotoxic than busulfan to C6 rat glioma cells. GSH and EdAG were equally effective in displacing a glutathione S-transferase (GST) isozyme (human GSTA1-1) from a GSH-agarose column. The finding of an electrophilic metabolite of GSH suggests that alteration of cellular GSH concentrations, irreversible nonreducible glutathionylation of proteins, and interference with GST function may contribute to the toxicity of busulfan.
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PMID:Dehydroalanine analog of glutathione: an electrophilic busulfan metabolite that binds to human glutathione S-transferase A1-1. 1879 Oct 61


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