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)

We isolated a peptide from calf spleen that specifically inhibits murine granulopoiesis in vitro. Human T-lymphocyte colony growth was not affected. Formation of erythroid colony-forming units (CFU-E) was only slightly inhibited at a concentration 1000-fold higher compared to granulocyte-macrophage colony-forming cell (GM-CFC) assay. After high performance liquid chromatography purification we isolated a monomer (reduced peptide) showing the inhibitory activity and a dimer (oxidized peptide) with stimulatory activity. The isolated peptide was identified as glutathione. The reduced form of this well-known tripeptide (GSH) specifically inhibits murine granulopoiesis in vitro at 10(-7)-10(-8) M concentration. Oxidized glutathione (GSSG) stimulates GM-CFC formation; the extent of stimulation depends on the colony-stimulating factor concentration. The striking finding that GSH and GSSG modulate granulopoiesis at nanomolar concentrations requires further studies on the molecular interaction between either peptide with GM-CSF and its receptor protein.
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PMID:Glutathione: an in vitro granulopoiesis inhibitor at nanomolar concentration, isolated from calf spleen. 232 68

Reducing agents such as glutathione (GSH), glutathione ester (GSE), and N-acetylcysteine (NAC) have been shown to suppress the induction of HIV expression in chronically infected cells stimulated by cytokines. We present data which show the effects of the organic thiophosphate WR-151327 on the expression of latent HIV in U1 cells. The chronically infected promonocytic cell line U1 constitutively expresses low levels of HIV that can be increased by 13-phorbol 12-myristate acetate (PMA), tumor necrosis factor alpha (TNF-alpha), and granulocyte/monocyte colony-stimulating factor (GM-CSF). WR-151327 suppressed, in dose-dependent fashion, the reverse transcriptase (RT) activity induced by TNF-alpha, GM-CSF, and PMA. The maximal decrease in RT activity was 70, 80, and 50%, respectively. Pretreatment with WR-151327 also suppressed the induction of total HIV protein synthesis, as shown by Western blot analysis. In addition, WR-151327 suppressed HIV-LTR-CAT activity in transfected human rhabdomyosarcoma cells (RD). Suppression of HIV expression by WR-151327 was observed in the absence of a cytotoxic or cytostatic effect. Incubation of WR-151327 with human recombinant TNF-alpha for 6 hr at 37 degrees C did not alter the capacity of TNF-alpha to induce the expression of HIV. Our observations further support the hypothesis that reducing agents are important in the control of HIV replication and that the clinical evaluation of WR-151327 may be indicated.
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PMID:Organic thiophosphate WR-151327 suppresses expression of HIV in chronically infected cells. 752 Nov 93

The expression of the ectoenzyme gamma-glutamyl transpeptidase (EC2.3.2.2., gamma GT) was investigated by flow cytometry on populations of peripheral blood mononuclear cells (PBMC) from healthy subjects and patients suffering from several types of leukemia before and under chemotherapy. In unstimulated PBMC, 28% of these cells were found to be gamma GT positive. The highest expression was measured on monocytes (CD14/gamma GT+ cells: 60%). Within the subsets of T lymphocytes (CD3/gamma GT+ cells: 18%) we saw no clear differences between CD4+ and CD8+ cells. B lymphocytes, NK cells, and activated cells showed low expressions (up to 10%). Treatment of PBMC with mitogens, alpha-IFN, IL-2, and GM-CSF did not affect the enzyme expression on normal mononuclear cells (MNC). However, a rapid increase of gamma GT+ cells was found in the presence of glutathione (GSH) and n-acetyl cysteine (nAC), particularly on monocytes, B cells, and NK cells. Comparing 40 healthy subjects and untreated patients suffering from leukemias, a significantly higher expression of gamma GT+ cells in the total MNC populations (B-CLL: 57%, CML: 62% gamma GT+ cells) was observed in B-chronic lymphocytic leukemia (B-CLL) and chronic myelogenous leukemia (CML), whereas other leukemias did not show clear differences. Most interestingly, the gamma GT expression was diminished in all populations of CML cells after 5 h of incubation in the presence of 10 units/ml IFN-alpha. These data suggest a possible protective role of gamma GT in MNC and a regulatory function of this enzyme in the development of CML.
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PMID:gamma-Glutamyl transpeptidase-cellular expression in populations of normal human mononuclear cells and patients suffering from leukemias. 759 85

