Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.
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PMID:Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. 1219 73

The development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) has been a very significant development in the management of coronary artery disease. Large prospective clinical trials have provided unequivocal evidence that cholesterol lowering therapy with statins reduces all-cause mortality in patients with coronary artery disease. There is now accumulating data indicating that statin treatment should be initiated early after an acute coronary syndrome. This body of evidence is based on large databases in which investigators compared outcomes among patients taking statins with those patients who were not prescribed cholesterol lowering therapy. Prospective, randomized, clinical trials also indicate that early statin therapy reduces recurrent ischemia. Finally, studies examining long-term compliance with statin therapy suggest increased adherence to therapy when statins are prescribed during the initial hospitalization for an acute coronary syndrome. In tandem with these clinical observations, there is a large body of scientific data that highlights many important cellular and molecular mechanisms through which statins may confer early benefit. These effects involve relatively rapid improvement in endothelial function, antiischemic, antithrombotic and antiinflammatory actions of statins.
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PMID:Statins in acute coronary syndromes. 1253 69

The observation that almost half of all myocardial infarctions and strokes occur in persons without elevated levels of low-density lipoprotein cholesterol has prompted the study of factors other than hyperlipidemia that contribute to the development of atherosclerosis. A growing body of evidence indicates that inflammation plays a substantial role in plaque progression and rupture. Research interest has increasingly focused on biomarkers of inflammation as a means of predicting more accurately which patients are at high risk for cardiovascular disease (CVD). Clinical studies indicate that C-reactive protein (CRP), a marker of systemic inflammation, independently predicts cardiovascular risk in healthy persons as well as in persons with established CVD and those with acute ischemia. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to reduce levels of CRP through mechanisms independent of their effects on lipid levels. Initial clinical studies also suggest that CRP levels may have utility in the targeting of statin therapy, particularly in primary prevention. These results need direct testing in large, prospective clinical trials to determine whether statin therapy will benefit persons without overt hyperlipidemia but with evidence of systemic inflammation. Confirmation of these preliminary findings, if incorporated into evidence-based guidelines, may profoundly change the approach to diagnosis and treatment of CVD.
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PMID:Connecting the role of C-reactive protein and statins in cardiovascular disease. 1270 38

Previous studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors attenuate ischemia-reperfusion injury by increasing the activity of endothelial nitric oxide synthase (eNOS). We assessed whether short-term treatment with atorvastatin reduces myocardial infarct size in the rat. Rats (male Sprague-Dawley) received atorvastatin 2 mg/kg per day (n = 9), 10 mg/kg per day (n = 8), or 75 mg/kg per day (n = 11), or placebo (n = 11) by gastric gavage for 3 days. Two additional groups received atorvastatin 10 mg/kg (n = 7) or placebo (n = 7) for 3 days and the nonselective nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), 15 mg/kg intravenously 15 min before surgery. All rats underwent 30 min of coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium at risk was assessed with blue dye and infarct size by triphenyltetrazolium chloride. Ischemic myocardium at risk was comparable among groups. Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the atorvastatin 75 mg/kg group (22.6 +/- 2.8%; p = 0.035 vs. placebo) and atorvastatin 10 mg/kg (20.3 +/- 3.8%; p = 0.022 vs. placebo) compared with placebo (37.5 +/- 4.3%). The effect of atorvastatin 2 mg/kg was of smaller magnitude and did not reach statistical significance (infarct size 30.6 +/- 4.2% of the myocardium at risk). L-NAME abolished the protective effect of atorvastatin 10 mg/kg per day. Infarct size was 43.0 +/- 4.1% in the atorvastatin group and 39.4 +/- 3.3% in the placebo group (p = 0.503). In conclusion, short-term (3 days) atorvastatin (10-75 mg/kg/d) significantly reduced myocardial infarct size. The protective effect was completely abolished by L-NAME, strongly suggesting that this protective effect is mediated via the nitric oxide synthase pathway.
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PMID:Reduction of infarct size by short-term pretreatment with atorvastatin. 1284 84

