UMLS:C1260386 - FACTA Search

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Query: UMLS:C1260386 (GSH)
38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis: (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK3, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway.
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PMID:Cytotoxic effect through fas/APO-1 expression due to vitamin K in human glioma cells. 1093 97

Glutamate toxicity on PC12 cells is mediated by oxidative stress as a consequence of the inhibition of a cystine uptake system with depletion of GSH. In this study we report that glutamate decreases PC12 cell viability, inhibiting the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). This decrease was prevented by the antioxidants vitamin E, idebenone and L-deprenyl, which were also shown to be effective in reducing the accumulation of reactive oxygen species (ROS) in cells exposed to glutamate, decreasing the fluorescence of 2',7'-dichlorofluorescein (DCF). Incubation of PC12 cells with high glutamate concentrations induced mitochondrial dysfunction, leading to the loss of mitochondrial transmembrane potential, evaluated as a decrease in rhodamine 123 (Rh123) retention by mitochondria, and to the decrease of intracellular ATP levels. The mitochondrial dysfunction, induced by glutamate, can be involved in the observed increase of [Ca2+]i. The elevation of [Ca2+]i occurred after GSH depletion, suggesting that oxidative stress is involved in the disturbances of intracellular calcium homeostasis. In conclusion, our data indicate that glutamate, at concentrations which block cystine uptake in PC12 cells leading to GSH depletion and inducing oxidative stress, increases ROS accumulation and decreases cell survival by a mechanism involving mitochondrial dysfunction and impairment of Ca2+ homeostasis.
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PMID:Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis. 1094 Apr 57

Forty-seven ovarian cancer cases in which 20 were previously treated with cisplatin (cisPt) based chemotherapy, were checked for in vitro chemosensitivity using MTT assay. The drugs included in the study were cisPt, adriamycin (ADR), epirubicin (EPR) and etoposide (ETO). The logarithemic concentrations (0.1, 1.0, 10.0 and 100.0 micrograms/ml) of these drugs were used in the MTT assay. The IC50 values for these drugs in the above tumor samples were calculated. The effect of pretreatment with cisPt based chemotherapy on the emergence of drug resistance, expression of p53 protein (detected using immunohistochemical method by employing monoclonal antibody to p53) and intracellular glutathione (GSH) levels was also studied. Our results demonstrated the superiority of EPR in terms of its efficacy as compared to the other drugs used in the study. EPR was effective in both, previously cisPt-exposed and cisPt-unexposed ovarian cancer cases indicating its importance as a second line chemotherapy in the refractory ovarian carcinoma cases. Pre-exposure to cisPt based chemotherapy appears to result in the emergence of cisPt resistance, elevated intracellular GSH levels as well as p53 positivity. A statistically significant correlation was also observed between ADR and EPR resistance and p53 positivity (P < 0.01 and 0.05 respectively).
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PMID:Effect of cisplatin-based chemotherapy on emergence of cisplatin resistance, and its correlation with intracellular glutathione levels and accumulation of p53 protein in human ovarian cancer. 1094 37

Adenophora triphylla (AT), an oriental medicinal plant, was extracted using water and several organic solvents and each fraction was assayed for its tumoricidal effects on human Jurkat T cells with 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT). The influence on induction of apoptosis and G1 arrest was also examined. The ethyl acetate fraction showed the most pronounced inhibitory effects on proliferation of Jurkat T cells. Apoptosis was induced in line with up-regulation of FasL, tyrosine phosphorylation and c-fos mRNA levels. Arrest in G1 of the cell cycle was observed in A2780 cells with a wild type p53 gene but not HT-29 cells with a mutant p53 gene. Modifying effects of AT on cell turnover and glutathione(GSH) levels in vivo were also investigated in the stomach of rats given 150 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by gavage and then fed a diet supplemented with 5% or 1% pulverized AT and 0.5% or 0.2% ethylacetate-extracted AT for 42 hours. The 5% AT and both of the ethylacetate fractions caused significant reduction in proliferating cell nuclear antigen (PCNA)-labeling in the glandular stomach epithelium as compared with the value for the MNNG alone group. In addition, the treatments significantly increased the gastric GSH levels. These results suggest that AT could be a chemopreventive agent against gastric cancer.
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PMID:Suppressive effects of Adenophora triphylla extracts on in vitro tumor cell growth and in vivo gastric epithelial proliferation. 1106 47

