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)

Ischemia and reperfusion result in a hepatocellular stress gene response, characterized by a zonal heterogeneity with pericentral hepatocytes being the primary target. In the present study, we assessed cell type-specific and zonal pattern of activation of redox-sensitive transcription factors nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP-1) in a graded model of hemorrhage and their modulation by the antioxidants trolox and tempol. Hemorrhagic hypotension (35-40 mm Hg) up to 3 h without subsequent resuscitation led to an only moderate activation of NFkappaB and AP-1. In contrast, fluid resuscitation after 1 or 2 h of hemorrhage induced a profound activation of AP-1 within the first hour of reperfusion. Consistent with a regulation by oxygen free radicals, activation of AP-1 was substantially attenuated by antioxidants. The faint activation of NFkappaB with various intervals of hemorrhage was unaffected by antioxidants and did not exceed activation with sham operation. Immunohistochemistry for the AP-1 subunit c-Jun revealed a predominant expression in nuclei of pericentral and midzonal hepatocytes. These data suggest activation of AP-1 in hepatocytes most susceptible to injury and reprogramming of gene expression in low-flow ischemia. Whereas activation of NFkappaB is weak in this model and is not modulated by either reperfusion or antioxidants, regulation of AP-1 after hemorrhage and subsequent resuscitation seems to depend on oxygen free radical formation because it requires reperfusion and is inhibitable by antioxidants.
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PMID:Hepatic redox regulation of transcription factors activator protein-1 and nuclear factor-kappaB after hemorrhagic shock in vivo. 1247 Apr 98

To determine whether c-Fos and c-Jun are involved in the repair of small intestinal mucosa after ischemia-reperfusion (I/R), we investigated the mechanism of regeneration following acute I/R injury in rats by evaluating changes in DNA synthesis, fractional synthesis rate (FSR) of proteins, and alkaline phosphatase (ALP) activity. Furthermore, we examined the sequential expression of c-Fos and c-Jun using western blot analysis and immunohistochemical staining. Proliferating cell nuclear antigen (PCNA) labeling index (LI) demonstrated that the LI of the I/R group at 2 and 6 hr after reperfusion was significantly higher than that of the controls. Statistically significant differences were found between the FSRs of the I/R group and the corresponding conventional group at 2, 6, and 12 hr. The expression of c-Fos and c-Jun proteins increased markedly after I/R and these proteins decreased with time. The levels of ALP in the I/R group were significantly decreased at 2 and 6 hr after reperfusion compared to controls. These results indicate that c-Fos and c-Jun play a central role in the repair process that results in complete restoration of intestinal mucosal function after I/R.
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PMID:Regeneration of small intestinal mucosa after acute ischemia-reperfusion injury. 1249 89

Stress-activated protein kinase/extracellular signal-regulated kinase-1 (SEK1/MKK4) was examined in a rat model of global brain ischemia. Western blot assay showed that SEK1 activation was biphasic in CA1 but not CA3/dentate gyrus. The second activation peak (3 days after ischemia) was prevented by pretreatment with l-naphthyl acetyl spermine (Naspm), a channel blocker of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, or N-acetylcysteine (NAC), a free radical scavenger. Concomitantly, the late activation of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal protein kinase (JNK) was also prevented by Naspm or NAC. Moreover, phospho-SEK1 and phospho-JNK co-immunoprecipitated with ASK1 and the bindings peaked at 3 days of reperfusion. Together with previous results, these findings indicate that Ca(2+)-permeable AMPA receptors are important routes to mediate the late activation of ASK1-SEK1-JNK pathway involving oxidative stress in hippocampal CA1 region after ischemia.
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PMID:Biphasic activation of apoptosis signal-regulating kinase 1-stress-activated protein kinase 1-c-Jun N-terminal protein kinase pathway is selectively mediated by Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors involving oxidative stress following brain ischemia in rat hippocampus. 1252 69

Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes connecting cell-surface receptors to critical regulatory targets within cells. The three major MAPK cascades are known, the extracellular signal-regulated protein kinase (ERK) cascade, c-Jun amino-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) cascade and p38-MAPK cascade. This paper is focused on characterization of these MAPK cascades in terms of their distribution and biological role in some pathological processes (apoptosis, hypertrophy) with a special orientation on the role of MAPKs in cardiovascular system during ischemia/reperfusion.
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PMID:Mitogen-activated protein kinases and their role in regulation of cellular processes. 1253 49

NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) are protein molecules (MW 26 and 13.6 kDa, respectively) that are neuroprotective in the middle cerebral artery occlusion (MCAO) rat stroke model. Their mechanism of action involves the activation of transcription factor AP-1 that turns on neuronal growth genes. In our ongoing studies we are designing short peptides that mimic some of the properties of full-length neurotrophic factors. We have synthesized a neuroprotective 14-amino acid peptide (CMX-9236) with an N-terminal docosahexaenoic acid (DHA). DHA enhances entry through the blood-brain barrier. Using primary rat brain cortical cultures and a fluorescent assay we found that CMX-9236 can counteract the excitotoxic effects of glutamate or kainate, reversing the intracellular accumulation of Ca(2+) to normal levels. Administration (i.v.) of CMX-9236 post initiation of ischemia reduced the lesion volumes from 178+/-50 to 117+/-55 mm(3) in the temporary rat MCAO model (90 min), and from 216+/-58 to 127+/-57 mm(3) in the permanent (24 h) model for stroke, corresponding to 34+/-28% (P=0.01) and 41+/-19% (P=0.038) reductions of the infarct volumes. Neurological behavior scores showed 57 and 47% improvements for treated temporary and permanent models, respectively. Dose-response studies indicated a 60-fold activation of AP-1 transcription factor in cells treated with 100 ng/ml of the peptide. These studies illustrate that a small peptide can function as a neuroprotective agent and an activator of a beneficial signal transduction pathway.
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PMID:Neuroprotective effects of a new synthetic peptide, CMX-9236, in in vitro and in vivo models of cerebral ischemia. 1256 Jan 27

Oxidative stress appears to contribute to neurodegenerative outcomes after ischemia, hypoxia, and hyperoxia. The AP-1 transcription factor is made up of a family of regulatory proteins that can be activated by oxidative stress. In the present study, we examined AP-1 DNA binding activity in terms of specific participating AP-1 proteins in rat brain after hyperoxia. Male Sprague-Dawley rats were exposed to 100% oxygen under isobaric conditions over time. The AP-1 DNA binding activity present in the rat hippocampus and basal forebrain was characterized by electrophoretic mobility shift analysis (EMSA) and the participating AP-1 proteins identified by immunodepletion/supershift and Western blotting analyses. The Fos and Jun proteins were localized by immunohistochemistry to hippocampus. There were significant increases in AP-1 DNA binding in both hippocampus and basal forebrain after hyperoxia. There was also a significant increase in c-Jun protein levels and the proportion of c-Jun present in AP-1 DNA binding complexes in hippocampal nuclei after hyperoxia. These results suggest that AP-1 activation via c-Jun binding to DNA is an important component of brain responses to oxidative stress.
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PMID:Hyperoxia increases AP-1 DNA binding in rat brain. 1258 69

Delayed ischemic death of neurones is observed selectively in CA1 region of hippocampus at 3-4 days of reperfusion. Signals generated immediately during and after ischemia are further propagated by a variety of kinases, proteases and phosphatases. Tissue samples from dorsal (vulnerable) and abdominal (resistant) parts of gerbil hippocampi were collected to determine the activation state of key signaling molecules: Akt, Raf-1, JNK, ERK1/2 in the course of reperfusion after 5 min of global cerebral ischemia. Western blot analysis of phosphorylated forms of the kinases revealed persistent activation of JNK, being limited mostly to vulnerable CA1 region. On the contrary, activation of ERK, although observed transiently in both parts, was enhanced for a longer time in the abdominal hippocampus. The levels of the active/phosphorylated Akt and Raf-1 kinases did not change significantly during the recovery period. No significant correlation between postischemic JNK activation and c-Jun phosphorylation or its contribution to AP1-like complex formation was found. In contrast, the amount of active JNK linked with mitochondrial membranes was significantly increased and preceded neuronal death in CA1. In the same period of time the AP1 complex, augmented in CA1 region, did not appear to contain a classical c-Fos protein. These results are consistent with the theory that either long-lasting activation of JNK and/or contrasting ERK and JNK activities in critical time of reperfusion, contribute to selective apoptosis of CA1 neurons. This, in connection with the translocation of activated JNK to mitochondria and time/regional differences in AP1 binding protein complexes can affect final postischemic outcome.
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PMID:Opposite reaction of ERK and JNK in ischemia vulnerable and resistant regions of hippocampus: involvement of mitochondria. 1259 Nov 60

