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)

The purpose of this study was to examine the activation, topographic distribution, and cellular location of three mitogen-activated protein kinases (MAPKs) after permanent middle cerebral artery occlusion (MCAO) in mice. Phosphorylated MAPKs expression in the ischemic region was quantified using Western blot analysis and localized immunohistochemically using the diaminobenzide staining and double-labeled immunostaining. Extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38 mitogen-activated protein (p38), and c-Jun NH2-terminal kinase or stress-activated protein kinase (SAPK/JNK) were initially activated at 30 minutes, 10 minutes, and 5 minutes, respectively, after focal cerebral ischemia. Peak expression represented a 2.7-fold, 3.7-fold, and 4.8-fold increase in each of these MAPKs, respectively. The immunohistochemical expressions of ERK1, ERK2, p38, and SAPK/JNK protein paralleled the Western blot analysis results. Double-labeled immunofluorescent staining demonstrated that the neurons and astrocytes expressed ERK1, ERK2, p38, and SAPK/JNK during the early time points after MCAO. The current results demonstrate that brain damage after ischemia rapidly triggers time-dependent ERK1, ERK2, p38, and SAPK/ JNK phosphorylation, and reveals that neurons and astrocytes are involved in the activation of the MAPK pathway. This very early expression of MAPKs suggests that MAPKs may be closely involved in signal transduction during cerebral ischemia.
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PMID:Activation of mitogen-activated protein kinases after permanent cerebral artery occlusion in mouse brain. 1099 54

We investigated the activation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) during transient forebrain ischemia to clarify the roles of these stress kinases during brain ischemia. Mice were subjected bilateral common carotid artery (BCCA) occlusion for 20 min followed by reperfusion. Immunohistochemical analysis and Western blot analysis for active JNK and active p38 MAPK were performed at 0, 5, 10, 30 and 150 min after reperfusion. After 5 min of reperfusion, active JNK and p38 MAPK immunoreactivities were enhanced in neurons in the cerebral cortex and hippocampus; this activation peaked at 30 min of reperfusion. Stress kinases activation dominantly occurred in the similar regions, in which neurons with fragmented DNA were detected at 72 h after reperfusion. Western blot analysis indicated that JNK 1, JNK 2 and p38 MAPK were activated at 10 and 30 min after reperfusion. These findings indicate that JNK and p38 MAPK pathways may play important roles in neuronal death during brain ischemia.
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PMID:Phosphorylation of c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase after transient forebrain ischemia in mice. 1105 1

We generated transgenic (TG) mice overexpressing fibroblast growth factor (FGF)-2 protein (22- to 34-fold) in the heart. Chronic FGF-2 overexpression revealed no significant effect on heart weight-to-body weight ratio or expression of cardiac differentiation markers. There was, however, a significant 20% increase in capillary density. Although there was no change in FGF receptor-1 expression, relative levels of phosphorylated c-Jun NH(2)-terminal kinase and p38 kinase as well as of membrane-associated protein kinase C (PKC)-alpha and total PKC-epsilon were increased in FGF-2-TG mouse hearts. An isolated mouse heart model of ischemia-reperfusion injury was used to assess the potential of increased endogenous FGF-2 for cardioprotection. A significant 34-45% increase in myocyte viability, reflected in a decrease in lactate dehydrogenase released into the perfusate, was observed in FGF-2 overexpressing mice and non-TG mice treated exogenously with FGF-2. In conclusion, FGF-2 overexpression causes augmentation of signal transduction pathways and increased resistance to ischemic injury. Thus, stimulation of endogenous FGF-2 expression offers a potential mechanism to enhance cardioprotection.
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PMID:Overexpression of FGF-2 increases cardiac myocyte viability after injury in isolated mouse hearts. 1117 45

Heme is considered to play an instrumental role in the pathology of hemolysis, trauma, and reperfusion following ischemia. However, data are sparse and experimental models are required. The transport of heme by hemopexin to tissues is a specific, membrane receptor-mediated process. Hemopexin recycles after endocytosis like transferrin. Heme oxygenase-1 (HO-1), transferrin, the transferrin receptor, and ferritin are regulated by heme-hemopexin. Genes that encode proteins important for cellular defenses against oxidative stress, such as the cysteine-rich metallothioneins (MTs), are also activated by hemopexin, as are proteins that regulate cell cycle control including p21WAF1 and the tumor suppressor p53. The hemopexin system is being investigated to establish how intracellular events are affected by signal(s) from the plasma membrane due to hemopexin receptor occupancy and heme transport. A transient oxidative modification of proteins, shown by carbonyl production, takes place. Redox processes at the cell surface, which generate cuprous ions, are involved in the regulation of the MT-1 and HO-1 genes by heme-hemopexin before heme catabolism and intracellular release of iron. The "redox-sensitive" transcription factors activated by the hemopexin system include c- Jun, RelA/NFkappaB and MTF-1. The specific copper chelator bathocuproine disulfonate prevents carbonyl production, the nuclear translocation of MTF-1, and the induction of MT-1 revealing a novel, pivotal role for copper in the hemopexin system. In addition, surface redox-active copper is the first link shown for the concomitant regulation of HO-1 and MT-1 and is required for the activation of the amino-terminal c-Jun kinase (JNK) by heme-hemopexin.
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PMID:Links between cell-surface events involving redox-active copper and gene regulation in the hemopexin heme transport system. 1122 23

Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT1-A), angiotensin II type 2 receptor antagonist (AT2-A) or ACE-I plus bradykinin B2 antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT2-A and ACE-I, and increased by AT1-A and ACE-I+icatibant. ACE-I and AT2-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT1-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT2 receptor are cardioprotective against IR injury through the activation of ERK, but not JNK.
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PMID:Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. 1132 78

We determined the role of p38 mitogen-activated protein kinase (MAPK), 72-kDa heat shock protein (HSP72), and antioxidant enzymes in whole body heat stress (HS)-induced cardioprotection in mouse hearts. Adult male mice were treated with either HS or anesthesia only. At 0.5, 48, 72, or 120 h later, the hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. A significant protection against ischemia-reperfusion injury was observed 48 h after HS as demonstrated by: 1) reduction in infarct size; 2) decrease in leakage of lactate dehydrogenase; and 3) enhanced postischemic ventricular contractile function. No such protection was observed at other post-HS time points. HS caused an ~25% increase in phosphorylated c-Jun NH2-terminal kinase (JNK) but not p38 MAPK in the heart during the first 2-h post-HS time period. Cardioprotection was abolished by the MAPK inhibitor SB-203580, which also partially suppressed the HS-induced JNK phosphorylation. The protective effect was associated with a two- to threefold increase in HSP72 protein accumulation, but not antioxidant enzyme activities (catalase and Cu/Zn and Mn SOD) in the myocardium. Although HSP72 levels remained high 72 h after HS, the cardioprotection had already disappeared. We conclude that HS induces a transient delayed cardioprotection at 48 h after thermal stress in mice which appears to be mediated via a MAPK-signaling pathway.
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PMID:Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart. 1145 53

Chemokine expression is associated with reperfusion of infarcted myocardium in the setting of tissue necrosis, intense inflammation, and inflammatory cytokine release. The specific synthesis of monocyte chemotactic protein (MCP)-1 mRNA by cardiac venules in reperfused infarcts corresponded to the region where leukocytes normally localize. MCP-1 could be induced by exogenous tumor necrosis factor (TNF)-alpha or by postischemic cardiac lymph containing TNF-alpha. However, the release of TNF-alpha during early reperfusion did not explain the venular localization of MCP-1 induction. To better understand the factors mediating MCP-1 induction, we examined the role of ischemia/reperfusion in a model of brief coronary occlusion in which no necrosis or inflammatory response is seen. Adult mongrel dogs were subjected to 15 minutes of coronary occlusion and 5 hours of reperfusion. Ribonuclease protection assay revealed up-regulation of MCP-1 mRNA only in ischemic segments of reperfused canine myocardium. Pretreatment with the reactive oxygen scavenger N-(2-mercaptopropionyl)-glycine completely inhibited MCP-1 induction. In situ hybridization localized MCP-1 message to small venular endothelium in ischemic areas without myocyte necrosis. Gel shift analysis of nuclear extracts from the ischemic area showed enhanced DNA binding of the transcription factors AP-1 and nuclear factor (NF)-kappaB, crucial for MCP-1 expression, in ischemic myocardial regions. Immunohistochemical staining demonstrated reperfusion-dependent nuclear translocation of c-Jun and NF-kappaB (p65) in small venular endothelium, only in the ischemic regions of the myocardium, that was inhibited by N-(2-mercaptopropionyl)-glycine. In vitro, treatment of cultured canine jugular vein endothelial cells with the reactive oxygen intermediate H2O2 induced a concentration-dependent increase in MCP-1 mRNA levels, which was inhibited by the antioxidant N-acetyl-L-cysteine, a precursor of glutathione, but not pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and activator of AP-1. In contrast to our studies with infarction, incubation of canine jugular vein endothelial cells with postischemic cardiac lymph did not induce MCP-1 mRNA expression suggesting the absence of cytokine-mediated MCP-1 induction after a sublethal ischemic period. These results suggest that reactive oxygen intermediate generation, after a brief ischemic episode, is capable of inducing MCP-1 expression in venular endothelium through AP-1 and NF-kappaB. Short periods of ischemia/reperfusion, insufficient to produce a myocardial infarction, induce MCP-1 expression, potentially mediating angiogenesis in the ischemic noninfarcted heart.
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PMID:Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. 1158 58

