Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that the alpha-class glutathione S-transferases (GSTs) protect various cell types from oxidative stress and lipid peroxidation (LPO). In order to examine the protective role of alpha-class GST isozyme hGSTA1-1 against doxorubicin (DOX)-induced lipid peroxidation, cytotoxicity, and apoptosis, human small cell lung cancer (SCLC) H69 cells were stably transfected with hGSTA1. Immunological and biochemical characterization of hGSTA1-transfected cells revealed the expression of functionally active hGSTA1-1 localized near the cellular plasma membranes. hGSTA1-transfected cells acquired significantly increased resistance to the DOX-induced cytotoxicity by suppressing lipid peroxidation levels in these cells. Overexpression of hGSTA1-1 in cells inhibited DOX-mediated depletion of GSH and higher GSH levels were found in DOX-treated hGSTA1-transfected cells as compared with empty vector-transfected controls. hGSTA1-1 overexpression also provided protection to cells from DOX-induced apoptosis by inhibiting phosphorylation of c-Jun-N-terminal kinases (JNK), caspase-3 activation, and by preserving the levels of anti-apoptotic protein Bcl-2. These results are consistent with the idea that the alpha-class GSTs provide protection against oxidative stress by attenuating lipid peroxidation and these enzymes can modulate signaling for apoptosis.
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PMID:Glutathione S-transferases as antioxidant enzymes: small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis. 1689 Jan 85

The mechanism of selective and age-dependent motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) has not been defined and the role of glutathione (GSH) in association with motor neuron death remains largely unknown. A motor neuron-like cell culture system and a transgenic mouse model were used to study the effect of cellular GSH alteration on motor neuron cell death. Exposure of NSC34 motor neuron-like cells to ethacrynic acid (EA) or l-buthionine sulfoximine (BSO) dramatically reduced the cellular GSH levels, and was accompanied by increased production of reactive oxygen species (ROS) measured by the dichlorofluorescin (DCF) fluorescent oxidation assay. In addition, GSH depletion enhanced oxidative stress markers, AP-1 transcriptional activation, c-Jun, c-Fos and heme oxygenase-1 (HO-1) expression in NSC34 cells analyzed by a luciferase reporter, Western blotting and quantitative PCR assays respectively. Furthermore, depletion of GSH decreased mitochondrial function, facilitated apoptosis inducing factor (AIF) translocation, cytochrome c release, and caspase 3 activation, and consequently led to motor neuron-like cell apoptosis. In an ALS-like transgenic mouse model overexpressing mutant G93A-Cu, Zn-superoxide dismutase (SOD1) gene, we showed that the reduction of GSH in the spinal cord and motor neuron cells is correlated with AIF translocation, caspase 3 activation, and motor neuron degeneration during ALS-like disease onset and progression. Taken together, the in vitro and in vivo data presented in the current report demonstrated that decreased GSH promotes multiple apoptotic pathways contributing, at least partially, to motor neuron degeneration in ALS.
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PMID:Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo. 1715 Mar 7

Doxorubicin (DOX) is a potent anticancer drug, whose clinical use is limited on account of its toxicity. DOX cytotoxic effects have been associated with reactive oxygen species (ROS) generated during drug metabolism. ROS induce signaling cascades leading to changes in the phosphorylation status of target proteins, which are keys for cell survival or apoptosis. The mitogen-activated protein kinase (MAPK) cascades are routes activated in response to oxidative stress. In this work, the effects of DOX on cytotoxicity, indicators of oxidative stress (malondialdehyde -MDA- and GSH), and the phosphorylation status of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 kinases were analyzed in primary cultures of rat hepatocytes. DOX (1-50 microM) did not modify lactate dehydrogenase (LDH) release into the medium, the levels of MDA (determined by high-performance liquid chromatography [HPLC]) or the intracellular GSH during the incubation time up to 6 h. GSH levels from mitochondria extracted by Percoll gradient from cultured hepatocytes were not modified by DOX, thus excluding its depletion or any impaired mitochondrial uptake. Characterization of proteins by Western blot analysis revealed that DOX increased phosphorylation of p38 kinases and JNK1 and JNK2 in a dose- and time-dependent manner. DOX also increased ERK2 phosphorylation at latter time points. In conclusion, DOX triggers activation of ERK, JNK, and p38 kinases in primary cultures of rat hepatocytes independently of oxidant damage.
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PMID:Doxorubicin-induced MAPK activation in hepatocyte cultures is independent of oxidant damage. 1738 85

