Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms underlying the protective effects of heat shock pretreatment on heatstroke remain unclear. Here we attempted to ascertain whether the possible occurrence of oxidative stress and energy depletion exhibited during heatstroke can be reduced by heat shock preconditioning. In the present study, colonic temperature, mean arterial pressure, heart rate, striatal levels of heat shock protein 72 (HSP72), local Po2, brain temperature, cerebral blood flow, cellular ischemia and damage markers, dihydroxybenzoic acid (DHBA), lipid peroxidation, glutathione, glutathione peroxidase and reductase activities, and ATP were assayed in normothermic control rats and in heatstroke rats with or without preconditioning 16 or 96 h before initiation of heatstroke. Heatstroke was induced by exposing the anesthetized rats to a high ambient temperature (Ta = 43 degrees C) until the moment at which MAP decreased from its peak level. Sublethal heat shock pretreatment 16 h before initiation of heatstroke, in addition to increasing striatal HSP72 levels, conferred significant protection against heatstroke-induced arterial hypotension, striatal ischemia and damage, increment of hydroxyl radical formation, lipid peroxidation, glutathione oxidation, and decrement of glutathione peroxidase activity and ATP. However, at 96 h after heat shock, when striatal HSP72 expression returned to basal levels, the above responses that occurred during onset of heatstroke were indistinguishable between the two groups. These results suggest that heat shock pretreatment induces HSP72 overexpression in striatum and confers protection against heatstroke-induced striatal ischemia and damage by reducing oxidative stress and energy depletion.
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PMID:Heat shock pretreatment may protect against heatstroke-induced circulatory shock and cerebral ischemia by reducing oxidative stress and energy depletion. 1566 32

Fertility in patients treated for unilateral testicular torsion has been shown to be significantly reduced in all the reported series to date, implying that the present-day treatment requires further refinement in the form of adjunct pharmacotherapeutic intervention (Lomodex and MgSO(4)) in addition to scrotal exploration. Prepubertal Holtzman strain rats (35 days old) were used for our study. Two sets were formed with six groups of rats in each set. Rats were treated as follows: group 1, sham-operated group; group 2, torsion (4 h); group 3, torsion + detorsion (1 h); group 4, torsion + ATP-MgCl(2) + detorsion; group 5, torsion + Lomodex-MgSO(4) + detorsion; group 6, torsion + normal saline + detorsion. Whereas the first set of animals was sacrificed immediately at the end of experiment, animals in set 2 were sacrificed 8 weeks after the end of the experiment to look for the development of antisperm antibodies. Parameters studied were thiobarbituric acid reductase (TBAR) assay, histology of testicular tissue, and sperm agglutination test. Student's t-test was used for significance. With detorsion (149.95+/-30.68) there was a significant rise in the TBAR values (P<0.05) compared with torsion (57.39+/-14.47). Treatment with both Lomodex-MgSO(4) (40.74+/-6.39) and ATP-MgCl(2) (48.30+/-18.35) yielded TBAR levels comparable to those in the sham group (31.35+/-11.96). Similar injury was also seen on the contralateral testis, with detorsion (114.28+/-10.68) much more detrimental than torsion (40.59+/-15.02) and rescue seen following treatment with Lomodex-MgSO(4) (27.55+/-8.64) as well as ATP-MgCl(2) (38.61+/-12.23). Regarding th histology, with detorsion there was evidence of severe distortion of tubules, with almost all the tubules showing maturation arrest and a few tubules completely devoid of any germinal cells. Treatment with Lomodex-MgSO(4) as well as ATP-MgCl(2) showed preservation of tubular morphology. Our study failed to document the presence of agglutinating antibodies (antisperm antibodies) in any of the groups. Unilateral testicular torsion has bilateral effects and is a form of ischemia-reperfusion injury. Treatment of torsion by detorsion alone does not prevent testicular damage. The results of the present study show that administration of Lomodex + MgSO(4) prior to detorsion results in prolonged testicular salvage with a potential of subsequent improvement in semen quality and fertility and reduction in long-term morbidity. The presence of agglutinating antibodies could not be detected in the present study.
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PMID:Effect of Lomodex-MgSO(4) in the prevention of reperfusion injury following unilateral testicular torsion: an experimental study in rats. 1571 60

Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wild-type mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.
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PMID:Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. 1571 55

