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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caffeine was found to potentiate X-ray-induced killing of human diploid fibroblasts from a normal subject and an ataxia-telangiectasia (AT) patient when it was present at 2 mM concentration for 30 to 66 hr postirradiation. The dose-modifying factor for caffeine-treated normal cells had an average value of 1.26 +/- 0.13 which did not vary significantly with treatment time or X-ray dose. The dose-modifying factor for caffeine-treated AT cells was 1.12 +/- 0.12 at 30 hr, rose to 1.66 +/- 0.17 at 41 hr, and decreased to 1.31 +/- 0.13 at 66 hr. Thus no clear difference was observed between these two cell strains' susceptibility to postirradiation caffeine treatment.
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PMID:The potentiation by caffeine of X-ray damage to cultured human skin fibroblasts from normal subjects and ataxia-telangiectasia patients. 687 30

Two-methyl-methanesulfonate-sensitive strains have been isolated, one of which, M10, was cross-sensitive to X-rays as reported before. Sensitivities of parental L5178Y, M10, and newly isolated MS-1 cells to various mutagens were examined. Mutagens tested were UV, X-rays, 4-nitroquinoline 1-oxide (4NQO), caffeine and alkylating agents; methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS) and mitomycin C (MMC). In terms of D37 values, M10 cells were 2.5-7 times more sensitive to EMS, MMC and 4NQO as well as to MMS and X-rays than were parental L5178Y cells, while the new mutant MS-1 was about 3 times more sensitive to MMS, EMS, MMC and caffeine than were parental cells. The characteristics in sensitivities of M10 cells to X-rays, alkylating agents and 4NQO resemble resemble some ataxia telangiectasia cells; and MS-1 cells to alkylating agents and caffeine are novel among mammalian cell mutants so far reported. Sensitivity of M10 cells to mutagens has so far been stable for one year, and that of MS-1 cells was stable for 6 months in continuous culture.
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PMID:A novel mutant of mouse lymphoma cells sensitive to alkylating agents and caffeine. 705 85

Cells from patients with the autosomal recessive genetic disease ataxia telangiectasia (AT) are more sensitive to killing by ionizing radiation than are cells from normal individuals. In contrast, ionizing radiation inhibits the rate of DNA synthesis much less in AT cells than in normal cells. This radioresistant DNA synthesis can be partly mimicked by treating normal cells with caffeine or by incubating normal cells in hypertonic medium after irradiation. Because both of these treatments seem to affect chromatin structure, it is possible that the radioresistant DNA synthesis in AT cells is due to an intrinsic difference in chromatin structure between AT cells and normal cells. This difference allows normal cells to recognize chromatin damage and to pause and repair it, whereas AT cells fail to recognize this damage, which leads to chromosomal aberrations.
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PMID:Structural changes in chromatin as the basis for radiosensitivity in ataxia telangiectasia. 711 35

Replicative DNA synthesis in normal human fibroblasts was inhibited by 50% when they were X-irradiated (8 Gy) and made permeable 30 min later, whereas only a slight inhibition (20%) was observed in similarly treated ataxia-telangiectasia cells. Treatment of irradiated normal cells with caffeine (2 mM) before permeabilization reversed the inhibitory effects of X-rays, buf caffeine had no effect on DNA synthesis in permeable ataxia-telangiectasia cells. Diadenosine tetraphosphate (0.1 mM) did not affect DNA synthesis in permeable normal fibroblasts.
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PMID:Replicative DNA synthesis in permeable fibroblasts from normal individuals and ataxia-telangiectasia patients. 713 18

Cell cycle delay has long been known to occur in mammalian cells after exposure to DNA-damaging agents. It has been hypothesized that the function of this delay is to provide additional time for repair of DNA before the cell enters critical periods of the cell cycle, such as DNA synthesis in S phase or chromosome condensation in G2 phase. Recent evidence that p53 protein is involved in the delay in G1 in response to ionizing radiation has heightened interest in the importance of cell cycle delay, because mutations in p53 are commonly found in human cancer cells. Because mammalian cells defective in p53 protein show increased genomic instability, it is tempting to speculate that the instability is due to increased chromosome damage resulting from the lack of a G1 delay. Although this appears at first glance to be a highly plausible explanation, a review of the research performed on cell cycle regulation and DNA damage in mammalian cells provides little evidence to support this hypothesis. Studies involving cells treated with caffeine, cells from humans with the genetic disease ataxia telangiectasia, and cells that are deficient in p53 show no correlation between G1 delay and increased cell killing or chromosome damage in response to ionizing radiation. Instead, G1 delay appears to be only one aspect of a complex cellular response to DNA damage that also includes delays in S phase and G2 phase, apoptosis and chromosome repair. The exact mechanism of the genomic instability associated with p53, and its relationship to the failure to repair DNA before progression through the cell cycle, remains to be determined.
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PMID:Cell cycle regulation in response to DNA damage in mammalian cells: a historical perspective. 760 17