Inhibition of astrocytic apoptosis has been regarded as a novel prospective strategy for treating neurodegenerative disorders such as Parkinson's disease. In the present study, we demonstrated that iptakalim (IPT), an ATP-sensitive potassium channel (K(ATP) channel) opener, exerted protective effect on MPP(+)-induced astrocytic apoptosis, which was reversed by selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate. Further study revealed that IPT inhibited glutathione (GSH) depletion, mitochondrial membrane potential loss and subsequent release of pro-apoptotic factors (cytochrome c and apoptosis-inducing factor (AIF), and c-Jun NH(2)-terminal kinase/mitogen-activated protein kinases (MAPK) phosphorylation induced by MPP(+). Meanwhile, extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 inhibited the protective effect of IPT on MPP(+)-induced astrocytic apoptosis. Furthermore, IPT could also activate ERK/MAPK and maintain increased phospho-ERK1/2 level after MPP(+) exposure. Taken together, these findings reveal for the first time that IPT protects against MPP(+)-induced astrocytic apoptosis via inhibition of mitochondria apoptotic pathway and regulating the MAPK signal transduction pathways by opening mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in astrocytes. And targeting K(ATP) channels expressed in astrocytes may provide a novel therapeutic strategy for neurodegenerative disorders.
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PMID:ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. 1763 69

Because mitogen-activated protein kinases (MAPK) are downstream effectors of antioxidant responses, changes in GSH levels in an organism might induce organ-specific responses. To test our hypothesis, mice were treated intraperitoneally with L-buthionine-S-R-sulfoximine (BSO) to inhibit GSH synthesis. A time-related GSH depletion in the liver and kidney correlated with p38(MAPK) phosphorylation and induction of thioredoxin 1 (Tx-1) transcription. This positive regulation was associated with nuclear translocation of NF-kappaB and ATF-2 and c-Jun phosphorylation in the liver, but only c-Jun phosphorylation in the kidney. Increased levels of GSH were observed in the brain together with extracellular regulated kinase 2 (ERK2) activation, Nrf2 nuclear accumulation, and increases in transcription of Nrf2, xCT, gamma-glutamylcysteine synthetase (gammaGCSr), and Tx-1. Pretreatment with MAPK inhibitors SB203580 and U0126, or addition of the exogenous thiol N-acetylcysteine, abrogated both p38(MAPK) and ERK2 activation as well as downstream effects on gene expression. No effect on gammaGCSr was observed. These results indicate that in mice, GSH depletion is associated with p38(MAPK) phosphorylation in the liver and kidney and with ERK2 activation in the brain, in what could be considered part of the brain's protective response to thiol depletion.
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PMID:Glutathione depletion activates mitogen-activated protein kinase (MAPK) pathways that display organ-specific responses and brain protection in mice. 1789 47

Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen that exerts opposing effects depending on cell density. Glutathione (GSH) is the main non-protein thiol in mammalian cells that modulates growth and apoptosis. We previously showed that GSH level is inversely related to cell density of hepatocytes and is positively related to growth. Our current work examined whether HGF can modulate GSH synthesis in a cell density-dependent manner and how GSH in turn influence HGF's effects. We found HGF treatment of H4IIE cells increased cell GSH levels only under subconfluent density. The increase in cell GSH under low density was due to increased transcription of GSH synthetic enzymes. This correlated with increased protein levels and nuclear binding activities of c-Jun, c-Fos, p65, p50, Nrf1 and Nrf2 to the promoter region of these genes. HGF acts as a mitogen in H4IIE cells under low cell density and protects against tumor necrosis factor alpha (TNFalpha)-induced apoptosis by limiting JNK activation. However, HGF is pro-apoptotic under high cell density and exacerbates TNFalpha-induced apoptosis by potentiating JNK activation. The increase in cell GSH under low cell density allows HGF to exert its full mitogenic effect but is not necessary for its anti-apoptotic effect.
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PMID:Effects of hepatocyte growth factor on glutathione synthesis, growth, and apoptosis is cell density-dependent. 1795 Jul 27