The methylation and transsulfuration pathways are intimately linked and have been implicated in the progression of neurologic damage and immune cell depletion caused by human immunodeficiency virus (HIV) infection. We studied the following metabolites related to these pathways: S-adenosylmethionine (SAMe), homocysteine, cysteine, cysteinyl-glycine, and glutathione (GSH) in blood and CSF of 16 HIV-infected patients with neurologic complications and 20 HIV-negative control patients undergoing lumbar punctures for other medical reasons. We confirmed recent studies of decreased CSF SAMe concentrations in HIV infection and demonstrated that diastereomers of SAMe are present in CSF but not in plasma or erythrocytes from both HIV-infected and HIV-negative patients. In HIV-infected patients, CSF GSH and cysteinyl-glycine, but not homocysteine or cysteine, were significantly reduced. This is the first report of decreased CSF GSH induced by HIV infection. GSH has a regulatory effect on the synthesis of SAMe in hepatic tissue, and the same mechanism may also apply in the CNS. Administration of SAMe-butanedisulphonate, 800 mg/d intravenously for 14 days, was associated with significant increases in CSF SAMe and GSH. These findings have potentially important therapeutic implications for the use of SAMe in protecting against SAMe and GSH deficiency in the CNS of HIV-infected patients.
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PMID:Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: effect of parenteral treatment with SAMe. 767 26

A very early event in the pathogenesis of idiopathic Parkinson's disease (PD) has been proposed to be an elevated translocation of L-cysteine (CySH) and/or glutathione (GSH) into pigmented dopaminergic cell bodies in the substantia nigra (SN) in which cytoplasmic dopamine (DA) is normally autoxidized to DA-o-quinone as the first step in a reaction leading to black neuromelanin polymer. Such an elevated influx of CySH and GSH would be expected to initially result in formation of 5-S-cysteinyldopamine (5-S-CyS-DA) and 5-S-glutathionyldopamine (5-S-Glu-DA), respectively, and might account for the massive irreversible loss of GSH and progressive depigmentation of SN cells that occurs in the Parkinsonian brain. However, 5-S-Glu-DA has not been detected in the Parkinsonian brain. Furthermore, although the 5-S-CyS-DA/DA and 5-S-CyS-DA/homovanillic acid concentration ratios increase significantly in the SN and cerebrospinal fluid, respectively, of PD patients, the absolute concentrations of 5-S-CyS-DA are extremely low and similar to those measured in age-matched control patients. One explanation for these observations is that 5-S-CyS-DA might be intraneuronally oxidized to more complex cysteinyldopamines and a number of dihydrobenzothiazines (DHBTs) and benzothiazines (BTs). Similarly, 5-S-Glu-DA might be intraneuronally oxidized to more complex glutathionyldopamines. In this investigation, however, it is demonstrated that 5-S-Glu-DA is rapidly metabolized in rat brain to 5-S-CyS-DA and 5-S-(N-acetylcysteinyl) dopamine (5) in reactions mediated by gamma-glutamyl transpeptidase (gamma-GT) and cysteine conjugate N-acetyltransferase. Similarly, 5-S-CyS-DA is metabolized to 5 in rat brain although more slowly than 5-S-Glu-DA. These reactions occur most rapidly in the midbrain, a region that contains the SN. Furthermore, 5, 2-S-(N-acetylcysteinyl)dopamine (6) and 2,5-di-S-(N-acetylcysteinyl)-dopamine (9) are toxic when administered into mouse brain having LD50 values of 14, 25, and 42 micrograms, respectively, and evoke a profound hyperactivity syndrome. These results suggest that the failure to detect 5-S-Glu-DA and the presence of only very low levels of 5-S-CyS-DA in Parkinsonian SN tissue and CSF might be related to both their intraneuronal oxidation and extraneuronal metabolism to N-acetylcysteinyl conjugates of DA. Furthermore, the toxic properties and neurobehavioral responses evoked by 5, 6, and 9 raise the possibility that these N-acetylcysteinyl conjugates of DA, in addition to certain cysteinyldopamines, DHBTs and BTs, might include endotoxins that contribute to SN cell death and other neuronal damage that occurs in PD. Methods are described for the synthesis of several N-acetylcysteinyl conjugates of DA, and their redox behaviors have been studied using cyclic voltammetry.
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PMID:Synthesis, redox properties, in vivo formation, and neurobehavioral effects of N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson's disease. 890 66

