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)

Synapse loss, deposits of amyloid beta-peptide (Abeta), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to Abeta25-35 (Abeta) and FeSO4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na+/K+-ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17beta-estradiol or estriol largely prevented impairment of Na+/K+-ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17Beta-estradiol suppressed membrane lipid peroxidation induced by Abeta and FeSO4, but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17beta-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.
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PMID:17Beta-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron. 940 14

Estrogen replacement therapy in postmenopausal women is associated with a decreased mortality and morbidity from stroke. The present study was undertaken to investigate the effects of estrogen on endothelial cell glucose transporter 1 (GLUT 1) and on the cell viability during focal ischemia in a rat model. Female rats were ovariectomized (OVX) and 2 weeks later 17beta-estradiol (E2) was injected subcutaneously at a dose of 100 microg/kg 2 h before unilateral middle cerebral artery (MCA) occlusion. Ischemic lesion size was quantified using 2,3,5-triphenyl tetrazolium chloride (TTC) staining and GLUT 1 protein was analyzed by Western blotting. E2 treatment decreased ischemic lesion size in slices taken at 9 and 11 mm posterior from the olfactory bulb by 46.3% and 44.1%, respectively (P < 0.05). GLUT 1 protein decreased in both OVX and E2 groups by 24.6% and 22.7% respectively (P < 0.05) compared with the non-lesioned side in the core ischemic region, including the basal ganglia. GLUT 1 protein was increased in the E2-treated group compared with the control group (23.3%, P < 0.05) in the penumbral ischemic region of the cortex. Primary rat brain capillary endothelial cell (BCEC) cultures were established as an in vitro model for ischemic effects on endothelial cells. Estrogen reduced BCEC loss by 35.9%, 28.4% and 23.5% (P < 0.05) when glucose in the culture medium was reduced to 50%, 20% and 10%, respectively; and by 28.4% and 18.4% (P < 0.05) following 1 or 4 h of anoxia, respectively. This study demonstrates that estrogen treatment increases GLUT 1 transporters and protects BCEC loss which may in turn reduce focal ischemic brain damage.
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PMID:Effects of 17beta-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats. 941 67

Glucose and fructose enter mammalian cells via facilitated diffusion, a process regulated by five glucose transporter isoforms (GLUT1-5) at the plasma membrane. The tissue-specific pattern of GLUT isoform expression likely reflects differing needs for glucose transport by various tissues. Myocytes must respond expeditiously to increased metabolic demand. A basal isoform, GLUT1, and the insulin-regulatable glucose transporter, GLUT4, have been demonstrated in human myocytes. GLUT3 has a high affinity for glucose, but its presence in human myocardium has not been clearly established. The purpose of this study was to determine whether GLUT3 protein is present in human cardiac myocytes. We examined rapidly frozen myocardial tissue from the explanted heart of seven patients undergoing cardiac transplantation, from the heart of a young, previously healthy male organ donor, from the heart of a 67-year-old woman without known cardiac disease who had a fatal stroke, and from the heart of six human fetuses. GLUT3 protein was detected by immunoblots and localized by light and electron microscopy immunohistochemistry. The presence of GLUT3 protein was verified in myocardial tissue by both immunoblots and immunohistochemistry. Light and electron microscopy confirmed that GLUT3 was in cardiac myocytes. GLUT3 was also demonstrated as a 48 kDa protein in fetal myocardium, which was present at 10 weeks, increased at 15 weeks, then decreased at 20 weeks of gestation. GLUT3 is present in human adult and fetal myocardium. Human myocardial GLUT3 regulation and its role in myocardial glucose uptake remain to be elucidated.
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PMID:Glucose transporter 3 (GLUT3) protein is present in human myocardium. 988 55

Previous studies from our laboratory have demonstrated that chronic stress produces molecular, morphological, and ultrastructural changes in the rat hippocampus that are accompanied by cognitive deficits. Glucocorticoid attenuation of glucose utilization is proposed to be one of the causative factors involved in stress-induced changes in the hippocampus, producing an energy-compromised environment that may make hippocampal neuronal populations more vulnerable to neurotoxic insults. Similarly, diabetes potentiates neuronal damage in acute neurotoxic events, such as ischemia and stroke. Accordingly, the current study examined the regulation of the neuron-specific glucose transporter, GLUT-3, in the hippocampus of streptozotocin-induced diabetic rats subjected to restraint stress. Diabetes leads to significant increases in GLUT-3 mRNA and protein expression in the hippocampus, increases that are not affected by stress. Collectively, these results suggest that streptozotocin-induced increases in GLUT-3 mRNA and protein expression in the hippocampus may represent a compensatory mechanism to increase glucose utilization during diabetes and also suggest that modulation of GLUT-3 expression is not responsible for glucocorticoid impairment of glucose utilization.
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PMID:Regulation of GLUT-3 glucose transporter in the hippocampus of diabetic rats subjected to stress. 1032 82

