Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between chromatin structure and endonuclease sensitivity was investigated. The cells used in this study were a) human myelogenous leukemic cell lines (HL-60, ML-I, U-937, THP-I) (Group I), which produced internucleosomal DNA cleavage, and b) human T-cell leukemia (MOLT-4), erythroleukemia (K562), glioblastoma (T98G, U87MG) and glioma (KG-1-C) cell lines (Group II), which produced no internucleosomal DNA cleavage, upon treatment with various apoptosis-inducing agents. When the nuclei, isolated from these cells were digested with micrococcal nuclease, chromatin DNA was cleaved into oligonucleosomal units. Although sensitivity to micrococcal nuclease considerably differed from cell to cell, Group I cells were generally more sensitive to micrococcal nuclease digestion than Group II cells. Similar sensitivity to DNase I was observed in both groups of cells. Acid-urea polyacrylamide gel electrophoresis of histone fractions from control and apoptosing HL-60 cells (induced either by hydrogen peroxide or UV irradiation) revealed no significant change in the relative composition of five major histones, indicating the absence of selective degradation of histone HI, but rather the nonspecific degradation of many nuclear proteins. These data suggest a difference in a chromatin structure between Group I and II cells, which might result in the selective production of internucleosomal DNA cleavage only in Group I cells.
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PMID:Chromatin structure and endonuclease sensitivity in human leukemic cell lines. 870 41

We have previously shown that a recombinant carboxyl-terminal 105-amino-acid fragment (CT105) of the amyloid precursor protein (APP) induced strong non-selective inward currents in Xenopus oocytes. Here we investigated the toxic effect of CT105 peptide on the cultured mammalian cells. The CT105 peptide induced a significant lactate dehydrogenase (LDH) release from cultured rat cortical neurons and PC12 cells in a concentration (from 10 microM)- and time (from 48 h)-dependent manner. The toxic effect of CT105 was more potent than that of any fragments of amyloid beta protein (A beta). However, CT105 peptide did not affect the viability of U251 human glioblastoma cells. In contrast to CT105, A beta increased LDH release only slightly even at 50 microM but significantly inhibited 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction at submicromolar concentrations. Among the various neuroprotective drugs tested, only cholesterol, which alters membrane fluidity, could attenuate the cytotoxicity of CT105 significantly. The CT105 peptide formed multiple self-aggregates on solubilization. Pretreatment with a sublethal concentration of CT105 did not significantly alter the susceptibility of cells to hydrogen peroxide and glutamate. Endogenous CT peptides were found not only in the cell lysates but also in the conditioned medium of PC12 cells. These results imply that CT peptide can directly attack the cell membrane probably by making pores or nonselective ion channels, whereas A beta impairs the intracellular metabolic pathway first. Thus, it is thought that both CT and A beta, which are formed during the processing of APP, may participate in the neuronal degeneration in Alzheimer's disease by different mechanisms.
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PMID:Neurotoxicity of a carboxyl-terminal fragment of the Alzheimer's amyloid precursor protein. 875 24

Elevated vascular endothelial growth factor (VEGF) levels are required for ocular and tumor angiogenesis in animal models. Ischemic hypoxia is strongly correlated with increased VEGF expression in these systems and is considered a physiologically relevant stimulus. Because ischemic hypoxia is often followed by reperfusion and reactive oxygen intermediate (ROI) generation, we examined the potential role of ROI in the control of VEGF gene expression. Human retinal pigment epithelial cells exposed to superoxide or hydrogen peroxide rapidly increased VEGF mRNA levels. Superoxide-associated mRNA increases were dose dependent, blocked by antioxidants, and associated with elevated VEGF protein levels in conditioned media. Increases in VEGF mRNA levels were also observed in cultured human melanoma and rat glioblastoma cells with superoxide or hydrogen peroxide. Cycloheximide prevented the ROI-associated increases in VEGF mRNA. Transcriptional inhibition with actinomycin D revealed an inducible increase in VEGF mRNA half-life, but nuclear run-on experiments showed no increase in VEGF transcriptional rate. Reoxygenation of human retinal pigment epithelial cells in vitro and ocular reperfusion in vivo increased retinal VEGF mRNA levels. Antioxidants prevented the reperfusion-associated VEGF mRNA increases in retina. We conclude that ROIs increase VEGF gene expression in vitro and during the reperfusion of ischemic retina in vivo. The ROI-associated increases are mediated largely through increases in VEGF mRNA stability.
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PMID:Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. 883 17

