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

Nitrogen oxides (NOx) are important indoor air pollutants and an occupational hazard. Many studies demonstrated that NOx causes lung tissue damage based on the oxidation properties and the free-radical potentials of these gases. In this study we found that NOx delivered as a NO gas-saturated solution induced proliferation of human lung fibroblast MCR-5 cells as evidenced by increasing cell number and S phase distribution. Western data showed that NOx increased the expressions of c-Fos, c-Jun, and signaling kinases including MEKK1, JNK1, and p38 (with induction fold of 3.3, 2.8, and 3.2, respectively) in the cells 12 h after treatment. The levels of phospho-MEKK1 and phospho-JNK1 were also increased. The application of iNOS inhibitor, NAME, partially blocked the activation of MEKK4 and JNK1. These data suggested that JNK and p38 signaling kinases are activated partly by endogenous NO that are generated from NOx-activated iNOS in MRC-5 cells. Therefore, the NOx-induced cell proliferation via activation of MEKK1, JNK1, and p38 might contribute to lung tissue damage caused by NOx pollutants.
 ...
PMID:Induced proliferation of human MRC-5 cells by nitrogen oxides via direct and indirect activation of MEKK1, JNK, and p38 signals. 1207 29

Bacteria-derived synthetic lipoproteins constitute potent macrophage activators in vivo and are effective stimuli, enhancing the immune response especially with respect to low or non-immunogenic compounds. N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3-lysine (P3CSK4), exhibiting one of the most effective lipopeptide derivatives, represents a highly efficient immunoadjuvant in parenteral, oral, nasal and genetic immunization either in combination with or after covalent linkage to antigen. In order to further elucidate its molecular mode of action with respect to the transcriptional level, we focused our investigations on the P3CSK4-induced modulation of gene transcription. We could show that P3CSK4 activates/represses an array of at least 140 genes partly involved in signal transduction and regulation of the immune response. P3CSK4 activates the expression of tumor suppressor protein p53 (p53), c-rel, inhibitor of nuclear factor kappa B (NFkappaB) alpha (IkappaB alpha), type 2 (inducible) nitric oxide (NO) synthase (iNOS), CD40-LR, intercellular adhesion molecule-1 (ICAM-1) and interleukin 1/6/15 (IL-1/6/15). We detected no activation of heat shock protein (HSP) 27, 60, 84 and 86, osmotic stress protein 94 (Osp 94), IL-12, extracellular signal-regulated protein kinase 1 (ERK1), p38 mitogen activated protein (MAP)-kinase (p38), c-Jun NH2-terminal kinase (JNK), signal transducer and activator of transcription 1 (STAT1), CD14 and caspase genes. Furthermore, we monitored inhibition of STAT6, Janus kinase 3 (Jak3) and cyclin D1/D3 gene transcription after stimulating bone marrow-derived macrophages (BMDM) with lipopeptide. In addition, we monitored significant differences after lipopeptide and lipopolysaccharide (LPS) stimulation of bone marrow-derived murine macrophages. Our findings are of importance for further optimizing both conventional and genetic immunization, and for the development of novel synthetic vaccines.
 ...
PMID:Lipopeptide adjuvants: monitoring and comparison of P3CSK4- and LPS-induced gene transcription. 1234 44

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.
 ...
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

