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)

Activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) are two important transcription factors responsible for the regulation of cytokines, which are involved in cell proliferation and inflammation. Coal workers' pneumoconiosis (CWP) is an occupational lung disease that may be related to chronic inflammation caused by coal dust exposure. In the present study, we demonstrate that coal from the Pennsylvania (PA) coalmine region, which has a high prevalence of CWP, can activate both AP-1 and NFAT in JB6 mouse epidermal cells. In contrast, coal from the Utah (UT) coalmine region, which has a low prevalence of CWP, has no such effects. The PA coal stimulates mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-Jun-NH(2)-terminal kinases, as determined by the phosphorylation assay. The increase in AP-1 by the PA coal was completely eliminated by the pretreatment of cells with PD98059, a specific MAPK kinase inhibitor, and SB202190, a p38 kinase inhibitor, further confirming that the PA coal-induced AP-1 activation is mediated through ERKs and p38 MAPK pathways. Deferoxamine (DFO), an iron chelator, synergistically enhanced the PA coal-induced AP-1 activity, but inhibited NFAT activity. For comparison, cells were treated with ferrous sulfate and/or DFO. We have found that iron transactivated both AP-1 and NFAT, and DFO further enhanced iron-induced AP-1 activation but inhibited NFAT. These results indicate that activation of AP-1 and NFAT by the PA coal is through bioavailable iron present in the coal. These data are in agreement with our previous findings that the prevalence of CWP correlates well with levels of bioavailable iron in coals from various mining regions.
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PMID:Role of bioavailable iron in coal dust-induced activation of activator protein-1 and nuclear factor of activated T cells: difference between Pennsylvania and Utah coal dusts. 1239 16

Oxidative stress induced by reactive oxygen species has been implicated in the pathophysiology of many neurodegenerative disorders including Alzheimer's disease (AD). In this study, we have investigated the molecular mechanisms underlying oxidative cell death induced by beta-amyloid, a neurotoxic peptide associated with senile plaques found in the brains of patients with AD. PC12 cells treated with beta-amyloid underwent apoptotic cell death as determined by characteristic morphological features, cleavage of poly(ADP-ribose)polymerase, and positive in situ terminal-end labeling (TUNEL). Furthermore, beta-amyloid treatment led to activation of c-Jun N terminal kinase (JNK) and intracellular accumulation of ROS. In another experiment, beta-amyloid caused strand scission in phiX174 DNA in the presence of ferrous iron. These findings suggest that production of ROS and subsequent activation of JNK play an important role in beta-amyloid-induced apoptotic cell death.
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PMID:beta-Amyloid induces oxidative DNA damage and cell death through activation of c-Jun N terminal kinase. 1248 67

In the present study, we investigated the effects and mechanisms of a novel potent antioxidant, octyl caffeate, on the induction of iNOS expression by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in cultured primary rat aortic smooth muscle cells (RASMCs) in vitro and LPS-induced hypotension in vivo. Octyl caffeate (0.1-1.0 microM) exerted a concentration-dependent inhibition of iron-catalyzed lipid peroxidation in rat brain homogenates. Furthermore, octyl caffeate (20, 50, and 100 microM) concentration-dependently diminished the initial rate of superoxide-induced NBT reduction and the enzymatic activity of xanthine oxidase. It also concentration-dependently (1-50 microM) inhibited the NO production, iNOS protein and messenger RNA expressions upon stimulation by LPS (100 microg/mL)/IFN-gamma (100U/mL) in RASMCs. In addition, we found that octyl caffeate did not significantly affect IkappaBalpha degradation stimulated by LPS/IFN-gamma in RASMCs. On the other hand, octyl caffeate (10 and 50 microM) significantly suppressed activation of c-Jun-N-terminal kinase and extracellular signal-regulated kinase. Moreover, octyl caffeate (10mg/kg, i.v.) significantly inhibited the fall in mean arterial pressure stimulated by LPS (7.5mg/kg) in rats. In conclusion, we demonstrate that a novel potent antioxidant, octyl caffeate, significantly ameliorates circulatory failure of endotoxemia in vivo by a mechanism involving suppression of iNOS expression through inactivation of mitogen-activated protein kinases in RASMCs.
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PMID:A novel antioxidant, octyl caffeate, suppression of LPS/IFN-gamma-induced inducible nitric oxide synthase gene expression in rat aortic smooth muscle cells. 1269 79