The potential anti-radical properties and cytoprotective effects of Mg-gluconate were studied. When microsomal membranes were peroxidized by a *O2- driven, Fe-catalyzed oxy-radical system (R* = dihydroxyfumarate + Fe2+), Mg-gluconate inhibited lipid peroxidation (TBARS formation) in a concentration-dependent manner with IC50 being 2.3 mM. For the entire range of .25-2 mM, MgSO4 or MgCl2 were < or = 20% effective compared to Mg-gluconate. When cultured bovine aortic endothelial cells were incubated with the R* for 50 min. at 37 degrees C, 56% loss of total glutathione occurred. Pre-treatment (10 min.) of the cells with 0.25-4 mM Mg-gluconate before R* exposure significantly (p<0.05) prevented the GSH loss to varying degrees; the EC50 was 1.1 mM. In separate experiments, with 30 min. of free radical incubation of endothelial monolayers (approximately 65% confluent), cell survival/proliferation determined by the tetrazolium salt MTT assay, decreased to 38% of control at 24 hrs; Mg-gluconate concentration-dependently attenuated the lost cell survival with EC50 of approximately 1.3 mM. For comparison, the effects provided by MgSO4 or MgCl2 were significantly lower and were < or = 1/3 as potent as that produced by Mg-gluconate. In a Fenton-reaction system consisting of Fe(II)+ H2O2, Mg-gluconate but not other Mg-salts, significantly inhibited the formation of OH radicals as determined by the ESR DMPO-OH signal intensity. Mg-gluconate also dose-dependently inhibited the 'Fe-catalyzed' deoxyribose degradation suggesting that Mg-gluconate could displace Fe from 'catalytic sites' of oxidative damage. These data suggest that Mg-gluconate may serve as a more advantageous Mg-salt for clinical use due to its additional anti-radical and cytoprotective activities.
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PMID:Protective mechanisms of Mg-gluconate against oxidative endothelial cytotoxicity. 1115 79

To overcome the drug resistance, which is the major obstacle in the successful treatment of cancer patients, various compounds have been tested. Glutathione is one of the most promising targets for modulation. In the present study, we examined the influence of five new synthesized compounds--diazenes on the reduction of the intracellular level of GSH. Further, we investigated their ability to increase the cytotoxicity of cisplatin, vincristine and doxorubicin. In experiments human parental cervical (HeLa) and laryngeal (HEp2) carcinoma cells and their drug-resistant cell sublines (HeLaCA and CK2, respectively) were used. Intracellular GSH content was examined spectrophotometrically by the procedure developed by Tietze. The cell sensitivity to drugs was determined using a modified colorimetric MTT assay. Results showed that the rate of reduction of GSH concentration was dependent on the cell type and the type of diazenes. We did not find a correlation between the reduction in GSH level and increased cytotoxicity to selected anticancer drugs. Nevertheless, we found that: a) diazenes LV-35 and VZ-19 increased the cytotoxicity of cisplatin in HEp2 cells, b) diazene MG-19 potentiated the cytotoxicity of vincristine in HEp2 cells, and c) diazene VZ-19 in HeLaCA cells. These data suggest that specific combination of diazene and anticancer drug may be useful in the treatment of certain tumor types.
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PMID:Diazenes as modificators of drug-resistance in tumor cells. 1126 64

