Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

1. Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD-1 cells. 2. In DLD-1 cells, interferon--gamma alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon-gamma, tumour necrosis factor-alpha and interleukin-1beta produced maximal NOS II induction. 3. Activators of protein kinase A (forskolin, 8-dibutyryl-cyclic AMP), of protein kinase C (tetradecanoylphorbol-13-acetate), and of protein kinase G (8-bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines. 4. Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3-kinase (wortmannin), of p38 mitogen-activated protein kinase (compound SB 203580) and of extracellular signal-regulated kinase (compound PD 98059) also had no influence on basal or cytokine-induced NOS II mRNA expression. 5. Immunoprecipitation kinase assays showed no activation of extracellular signal-regulated kinase or p38 mitogen-activated protein kinase in cytokine-incubated DLD-1 cells. The c-Jun NH2-terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor-alpha which did not induce NOS II by itself. 6. In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon-gamma-activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM-induced NOS II mRNA expression in a concentration-dependent manner. 7. These results suggest that activation of NOS II expression in DLD-1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3-kinase, extracellular signal regulated kinase and p38 mitogen-activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon-gamma-activated janus kinase 2.
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PMID:Involvement of protein kinases in the induction of NO synthase II in human DLD-1 cells. 960 80

The time course of c-jun expression and the effect of a peripheral nerve (PN) graft on axonal regeneration and c-jun expression in the lateral vestibular nucleus (LVN) were investigated in this study. c-Jun was found in LVN neurons 1 day after hemisection of the spinal cord at C3, with weak immunoreactivity. Strong c-Jun positive immunoreactivity was found 3 days post-injury. The expression of c-jun reached its maximum level (45% +/- 2.5, mean +/- SD) 1 week post-injury and gradually decreased to about a third of its peak value 6 weeks after the inflicted lesion. The PN graft implanted at the lesion site significantly enhanced the number of neurons expressing c-jun 4 weeks after PN transplantation (from 20% of LVN neurons in axotomy alone to 30% in PN graft transplantation, P < 0. 05). The PN graft induced injured neurons to regrow into the PN graft. About 91 FG-labeled neurons were found in the LVN and approximately 87% of these neurons showed c-Jun positive immunoreactivity. The high percentage of regenerating neurons expressing c-jun suggested that c-Jun might be involved in the regenerative process. The result of double staining for c-Jun and NOS showed that approximately 93% NOS positive neurons co-expressed c-Jun. Comparing the time course of the appearance of c-Jun with that of NOS, the expression of c-jun preceded that of NOS. Although a high percentage of NOS reactive neurons expressed c-jun, the expression of NOS in damaged LVN neurons needs to be further investigated.
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PMID:Expression of c-jun in the lateral vestibular nucleus following spinal cord injury and peripheral nerve graft transplantation in adult rats. 1106 37

To assess whether diabetes alters the content and/or expression of neuroactive agents and protooncogenes in afferent neurons of the vagus nerve, the nodose ganglia of streptozotocin (STZ)-induced diabetic rats were studied at 8, 16, and 24 weeks after induction of diabetes. Neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), the immediate early gene c-Jun, vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP) content and expression were measured in nodose ganglia of control, diabetic, and diabetic+insulin-treated rats using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The numbers of nNOS-immunoreactive (ir) neurons were increased in the nodose ganglion of diabetic compared to control rats at the 8- and 16-week time points. However, no change was noted in the nNOS mRNA content of the diabetic nodose ganglion at either time point. Moreover, no alterations in the numbers of vagal efferent NOS-containing neurons (labeled with NADPH-diaphorase histochemistry) were noted in the dorsal motor nucleus of the vagus (DMV) or the nucleus ambiguous (NA) of control, diabetic, and diabetic+insulin-treated rats at any time point. Neither the numbers of TH-ir neurons nor the content of TH mRNA was altered in the diabetic rats at the 8- and 16-week time points. However, 24 weeks of diabetes resulted in a reduction in the numbers of TH-ir neurons in the diabetic nodose ganglia when compared to control, an effect not seen in diabetic rats receiving insulin. The number of nodose ganglion neurons labeled for the protooncogene, c-Jun, was small yet slightly increased in the diabetic nodose ganglia at the 8-week time point and was reversed with insulin treatment. The increase in c-Jun-ir neurons was not found at 16 or 24 weeks of diabetes. VIP-ir and CGRP-ir were unchanged at any of the time points. These data show that diabetes affects the content of some, but not all, neuroactive agents in the nodose ganglion and may reflect a modest level of diabetes-induced damage and/or alterations in axonal transport in the vagus nerve.
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PMID:Streptozotocin-induced diabetes and the neurochemistry of vagal afferent neurons. 1203 29

