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)

In view of the crucial involvement of oxidative and electrophilic stress in various kidney disorders, this study was undertaken to test the hypothesis that pharmacologically-mediated coordinated upregulation of endogenous renal antioxidants and phase 2 enzymes is an effective strategy for renal protection. Notably, studies on the pharmacological inducibility of a series of antioxidants and phase 2 enzymes in renal tubular cells are lacking. Here we reported that incubation of normal rat kidney (NRK-52E) proximal tubular cells with low micromolar concentrations (10-50 microM) of the cruciferous nutraceutical, 1,2-dithiole-3-thione (D3T), led to a significant concentration-dependent induction of a wide spectrum of antioxidants and phase 2 enzymes, including catalase (CAT), reduced form of glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and heme oxygenase (HO). We further observed that D3T treatment also increased the protein and mRNA expression for CAT, gamma-glutamylcysteine ligase, GR, GST-A, GST-M, NQO1, and HO-1. Incubation of the renal tubular cells with H(2)O(2), SIN-1-derived peroxynitrite, or 4-hydroxy-2-nonenal led to concentration-dependent decreases in cell viability. Pretreatment of the renal tubular cells with 10-50 microM D3T afforded remarkable protection against the nephrocytotoxicity elicited by the above oxidative and electrophilic species. The D3T-mediated cytoprotection showed a concentration-dependent relationship. Taken together, this study for the first time comprehensively characterized the inducibility by a unique nutraceutical of a wide spectrum of antioxidative and phase 2 defenses in renal tubular cells at the levels of enzyme activity as well as protein and mRNA expression, and demonstrated that such a coordinated upregulation of cellular defenses led to remarkable protection of renal tubular cell from oxidative and electrophilic stress. Because of the crucial role of oxidative and electrophilic stress in inflammatory injury, D3T-mediated coordinated induction of endogenous antioxidative and phase 2 defenses may also serve as an important anti-inflammatory mechanism in kidneys.
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PMID:Coordinated upregulation of a series of endogenous antioxidants and phase 2 enzymes as a novel strategy for protecting renal tubular cells from oxidative and electrophilic stress. 1840 43

Our previous study showed that a methanol extract of Inula helenium had the potential to induce detoxifying enzymes such as quinone reductase (QR) and glutathione S-transferase (GST) activity. In this study the methanol extract was further fractionated using silica gel chromatography and vacuum liquid chromatography, to yield pure compounds alantolactone and isoalantolactone as QR inducers. Alantolactone caused a dose-dependent induction of antioxidant enzymes including QR, GST, gamma-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1 in hepa1c1c7 mouse hepatoma cells. The compound increased the luciferase activity of HepG2-C8 cells, transfectants carrying antioxidant response element (ARE)-luciferase gene, in a dose-dependent manner, suggesting ARE-mediated transcriptional activation of antioxidant enzymes. Alantolactone also stimulated the nuclear accumulation of Nrf2 that was inhibited by phosphatidylinositol 3-kinase (PI3K) inhibitors. In conclusion, alantolactone appears to induce detoxifying enzymes via activation of PI3K and JNK signaling pathways, leading to translocation of Nrf2, and subsequent interaction between Nrf2 and ARE in the encoding genes.
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PMID:Nrf2-mediated induction of detoxifying enzymes by alantolactone present in Inula helenium. 1870 92

The effect of Schisandra fructus extract (SFE) on doxorubicin (Dox)-induced cardiotoxicity was investigated in H9c2 cardiomyocytes. Dox, which is an antineoplastic drug known to induce cardiomyopathy possibly through production of reactive oxygen species, induced significant cytotoxicity, intracellular reactive oxygen species (ROS), and lipid peroxidation. SFE treatment significantly increased cell survival up to 25%, inhibited intracellular ROS production in a time- and dose-dependent manner, and inhibited lipid peroxidation induced by Dox. In addition, SFE treatment induced expression of cellular glutathione S-transferases (GSTs), which function in the detoxification of xenobiotics, and endogenous toxicants including lipid peoxides. Analyses of 31,100 genes using Affymetrix cDNA microarrays showed that SFE treatment up-regulated expression of genes involved in glutathione metabolism and detoxification [GST theta 1, mu 1, and alpha type 2, heme oxygenase 1 (HO-1), and microsomal epoxide hydrolase (mEH)] and energy metabolism [carnitine palmitoyltransferase-1 (CPT-1), transaldolase, and transketolase]. These data indicated that SFE might increase the resistance to cardiac cell injury by Dox, at least partly, together with altering gene expression, especially induction of phase II detoxification enzymes.
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PMID:Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes. 1885 Feb 28

