Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that have promoting activity in the liver. PCBs induce oxidative stress, which may influence carcinogenesis. Epidemiological studies strongly suggest an inverse relationship between dietary selenium (Se) and cancer. Despite evidence linking Se deficiency to hepatocellular carcinoma and liver necrosis, the underlying mechanisms for Se cancer protection in the liver remain to be determined. We examined the effect of dietary Se on the tumor promoting activities of two PCBs congeners, 3,3', 4,4'-tetrachlorobiphenyl (PCB-77) and 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB-153) using a 2-stage carcinogenesis model. An AIN-93 torula yeast-based purified diet containing 0.02 (deficient), 0.2 (adequate), or 2.0 mg (supplemental) selenium/kg diet was fed to Sprague-Dawley female rats starting ten days after administering a single dose of diethylnitrosamine (150 mg/kg). After being fed the selenium diets for 3 weeks, rats received four i.p. injections of either PCB-77 or PCB-153 (150 micromol/kg) administered every 14 days. The number of placental glutathione S-transferase (PGST)-positive foci per cm(3) and per liver among the PCB-77-treated rats was increased as the Se dietary level increased. Unlike PCB-77, rats receiving PCB-153 did not show the same Se dose-response effect; nevertheless, Se supplementation did not confer protection against foci development. However, the 2.0 ppm Se diet reduced the mean focal volume, indicating a possible protective effect by inhibiting progression of preneoplastic lesions into larger foci. Cell proliferation was not inhibited by Se in the liver of the PCB-treated groups. Se did not prevent the PCB-77-induced decrease of hepatic Se and associated reduction in glutathione peroxidase (GPx) activity. In contrast, thioredoxin reductase (TrxR) activity was not affected by the PCBs treatment or by Se supplementation. These findings indicate that Se does not inhibit the number of PGST-positive foci induced during promotion by PCBs, but that the size of the lesions may be inhibited. The effects of Se on altered hepatic foci do not correlate with its effects on GPx and TrxR.
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PMID:Effect of dietary selenium on the promotion of hepatocarcinogenesis by 3,3', 4,4'-tetrachlorobiphenyl and 2,2', 4,4', 5,5'-hexachlorobiphenyl. 1829 42

Cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD). Terminal bronchioles are critical zones in the pathophysiology of COPD, but little is known about the cellular and molecular changes that occur in cells lining terminal bronchioles in response to CS. We subjected C57BL/6 mice to CS (6 d/wk, up to 6 mo), looked for morphologic changes lining the terminal bronchioles, and used laser capture microdissection to selectively isolate cells in terminal bronchioles to study gene expression. Morphologic and immunohistochemical analyses showed that Clara cell predominance remained despite 6 months of CS exposure. Since Clara cells have a role in protection against oxidative stress, we focused on the expression of antioxidant/detoxification genes using microarray analysis. Of the 35 antioxidant/detoxification genes with at least 2.5-fold increased expression in response to 6 months of CS exposure, 21 were NF-E2-related factor 2 (Nrf2)-regulated genes. Among these were cytochrome P450 1b1, glutathione reductase, thioredoxin reductase, and members of the glutathione S-transferase family, as well as Nrf2 itself. In vitro studies using immortalized murine Clara cells (C22) showed that CS induced the stabilization and nuclear translocation of Nrf2, which correlated with the induction of antioxidant and detoxification genes. Furthermore, decreasing Nrf2 expression by siRNA resulted in a corresponding decrease in CS-induced expression of several antioxidant and detoxification genes by C22 cells. These data suggest that the protective response by Clara cells to CS exposure is predominantly regulated by the transcription factor Nrf2.
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PMID:Distal airways in mice exposed to cigarette smoke: Nrf2-regulated genes are increased in Clara cells. 1844 Dec 82

BMP6 is a potent protein for future treatment strategies of bone regeneration as it is a very important regulator of bone homeostasis. Active BMP6 is a dimer containing multidisulfide bonds and is a highly hydrophobic protein prone to aggregation. To obtain soluble and active BMP6 in Escherichia coli, we compared the effects of four N-terminal fusion tags (TRX, GST, MBP and CBD) and N-terminal His6-tag. The expression and solubility were tested under the different conditions (expression hosts, temperatures and inductor concentrations). A series of experiments leads to the finding that the placement of MBP before the BMP6 is best in availing the soluble expression of the protein. Our study alsodemonstrates that in E. coli BL21trxB(DE3) cytoplasm, which is a thioredoxin reductase mutant strain, soluble homodimeric BMP6 can be formed. The overexpressed MBP-BMP6 fusion protein is purified by chromatography, and shown to be functionally active.
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PMID:[Soluble expression of recombinant human BMP6 in Escherichia coli and its purification and bioassay in vitro]. 1858 22

