Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione depletion occurs in several forms of apoptosis and is associated with Parkinson's disease and HIV toxicity. The neurotransmitter glutamate kills immature cortical neurons and a hippocampal nerve cell line via an oxidative pathway associated with glutathione depletion. It is shown here that soluble guanylyl cyclase (sGC) activity is required for nerve cell death caused by glutathione depletion. Inhibitors of sGC block glutamate toxicity and a cGMP analogue potentiates cell death. Glutamate also induces an elevation of cGMP that occurs late in the cell death pathway. The resultant cGMP modulates the increase in intracellular calcium that precedes cell death because sGC inhibitors prevent calcium elevation and the cGMP analogue potentiates the increase in intracellular calcium. These results suggest that the final pathway of glutamate induced nerve cell death is through a cGMP-modulated calcium channel.
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PMID:Requirement for cGMP in nerve cell death caused by glutathione depletion. 938 76

Primary murine embryonic fibroblasts transfected with HIV-1 TAT demonstrated decreased levels of high energy phosphates (ATP, GTP, UTP/CTP), adenine nucleotides (ATP, ADP, AMP), and both NAD+/NADH redox pairs, resulting in a substantial loss of redox poise. A greater than 50% decrease in intracellular reduced glutathione (GSH) concentration was accompanied by the extracellular appearance of acidic fibroblast growth factor (FGF-1). Addition of either N-acetyl-L-cysteine or glutathione ester (GSE), but not L-2-oxothiazolidine 4-carboxylate, partially restored intracellular GSH levels and resulted in loss of extracellular FGF-1. Treatment of FGF-1-transduced cells with buthionine sulfoximine (BSO) resulted in a time- and dose-dependent decrease in total cellular GSH concentration that was accompanied by the extracellular appearance of FGF-1. Inclusion of GSE during BSO treatment eliminated the extracellular appearance of FGF-1. BSO treatment of cells transfected with a mutant form of FGF-1, in which all three cysteine residues were replaced with serines, also decreased total cellular GSH concentration but failed to induce the extracellular appearance of FGF-1. Collectively, these results suggest that HIV-1 TAT induces a condition of oxidative stress, which mediates cellular secretion of FGF-1, an observation relevant to the pathophysiologic development and progression of AIDS-associated Kaposi's sarcoma.
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PMID:Glutathione depletion associated with the HIV-1 TAT protein mediates the extracellular appearance of acidic fibroblast growth factor. 950 19

Both clinical and experimental evidence indicates that AIDS-related Kaposi's sarcoma (AIDS-KS) has a multifactorial pathogenesis with factors such as HIV viral load, latent virus induction, and opportunistic infections contributing to disease progression. However, a consistent feature that unites these apparently diverse putative etiologic agents is sustained serum elevations of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). While virtually every cell responds to TNF-alpha with gene activation, the extent of TNF-alpha-mediated cellular signaling is regulated by a delicate balance between signal activation and signal arresting events. Reactive oxygen intermediates (ROI), which are generated as a consequence of TNF-alpha membrane interaction, are part of this TNF-alpha-initiated cellular activation cascade. Previous studies in our laboratory have shown that AIDS-KS cells possess impaired oxygen intermediate scavenging capacities, thereby establishing conditions permissive for the intracellular retention of ROI. In this study, we used cellular capacity to upregulate the cytoprotective enzyme superoxide dismutase (SOD) to address the extent of cellular response to TNF-alpha. Concurrent with the SOD analyses, nucleotide profiles were obtained to assess cellular bioenergetic responses during TNF-alpha challenge. Proliferative growth levels of mitochondrial (Mn)SOD activities showed an activity spectrum ranging from lowest activity in AIDS-KS cells, to intermediate levels in matched, nonlesional cells from the AIDS-KS donors, to highest activities in HIV normal fibroblasts. In contrast, following TNF-alpha challenge, the AIDS-KS and KS donor nonlesional cells showed a 11.89- and 5.86-fold respective increase in MnSOD activity, while the normal fibroblasts demonstrated a 1.35-fold decrease. Subsequent thiol redox modulation studies showed that only the normal fibroblast cultures showed a potentiation of TNF-alpha-mediated MnSOD upregulation following GSH depletion. In addition, provision of the GSH precursor, N-acetylcysteine during TNF-alpha challenge only diminished MnSOD activity and mitochondrial compartmentalization in the AIDS-KS cells, a finding that likely reflects the lower levels of reduced thiols in this cellular population. Our data, which show that a perturbation in their cellular thiol redox status accentuates AIDS-KS cellular responsiveness to TNF-alpha, suggest a biochemical rationale for the recognized TNF-alpha AIDS-KS clinical correlation.
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PMID:Thiol redox modulation of tumor necrosis factor-alpha responsiveness in cultured AIDS-related Kaposi's sarcoma cells. 951 60