We previously reported that depletion of glutathione in murine hepatocytes by diethylmaleate (DEM) or acetaminophen (APAP) leads to oxidative stress-dependent necrosis and sensitizes to tumor necrosis factor (TNF)-induced apoptosis in an oxidative stress-independent fashion, which could not be explained by interference with nuclear factor kappaB (NF-kappaB) nuclear translocation. The present report explores the mechanisms of these effects. We observed that DEM led to necrosis when both mitochondrial and cytosol glutathione were depleted profoundly but sensitized to TNF-induced apoptosis when cytosol glutathione was depleted selectively. DEM and APAP lead to a significant decrease in reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio. Glutathione depletion by DEM or APAP was associated with inhibition of TNF-induced NF-kappaB transactivation of anti-apoptotic genes, including inducible nitric oxide synthase (i-NOS). Provision of exogenous NO partially abrogated the sensitization to TNF in response to glutathione depletion. Glutathione depletion alone led to sustained increase in phospho-jun levels and c-Jun-N-terminal kinase (JNK) activity. JNK inhibitor partially blocked the sensitization to TNF-induced apoptosis accompanying glutathione depletion. In conclusion, these findings suggest that extramitochondrial glutathione depletion alters the thiol-disulfide redox state, leading to inhibition of NF-kappaB transactivation of survival genes and to sustained activation of JNK, both of which contribute to the sensitization to TNF-induced apoptosis.
 ...
PMID:Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytes. 1277 22

The stress-activated protein kinase c-Jun NH2-terminal kinase (JNK) is a central signal for interleukin-1beta (IL-1beta)-induced apoptosis in insulin-producing beta-cells. The cell-permeable peptide inhibitor of JNK (JNKI1), that introduces the JNK binding domain (JBD) of the scaffold protein islet-brain 1 (IB1) inside cells, effectively prevents beta-cell death caused by this cytokine. To define the molecular targets of JNK involved in cytokine-induced beta-cell apoptosis we investigated whether JNKI1 or stable expression of JBD affected the expression of selected pro- and anti-apoptotic genes induced in rat (RIN-5AH-T2B) and mouse (betaTC3) insulinoma cells exposed to IL-1beta. Inhibition of JNK significantly reduced phosphorylation of the specific JNK substrate c-Jun (p<0.05), IL-1beta-induced apoptosis (p<0.001), and IL-1beta-mediated c-fos gene expression. However, neither JNKI1 nor JBD did influence IL-1beta-induced NO synthesis or iNOS expression or the transcription of the genes encoding mitochondrial manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase rho (GSTrho), heat shock protein (HSP) 70, IL-1beta-converting enzyme (ICE), caspase-3, apoptosis-inducing factor (AIF), Bcl-2 or Bcl-xL. We suggest that the anti-apoptotic effect of JNK inhibition by JBD is independent of the transcription of major pro- and anti-apoptotic genes, but may be exerted at the translational or posttranslational level.
 ...
PMID:The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines. 1456 87

The pro-inflammatory cytokine interleukin-1beta (IL-1) induces articular chondrocytes to produce reactive oxygen species (ROS), including hydrogen peroxide (H2O2), which mediate some IL-1-induced responses. This study aimed at elucidating the role of ROS, particularly H2O2, in mediating IL-1-induced activation of the transcription factor activator protein-1 (AP-1) in primary cultures of articular chondrocytes. AP-1 may function either as an inducer or as a repressor of the inducible nitric oxide synthase (iNOS) gene promoter. Since we observed that AP-1 is not required for iNOS expression in chondrocytes, we also investigated whether it is a repressor of this gene. The results of electrophoretic mobility shift assays showed that both IL-1 and H2O2 activated AP-1 and that inhibition of IL-1-induced ROS production abrogated AP-1 activation. The AP-1 complexes, induced by either IL-1 or H2O2, contained c-Fos/c-Jun and c-Fos/JunD heterodimers, but IL-1 activated AP-1 with a kinetics slower than that observed with H2O2. Pre-activation of AP-1, before stimulation of the cells with IL-1, did not inhibit iNOS mRNA and protein synthesis, relative to cells treated with IL-1 alone. These results indicate that H2O2 is a major mediator of IL-1-induced AP-1 activation in articular chondrocytes and that inhibition of ROS production is an effective strategy to block this IL-1-induced response. This study also identifies c-Fos/c-Jun and c-Fos/JunD heterodimers as the AP-1 transcription factors induced by IL-1, which, although not involved in the transcriptional regulation of the iNOS gene, may be important for the regulation of other genes also relevant in arthritic diseases, namely the collagenase-1 and IL-8 genes.
 ...
PMID:Hydrogen peroxide mediates interleukin-1beta-induced AP-1 activation in articular chondrocytes: implications for the regulation of iNOS expression. 1468 13

