Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of heritable hypertension-associated cerebrovascular injury. This study sought to compare SHRSP to the stroke-resistant SHR strain to identify genes and protein pathways whose expression and/or function was significantly altered between the strains prior to the onset of stroke. Cerebral cortex gene expression profiles from male SHRSPs and matched SHRs were examined by Affymetrix microarray analysis. mRNAs encoding the brain-derived neurotrophic factor receptor (TrkB) and multiple kinases of the MAPK/AKT signaling pathways, including JNK2, AKT2, and PI3K, were differentially expressed between SHRSP and SHR. Because these data suggest altered function in pathways involving MAP and AKT kinase activity, we performed Western blot using phosphorylation state-specific antibodies to characterize activity of MAP kinase and PI3K/AKT pathways. Changes in the levels of the phosphorylated forms of these kinases paralleled the changes in transcript levels observed between the strains. Two-dimensional gel electrophoresis and peptide fragment mass fingerprinting were used to identify altered protein substrates of these kinases. Protein profiling of kinase substrates further supported the notion of perturbed kinase-mediated signaling in SHRSP and identified adenylyl cyclase associated protein 2, TOAD-64, propionyl CoA carboxylase, APG-1, and valosin-containing protein as kinase targets whose phosphorylation state is altered between these strains. Altered gene and protein expression patterns in SHRSP are consistent with increased vulnerability of this strain to cerebrovascular injury.
 ...
PMID:Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility. 1290 46

Neuronal death in cerebral ischemia is largely due to excitotoxic mechanisms, which are known to activate the c-Jun N-terminal kinase (JNK) pathway. We have evaluated the neuroprotective power of a cell-penetrating, protease-resistant peptide that blocks the access of JNK to many of its targets. We obtained strong protection in two models of middle cerebral artery occlusion (MCAO): transient occlusion in adult mice and permanent occlusion in 14-d-old rat pups. In the first model, intraventricular administration as late as 6 h after occlusion reduced the lesion volume by more than 90% for at least 14 d and prevented behavioral consequences. In the second model, systemic delivery reduced the lesion by 78% and 49% at 6 and 12 h after ischemia, respectively. Protection correlated with prevention of an increase in c-Jun activation and c-Fos transcription. In view of its potency and long therapeutic window, this protease-resistant peptide is a promising neuroprotective agent for stroke.
 ...
PMID:A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. 1293 12

Experimentally and clinically, stroke is followed by both acute and prolonged inflammatory responses characterized by the production of inflammatory cytokines and leukocyte infiltration into the brain. A debate on whether inflammation after stroke is neurotoxic or participates in brain repair remains unresolved. However, the need to pharmacologically control inflammatory amplification has been commonly acknowledged. The principal challenge of devising successful anti-inflammatory strategies for stroke is to understand molecular and temporal interplay of inflammatory and cell-death-inducing processes triggered by cerebral ischemia in both parenchymal and vascular brain cells. This article will review a number of experimental and clinically tested approaches to reduce brain inflammation and damage after stroke (e.g., anti-neutrophil, anti-ICAM-1, anti-cytokine strategies) and will suggest potential pathways where novel therapeutic targets may emerge, including transcriptional regulators of inflammatory gene expression (e.g., NF-kappaB, proteasome) and signaling pathways (e.g., ICE-cascade, MAPK/MKK/ERK cascade) linked to both inflammation and neuronal cell death. Finally, we will discuss applications of functional genomics technologies in the discovery of stroke diagnostics and therapies.
 ...
PMID:Current and future therapeutic strategies to target inflammation in stroke. 1456 Nov 97