Heme oxygenase (HO) produced biliverdin and bilirubin, which are powerful antioxidants, therefore, it has been proposed as helpful against oxidative stress. In contrast, HO also produces iron, and it could increase oxidative stress if not handled property. To clarify the effect of HO, i.e., helpful or harmful, we examined the expression, localization, and induction mechanism of HO-1 in the rat hippocampus after transient forebrain ischemia and injection of kainic acid (KA). Following ischemia, HO-1 expression was observed early but transiently in the CA1 pyramidal neurons and later but continuously in glial cells. In addition, HO-1-expressing pyramidal neurons were colocalized well with phosphorylated c-Jun, which is a critical step in neuronal apoptosis. After injection of KA, HO-1 expression was observed only in glial cells but not neurons, and HO-1 expression was observed in predominantly ameboid microglia, along with a few astrocytes. HO-1-expressing ameboid microglia expressed major histocompatibility complex class II antigen, suggesting strong activation. These results suggested that HO-1 may have double-edged effects, and its effects may be depend on the cell type. This short review is intended to highlight on the effect of HO-1 in neurodegeneration.
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PMID:Induction of inducible heme oxygenase (HO-1) in the central nervous system: is HO-1 helpful or harmful? 1283 7

Epidemiologic studies have shown positive associations between changes in ambient particulate matter (PM) levels in Utah Valley during 1986-1988, and the respiratory health of the local population. Ambient PM reductions coincided with closure of an open-hearth steel mill, the major industrial source of particulate emissions in the valley. In this report, water extracts of PM filters from steel mill operational (UE-86, UE-88) and closure (UE-87) periods were analyzed for their elemental composition. Their relative toxicity was determined by exposing primary rodent airway epithelial cultures to equal masses of extracted material. To elucidate extract subcomponents mediating the effects observed, cells were also exposed to surrogate metal mixtures. Potential interactions between the two predominant metals in the UE-86/88 samples, zinc (Zn) and copper (Cu), were further investigated. Data indicated that, relative to the UE-87 (plant closed) sample, UE-86/88 samples contained more sulfate, calcium, potassium,magnesium and, although present in much lower amounts, a variety of metals including Zn,Cu, iron, lead, strontium, nickel, manganese, and vanadium (V). Cell exposure to UE-86 and UE-88, but not UE-87, resulted in time- and concentration-dependent epithelial injury based on biochemical and light/electron microscopic changes. Cell injury induced by metal mixtures containing equivalent amounts of Zn + Cu + V was commensurate with that induced by the corresponding extract, although divergent antioxidant responses were observed. Exposure to Zn + Cu resulted in significantly greater epithelial toxicity and stress (c-Jun N-terminal protein kinase activation) responses than did exposure to Zn or Cu individually. The parallel epithelial injury induced by the extracts and their surrogate Zn + Cu + V mixtures suggests that these metals are mediating the acute airway epithelial effects observed; however, metal interactions appear to play a critical role in the overall cellular effects induced by the PM-derived extracts. These experimental findings are in good accord with epidemiologic reports of adverse airway and respiratory health health effects in Utah Valley residents.
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PMID:Metals mimic airway epithelial injury induced by in vitro exposure to Utah Valley ambient particulate matter extracts. 1285 32

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

NF-kappaB/Rel transcription factors block apoptosis or programmed cell death (PCD) induced by tumor necrosis factor (TNF) alpha. The antiapoptotic activity of NF-kappaB is also crucial for immunity, lymphocyte development, tumorigenesis, and cancer chemoresistance. With respect to TNFalpha, the NF-kappaB-mediated suppression of apoptosis involves inhibition of the c-Jun-N-terminal kinase (JNK) cascade. This inhibitory activity of NF-kappaB depends upon transcriptional upregulation of blockers of the JNK cascade such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase Gadd45beta/Myd118. Moreover, NF-kappaB blunts accumulation of reactive oxygen species (ROS) induced by TNFalpha, and this antioxidant effect of NF-kappaB is also critical for inhibition of TNFalpha-induced JNK activation. Suppression of ROS by NF-kappaB is mediated by Ferritin heavy chain (FHC)--the primary iron-storage mechanism in cells--and possibly, by the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Thus, induction of FHC and Mn-SOD represents an additional, indirect means by which NF-kappaB controls proapoptotic JNK signaling. These findings identify potential new targets for anti-inflammatory and anti-cancer therapy.
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PMID:NF-kappaB and JNK: an intricate affair. 1561 22

