Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flying-foxes are better able to defend haemoglobin against autoxidation than non-volant mammals such as sheep. When challenged with the common physiological oxidant, hydrogen peroxide, haemolysates of flying-fox red blood cells (RBC) were far less susceptible to methaemoglobin formation than sheep. Challenge with 1-acetyl-2-phenylhydrazine (APH) caused only half as much methaemoglobin formation in flying-fox as in ovine haemolysates. When intact cells were challenged with phenazine methosulfate (PMS), flying-fox RBC partially reversed the oxidant damage, and reduced methaemoglobin from 40 to 20% over 2 h incubation, while ovine methaemoglobin remained at 40%. This reflected flying-fox cells' capacity to replenish GSH fast enough that it did not deplete beyond 50%, while ovine RBC GSH was depleted to around 20%. The greater capacity of flying-foxes to defend haemoglobin against oxidant damage may be explained in part by antioxidant enzymes catalase, superoxide dismutase and cytochrome-b ( 5 ) reductase having two- to four-fold higher activity than in sheep (P < 0.001). Further, their capacity to limit GSH depletion to 50% and reduce methaemoglobin (in the presence of glucose), despite ongoing exposure to PMS may result from having ten-fold higher activity of G6PD and 6PGD than sheep (P < 0.001), indicating the presence of a very efficient pentose phosphate pathway in flying-foxes.
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PMID:High activity antioxidant enzymes protect flying-fox haemoglobin against damage: an evolutionary adaptation for flight? 1675 14

Gastric cancer and colon cancer are major causes of mortality and morbidity worldwide. Many cancers manifest due to changes in gene expression, particularly those involved in cellular proliferation and apoptosis. Apoptosis is an important process that removes damaged or deleterious cells and contributes to normal cellular and tissue homeostasis. Apoptosis is a tightly regulated process mediated by caspases, and the involvement of the Bcl-2 superfamily of membrane bound proteins, among others. Thus, the therapeutic induction of apoptosis has been proposed as a novel method to eliminate cancer cells. The oxidative pentose pathway (OPP) and the glutathione (GSH) antioxidant defense system play an important role in the regulation of cell growth and apoptosis. The OPP regulates intracellular redox status and provides NADPH for the synthesis of GSH, an important antioxidant. GSH is required to inactivate intracellular reactive oxygen species (ROS) which induce apoptosis and cell injury. Depletion of GSH increases the sensitivity of cells to ROS. Many chemotherapeutic agents induce apoptosis through ROS-mediated cell damage. Therefore, we speculate that the therapeutic inhibition of the OPP and/or the GSH defense system may increase the sensitivity of gastric and colon cancer cells to anti-cancer therapy. Moreover, we hypothesize that the short-chain fatty acid, butyrate, will induce apoptosis in gastric cancer cells and, secondly, that differences in butyrate metabolism will exist between these cancer cell lines.
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PMID:Nutrient and antioxidant modulation of apoptosis in gastric and colon cancer cells. 1676 Jun 45

Tub is a member of a small gene family, the tubby-like proteins (TULPs), with predominant expression in neurons. Mice carrying a mutation in Tub develop retinal and cochlear degeneration as well as late-onset obesity with insulin resistance. During behavioral and metabolic testing, we found that homozygous C57BL/6J-Tub(tub) mice have a lower respiratory quotient than C57BL/6J controls before the onset of obesity, indicating that tubby homozygotes fail to activate carbohydrate metabolism and instead rely on fat metabolism for energy needs. In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver. Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase (G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction. Reduced G6PDH protein levels and enzymatic activity in tubby mice lead accordingly to lower levels of NADPH and reduced glutathione (GSH), respectively. mRNA levels for the lipolytic enzymes acetyl-CoA synthetase and carnitine palmitoyltransferase are increased during the dark cycle and decreased during the light period, and several citric acid cycle genes are dysregulated in tubby mice. Examination of hypothalamic gene expression showed high levels of preproorexin mRNA leading to accumulation of orexin peptide in the lateral hypothalamus. We hypothesize that abnormal hypothalamic orexin expression leads to changes in liver carbohydrate metabolism and may contribute to the moderate obesity observed in tubby mice.
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PMID:Defective carbohydrate metabolism in mice homozygous for the tubby mutation. 1684 32