Spermatogenesis is a temperature-dependent process, and increases in scrotal temperature can disrupt its progression. We previously showed that heat stress causes DNA damage in germ cells, an increase in germ cell death (as seen on TUNEL staining), and subfertility. The present study evaluated the stress response in mouse testes following a single mild transient scrotal heat exposure (40 degrees C or 42 degrees C for 30 min). We investigated markers of three types of stress response, namely, hypoxia, oxidative stress, and apoptosis. Heat stress caused an increase in expression of hypoxia-inducible factor 1 alpha (Hif1a) mRNA expression and translocation of HIF1A protein to the germ cell nucleus, consistent with hypoxic stress. Increased expression of heme oxygenase 1 (Hmox1) and the antioxidant enzymes glutathione peroxidase 1 (GPX1) and glutathione S-transferase alpha (GSTA) was consistent with a robust oxidative stress response. Germ cell death was associated with an increase in expression of the effector caspase cleaved caspase 3 and a decrease in expression of the protein inhibitor of caspase-activated DNase (ICAD). Reduced expression of ICAD contributes to increased activity of caspase-activated DNase and is consistent with the increased rates of DNA fragmentation that have been detected previously using TUNEL staining. These studies confirmed that transient mild testicular hyperthermia results in temperature-dependent germ cell death and demonstrated that elevated temperature results in a complex stress response, including induction of genes associated with oxidative stress and hypoxia.
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PMID:A single, mild, transient scrotal heat stress causes hypoxia and oxidative stress in mouse testes, which induces germ cell death. 1914 62

3H-1,2-dithiole-3-thione (D3T), a cruciferous organosulfur compound, induces cytoprotective enzymes in animal cardiovascular cells. However, it remains unknown if D3T also upregulates antioxidants and phase 2 enzymes in human cardiomyocytes, and protects against cell injury induced by oxidative/electrophilic species as well as doxorubicin. In this study, we found that D3T (10-50 muM) potently induced a series of antioxidants and phase 2 enzymes in primary cultured human cardiomyocytes, including superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), aldose reductase (AR), and heme oxygenase (HO). D3T treatment also caused elevation of SOD, GSH, GR, GPx and GST in the isolated mitochondria. We also observed a time-dependent induction by D3T of mRNA expression for Cu,ZnSOD, MnSOD, gamma-glutamylcysteine ligase, GR, GSTA1, GSTM1, NQO1, AR, and HO-1. Pretreatment with D3T conferred concentration-dependent protection against cell injury induced by xanthine oxidase (XO)/xanthine, H(2)O(2), 3-morpholinosydnonimine, 4-hydroxy-2-nonenal, and doxorubicin. Pretreatment with D3T also reduced the formation of intracellular reactive oxygen species by XO/xanthine, H(2)O(2), and doxorubicin. In conclusion, this study demonstrated that D3T potently upregulated many antioxidants and phase 2 enzymes in human cardiomyocytes, which was accompanied by increased resistance to oxidative/electrophilic stress and doxorubicin toxicity.
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PMID:Cruciferous dithiolethione-mediated coordinated induction of total cellular and mitochondrial antioxidants and phase 2 enzymes in human primary cardiomyocytes: cytoprotection against oxidative/electrophilic stress and doxorubicin toxicity. 1917 75

