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 reported previously that low levels of nitric oxide (NO) induced cell death with properties of apoptosis, including chromatin fragmentation and condensation in undifferentiated PC12 pheochromocytoma cells. The present study demonstrates that cytotoxicity of low concentrations of NO is mediated by inhibition of mitochondrial cytochrome c oxidase and generation of reactive oxygen species (ROS). An NO donor, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) induced cell death even at low concentrations (10-100 microM), whereas peroxynitrite and a peroxynitrite generator, 3-(4-morpholinyl)-sydnonimine (SIN-1), did not have a significant effect on cell viability up to a concentration of 0.5 mM. The NOR3-induced cell death was unaffected by pretreatment with superoxide dismutase (SOD) or its mimetic peroxynitrite scavenger, manganese(III) tetrakis(benzoic acid)porphyrin chloride (Mn-TBAP), or with uric acid. These findings indicate that peroxynitrite does not contribute to this cell death. Furthermore, neither the release of cytochrome c from mitochondrial membranes, the cleavage of poly-ADP ribose polymerase (PARP), nor the activation of caspase-3-like activities was observed. Inhibitors of PARP, benzamide, and aminobenzamide, had no effect on the NOR3-induced cell death. In addition, pretreatment with general or selective caspase inhibitors, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), N-acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), and benzyloxycarbonyl-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp-Ch(2)-DCB) did not prevent NOR3-induced cell death. Taken together, these findings suggest that cell death induced by NOR3 occurs by a caspase-independent mechanism. In contrast, we found an early increase in mitochondrial H(2)O(2) production during NOR3 exposure using the fluorescent dye 2',7'-dichlorofluorescin-diacetate (DCFH-DA) and dihydrorohdamine123 (DHR123), and these events were accompanied by strong inhibition of cytochrome c oxidase activity in the cells. Furthermore, we observed that several antioxidants, such as ascorbate, glutathione (GSH), cysteine, tetrahydrobiopterin, and dithiothreitol (DTT), all effectively prevented the NOR3-induced cell death. NOR3 treatment decreased the level of total intracellular GSH, but did not affect the activities of antioxidant enzymes SOD, GSH-peroxidase (GPX), and catalase. These results suggest that cell death induced at physiologically low concentrations of NO is mediated by ROS production in mitochondria, most likely resulting from the inhibition of cytochrome c oxidase, with ROS acting as an initiator of caspase-independent cell death.
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PMID:Caspase-independent cell death by low concentrations of nitric oxide in PC12 cells: involvement of cytochrome C oxidase inhibition and the production of reactive oxygen species in mitochondria. 1286 69

Whereas ch/ch wild-type mice and ch/14CoS heterozygotes are viable, 14CoS/14CoS mice homozygous for a 3800 kb deletion on chromosome 7 die during the first day postpartum. Death is caused by disruption of the fumarylacetoacetate hydrolase (Fah) gene; absence of FAH, final enzyme in the tyrosine catabolism pathway, leads to accumulation of reactive electrophilic intermediates. In this study, we kept 14CoS/14CoS mice alive for 60 d with oral 2-(2-nitro-4-trifluoromethyl-benzyol)-1,3-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, second enzyme in the tyrosine catabolic pathway. The 70% of NTBC-treated 14CoS/14CoS mice that survived 60 d showed poor growth and developed corneal opacities, compared with ch/14CoS littermates; NTBC-rescued Fah(-/-) knockout mice did not show growth retardation or ocular toxicity. NTBC-rescued 14CoS/14CoS mice also exhibited a striking oxidative stress response in liver and kidney, as measured by lower GSH levels and mRNA induction of four genes: glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, NAD(P)H:quinone oxidoreductase (Nqo1), and heme oxygenase-1 (Hmox1). Withdrawal of NTBC for 24-48 h from rescued adult 14CoS/14CoS mice resulted in severe apoptosis of the liver, detected histologically and by cytochrome c release from the mitochondria, increased caspase 3-like activity, and further decreases in GSH content. In kidney, proximal tubular epithelial cells were abnormal. Human hereditary tyrosinemia type I (HT1), caused by mutations in the FAH gene, is an autosomal recessive disorder in which the patient usually dies of liver fibrosis and cirrhosis during early childhood; NTBC treatment is known to prolong HT1 children's lives-although liver fibrosis, cirrhosis, hepatocarcinoma, and corneal opacities sometimes occur. The mouse data in the present study are consistent with the possibility that endogenous oxidative stress-induced apoptosis may be the underlying cause of liver pathology seen in NTBC-treated HT1 patients.
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PMID:Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress. 1289 38