Dysregulated apoptosis may underlie the etiology of T cell depletion by human immunodeficiency virus type 1 (HIV-1). We show that HIV-induced apoptosis is preceded by an exponential increase in reactive oxygen intermediates (ROIs) produced in mitochondria. This leads to caspase-3 activation, phosphatidylserine (PS) externalization, and GSH depletion. Since mitochondrial ROI levels are regulated by the supply of NADPH from the pentose phosphate pathway (PPP), the effect of transaldolase (TAL), a key enzyme of PPP, was investigated. Jurkat and H9 human CD4+ T cells were transfected with TAL expression vectors oriented in the sense or antisense direction. TAL overexpression down-regulated glucose-6-phosphate dehydrogenase activities and GSH levels. Alternatively, decreased TAL expression up-regulated glucose-6-phosphate dehydrogenase activities and GSH levels. HIV-induced 1) mitochondrial ROI production, 2) caspase-3 activation, 3) proteolysis of poly(ADP-ribose) polymerase, and 4) PS externalization were accelerated in cells overexpressing TAL. In contrast, suppression of TAL abrogated these four activities. Thus, susceptibility to HIV-induced apoptosis can be regulated by TAL through controlling the balance between mitochondrial ROI production and the metabolic supply of reducing equivalents by the PPP. The dominant effect of TAL expression on oxidative stress, caspase activation, PS externalization, and cell death suggests that this balance plays a pivotal role in HIV-induced apoptosis.
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PMID:Molecular ordering in HIV-induced apoptosis. Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase. 956 23

Glutathione is the main intracellular defence against oxidative stress and regulates the cellular redox potential. HIV infection is accompanied by severe metabolic and immune dysfunctions. Several laboratories have demonstrated that the intracellular redox balance is disturbed in CD4+ T cells from HIV-seropositive subjects, which may potentiate HIV replication and partly explain the immunological abnormalities associated with HIV disease. The importance of glutathione for immune function, regulation of gene expression, as well as therapeutic interventions with redox-active drugs are discussed in this commentary.
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PMID:Glutathione and HIV infection: reduced reduced, or increased oxidized? 956 64

N-acetylcysteine (NAC), the acetylated variant of the amino acid L-cysteine, is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. Administration of NAC has historically been as a mucolytic agent in a variety of respiratory illnesses; however, it appears to also have beneficial effects in conditions characterized by decreased GSH or oxidative stress, such as HIV infection, cancer, heart disease, and cigarette smoking. An 18-dose oral course of NAC is currently the mainstay of treatment for acetaminophen-induced hepatotoxicity. N-acetylcysteine also appears to have some clinical usefulness as a chelating agent in the treatment of acute heavy metal poisoning, both as an agent capable of protecting the liver and kidney from damage and as an intervention to enhance elimination of the metals.
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PMID:Clinical applications of N-acetylcysteine. 957 47

The anti-human immunodeficiency virus type I (anti-HIV-1) effects of gamma-glutamylcysteine ethyl ester (gamma-GCE; TEI-2306) were examined in vitro. In initial studies using a vigorously HIV-1-producing human T-lymphocytic cell line, gamma-GCE displayed a novel biphasic repressive effect on chronic HIV-1 infection that was unlike that of other glutathione prodrugs or other reported antioxidants. In high doses, up to a concentration of 2.5 mM, at which neither glutathione (GSH) nor another GSH precursor has shown inhibitory effects, gamma-GCE potently inhibited the production of HIV-1 by a selective cytopathic effect against infected cells, while the viability and growth of uninfected cells were unaffected at the same gamma-GCE concentrations. At lower concentrations (200 to 400 microM), gamma-GCE significantly repressed the virus production from chronically HIV-1-expressing cells without affecting their viability. The discrepancy of the thresholds of the toxic doses between infected and uninfected cells was found to be more than 10-fold. Relatively high doses of gamma-GCE, utilized in acute HIV-1 infection of T-lymphocytic cells, entirely blocked the propagation of HIV-1 and rescued the cells from HIV-1-induced cell death. Furthermore, gamma-GCE at such concentrations was found to directly inhibit the infectivity of HIV-1 within 4 h. Repressive effects of gamma-GCE on acute HIV-1 infection in human primary human peripheral blood mononuclear cells were also demonstrated. Here, the anti-HIV-1 strategy utilizing gamma-GCE is removal of both HIV-1-producing cells and free infectious HIV-1 in vitro, in place of specific immunoclearance in vivo, which might lead to an arrest or slowing of viral propagation in HIV-1-infected individuals.
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PMID:Novel inhibitory effects of gamma-glutamylcysteine ethyl ester against human immunodeficiency virus type 1 production and propagation. 959 50

