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)

We investigated if the loss of nicotinamide coenzymes in ischemic-infarcted myocardium may be responsible for the transition from reversibly ischemic to irreversibly infarcted cell damage. The LAD was occluded in 6 dogs for 4 h. Transmural needle biopsies were taken from he ischemic-infarcted region after 1/2, 1, 11/2, 2, and 4 h of ischemia and further divided into subepicardial and subendocardial halves. At each time interval the concentration of the nicotinamide coenzymes NAD, NADH, and NADPH were measured, and the degree of cellular injury was evaluated by electron microscopy. The glycohydrolase activity (EC 3.2.2.5), the enzyme which splits NAD, was determined in brain, myocardium, kidney, and skeletal muscle of 4 rats. Total NAD, the sum of NAD and NADH, started to decrease significantly in the ischemic subendocardium 1 h after onset of ischemia. Degradation of NADPH occurred later. Loss ot total NAD was about 60-70% when electron microscopy diagnosed irreversible cell injury. The glycohydrolase activity was the highest in brain followed by myocardium, kidney, and skeletal muscle, reflecting the different tolerances of these tissues towards ischemia. The key mechanism for ischemic injury seems to be the tissue acidosis which activates the glycohydrolase leading to a loss of the vital coenzymes.
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PMID:Loss of canine myocardial nicotinamide adenine dinucleotides determines the transition from reversible to irreversible ischemic damage of myocardial cells. 627 93

Inhibition of complex I has been considered to be an important contributor to mitochondrial dysfunction in tissues subjected to ischemia-reperfusion. We have investigated the role of complex I in a severe energetic deficit that develops in kidney proximal tubules subjected to hypoxia-reoxygenation and is strongly ameliorated by supplementation with specific citric acid cycle metabolites, including succinate and the combination of -ketoglutarate plus malate. NADH: ubiquinone reductase activity in the tubules was decreased by only 26% during 60-min hypoxia and did not change further during 60-min reoxygenation. During titration of complex I activity with rotenone, progressive reduction of NAD+ to NADH was detected at >20% complex I inhibition, but substantial decreases in ATP levels and mitochondrial membrane potential did not occur until >70% inhibition. NAD+ was reduced to NADH during hypoxia, but the NADH formed was fully reoxidized during reoxygenation, consistent with the conclusion that complex I function was not limiting for recovery. Extensive degradation of cytosolic and mitochondrial NAD(H) pools occurred during either hypoxia or severe electron transport inhibition by rotenone, with patterns of metabolite accumulation consistent with catabolism by both NAD+ glycohydrolase and pyrophosphatase. This degradation was strongly blocked by alpha-ketoglutarate plus malate. The data demonstrate surprisingly little sensitivity of these cells to inhibition of complex I and high levels of resistance to development of complex I dysfunction during hypoxia-reoxygenation and indicate that events upstream of complex I are important for the energetic deficit. The work provides new insight into fundamental aspects of mitochondrial pathophysiology in proximal tubules during acute renal failure.
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PMID:Preservation of complex I function during hypoxia-reoxygenation-induced mitochondrial injury in proximal tubules. 1466 31

NAD+, a co-enzyme involved in a great deal of biochemical reactions, has been found to be a network node of diverse biological processes. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Correspondingly, aberrant NAD+ metabolism is observed in many diseases. In this review, we discuss how the homeostasis of NAD+ is maintained in healthy condition and provide several age-related pathological examples related with NAD+ unbalance. The sirtuins family, whose functions are NAD-dependent, is also reviewed. Administration of NMN surprisingly demonstrated amelioration of the pathological conditions in some age-related disease mouse models. Further clinical trials have been launched to investigate the safety and benefits of NMN. The NAD+ production and consumption pathways including NMN are essential for more precise understanding and therapy of age-related pathological processes such as diabetes, ischemia-reperfusion injury, heart failure, Alzheimer's disease, and retinal degeneration.
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PMID:Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism. 3241