Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.
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PMID:MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia. 1709 Dec 94

The c-Jun N-terminal kinase (JNK) pathway plays an important role in neuronal apoptosis both during normal CNS development and following stroke in adult animals. As with other MAP kinase pathways, scaffold proteins regulate JNK signaling. The scaffold protein POSH (Plenty of SH3s) enhances JNK activation and apoptosis. We identified a POSH homologue, POSH2, which was cloned from rat brain and is present in cortical neurons in vitro. POSH2 mRNA is expressed in a variety of tissues including brain, and this distribution partially overlaps with that of POSH. POSH2 overexpression promotes JNK activation in HEK293 cells and promotes apoptosis in neuronal PC12 cells, which is blocked by a dominant-negative c-Jun. Finally POSH2 contains a functional RING domain and enhances the stability of coexpressed mixed-lineage kinases. These results indicate that POSH2 may regulate JNK activation and consequent apoptosis under conditions of increased expression.
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PMID:Identification of POSH2, a novel homologue of the c-Jun N-terminal kinase scaffold protein POSH. 1776 3

As clinical trials of pharmacological neuroprotective strategies in stroke have been disappointing, attention has turned to the brain's own endogenous strategies for neuroprotection. Recently, a hypothesis has been offered that modified reperfusion subsequent to a prolonged ischemic episode may also confer ischemic neuroprotection, a phenomenon termed 'postconditioning'. Here we characterize both in vivo and in vitro models of postconditioning in the brain and offer data suggesting a biological mechanism for protection. Postconditioning treatment reduced infarct volume by up to 50% in vivo and by approximately 30% in vitro. A duration of 10 mins of postconditioning ischemia after 10 mins of reperfusion produced the most effective postconditioning condition both in vivo and in vitro. The degree of neuroprotection after postconditioning was equivalent to that observed in models of ischemic preconditioning. However, subjecting the brain to both preconditioning as well as postconditioning did not cause greater protection than each treatment alone. The prosurvival protein kinases extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and Akt show prolonged phosphorylation in the cortex of postconditioned rats. Neuroprotection after postconditioning was inhibited only in the presence of LY294002, which blocks Akt activation, but not U0126 or SB203580, which block ERK and P38 MAP kinase activity. In contrast, preconditioning-induced protection was blocked by LY294002, U0126, and SB203580. Our data suggest that postconditioning may represent a novel neuroprotective approach for focal ischemia/reperfusion, and one that is mediated, at least in part, by the activation of the protein kinase Akt.
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PMID:In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischemic postconditioning. 1788 62

The cytokine granulocyte colony-stimulating factor (G-CSF) is produced by numerous cell types including immune and endothelial cells. G-CSF binding to its receptor G-CSF-R which belongs to the cytokine receptor type I family depends on the interaction of alpha-helical motifs of the former and two fibronectin type III as well as an immunoglobulin-like domain of the latter. It activates several signalling transduction pathways including PI3K/Akt, Jak/Stat and MAP kinase, thereby promoting survival, proliferation, differentiation and mobilisation of haematopoietic stem and progenitor cells. Accordingly, recombinant human (rh)G-CSF has been extensively used in clinical haematology and oncology to enable bone marrow transplantation or to treat chemotherapy-associated neutropenia. Using animal models it has been recently shown that G-CSF, alone or in combination with other cytokines such as stem cell factor (SCF), causes an accumulation of bone marrow-derived cells in the infarcted heart which, however, do not differentiate into cardiac cells. Nevertheless, since beneficial effects on structural and functional properties were observed in animal models of cardiac, brain and hindlimb ischaemia other mechanisms of G-CSF action must be operative. Recent evidence suggests paracrine effects mediated by the immigrated bone marrow-derived cells and/or direct effects of the cytokine on resident G-CSF-R expressing cells. In both cases these may include promotion of cellular survival, proliferation and differentiation. First clinical studies in patients with myocardial infarction, heart failure and stroke have been accomplished and are reviewed in this paper.
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PMID:Granulocyte colony-stimulating factor (G-CSF) for cardio- and cerebrovascular regenerative applications. 1839 54

Tumor necrosis factor (TNF)-alpha stimulated interleukin (IL)-6 release and induced the phosphorylation of myosin phosphatase targeting subunit (MYPT)-1, a Rho-kinase substrate. The IL-6 release was significantly suppressed by Y-27632 and fasudil, Rho-kinase inhibitors. Although IkappaB inhibitor suppressed the TNF-alpha-induced IL-6 release, the Rho-kinase inhibitors did not affect the TNF-alpha-induced IkappaB phosphorylation. TNF-alpha induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), and p44/p42 MAP kinase. The TNF-alpha-induced IL-6 release was suppressed by SB203580, a p38 MAPK inhibitor, or SP600125, a SAPK/JNK inhibitor, but not by PD98059, a MAP kinase/extracellular signal-regulated kinase kinase inhibitor. The Rho-kinase inhibitors attenuated the TNF-alpha-induced phosphorylation of both p38 MAP kinase and SAPK/JNK. Rho-kinase, which has been used for the clinical treatment of cerebral vasospasms, may be involved in other central nervous system (CNS) disorders such as traumatic injury, stroke, neurodegenerative disease and neuropathic pain. TNF-alpha, a proinflammatory cytokine that affects the CNS through cytokines, such as IL-6, release from neurons, astrocytes and microglia. Therefore, we investigated the involvement of Rho-kinase in the TNF-alpha-induced IL-6 release from rat C6 glioma cells. These results strongly suggest that Rho-kinase regulates the TNF-alpha-induced IL-6 release at a point upstream from p38 MAPK and SAPK/JNK in C6 glioma cells. Therefore, Rho-kinase inhibitor may be considered to be a new clinical candidate for the treatment of CNS disorders in addition to cerebral vasospasms.
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PMID:Involvement of Rho-kinase in tumor necrosis factor-alpha-induced interleukin-6 release from C6 glioma cells. 1942 47