The redox chemistry of two synthetic model peptides for the 603-609 disulfide loop found in envelope glycoprotein gp41 of the human immunodeficiency virus type 1 (HIV-1) are reported. The two peptides: N-Ac-Trp-Gly-Cys-Ser-Gly-Lys-Leu-Ile-Cys-Thr-Thr-NH2 (I) and N-Ac-Trp-Gly-Cys-Ser-Gly-Arg-His-Ile-Cys-Thr-Thr-NH2 (II) were synthesized by the solid phase method. Peptide I corresponds to amino acids 601-611 of gp41 of the North American/European strain of HIV-1. Peptide II incorporates amino acid replacements frequent in African HIV-1 isolates. The redox chemistry of the disulfide bonds in the two peptides was characterized in aqueous and aqueous/urea solution by studying their thiol-disulfide exchange reactions with the tripeptide glutathione (GSH). GSH reacts with the disulfide bonds to form mixed disulfides, which in turn react with another molecule of GSH to give the dithiol form of the peptide and GSSG. Equilibrium constants were determined for each step and for the overall reduction reactions. Redox potentials of -0.246V and -0.241V were calculated from the equilibrium constants for the disulfide bonds in peptides I and II in aqueous solution at 25 degrees C and pH 7.0. The overall equilibrium constants are less in 8 M urea solution, which indicates a stabilization of the reduced, dithiol form of both peptides by secondary structure which can be denatured by urea. This conclusion is supported by nuclear Overhauser enhancement data obtained from 2D-ROESY NMR spectra which provide evidence of elements of secondary structure for the reduced forms of both peptides. The results are discussed in terms of a protein disulfide isomerase catalyzed reduction of the disulfide bond in gp41.
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PMID:Characterization of the thiol/disulfide chemistry of peptides corresponding to the 603-609 disulfide loop of the human immunodeficiency virus (HIV) envelope glycoprotein gp41. 965 Jul 18

The cellular coenzymatic role of NAD, being a pleiotropic cofactor for diverse cellular reactions, is extended to poly(ADP-ribose) and to the highly abundant nuclear protein, poly(ADP-ribose) polymerase, with special focus on the pharmacological action of ligands on the latter. The polymer is defined to possess a helical configuration. From direct analyses of the polymer under physiological conditions, it is concluded that the polymerase is dormant in normal tissues, but is activated under certain pathological conditions: malignancy, retroviral integrate containing cells, and in a variety of inflammatory states. The interaction of poly(ADP-ribose) polymerase ligands with the DNA component of the active poly (ADP-ribose) polymerase - DNA complex is shown. A major cellular function of the poly(ADP-ribose) polymerase protein is its binding capacity to a large number of nuclear proteins and DNA sites, an effect which is induced by drugs that inhibit the polymerase activity. The malignancy-reverting effect of poly(ADP-ribose) polymerase ligand drugs is illustrated in chemically and oncovirally transformed cancer cells. The poly(ADP-ribose) polymerase ligand-induced cessation of HIV replication is analyzed. Peroxynitrite-induced DNA damage-initiated pathological responses are shown to be inhibited by a specific poly(ADP-ribose) polymerase ligand. The irreversibly acting C-NO drugs oxidize asymmetric zinc fingers [poly(ADP-ribose) polymerase, HIV gag-precursor protein] and act as anti-cancer and anti-HIV agents, an effect that is regulated by cellular concentration of GSH.
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PMID:Poly(ADP-ribose) polymerase, a potential target for drugs: Cellular regulatory role of the polymer and the polymerase protein mediated by catalytic and macromolecular colligative actions (Review). 985 79

Although several studies have documented intra- and extracellular glutathione (GSH) deficiency in asymptomatic human immunodeficiency virus (HIV) infection, the mechanisms responsible for the altered GSH homeostasis remain unknown. To determine whether decreased synthesis contributes to this alteration of GSH homeostasis, a primed-constant infusion of [2H2]glycine was used to measure the fractional and absolute rates of synthesis of GSH in five healthy and five symptom-free HIV-infected subjects before and after supplementation for 1 wk with N-acetylcysteine. The erythrocyte GSH concentration of the HIV-infected group was lower (P < 0.01) than that of the control group (1.4 +/- 0.16 vs. 2.4 +/- 0.08 mmol/l). The smaller erythrocyte GSH pool of the HIV-infected group was associated with a significantly slower (P < 0.01) absolute synthesis rate of GSH (1.15 +/- 0.14 vs. 1.71 +/- 0.15 mmol. l-1. day-1) compared with controls. Cysteine supplementation elicited significant increases in both the absolute rate of synthesis and the concentration of erythrocyte GSH. These results suggest that the GSH deficiency of HIV infection is due in part to a reduced synthesis rate secondary to a shortage in cysteine availability.
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PMID:Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. 988 68


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