The aim of the present study was to assess the toxic potential of drugs of abuse and other neuropharmacological agents in the pathogenesis of AIDS dementia complex (ADC), the neurological complication of AIDS. Neuroblastoma and glioblastoma cell lines expressing the dopamine transporter, as well as primary macrophages exposed to human immunodeficiency virus-1 (HIV-1), were used to investigate the possibility of any synergistic effect between the mode of toxicity of such substances and virus exposure. The drugs of abuse used in our experiments were cocaine and morphine, which exert their action, among others, on the dopaminergic system. Effects were compared to treatment with dopamine itself and a typical dopaminergic drug used pharmaceutically, selegiline. In macrophage cultures, glutathione (GSH) was upregulated strongly after treatment with dopamine, morphine or selegiline, and this effect was enhanced when cells were pre-exposed to virus. This upregulation is discussed as a compensatory reaction to an oxidative signal. When hydrogen peroxide plus iron sulfate was used as a strong oxidant in macrophages, GSH concentrations decreased as a result of cell injury. Cell numbers remained constant in all treatment groups. In contrast, in both neuroblastoma and glioblastoma cell lines, the modulation of GSH concentrations by neurotropic substances was accompanied by significant cell loss, which was exacerbated by HIV-1 pretreatment. Selegiline did not change cell numbers when incubated alone. However, when incubated following treatment with HIV-1 cell death was highly significant. Ascorbic acid (AA), included as antioxidant, totally restored cell loss in cultures treated with dopamine. However, no effect was observed in combined treatment of AA and morphine or selegiline. The results demonstrate a synergistic role in cellular toxicity due to neurotropic substances and HIV-1, and suggest that neuropharmacological agents may contribute to the pathogenesis of ADC.
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PMID:Regulation of glutathione and cell toxicity following exposure to neurotropic substances and human immunodeficiency virus-1 in vitro. 937 55

Protein tyrosine phosphorylation was examined on a human glioblastoma cell line, T98G, after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of a 125 kDa protein at 30 min after stimulation. The 125-kDa molecule phosphorylated was revealed to be a focal adhesion kinase (FAK). Tyrosine phosphorylation of p125FAK continued at least up to 5 h, and decreased after 8 h concomitant with apoptosis. Tyrosine phosphorylation of p125FAK was blocked by herbimycin A, a potent inhibitor of protein tyrosine kinases, while apoptosis was accelerated. When T98G cells were incubated with FAK antisense oligonucleotide, apoptosis was also accelerated. These results suggest that tyrosine phosphorylation of p125FAK plays a suppressive role in hydrogen peroxide-induced apoptosis.
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PMID:A suppressive role of p125FAK protein tyrosine kinase in hydrogen peroxide-induced apoptosis of T98G cells. 943 84

We studied 14 young people with newly diagnosed hemisphere tumors, aged from 3 to 20 years (average 10 years). All underwent surgery following MR imaging (MRI) and spectroscopy (MRS). The tumors studied were three glioblastomas, one each of ganglio-glioblastoma, primitive neuroectodermal tumor (PNET), rhabdoid teratoid tumor, pilocytic astrocytoma, ependymoma, anaplastic ependymoma, and gliomatosis cerebri, and four gangliogliomas. Four patients died; ten patients are alive (five with stable residual tumor, five with no evident tumor). Images and spectra were acquired on a 1.5-T imager. Proton MRS was performed before gadolinium injection in all but one case. Single-voxel techniques were utilized in all cases, using a spin-echo or STEAM sequence with a long echo time (135 or 270 ms). Peak areas of N-acetyl aspartate (NAA), choline (Cho), and creatine and phosphocreatine (Cr) were assessed. The NAA/Cho peak-area ratio was very low in the patients who died (mean +/- s.d. 0.20 +/- 0.14), and higher in the patients who are alive (0.74 +/- 0.47; P = 0.007 by two-tailed t-test). The Cr/Cho peak-area ratio also followed a similar trend for the two groups (mean +/- s.d. 0.17 +/- 0.07 and 0.49 +/- 0.30, respectively; P = 0.01 by two-tailed t-test).
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PMID:Prognostic value of proton MR spectroscopy of cerebral hemisphere tumors in children. 954 23