Cadmium (Cd), which accumulates primarily in the liver and the kidney, induces apoptosis and also causes necrotic cell death in certain pathophysiologic situations. Previously, we have shown that Cd activated mitogen-activated protein kinases and that sulfur amino acid deficiency potentiated Cd-induced cytotoxicity via activation of mitogen-activated protein kinases. In the present study, we established the mechanistic basis of apoptotic and non-apoptotic cell death induced by Cd in H4IIE cells a rat-derived hepatocyte cell line. Cd at 0.3-10 microM decreased viability of cells in a concentration-dependent manner. Cd-induced cytotoxicity was enhanced by pretreatment with buthionine sulfoximine (BSO). Cd at 0.3 microM induced translocation of Bad to mitochondria, decreased the level of mitochondrial BcL(XL) with the release of cytochrome c, and induced procaspase-9 activation and poly(ADP-ribose) polymerase (PARP) cleavage. Sulfhydryl deficiency by BSO, however, blocked PARP cleavage in spite of the decrease in procaspase-9. Cytochrome c release, procaspase-9 activation and PARP cleavage were all increased by 1 microM Cd irrespective of BSO pretreatment. We also used H(2)O(2) (10-100 microM) as a source of oxidative stress. Cd (0.3-1 microM) + H(2)O(2) (70 microM) resulted in greater extents of cytochrome c release, procaspase-9 activation and PARP cleavage in H4IIE cells than Cd alone. Flow cytometric analysis confirmed apoptotic and non-apoptotic cell death by Cd depending on cellular glutathione (GSH) content. These results provide evidence that Cd at the physiologically obtainable concentration causes non-apoptotic cell death under the condition of sufhydryl deficiency, whereas Cd at the micromolar level induces apoptosis. The cell death mechanism involves cytochrome c release from mitochondria and decrease in the level of procaspase-9, but not PARP cleavage, implying that alterations in cellular sulfhydryls may be the major determining factor for the path of cell death in response to low level of Cd.
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PMID:Cadmium-induced non-apoptotic cell death mediated by oxidative stress under the condition of sulfhydryl deficiency. 1292 50

Arsenic trioxide (As(2)O(3)) has been used successfully in the treatment of acute promyelocytic leukemia. However, effects of As(2)O(3) in normal peripheral blood T cells have not been studied in detail. The purpose of this study was to investigate whether As(2)O(3) would induce apoptosis in normal T cells and therefore may have immunosuppressive side effects. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, caspase activation by flow cytometry and colorimetric assay, mitochondrial transmembrane potential (deltapsi(m)), intracellular reactive oxygen species (ROS), and intracellular reduced glutathione (GSH) by flow cytometry. The release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria was measured by confocal microscopy, and the expression of molecules regulating apoptosis was measured by Western blotting. As(2)O(3), at clinically achievable therapeutic concentrations, induces apoptosis in peripheral blood T cells. As(2)O(3)-induced apoptosis was associated with reduced deltapsi(m), enhanced generation of intracellular ROS, decreased levels of intracellular GSH, release of cytochrome c and AIF from the mitochondria, activation of caspases, down-regulation of Bcl-2 and Bcl-x(L), and up-regulation of Bax expression. In addition, exogenous GSH protected lymphocytes from As(2)O(3)-induced apoptosis. Furthermore, overexpression of Bcl-2 inhibited As(2)O(3)-induced apoptosis and blocked depolarization of deltapsi(m), generation of ROS, and release of both cytochrome c and AIF. These data indicate that As(2)O(3) induces apoptosis in T cells by enhancing oxidative stress and that Bcl-2 appears to play a major role in As(2)O(3)-induced apoptosis.
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PMID:Arsenic trioxide induces apoptosis in peripheral blood T lymphocyte subsets by inducing oxidative stress: a role of Bcl-2. 1293 60