The effects of dithiothreitol (DTT), a sulfhydryl-containing agent and verapamil (VRP), a calcium channel blocker as possible cytoprotectants against the atractyloside-induced toxicity were characterized in rat kidney and liver slices in vitro using multiple markers of toxicity. Precision-cut slices (200 microM thick) were either incubated with atractyloside (2 mM) or initially preincubated with either DTT (5 mM) or VRP (100 microM) for 30 min followed by exposure to atractyloside (2 mM) for 3 h at 37 degrees C on a rocker platform rotated at approximately 3 rpm. All of the toxicity parameters were sensitive to exposure to atractyloside, but treatment with DTT or VRP alone did not provide any indication of damage to the tissues. Preincubation of slices containing either DTT or VRP for 30 min provided total protection against atractyloside-induced increase in LDH leakage in both kidney and liver slices. Increased induction of lipid peroxidation by atractyloside in liver slices was completely abolished by DTT and VRP. Both DTT and VRP provided partial protection against atractyloside-induced inhibition of gluconeogenesis in both kidney and liver slices. Atractyloside-induced ATP depletion in both kidney and liver slices was partially abolished by VRP but not DTT. The significant depletion of GSH in the kidney slices by atractyloside was completely reversed by DTT only, while VRP alone reversed the same process in liver slices. Decreased MTT reductive capacity and significant increase in ALT leakage caused by atractyloside in liver slices was partially reversed. Complete protection was achieved with both DTT and VRP against atractyloside-induced inhibition of PAH uptake in kidney slices. These findings suggest that both DTT and VRP exert cytoprotective effects in atractyloside-induced biochemical perturbation, effects that differ in liver and kidney. The effect of these agents on atractyloside has provided us with a further understanding of the molecular mechanism of its action.
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PMID:Effects of the calcium channel blocker verapamil and sulphydryl reducing agent dithiothreitol on atractyloside toxicity in precision-cut rat renal cortical and liver slices. 1152 39

Sulfur mustard (bis(2-chloroethyl)sulfide, SM) is a highly reactive bifunctional alkylating agent that forms sulfonium ions in the body. SM alkylates DNA, leading to DNA strand breaks and cell death in a variety of cell types and tissues. Although several approaches have been proposed to challenge the toxic action(s) of SM, no satisfactory treatment regimen has evolved. The synthetic aminothiol amifostine, earlier known as WR-2721 (S-2-(3-aminopropylamino)ethyl phosphorothioate), has been extensively used as a chemical radioprotector for the normal tissues in cancer radiotherapy and chemotherapy. SM is known as a radiomimetic agent and this prompted us to evaluate the protective efficacy of amifostine (2.5 mM) and three of its analogues, DRDE-06 (S-2 (3-aminopropylamino) ethyl phenyl sulfide), DRDE-07 (S-2 (2-aminoethylamino) ethyl phenyl sulfide), and DRDE-08 (S-2 (4-aminobutylamino) ethyl phenyl sulfide), against SM toxicity in rat liver slices. Of the four agents tested, a 30-min pretreatment of amifostine and DRDE-07 enhanced the LC50 (a concentration producing 50% leakage of lactate dehydrogenase (LDH) or alanine aminotransferase (ALT)) of SM by 5.9- and 3.3-fold for LDH and 10.2- and 5.5-fold for ALT, respectively. Except DNA fragmentation, both these agents significantly attenuated the loss of intracellular K(+) and mitochondrial integrity (MTT assay), depletion of GSH levels, and histopathology produced by a toxic concentration (80 microM) of SM. However, when amifostine and DRDE-07 were introduced 2 h after SM, no significant protection was observed. SM (77.5 or 155 mg/kg) was also applied dermally on female albino mice and challenged by 0.20 LD50 (po) of amifostine, DRDE-06, DRDE-07, or DRDE-08 at -30 min, 0 min, or +6 h. Protection was observed only when the agents were administered at -30 min or 0 min; posttreatment (+6 h) did not offer any protection. The magnitude of in vivo protection was in the following order: DRDE-07 >or= amifostine > DRDE-08 > DRDE-06. Gas chromatographic analysis showed that there was no direct chemical interaction between SM and the antidotes. The po LD50s of amifostine, DRDE-06, DRDE-07, and DRDE-08 were 1049, 1345, 1248, and 951 mg/kg, respectively. Both in vitro and in vivo data indicate promising roles of amifostine and DRDE-07 as prophylactic agents against SM poisoning.
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PMID:Protective effects of amifostine and its analogues on sulfur mustard toxicity in vitro and in vivo. 1157 46