There is increasing evidence that proinflammatory products of the 5-lipoxygenase pathway play an important role in cardiovascular disease. In the present study, we found that human endothelial cells rapidly oxidize the 5-lipoxygenase product 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent chemoattractant for myeloid cells. 5-Oxo-ETE synthesis is strongly stimulated by oxidative stress. This effect is enhanced following inhibition of the pentose phosphate pathway with dehydroepiandrosterone and is mimicked by diamide, which oxidizes intracellular GSH to GSSG. Conversely, it is blocked by depletion of intracellular GSH/GSSG. The kinetics of H2O2-induced 5-oxo-ETE synthesis by endothelial cells correlate well with changes in the intracellular levels of GSSG and NADP+. These results suggest that exposure of the endothelium to oxidative stress and inflammation could result in the synthesis of 5-oxo-ETE, which could then induce the infiltration of inflammatory cells into the tissue.
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PMID:Metabolism of 5-hydroxy-6,8,11,14-eicosatetraenoic acid by human endothelial cells. 1699 73

Cardiovascular complications of diabetes mellitus involve oxidative stress and profound changes in reduced glutathione (GSH), an essential tripeptide that controls many redox-sensitive cell functions. This study examined regulation of GSH by insulin to identify mechanisms controlling cardiac redox state and to define the functional impact of GSH depletion. GSH was measured by fluorescence microscopy in ventricular myocytes isolated from Sprague-Dawley rats made diabetic by streptozotocin, and video and confocal microscopy were used to measure mechanical properties and Ca(2+) transients, respectively. Spectrophotometric assays of tissue extracts were also done to measure the activities of enzymes that control GSH levels. Four weeks after injection of streptozotocin, mean GSH concentration ([GSH]) in isolated diabetic rat myocytes was approximately 36% less than in control, correlating with decreased activities of two major enzymes regulating GSH levels: glutathione reductase and gamma-glutamylcysteine synthetase. Treatment of diabetic rat myocytes with insulin normalized [GSH] after a delay of 3-4 h. A more rapid but transient upregulation of [GSH] occurred in myocytes treated with dichloroacetate, an activator of pyruvate dehydrogenase. Inhibitor experiments indicated that insulin normalized [GSH] via the pentose pathway and gamma-glutamylcysteine synthetase, although the basal activity of glucose-6-phosphate dehydrogenase was not different between diabetic and control hearts. Diabetic rat myocytes were characterized by significant mechanical dysfunction that correlated with diminished and prolonged Ca(2+) transients. This phenotype was reversed by in vitro treatment with insulin and also by exogenous GSH or N-acetylcysteine, a precursor of GSH. Our data suggest that insulin regulates GSH through pathways involving de novo GSH synthesis and reduction of its oxidized form. It is proposed that a key function of glucose metabolism in heart is to supply reducing equivalents required to maintain adequate GSH levels for the redox control of Ca(2+) handling proteins and contraction.
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PMID:Insulin regulation of glutathione and contractile phenotype in diabetic rat ventricular myocytes. 1705 75

Energy homeostasis of the oocyte is a crucial determinant of fertility. Following ovulation, the oocyte is exposed to the unique environment of the Fallopian tube, and this is reflected in a highly specialised biochemistry. The minute amounts of tissue available have made the physiological analysis of oocyte intermediary metabolism almost impossible. We have therefore used confocal imaging of mitochondrial and cytosolic redox state under a range of conditions to explore the oxidative metabolism of intermediary substrates. It has been known for some time that the early mouse embryo metabolises external pyruvate and lactate but not glucose to produce ATP. We now show at the level of single oocytes, that supplied glucose has no effect on the redox potential of the oocyte. Pyruvate is a cytosolic oxidant but a mitochondrial reductant, while lactate is a strong cytosolic reductant via the activity of lactate dehydrogenase. Unexpectedly, lactate-derived pyruvate appears to be diverted from mitochondrial oxidation. Our approach also reveals that the level of reduced glutathione (GSH) in the oocyte is maintained by glutathione reductase, which oxidises intracellular NADPH to reduce oxidised glutathione. Surprisingly, NADPH does not seem to be supplied by the pentose phosphate pathway in the unfertilised oocyte but rather by cytosolic NADP-dependent isocitrate dehydrogenase. Remarkably, we also found that the oxidant action of pyruvate impairs development, demonstrating the fundamental importance of redox state on early development.
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PMID:Regulation of redox metabolism in the mouse oocyte and embryo. 1718 19