Salicylideneamino-2-thiophenol (Sal) regulated the redox status and the expression of chemokines induced by tert-butyl hydroperoxide (t-BHP). Sal (100 microM) increased reduced/oxidized glutathione (GSH/GSSG) ratios and thiol (SH) levels by 210 and 157%, respectively, and decreased reactive oxygen species (ROS) levels by 60% in t-BHP-treated macrophages. The inductions of regulated upon activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8) and hypoxia inducible factor-1alpha (HIF-1alpha) by t-BHP (10 microM) were decreased to 250, 80, 80 and 500% by Sal (100 microM), respectively. In the Sal signaling pathway, c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK) and p38 signaling protein modulation were decreased by 67, 69 and 119%, respectively, by Sal at 100 microM. Sal (100 microM) also altered cytosol and nuclear NF-kappaB protein expression by 169 and 5%, respectively. Sal also attenuated NF-kappaB nuclear binding activity. Sal thus has a protective effect against t-BHP-induced inflammation and that this, in part, is due to the inhibition of the production of RANTES, MCP-1, IL-8 and HIF-1alpha via the modulation of the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways.
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PMID:Salicylideneamino-2-thiophenol inhibits inflammatory mediator genes (RANTES, MCP-1, IL-8 and HIF-1alpha) expression induced by tert-butyl hydroperoxide via MAPK pathways in rat peritoneal macrophages. 1847 84

Fibroblasts are key structural cells that can be damaged by cigarette smoke. Cigarette smoke contains many components capable of eliciting oxidative stress, which may induce heme oxygenase (HO)-1, a cytoprotective enzyme. There are no data on HO-1 expression in primary human lung fibroblasts after cigarette smoke extract (CSE) exposure. We hypothesized that human lung fibroblasts exposed to cigarette smoke would increase HO-1 though changes in intracellular glutathione (GSH). Primary human lung fibroblasts were exposed to CSE, and changes in HO-1 expression and GSH levels were assessed. CSE induced a time- and dose-dependent increase in expression of HO-1, but not HO-2 or biliverdin reductase, in two different primary human lung fibroblast strains, a novel finding. This induction of HO-1 paralleled a decrease in intracellular GSH, and a sustained reduction in GSH resulted in a dramatic increase in HO-1. Treatment with the antioxidants N-acetyl-l-cysteine or GSH reduced the expression of HO-1 induced by CSE. We also examined the signal transduction mechanism responsible for HO-1 induction. Nuclear factor erythroid-derived 2, like 2 (Nrf2) was not involved in HO-1 induction by CSE. Activator protein-1 (AP-1) is a redox-sensitive transcription factor shown in other systems to regulate HO-1 expression. CSE exposure resulted in nuclear accumulation of c-Fos and c-Jun, two key AP-1 components. Reduction of c-Fos and c-Jun nuclear translocation by SP-600125 attenuated the CSE-induced expression of HO-1. These data support the concept that changes in the cellular redox status brought on by cigarette smoke induce HO-1 in fibroblasts. This increase in HO-1 may help protect against cigarette smoke-induced inflammation and/or cell death.
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PMID:Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione. 1868 4

In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1) in denbinobin-induced apoptosis in human lung adenocarcinoma (A549) cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN), two antioxidants (N-acetyl-L-cysteine (NAC) and glutathione (GSH)), a c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and an activator protein-1 (AP-1) inhibitor (curcumin). Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS) production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.
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PMID:Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells. 1940 83

Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most popular herbal supplements, taken for its multivalent properties. In this study, dosage effects of EGb761 on hydrogen peroxide (H(2)O(2))-induced apoptosis of human neuroblastoma SH-SY5Y cells were investigated. It was found that H(2)O(2)-induced apoptotic cell death in SH-SY5Y cells, which was revealed in DNA fragmentation, mitochondrial membrane potential depolarization, and activation of Akt, c-Jun N-terminal kinases (JNK) and caspase 3. Low doses of EGb761 (50-100 microg/ml) inhibited H(2)O(2)-induced cell apoptosis via inactivation of Akt, JNK and caspase 3 while high doses of EGb761 (250-500 microg/ml) enhanced H(2)O(2) toxicities via inactivation of Akt and enhancement of activation of JNK and caspase 3. Additional experiments revealed that H(2)O(2) decreased intracellular GSH content, which was also inhibited by low concentrations of EGb761 but enhanced after high concentrations of EGb761 treatment. This further suggests to us that dosage effects of EGb761 on apoptotic signaling proteins may be correlated with regulation of cell redox state. Therefore, treatment dosage may be one of the vital factors that determine the specific action of EGb761 on oxidative stress-induced cell apoptosis. To understand the mechanisms of dosage effects of EGb761 may have important clinical implications.
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PMID:Dosage effects of EGb761 on hydrogen peroxide-induced cell death in SH-SY5Y cells. 1941 4


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