Permanent or temporary disruption of cerebral blood flow rapidly depletes brain regions of their limited energy reserves (glycogen, glucose, oxygen, ATP) leading to an energy crisis. Tissue damage occurs due to the energy crisis. The central part of the damage, the ischaemic "core" region is surrounded by zones of the shell-like penumbra. Necrotic, as well as apoptotic cell death could be identified in the penumbra. Going away from the ischaemic core different neurochemical processes are occurring by space and time. "Immediate early response" genes (c-fos, fos-B, c-Jun, krox 20, 24) are activated, heatshock proteins (hsp 70, 72, HSF, HSE, HIF), cytokines (TNF-alpha, IL-1 beta), inflammatory factors (COX), adhesion and glial factors (ICAM-1, ELAM-1, P-selectin), vasoactive factors (IL-6, -10, PAF), reactive oxigen radicals and connected factors (O2, OH, NO, NOS, SOD) are produced within minutes and hours. Cell deaths, necrosis and apoptosis due to the activation of calpains, caspases and nucleases occur in days. In parallel, growth factors and plasticity proteins (BDNF, NGF, TGF-beta, VEGF, PDGF, GAP-43) are activated as a basis of functional rehabilitation.
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PMID:[Regulatory mechanisms in focal cerebral ischemia. New possibilities in neuroprotective therapy]. 1212 84

Based on its trophic influence on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for stroke treatment. VEGF's survival-promoting effects are purchased at the expense of an increased blood brain barrier permeability, which potentially compromises tissue survival. The mechanisms via which VEGF protects the brain against ischemia remained unknown. We examined signaling pathways underlying VEGF's neuroprotective activity in our transgenic mouse line, which expresses human VEGF165 under a neuron-specific enolase (NSE) promoter. We show that VEGF receptor-2 (Flk-1) is expressed on ischemic neurons and astrocytes and is activated by VEGF. Following 90-min episodes of middle cerebral artery occlusion, VEGF increased phosphorylated (but not total) Akt and ERK-1/-2 and reduced phosphorylated mitogen activated protein kinase/p38 and c-Jun NH2-terminal kinase (JNK)-1/-2 levels, at the same time decreasing inducible NO synthase expression in ischemic neurons. Inhibition of Akt with Wortmannin reversed VEGF's neuroprotective properties, diminished brain swelling, and restored the vascular permeability induced by VEGF to below levels in WT animals. The aggravation of brain injury by Wortmannin was associated with the restitution of p38, but not of JNK-1/-2, ERK-1/-2, or inducible NOS (iNOS). Our data demonstrate that VEGF mediates both neuroprotection and blood brain barrier permeability via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Based on our observation that VEGF neuroprotection and vascular leakage depend on PI3K/Akt, which is putatively regulated by VEGF receptor-2, we predict that it may not easily be possible to make use of VEGF's neuroprotective function without accepting its unfavorable consequence, the increased vascular permeability.
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PMID:The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. 1664 Nov 98

