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)

The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C60) and water-soluble polyhydroxylated fullerene [C60(OH)n] were investigated. Crystal violet assay for cell viability demonstrated that nano-C60 was at least three orders of magnitude more toxic than C60(OH)n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C60(OH)n caused delayed, ROS-independent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C60 toxicity, but not C60(OH)n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C60(OH)n-induced apoptosis, but not nano-C60-mediated necrosis. Finally, C60(OH)n antagonized, while nano-C60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.
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PMID:Distinct cytotoxic mechanisms of pristine versus hydroxylated fullerene. 1647 88

It is unclear whether the two enantiomeric forms (R & S) of lipoic acid (LA) share similar pharmacological activity and the exact cellular targets of LA are not well identified. We oxidatively stressed 3 cell culture systems representing different cell types. Mitochondrial metabolism was the primary endpoint. When C6 glioma was damaged by hydrogen peroxide (H2O2), all forms of LA protected. Racemic and S-LA were less effective than the R-isomer that was also protective in tertiary butyl hydroperoxide (TBHP)-damaged C6 glioma. In PC12 cells, little damage was produced by TBHP; R-LA increased mitochondrial metabolism above the level of non-damaged control. In H2O2 damaged PC12 cells, R-LA and racemic LA (but not S-LA) not only protected against damage, but increased mitochondrial metabolism above the non-damaged control level. When BAE cells were damaged with H2O2, R- and racemic LA protected while S-LA was ineffective.
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PMID:Differential activity of lipoic acid enantiomers in cell culture. 1652 Feb 97

In the present study, we examined the protective mechanism of baicalein (BE) and its glycoside, baicalin (BI), on hydrogen-peroxide (H(2)O(2))-induced cell death in rat glioma C6 cells. Results of the MTT assay, LDH release assay, and morphological observation showed that H(2)O(2) addition reduced the viability of C6 cells, and this was prevented by the addition of BE but not BI. Incubation of C6 cells with BE significantly decreased the intracellular peroxide level induced by H(2)O(2) according to flow cytometric analysis using DCHF-DA as a fluorescent substrate. Suppression of H(2)O(2)-induced apoptotic events including DNA ladders, hypodiploid cells, and activation of caspases 3, 8, and, 9 by BE but not BI was identified in C6 cells. The cytotoxicity and phosphorylation of ERK proteins induced by H(2)O(2) were blocked by the ERK inhibitor PD98059. Catalase addition prevented H(2)O(2)-induced ROS production, ERKs protein phosphorylation, and cell death, and BE dose-dependently inhibited H(2)O(2)-induced ERK protein phosphorylation in C6 cells. These data suggest that ROS-scavenging activity is involved in BE prevention of H(2)O(2)-induced cell death via blocking ERKs activation. Additionally, BE but not BI induced heat shock protein 32 (HSP32; HO-1) protein expression in both time- and dose-dependent manners, but not heme oxygenase 2 (HO-2), heat shock protein 70 (HSP70), or heat shock protein 90 (HSP90) protein expression. In the absence of H(2)O(2), BE induces ERKs protein phosphorylation, and HO-1 protein expression induced by BE was blocked by the addition of cycloheximide, actinomycin D, and the ERK inhibitor PD98059. The addition of the HO inhibitor ZnPP inhibited the protective effect of BE against H(2)O(2)-induced cytotoxicity in C6 cells according to the MTT assay and apoptotic morphology under microscopic observation, accompanied by blocking the ROS-scavenging activity of BE in C6 cells. However, BE treatment was unable to protect C6 cells from C2-ceramide-induced cell death. These data indicate that BE possesses abilities to inhibit ROS-mediated cytotoxic effects through modulation of ERKs activation and induction of HO-1 protein expression. The role of HO-1 in ROS-scavenging activity of BE is proposed.
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PMID:Baicalein inhibition of oxidative-stress-induced apoptosis via modulation of ERKs activation and induction of HO-1 gene expression in rat glioma cells C6. 1681 38