Various reagents are known to open the mitochondrial permeability pore (PTP) and induce a permeability transition (PT), releasing apoptogenic proteins from the intermembrane space and triggering apoptosis. In this study, we examined the effect of Ag(+), a known cytotoxic sulfhydryl-reactive heavy metal, on isolated rat liver mitochondria. The following results were obtained: (1) Upon addition, Ag(+) instantly induced mitochondrial swelling and acceleration of respiration. (2) Cyclosporine A, a specific inhibitor of classical PT, was ineffective against the effect of Ag(+), indicating that silver ions induced non-classic PT. (3) Sulfhydryl reagents such as reduced glutathione completely inhibited the effects of Ag(+) on the mitochondria. (4) Experimental results using polyethylene glycol indicated that Ag(+) induced opening of a pore in the inner mitochondrial membrane, which could be PTP of another open state or a distinct pore. (5) Electron microscopic analysis of mitochondria treated with Ag(+) showed a novel mitochondrial configuration that was apparently different from that of normal mitochondria or Ca(2+)-treated mitochondria. (6) Ag(+) also induced the release of apoptogenic cytochrome c in a CsA-insensitive but GSH-sensitive manner. These results suggest that Ag(+) promotes a nonclassical permeability increase in the mitochondrial inner membrane that is clearly distinguishable from the classical PT and releases apoptogenic cytochrome c in a classical PT-independent manner.
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PMID:Silver ion induces a cyclosporine a-insensitive permeability transition in rat liver mitochondria and release of apoptogenic cytochrome C. 1294 69

Caloric restriction (CR) can extend the life-span of multiple species and is the only intervention known to attenuate aging in mammals. Mechanisms mediating the CR influence are as yet unclear. To get insight into these mechanisms we took advantage of alphaMUPA transgenic mice that have previously been reported to spontaneously eat less and live longer compared with their wild-type (WT) control. Here we report that mitochondria isolated from young adult alphaMUPA livers showed increased susceptibility to calcium-induced high-amplitude swelling, increased cytochrome c release and enhanced glutathione levels. Furthermore, young adult alphaMUPA mice showed significantly enhanced caspase-3 activity in liver homogenates, increased fraction of apoptotic hepatocytes, and a lower level of serum IGF-1. In addition, alphaMUPA mice showed a decreased rate of spontaneously occurring lung tumors at an old age. Short-term (8 weeks) calorically restricted WT mice also showed an increase of mitochondrial swelling and caspase-3 activity compared with ad libitum (AL) fed WT mice. These results provide the first indication that CR can enhance mitochondrion-mediated apoptotic capacity. Collectively, the results are consistent with the possibility that long lasting, moderately increased apoptotic capacity, possibly linked in part to IGF-1 and GSH modulation, could play a role in the CR-induced anti-aging influence in mice.
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PMID:Mitochondrion-mediated apoptosis is enhanced in long-lived alphaMUPA transgenic mice and calorically restricted wild-type mice. 1295 82

Reduced glutathione, in concentrations approximating those occurring in intact rat liver, causes swelling of rat liver mitochondria in vitro which is different in kinetics and extent from that yielded by L-thyroxine. The effect is also given by cysteine, which is more active, and reduced coenzyme A, but not by L-ascorbate, cystine, or oxidized glutathione. The optimum pH is 6.5, whereas thyroxine-induced swelling is optimal at pH 7.5. The GSH-induced swelling is not inhibited by DNP or dicumarol, nor by high concentrations of sucrose, serum albumin, or polyvinylpyrrolidone, in contrast to thyroxine-induced swelling. ATP inhibits the GSH swelling, but ADP and AMP are ineffective. Mn(-+) is a very potent inhibitor, but Mg(++) is ineffective. Ethylenediaminetetraacetate is also an effective inhibitor of GSH-induced swelling. The respiratory inhibitors amytal and antimycin A do not inhibit the swelling action of GSH, but cyanide does; these findings are consistent with the view that the oxidation-reduction state of the respiratory chain between cytochrome c and oxygen is a determinant of GSH-induced swelling. Reversal of GSH-induced swelling by osmotic means or by ATP in KCl media could not be observed. Large losses of nucleotides and protein occur during the swelling by GSH, suggesting that the action is irreversible. The characteristically drastic swelling action of GSH could be prevented if L-thyroxine was also present in the medium.
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PMID:Mitochondrial swelling induced by glutathione. 1363 Sep 41

