Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress is a major contributing factor in neurodegeneration and can arise from dietary, environmental, and genetic sources. Here we examine the separate and combined impact of deprivation of folate and vitamin E, coupled with dietary iron as a prooxidant, on normal mice and transgenic mice lacking apolipoprotein E (ApoE-/- mice). Both mouse strains exhibited increased levels of glutathione when deprived of folate and vitamin E, but a substantial further increase was observed in ApoE-/- mice. To determine the mechanism(s) underlying this increase, we quantified transcription and activity of glutathione synthase (GS). Both normal and ApoE-/- mice demonstrated increased GS activity when deprived of folate and vitamin E. However, transcription was increased only in ApoE-/- mice deprived of folate and vitamin E. These findings demonstrate that deficiency in one gene can result in compensatory up-regulation in a second relevant gene and, furthermore, indicate that compensation for oxidative stress can occur in brain tissue at epigenetic and genetic levels depending on the nature and/or extent of oxidative stress.
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PMID:Increased transcription and activity of glutathione synthase in response to deficiencies in folate, vitamin E, and apolipoprotein E. 1474 34

Increased oxidative stress, which can arise from dietary, environmental and/or genetic sources, contributes to the decline in cognitive performance during normal aging and in neurodegenerative conditions such as Alzheimer's disease. Supplementation with fruits and vegetables that are high in antioxidant potential can compensate for dietary and/or genetic deficiencies that promote increased oxidative stress. We have recently demonstrated that apple juice concentrate (AJC) prevents the increase in oxidative damage to brain tissue and decline in cognitive performance observed when transgenic mice lacking apolipoprotein E (ApoE-/-) are maintained on a vitamin-deficient diet and challenged with excess iron (included in the diet as a pro-oxidant). However, the mechanism by which AJC provided neuroprotection was not conclusively determined. Herein, we demonstrate that supplementation with AJC also prevents the compensatory increases in glutathione synthase transcription and activity that otherwise accompany maintenance of ApoE-/- mice on this vitamin-free diet in the presence of iron. Inclusion of the equivalent composition and concentration of sugars of AJC did not prevent these increases. These findings provide further evidence that the antioxidant potential of AJC can compensate for dietary and genetic deficiencies that otherwise promote neurodegeneration.
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PMID:Dietary supplementation with apple juice concentrate alleviates the compensatory increase in glutathione synthase transcription and activity that accompanies dietary- and genetically-induced oxidative stress. 1554 22

Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1 g/kg diet), a cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders.
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PMID:N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency. 1585 51

Folate deficiency increases neuronal oxidative damage and potentiates the deleterious effects of apolipoprotein E (ApoE) deficiency. Mice lacking ApoE (ApoE -/- mice) upregulate the expression and activity of another enzyme, glutathione synthase (GS), when deprived of folate, in an apparent attempt to compensate for increased oxidative damage. Herein, we examined the influence of ApoE and folate deficiency on expression and activity of several enzymes of the methionine cycle. Expression and activity of methylene tetrahydrofolate reductase was increased in the order ApoE +/+ < ApoE +/- < ApoE -/- in response to folate deprivation. Expression of cystathione beta synthase followed a similar pattern. By contrast, expression and activity of methionine synthase decreased following folate deprivation in the order ApoE +/+ < ApoE +/- < ApoE -/-. These studies demonstrate that folate deficiency induces compensatory regulation of methionine cycle genes, and that these effects are potentiated by ApoE deficiency in a gene-dosage manner. They further support the notion that latent genetic deficiencies, including those of methionine cycle, may contribute to Alzheimer's disease, especially in concert with age-related nutritional deficiencies.
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PMID:Expression and activity of methionine cycle genes are altered following folate and vitamin E deficiency under oxidative challenge: modulation by apolipoprotein E-deficiency. 1691 Jan 66