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
 ...
PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

The aim of this study was to determine whether hemorrhage affects the levels of a variety of stress-related proteins and whether changes can be inhibited by drugs reported to provide protection from ischemia and reperfusion injury. Male Swiss Webster mice were subjected to a 40% hemorrhage without resuscitation. Western blot analysis indicated that c-Jun (an AP-1 protein), Kruppel-like factor 6 (KFL6), and inducible nitric oxide synthase (iNOS) were upregulated sequentially in that order. Pretreatment of mice with geldanamycin (GA) 16 h before hemorrhage effectively inhibited the expression of the proteins KLF6 and iNOS, whereas caffeic acid phenethyl ester did not. GA pretreatment increased inducible heat shock protein (HSP) 70 but not HSP90 in both sham and hemorrhagic tissues. The overexpressed inducible HSP70 formed complexes with KLF6 and iNOS. These results suggest that GA may be therapeutically useful for reducing hemorrhage-induced injury when used as a presurgical treatment or when added to resuscitation fluids.
 ...
PMID:Geldanamycin treatment inhibits hemorrhage-induced increases in KLF6 and iNOS expression in unresuscitated mouse organs: role of inducible HSP70. 1509 Apr 81

cAMP significantly inhibits IL-1beta+IFNgamma-induced iNOS gene expression in hepatocytes, but the signaling pathways responsible for the effect are not known. PKA inhibitors, H89, PKI, and KT5720, had no effect on the recovery of the inhibitory effects of cAMP on cytokine-induced hepatocyte iNOS expression and activity. The JNK inhibitor, SP 600125, effectively reversed the inhibitory effects of cAMP on iNOS expression and significantly increased iNOS promoter activity. A cAMP analogue, dbcAMP, significantly induced JNK signaling and increased AP-1 binding activity in hepatocytes. The JNK activator, anisomycin, inhibited iNOS expression and transcription in hepatocytes as well as AP-1 binding activity; and SP600125 reversed this effect of anisomycin. Overexpression of c-Jun in hepatocytes inhibited IL-1beta+IFNgamma-induced nitrite accumulation and iNOS promoter activity while dominant negative c-Jun partially reversed the inhibitory effects of cAMP on nitrite accumulation. We conclude that JNK signaling plays an important role in the inhibitory effects of cAMP on IL-1beta+IFNgamma-induced iNOS gene expression in cultured hepatocytes.
 ...
PMID:JNK signaling involved in the effects of cyclic AMP on IL-1beta plus IFNgamma-induced inducible nitric oxide synthase expression in hepatocytes. 1511 62

Triptolide (PG490) is a natural, biologically active compound extracted from the Chinese herb Tripterygium wilfordii. It has been shown to possess potent anti-inflammatory and immunosuppressive properties. In Raw 264.7 cells stimulated with lipopolysaccharide (LPS) to mimic inflammation, triptolide inhibits nitric oxide (NO) production in a dose-dependent manner and abrogates inducible nitric oxide synthase (iNOS) gene expression. To investigate the mechanism by which triptolide inhibits murine iNOS gene expression, we examined activation of mitogen-activated protein kinases (MAP kinases) and nuclear factor-kappa B (NF-kappa B) in these cells. Addition of triptolide inhibited phosphorylation of c-Jun NH(2)-terminal kinase (JNK) but not that of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase. In addition, triptolide significantly inhibited the DNA binding activity of NF-kappa B. Taken together, these results suggest that triptolide acts to inhibit inflammation through inhibition of NO production and iNOS expression through blockade of NF-kappa B and JNK activation.
 ...
PMID:Triptolide inhibits murine-inducible nitric oxide synthase expression by down-regulating lipopolysaccharide-induced activity of nuclear factor-kappa B and c-Jun NH2-terminal kinase. 1519 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>