The short-chain fatty acid (SCFA) butyrate is known to induce apoptosis in colon cancer cells in vitro and in vivo, however, its mode of action is poorly defined, whilst less is known regarding the effects of the SCFA propionate. This study investigated the potential for butyrate and propionate to alter cell viability, cell cycle regulation and intracellular protective mechanisms in a human gastric cancer cell line (Kato III). Kato III cells were incubated with butyrate or propionate for 24, 48 and 72 hr. At each time point, cells were assessed for the induction of apoptosis and cell cycle alterations using flow cytometry. Oxidative pentose pathway (OPP) activity and glutathione (GSH) availability were also measured as an index of intracellular protection. Butyrate and propionate differentially induced apoptosis and necrosis in Kato III cells and arrested cells in the G2-M phase. OPP activity was significantly increased by both SCFAs although butyrate induced a 10-fold greater increase than propionate. GSH availability was significantly decreased in Kato III cells by butyrate and propionate. These findings demonstrate that butyrate and propionate induce apoptosis and cell cycle alterations in Kato III gastric cancer cells. Moreover, the effects of butyrate were significantly greater than propionate. We propose that alterations to intracellular redox state and GSH availability play an important role in SCFA-mediated cell death in this cell type. The inclusion of butyrate and propionate as adjunctive cancer therapies has the potential to enhance the efficacy of current chemotherapeutics in the treatment of gastric cancer.
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PMID:Short-chain fatty acid modulation of apoptosis in the Kato III human gastric carcinoma cell line. 1761 4

The intensity of lipid peroxidation (LPO), reduced and oxidized glutathione (GSH and GSSG) contents, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase (G-6-PDH), and NADP-isocitrate dehydrogenase (NADP-IDH) activities were studied in the heart of male rats exposed to two modes of intermittent hypoxic training (IHT): I-breathing in normobaric chamber with 7% O2 gas mixture for 5 min with 15 min normoxic intervals 4 times daily during 3 weeks; II-breathing by 12% O2 gas mixture in the same manner). After adaptation to hypoxia, the rats were subjected to 6h-immobilization stress. It has been shown that stress action after IHT (regime I) caused the increase in LPO and the shift of GSH/GSSG to disulfides. A disbalance in antioxidative defense system was determined by the decrease in glutatione peroxidase, G-6-PDH activities, and GSH content. The support of glutathione reductase activity under stress in this group with simultaneous decrease of enzyme activity in the pentose phosphate pathway was realized through the participation of NADP-IDH. Hypoxic training in regime II induced LPO decrease in the heart tissue after stress. The increase in the heart GSH content, optimal balance of glutathione-related enzymes in this group evidences for the dependence of adaptation effects on the vigor of hypoxic exposition. Our results suggest the active participation of glutathione system in the formation of adaptation reactions under the extreme factor influences through the action on intracellular red/ox potential as well as effectiveness of antioxidant defense.
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PMID:[Glutathione system adaptation to acute stress in the heart of rats during different regimes of hypoxia training]. 1798 18

Friedreich's ataxia is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. The main phenotypic features of frataxin-deficient human and yeast cells include iron accumulation in mitochondria, iron-sulphur cluster defects and high sensitivity to oxidative stress. Glutathione is a major protective agent against oxidative damage and glutathione-related systems participate in maintaining the cellular thiol/disulfide status and the reduced environment of the cell. Here, we present the first detailed biochemical study of the glutathione-dependent redox status of wild-type and frataxin-deficient cells in a yeast model of the disease. There were five times less total glutathione (GSH+GSSG) in frataxin-deficient cells, imbalanced GSH/GSSG pools and higher glutathione peroxidase activity. The pentose phosphate pathway was stimulated in frataxin-deficient cells, glucose-6-phosphate dehydrogenase activity was three times higher than in wild-type cells and this was coupled to a defect in the NADPH/NADP(+) pool. Moreover, analysis of gene expression confirms the adaptative response of mutant cells to stress conditions and we bring evidence for a strong relation between the glutathione-dependent redox status of the cells and iron homeostasis. Dynamic studies show that intracellular glutathione levels reflect an adaptation of cells to iron stress conditions, and allow to distinguish constitutive stress observed in frataxin-deficient cells from the acute response of wild-type cells. In conclusion, our findings provide evidence for an impairment of glutathione homeostasis in a yeast model of Friedreich's ataxia and identify glutathione as a valuable indicator of the redox status of frataxin-deficient cells.
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PMID:Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich's ataxia. 1856 74

Neurons and cancer cells use glucose extensively, yet the precise advantage of this adaptation remains unclear. These two seemingly disparate cell types also show an increased regulation of the apoptotic pathway, which allows for their long-term survival. Here we show that both neurons and cancer cells strictly inhibit cytochrome c-mediated apoptosis by a mechanism dependent on glucose metabolism. We report that the pro-apoptotic activity of cytochrome c is influenced by its redox state and that increases in reactive oxygen species (ROS) following an apoptotic insult lead to the oxidation and activation of cytochrome c. In healthy neurons and cancer cells, however, cytochrome c is reduced and held inactive by intracellular glutathione (GSH), generated as a result of glucose metabolism by the pentose phosphate pathway. These results uncover a striking similarity in apoptosis regulation between neurons and cancer cells and provide insight into an adaptive advantage offered by the Warburg effect for cancer cell evasion of apoptosis and for long-term neuronal survival.
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PMID:Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. 1902 8


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