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)

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

Atherosclerosis is main cause of arteriosclerosis. The pivotal role of low-density lipoprotein (LDL) oxidation in atherogenesis suggests antioxidants may help prevent cardiovascular disease. Fraxinus rhynchophylla DENCE (Oleaceae) is a traditional medicinal plant from East Asia. During the course of characterizing potential drug candidates from natural products, we isolated two major coumarins, esculetin and fraxetin and found that fraxetin has dual-antioxidative functions. Low concentrations (1-5 microM) of fraxetin potently inhibited LDL oxidation induced by metal and free radicals. Moreover, treatment of vascular smooth muscle cells (VSMCs) with higher concentrations (above 30 microM) of fraxetin significantly increased the protein level of heme oxygenase-1 (HO-1), a key enzyme that inhibits vascular proliferation and atherosclerosis. Subcellular fractionation and reporter gene analysis using an antioxidant response element (ARE) construct revealed that fraxetin increased the level of nuclear factor (NF)-E2-related factor 2 (Nrf2) and reporter activity, and these were associated with the induction of antioxidant enzymes, such as HO-1 and glutathione S-transferase-alpha. In conclusion, fraxetin has direct protective properties against LDL oxidation at lower concentrations, and higher concentrations of fraxetin induce antioxidant enzymes via Nrf2/ARE activation. These effects suggest potential anti-atherosclerosis effects of Fraxinus rhynchophylla D.
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PMID:Dual anti-oxidative effects of fraxetin isolated from Fraxinus rhinchophylla. 1972 Dec 27

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

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

Our previous study demonstrated that methanolic extract of Inula helenium (Elecampane) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) activity and glutathione S-transferase (GST) and found isoalantolactone and alantolactone as the active components. In this study we investigated the detoxifying enzyme-inducing potential of isoalantolactone, which is present in I. helenium and has a structure similar to that of alantolactone. The compound induced QR in a dose-dependent manner in both Hepa1c1c7 cells and its mutant BPRc1 cells lacking the arylhydrocarbon receptor translocator. Like with most phase 2 enzyme inducers, other phase 2 detoxifying enzymes, including GST, glutathione reductase, gamma-glutamylcysteine synthetase, and heme oxygenase-1, were also induced by isoalantolactone in a dose-dependent manner in the cultured cells. Furthermore, isoalantolactone caused a proportionate increase in luciferase activity depending upon concentration and exposure time in the reporter assay in which HepG2-C8 cells, transfectants carrying antioxidant response element-luciferase gene, were used. The nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) was stimulated by the compound and attenuated by phosphatidylinositol 3-kinase inhibitors such as LY294002 and wortmannin. In conclusion, isoalantolactone is a candidate for chemoprevention and acts as potent phase 2 enzyme inducer by stimulating the accumulation of Nrf2 in the nucleus.
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PMID:Isoalantolactone from Inula helenium caused Nrf2-mediated induction of detoxifying enzymes. 1985 67

Human milk contains biological factors that are involved in a newborn's growth and immune system regulation. By integrating standard biochemical experimental protocols with computational methods, the present study investigates the presence of heme oxygenase-1 (HO-1), a cytoprotective enzyme, in human milk at different levels of maturation and in milk formulae. Furthermore, we evaluated cytokine and glutathione S-transferase (GSH) levels. Samples were collected from colostrum (on Day 1 after birth), from transition milk (on Postdelivery Days 7 and 14) and from mature milk (on Day 30 after delivery) in 14 healthy women. HO-1 protein, GSH and cytokines levels were measured using enzyme-linked immunosorbent assay and flow cytometry. HO-1 protein levels were significantly higher in colostrum (1.33 ng/ml; 5th centile 0.92; 95th centile 2.38) and in transition milk at 14 days (0.97 ng/ml; 5th centile 0.87; 95th centile 1.45) than in mature milk (0.9 ng/ml; 5th centile 0.8; 95th centile 1.38). Levels of HO-1 in milk formulae were similar to those in colostrum. No significant differences in GSH content were observed in mature milk, transition milk and colostrum, whereas significantly higher GSH levels were observed in milk formulae. No significant levels of cytokines, with the exception of interleukin-8, were found. Computational studies on the possible interactions between HO-1 and CD91 were carried out by a battery of softwares, namely, GRAMM (version 1.03), DALI, CLUSTALW (version 2.0), PatchDock and FireDock, mutually counterchecking and validating each other. The computational results, the strong convergence (to the same "solution") of which finally leads to an "experimental-like" character, showed that HO-1 may bind to CD91, thus suggesting its major role as a new chaperokine in immune response regulation. These findings, which connect and integrate biochemical data and computational data interpretation, represent a synergistic and powerful means of conducting biological research.
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PMID:Potential immunoregulatory role of heme oxygenase-1 in human milk: a combined biochemical and molecular modeling approach. 1987 47