Activation of the c-Jun N-terminal (JNK) or stress-activated protein kinases (SAPK) is associated with a wide range of disparate cellular responses to extracellular stimuli, including either induction of or protection from apoptosis. This study investigates the effect of ischemia and reperfusion on JNK isoform activities using a reversible rabbit spinal cord ischemia model. High basal JNK activity, attributed to the p46 JNK1 isoform, was expressed in the CNS of untreated rabbits. JNK activity decreased in the lumbar spinal cord of rabbits occluded for 15-60 min. During reperfusion animals occluded for 15 min recovered neurological function and JNK activity returned to normal levels. In contrast animals occluded for 60 min remained permanently paraplegic and JNK activity was half the control activity after 18 h of reperfusion. In these animals proteolytic fragments of JNK1 and JNK3 were observed and protein levels, but not activity, of JNK isoforms increased in a detergent-insoluble fraction. Two novel c-Jun (and ATF-2) kinase activities increased during reperfusion of animals occluded for 60 min. An activity designated p46(slow) was similar in M(r) to a JNK2 isoform induced in these animals. A second 30-kDa activity associated with the detergent-insoluble fraction co-migrated with a JNK3 N-terminal fragment. The results show that JNK1 is active in the normal CNS and increased activity is not associated with durations of ischemia and reperfusion that induce cell death. However, specific JNK isoform activation may participate in the cell death pathways as increased activity of novel c-Jun (ATF-2) kinase activities was observed in paraplegic animals.
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PMID:Differential effects of ischemia and reperfusion on c-Jun N-terminal kinase isoform protein and activity. 1159 78

Bursts in reactive oxygen species production are important mediators of contractile dysfunction during ischemia-reperfusion injury. Cellular mechanisms that mediate reactive oxygen species-induced changes in cardiac myocyte function have not been fully characterized. In the present study, H(2)O(2) (50 microM) decreased contractility of adult rat ventricular myocytes. H(2)O(2) caused a concentration- and time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in adult rat ventricular myocytes. H(2)O(2) (50 microM) caused transient activation of ERK1/2 and p38 MAP kinase that was detected as early as 5 min, was maximal at 20 min (9.6 +/- 1.2- and 9.0 +/- 1.6-fold, respectively, vs. control), and returned to baseline at 60 min. JNK activation occurred more slowly (1.6 +/- 0.2-fold vs. control at 60 min) but was sustained at 3.5 h. The protein kinase C inhibitor chelerythrine completely blocked JNK activation and reduced ERK1/2 and p38 activation. The tyrosine kinase inhibitors genistein and PP-2 blocked JNK, but not ERK1/2 and p38, activation. H(2)O(2)-induced Na(+)/H(+) exchanger phosphorylation was blocked by the MAP kinase kinase inhibitor U-0126 (5 microM). These results demonstrate that H(2)O(2)-induced activation of MAP kinases may contribute to cardiac myocyte dysfunction during ischemia-reperfusion.
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PMID:Differential MAP kinase activation and Na(+)/H(+) exchanger phosphorylation by H(2)O(2) in rat cardiac myocytes. 1160 Apr 17

Protection against ischemic kidney injury is afforded by 24 h of ureteral obstruction (UO) applied 6 or 8 days prior to the ischemia. Uremia or humoral factors are not responsible for the protection, since unilateral UO confers protection on that kidney but not the contralateral kidney. Prior UO results in reduced postischemic outer medullary congestion and leukocyte infiltration. Prior UO results in reduced postischemic phosphorylation of c-Jun N-terminal stress-activated protein kinase 1/2 (JNK1/2), p38, mitogen-activated protein kinase (MAPK) kinase 4 (MKK4), and MKK3/6. Very few cells stain positively for proliferating cell nuclear antigen after obstruction, indicating that subsequent protection against ischemia is not related to proliferation with increased numbers of newly formed daughter cells more resistant to injury. UO increases the expression of heat shock protein (HSP)-25 and HSP-72. The increased HSP-25 expression persists for 6 or 8 days, whereas HSP-72 does not. HSP-25 expression is increased in the proximal tubule cells in the outer stripe of the outer medulla postobstruction, prior to, and 24 h after ischemia. In LLC-PK(1) renal epithelial cells, adenovirus-expressed human HSP-27 confers resistance to chemical anoxia and oxidative stress. Increased HSP-27 expression in LLC-PK(1) cells results in reduced H(2)O(2)-induced phosphorylation of JNK1/2 and p38. In conclusion, prior transient UO renders the kidney resistant to ischemia. This resistance to functional consequences of ischemia is associated with reduced postischemic activation of JNK, p38 MAP kinases, and their upstream MAPK kinases. The persistent increase in HSP-25 that occurs as a result of UO may contribute to the reduction in phosphorylation of MAPKs that have been implicated in adhesion molecule up-regulation and cell death.
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PMID:Prevention of kidney ischemia/reperfusion-induced functional injury, MAPK and MAPK kinase activation, and inflammation by remote transient ureteral obstruction. 1169 40


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