Signaling mechanisms in aniline-induced fibrogenic and/or tumorigenic response in the spleen are not known. Previous studies have shown that aniline exposure leads to iron accumulation and oxidative stress in the spleen, which may cause activation of redox-sensitive transcription factors and regulate the transcription of genes involved in fibrosis and/or tumorigenesis. To test this, male SD rats were treated with 0.5 mmol/kg/day aniline via drinking water for 30 days, and activation of transcription factor AP-1 was determined in the splenocyte nuclear extracts (NEs). AP-1 DNA-binding activity in the NEs of freshly isolated splenocytes from aniline-treated rats increased in comparison to the controls, as determined by electrophoretic mobility shift assay (EMSA). AP-1 binding was also determined in the NEs of cultured splenocytes (2 h and 24 h), which showed even a greater increase in binding activity at 2 h. The specificity of AP-1 binding for relevant DNA motifs was confirmed by competition EMSA and by supershift EMSA using antibodies specific to c-Jun and c-Fos. To further explore the signaling mechanisms in the AP-1 activation, phosphorylation patterns of mitogen-activated protein kinases (MAPKs) were pursued. Aniline exposure induced increases in the phosphorylation of the three classes of MAPKs: extracellular-signal-regulated kinase (ERK 1/2), c-Jun N-terminal kinase (JNK 1/2), and p38 MAPKs. Furthermore, TGF-beta1 mRNA expression showed a 3-fold increase in the spleens of aniline-treated rats. These observations suggest a strong association among MAPK phosphorylation, AP-1 activation, and enhanced TGF-beta1 gene expression. The observed sequence of events subsequent to aniline exposure could regulate genes that lead to fibrogenic and/or tumorigenic response in the spleen.
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PMID:Activation of transcription factor AP-1 and mitogen-activated protein kinases in aniline-induced splenic toxicity. 1616 68

NF-kappaB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-kappaB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radio- and chemoresistance in cancer. With regard to TNFalpha, the NF-kappaB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45beta/Myd118. Notably, NF-kappaB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFalpha, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-kappaB. The antioxidant activity of NF-kappaB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC)--a component of Ferritin, the primary iron-storage protein complex found in cells--and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-kappaB controls proapoptotic JNK signaling triggered by TNFalpha. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-kappaB, including some cancers and chronic inflammatory conditions.
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PMID:The NF-kappaB-mediated control of ROS and JNK signaling. 1626 88

Nitric oxide (NO) is a potent inducer of heme oxygenase (HO)-1, and NO-induced HO-1 expression is dependent on the cGMP-signaling pathway. Sodium nitroprusside (SNP) produces NO and iron. However, it is unclear whether NO is exclusively responsible for induction of HO-1 by SNP in RAW 264.7 cells. We tested our hypothesis that iron may contribute more to the SNP induction of HO-1 than does NO by comparing the HO-1 protein level and the production of NO in RAW 264.7 cells treated with SNP and S-nitroso-N-acetyl-DL-penicillamine (SNAP). Although SNP induced less NO production than SNAP, SNP induced the production of more HO-1 protein than did SNAP. Deferoxamine (DFO) decreased SNP- but not SNAP-induced HO-1 expression but did not decrease the production of NO. SNP-induced HO-1 was significantly inhibited by specific protein kinase A (PKA) inhibitors or an antagonist of cAMP but not by guanylyl cyclase inhibitors. Exogenous iron (ferric ammonium citrate or ferricyanide) and forskolin increased the level of HO-1, which was inhibited by PKA inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89). These results indicate that iron and cAMP, but not cGMP, play crucial roles in the induction of HO-1 in RAW 264.7 cells. Moreover, DFO and inhibitors of extracellular signal-related kinases 1/2 or c-Jun NH(2)-terminal kinase inhibited HO-1 production induced by SNP. This study illustrates that iron rather than NO from SNP contributes to HO-1 induction. Therefore, studies on the effects of SNP should consider the role of iron in some biological functions. We concluded that iron released by SNP contributes to HO-1 induction via the cAMP-PKA-mitogen-activated protein kinase pathway.
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PMID:Iron released by sodium nitroprusside contributes to heme oxygenase-1 induction via the cAMP-protein kinase A-mitogen-activated protein kinase pathway in RAW 264.7 cells. 1647 85


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