We previously reported that several markers on rat chromosome (Chr) 4 cosegregated with the occurrence of cerebral stroke and brain edema in stroke-prone spontaneously hypertensive rats (SHRSP). To obtain insights into the positional candidate genes for stroke susceptibility in this region, we mapped four genes, Taurine transporter (Tau), tumor necrosis factor receptor (Tnfr), GABA transporter (Gat1) and glucose transporter-3 (Glut3) genes, using newly developed simple sequence repeat (SSR) markers on rat Chr 4. We isolated the SSRs for the genes either by screening a rat genomic library or by searching the GenBank database. By linkage analysis using two sets of backcrosses, Gat1 and Tnfr were mapped in the region associated with stroke, while Taut was located distant from the region. The Glut3 locus was also assigned to rat Chr 4 using a rat x mouse hybrid clone panel. These results indicated that the Tnfr, Gat1 and Glut3 genes were good positional candidates for the stroke susceptibility in SHRSP, suggesting that further evaluation of these genes by functional studies could prove useful.
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PMID:Mapping of four simple sequence repeat (SSR) markers on rat chromosome 4. 1073 35

To elucidate the possible involvement of angiotensin II (AII) in the pathogenesis of microvascular changes in severe hypertension, we investigated the effects of angiotensin II type 1 (AT1) receptor antagonist and angiotensin-converting enzyme inhibitor (ACEI) on the expression of adhesion molecules of leukocytes and brain microvessels. Male stroke-prone spontaneously hypertensive rats (SHRSP) at 19 weeks of age were divided into three groups and age-matched Wistar-Kyoto rats (WKY) were used as the control group. AT1 receptor antagonist (TCV-116, 0.5 mg/kg/day) and ACEI (captopril, 20 mg/kg/day) were administered to SHRSP for 4 weeks. Mac-1 expression in leukocytes was investigated by flow cytometric analysis. For endothelial cells, we examined the expression of intercellular adhesion molecule-1 (ICAM-1), the AT1 receptor, and glucose transporter-1 (GLUT-1, a marker of the blood-brain barrier) using reverse transcription-polymerase chain reaction (RT-PCR). The blood pressure of AT1 receptor antagonist and ACEI-treated groups was slightly lower than that of the control, but was still greater than 220 mm Hg. Mac-1 expression, as well as ICAM-1 expression, was higher in control SHRSP than in WKY. Such enhanced expression of adhesion molecules in SHRSP was ameliorated by the administration of AT1 receptor antagonist or ACEI, the former being more effective. AT1 receptor expression was higher in control SHRSP than in WKY, and was lower in the AT1 receptor antagonist group, whereas no difference was found in the ACEI group. No significant differences were found in GLUT-1 expression among all groups. In the case of hypertensive cerebral injuries in SHRSP, leukocytes may have an important role for initiation via adhesion to endothelial cells. AT1 receptor antagonist showed a beneficial effect for the amelioration of enhanced expression of adhesion molecule in both leukocytes and endothelial cells. Thus, AII seems to be an important mediator for the hypertensive microvascular injuries.
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PMID:Effects of the AT1 receptor antagonist on adhesion molecule expression in leukocytes and brain microvessels of stroke-prone spontaneously hypertensive rats. 1107 85

Of particular physiological interest, ascorbate, the ionized form of ascorbic acid, possesses strong reducing properties. However, it has been shown to induce oxidative stress and lead to apoptosis under certain experimental conditions. Ascorbate in the brain is released during hypoxia, including stroke, and is subsequently oxidized in plasma. The oxidized product (dehydroascorbate) is transported into neurons via a glucose transporter (GLUT) during a reperfusion period. The dehydroascorbate taken up by cells is reduced to ascorbate by both enzymatic and non-enzymatic processes, and the ascorbate is stored in cells. This reduction process causes an oxidative stress, due to coupling of redox reactions, which can induce cellular damage and trigger apoptosis. Ascorbate treatment decreased cellular glutathione (GSH) content, and increased the rates of lipid peroxide production in rat cortical slices. Wortmannin, a specific inhibitor of phosphatidylinositol (PI)-3-kinase (a key enzyme in GLUT translocation), prevented the ascorbate induced-decrease of GSH content, and suppressed ascorbate-induced lipid peroxide production. However, wortmannin was ineffective in reducing hydrogen peroxide (H(2)O(2))-induced oxidative stress. The oxidative stress caused ceramide accumulation, which was proportionally changed with lipid peroxides when the cortical slices were treated with ascorbate. These differential effects support the hypothesis that GLUT efficiently transports the dehydroascorbate into neurons, causing oxidative stress.
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PMID:Oxidative stress induced by ascorbate causes neuronal damage in an in vitro system. 1125 61