In the present study we used radiotelemetry technology to investigate: 1) the time course for development of hypertension in 2-kidney, 1-clip (2K1C) rats and 2) the effect of chronic caffeine consumption on blood pressure in 2K1C rats. Rats received water or caffeine (0.1%) in drinking water and were instrumented with radiotelemetry devices to permit continuous monitoring of blood pressure. A clip was placed on the left renal artery of rats in both the water (WATER/CLIP) and caffeine (CAFFEINE/CLIP) groups. The clip was applied briefly to, then removed from, the renal artery of caffeine- and water-treated rats randomized to the sham-operated (SHAM) group. Mean arterial blood pressure (MABP) increased by approximately 35 mm Hg within 2 hr of clipping. MABP in the WATER/CLIP and CAFFEINE/CLIP groups differed significantly from the SHAM group, but not from each other, for the first 10 days after clipping. Thereafter, MABP was greater in the CAFFEINE/CLIP rats as compared to WATER/CLIP rats. At 4.5 weeks after clipping, MABP values differed significantly in the CAFFEINE/CLIP, WATER/CLIP and SHAM rats (140 +/- 4, 122 +/- 4 and 103 +/- 2 mm Hg, respectively). Involvement of the renin-angiotensin system was assessed by treatment with the AT1 receptor antagonist, losartan, and the converting enzyme inhibitor, captopril. Results from this study indicate: 1) hypertension develops rapidly after clipping in rats monitored with telemetry; 2) the renin-angiotensin system is involved in maintaining hypertension in 2K1C rats even beyond 4 weeks after clipping; and 3) caffeine augments the increase of blood pressure in 2K1C rats, apparently through the involvement of the renin-angiotensin system.
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PMID:Telemetric blood pressure monitoring in benign 2-kidney, 1-clip renovascular hypertension: effect of chronic caffeine ingestion. 793 54

The relationship between repair processes and chromosomal aberrations and X-ray-induced cell cycle perturbations were investigated in ataxia telangiectasia (AT) cells with 'intermediate' (AT-INT) and 'classical' radiosensitivity. In the cytogenetic experiments, three AT-INT lymphoblastoid cell lines were X-irradiated in G2-phase and incubated in the presence of inhibitors of DNA polymerases alpha/delta/epsilon (cytosine arabinoside, aphidicolin, 10% v/v DMSO), ribonucleotide reductase (hydroxyurea) and presumed inhibitors of protein kinases (caffeine). Flow cytometric analysis was performed in cells harvested 20 h after irradiation and stained with either propidium iodide or antibody against 5-bromodeoxiuridine in order to investigate cell cycle distribution focusing on G2/Mphase accumulation. From our data it appears that: (i) chromosomal sensitivity to radiation in AT does not always reflect clinical features; (ii) the effects of DNA repair inhibitors are inversely correlated with chromosomal radiosensitivity; and (iii) radiation-induced G2/M phase accumulation is a feature of AT cells and not necessarily correlated with cellular and chromosomal sensitivity to ionizing radiation.
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PMID:Modulation of radiation-induced chromosomal damage by inhibitors of DNA repair and flow cytometric analysis in ataxia telangiectasia cells with 'intermediate radiosensitivity'. 859 72