In response to stresses, mammalian cells induce heat shock proteins (HSP). Overproduction of a stress-inducible 70-kDa protein (Hsp70) results in the acquisition of tolerance against various types of stresses. An acyclic isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a non-toxic Hsp 70 inducer, which selectively and safely induced Hsp70 in cultured guinea pig gastric mucosal cells and rat gastric mucosa. GGA also primed other types of cells for enhanced induction of Hsp70, when exposed to stress. Pretreatment of rats with GGA markedly suppressed ischemia-reperfusion injury of the liver, small intestine, or heart, and improved survival after 95% hepatectomy as well as liver transplantation. GGA can block insult-induced apoptosis at multiple levels; it inhibited activation of c-Jun N-terminal kinases, decline of mitochondrial membrane potential, and formation of apoptosome by binding with Apaf-1. Recently, GGA has been shown to induce thioredoxin and anti-viral genes, suggesting that GGA may exhibit protective actions independently of Hsp70 induction. HSP are members of molecular chaperones that are essential for the quality control of intracellular proteins. New compounds specifically targeting molecular chaperones that function to prevent the accumulation of misfolded proteins may be useful for the treatment of neurodegenerative disorders in the near future.
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PMID:[Molecular chaperone inducers in medicine and diseases]. 1261 33

Focal ischemia induced by middle cerebral artery occlusion (MCAO) to adult rats results in necrosis at the infarct core and activation of complex signal pathways for cell death and cell survival in the penumbra. Upstream from the cell death promoters and executioners are several kinases that, once activated by phosphorylation, may activate several transcription factor substrates involved in cell death and cell survival. In the present study we examined, by immunohistochemistry, the expression of phosphorylated (active) mitogen-activated protein kinase, extracellular signal-regulated kinase (MAPK/ERK), stress-activated protein kinase (SAPK), c-Jun N-terminal kinase (JNK) and p-38 kinase at early stages (1-4 h) following 1 h of MCAO in the rat. The expression of phosphorylation-dependent, active transcription substrates of these kinases, including cyclic AMP-responsive element-binding protein (CREB) Alk-1, ATF-2, c-Myc and c-Jun was examined at early stages following reperfusion. Increased nuclear phosphorylated SAPK/JNK (SAPK/JNK-P) and c-Jun-PSer63, and reduced CREB-P, occurred in the infarct core at 1 h following reperfusion, suggesting increased phosphorylated SAPK/JNK and c-JunSer63, together with decreased phospho-CREB associated with cell death in the infarct core. However, increased cytoplasmic expression of MAPK/ERK-P, SAPK/JNK-P, p38-P, CREB-P, Elk-1-P, c-Myc-P, ATF-2-P and c-Jun-P occurred in the region bordering the infarct core (penumbra) at 4 h following reperfusion. This indicates that different signals converge in the cytoplasm of neurons located at the borders of the infarct at 4 h following reperfusion, revealing the struggle of death promoters and life facilitators at the penumbra. Whether phosphorylated kinases and specific substrates participate in promoting cell death or survival in the penumbra probably depends on additional factors and on the interaction with other proteins.
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PMID:Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia. 1267 42

It is unknown whether immediate early gene (IEG) induction and subsequent late gene regulation after ischemia is beneficial or deleterious. The aim of this study was to examine the effect of hypothermia on expression of c-Fos and c-Jun, and AP-1 DNA binding activity, after transient focal cerebral ischemia in rat brain, and clarify the role of IEGs and AP-1 after insults. Male Wistar rats underwent right middle cerebral artery occlusion for 1 h with the intraluminal suture method. During ischemia, animals were assigned to either normothermic (NT) or hypothermic (HT) groups. In the NT group, brain temperature was observed to spontaneously increase to 40 degrees C during ischemia. In the HT group, brain temperature decreased to 30 degrees C. Infarct volume in cortex was decreased in the HT group, compared with that in the NT group (P<0.001). Increased c-Fos immunoreactivity in the cortex was observed at 3 h after reperfusion in the HT, but not the NT group, while c-Jun expression was not affected by HT treatment. There was also a significant increase in AP-1 DNA binding activity at 3 h in the HT group when compared to the NT group (P<0.01). In conclusion, hypothermia decreased cerebral infarction in association with early increases in c-Fos expression and AP-1 DNA binding activity in peri-infarct cortex. It remains to be established whether such responses are a cause or consequence of cell survival, but these results clearly establish that altered transcription is a key feature of tissue spared following hypothermic focal ischemia.
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PMID:Effect of intra-ischemic hypothermia on the expression of c-Fos and c-Jun, and DNA binding activity of AP-1 after focal cerebral ischemia in rat brain. 1276 3


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