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)

Although previous studies have demonstrated that diabetic nephropathy is attributable to early extracellular matrix accumulation in glomerular mesangial cells, the molecular mechanism by which high glucose induces matrix protein deposition remains not fully elucidated. Rat mesangial cells pretreated with or without inhibitors were cultured in high-glucose or advanced glycation end product (AGE) conditions. Streptozotocin-induced diabetic rats were given superoxide dismutase (SOD)-conjugated propylene glycol to scavenge superoxide. Transforming growth factor (TGF)-beta1, fibronectin expression, Ras, ERK, p38, and c-Jun activation of glomerular mesangial cells or urinary albumin secretion were assessed. Superoxide, not nitric oxide or hydrogen peroxide, mediated high glucose- and AGE-induced TGF-beta1 and fibronectin expression. Pretreatment with diphenyliodonium, not allopurinol or rotenone, reduced high-glucose and AGE augmentation of superoxide synthesis and fibronection expression. High glucose and AGEs rapidly enhanced Ras activation and progressively increased cytosolic ERK and nuclear c-Jun activation. Inhibiting Ras by manumycin A reduced the stimulatory effects of high glucose and AGEs on superoxide and fibronectin expression. SOD or PD98059 pretreatment reduced high-glucose and AGE promotion of ERK and c-Jun activation. Exogenous SOD treatment in diabetic rats significantly attenuated diabetes induction of superoxide, urinary albumin excretion, 8-hydroxy-2'-deoxyguanosine, TGF-beta1, and fibronectin immunoreactivities in renal glomerular mesangial cells. Ras induction of superoxide activated ERK-dependent fibrosis-stimulatory factor and extracellular matrix gene transcription of mesangial cells. Reduction of oxidative stress by scavenging superoxide may provide an alternative strategy for controlling diabetes-induced early renal injury.
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PMID:Ras modulation of superoxide activates ERK-dependent fibronectin expression in diabetes-induced renal injuries. 1702 66

We have shown previously that generation of reactive oxygen species (ROS) is a critical event in G(2)-M phase cell cycle arrest caused by diallyl trisulfide (DATS), which is a highly promising anticancer constituent of processed garlic. Using DU145 and PC-3 human prostate cancer cells as a model, we now report a novel mechanism involving c-Jun NH(2)-terminal kinase (JNK) signaling axis, which is known for its role in regulation of cell survival and apoptosis, in DATS-induced ROS production. The DATS-induced ROS generation, G(2)-M phase cell cycle arrest and degradation, and hyperphosphorylation of Cdc25C were significantly attenuated in the presence of EUK134, a combined mimetic of superoxide dismutase and catalase. Interestingly, the DATS-induced ROS generation and G(2)-M phase cell cycle arrest were also inhibited significantly in the presence of desferrioxamine, an iron chelator, but this protection was not observed with iron-saturated desferrioxamine. DATS treatment caused a marked increase in the level of labile iron that was accompanied by degradation of light chain of iron storage protein ferritin. Interestingly, DATS-mediated degradation of ferritin, increase in labile iron pool, ROS generation, and/or cell cycle arrest were significantly attenuated by ectopic expression of a catalytically inactive mutant of JNK kinase 2 and RNA interference of stress-activated protein kinase/extracellular signal-regulated kinase 1 (SEK1), upstream kinases in JNK signal transduction pathway. In conclusion, the present study provides experimental evidence to indicate existence of a novel pathway involving JNK signaling axis in regulation of DATS-induced ROS generation.
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PMID:c-Jun NH(2)-terminal kinase signaling axis regulates diallyl trisulfide-induced generation of reactive oxygen species and cell cycle arrest in human prostate cancer cells. 1670 65

Proliferation and migration of vascular smooth muscle cells (VSMCs) are believed to develop atherosclerosis and venous bypass graft disease. Ligustilide is widely used to treat some pathological settings such as atherosclerosis and hypertension. The aim of this study was to examine the effect of ligustilide on VSMCs proliferation. The results show that ligustilide significantly inhibited VSMCs proliferation and cell cycle progression. Further analysis shows that ligustilide suppressed reactive oxygen species production and extracellular signal-related kinases (ERK), c-Jun N-terminal protein kinase (JNK), and p38 MAP kinase. Cells were treated with antioxidant, superoxide dismutase, catalase, and DPI, respectively, leading to repress ERK, JNK, and p38 activation. The inhibitors of mitogen activated protein kinase (MAPK), PD98059, SB203580, and Sp600125, inhibited cell proliferation. These findings suggest the antiproliferative effect of ligustilide was associated with the decrement of reactive oxygen species resulting in the suppression of MAPK pathway. Thus, ligustilide contribute to be the effective agent in preventing cardiovascular diseases.
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PMID:Ligustilide inhibits vascular smooth muscle cells proliferation. 1680 64

