Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of glutathione (GSH) and two enzymes involved in GSH metabolism, glutathione reductase (GR) and glutathione-S-transferase(s) (GST), were measured in four SV40-transformed human fibroblast cell lines. MRC5-V1 and GM0637, derived from normal individuals, had mean GSH levels of 4.2 and 6.5 nmoles/10(6) cells, respectively. TAT2SF and AT5BIVA, both from ataxia-telangiectasia (A-T) patients, respectively had 6.5 and 4.2 nmol/10(6) cells, indicating that basal GSH levels were similar in A-T and normal cells. There was some variation in GST activity among the four cell lines but deficiency in this enzyme cannot be associated with radiosensitivity in A-T. When GR activity was measured, A-T cells had approximately 82 per cent of the mean normal activity. Though statistically significant, (P = 0.05), this small deficiency could be due to chance and is unlikely to be responsible for the radiosensitive phenotype of A-T.
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PMID:Some aspects of glutathione metabolism in ataxia-telangiectasia fibroblasts. 349 9

Cell lines established from donors with the inherited disorder ataxia-telangiectasia (A-T) exhibit exceptional sensitivity to ionizing radiation and chemicals known to produce increased levels of intracellular H2O2, suggesting a deficiency in glutathione-dependent detoxication reactions. Glutathione (GSH) biosynthesis in fibroblast and lymphoblast cultures derived from individuals known to be clinically unaffected, homozygous, or heterozygous for A-T was assessed. Following GSH depletion by diethylmaleate, fibroblasts (GM 3492) from a clinically unaffected individual resynthesized GSH at a rate approximately twice that observed in fibroblasts from known heterozygotes (GM 3488 and GM 3489). Unrelated A-T homozygote fibroblast lines GM 3487B and GM 5823 resynthesized GSH only very slowly. GM 3492 cells repleted intracellular GSH by 6 h after depletion, the heterozygote lines by 18 h. The A-T homozygotes replaced only 30% of the intracellular GSH pool by 24 h. A lymphoblast cell line from the A-T homozygote (GM 3189) also exhibited slow resynthesis after depletion. However, if these cells were permeabilized by treatment with digitonin, GSH synthesis proceeded at a rate exceeding synthesis in permeabilized or untreated normal lymphoblasts (GM 3323). The first enzyme in GSH synthesis, gamma-glutamylcysteine synthetase, was found to be elevated about 2.7-fold in A-T homozygote fibroblasts, suggesting that a substrate for GSH synthesis may be rate limiting. A-T homozygote lymphoblasts contained about 2-fold more gamma-cystathionase activity over other cell lines tested suggesting increased flux through the transsulfuration pathway for cysteine production in response to reduced cysteine supply. Transport of cysteine and cystine was found to be 8- and 5-fold slower in A-T homozygotes that did not affect fibroblasts while glutamate and methionine transport Vmax did not differ among the cell lines tested. These experiments demonstrate that cells from A-T homozygotes are deficient in cysteine transport, thus limiting GSH resynthesis after a depleting challenge such as radiation or GSH-depleting xenobiotic compounds.
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PMID:Imparied glutathione biosynthesis in cultured human ataxia-telangiectasia cells. 362 Nov 55

Ataxia telangiectasia (AT) is a rare genetic disorder. Symptoms of the disease include cerebellar ataxia, depressed immunoresponsiveness, increased sensitivity to radiation, and leukemias. Various kinds of AT cells show reduced efficiency of differentiation. The ataxia telangiectasia gene (ATM) may reduce differentiation by suppressing cell responsivity to insulin. Insulin sensitivity seems lower in AT. Tumor necrosis factor may overactivate NF-kappa B in AT, and this increases the radiosensitivity of AT cells. Intracellular reduced glutathione may also become depleted. The reduced levels of glutathione may further alter differentiation of AT cells. Serine protease inhibitors may counteract the effects of tumor necrosis factor. Glutathione enhancers may also prove valuable as therapy.
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PMID:An ataxia telangiectasia model: inefficient cell differentiation and possible reversal by serine protease inhibitors, tumor necrosis factor inhibitors, dexamethasone, and glutathione enhancers. 988 37