Recombinant human macrophage colony-stimulating factor (rhM-CSF), a homodimeric, disulfide bonded protein, was expressed in Escherichia coli in the form of inclusion bodies. Reduced and denatured rhM-CSF monomers were refolded in the presence of a thiol mixture (reduced and oxidized glutathione) and a low concentration of denaturing agent (urea or guanidinium chloride). Refolding was monitored by nonreducing gel electrophoresis and recovery of bioactivity. The effects of denaturant type and concentration, protein concentration, concentration of thiol/disulfide reagents, temperature, and presence of impurities on the kinetics of rhM-CSF renaturation were investigated. Low denaturant concentrations (<0.5 M urea) and high protein concentrations (>0.4 mg/ml) in the refolding mixture resulted in increased formation of aggregates, although aggregation was never significant even when refolding was carried out at room temperature. Higher protein concentration resulted in higher rates but did not lead to increased yields, due to the formation of unwanted aggregates. Experiments conducted at room temperature resulted in slightly higher rates than those conducted at 4 degrees C. Although the initial renaturation rate for solubilized inclusion body protein without purification was higher than that of the reversed-phase purified reduced denatured rhM-CSF, the final renaturation yield was much higher for the purified material. A maximum refolding yield of 95% was obtained for the purified material at the following refolding conditions: 0.5 M urea, 50 mM Tris, 1.25 mM DTT, 2 mM GSH, 2 mM GSSG, 22 degrees C, pH 8, [protein] = 0.13 mg/ml.
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PMID:Renaturation of Escherichia coli-derived recombinant human macrophage colony-stimulating factor. 1033 76

Overdose of acetaminophen (APAP) causes severe centrilobular hepatic necrosis in humans and experimental animals. Here, to explore its mechanism, we administered APAP at subtoxic (150 mg/kg ip) and toxic (500 mg/kg ip) doses to overnight fasted mice. Animals were sacrificed at different time points from 15 min to 4 h postinjection. We assessed liver toxicity by plasma ALT activity and by electron microscopy. Using nylon filter arrays and RTQPCR, we performed genomics analysis in liver. We ran proteomics on liver mitochondrial subfractions using the newly developed quantitative fluorescent 2D-DIGE method (Amersham Pharmacia Biotech UK Limited). As soon as 15 min postinjection, centrilobular hepatocyte mitochondria were already slightly enlarged and GSH total content dropped by a third at top dose. GM-CSF mRNA, which is a granulocyte specific gene likely coming from resident Kupffer cells, was also induced to its maximum of 3-fold at both doses. Chaperone proteins Hsp10 and Hsp60 were readily decreased by half in mitochondria at both doses, most likely by leaking into cytoplasm. Although APAP is known as an apoptotic trigger, no apoptosis was observed at any time point. Most of the protein changes in mitochondria were present at 15 min postinjection, thus preceding most of the gene regulations. The decrease of ATP synthase subunits and beta-oxidation pathway proteins indicated a loss of energy production. As the morphology of mitochondria was also affected very early at top dose, we concluded that APAP toxicity was a direct action of its known reactive metabolite NAPQI, rather than a consequence of gene regulation. However, the latter will either worsen the toxicity or lead toward cell recovery depending on the cellular damage level.
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PMID:Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. 1175 93

