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)

Sorbitol dehydrogenase (SDH) is a polyol pathway enzyme that catalyzes conversion of sorbitol to fructose. Recent studies have demonstrated that activation of aldose reductase, the first enzyme of the polyol pathway, is a key response to ischemia and that inhibition of aldose reductase reduces myocardial ischemic injury. In our efforts to understand the role of pathway in affecting metabolism under normoxic and ischemic conditions, as well as in ischemic injury in myocardium, we investigated the importance of SDH by use of a specific inhibitor (SDI), CP-470,711. SDH inhibition increased glucose oxidation, whereas palmitate oxidation remained unaffected. Global ischemia increased myocardial SDH activity by approximately 1.5 fold. The tissue lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, was reduced by SDH inhibition under both normoxic and ischemic conditions. ATP was higher in SDI hearts during ischemia and reperfusion. Creatine kinase release during reperfusion, a marker of myocardial ischemic injury, was markedly attenuated in SDH-inhibited hearts. These data indicate that myocardial SDH activation is a component of ischemic response and that interventions that inhibit SDH protect ischemic myocardium. Furthermore, these data identify SDH as a novel target for adjunctive cardioprotective interventions.
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PMID:Sorbitol dehydrogenase: a novel target for adjunctive protection of ischemic myocardium. 1452 43

This study evaluated the effects of retinal ischemia-reperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-glucamine) or fidarestat, 32 mg kg(-1) d(-1) for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the IR group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the non-ischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death, elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of fidarestat and other AR inhibitors.
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PMID:Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina. 2051 33

Sorbitol dehydrogenase (SDH), a key enzyme of the polyol pathway, has recently been demonstrated to have an important role in mediating tissue ischemia/reperfusion (I/R) injury. The present study investigated how this enzyme may affect the ischemic liver and the mechanism underlying its effect. Firstly, C57BL/6 mice were subjected to oral administration of CP-470,711 (5 mg/kg body weight/day for five days) and 70% hepatic I/R. Next the present study further investigated the changes in liver function, histology, inflammation, apoptosis and necrosis; the cytosolic adenosine triphosphate (ATP) and nictotinamide adenine dinucleotide [NAD(H)] contents and the protein level of caspase 3 and sirtuin 1 (SIRT1). The data demonstrated that sorbitol dehydrogenase inhibitor (SDI)-administration significantly alleviated I/R-induced liver injury, palliated histological changes and lowered the level of hepatocyte apoptosis and necrosis. In addition, SDI-pretreatment in ischemic liver markedly maintained the cytosolic ATP and NAD(H) proportion, enhanced SIRT1 and suppressed the activation of caspase 3 at the protein level. The findings in the present study revealed that the flux through SDH may render the liver more vulnerable to I/R-induced injury and interventions targeting this enzyme may provide a novel adjunctive approach to protect from severe tissue injury following liver ischemia.
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PMID:Sorbitol dehydrogenase inhibitor protects the liver from ischemia/reperfusion-induced injury via elevated glycolytic flux and enhanced sirtuin 1 activity. 2533 77