Recent evidence suggests p38 mitogen-activated protein kinase (MAPK) signal transduction plays an important role in the pathogenesis of progressive renal disease. Using dynamic contrast enhanced magnetic resonance imaging (MRI), we evaluated chronic treatment with a p38 MAPK inhibitor, trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl-methoxypyridimidin-4-yl)imidazole (SB-239063), on renal function in a hypertension model of progressing renal dysfunction. Spontaneously hypertensive-stroke prone rats were placed on a high salt/fat diet (SFD) or maintained on normal chow diet (ND). SFD animals with albuminuria at 4 to 8 weeks (> or =10 mg/day inclusion criteria), were randomized into p38 MAPK inhibitor treatment (SB-239063, 1200 ppm in diet) or vehicle groups. The progression of blood pressure and albuminuria during the treatment period (approximately 6 weeks) was decreased by 12 and 60%, respectively, in the SFD + SB-239063 versus SFD control group. Renal perfusion and filtration were assessed by in vivo MRI at the end of the study. Relative cortical perfusion was increased in the SFD + SB-239063 group compared with the SFD control group as reflected by a 29% decrease in time to peak of contrast agent in the cortex. Additionally, the regional renal glomerular filtration rate index (Kcl) was increased by 39% in the SFD + SB-239063 versus SFD control group and was normalized to the ND control group. Greater functional heterogeneity was observed in the SFD control versus SFD + SB-239063 or ND control group. All alterations of renal function were supported by histopathological findings. In conclusion, chronic treatment with a p38 MAPK inhibitor, SB-239063, attenuates functional and structural renal degeneration in a hypertensive model of established renal dysfunction.
 ...
PMID:p38 MAPK inhibitors ameliorate target organ damage in hypertension: Part 2. Improved renal function as assessed by dynamic contrast-enhanced magnetic resonance imaging. 1456 50

Numerous mediators, believed to play a role in endothelial dysfunction (e.g., neurohormones, cytokines, hypoxia, and stretch), have been shown to activate p38 mitogen-activated protein kinase (MAPK) in a variety of cell types. The purpose of the present study was to examine the regulation of p38 MAPK in endothelium and its role in endothelial dysfunction and salt sensitivity. In cultured human umbilical vein endothelial cells (HUVECs), tumor necrosis factor-alpha and lipopolysaccharide increased phosphorylation of p38 MAPK (P-p38 MAPK) and increased ICAM-1 expression. Preincubation with highly selective p38 MAPK inhibitors, 1-(1,3-dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-[2-phenoxypyrimidin-4-yl] imidazole (SB-239063AN) or SB-239063, dose dependently reduced intercellular adhesion molecule-1 expression in HUVECs. In spontaneously hypertensive-stroke prone rats (SHR-SP), P-p38 MAPK was localized by immunohistochemistry to the aortic endothelium and adventitia but was undetectable in aortae from normotensive rats. Introduction of a salt/fat diet (SFD) to the SHR-SP strain induced endothelial dysfunction (ex vivo vascular reactivity analysis), albuminuria, and an increase in blood pressure within 4 weeks. Chronic dietary dosing (approx. 100 mg/kg/day) with SB-239063AN inhibited the SFD diet-induced hypertension. In addition, delayed treatment also significantly improved survival and restored nitric oxide-mediated endothelium-dependent relaxation in SFD-SHR-SPs with established endothelial dysfunction. These results suggest an important role for p38 MAPK in endothelial inflammation and dysfunction as well as providing the first evidence for p38 MAPK-dependent hypertension.
 ...
PMID:p38 MAPK inhibitors ameliorate target organ damage in hypertension: Part 1. p38 MAPK-dependent endothelial dysfunction and hypertension. 1456 51

Hypoxia/reoxygenation causes cellular injury and death associated with a number of pathophysiological conditions, including myocardial ischemia/reperfusion injury and stroke. The cell death pathways induced by hypoxia/reoxygenation and their underlying regulatory mechanisms remain poorly understood. Recent studies have shown that hypoxia/reoxygenation can induce Bax translocation and cytochrome c release. Using murine lung endothelial cells as a model, we found that the induction of apoptosis by hypoxia/reoxygenation involved the activation of both Bax-dependent and death receptor-mediated pathways. We demonstrated the activation of the death-inducing signal complex and Bid pathway after hypoxia/reoxygenation. Hepatocyte growth factor markedly inhibited hypoxia/reoxygenation-induced endothelial cell apoptosis. The cytoprotection afforded by hepatocyte growth factor was mediated in part by the stimulation of FLICE-like inhibiting protein expression, the attenuation of death-inducing signal complex formation, and the inhibition of Bid and Bax activation. Hepatocyte growth factor also prevented cell injury and death by increasing the expression of the antiapoptotic Bcl-XL protein. The inhibition of Bid/Bax-induced cell death by hepatocyte growth factor primarily involved p38 MAPK and in part Akt-dependent pathways but not ERK1/ERK2.
 ...
PMID:Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells. 1462 9