Catastrophic antiphospholipid syndrome (CAPS) is a severe and rare variant of antiphospholipid syndrome (APS) characterized by acute multiorgan failure due to small vessel thrombi in patients with positive antiphospholipid antibodies. We report a fatal case of catastrophic antiphospholipid syndrome in a young woman with a history of polymyositis and Hodgkin lymphoma. The patient was admitted to hospital because of severe foot pain following several weeks of skin ulcerations. Doppler ultrasonography showed evidence of arterial ischemia of the both lower extremities. Despite anticoagulation, immunosuppression, plasmapheresis and antibiotic therapy, she developed cutaneous gangrene, retroperitoneal hematoma, ileus, and acute respiratory and renal failure that resulted in death. Autopsy showed multifocal vascular injury and microthrombi with associated hemorrhages and infarcts in multiple organs. The patient had normal levels of functional protein C and protein S and a normal level of plasma homocysteine. Tests for common thromophilic gene mutations including prothrombin 20210, factor V Leiden 1691, and methylene tetrahydrofolate reductase 677 were negative. To our knowledge, this is the first CAPS patient with molecular studies for genetic prothrombotic mutations. Our report showed that there was no association between the development of CAPS and inherited thromophilia.
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PMID:Catastrophic antiphospholipid syndrome: a rare cause of disseminated microvascular thrombotic injury - a case report with pathological and molecular correlative studies. 1574 23

Recent studies suggest that postnatal neovascularization relies not exclusively on sprouting of preexisting vessels ("angiogenesis"), but also involves the contribution of bone marrow-derived circulating endothelial progenitor cells (EPCs). EPCs can be isolated from peripheral blood or bone marrow mononuclear cells, CD34(+) or CD133(+) hematopoietic progenitors. Infusion of EPCs was shown to promote postnatal neovascularization of ischemic tissue after myocardial infarction in animal models and initial clinical trials. Moreover, circulating endothelial precursor cells can home to denuded arteries after balloon injury and contribute to endothelial regeneration, thereby limiting the development of restenosis. Thus, circulating endothelial cells may exert an important function as endogenous repair mechanism to maintain the integrity of the endothelial monolayer and to promote ischemia-induced neovascularization. However, risk factors for coronary artery disease, such as diabetes, hypercholesterolemia, and hypertension are associated with impaired number and function of EPC in patients with coronary artery disease. Therapeutically, the reduction of EPC number and the decreased functional activity in patients with coronary artery disease was counteracted by 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors (statins), vascular endothelial growth factor (VEGF), estrogen, or exercise. At the molecular level, these factors are well established to activate the phosphatidyl-inositol-3-kinase (PI3K)-Akt-dependent activation of the endothelial nitric oxide synthase (eNOS), suggesting that the PI3K-Akt-eNOS signaling pathway may be involved in the transduction of atheroprotective factors. Taken together, the balance of atheroprotective and proatherosclerotic factors may influence EPC levels and their functional capacity to improve neovascularization and endothelial regeneration.
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PMID:Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors. 1584 10

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has long been thought to exert its benefits by reducing cholesterol synthesis, and has been shown to significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease. However, it is still unknown whether acute administration of simvastatin beneficially affects the cardiac function prior or during ischemia-reperfusion. The aim of this study is to evaluate the cardioprotective effect of acute simvastatin treatment on isolated rat hearts or isolated ischemia-reperfusion hearts. Hearts were isolated from male Sprague-Dawley rats and attached to a Langendorff apparatus. The isolated hearts with or without ischemia (15 min) and reperfusion (60 min) were perfused with different concentrations of simvastatin. The parameters of cardiac function (such as left ventricular developed pressure [LVDP], +dp/dt max, and -dp/dt max), heart rate, and coronary flow were recorded. Simvastatin (3-30 micromol/l) significantly increased LVDP, +dp/dt max, and -dp/dt max in isolated rat hearts perfused for 60 min. Heart rate was depressed by 30 micromol/l simvastatin and the coronary flow was increased by 10 and 30 micromol/l simvastatin. At a concentration of 100 micromol/l simvastatin, worsening of heart function and subsequent cardiac arrest occurred. Administration of simvastatin (3-30 micromol/l) significantly preserved cardiac function detected by LVDP, +dp/dt max, and -dp/dt max in the isolated ischemia/reperfused (15/60 min) rat hearts. Simvastatin also significantly decreased heart rate at 30 micromol/l, and increased coronary flow at 10 and 30 micromol/l in these rat hearts. However, the protective effect of simvastatin reverted to increased damage at 100 micromol/l. Only 3 micromol/l simvastatin pretreatment before 15/60 min ischemia-reperfusion altered LVDP, +dp/dt max, and -dp/dt max. Both heart rate and coronary flow were unaltered after simvastatin pretreatment. Since simvastatin at a concentration lower than 100 micromol/l exerted beneficial effects on cardiac function in isolated perfused rat hearts, it could be applied just after myocardial ischemia and reperfusion.
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PMID:Effects of simvastatin on cardiohemodynamic responses to ischemia-reperfusion in isolated rat hearts. 1655 Mar 13