Oxidative mechanisms of injury are involved in many neurodegenerative diseases such as stroke, ischemia-reperfusion injury and multiple sclerosis. G protein-coupled receptor kinase 2 (GRK2) plays a key role in G protein-coupled receptor (GPCR) signaling modulation, and its expression levels are decreased after brain hypoxia/ischemia and reperfusion as well as in several inflammatory conditions. We report here that hydrogen peroxide downregulates GRK2 expression in C6 rat glioma cells. The hydrogen peroxide-induced decrease in GRK2 is prevented by a calpain protease inhibitor, but does not involve increased GRK2 degradation or changes in GRK2 mRNA level. Instead we show that hydrogen peroxide treatment impairs GRK2 translation in a process that requires Cdk1 activation and involves the mTOR pathway. This novel mechanism for the control of GRK2 expression in glial cells upon oxidative stress challenge may contribute to the modulation of GPCR signaling in different pathological conditions.
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PMID:Hydrogen peroxide impairs GRK2 translation via a calpain-dependent and cdk1-mediated pathway. 1696 27

Effects of hydrogen peroxide on morphological characteristics, proliferation index, menadione-dependent lucigenin-enhanced chemiluminescence of C6 glioma cells were studied. It was established that H2O2 at 1 x 10(-8) - 5 x 10(-7) M concentrations acts as a regulator of morphological and functional properties of astrocytes by inducing their reactivation that is manifested as a cell body hypertrophy and an increase of proliferative activity and of menadione-dependent production of superoxide (O2- ). Cytodestructive action of hydrogen peroxide at a concentration higher than 1 microM on C6 glioma cells shows itself as a decrease of their proliferation index and the ability to generate O2- under menadione action. Using lipopolysaccharide B as a functional stimulator it has been shown that H2O2 modifies signaling pathways leading to the increase of mitotic activity of C6 glioma cells and decreases the yield of lucigenin-enhanced chemiluminescence of astrocytes under menadione action to the level of control values.
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PMID:[Regulation of morphologicaland functional properties of astroglial cells by hydrogen peroxide]. 1723 75

Gliomas are extremely resistant to anticancer therapies resulting in poor patient survival, due, in part, to altered expression of antioxidant enzymes. The primary antioxidant enzyme, catalase, is elevated constitutively in gliomas compared to normal astrocytes. We hypothesized that downregulating catalase in glioma cells would sensitize these cells to oxidative stress. To test this hypothesis, we implemented two approaches. The first, a pharmacological approach, used 3-amino-1,2,4-triazole, an irreversible inhibitor that reduced catalase enzymatic activity by 75%. Pharmacological inhibition of catalase was not associated with a reduction in rat 36B10 glioma cell viability until the cells were challenged with additional oxidative stress, i.e., ionizing radiation or hydrogen peroxide (H(2)O(2)). In the second molecular approach, we generated 36B10 glioma cells stably expressing catalase shRNA; a stable cell line displayed a 75% reduction in catalase immunoreactive protein and enzymatic activity. This was accompanied by an increase in intracellular reactive oxygen species and extracellular H(2)O(2). These cells exhibited increased sensitivity to radiation and H(2)O(2), which was rescued by the antioxidant, N-acetylcysteine. These results support the hypothesis that catalase is a major participant in the defense of 36B10 glioma cells against oxidative stress mediated by anticancer agents capable of increasing steady-state levels of H(2)O(2).
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PMID:Inhibiting catalase activity sensitizes 36B10 rat glioma cells to oxidative stress. 1732 Jul 61

In the present study, we have evaluated the possible functionality in astrocytes of the glutamine (Gln) transporter (GlnT) known to predominate in neurons for the neurotransmitter pool of glutamate. Sustained exposure to the adenylyl cyclase activator forskolin for 24 h led to a significant increase in mRNA expression of GlnT among different membrane transporters capable of transporting Gln, with an increase in [(3)H]Gln accumulation sensitive to a system A transporter inhibitor, in cultured rat neocortical astrocytes, but not neurons. Forskolin drastically stimulated GlnT promoter activity in a manner sensitive to a protein kinase A (PKA) inhibitor in rat astrocytic C6 glioma cells, while deletion mutation analysis revealed that the stimulation was mediated by a cAMP responsive element (CRE)/activator protein-1 (AP-1) like site located on GlnT gene promoter. Forskolin drastically stimulated the promoter activity in a fashion sensitive to a PKA inhibitor in C6 glioma cells transfected with a CRE or AP-1 reporter plasmid, in association with the phosphorylation of CRE binding protein on serine133. Transient overexpression of GlnT significantly exacerbated the cytotoxicity of hydrogen peroxide in cultured astrocytes. These results suggest that GlnT expression is upregulated by cAMP/PKA signals for subsequent exacerbation of the vulnerability to oxidative stress in astrocytes.
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PMID:Upregulation of the glutamine transporter through transactivation mediated by cAMP/protein kinase A signals toward exacerbation of vulnerability to oxidative stress in rat neocortical astrocytes. 1732 79