Reactive oxygen species, either directly or via the formation of lipid peroxidation products, may play a role in enhancing inflammation through the activation of stress kinases (c-Jun activated kinase, extracellular signal-regulated kinase, p38) and redox-sensitive transcription factors, such as nuclear factor (NF)-kappaB and activator protein-1. This results in increased expression of a battery of distinct pro-inflammatory mediators. Oxidative stress activates NF-kappaB-mediated transcription of pro-inflammatory mediators either through activation of its activating inhibitor of kappaB-alpha kinase or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-kappaB-co-activator complex formation results in targeted increases in histone modifications, such as acetylation leading to inflammatory gene expression. Emerging evidence suggests the glutathione redox couple may entail dynamic regulation of protein function by reversible disulphide bond formation on kinases, phosphatases and transcription factors. Oxidative stress also inhibits histone deacetylase activity and in doing so further enhances inflammatory gene expression and may attenuate glucocorticoid sensitivity. The antioxidant/anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn, erdosteine), dietary polyphenols (curcumin-diferuloylmethane, cathechins/quercetin and reserveratol), specific spin traps, such as alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (extracellular superoxide dismutase (SOD) mimetic, SOD mimetic M40419 and SOD, and catalase manganic salen compound, eukarion-8), porphyrins (AEOL 10150 and AEOL 10113) and theophylline have all been shown to play a role in either controlling NF-kappaB activation or affecting histone modifications with subsequent effects on inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both key signal transduction pathways and histone modifications involved in lung inflammation. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in chronic obstructive pulmonary disease are also discussed.
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PMID:Oxidative stress and redox regulation of lung inflammation in COPD. 1681 50

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

Cis-parinaric acid (c-PNA), a natural four conjugated polyunsaturated fatty acid, increases free radical production and it is preferentially cytotoxic to malignant glial cells compared to normal astrocytes in-vitro. In order to explain the increased cytotoxicity of c-PNA in malignant glial cells, we compared the effects of c-PNA on the oxidative stress-dependent signal transducing events in 36B10 cells, a malignant rat astrocytoma cell line, and in fetal rat astrocytes. Our results show that c-PNA treatment in 36B10 cells caused a persistent activation of c-Jun N-terminal protein kinase (JNK) at RNA and protein levels. Specific inhibitors of the kinase significantly reversed the cytotoxicity of c-PNA. Additionally, c-PNA caused the phosphorylated inactivation of forkhead transcription factor-3a (FKHR-L1, FOXO3a) and drastically decreased the activity of mitochondrial superoxide dismutase (Mn-SOD) that protects cells from oxidative stress. On the other hand, identical c-PNA treatments in normal astrocytes increased the dephosphorylated activation of FKHR-L1, maintained activity of Mn-SOD and failed to phosphorylate JNK. Taken together, the results imply that a selective activation of JNK and the opposite regulation of FKHR-L1 and Mn-SOD contribute to the differential cytotoxicity of c-PNA in malignant and normal glial cells.
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PMID:Cis-parinaric acid effects, cytotoxicity, c-Jun N-terminal protein kinase, forkhead transcription factor and Mn-SOD differentially in malignant and normal astrocytes. 1716 May 3

The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some of the molecular mechanisms involved. Starting at 8 weeks of diabetes, pioglitazone (10 mg/kg) was administered to STZ-induced diabetic rats for 4 weeks. In untreated STZ rats (vs age-matched control rats): (1) ACh-induced relaxation, cGMP accumulation, phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein at Ser-239 [an established biochemical end-point of nitric oxide (NO)/cGMP signaling], and Cu/Zn-superoxide dismutase (SOD) expression and SOD activity were all reduced; (2) aortic superoxide generation, nitrotyrosine expression, and NAD(P)H oxidase activity were increased; (3) plasma endothelin-1 (ET-1) and aortic c-Jun (AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. Collectively, these results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P)H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway.
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PMID:Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats. 1734 27