Ascorbate is a reducing agent, but it is also known to oxidize cellular components under specific conditions. The mechanism of this oxidative action, however, is not well established. Ascorbate treatment increased lipid peroxide content in PC12 cells, but did not increase quantities of lipid peroxide when homogenates of PC12 cells were treated with ascorbate, suggesting that cellular integrity is required for ascorbate to generate lipid peroxidation. However, dehydroascorbate increased lipid peroxide production in both intact PC12 cells and the cell homogenates. These differential effects of ascorbate and dehydroascorbate on intact cells versus homogenates suggest that the dehydroascorbate in cytosol induces an oxidative stress. Ascorbate in culture medium is rapidly oxidized to dehydroascorbate, which is transported into cells by a glucose transporter (GLUT). The GLUT antagonists wortmannin and cytochalasin B, or a high concentration of glucose, blocked (14)C uptake (from ascorbate) in a time-dependent manner and suppressed lipid peroxide production in PC12 cells. These observations support the concept that ascorbate is oxidized to dehydroascorbate, which is transported into cells via GLUT. The dehydroascorbate induces oxidative stress. The oxidative stress triggered apoptosis according to ceramide production, caspase-3 activation, and TUNEL. We have concluded that ascorbate is taken up after oxidation to dehydroascorbate via a "dehydroascorbate transporter" (GLUT), and the dehydroascorbate generates an oxidative stress which triggers apoptosis. These studies have significant implications for conditions under which a high concentration of ascorbate in a tissue is released during a period of hypoxia (e.g., stroke) and taken up during a reperfusion period as dehydroascorbate. Inhibiting uptake of dehydroascorbate may offer novel therapeutic strategies to alleviate brain damage during a reperfusion period.
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PMID:Involvement of oxidative stress in ascorbate-induced proapoptotic death of PC12 cells. 1135 56

In order to investigate the role of Angiotensin II (AII) for the vasogenic cerebral edema, the AT1 receptor antagonist (TCV-116) was administered to 19-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 2 weeks at a dosage which did not decrease the blood pressure. Although no remarkable changes were found in blood pressure after treatment, the average brain weight of the treated group was relatively lower as compared to that of control SHRSP and no edematous changes were found in any brains. The immunohistochemical expression of intercellular adhesion molecule-1 (ICAM-1) was less and the glucose transporter-1 (GLUT-1) expression was much more intense in the endothelial cells of the micro vessels in the cerebral cortex of the treated group. Fibrinogen expression around micro-vessels was also remarkably reduced in the treated group. A decreased expression of ICAM-1 in the treated group was confirmed by RT-PCR analysis. These results indicate that the AT1 receptor blockade ameliorates hypertensive cerebral injury in a blood pressure-independent manner and suggest that AII may have an important role for endothelial injury in severe hypertension.
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PMID:AT1 receptor antagonist prevents brain edema without lowering blood pressure. 1144 94

In order to clarify the causative role of cytotoxic nitric oxide (NO) in hypertensive cerebral injury, the effects of inducible nitric oxide synthase (iNOS) inhibition on leukocytes and endothelial function were examined using stroke-prone spontaneously hypertensive rats (SHRSP). For the iNOS inhibition, S-methylisothiourea (SMT) was administered to 12-week-old male SHRSP for 3 weeks. Immunohistochemical examination were carried out for the expression of intercellular adhesion molecule-1 (ICAM-1), glucose transporter-1 (GLUT-1), fibrinogen and glial fibrillary acidic protein (GFAP) in cerebral cortex. The effects of iNOS inhibition was also examined for Mac-1 expression by flow cytometric analysis. Plasma NO metabolites level was significantly lower in the SMT group than in the control group. Mac-1 expression was inhibited by SMT. In the SMT group, brain weight was significantly lower than in the control. By SMT administration, ICAM-1 expression was suppressed, GLUT-1 was enhanced, fibrinogen was decreased and GFAP was decreased as compared to those in control group. In hypertensive cerebral injury in SHRSP, iNOS-derived NO, mainly in activated leukocytes, could be an important causative factor for endothelial injury.
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PMID:Effects of inducible nitric oxide synthase inhibition on cerebral edema in severe hypertension. 1145 38


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