The novel oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) induces apoptosis of human leukemia cells by activation of the extrinsic caspase-8 pathway. The mechanisms responsible for the proapoptotic effects of CDDO are unknown. The present studies demonstrate that CDDO activates the c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase in U-937 leukemia cells. The results also show that CDDO activates stress kinases by increasing levels of reactive oxygen species and decreasing intracellular glutathione (GSH) concentrations. Similar findings were obtained with the C-28 methyl ester (CDDO-Me) and C-28 imidazolide ester (CDDO-Im) derivatives. The results also demonstrate that CDDO-induced: (a) stimulation of Jun NH(2)-terminal kinase; (b) activation of caspase-8; (c) loss of mitochondrial transmembrane potential; (d) release of cytochrome c; and (e) cleavage of caspase-3 are blocked by pretreatment with the antioxidant N-acetyl-L-cysteine and GSH but not with cysteine. In concert with these results, CDDO-induced apoptosis is also abrogated by N-acetyl-L-cysteine and GSH. These findings demonstrate that CDDO and its derivatives disrupt intracellular redox balance and thereby induce apoptosis.
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PMID:The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance. 1450 Mar 94

The mitochondrial permeability transition is recognized to be involved in toxic and oxidative forms of cell injury. In the present study, we investigated the effect of ambroxol against the cytotoxicity of bleomycin (BLM) by looking at the effect on the mitochondrial membrane permeability in alveolar macrophages and lung epithelial cells. Alveolar macrophages or lung epithelial cells exposed to BLM revealed the loss of cell viability and increase in caspase-3 activity. Ambroxol (10-100 microM) reduced the 75 mU/mL BLM-induced cell death and activation of caspase-3 in macrophages or epithelial cells. It reduced the condensation and fragmentation of nuclei caused by BLM in macrophages. Ambroxol alone did not significantly cause cell death. Treatment of alveolar macrophages with BLM resulted in the decrease in transmembrane potential in mitochondria, cytosolic accumulation of cytochrome c, increase in formation of reactive oxygen species (ROS) and depletion of GSH. Ambroxol (10-100 microM) inhibited the increase in mitochondrial membrane permeability, ROS formation and decrease in GSH contents due to BLM in macrophages. Ambroxol exerted a scavenging effect on hydroxyl radicals and nitric oxide and reduced the iron-mediated formation of malondialdehyde and carbonyls in liver mitochondria. It prevented cell death due to SIN-1 in lung epithelial cells. The results demonstrate that ambroxol attenuates the BLM-induced viability loss in alveolar macrophages or lung epithelial cells. This effect may be due to inhibition of mitochondrial damage and due to the scavenging action on free radicals.
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PMID:Inhibition of bleomycin-induced cell death in rat alveolar macrophages and human lung epithelial cells by ambroxol. 1450 9

Mitochondria under oxidative stress are thought to play a key role in various neurodegenerative disorders by directing neurons to cell death. Protection by antioxidants against oxidative stress to mitochondria may prove to be beneficial in delaying onset or progression of these diseases. We have investigated the ability of gamma-glutamylcysteine ethyl ester (GCEE) to upregulate mitochondrial glutathione (GSH) in vivo or in vitro and protect against subsequent in vitro peroxynitrite (ONOO-) damage. Mitochondria pretreated in vitro with GCEE were protected against oxidative damage induced by peroxynitrite, as assessed by mitochondrial swelling, changes in mitochondrial membrane potential, 3-nitrotyrosine formation, protein carbonyl formation, and cytochrome c release. Loss of mitochondrial function in neuronal cell cultures by the oxidants 2,2,'Azobis(2-amidino-propane)dihydrochloride (AAPH) and ONOO- was ameliorated by treatment with GCEE. In vivo studies showed that mitochondria isolated from animals injected intraperitoneally with GCEE were protected partially against oxidative modifications induced by ONOO-. Taken together, these results suggest that GCEE may be effective in increasing mitochondrial GSH and may be prove to have therapeutic relevance in neurodegenerative disorders associated with oxidative stress and mitochondrial dysfunction.
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PMID:Elevation of mitochondrial glutathione by gamma-glutamylcysteine ethyl ester protects mitochondria against peroxynitrite-induced oxidative stress. 1464 97


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