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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Right/left matching in the total artificial heart (TAH) is essential to prevent fatal volume displacement into the pulmonary circuit. Measurements were made with three different sized Rostock pneumatic artificial ventricles incorporated in the Donovan mock circulatory system together with the heart driver AKT 86. First for each ventricle we determined the dependence of the maximum effective stroke volume on the systolic driving pressure and the afterload. The right ventricle (RV) is about 10% more effective than the left ventricle (LV). Control of the TAH permits different or equal frequencies for the RV and LV. For control with equal frequencies and full-to-empty regimen of one ventricle (RV-Master or LV-Master) the ratio of designed stroke volumes between RV and LV is important. This follows from the smaller efficiency of the LV and the left-to-left shunt. Otherwise a control mode with different heart rates must be used.
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PMID:Relationship between design and control of artificial heart for protection of the right/left balance. 239 95

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.
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PMID:Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility. 1290 46

Protein kinase B/Akt possesses prosurvival and antiapoptotic activities and is involved in growth factor-mediated neuronal protection. In this study we establish Akt deactivation as a causal mediator of cell death. Akt deactivation occurs in multiple models of cell death including N-methyl-d-aspartate excitotoxicity, vascular stroke, and nitric oxide (NO)- and hydrogen peroxide (H2O2)-elicited death of HeLa, PC12, and Jurkat T cells. Akt deactivation characterizes both caspase-dependent and -independent cell death. Conditions rescuing cell death, such as treatment with poly(ADP-ribose) polymerase or NO synthase inhibitors and preconditioning with sublethal concentrations of N-methyl-d-aspartate, restore Akt activity. Infection of neurons with adenovirus expressing constitutively active Akt prevents excitotoxicity, whereas phosphatidylinositol 3-kinase inhibitors or infection with dominant negative Akt induce death of untreated neuronal cells.
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PMID:Akt as a mediator of cell death. 1450 98

Hibernation in mammals is a reversible state of suspended animation associated with tolerance to an otherwise lethal reduction of core body temperature and metabolism. An integral aspect of hibernation is tolerance to a profound decrease of cerebral perfusion. Identification of regulatory mechanisms that control hibernation in ground squirrels can guide efforts to develop improved treatment for stroke and brain trauma. In this study, we show in multiple tissues that S473 phosphorylation of Akt (Protein kinase B), a phosphatidylinositol-3 kinase-regulated serine/threonine kinase, was significantly reduced (P<0.001) as was its kinase activity (P=0.023) in the 13-lined ground squirrel, Spermophilus tridecemlineatus, during hibernation. T308 phosphorylation of Akt was relatively preserved. Brain immunohistochemical staining confirmed these results. In hibernating animals, reduction of immunoreactive phospho (S473)-Akt was noted throughout the brain. Akt is a key molecule in the insulin/insulin-like growth factor signal transduction pathway, which plays a critical role in the balance between survival and apoptosis. The data presented here raise the possibility that down-regulation of Akt phosphorylation plays a regulatory role in hibernation. This would resemble dauer larva formation in Caenorhabditis elegans where Akt inhibition is associated with energy conservation, fat storage, expression of antioxidant enzymes and growth arrest.
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PMID:Akt phosphorylation and kinase activity are down-regulated during hibernation in the 13-lined ground squirrel. 1521 87

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.
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PMID:Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. 1703 24

Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has entered Phase I/II clinical trials for treatment of ischemic stroke. Severe intraoperative hypotension can lead to global cerebral ischemia and apoptotic neuron loss within the hippocampus. We tested G-CSF in a rat model of global cerebral ischemia. Global cerebral ischemia was induced in male Sprague-Dawley rats (280-330 g) with the 2-vessel occlusion model (hemorrhagic hypotension to a mean arterial pressure of 30-35 mm Hg and bilateral common carotid artery occlusion for 8 min). Three groups of animals were used: global ischemia without treatment (GI, n=49), global ischemia with G-CSF treatment (GI+G-CSF, n=42), and sham surgery (Sham, n=26). Rats in the treatment group received G-CSF (50 mug/kg, subcutaneously) 12 h before surgery, on the day of surgery, and on postoperative Day 1 and were euthanized on Days 2, 3, and 14. Mild hyperglycemia was observed in all groups. T-maze testing for spontaneous alternation demonstrated initial improvement in the G-CSF treatment group but no long-term benefit. Measurement of daily body weight demonstrated an initial trend toward improvement in the G-CSF group. Quantitative Nissl histology of the hippocampus demonstrated equivalent outcomes on Days 3 and 14, which was supported by quantitative TUNEL stain. Immunohistochemistry and Western blot demonstrated an initial increase in phosphorylated-AKT in the GI+G-CSF group on Day 2. We conclude that G-CSF treatment is associated with transient early improvement in neurobehavioral outcomes after global ischemia complicated by mild hyperglycemia, but no long-term protection.
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PMID:The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats. 1721 Jan 48

The prostanoid synthesizing enzyme cyclooxygenase-2 (COX-2) is involved in the mechanisms of cerebral ischemia, an effect mediated by prostaglandin E2 through activation of EP1 receptors. Thus, inhibition of EP1 receptors is neuroprotective in models of ischemic stroke, but the molecular mechanisms of the effect have not been fully elucidated. We used oxygen glucose deprivation (OGD) in hippocampal slices as an injury model to investigate whether the neuroprotection afforded by EP1 receptor inhibition involves the PI3K/AKT survival pathway. EP1 receptor inhibition with SC51089 or SC51322 reduced the hippocampal damage produced by ODG by 28+/-2% and 32+/-3%, respectively (p<0.05). OGD induced a transient reduction of AKT activity that was partly counteracted by SC51089. LY294002 blocked the increase in phospho-AKT evoked by SC51089 and abolished the associated protective effect. The AKT activation induced by SC51089 was associated with phosphorylation of PTEN, the phosphatase that negatively regulates AKT. Furthermore, SC51089 attenuated the mitochondrial translocation of the proapoptotic protein BAD. These data indicate that EP1 receptor inhibition improves the survival of hippocampal slices by preventing the attenuation in AKT activity induced by OGD, and by reducing the mitochondrial translocation of BAD. The findings provide evidence for a link between EP1 receptors and the PI3K/AKT survival pathway and shed light on the molecular mechanisms of the prosurvival effect of EP1 receptor inhibition.
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PMID:Neuroprotection by PGE2 receptor EP1 inhibition involves the PTEN/AKT pathway. 1817 94