c-Jun N-terminal kinase (JNK) signaling is an important contributor to stress-induced apoptosis, but it is unclear whether JNK and its isoforms (JNK1, JNK2, and JNK3) have distinct roles in cerebral ischemia. Here we show that JNK1 is the major isoform responsible for the high level of basal JNK activity in the brain. In contrast, targeted deletion of Jnk3 not only reduces the stress-induced JNK activity, but also protects mice from brain injury after cerebral ischemia-hypoxia. The downstream mechanism of JNK3-mediated apoptosis may include the induction of Bim and Fas and the mitochondrial release of cytochrome c. These results suggest that JNK3 is a potential target for neuroprotection therapies in stroke.
 ...
PMID:A critical role of neural-specific JNK3 for ischemic apoptosis. 1465 93

In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.
 ...
PMID:A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia. 1466 49

Tumor necrosis factor-alpha (TNF-alpha) stimulates expression of endothelial cell (EC) genes that may promote atherosclerosis in part by an activation of mitogen-activated protein (MAP) kinases. Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one), a selenoorganic compound, is effective for acute ischemic stroke; however, its effect on EC has not yet been elucidated. We examined the effect of ebselen on TNF-alpha-induced MAP kinase activation and adhesion molecule expression in cultured human umbilical vein endothelial cells (HUVEC). Extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 were rapidly and significantly activated by TNF-alpha in HUVEC. TNF-alpha-induced JNK activation was inhibited by ebselen, whereas ERK1/2 and p38 were not affected. Apoptosis signal-regulated kinase 1 (ASK1) was suggested to be involved in TNF-alpha-induced JNK activation because transfection of kinase-inactive ASK1 inhibited TNF-alpha-induced JNK activation. Ebselen inhibited TNF-alpha-induced TNF receptor-associated factor 2 (TRAF2)-ASK1 complex formation and phosphorylation of stress-activated protein kinase ERK kinase 1 (SEK1), which is an upstream signaling molecule of JNK. Finally, TNF-alpha-induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation and resultant intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions were inhibited by ebselen. Specific inhibitors for JNK and NF-kappaB also inhibited TNF-alpha-induced ICAM-1 and VCAM-1 expressions in HUVEC. These findings suggest that ebselen prevents TNF-alpha-induced EC activation through the inhibition of TRAF2-ASK1-SEK1 signaling pathway, which leads to JNK activation. Inhibition of JNK by ebselen may imply its usefulness for the prevention of atherosclerosis relevant to EC activation.
 ...
PMID:Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. 1472 May 1

Stabilizing the survival of oligodendrocytes and oligodendrocyte precursors within and near lesions in patients suffering from multiple sclerosis (MS) and other demyelinating diseases is an important therapeutic goal. Previous studies have identified a human-derived monoclonal IgM antibody designated rHIgM22 that induces remyelination in a mouse model of MS. We provide evidence that this antibody, directed against myelin, induces antiapoptotic signaling in premyelinating oligodendrocytes and reduces caspase-3 activation and caspase gene expression in mice undergoing antibody-induced remyelination. This effect was dependent on calcium entry via CNQX-sensitive channels and on lipid raft integrity, and was correlated with suppression of JNK signaling. We conclude that rHIgM22 may induce remyelination via rescue of oligodendrocytes, and suggest that such autoantibody-mediated signaling may have important therapeutic implications for a variety of neurological diseases, including stroke and Alzheimer's disease.
 ...
PMID:Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. 1475 77


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