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)

We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
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PMID:X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants. 1805 85

The present paper serves as a review of the associations between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), with a focus on common and combined pathways for treatment. LUTS and ED are common conditions seen in general urologic practice. Research has started to establish epidemiologic and pathophysiologic links between the two conditions and a strong association confirmed across multiple studies. Men seeking care for one condition should always be interviewed for complaints of the other condition. Proposed common pathways include alpha-1 adrenergic receptor imbalance, Rho-kinase overactivity, endothelial cell dysfunction and atherosclerosis-induced ischemia. Medical therapy has replaced surgery as the first-line treatment for LUTS in most patients, with the incorporation of alpha-adrenergic receptor antagonists (alpha-ARAs) and 5-alpha-reductase inhibitors (5-ARIs) into everyday practice. Treatment with alpha-ARAs contributes to some improvement in ED, whereas use of 5-ARIs results in worsened sexual function in some patients. Phosphodiesterase-5 (PDE-5) inhibitors have revolutionized the treatment of ED with a simple oral regimen, and new insights demonstrate a benefit of combined use of PDE-5 inhibitors and alpha-ARAs. The mechanisms of action of these medications support these observed benefits, and they are being studied in the basic science and clinical settings. In addition, novel mechanisms for therapy have been proposed based on clinical and research observations. The minimally invasive and surgical treatments for LUTS are known to have adverse effects on ejaculatory function, while their effects on erectile function are still debated. Much remains to be investigated, but it is clear that the associations between LUTS and ED lay the foundation for future therapies and possible preventative strategies.
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PMID:Common approach to managing lower urinary tract symptoms and erectile dysfunction. 1808 43

The thioredoxin (TRX) system consists of TRX, TRX reductase, and NAD(P)H, and is able to reduce reactive oxygen species (ROS) through interactions with the redox-active center of TRX, which in turn can be reduced by TRX reductase in the presence of NAD(P)H. Among the TRX superfamily is peroxiredoxin (PRX), a family of non-heme peroxidases that catalyzes the reduction of hydroperoxides into water and alcohol. The TRX system is active in the vessel wall and functions either as an important endogenous antioxidant or interacts directly with signaling molecules to influence cell growth, apoptosis, and inflammation. Recent evidence implicates TRX in cardiovascular disease associated with oxidative stress, such as cardiac failure, arrhythmia, ischemia reperfusion injury, and hypertension. Thioredoxin activity is influenced by many mechanisms, including transcription, protein-protein interaction, and post-translational modification. Regulation of TRX in hypertensive models seems to be related to oxidative stress and is tissue- and cell-specific. Depending on the models of hypertension, TRX system could be upregulated or downregulated. The present review focuses on the role of TRX in vascular biology, describing its redox activities and biological properties in the media and endothelium of the vessel wall. In addition, the pathopysiological role of TRX in hypertension and other cardiovascular diseases is addressed.
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PMID:Thioredoxin in vascular biology: role in hypertension. 1831 95

Incomplete recovery of myocardial contraction after reperfusion following brief ischemia is called the "stunning phenomenon" in an animal experiment. A hydrophilic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) does not affect this phenomenon, but lipophilic statins further reduce the contraction during reperfusion. The effects of novel hydrophilic rosuvastatin and lipophilic pitavastatin on myocardial stunning in dogs were examined. In a preliminary experiment in vitro, pitavastatin reduced L6 cell viability at 10(-6) M and higher, whereas rosuvastatin and pravastatin up to 10(-5) M did not show such effects. An empty capsule or a capsule filled with rosuvastatin (2 mg/kg per day) or pitavastatin (0.4 mg/kg per day) was orally administered to dogs. After 3 weeks, both statins lowered the serum cholesterol level to the same extent. Under pentobarbital anesthesia, dogs were subjected to 15-min ischemia followed by 120-min reperfusion. Ischemia arrested the myocardial contraction in the ischemic area, and reperfusion recovered it but incompletely, showing the stunning phenomenon. Rosuvastatin did not modify the stunning phenomenon, while pitavastatin further deteriorated the myocardial contraction during reperfusion.
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PMID:Effects of rosuvastatin and pitavastatin on ischemia-induced myocardial stunning in dogs. 1840