1. We investigated the immunohistochemical alterations of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus 1 h to 14 days after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against the changes of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus after cerebral ischemia in the hippocampus after ischemia. 2. The transient cerebral ischemia was carried out by clamping the carotid arteries with aneurismal clips for 5 min. 3. In the present study, the alteration of HSP 70 and ubiquitin immunoreactivity in the hippocampal CA1 sector was more pronounced than that of BDNF and NGF immunoreactivity after transient cerebral ischemia. In double-labeled immunostainings, BDNF, NGF and ubiquitin immunostaining was observed both in GFAP-positive astrocytes and MRF-1-positive microglia in the hippocampal CA1 sector after ischemia. Furthermore, prophylactic treatment with pitavastatin prevented the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after ischemia. 4. These findings suggest that the expression of stress protein including HSP 70 and ubiquitin may play a key role in the protection against the hippocampal CA1 neuronal damage after transient cerebral ischemia in comparison with the expression of neurotrophic factor such as BDNF and NGF. The present findings also suggest that the glial BDNF, NGF and ubiquitin may play some role for helping surviving neurons after ischemia. Furthermore, our present study indicates that prophylactic treatment with pitavastatin can prevent the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after transient cerebral ischemia. Thus our study provides further valuable information for the pathogenesis after transient cerebral ischemia.
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PMID:Postischemic alterations of BDNF, NGF, HSP 70 and ubiquitin immunoreactivity in the gerbil hippocampus: pharmacological approach. 1681 May 63

The purpose of the present study was to assess the therapeutic effect of hypothermic retrograde jugular vein flush (HRJVF) on heatstroke. HRJVF was accomplished by infusion of 4 degrees C isotonic sodium chloride solution via the external jugular vein (1.7 mL/100 g of body weight over 5 min). Immediately after the onset of heatstroke, anesthetized rats were divided into 2 major groups and given the following: 36 degrees C or 4 degrees C isotonic sodium chloride solution, i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. When the 36 degrees C saline-treated rats underwent heat exposure, their survival time values were found to be 23 to 28 min. Immediately after the onset of heatstroke, resuscitation with an i.v. dose of 4 degrees C saline significantly improved survival during heatstroke (208-252 min). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor alpha, prothrombin time, activated partial thromboplastin time, and d-dimer, and decreased platelet count and protein C. Biochemical markers evidenced cellular ischemia and injury/dysfunction: plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase; and striatal levels of glycerol, glutamate, and lactate/pyruvate; dihydroxy benzoic acid, lipid peroxidation, oxidized-form glutathione reduced-form glutathione, dopamine, and serotonin were all elevated during heatstroke. Core and brain temperatures and intracranial pressure were also increased during heatstroke. In contrast, the values of mean arterial pressure, cerebral perfusion pressure, and striatal levels of local blood flow, partial pressure of oxygen, superoxide dismutase, catalase, glutathione peroxidase, and glutathions reductase activities were all significantly lower during heatstroke. The circulatory dysfunction, systemic inflammation, hypercoagulable state, and cerebral oxidative stress, ischemia, and damage during heatstroke were all significantly suppressed by HRJVF. These findings demonstrate that brain cooling caused by HRJVF therapy may resuscitate persons who had a stroke by attenuating cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke.
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PMID:Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke. 1687 31

Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion where at infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 +/- 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 +/- 2% (P<0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77 +/- 2%, P<0.01 vs. rosuvastatin) but not methanol (65 +/- 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 +/- 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium (P<0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury.
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PMID:Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation. 1732 12

Pleiotropic mechanisms beyond their cholesterol lowering effect of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins such as pravastatin are known. We used a temporary middle cerebral artery occlusion (tMCAO) model in 114 Wistar rats to assess i) whether repeated injections of various doses of pravastatin (0.1, 0.5, 1 and 2 mg/kg) at 30 min, 6 h, 1, 2, 3, and 4 days after stroke onset are neuroprotective, ii) whether attenuation of striatal glutamate and interleukin-6 (IL-6) release is part of the neuroprotective mechanism, and iii) how local cerebral blood flow (CBF) is influenced by pravastatin both in the acute and late stage of ischemia. Animals were sacrificed 5 days after MCAO, infarct size was analyzed with 2,3,5-triphenyltetrazolium chloride (TTC) staining. As compared to saline (139+/-14 mm3, n=11), higher doses of pravastatin beyond 0.1 mg/kg significantly reduced infarct size with the greatest effect obtained with 1 mg/kg (60+/-14 mm3, n=11, P=0.0004). Using cerebral microdialyis in this dose group, we demonstrated that striatal glutamate increase in the ischemic hemisphere was attenuated by pravastatin compared to placebo. Likewise, IL-6 release was diminished at 2 h, but not at 6 h after tMCAO. Improvement of local CBF by pravastatin was observed at day 5, but not at 5 h after tMCAO, thus representing a more long term effect of pravastatin. In conclusion, a relatively high dose of pravastatin administered repetitively after stroke onset improved neurological outcome through various cholesterol-independent mechanisms.
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PMID:Neuroprotection by pravastatin in acute ischemic stroke in rats. 1803 23


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