The relation between the intracellular glutathione (GSH) concentration and hydrogen-peroxide(H2O2)-induced cytotoxicity was investigated. The intracellular GSH concentration in human glioblastoma (T98G, U87MG) and glioma (KG1C) cell lines was one or two orders of magnitude higher than that in a human myelogenous leukemic cell line (HL-60), which showed higher sensitivity to H2O2. Pretreatment of these cell lines with L-buthionine-[S,R]-sulfoximine, which significantly reduced the intracellular GSH concentration, increased their sensitivity against H2O2, whereas pretreatment with N-acetyl-L-cysteine, which did not significantly change the intracellular GSH concentration, only marginally protected the cells from the cytotoxic effect of H2O2. The results suggest that drug sensitivity of tumor cells can be modified by glutathione-modulating compounds.
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PMID:Effect of glutathione-modulating compounds on hydrogen-peroxide-induced cytotoxicity in human glioblastoma and glioma cell lines. 962 Feb 20

It has been shown that astrocytes (human glioblastoma U118 cell line) release reactive oxygen species (ROS), including superoxide O2.- and hydrogen peroxide H2O2 following the action of C5a complement component C5a (but not C3a). The effect of C5a (1 nM) is accompanied with hyperpolarization of the astrocyte plasma membrane. Component C3a (100 nM), which is not an inducer of ROS, caused a prolonged depolarization of astrocytes. However, both the agents induced a transient increase in intracellular Ca2+ concentration. The data obtained permit a conclusion that O2.- participates in the intracellular signal transduction, and is involved in the mechanism of hyperpolarization response of astrocytes to the effect of the inducer of ROS, complement component C5a.
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PMID:[Activation of astrocytes of by anaphylatoxins of the complement system]. 982 Dec 47

It is now generally accepted that massive neuronal death due to oxidative stress is a regular feature of brains in neurodegenerative diseases. However, much less attention has been given to the death of glial cells. In this study, we examined p53-sensitive apoptosis of cells by using human glioblastoma A172 cells and p53-deficient mouse astrocytes. In human A172 cells, hydrogen peroxide (H2O2) caused cell death in a time- and concentration-dependent manner, accompanied by nucleosomal DNA fragmentation and chromatin condensation. After treatment with H2O2, p53 protein was highly expressed and protein levels of Bak, p21WAF1/CIP1 and GADD45 were also enhanced. However, the protein levels of Bcl-2 and Bax did not change. On the other hand, primary cultured astrocytes from p53-deficient mouse brain grew faster than wild-type and heterozygous astrocytes. In addition, p53-deficient astrocytes were more resistant to H2O2-induced apoptosis than wild-type and heterozygous astrocytes. These results suggest that glial proliferation and the repair of damaged DNA may be regulated by p53-induced p21WAF1/CIP1 and GADD45, and that glial apoptosis caused by oxidative stress may be mediated by p53-induced Bak.
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PMID:Hydrogen peroxide-induced apoptosis mediated by p53 protein in glial cells. 989 Jun 30

Protein phosphorylation in a human glioblastoma cell line, T98G, was examined after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of focal adhesion kinase (FAK) and serine phosphorylation of Akt at 1 h after stimulation. Concommitantly, the association of FAK with phosphatidylinositide 3'-OH-kinase (PI 3-kinase) was also observed by the hydrogen peroxide stimulation. When T98G cells were incubated with wortmannin, a PI 3-kinase inhibitor, both PI 3-kinase activity and phosphorylation of Akt were inhibited, whereas apoptosis by oxidative stress was accelerated. Concomitant with apoptosis, elevated level of CPP32 protease activity (caspase-3) was observed, with decreases in Bcl-2 protein and increases in Bax protein. These results suggested that in the signal transduction pathway from FAK to PI 3-kinase, Akt promotes survival. Thus, it became apparent that FAK is the upstream signal protein of the PI 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis in T98G cells.
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PMID:FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. 1018 51


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