The quaternary benzo[c]phenanthridine alkaloids (QBA) produce a plethora of species- and tissue-specific effects but the molecular basis of their biological activities remain mysterious. The objective of the present study was to investigate the cytotoxicity of QBA alkaloids, sanguinarine (SA), chelerythrine (CHE), fagaronine (FA), and the extract from Macleaya cordata in primary cultures of human and porcine hepatocytes. The cellular damage was assessed by the MTT assay, lactate dehydrogenase (LDH) leakage and the determination of intracellular glutathione (GSH) levels. The results are summarised as follows: (i) The alkaloids tested in doses 0.1 and 10 microM did not display statistically significant cytotoxicity for 0-3 h incubation; (ii) SA and CHE showed the dose- and time-dependent toxicity within the range 25-100 microM whereas FA was not toxic; (iii) the LDH leakage into the medium was higher for SA than for CHE, thus revealing a potent potential of SA to disturb cell-membrane integrity; (iv) after 3 h incubation with 100 microM SA/CHE, mitochondrial dehydrogenase activity (MTT assay) and the cellular GSH levels decreased to residual values of about 40% suggesting that mitochondria are unlikely to be a primary target for SA/CHE in the cell; (v) no differences were found in the response to QBA application in human vs porcine hepatocyte.
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PMID:Cytotoxicity of natural compounds in hepatocyte cell culture models. The case of quaternary benzo[c]phenanthridine alkaloids. 1170 Dec 31

Oxidative stress elicits an adaptive antioxidant response, which varies with tissue type. Diquat, a potent redox cycler that generates reactive oxygen species, has been used to study oxidative stress; however, its effect on the antioxidant system has not been characterized in neuronal cells. Accordingly, we measured antioxidant parameters and cell growth in human neuroblastoma SH-SY5Y cells cultured for 48 h in medium containing 5, 10, or 25 microM diquat dibromide or phosphate-buffered saline. Viable cells were assayed for glutathione (GSH) and activities of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPX), and glucose-6-phosphate dehydrogenase (GPDH). Mitochondrial function was evaluated by glutamate dehydrogenase (GDH) activity and MTT reduction. Diquat caused a marked concentration-related decrease in viable cell count ( by 26, 51, and 87% at 5, 10, and 25 microM diquat). Cell viability was only affected at 10 and 25 microM diquat and did not fully account for the decreased viable cell count. Concentration-related increases also occurred with GSH levels and a majority of antioxidant enzymes activities; however, the mode and magnitude varied with parameter. Increases in GSH, CAT, SOD, and GR were maximal at 25 microM diquat (to 3-, 6-, 2-, and 1.5-fold control values, respectively). GPDH activity was maximal at 10 microM diquat and then decreased to 86% of control activity at 25 microM diquat. GPX activity showed a concentration-related decrease (to 35% of control). Activity of the mitochondrial enzyme GDH increased 3-fold at 25 microM diquat, along with a lesser increase in MTT reduction. We conclude that diquat reduces cell growth in neuroblastoma cells and induces an adaptive antioxidant response, which are concentration dependent and occur at sublethal concentrations. At higher concentrations, diquat alters mitochondrial function and becomes increasingly toxic.
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PMID:Effect of diquat on the antioxidant system and cell growth in human neuroblastoma cells. 1181 26

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