A disintegrin and metalloproteinase-17 (ADAM17) is involved in proteolytic ectodomain shedding of several membrane-bound growth factors and cytokines. The expression and activity of ADAM17 increase under some pathological conditions such as stroke and glioma. ADAM17 promotes neural progenitor cell migration and contributes to stroke-induced neurogenesis after stroke and brain tumor growth and invasion. In the present study, we sought to elucidate whether ADAM17 contributes to breast cancer progression and its mechanisms. To this end, we examined the role of ADAM17 in the proliferation, invasion and tube formation of MDA-MB-231 breast cancer cells in vitro. Stable transfection of the MDA-MB-231 cell line with either a plasmid for overexpression of human ADAM17, or a siRNA to ADAM17 was employed in this study to establish high or low ADAM17 expression in breast cancer cells, respectively. For study of mechanism, the ADAM17 inhibitor TAPI-2 and the PI3K-AKT inhibitor LY294002 were used to counteract high ADAM17 expression or the activated PI3K-AKT pathway. Proliferation of MDA-MB-231 breast cancer cells were tested by MTT, Bromodeoxyuridine incorporation assay, growth curve and sulforhodamine B assay. Matrigel invasion assays were used to assess the ability of MDA-MB-231 cells to penetrate the Extra Cellular Matrix. A Matrigel tube formation assay was performed to test capillary tube formation ability. EGFR-PI3K-Akt pathway activation in MDA-MB-231 cells under different ADAM17 expression levels were tested by western blot and ELISA. Our data show that ADAM17 promotes the MDA-MB-231 malignant phenotype by increased proliferation, invasion and angiogenesis. TGFalpha, VEGF secretion and VEGF expression was increasing by ADAM17 and counteracted by ADAM17 siRNA, TAPI-2 and LY294002 in MDA-MB-231 cells. ADAM17 activated, whereas ADAM17 siRNA, TAPI-2 and LY294002 deactivated the EGFR-PI3K-AKT signal pathway, which correlated with MDA-MB-231 cell malignant phenotype changes. This study suggests ADAM17 contributes to breast cancer progression through activation of the EGFR-PI3K-AKT signal pathway.
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PMID:ADAM17 promotes breast cancer cell malignant phenotype through EGFR-PI3K-AKT activation. 1943 Feb 1

Mediator lipidomics is a field of study concerned with the characterization, structural elucidation and bioactivity of lipid derivatives actively generated by enzymatic activity. It is well known that omega-3 fatty acids are beneficial for brain function. Docosahexaenoic acid [DHA; 4 22:6(n-3)] is the most abundant essential omega-3 fatty acid present in the brain and it has multiple mechanisms of exerting protective effects after cellular injury. Certain lipid species produced from DHA early during the reperfusion stage of brain ischemia-reperfusion injury are generated in order to help the cell cope as the injury progresses. We explore these newly discovered lipid mediators in order to understand their role in the cell. We have identified one of these potentially protective lipid mediators as a novel stereospecific DHA-derived fatty acid, called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,15E,19Z hexaenoic acid). DHA also has important roles in pro-survival signaling cascades after ischemia-reperfusion in injury. It has been shown to accelerate AKT translocation and activation and has binding affinity with an important PPAR-gamma family of ligand-activated nuclear receptors that have been implicated in various aspects of lipid metabolism and have been shown to have anti-inflammatory actions. Here we present an overview of these mechanisms and discuss the potential of using DHA signaling in the development of treatments for the large population of patients suffering from the devastating consequences of stroke.
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PMID:Docosahexaenoic acid neurolipidomics. 1980 38

Recently more evidences support baicalein (Bai) is neuroprotective in models of ischemic stroke. This study was conducted to determine the molecular mechanisms involved in this effect. Either permanent or transient (2 h) middle cerebral artery occlusion (MCAO) was induced in rats in this study. Permanent MCAO led to larger infarct volumes in contrast to transient MCAO. Only in transient MCAO, Bai administration significantly reduced infarct size. Baicalein also markedly reduced apoptosis in the penumbra of transient MCAO rats. Additionally, oxygen and glucose deprivation (OGD) was used to mimic ischemic insult in primary cultured cortical neurons. A rapid increase in the intracellular reactive oxygen species level and nitrotyrosine formation induced by OGD was counteracted by Bai, which is parallel with attenuated cell injury. The reduction of phosphorylation Akt and glycogen synthase kinase-3beta (GSK3beta) induced by OGD was restored by Bai, which was associated with preserved levels of phosphorylation of PTEN, the phophatase that negatively regulates Akt. As a consequence, Bcl-2/Bcl-xL-associated death protein phosphorylation was increased and the protein level of Bcl-2 in motochondria was maintained, which subsequently antagonize cytochrome c released in cytosol. LY294002 blocked the increase in phospho-AKT evoked by Bai and abolished the associated protective effect. Together, these findings provide evidence that Bai protects neurons against ischemia injury and this neuroprotective effect involves PI3K/Akt and PTEN pathway.
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PMID:Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. 2005 Sep 73


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