1. The action of angiotensin II (AII) was studied in single myocytes from rat portal vein in which the cytoplasmic Ca2+ concentration was estimated by emission from dyes Fura-2 or Indo-1 and the Ca2+ channel current was measured with the whole-cell mode of the patch-clamp technique. 2. Most of the AII-evoked increases in [Ca2+]i were reduced by about 60% after pretreatment with ryanodine and caffeine to deplete intracellular Ca2+ stores. However, in some cells the AII-induced Ca2+ responses were of small amplitude and resembled those obtained in the presence of ryanodine and caffeine. Both types of Ca2+ responses induced by AII were selectively inhibited by losartan, suggesting that the AII effects resulted from activation of the angiotensin AT1 receptors. 3. The concentration-response curve to AII had an EC50 value close to 1 nM for the increase in [Ca2+]i obtained after depletion of intracellular Ca2+ stores. This value was increased to around 18 nM in experiments where the intracellular Ca2+ stores were not depleted. 4. AII-evoked Ca2+ responses were abolished in the absence of external Ca2+ and in the presence of 1 microM oxodipine to block L-type Ca2+ channels. 5. Intracellular applications of the InsP3 receptor antagonist, heparin or an anti-PdtIns antibody did not modify AII-induced Ca2+ responses. 6. Our results show that AII releases Ca2+ from intracellular stores without involving InsP3 but through a Ca2+ release mechanism activated by Ca2+ influx through L-type Ca2+ channels.
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PMID:Angiotensin II-activated Ca2+ entry-induced release of Ca2+ from intracellular stores in rat portal vein myocytes. 873 78

The action of angiotensin II (ANG II) was studied in single myocytes from rat portal vein, in which the cytoplasmic Ca++ concentration was estimated by emission from fluorescent dyes and the Ca++ channel current was measured with the whole-cell mode of the patch-clamp technique. ANG II stimulated Ca++ channel current through L-type Ca++ channels and initiated a slow and small increase in the cytoplasmic Ca++ concentration in cells in which intracellular Ca++ stores had been depleted by pretreatment with ryanodine and caffeine. Both Ca++ channel current stimulation and Ca++ responses were selectively inhibited by losartan, indicating activation of angiotensin AT1 receptors. Activation of Ca++ channels by ANG II was insensitive to treatment with pertussis toxin and cholera toxin. Intracellular applications of anti-G alpha q/alpha 11 and anti-phosphatidylinositol antibodies had no effect on the ANG II-induced stimulation of Ca++ channel current, indicating that phosphatidylinositol-specific phospholipase C was not involved in this signaling pathway. Down-regulation of protein kinase C and application of an inhibitor of protein kinase C blocked the ANG II-induced effects. Tricyclodecan-9-yl xanthogenate (an inhibitor of non-phosphatidylinositol-specific phospholipases C and phospholipases D) but not propranolol (an inhibitor of phospholipase D-derived diacylglycerol formation) suppressed the ANG II-induced effects. These data suggest that phosphatidylcholine-specific phospholipase C is involved in the ANG II signaling pathway leading to stimulation of L-type Ca++ channels by protein kinase C.
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PMID:Angiotensin II-mediated activation of L-type calcium channels involves phosphatidylinositol hydrolysis-independent activation of protein kinase C in rat portal vein myocytes. 876 93

The effect of angiotensin II (ANG II) on the cytosolic calcium concentration ([Ca2+]i) was studied in freshly (2-8 h) isolated myocytes from the main pulmonary artery of the rat. Myocytes were loaded with the fluorescent indicator indo 1 (1 microM for 30 min) and experiments were performed at room temperature. Short (30 s) applications of ANG II (0.01-10 microM) induced cyclic variations oscillations in [Ca2+]i. The ANG II-induced response was typically composed of three to six oscillations of constant duration (9.8 +/- 0.5 s, n = 40) but of decreasing amplitude. The first oscillation increased [Ca2+]i from 119 +/- 4 to 884 +/- 33 nM (n = 32). ANG II-induced response was concentration dependently inhibited by previous addition to the bathing solution of losartan or SR-47436 (0.01-0.1 microM, each), two specific AT1 receptor-antagonists. In Ca(2+)-free external solutions (containing 0.4-1 mM EGTA), ANG II still produced oscillation in [Ca2+]i. These oscillations disappeared in myocytes pretreated with neomycin (0.1 microM), thapsigargin (1 microM), or phorbol 12,13-dibutyrate (PDBu, 1 microM). In contrast to ANG II, caffeine (o.5-10 mM) induced only one transient rise in [Ca2+]i, which was unaltered by neomycin or PDBu but blocked by thapsigargin. These results show that ANG II produces oscillations in [Ca2+]i in pulmonary arterial myocytes via stimulation of AT1 receptors coupled to phospholipase C activation. ANG II-induced oscillations appear to be related to the cycling of Ca2+ ions from an intracellular store (presumably the sarcoplasmic reticulum) by a primarily inositol trisphosphate-dependent Ca2+ release.
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PMID:Angiotensin II-induced Ca(2+)-oscillations in vascular myocytes from the rat pulmonary artery. 892 24


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