Invasive species represent a risk to natural ecosystems and a biodiversity hazard. The present work aims to determine the antioxidant enzyme response - superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), the phase II detoxifying enzyme - glutathione S-transferase (GST) - and markers of oxidative damage - thioredoxin reductase (TR) and malondialdehyde (MDA) - in gills and digestive gland of Pinna nobilis and to study the antioxidant response effects in the bivalve colonised by the invasive macroalgae Lophocladia lallemandii. Colonised specimens were collected in a control area without L. lallemandii and another area completely colonised by L. lallemandii. All enzyme activities were found to be present in gills and digestive gland, with some tissue differences. CAT and SOD activities were higher in gills than digestive gland, whereas GST activity and MDA levels were higher in digestive gland. The presence of L. lallemandii induced a significant increase in the activities of antioxidant enzymes in both gills and digestive gland, except for CAT activity in gills. GST and TR activities were also increased in both tissues, as well as the MDA concentration. We can conclude that the presence of L. lallemandii colonising P. nobilis induces a biological stress and oxidative damage to the fan mussel.
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PMID:Antioxidant response of the bivalve Pinna nobilis colonised by invasive red macroalgae Lophocladia lallemandii. 1901 Apr 48

The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
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PMID:Compounds structurally related to ellagic acid show improved antiplasmodial activity. 1901 51

Exposure to benzene, toluene and xylene in the human population may pose a health risk. We tested a working hypothesis that these test chemicals cause cellular toxicity to a non-target organism, Drosophila melanogaster. Third instar larvae of D. melanogaster transgenic for hsp70, hsp83 and hsp26 and Oregon R(+) strain were exposed to 1.0-100.0 mM benzene, toluene and xylene for 2-48 h to examine the heat shock proteins (hsps), ROS generation, anti-oxidant stress markers and developmental end points. The test chemicals elicited a concentration- and time-dependent significant (p<0.01) induction of the hsps in the exposed organism in the order of hsp70>hsp83>or=hsp26 as evident by beta-galactosidase activity after 24 h. RT-PCR amplification studies in Oregon R(+) larvae revealed a similar induction pattern of these genes along with hsp60 in the order of hsp70>hsp60>hsp26>or=hsp83. Under similar experimental conditions, a significant induction of ROS generation and oxidative stress markers viz. superoxide dismutase, catalase, glutathione S-transferase, thioredoxin reductase, glutathione, malondialdehyde and protein carbonyl content was observed. Sub-organismal response was propagated towards organismal response i.e., a delay in the emergence of flies and their reproductive performance. While hsp70 was predominantly induced in the organism till 24 h of treatment with the test chemicals, a significant or insignificant regression of Hsp70 after 48 h was concurrent with a significant induction (p<0.01) of hsp60>hsp83>or=hsp26 in comparison to the former. A significant positive correlation was observed between ROS generation and these hsps in the exposed organism till 24 h and a negative correlation between ROS generation and hsp70 in them after 48 h indicating a modulatory role of ROS in the induction of hsps. The study suggests that among the tested hsps, hsp70 may be used as an early bioindicator of cellular toxicity against benzene, toluene and xylene and D. melanogaster as an alternative animal model for screening the risk posed by environmental chemicals.
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PMID:Induction of hsp70, hsp60, hsp83 and hsp26 and oxidative stress markers in benzene, toluene and xylene exposed Drosophila melanogaster: role of ROS generation. 1911 69

The tripeptide glutathione is involved in cellular defense mechanisms for xenobiotics and reactive oxygen species. This study investigated glutathione-dependent mechanisms in the model organism Aspergillus nidulans. A recombinant dimeric protein of A. nidulans glutathione reductase (GR) contained FAD and reduced oxidized glutathione (GSSG) using NADPH as an electron donor. A deletion strain of the GR gene (glrA) accumulated less intracellular reduced glutathione (GSH), indicating that the fungal GR contributes to GSSG reduction in vivo. Growth of the deletion strain of glrA was temperature-sensitive, and this phenotype was suppressed by adding GSH to the medium. The strain subsequently accumulated more intracellular superoxide, and cell-free respiration activity was partly defective. Growth of the strain decreased in the presence of oxidants, which induced glrA expression 1.5-6-fold. These results indicated that the fungal glutathione system functions as an antioxidant mechanism in A. nidulans. Our findings further revealed an initial proteomic differential display on GR-depleted and wild type strains. Up-regulation of thioredoxin reductase, peroxiredoxins, catalases, and cytochrome c peroxidase in the glrA-deletion strain revealed interplay between the glutathione system and both the thioredoxin system and hydrogen peroxide defense mechanisms. We also identified a hypothetical, up-regulated protein in the GR-depleted strains as glutathione S-transferase, which is unique among Ascomycetes fungi.
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PMID:The glutathione system of Aspergillus nidulans involves a fungus-specific glutathione S-transferase. 1917 36