The c-Jun N-terminal kinases (JNKs) form a subfamily of the mitogen-activated protein kinases (MAPK). These signalling pathways regulate various processes such as mitosis, cellular differentiation, stress response or apoptosis in multicellular organisms. There is rising evidence about the role of JNKs activities in neurodegenerative and metabolic diseases as well as in immunological disorders. The physiological functions of JNKs, however, remain to be elucidated. Recent data have demonstrated an essential role of JNKs in the cardiovascular system and the regulation of carbon hydrate and glucose metabolism. Therefore, we have investigated the contractility of blood vessels in mice with genetically deleted JNK1, JNK2, JNK3 and JNK2+3 isoforms and their respective wildtypes. The contractility of the isolated segments from A. carotis communis was measured by small blood vessel wire myograph. Contraction induced by 80 mM KCl was significantly increased in arteries from JNK2+3 double knockout compared to controls and single knockouts. The maximal contraction generated by the alpha-agonists phenylephrine or noradrenaline (10 microM) was significantly enhanced in JNK2+3 knockout arteries compared with arteries from the remaining strains. Inhibition of NOS by Nw-nitro-l-arginine did not change the pattern of vasoconstriction, but vasoconstriction by noradrenaline following NOS inhibition was significantly enhanced in the arteries from JNK2+3 double knockout mice. In conclusion, genetic deletion of JNK2+3 in mice results in altered contractility of carotid arteries and this might depend on the function of the smooth muscles rather than on the endothelium. These findings have implications for the long-term treatment with pharmacological JNK inhibitors for neurodegenerative or metabolic diseases such as stroke or diabetes.
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PMID:Enhanced contractility of small blood vessels in JNK knockout mice. 1694 3

Wogonin (Wog; 5,7-dihydroxy-8-methoxy flavone) has been shown to effectively inhibit lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) gene expression and nitric oxide production in our previous study. In the present study, we found that Nor-wogonin (N-Wog; 5,7,8-trihydroxyl flavone), a structural analogue of Wog with an OH substitution at C8, performed different effect on LPS- or lipoteichoic acid (LTA)-induced iNOS gene expression and nitric oxide (NO) production in macrophages. Wog, but not N-Wog, significantly inhibits LPS- or LTA-induced NO production through suppressing iNOS gene expression at both protein and mRNA without affecting NO donor sodium nitroprusside-induced NO production, NOS enzyme activity, and cells viability. Activation of JNKs (not ERKs) via phosphorylation induction, and an increase in c-Jun (not c-Fos) protein expression were involved in LPS- and LTA-treated RAW264.7 cells, and those events were blocked by Wog, but not N-Wog, addition. Furthermore, 5,7-diOH flavone, but not 5-OH flavone, 7-OH flavone, 5-OH-7-OCH(3) flavone, significantly inhibits LPS-induced iNOS protein expression and NO production, and 7,8-diOCH(3) flavone performs more effective inhibitory activity on LPS-induced NO production and iNOS protein expression than 7-OCH(3)-8-OH flavone. These data suggest that OHs at both C5 and C7 are essential for NO inhibition of flavonoids, and OCH(3) at C8 may contribute to this activity, and suppression of JNKs-c-Jun activation is involved.
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PMID:Wogonin but not Nor-wogonin inhibits lipopolysaccharide and lipoteichoic acid-induced iNOS gene expression and NO production in macrophages. 1757 Mar 22

Despite extensive studies have shown that increased endothelial nitric oxide synthase (NOS3) expression in the uterine artery endothelial cells (UAEC) plays a key role in uterine vasodilatation, the molecular mechanism controlling NOS3 expression in UAEC is unknown. According to the sheep NOS3 promoter sequence isolated in our laboratory, we hypothesize that the activator protein-1 (AP-1) site in the proximal sheep NOS3 promoter (TGAGTCA, -682 to -676) is important for NOS3 expression. We developed a c-Jun adenoviral expression system to overexpress c-Jun protein into UAEC to investigate the effects of c-Jun/AP-1 on NOS3 expression. Basal levels of c-Jun protein and mRNA were detected in UAEC. c-Jun protein was overexpressed in a concentration and time-dependent fashion in UAEC infected with sense c-Jun (S-c-Jun), but not sham and antisense c-Jun (A-c-Jun) adenoviruses. Infection with S-c-Jun adenovirus (25 MOI, multiplicity of infection) resulted in efficient c-Jun protein overexpression in UAEC up to 3 days. In S-c-Jun, but not sham and A-c-Jun adenovirus infected UAEC, NOS3 mRNA and protein levels were increased (P<0.05) compared to noninfected controls. Increased NOS3 expression was associated with increased total NOS activity. Transient transfections showed that c-Jun overexpression augmented the transactivation of the sheep NOS3 promoter-driven luciferase/reporter constructs with the AP-1 site but not of deletion constructs without the AP-1 site. When the AP-1 site was mutated, c-Jun failed to trans-activate the sheep NOS3 promoter. AP-1 DNA binding activity also increased in c-Jun overexpressed UAEC. Lastly, the pharmacological AP-1 activator phorbol myristate acetate increased AP-1 binding, trans-activated the wild-type but not the AP-1 mutant NOS3 promoter and dose-dependently stimulated UAEC NOS3 and c-Jun protein expression. Hence, our data show that c-Jun/AP-1 regulates NOS3 transcription involving the proximal AP-1 site in the 5'-regulatory region of the sheep NOS3 gene.
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PMID:Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1. 1793 57

