Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D00031 (Glutathione)
 5,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (GSH), its derivatives and N-acetylcysteine (NAC) inhibit the induction of HIV-1 expression in a chronically HIV-1-infected promonocytic cell line (U1/HIV) and peripheral blood mononuclear cells (PBMC). We have examined the effects of GSH and NAC on HIV-1 replication in human primary monocyte/macrophages cultured in vitro. Ficoll-gradient purified human monocytes were cultivated in vitro for 7-10 days and then infected with HIV-1 (Bal and Ada-M). Infection was blocked or substantially reduced by GSH or NAC (5-20 mM). Significant reduction (greater than or equal to 90%) in the amount of virus released, as determined by measuring supernatant reverse transcriptase activity and secreted p24 protein, was obtained when the cells were treated for 4 h with greater than or equal to 10 mM of GSH or NAC. The inhibitory effects of GSH and NAC were concentration dependent. This anti-HIV-1 effect persisted in these cultures for at least 35 days without evidence of significant increase in HIV-1 expression. Thus, a single pulse exposure of HIV-1-infected monocyte/macrophages with GSH or NAC led to a sustained, concentration-dependent decrease in HIV-1 p24 antigen levels, as well as, reverse transcriptase activity without producing detectable cellular toxicity in monocyte/macrophages.
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PMID:Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro. 152 May 37

Glutathione (GSH) is known to play an important role in various lymphocyte functions. We now report that different T cell subsets express different requirements for intracellular GSH. Depletion of intracellular GSH by buthionine sulfoximine (BSO), a specific inhibitor of GSH biosynthesis, decreases the proportion of CD8+ cells (i.e., increases the CD4+/CD8+ ratio), and inhibits particularly the generation of large blast-like CD8+ cells and cytotoxic T lymphocyte (CTL) activity. CTL activity is restored by administration of exogenous GSH. Differential effects of GSH depletion were also seen at the level of individual T cell clones. The CD4+ helper T cell clone D10.G4.1.HD was found to express a high rate of interleukin 2 (IL-2) dependent DNA synthesis even after severe depletion of intracellular GSH, whereas other T cell clones including the clone 29 were severely inhibited by BSO. The results of these studies suggest that the decreased intracellular GSH levels of HIV-1 seropositive persons are probably not (directly) responsible for the selective depletion of the CD4+ T cell subset but may be responsible for a cellular dysfunction of the CD8+ subset and for the ultimate failure of the CTL to control the viral infection in these patients.
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PMID:Differential effects of glutathione depletion on T cell subsets. 191 38

Evidence has accumulated suggesting that HIV-infected patients are under chronic oxidative stress. Perturbations to the antioxidant defense system, including changes in levels of ascorbic acid, tocopherols, carotenoids, selenium, superoxide dismutase, and glutathione, have been observed in various tissues of these patients. Elevated serum levels of hydroperoxides and malondialdehyde also have been noted and are indicative of oxidative stress during HIV infection. Indications of oxidative stress are observed in asymptomatic HIV-infected patients early in the course of the disease. Oxidative stress may contribute to several aspects of HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss, and increased sensitivity to drug toxicities. Glutathione may play a role in these processes, and thus, agents that replete glutathione may offer a promising treatment for HIV-infected patients. Clinical studies are underway to evaluate the efficacy of the glutathione-repleting agents, L-2-oxothiazolidine-4-carboxylic acid (OTC) and N-acetylcysteine (NAC), in HIV-infected patients.
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PMID:The role of oxidative stress in HIV disease. 759 Apr 4

Glutathione depletion may play a pivotal role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection. Since certain compounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potencies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunctional inducers tested elevated the levels of glutathione and quinone reductase, a marker for phase II enzyme induction. However, only oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at inhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 microM). The antiviral effect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of anti-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibitor of HIV-1 reverse transcriptase in the template-primer binding domain. Oltipraz has been used to treat schistosomiasis in humans and is undergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (and other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1-infected individuals, not only because of their antiretroviral activity, but also by preventing the development of HIV-1-associated neoplasms.
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PMID:Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. 768 14

Glutathione (GSH) levels are markedly depleted in patients infected with human immunodeficiency virus type 1 (HIV-1) and supplementation of media with high concentrations (5-20 mM) of low-molecular weight thiols prevents HIV-1 replication in cultured cells. We were intrigued whether chemopreventive enzyme inducers might represent a more pharmacologically feasible method to inhibit HIV-1 replication since these compounds elevate intracellular concentrations of GSH at nontoxic doses in vivo. After establishing that all inducers surveyed were able to elevate GSH levels in human T-cell and monocytoid cell lines, we were surprised to find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was uniquely able to inhibit HIV-1 replication (IC50 = 5-15 microM). Oltipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to inhibit acute HIV-1 replication by inactivating reverse transcriptase (RT). However, among DTTs that inhibit HIV-1 replication in acutely infected cells, only oltipraz was able to inhibit HIV-1 replication in a chronic infection model. Thus, in addition to inactivating RT, oltipraz appears to have an additional antiviral mechanism distal to viral integration. Our laboratories are attempting to determine the mechanism by which oltipraz inhibits HIV-1 replication in chronically infected cells; we are also attempting to determine the bioorganic mechanism for the inactivation of RT. Since the covalent modification of schistosomal proteins and transcription factor(s) are thought to be responsible for the antiparasitic and chemopreventive activities of DTTs, respectively, our studies should be relevant to understanding the diverse medicinal properties of DTTs. Oltipraz, an antischistosomal drug undergoing clinical evaluation as an anticarcinogen, inhibits HIV-1 replication at concentrations achievable in human serum. It is intriguing to consider oltipraz as a therapeutic agent not only for its antiretroviral activity, but also for the prevention of HIV-1 associated neoplasms.
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PMID:Oltipraz, a novel inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. 853 88