3-Hydroxy-3-methyl-glutaryl CoA reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. The effectiveness of statins in reducing the risk of coronary events has been shown even in patients with diabetes, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. As a result, STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous endothelial nitric oxide (NO) synthase (eNOS) expression. Furthermore, the inhibition of NO synthesis by the administration of N(omega)-nitro-l-arginine methyl ester impaired the ability of statins to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. In conclusion, these findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.
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PMID:Statins restore ischemic limb blood flow in diabetic microangiopathy via eNOS/NO upregulation but not via PDGF-BB expression. 1844 Dec 6

NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission, and critical for normal CNS function. However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity. Mitochondrial dysfunction associated with loss of Ca(2+)homeostasis and enhanced cellular oxidative stress has long been recognized to play a major role in cell damage associated with excitotoxicity. In this experiment, we attempted to explore whether treatment with memantine (an NMDA receptor antagonist) and tea polyphenol (an antioxidant and anti-inflammatory agent), either alone or in combination, is effective in neuroprotection in a mouse excitotoxic injury model. Memantine (10 mg/kg/day), tea polyphenol (60 mg/kg/day), or a combination (memantine 5 mg/kg/day plus tea polyphenol 30 mg/kg/day) was administered by oral gavage for 2 consecutive days before causing excitotoxic injury. Mice received a 0.3-microL NMDA [335 mM (pH 7.2)] injection into the left striatum. Locomotor activity was assessed 24 hr before and after excitotoxic injury. Brain synaptosomes were harvested 24 hr after excitotoxic injury for assessment of Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, reactive oxygen species production, mitochondrial membrane potential (Delta Psi m), mitochondrial reductase activity (MTT test), and Ca(2+)concentration. The results showed that treatment with memantine could significantly rescue mitochondrial function by attenuating the decreased mitochondrial membrane potential (Delta Psi m) and mitochondrial reductase activity in mouse excitotoxic injury. Treatment with tea polyphenol could significantly decrease the increased production of synaptosomal reactive oxygen species (ROS) and thus reduced the deteriorative ROS-sensitive Na(+), K(+)-ATPase and Mg(2+)-ATPase activity. However, neither memantine nor tea polyphenol alone could significantly improve the impaired locomotor activity unless treatment was combined. Combined treatment with memantine and tea polyphenol could significantly protect mice against excitotoxic injury by reducing the increased synaptosomal ROS production, attenuating the decreased Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, the mitochondrial membrane potential (Delta Psi m), the mitochondrial reductase activity, and the increased synaptosomal Ca(2+)concentration. In addition, the impairment in locomotor activity was also significantly improved. Therefore, the combined treatment of memantine and tea polyphenol is more effective in neuroprotection than either memantine or tea polyphenol alone in mouse excitotoxic injury. These findings provide useful information about the potential application of memantine and tea polyphenols in preventing clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimer's disease.
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PMID:Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity. 1847 43

Severe ischemia to nerve results in fiber degeneration and reperfusion results in oxidative injury to endothelial cells and augments fiber degeneration. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, the most widely used lipid-lowering drugs, have been demonstrated to play a neuroprotective role. So we evaluated the effectiveness of simvastatin in protecting sciatic nerve from ischemia-reperfusion injury using the model of experimental nerve ischemia. Sixty adult male Sprague-Dawley rats weighing 250-300 g were used. They were divided into ten groups (N=6 per group). We used ischemia model in these groups by occluding the femoral artery and vein with a silk suture 6-0 using slipknot technique. All ischemia groups were rendered in ischemic for 3 h reperfused for various times of zero (0 h), 3 h (3 hour reperfusion), 7 days (7 day reperfusion), 14 days (14 day reperfusion). Half of the groups had experimental simvastatin (1 mg/kg) i.v. injection treatment via tail vein 1 h before ischemia. The other half experienced only ischemia-reperfusion as control groups. After euthanasia, histological samples were taken from distal part of the sciatic nerve. Sections were cut at 5 microm and then were stained with H and E and modified trichrome. We used H and E stain for edema and trichrome gomori for ischemic fiber degeneration. Samples were observed to assess their fiber degeneration and edema changes. By observation the level of fiber degeneration and endoneurial edema were also decreased in these recent groups (in both ischemia and reperfusion duration). In conclusion, pre-ischemic administration of simvastatin exhibits neuroprotective properties in ischemia-reperfusion nerve injury.
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PMID:The effects of simvastatin on ischemia-reperfusion injury of sciatic nerve in adult rats. 1858 25

Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are most frequently used drugs in the prevention of coronary artery disease due to their cholesterol-lowering activity. However, it is not exactly known whether these effects of statins or those independent of cholesterol decrease account for the protection against myocardial ischemia-reperfusion (I/R) injury. In this study, we investigated the effect of 5-day treatment with simvastatin (10 mg/kg) in Langendorff-perfused hearts of healthy control (C) and diabetic-hypercholesterolemic (D-H; streptozotocin + high fat-cholesterol diet, 5 days) rats subjected to 30-min global ischemia followed by 40-min reperfusion for the examination of postischemic contractile dysfunction and reperfusion-induced ventricular arrhythmias or to 30-min (left anterior descending) coronary artery occlusion and 2-h reperfusion for the infarct size determination (IS; tetrazolium staining). Postischemic recovery of left ventricular developed pressure (LVDP) in animals with D-H was improved by simvastatin therapy (62.7+/-18.2 % of preischemic values vs. 30.3+/-5.7 % in the untreated D-H; P<0.05), similar to the values in the simvastatin-treated C group, which were 2.5-fold higher than those in the untreated C group. No ventricular fibrillation occurred in the simvastatin-treated C and D-H animals during reperfusion. Likewise, simvastatin shortened the duration of ventricular tachycardia (10.2+/-8.1 s and 57.8+/-29.3 s in C and D-H vs. 143.6+/-28.6 s and 159.3+/-44.3 s in untreated C and D-H, respectively, both P<0.05). The decreased arrhythmogenesis in the simvastatin-treated groups correlated with the limitation of IS (in % of risk area) by 66 % and 62 % in C and D-H groups, respectively. However, simvastatin treatment decreased plasma cholesterol levels neither in the D-H animals nor in C. The results indicate that other effects of statins (independent of cholesterol lowering) are involved in the improvement of contractile recovery and attenuation of lethal I/R injury in both, healthy and diseased individuals.
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PMID:Simvastatin alleviates myocardial contractile dysfunction and lethal ischemic injury in rat heart independent of cholesterol-lowering effects. 1962 75

AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to 'cell stress', including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed.
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PMID:Effects of AMP-activated protein kinase in cerebral ischemia. 2001 Sep 58

Recently, the circulating anion nitrite (NO2-), the largest physiological reservoir of nitric oxide (NO) in the body, has revealed itself as a signalling molecule mediating numerous biological responses. Since it was estimated that as much as 70% of plasma nitrite originates from nitric oxide synthases (NOSs), mainly in the endothelium by endothelial NOS, nitrite is considered an index of NOSs activity. Exogenous sources, principally environmental pollutants and intake of vegetables, also contribute to this NO reserve. In mammalian blood, nitrite, present at nanomolar concentrations, can be reduced to bioactive NO along a physiological oxygen and pH gradient either non-enzymatically (acidic disproportionation) or by a number of enzymes including xanthine oxidoreductase, NOS, mitochondrial cytochromes and deoxygenated haemoglobin and myoglobin. The various NO-dependent nitrite-induced biological responses include hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion, and regulation of protein and gene expression. Since NO is a major paracrine-autocrine cardiovascular modulator and nitrite acts mainly as an endocrine store of NO, it is not surprising that NO2 - exerts important cardiovascular actions both under normal and physio-pathological conditions. In the interdisciplinary framework of the NO cycle concept, this review illustrates the actions exerted by nitrite on the cardiovascular system. Since the majority of the NO2 - -oriented studies focused on the systemic and regional control of blood flow both under physiological and ischemia/reperfusion conditions, we will firstly consider this issue. Secondly, the nitrite- induced effects on myocardial contractile and relaxation processes will be discussed, emphasizing the biomedical interest of nitrite as a new therapeutic agent. The importance of cardiac myoglobin as nitrite-reductase able to exert cardioprotection through a novel function, in addition to its role as classical respiratory protein, will be highlighted. Finally, using recent data from others and our labs, we will emphasize the importance of fish and amphibian heart models with diverse morphologies and blood supply for providing remarkable insights on "ancestral" functions of the nitrite-NO system in vertebrates, which, in turn, may help to expand its actual significance in human physiology.
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PMID:The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function. 2037 13


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