Implication of AT1 receptors (AT1R) in functional and metabolic modifications associated with ischemia-reperfusion is not clearly defined. The aim of this study was:--to evaluate the role of AT1R in isolated rat hearts subjected to a reversible ischemia:--to establish possible relationships between functional parameters and oxidative stress during reperfusion period. Isolated hearts perfused by the Langendorff method underwent 30 min of a global total ischemia followed by 30 min of reperfusion. Functional parameters and LDH release were recorded under AT1R stimulation by angiotensin II (AII) (10(-7) M) and/or AT1R blockade by losartan (10(-6) M). Quantification of oxidative stress was performed in coronary effluents 1) directly, using ESR spectroscopy associated with PBN spin trapping and 2) indirectly, using HPLC method to detect glutathione (GSH + GSSG) release. Our results showed that All induced vasoconstrictive and negative inotropic effects during control period. During reperfusion. All reduced incidence of reperfusion arrhythmia and LDH release. From the onset of reperfusion, a large and long lasting release of alkyl/alkoxyl radicals and glutathione was detected and the intensity of the oxidative stress was not significantly changed in the groups treated will All and/or losartan. In conclusion, no relationship has been clearly demonstrated between the oxidative stress intensity and AT1R activation, but these results couldn't exclude the contribution of free radical in some myocardial effects of AT1R stimulation such as vasoconstriction and negative inotropic effect.
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PMID:[Role of AT1 receptors in functional adaptation to ischemia-reperfusion in solated rat hearts in relationship to oxidative stress]. 1157 7

Expression levels of 767 genes were measured in HepG2 cells at eight time points (0, 0.5, 1, 6, 12, 16, 20, and 24 h) following exposure to the oxidizing agent, diethyl maleate (DEM). DEM treatment caused an immediate and sustained loss of intracellular GSH, with a concomitant increase in GSSG. From 6-12 h after exposure, there was a substantial increase in the percentage of cells undergoing S phase arrest and apoptosis. Expression profiles of approximately 90% of the genes fell into one of five clusters generated using hierarchical-clustering software, indicating the well-ordered nature of the stress response. The directional movement and timing of induction for many genes matched closely the known physiological role of the proteins they encode. Inhibitors of the cell cycle (CDKN1, CDKN4D, ATM) were induced, whereas cyclins [proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin K] were downregulated during the period from 6--20 h. Likewise, pro-apoptotic genes such as the caspases (CASP9, CASP3, CASP2) and apoptotic protease activating factor (APAF) were induced during the same period. Results of this study indicate that there is a good correlation between time-dependent physiological, biochemical, and gene expression data.
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PMID:Transcriptional and physiological responses of HepG2 cells exposed to diethyl maleate: time course analysis. 1187 89

The human genetic disorder ataxia-telangiectasia (A-T) is due to lack of functional ATM, a protein kinase which is involved in cellular responses to DNA double strand breaks (DSBs) and possibly other oxidative stresses, as well as in regulation of several fundamental cellular functions. Studies regarding responses in A-T cells to the induction of DSBs utilize ionizing radiation or radiomimetic chemicals, such as neocarzinostatin (NCS), which induce DNA DSBs. This critical DNA lesion activates many defense systems, such as the cell cycle checkpoints. The cell cycle is also regulated through a timed and coordinated degradation of regulatory proteins via the ubiquitin pathway. Our recent studies indicate that the ubiquitin pathway is influenced by the cellular redox status and that it is the major cellular pathway for removal of oxidized proteins. Accordingly, we hypothesized that the absence of a functional ATM protein might involve perturbations to the ubiquitin pathway as well. We show here that upon treatment with NCS, there was a transient 50-70% increase in endogenous ubiquitin conjugates in A-T and wt lymphoblastoid cells. Ubiquitin conjugation capabilities per se and levels of substrates for conjugation were also similarly enhanced in wt and A-T cells upon NCS treatment. We also compared the ubiquitination response in A-T and wt cells using H(2)O(2) as the stress, in view of preexisting evidence of the effects of H(2)O(2) on ubiquitination capabilities in other types of cells. As with NCS treatment, there was an approximately 45% increase in endogenous ubiquitin conjugates by 2-4 h after exposure to H(2)O(2). Both cell types showed a rapid 50-150% increase in de novo formed 125I-ubiquitin conjugates. As compared with wt cells, unexposed A-T cells had higher endogenous levels of conjugates and enhanced conjugation capability. However, A-T cells mounted a more muted ubiquitination response to the stress. The enhanced ubiquitin conjugation in unstressed A-T cells and attenuated ability of these cells to respond to stress are consistent with the A-T cells being under oxidative stress and with their having an 'aged' phenotype. The indication that ubiquitin conjugate levels and ubiquitin conjugation capabilities are enhanced upon oxidative stress without significant changes in GSSG/GSH ratios indicates that assays of ubiquitination provide a sensitive measure of cellular stress. The data also add support to the impression that potentiated ubiquitination response to mild oxidative stress is a generalizable phenomenon.
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PMID:Ubiquitination capabilities in response to neocarzinostatin and H(2)O(2) stress in cell lines from patients with ataxia-telangiectasia. 1208 Apr 67