Dithiocarbamates are a commercially important class of compounds that can produce peripheral neuropathy in humans and experimental animals. Previous studies have supported a requirement for copper accumulation and enhanced lipid peroxidation in dithiocarbamate-mediated myelinopathy. The study presented here extends previous investigations in two areas. Firstly, although total copper levels have been shown to increase within the nerve it has not been determined whether copper is increased within the myelin compartment, the primary site of lesion development. Therefore, the distribution of copper in sciatic nerve was characterized using synchrotron X-ray fluorescence microscopy to determine whether the neurotoxic dithiocarbamate, N,N-diethyldithiocarbamate, increases copper levels in myelin. Secondly, because lipid peroxidation is an ongoing process in normal nerve and the levels of lipid peroxidation products produced by dithiocarbamate exposure demonstrated an unusual cumulative dose response in previous studies the biological impact of dithiocarbamate-mediated lipid peroxidation was evaluated. Experiments were performed to determine whether dithiocarbamate-mediated lipid peroxidation products elicit an antioxidant response through measuring the protein expression levels of three enzymes, superoxide dismutase 1, heme oxygenase 1, and glutathione transferase alpha, that are linked to the antioxidant response element promoter. To establish the potential of oxidative injury to contribute to myelin injury the temporal relationship of the antioxidant response to myelin injury was determined. Myelin structure in peripheral nerve was assessed using multi-exponential transverse relaxation measurements (MET(2)) as a function of exposure duration, and the temporal relationship of protein expression changes relative to the onset of changes in myelin integrity were determined. Initial assessments were also performed to explore the potential contribution of dithiocarbamate-mediated inhibition of proteasome function and inhibition of cuproenzyme activity to neurotoxicity, and also to assess the potential of dithiocarbamates to promote oxidative stress and injury within the central nervous system. These evaluations were performed using an established model for dithiocarbamate-mediated demyelination in the rat utilizing sciatic nerve, spinal cord and brain samples obtained from rats exposed to N,N-diethyldithiocarbamate (DEDC) by intra-abdominal pumps for periods of 2, 4, and 8 weeks and from non exposed controls. The data supported the ability of DEDC to increase copper within myelin and to enhance oxidative stress prior to structural changes detectable by MET(2). Evidence was also obtained that the excess copper produced by DEDC in the central nervous system is redox active and promotes oxidative injury.
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PMID:N,N-diethyldithiocarbamate promotes oxidative stress prior to myelin structural changes and increases myelin copper content. 1946 51

The transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a major regulator of genes encoding Phase II detoxifying enzymes and antioxidant proteins, is important for protecting cells against oxidative damage. In this work, we report that in the immune-mediated motor neuron injury animal model, expression of Nrf2 and antioxidative enzymes including glutathione S-transferase, nicotinamide adenine dinucleotide phosphate (reduced)-quinone oxidoreductase 1 and heme oxygenase 1 were greatly reduced in motor neurons of spinal cord anterior horn in paralyzed guinea pigs, whereas the antioxidant enzymes in the dorsal horn of paralyzed guinea pigs were generally preserved. Our findings suggest that declined antioxidative capacity may contribute to the damage to motor neurons in the process of immune-mediated motor neuron injury. Although the exact mechanism of immune reactivity and Nrf2-antioxidant response element pathway inactivation remains to be elucidated, inducers of Phase II detoxification enzymes may be an attractive therapeutic target for immune-mediated motor neuron degeneration.
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PMID:Reduced Nrf2 and Phase II enzymes expression in immune-mediated spinal cord motor neuron injury. 1958 99

The goal of study was directed to investigate the effects of resveratrol (RES) pretreatment on the enhancing action of D-galactosamine (D-GalN; 800 mg/kg) on lipopolysaccharide (LPS; 0.5 microg/kg) inducing liver failure in rats. Liver function was assessed by determination of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alpha-glutathione S-transferase (alpha GST) and bilirubin (BILI). Plasma NO(2)(-) was assessed by NO(2)(-)/NO(3)(-) colorimetric kit. The estimation of nonenzymatic and enzymatic antioxidants (glutathione and catalase) was performed in plasma and liver homogenate. Lipid peroxidation was evaluated by the thiobarbituric acid reacting substances (TBARS) and the conjugated dienes (CD). Morphological examinations using light and electron microscopy were performed. Observations related to pharmacological increases of inducible nitric oxide synthase (NOS-2)/nitric oxide (NO) and inducible heme oxygenase (HO-1) in fulminant hepatic failure and modulation by resveratrol were followed up by real-time reverse transcription PCR (RT-PCR) in liver tissue. In the present study we found that among the mechanisms responsible for the hepatoprotective effect of resveratrol in the LPS/D-GalN liver toxicity model are reduction in NO, downregulation of NOS-2, modification of oxidative stress parameters and modulation of HO-1 which led to overall improvement in hepatotoxic markers and morphology after the hepatic insult.
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PMID:Resveratrol attenuates lipopolysaccharide-induced hepatitis in D-galactosamine sensitized rats: role of nitric oxide synthase 2 and heme oxygenase-1. 1979 4