Neurons need iron, which is reflected in their expression of the transferrin receptor. The concurrent expression of the ferrous iron transporter, divalent metal transporter I (DMT1), in neurons suggests that the internalization of transferrin is followed by detachment of iron within recycling endosomes and transport into the cytosol via DMT1. To enable DMT1-mediated export of iron from the endosome to the cytosol, ferric iron must be reduced to its ferrous form, which could be mediated by a ferric reductase. The presence of nontransferrin-bound iron in brain extracellular fluids suggests that neurons can also take up iron in a transferrin-free form. Neurons are thought to be devoid of ferritin in many brain regions in which there is an association between iron accumulation and cellular damage, for example, neurons of the substantia nigra pars compacta. The general lack of ferritin together with the prevailing expression of the transferrin receptor indicates that iron acquired by activity of transferrin receptors is directed toward immediate use in relevant metabolic processes, is exported, or is incorporated into complexes other than ferritin. Iron has long been considered to play a significant role in exacerbating degradation processes in brain tissue subjected to acute damage and neurodegenerative disorders. In brain ischemia, the damaging role of iron may depend on the inhibition of detoxifying enzymes responsible for catalyzing the oxidation of ferrous iron. Brain ischemia may also lead to an increase in iron supply to neurons as transferrin receptor expression by brain capillary endothelial cells is increased. Pharmacological blockage of the transferrin receptor/DMT1-mediated uptake could be a target to prevent further iron uptake. In chronic neurodegenerative settings, a deleterious role of iron is suggested since cases of Alzheimer's disease, Parkinson's disease, and Huntington's disease have a significantly higher accumulation of iron in affected regions. Dopaminergic neurons are rich in neuromelanin, shown to be more redox-active in Parkinson's disease cases. Iron-containing inflammatory cells may, however, account for the main portion of iron present in neurodegenerative disorders. More knowledge about iron metabolism in normal and diseased neurons is warranted as this may identify pharmaceutical targets to improve neuronal iron management.
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PMID:The metabolism of neuronal iron and its pathogenic role in neurological disease: review. 1510 52

Molecular biology has recently contributed significantly to the recognition of selenium (Se)2 and Se-dependent enzymes as modulators of brain function. Increased oxidative stress has been proposed as a pathomechanism in neurodegenerative diseases including, among others, Parkinson's disease, stroke, and epilepsy. Glutathione peroxidases (GPx), thioredoxin reductases, and one methionine-sulfoxide-reductase are selenium-dependent enzymes involved in antioxidant defense and intracellular redox regulation and modulation. Selenium depletion in animals is associated with decreased activities of Se-dependent enzymes and leads to enhanced cell loss in models of neurodegenerative disease. Genetic inactivation of cellular GPx increases the sensitivity towards neurotoxins and brain ischemia. Conversely, increased GPx activity as a result of increased Se supply or overexpression ameliorates the outcome in the same models of disease. Genetic inactivation of selenoprotein P leads to a marked reduction of brain Se content, which has not been achieved by dietary Se depletion, and to a movement disorder and spontaneous seizures. Here we review the role of Se for the brain under physiological as well as pathophysiological conditions and highlight recent findings which open new vistas on an old essential trace element.
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PMID:Selenium and brain function: a poorly recognized liaison. 1521 Mar 2

The anti-atherogenic properties of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been well established in several circulatory beds. Increasing evidence suggests that statins may help attenuate ischemia-reperfusion injury, a beneficial effect that may be related to the antioxidant capabilities of statins; however, this remains controversial. We performed this study to determine whether the HMG-CoA reductase inhibitor cerivastatin can prevent oxidative stress-induced injury in cultured human aortic endothelial cells (HAEC). The HAEC were subjected to oxidative stress in the absence and presence of increasing concentrations of cerivastatin (50 nM-1,000 nM). Oxidative stress was induced by increasing concentrations of hydrogen peroxide or endogenous superoxide anions generated by the inhibition of superoxide dismutase using diethylthiocarbamate (10 mM). Cell viability and mitochondrial activity were measured by mitochondria-dependent 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) conversion. Cell morphology was also examined using light microscopy. Exposing HAEC to cerivastatin for 24 hours had no effect on cell viability using both cell morphology and MTT conversion: the HAEC incubated in 100 nM cerivastatin had 90% +/- 2.2% viability of the control. As expected, hydrogen peroxide produced a concentration-dependent decrease in cell viability. Varying concentrations of cerivastatin pretreatment for < or = 18 hours showed no protection of HAEC against hydrogen peroxide-induced injury. As a positive control, the prototype antioxidant N-acetyl-L-cysteine was cytoprotective even with the highest hydrogen peroxide concentration. Neither cerivastatin nor N-acetyl-L-cysteine protected HAEC against diethylthiocarbamate-induced oxidative injury at any concentration. In this study, cerivastatin did not protect cultured HAEC against oxidative stress induced by hydrogen peroxide or diethylthiocarbamate.
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PMID:Cerivastatin does not prevent oxidative injury of human aortic endothelial cells. 1521 20