Hyperhomocysteinemia is an independent risk factor for stroke and neurological abnormalities. However, the underlying cellular mechanisms by which elevated homocysteine can promote neuronal death is not clear. In the present study we have examined the role of NMDA receptor-mediated activation of the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase pathway in homocysteine-dependent neurotoxicity. The study demonstrates that in neurons l-homocysteine-induced cell death was mediated through activation of NMDA receptors. The study also shows that homocysteine-dependent NMDA receptor stimulation and resultant Ca2+ influx leads to rapid and sustained phosphorylation of ERK-MAP kinase. Inhibition of ERK phosphorylation attenuates homocysteine-mediated neuronal cell death thereby demonstrating that activation of ERK-MAP kinase signaling pathway is an intermediate step that couples homocysteine-mediated NMDA receptor stimulation to neuronal death. The findings also show that cAMP response-element binding protein (CREB), a pro-survival transcription factor and a downstream target of ERK, is only transiently activated following homocysteine exposure. The sustained activation of ERK but a transient activation of CREB together suggest that exposure to homocysteine initiates a feedback loop that shuts off CREB signaling without affecting ERK phosphorylation and thereby facilitates homocysteine-mediated neurotoxicity.
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PMID:Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. 1950 27

Reactive astrocytes are traditionally thought to impede brain plasticity after stroke. However, we previously showed that reactive astrocytes may also contribute to stroke recovery, partly via the release of a nuclear protein called high-mobility group box 1 (HMGB1). Here, we investigate the mechanisms that allow stimulated astrocytes to release HMGB1. Exposure of rat primary astrocytes to IL-1beta for 24 h elicited a dose-dependent HMGB1 response. Immunostaining and western blots of cell lysates showed increased intracellular levels of HMGB1. Western blots confirmed that IL-1beta induced a release of HMGB1 into astrocyte conditioned media. MAP kinase signaling was involved. Levels of phospho-ERK were increased by IL-1beta, and the MEK/ERK inhibitor U0126 decreased HMGB1 upregulation in the stimulated astrocytes. Since HMGB1 is a nuclear protein, the role of the nuclear protein exporter, chromosome region maintenance 1 (CRM1), was assessed as a candidate mechanism for linking MAP kinase signaling to HMGB1 release. IL-1beta increased CRM1 expression in concert with a translocation of HMGB1 from nucleus into cytoplasm. Blockade of IL-1beta-stimulated HMGB1 release with the ERK inhibitor U0126 was accompanied by a downregulation of CRM1. Our findings reveal that IL-1beta stimulates the release of HMGB1 from activated astrocytes via ERK MAP kinase and CRM1 signaling. These data suggest a novel pathway by which inflammatory cytokines may enhance the ability of reactive astrocytes to release prorecovery mediators after stroke.
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PMID:Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. 2022 44

Axon injury triggers regeneration through activation of a conserved kinase cascade, which includes the dual leucine zipper kinase (DLK). Although dendrites are damaged during stroke, traumatic brain injury, and seizure, it is not known whether mature neurons monitor dendrite injury and initiate regeneration. We probed the response to dendrite damage using model Drosophila neurons. Two larval neuron types regrew dendrites in distinct ways after all dendrites were removed. Dendrite regeneration was also triggered by injury in adults. Next, we tested whether dendrite injury was initiated with the same machinery as axon injury. Surprisingly, DLK, JNK, and fos were dispensable for dendrite regeneration. Moreover, this MAP kinase pathway was not activated by injury to dendrites. Thus, neurons respond to dendrite damage and initiate regeneration without using the conserved DLK cascade that triggers axon regeneration.
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PMID:Dendrite injury triggers DLK-independent regeneration. 2441 65

Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl, and water into the brain across an intact blood-brain barrier (BBB), together with swelling of astrocytes as they take up the ions and water crossing the BBB. Our previous studies provide evidence that luminal BBB Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC) are rapidly stimulated by the ischemic factors hypoxia, aglycemia, and AVP, and inhibition of NKCC and NHE activities by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. We examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundance. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemic factors. We found that hypoxia, aglycemia, and AVP increase CMEC NHE activity through 5 h and that NHE1, but not NHE2, abundance is increased by 1- to 5-h exposures to these factors. Furthermore, we found that these factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities.
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PMID:Ischemic factor-induced increases in cerebral microvascular endothelial cell Na/H exchange activity and abundance: evidence for involvement of ERK1/2 MAP kinase. 2464 44

With recent insight into the mechanisms involved in diseases, such as cardiovascular disease, cancer, stroke, neurodegenerative diseases, and diabetes, more efficient modes of treatment are now being assessed. Traditional medicine including the use of natural products is widely practiced around the world, assuming that certain natural products contain the healing properties that may in fact have a preventative role in many of the diseases plaguing the human population. This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (-)-epicatechin, with a focus on the latter. (-)-Epicatechin has several unique features responsible for a variety of its effects. One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (-)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation. Mutations in this pathway are often associated with malignancies, and the use of (-)-epicatechin holds promise as a preventative agent and as an adjunct for chemotherapy and radiation therapy to improve outcome. This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.
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PMID:Molecular Mechanisms and Therapeutic Effects of (-)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration. 2618 May 80


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