Studies using genetic isolates with limited genetic variation may be useful in chronic obstructive pulmonary disease (COPD) genetics, but are thus far lacking. The associations between single nucleotide polymorphisms (SNPs) in candidate genes and lung function in COPD were studied in a genetic isolate. In 91 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage >or=1 COPD, who were members of an extended pedigree including 6,175 people from the Genetic Research in Isolated Populations study, 32 SNPs were analysed in 13 candidate genes: a disintegrin and metalloprotease domain 33 gene (ADAM33), transforming growth factor-beta1 gene ( TGFB1), matrix metalloprotease-1 gene (MMP1), MMP2, MMP9, MMP12, tissue inhibitor of metalloprotease-1 gene (TIMP1), surfactant protein A1 gene (SFTPA1 ), SFTPA2, SFTPB, SFTPD, glutathione S-transferase P1 gene (GSTP1), and haem oxygenase 1 gene ( HMOX1). Their relation to forced expiratory volume in 1 s (FEV( 1)), inspiratory vital capacity (IVC) and FEV(1)/IVC were studied using restricted maximum likelihood linear mixed modelling, accounting for pedigree structure. Significant associations were replicated in the general Vlagtwedde/Vlaardingen study. Six SNPs in TGFB1, SFTPA1, SFTPA2 and SFTPD were significantly associated with FEV(1)/IVC in subjects with GOLD stage >or=1 COPD. Two SNPs in TGFB1 (C to T substitution at nucleotide -509 and substitution of leucine 10 with proline (Leu10Pro)), Leu50Val in SFTPA1 and Ala160Thr in SFTPD showed evidence suggestive of association with FEV(1)/IVC in subjects with GOLD stage >or=2 COPD. The TGFB1 associations were replicated in GOLD stage >or=2 patients from the Vlagtwedde/Vlaardingen population, with similar effect sizes. It was shown that a genetic isolate can be used to determine the genetics of lung function, which can be replicated in COPD patients from an independent population.
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PMID:Novel strategy to identify genetic risk factors for COPD severity: a genetic isolate. 1979 32

Chlorobenzene is a volatile organic compound (VOC) that is widely used as a solvent, degreasing agent and chemical intermediate in many industrial settings. Occupational studies have shown that acute and chronic exposure to chlorobenzene can cause irritation of the mucosa of the upper respiratory tract and eyes. Using in vitro assays, we have shown in a previous study that human bronchial epithelial cells release inflammatory mediators such as the cytokine monocyte chemoattractant protein-1 (MCP-1) in response to chlorobenzene. This response is mediated through the NF-kappaB signaling pathway. Here, we investigated the effects of monochlorobenzene on human lung cells, with emphasis on potential alterations of the redox equilibrium to clarify whether the chlorobenzene-induced inflammatory response in lung epithelial cells is caused via an oxidative stress-dependent mechanism. We found that expression of cellular markers for oxidative stress, such as heme oxygenase 1 (HO-1), glutathione S-transferase pi1 (GSTP1), superoxide dismutase 1 (SOD1), prostaglandin-endoperoxide synthase 2 (PTGS2) and dual specificity phosphatase 1 (DUSP1), were elevated in the presence of monochlorobenzene. Likewise, intracellular reactive oxygen species (ROS) were increased in response to exposure. However, in the presence of the antioxidants N-(2-mercaptopropionyl)-glycine (MPG) or bucillamine, chlorobenzene-induced upregulation of marker proteins and release of the inflammatory mediator MCP-1 are suppressed. These results complement our previous findings and point to an oxidative stress-mediated inflammatory response following chlorobenzene exposure.
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PMID:Chlorobenzene induces oxidative stress in human lung epithelial cells in vitro. 1980 Sep 2


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