We investigated the neuroprotective effects of a novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (pitavastatin) on ischemic neuronal damage in gerbils using immunohistochemistry. The animals were allowed to survive for 14 days after 5 min of ischemia induced by bilateral occlusion of the common carotid arteries. Five days after ischemia, severe neuronal cell loss was observed in the hippocampal CA1 sector. Prophylactic treatment with pitavastatin dose-dependently prevented the hippocampal CA1 neuronal cell loss 5 days after ischemia. Immunohistochemical study did not show the change of nNOS and iNOS expression in the hippocampus except for, in a few regions, up to 1 day after ischemia. Thereafter, the expression of iNOS was observed in the hippocampal CA1 sector 5 and 14 days after ischemia. In contrast, the expression of nNOS and eNOS gradually decreased in the hippocampal CA1 sector up to 14 days after ischemia. Prophylactic treatment with pitavastatin also prevented the expression of iNOS and the decrease of eNOS expression and the number of nNOS-positive cells in the hippocampal CA1 sector 5 days after ischemia. However, prophylactic treatment with pitavastatin at a dose of 10 mg kg(-1) did not change the immunoreactivity of iNOS and nNOS in the hippocampus at an early phase after ischemia. In contrast, this drug prevented the reduction of eNOS immunoreactivity in the hippocampal CA1 neurons at an early phase after ischemia. These findings demonstrate that the HMG-CoA reductase inhibitor pitavastatin can protect hippocampal CA1 neurons after transient forebrain ischemia through up-regulation of eNOS expression in this region. Thus pharmacological modulation of eNOS expression may offer a novel therapeutic strategy for cerebral ischemic stroke.
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PMID:Protective effect of pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, on ischemia-induced neuronal damage. 1532 60

Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is a potent cholesterol-lowering drug that reduces the risk of myocardial infarction and stoke. In this study, we examined its neuroprotective effects against hippocampal CA1 neuronal damage following transient cerebral ischemia in gerbils. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries for 5 min. Pitavastatin, at a dose of 3, 10 or 30 mg/kg, was administered orally twice a day for 5 consecutive days and transient cerebral ischemia was induced in mice 1 h after the last treatment with pitavastatin. Histopathological observations showed that neuronal damage to the hippocampal CA1 neurons, which was observed 5 days after ischemia in animals, was prevented by pitavastatin treatment. Immunohistochemical staining for copper/zinc superoxide dismutase (SOD) and manganese SOD decreased in the hippocampal CA1 sector of gerbils 2 days after ischemia when histological neuronal destruction was not yet found, but was clearly observed in pitavastatin-treated animals. These results indicate that pitavastatin can protect dose-dependently against ischemia-induced neuronal damage and that the mechanism of the neuroprotection may be related to the preservation of SODs, especially copper/zinc-SOD. This in part explains how pitavastatin therapy, which targets free radicals, has beneficial effects against disorders including ischemic stroke.
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PMID:Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, reduces hippocampal damage after transient cerebral ischemia in gerbils. 1533 28

Replacement of injured endothelial cells by bone marrow derived endothelial progenitor cells (EPC's) is a new pathway of vascular repair after ischemia. Endothelial progenitor cells contribute less than 0.01% to the peripheral venous compartment of mononuclear cells. The detection of EPC's requires a demonstration of CD 34 and VEGFR-2 (vascular endothelial growth factor receptor-2) antigenic cell membrane determinants and proof of endothelial characteristics after outgrowth and differentiation in cell culture. The most important stimuli to the mobilization and proliferation of EPC's are VEGF, GM-CSF (granulocyte-macrophage colony stimulating factor), erythropoietin, HMG-CoA-reductase inhibitors and tissue ischemia. In vivo in patients EPC's appear to contribute to endothelialization of vascular grafts, the formation of collaterals of ischemic limbs and the healing of myocardial infarcts. The role of EPC's in uremia is currently under investigation.
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PMID:Role of endothelial progenitor cells in cardiovascular pathology. 1563 37


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