The oxidative stress in human erythrocytes was studied in asymptomatic and symptomatic patients infected by the human immunodeficiency virus (HIV), and patients with the acquired immunodeficiency syndrome (AIDS). tert-Butyl hydroperoxide initiated chemiluminescence, superoxide dismutase and catalase activities, and total glutathione were evaluated in the erythrocytes and the total antioxidant capacity in the plasma of control, patients infected with HIV that have not yet developed acquired immunodeficiency syndrome, and patients in the later stage of AIDS. tert-Butyl hydroperoxide initiated chemiluminescence was increased by 33% in asymptomatic (stage A1) and symptomatic patients (stage B2) infected with HIV and 82% for patients with AIDS (stage B3) (P < 0.05). While catalase activity did not show any difference between patients and controls, other indices showed differences that, in some cases, reached statistical significance. Superoxide dismutase activity was increased by 24% in stages A1 and B2 of HIV infection and 65% in patients in stage B3 (P < 0.05). Glutathione was decreased by 20% in stages A1 and B2, and by 32% in stage B3 patients (P < 0.05). Total plasma antioxidant capacity was increased in 30 and 57% for the asymptomatic and AIDS patients groups, respectively (P < 0.05). The data indicate that erythrocyte's oxidative stress is associated with the progressive development of HIV disease. Parameters indicating oxidative stress could be an interesting form to screen the evolution of these patients and their response to anti-oxidant therapies.
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PMID:Oxidative stress in blood of HIV infected patients. 893 54

Glutathione is an important antioxidant tripeptide that is found in high concentrations in the epithelial lining fluid (ELF) of the lung. Previous investigators demonstrated a deficiency of glutathione (GSH) in the epithelial lining fluid of human immunodeficiency virus (HIV)-seropositive patients. The current investigation performed bronchoalveolar lavage (BAL) on 59 asymptomatic HIV-seropositive subjects (mean CD4: 365.9 +/- 31.2 cells/mm3) and 12 normal control subjects. The volume of ELF and the concentration of glutathione and oxidized glutathione were determined. The concentration of total GSH in ELF was not significantly different in HIV-seropositive individuals compared with normal subjects (628.1 +/- 63.9 microM versus 499.9 +/- 86.0 microM, p = 0.38). However, there was a significantly higher concentration of ELF GSH in HIV-seropositive cigarette smokers (n = 30) compared with nonsmokers (n = 29) (800.3 +/- 107.7 microM versus 443.6 +/- 45.3 microM, p = 0.004). The percentage of total GSH in the oxidized form (GSSG) was similar in both the HIV-seropositive and the normal subject groups (3.4 +/- 0.3% versus 3.0 +/- 0.4%, p = 0.559). There were no significant correlations between ELF GSH or GSSG concentrations and age, CD4 count, or pulmonary function. There was, however, a significant negative correlation between BAL lymphocyte percentage and GSH. The current study suggests that for those patients whose HIV infection is at a relatively early phase, the levels of GSH in the lung ELF are normal.
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PMID:Alveolar fluid glutathione is not reduced in asymptomatic HIV-seropositive subjects. 900 39

Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection (Kaplan-Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.
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PMID:Glutathione deficiency is associated with impaired survival in HIV disease. 905 Aug 88

HIV-gp120 sensitizes Th1 clones from seronegative donors to apoptosis, which occurs through two distinct events: expression of CD95L followed by its interaction with CD95 to trigger cell death. gp120-apoptosis of the Th1 clone 103 was inhibited by Cyclosporin A, the PTK inhibitors Genistein and PNU152518, as well as the anti-oxidants Ascorbic Acid and Glutathione. Cyclosporin A interfered with CD95L expression, Ascorbic Acid and Glutathione inhibited cell death triggered by CD95/CD95L interaction; Genistein and PNU152518 acted on both steps. The occurrence of oxidative stress during CD95-dependent apoptosis was supported by the direct evidence of ROI production.
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PMID:Apoptosis induced by HIV-gp120 in a Th1 clone involves the generation of reactive oxygen intermediates downstream CD95 triggering. 924 48

Previous studies have suggested that the two conserved cysteines of the HIV-1 protease may be involved in regulating protease activity. Here, we examined diglutathionylated wild type protease (Cys-67-SSG, Cys-95-SSG) and the monoglutathionylated protease mutants (C67A, Cys-95-SSG and C95A, Cys-67-SSG) as potential substrates for thioltransferase (glutaredoxin). Time-dependent changes in the extent of deglutathionylation of each protein were assayed by reverse phase-high performance liquid chromatography. Glutathione alone was not an effective reductant, whereas thioltransferase displayed differential catalysis toward the Cys-95-SSG and Cys-67-SSG sites. At low thioltransferase concentrations (5 nM), deglutathionylation occurred almost exclusively at Cys-95-SSG. With substantially more thioltransferase (100 nM) Cys-67-SSG was partially deglutathionylated but only at 20% of the rate of Cys-95-SSG reduction. Treatment of the diglutathionylated protease with thioltransferase not only restored protease activity but generated an enzyme preparation that had a 3- to 5-fold greater specific activity relative to the fully reduced form. Immunoblot analysis of HIV-1MN virus with an antibody to thioltransferase detected a band co-migrating with recombinant thioltransferase that persisted following subtilisin treatment, indicating the presence of thioltransferase within HIV-1. Our results implicate thioltransferase in the regulation and/or maintenance of protease activity in HIV-1 infected cells.
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PMID:Thioltransferase (glutaredoxin) is detected within HIV-1 and can regulate the activity of glutathionylated HIV-1 protease in vitro. 932 27


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