Low-level activation of N-methyl-d-aspartate receptors (NMDARs) results in a decrease in the ability of tetanic stimulation to induce long-term potentiation (LTP). This NMDAR-mediated LTP inhibition is observed with low micromolar concentrations of NMDA or chelation of ambient extracellular zinc. In rat hippocampal slices, we examined whether LTP inhibition by 1 muM NMDA and zinc chelation share common mechanisms. We found that both forms of LTP inhibition involve nitric oxide (NO) synthase (NOS) and calcineurin. Furthermore, both forms of LTP inhibition are overcome by block of p38 mitogen-activated protein kinase (MAPK), but not by inhibition of extracellular signal-regulated kinase 1/2 or c-Jun-N-terminal kinase. A p38 antagonist also overcame the block of LTP by sodium nitroprusside, an agent that releases NO, suggesting that NO release occurs upstream of MAPK activation. Despite the involvement of p38 MAPK in NMDAR-mediated LTP inhibition, p38 antagonism did not enhance LTP induction in response to weak tetanic stimulation under baseline conditions. These results indicate that p38 MAPK is part of a complex NMDAR-driven signaling pathway involving calcineurin and NO that helps to regulate synaptic plasticity in the CA1 region.
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PMID:Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase. 1800 Aug 19

NMDA receptors (NMDARs) mediate ischemic brain damage, for which interactions between the C termini of NR2 subunits and PDZ domain proteins within the NMDAR signaling complex (NSC) are emerging therapeutic targets. However, expression of NMDARs in a non-neuronal context, lacking many NSC components, can still induce cell death. Moreover, it is unclear whether targeting the NSC will impair NMDAR-dependent prosurvival and plasticity signaling. We show that the NMDAR can promote death signaling independently of the NR2 PDZ ligand, when expressed in non-neuronal cells lacking PSD-95 and neuronal nitric oxide synthase (nNOS), key PDZ proteins that mediate neuronal NMDAR excitotoxicity. However, in a non-neuronal context, the NMDAR promotes cell death solely via c-Jun N-terminal protein kinase (JNK), whereas NMDAR-dependent cortical neuronal death is promoted by both JNK and p38. NMDAR-dependent pro-death signaling via p38 relies on neuronal context, although death signaling by JNK, triggered by mitochondrial reactive oxygen species production, does not. NMDAR-dependent p38 activation in neurons is triggered by submembranous Ca(2+), and is disrupted by NOS inhibitors and also a peptide mimicking the NR2B PDZ ligand (TAT-NR2B9c). TAT-NR2B9c reduced excitotoxic neuronal death and p38-mediated ischemic damage, without impairing an NMDAR-dependent plasticity model or prosurvival signaling to CREB or Akt. TAT-NR2B9c did not inhibit JNK activation, and synergized with JNK inhibitors to ameliorate severe excitotoxic neuronal loss in vitro and ischemic cortical damage in vivo. Thus, NMDAR-activated signals comprise pro-death pathways with differing requirements for PDZ protein interactions. These signals are amenable to selective inhibition, while sparing synaptic plasticity and prosurvival signaling.
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PMID:Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. 1892 45


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