Pulmonary fibrosis can be observed as an end state in a number of chronic inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. Damage and alteration of alveolar epithelial cells is one of the hallmarks of interstitial lung fibrosis. Recently, it has been demonstrated that the presence of oxidative stress may lead to the damage, activation and/or apoptosis of alveolar epithelial cells either directly, through an imbalanced intracellular redox equilibrium, or indirectly, by activating redox-sensitive effector pathways, such as transcription factors and angiotensin converting enzyme, increasing the conversion of angiotensinogen into angiotensin II that can be considered a mediator of oxidative stress, capable of inducing apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a proinflammatory cytokine and is effective in activating fibroblasts through the release of transforming growth factor (TGF-beta). As well as activation, differentiation, proliferation and apoptosis of fibroblasts seem related to the oxidant/antioxidant balance, and the maintenance of a high intracellular level of reduced glutathione (GSH) is considered crucial in providing a reducing environment within the cell, able to protect against oxidative stress. In those conditions where oxidants, either inhaled or produced by inflammatory cell, increase, the ratio between GSH and oxidized glutathione (GSSH) may lower, influencing a variety of cellular redox-sensitive signaling processes such as the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead to a transcriptional up-regulation of a number of genes involved in inflammation and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1) and growth factors (GM-CSF). In addition, several studies have shown that oxidative stress may also affect the immune response by inducing an up-regulation of HLA-DR as well as the expression of two costimulatory molecules such as CD40 and CD86, determining a persistent state of immune activation, and affecting the Th1/Th2 balance, modulating the T-cell effector response towards the Th2 phenotype. It is clear that a better understanding of the precise sequence of events that make the difference between normal tissue repair and fibrosis, including the role played by oxidative stress, will certainly improve our therapeutic approach to pulmonary fibrosis.
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PMID:Role of oxidative stress in pulmonary fibrosis. 1261 77

Glutathione (GSH) is the main non-protein antioxidant and plays a critical role in protecting cells from damage by reactive oxygen species (ROS) generated by dopamine (DA) metabolism. We reported a decrease of GSH levels ([GSH]) in CSF and in prefrontal cortex in vivo in schizophrenics [Eur. J. Neurosci. 12 (2000) 3721]. A GSH deficit may lead to membrane peroxidation and microlesions around dopaminergic terminals, resulting in loss of connectivity. To test this hypothesis, we studied the effect of DA in cultured cortical neurons with low [GSH]. DA alone decreased [GSH] by 40%. This effect appears to result from direct conjugation of DA semiquinone/quinone with GSH. Ethacrynic acid (EA) decreased [GSH] in a concentration-dependent manner. When added to EA, DA further lowers [GSH]. As this additional decrease is blocked by superoxide dismutase (SOD) or D(1)/D(2) receptor antagonists, it likely involves the generation of superoxide via activation of DA receptors. It also reduces the mitochondrial membrane potential. Most interestingly, a significant decrease in number of neuronal processes (spines analogous) was induced by 24-h application of DA only in low [GSH]. These data, compatible with our hypothesis, is consistent with the dendritic spines reduction reported in schizophrenia and could be related to abnormalities in synaptic connectivity.
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PMID:Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. 1283 17

Major drawbacks of chemotherapeutic agents are their toxic side effects and lack of tumor specificity. Immunological and biochemical studies were here carried out to investigate protective effects of ethanolic extract of Andrographis paniculata against cyclophosphamide (CTX) induced toxicity in vivo. Intraperitoneal administration of the extract significantly increased the total WBC account (3256.5+/-196 cells/cm(2)), bone marrow cellularity (17.1+/-10.4x10(6) cells/femur) and betaesterase positive cells (849+/-23.2 cells/4000 cells) in CTX treated animals, when compared to CTX alone treated control mice. Weights of lymphoid organs such as a spleen and thymus, reduced by CTX administration, were also increased by A paniculata treatment. Reduction of GSH in liver (4.8+/-0.21nmol/mg protein) and in intestinal mucosa (13+/-0.67 nmol/mg protein) of CTX-treated controls was significantly reversed by A paniculata administration (liver: 6.4+/-0.13, intestinal mucosa: 17.11+/-0.06), with amelioration of changes in serum and liver ALP, GPT, LPO (lipid peroxidation). Histopathological analysis of small intestine also suggests that extract could reduce the CTX induced intestinal damage. The level of proinflammatory cytokine TNF-alpha, which was elevated during CTX administration, was significantly reduced by the A paniculata extract administration. The lowered levels of other cytokines like IFN-gamma, IL-2, GM-CSF, after CTX treatment were also found to be increased by extract administration.
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PMID:Ameliorating effects of Andrographis paniculata extract against cyclophosphamide-induced toxicity in mice. 1725 Apr 37


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