The antioxidant compound, trans-resveratrol, is found in substantial amounts in several types of red wine and has been proposed to have beneficial effects in brain pathologies that may involve oxidative stress. The objective of the present study was to investigate the genoprotective effects of resveratrol under conditions of oxidative stress induced by hydrogen peroxide in C6 glioma cells. DNA damage was assessed by the alkaline single-cell gel electrophoresis assay or comet assay. In order to investigate the genoprotective effects of resveratrol against oxidative stress induced by hydrogen peroxide on DNA damage, two models of oxidative stress induction were utilized. (I) 1mM hydrogen peroxide for 0.5h (10-250 microM of resveratrol) and (II) 0.1 or 0.5mM hydrogen peroxide for 6h (10-100 microM of resveratrol). Resveratrol was able to prevent oxidative damage to cellular DNA, induced in model I, at all concentrations tested; however, at 6h of incubation, resveratrol prevented DNA damage only partially. After 6h of incubation (up to 48h) resveratrol per se induced a slight time and dose-dependent DNA damage. In conclusion, these results provide evidence that resveratrol may act as a significantly bioactive compound, supporting the possibility that, due to its antioxidant properties, it may be important in health and disease for protecting against DNA damage through oxidative stress.
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PMID:Resveratrol attenuates oxidative-induced DNA damage in C6 Glioma cells. 1749 6

The glitazones (or thiazolidinediones) are synthetic compounds used in type-2 diabetes, but they also have broad antiproliferative and anti-inflammatory properties still not well understood. We described previously the apoptotic effects of glitazones on astroglioma cells ( J Biol Chem 279: 8976-8985, 2004 ). At certain concentrations, we found a selective lethality on glioma cells versus astrocytes that was dependent on a rapid production of reactive oxygen species (ROS) and seemed unrelated to the receptor peroxisome proliferator activated receptor-gamma. The present study was aimed at characterizing the oxygen derivatives induced by ciglitazone, rosiglitazone, and pioglitazone in C6 glioma cells and to investigate their intracellular source. We examined the interaction of ROS with nitric oxide (NO) and its consequences for glioma cell survival. Fluorescence microscopy and flow cytometry showed that glitazones induced superoxide anion, peroxynitrite, and hydrogen peroxide, with ciglitazone being the most active. ROS production was completely prevented by uncoupling of the electron transport chain and by removal of glucose as an energy substrate, whereas it was unaffected by inhibition of NADPH-oxidase and xanthine-oxidase. Moreover, glitazones inhibited state 3 respiration in permeabilized cells, and experiments with mitochondrial inhibitors suggested that complex I was the likely target of glitazones. Therefore, these results point to the mitochondrial electron transport chain as the source of glitazone-induced ROS in C6 cells. Glitazones also depolarized mitochondria and reduced mitochondrial pH. NO synthase inhibitors revealed that superoxide anion combines with NO to yield peroxynitrite and that the latter contributes to the cytotoxicity of glitazones in astroglioma cells. Future antitumoral strategies may take advantage of these findings.
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PMID:Glitazones induce astroglioma cell death by releasing reactive oxygen species from mitochondria: modulation of cytotoxicity by nitric oxide. 1750 46

We demonstrate the capacity of an herbal anthraquinone aloe emodin to reduce the cytotoxicity of the proinflammatory cytokine tumor necrosis factor (TNF) towards L929 mouse fibrosarcoma and U251 human glioma cell lines. Aloe emodin inhibited both TNF-induced cell necrosis and apoptosis, but it did not reduce cell death induced by UV radiation or hydrogen peroxide. Aloe emodin inhibited both basal and TNF-triggered activation of extracellular signal-regulated kinase (ERK), and a selective blockade of ERK activation mimicked the cytoprotective action of the drug. On the other hand, aloe emodin did not affect TNF-induced activation of p38 mitogen-activated protein kinase or generation of reactive oxygen species. The combination of aloe emodin and TNF caused an intracellular appearance of acidified autophagic vesicles, and the inhibition of autophagy with bafilomycin or 3-methyladenine efficiently blocked the cytoprotective action of aloe emodin. These data indicate that aloe emodin could prevent TNF-triggered cell death through mechanisms involving induction of autophagy and blockade of ERK activation.
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PMID:Aloe emodin inhibits the cytotoxic action of tumor necrosis factor. 1753 Dec 19


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