The present study was performed to investigate the anti-inflammatory potential of a 116-kDa glycoprotein isolated from Ulmus davidiana Nakai (UDN glycoprotein) in lipopolysaccaride (LPS)-treated cancerous human colon epithelial cells (HT-29 cells). UDN glycoprotein inhibited the production of intracellular superoxide anion (O (2) (.-) ), hydrogen peroxides (H(2)O(2)), and nitric oxide (NO), whereas normalized the activity of anti-oxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX)], accompanying the inhibition of manganese-superoxide dismutases (Mn-SOD) activity in LPS-treated HT-29 cells. In addition, UDN glycoprotein blocked the DNA binding activity of activator protein-1 (AP-1) through suppression of c-Jun and c-Fos activities, respectively. We also evaluated the anti-inflammatory potential of UDN glycoprotein based on the activity of the pro-inflammatory signal mediators [inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9)]. The results showed that UDN glycoprotein (200 mug/ml) has an inhibitory effect on the activation of iNOS, COX-2, and MMP-9 proteins in the LPS-treated HT-29 cells. From these results, we suggest that UDN glycoprotein is one of the potential anti-inflammatory agents that blocks LPS-mediated inflammatory signal pathway in HT-29 cells. Here, we speculate that UDN glycoprotein could be used as an antioxidative agent for inflammatory gastrointestinal cancers.
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PMID:UDN glycoprotein inhibits activator protein-1 and matrix metalloproteinase-9 via blocking of oxygen radicals in HT-29 cells. 1745 55

Guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, causes apoptosis in cancer cells but the sequence of events leading to cell death is poorly understood. We now show that guggulsterone-induced cell death in human prostate cancer cells is caused by reactive oxygen intermediate (ROI)-dependent activation of c-Jun NH(2)-terminal kinase (JNK). Exposure of PC-3 and LNCaP cells to apoptosis inducing concentrations of guggulsterone resulted in activation of JNK and p38 mitogen-activated protein kinase (p38 MAPK) in both cell lines and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LNCaP cells. The guggulsterone-induced apoptosis in PC-3/LNCaP cells was partially but statistically significantly attenuated by pharmacologic inhibition (SP600125) as well as genetic suppression of JNK activation. On the other hand, pharmacologic inhibition of p38 MAPK activation in PC-3 or LNCaP cells (SB202190) and ERK1/2 activation in LNCaP cells (PD98059) did not protect against guggulsterone-induced cell death. The guggulsterone treatment caused generation of ROI in prostate cancer cells but not in a normal prostate epithelial cell line (PrEC), which was also resistant to guggulsterone-mediated JNK activation. The guggulsterone-induced JNK activation as well as cell death in prostate cancer cells was significantly attenuated by overexpression of catalase and superoxide dismutase. In addition, guggulsterone treatment resulted in a decrease in protein level and promoter activity of androgen receptor in LNCaP cells. In conclusion, the present study reveals that the guggulsterone-induced cell death in human prostate cancer cells is regulated by ROI-dependent activation of JNK and guggulsterone inhibits promoter activity of androgen receptor.
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PMID:Guggulsterone-induced apoptosis in human prostate cancer cells is caused by reactive oxygen intermediate dependent activation of c-Jun NH2-terminal kinase. 1767 Dec 14

The aim of this study was to investigate the activation of JNK1/2 signalling pathway and the respective cellular phenotype of H9c2 cardiac myoblasts during two distinct types of oxidative insult. We examined the dose- and time-dependent activation of JNK1/2 pathway by exogenous H2O2, both under transient and sustained stimulation. At 2 h of either sustained or transient treatment, maximal phosphorylation of c-Jun was observed, coincidently with the activation of nuclear JNK1/2; under sustained stress, these phosphorylation levels remained elevated above basal for up to 6 h, whereas under transient stress they declined to basal ones within 4 h of withdrawal. Furthermore, the JNK1/2 selective inhibitor SP600125 abolished the c-jun phosphorylation induced by oxidative stress. Our results using cell viability assays and light microscopy revealed that sustained H2O2 stimulation significantly and time-dependently decreased H9c2 viability, in contrast to transient stimulation; SP600125 (10 microM) abolished cell death induced by sustained as well as cell survival induced by transient oxidative stress. Hoechst staining showed an increase in DNA condensation during sustained, but not during transient stimulation. Moreover, from the antioxidants tested, catalase and superoxide dismutase prevented oxidative stress-induced cell death. Flow cytometry studies reconfirmed that sustained oxidative stress induced apoptosis, whereas transient resulted in the recovery of cardiac myoblasts within 24 h. We conclude that in H9c2 myoblasts, sustained activation of JNK1/2 signalling pathway during oxidative stimulation is followed by an apoptotic phenotype, while transient JNK1/2 activation correlates well with cell survival, suggesting a dual role of this signalling pathway in cell fate determination.
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PMID:Transient and sustained oxidative stress differentially activate the JNK1/2 pathway and apoptotic phenotype in H9c2 cells. 1806 May 75


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