The study investigated whether the amelioration of endothelial dysfunction by candesartan (2 mg.kg-1.day-1; 10 wk) in spontaneously hypertensive rats (SHR) was associated with modification of hepatic redox system. Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in Wistar-Kyoto rats (WKY) and was reduced (P < 0.05) by candesartan in both strains. Acetylcholine (ACh) relaxations were smaller (P < 0.05) and contractions induced by ACh + NG-nitro-l-arginine methyl ester (l-NAME) were greater (P < 0.05) in SHR than in WKY. Treatment with candesartan enhanced (P < 0.05) ACh relaxations in SHR and reduced (P < 0.05) ACh + l-NAME contractions in both strains. Expression of aortic endothelial nitric oxide synthase (eNOS) mRNA was similar in WKY and SHR, and candesartan increased (P < 0.05) it in both strains. Aortic mRNA expression of the subunit p22phox of NAD(P)H oxidase was higher (P < 0.05) in SHR than in WKY. Treatment with candesartan reduced (P < 0.05) p22phox expression only in SHR. Malonyl dialdehyde (MDA) levels were higher (P < 0.05), and the ratio reduced/oxidized glutathione (GSH/GSSG) as well as glutathione peroxidase activity (GPx) were lower (P < 0.05) in liver homogenates from SHR than from WKY. Candesartan reduced (P < 0.05) MDA and increased (P < 0.05) GSH/GSSG ratio without affecting GPx. Vessel, lumen, and media areas were bigger (P < 0.05) in SHR than in WKY. Candesartan treatment reduced (P < 0.05) media area in SHR without affecting vessel or lumen area. The results suggest that hypertension is not only associated with elevation of vascular superoxide anions but with alterations of the hepatic redox system, where ANG II is clearly involved. The results further support the key role of ANG II via AT1 receptors for the functional and structural vascular alterations produced by hypertension.
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PMID:Effect of AT1 receptor blockade on hepatic redox status in SHR: possible relevance for endothelial function? 1277 56

Certain hexavalent chromium (Cr(VI))-containing compounds are recognized occupational human lung carcinogens and may pose an environmental health risk. The carcinogenicity of Cr(VI) is targeted to particulate forms of moderate to low solubility. Soluble Cr(VI) oxyanions in the immediate cellular microenvironment traverse the cell membrane by non-specific anionic transporters. Cr(VI) is reductively metabolized within cells by agents including ascorbic acid (Asc), glutathione (GSH) and cysteine (Cys). During Cr(VI) reduction, a diverse range of genetic lesions are generated including Cr-DNA binary (mono) adducts, Cr-DNA ternary adducts, DNA protein crosslinks (DPCs), bi-functional (DNA interstrand crosslinks (ICLs)) adducts, single-strand breaks (SSBs) and oxidized bases. Some forms of Cr damage, such as ICLs, present physical barriers to DNA replication/transcription and, thus, likely promote a terminal cell fate such as apoptosis or terminal growth arrest. Other lesions, such as ternary DNA adducts, are potentially pre-mutagenic. Cr(VI) exposure elicits a classical DNA damage response within cells including activation of the p53 signaling pathway and cell cycle arrest or apoptosis. Moreover, Cr(VI) also induces the ATM-dependent DNA damage response pathway which is paradoxically required for both apoptosis and survival after Cr(VI) insult. In yeast, moderately cytotoxic concentrations of Cr(VI) result in an initial G1 arrest and delayed S phase progression, whereas less toxic levels of Cr(VI) induce G2 arrest, which requires homologous recombination for exit and survival. The past several years has witnessed many important advances in our understanding of the genetic/cellular damage produced by exposure to Cr(VI). Further information is needed regarding the potential involvement of oxygen radicals in Cr genotoxicity, the specific DNA repair pathways activated by Cr and the complex signaling mechanisms involved in the cellular response to Cr(VI). These pertinent issues must be considered in relation to the potential role that each plays in the induction of human respiratory tract cancer by particulate Cr(VI) compounds.
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PMID:Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms. 1464 11