The retinoic acid receptor (RAR), as one of the retinoic acid (RA)-responsive transcription activators, mediates various biological processes by regulating RA target gene expression. In studying how RAR activity is regulated, we isolated thioredoxin glutathione reductase (TGR), a member of the thioredoxin reductase family. Systematic yeast two-hybrid assays showed that in the presence of RA, TGR interacts with RAR via the LxxLL motif (NR box) located between the Grx and TrxR domains of TGR. This interaction was confirmed by GST pull-down and immunoprecipitation assays. The stable over-expression or knockdown of TGR in TGR-deficient NIH3T3 or TGR-abundant TM4 Sertoli cells, respectively, revealed that TGR enhances the transcriptional activity of RAR by increasing its DNA-binding capacity and restores RAR activity after impairment by reactive oxygen species (ROS). Furthermore, we demonstrated that the transactivation potential and DNA-binding activity of RAR in response to ROS depends on the cellular level of TGR. Overall, our data suggest that the redox regulation function of TGR protects the DNA-binding activity of RAR against cellular ROS damage.
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PMID:Redox regulation of transcriptional activity of retinoic acid receptor by thioredoxin glutathione reductase (TGR). 1979 61

Sulforaphane, a well-characterised dietary isothiocyanate, has been demonstrated to be a potent anti-carcinogenic agent in numerous cancer models, including in bladder cancer cells. In the present study, sulforaphane up-regulated the expression of two Nrf2-dependent enzymes, glutathione transferase (GSTA1-1) and thioredoxin reductase (TR-1), and down-regulated cyclooxygenase 2 (COX-2) in human bladder cancer T24 cells. This action of sulforaphane was associated with the p38 MAPK activity. When a specific p38 MAPK inhibitor, SB202190, was used, both sulforaphane-induced up-regulation of GSTA1-1 and TR-1 and down-regulation of COX-2 were eliminated; in contrast, an activator of p38 MAPK, anisomycin, enhanced the effect of sulforaphane on modulation of GST, TR-1 and COX-2 expression. Moreover, it was established that anisomycin increased nuclear translocation of Nrf2, whereas SB202190 abrogated sulforaphane-induced Nrf2 translocation into the nucleus. In summary, these data suggest that p38 MAPK activation can regulate Nrf2-antioxidant response element (ARE)-driven enzymes and COX-2 expression, thereby facilitating the role of sulforaphane in cancer prevention. This study strongly supports the contention that p38 MAPK is a pivotal and efficient target of sulforaphane in the chemoprevention of bladder cancer.
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PMID:p38 MAPK plays a distinct role in sulforaphane-induced up-regulation of ARE-dependent enzymes and down-regulation of COX-2 in human bladder cancer cells. 2020 1

Ovarian cancer is primarily treated with platinum-based chemotherapy, with ROS generation implicated in cytotoxicity. We examined redox protein expression in ovarian tumors, focusing on the thioredoxin system, to determine the role it might play in mediating response to therapy. Nuclear and cytoplasmic expression of thioredoxin, thioredoxin reductase, thioredoxin-interacting protein, metallothionein, and glutathione S-transferase Pi was assessed, using standard immunohistochemical techniques, on a tissue microarray of 154 primary ovarian carcinomas obtained from patients subsequently treated with adjuvant platinum-based chemotherapy. Low cytoplasmic expression of thioredoxin (p=0.032) and negative nuclear expression of metallothionein (p=0.04) significantly correlated with better progression-free survival. When nuclear and cytoplasmic expression patterns were combined those patients with tumors with low cytoplasmic but high nuclear expression of thioredoxin exhibited better progression-free (p=0.003) and overall survival (p=0.004). This combination was, using multivariate analysis, an independent predictive factor for overall survival (p=0.034). Improved progression-free survival was also seen with negative expression of metallothionein, cytoplasmic and nuclear (p=0.038), and was independent of other clinical parameters (p=0.048). Such results support the suitability of using redox protein expression to predict response and, potentially, to alter treatment options accordingly.
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PMID:Redox protein expression predicts progression-free and overall survival in ovarian cancer patients treated with platinum-based chemotherapy. 2065 Mar 13


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