Fish primary hepatocyte cultures are commonly used for toxicological assessment of contaminants. So far no one has described a protocol on how to use Atlantic cod hepatocytes in bioassays. In this work we describe an experiment in which we were able to isolate intact liver cells from mature individuals. Hepatic cytochrome P450 1A (CYP1A) expression in the isolated cells was evaluated with in situ hybridization after intraperitoneal injection with the strong CYP1A inducer ss-naphthoflavone (BNF). Cod hepatocytes were further exposed to 1,2,3,7,8-polychlorinated dibenzo-p-dioxin (PCDD) and cadmium (Cd). Transcriptional responses of 11 genes were quantified (CYP1A, metallothionein (MT), aryl hydrocarbon receptor 2 (AhR2), UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), vitellogenin B (VTGB), hypoxia-inducible factor 1 (HIF1), heme oxygenase 1 (HO-1), transferrin, glutathione peroxidase (GPx) and heat shock protein 70 (HSP70)). Immunohistochemisty evaluation clearly showed elevated CYP1A mRNA expression in primary hepatocytes isolated from BNF-exposed fish. The transcriptional results showed that PCDD exposure resulted in a 311-fold up-regulation of CYP1A and Cd a 1.82-fold increase of MT. Unexpectedly, AhR2 and UGT mRNA levels were not significantly up-regulated in PCDD-exposed cod hepatocytes. HO-1 and transferrin showed a dose-dependent transcriptional response to Cd exposure. Cd appears to act as an endocrine-disrupting metal in exposed primary Atlantic cod hepatocytes. This study demonstrates the use of Atlantic cod primary hepatocyte cultures in toxicological research.
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PMID:Toxicological application of primary hepatocyte cell cultures of Atlantic cod (Gadus morhua)--effects of BNF, PCDD and Cd. 2006 45

Our preliminary experiment demonstrated that a n-hexane/EtOH (9:1, volume) extract of Glycyrrhiza uralensis (licorice) caused a significant induction of NAD(P)H:oxidoquinone reductase (NQO1), one of the well-known phase 2 detoxifying enzymes. We isolated dehydroglyasperin C (DGC) as a potent phase 2 enzyme inducer from licorice. DGC induced NQO1 both in wild-type murine hepatoma Hepa1c1c7 and ARNT-lacking BPRc1 cells, indicating that the compound is a monofunctional inducer. The compound induced not only NQO1 but also some other phase 2 detoxifying/antioxidant enzymes, such as glutathione S-transferase, gamma-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1. Similar to most monofunctional inducers, DGC caused the accumulation of Nrf2 in the nucleus in dose- and time-dependent manners and thereby activated expression of phase 2 detoxifying enzymes. It also resulted in a dose-dependent increase in the luciferase activity in the reporter assay, in which HepG2-C8 cells transfected with antioxidant response element (ARE)-luciferase construct were used, suggesting that the induction of phase 2 detoxifying and antioxidant enzymes could be achieved through the interaction of Nrf2 with the ARE sequence in the promoter region of their genes.
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PMID:Dehydroglyasperin C isolated from licorice caused Nrf2-mediated induction of detoxifying enzymes. 2008 9

1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.
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PMID:Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity. 2021 40

To investigate liver tumor promotion mechanisms of copper (Cu)- and iron (Fe)-overloading, immunolocalization of metal-related biomolecules and lipid peroxidation end products was examined in preneoplastic liver cell foci that expressed glutathione S-transferase placental form (GST-P) in early-stage tumor promotion over 6 weeks in a rat two-stage hepatocarcinogenesis model. Gene expression and concentrations of thiobarbituric acid-reactive substance (TBARS) in the liver were also analyzed. Cu-overloading alone exerted a weak promoting activity, which was enhanced by Fe-overloading. By Cu-overloading, GST-P(+) foci that co-expressed transferrin receptors or downregulated ceruloplasmin increased, suggesting preneoplastic lesion-specific enhancement of oxidative cellular stress. Cu-overloading also increased transcripts of antioxidant enzymes (Gstm3 and Gst Yc2 subunit), cell proliferation, and numbers of single liver cells expressing GST-P or heme oxygenase-1 (HO-1) in the liver, suggesting that oxidative stress induces single-cell toxicity, with the ensuing regeneration contributing to tumor promotion. Fe-overloading increased liver TBARS and HO-1-expressing Kupffer cells, the latter suggesting protection against inflammatory stimuli causing fluctuating proinflammatory cytokine mRNA levels. By co-overloading of Cu and Fe, Cu-overload-related single liver cell toxicity and regeneration increased, as did cytokine imbalances involving increased cyclooxygenase-2-producing Kupffer cells and accumulation of malondialdehyde within GST-P(+) foci. These results suggest an involvement of oxidative stress responses in Cu-induced tumor promotion and Fe-induced enhancement by increasing cytokine imbalances and GST-P(+) foci-specific lipid peroxidation.
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PMID:Tumor promotion by copper-overloading and its enhancement by excess iron accumulation involving oxidative stress responses in the early stage of a rat two-stage hepatocarcinogenesis model. 2030 51


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