The renin-angiotensin system (RAS) has been found in mammalian ovarian tissue; however, its physiological role is unclear. This study examined the content of angiotensin II (Ang II) in porcine follicular fluid (pFF), Ang II localization and its receptors in ovary, and the effects of Ang II on porcine oocyte maturation. The concentrations of Ang II were 6951.82 +/- 1295.83, 3502.99 +/- 679.10, 3147.89 +/- 690.60, and 2545.92 +/- 407.01 pg/ml in pFF from small, medium, large, and extra-large follicles, respectively. In addition, Ang II was found on zona pellucidae (ZP) and granulosa cells by immunoreactive staining. The distribution of AT1, an Ang II receptor subtype, was in accordance with that of Ang II. However, AT2, another Ang II receptor, was mainly distributed in the stroma and thecal layers of follicles. When oocytes were cultured in media containing various concentrations of Ang II, a higher (P<0.05) proportion of oocytes reached metaphase II (MII) in the medium with 100 ng/ml (87.0%) than without Ang II (61%). When oocytes from different sizes of follicles were separately cultured in media containing 100 ng/ml Ang II, maturation rates were significantly higher in oocytes from small (61.5%) and medium (85.1%) follicles than that of their controls (45.1 and 72.6%, respectively). However, addition of Ang II inhibited nuclear maturation in oocytes from large follicles (77.8% versus 87.3%). Fertilization and male pronuclear (MPN) formation rates of oocytes matured in medium containing 100 or 1000 ng/ml of Ang II were higher (P<0.05) than that of oocytes matured in medium containing 0 or 10 ng/ml Ang II. Glutathione content in oocytes cultured for 44 h in medium containing 100 or 1000 ng/ml of Ang II was also higher (P<0.01) than that of oocytes cultured in medium containing 0 or 10 ng/ml Ang II. In conclusion, Ang II was present in porcine ovaries and may regulate follicle growth and oocyte maturation.
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PMID:Localization of angiotensin II in pig ovary and its effects on oocyte maturation in vitro. 1466 43

The aim of this work was to investigate the production of oxidative damage in homogenized kidney, liver and brain of spontaneously hypertensive rats (SHR), as well as the involvement of angiotensin (Ang) II in this process. Groups of 12-week-old SHR and Wistar Kyoto rats (WKY) were given 10 mg/kg/day losartan in the drinking water during 14 days. Other groups of WKY and SHR without treatment were used as controls. The production of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were determined. No significant difference in TBARS was observed between untreated SHR or WKY rats; GSH content was lower in the liver but higher in the brain of SHR compared to WKY rats. In tissues from the SHR group, SOD and Gpx activities were reduced, whereas CAT activity was slightly increased in kidney. TBARS levels did not change in WKY rats after losartan administration, but were reduced in SHR liver and brain. Losartan treatment decreased GSH content in WKY kidney, but increased GSH in SHR liver. The activity of the antioxidant enzymes was not modified by losartan in WKY rats; however, their activities increased in tissues from treated SHR. The lower activity of antioxidant enzymes in tissues from hypertensive rats compared to those detected in normotensive controls, indicates oxidative stress production. Ang II seems to play no role in this process in normotensive animals, although AT1 receptor blockade in SHR enhances the enzymatic activity indicating that Ang II is implicated in oxidative stress generation in the hypertensive animals.
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PMID:Effects of angiotensin II type 1 receptor blockade on the oxidative stress in spontaneously hypertensive rat tissues. 1572 81


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