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)

To investigate the sites of nitric oxide synthase (NOS) expression after brain injury, NADPH-d histochemistry was performed on the hypothalamo-neurohypophysial system (HNS) of adult rats several days after both ischemia and trauma. Electron-microscopic examination revealed the sites of formazan end-product of the diaphorase reaction in some neurons, astrocytes, cells and vascular pericytes, and in all activated microglial/macrophagal cells in perivascular and juxtaneuronal regions of hypothalamus. In neurohypophysis, positive NADPH-d staining was present in cytosol of many pituicytes, endothelial cells, pericytes and corresponding axonal endings. NADPH-d activity was also present in perivascular macrophages or microglial cells of neurohypophysis. Finally, we suppose that NOS expression and the consequent productions of nitric oxide could be involved in pathophysiology of HNS injury by ischemia and trauma, where activations inducible isoform of NOS especially, may contribute to a variety of neurogenerative processes. The imbalance in regulation of nitric oxide could disturb the physiological function of this neuroendocrine system.
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PMID:Expression of NADPH-diaphorase (NOS) in rat hypothalamo-neurohypophysial system after ischemic and traumatic brain injury. 1145 99

The aims of the present study were to establish if myocardial ischemia/reperfusion is associated with altered eNOS activity and if myocardial eNOS detection depends on its activity. We determined detectable eNOS in (1) myocardium of isolated perfused rat hearts subjected to either global or regional ischemia and (2) in left ventricular biopsies from patients undergoing two different methods of myocardial protection (i.e., intermittent cold blood cardioplegia and continuous coronary perfusion with warm, beta-blocker-enriched blood) during coronary artery surgery. NOS detection was performed by NADPH-d staining and three eNOS-antibodies against different eNOS epitopes. In addition, activity dependent alteration of detectable eNOS was proofed by bradykinin treatment for 2 to 10 min. Ischemic and receptor mediated eNOS activation increased NADPH-d reactivity and eNOS immunoreaction as measured by antibodies against either amino acids of a central bovine eNOS domain or the human eNOS N-terminal end. In contrast, the antibody against the human eNOS C-terminal end exhibited no alteration of eNOS immunoreaction. The transient eNOS activation was associated with increased cGMP content. In human myocardium subjected to ischemia during cardiac surgery we found that early reperfusion increases eNOS activity. These data demonstrate a strong association between myocardial ischemia/reperfusion and increased eNOS activity as measured by immunocytochemical staining against specific eNOS epitopes. It appears that eNOS activation and subsequent NO release may act as a regulatory system to counter balance the potentially deleterious effects of myocardial ischemia/reperfusion.
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PMID:Ischemia increases detectable endothelial nitric oxide synthase in rat and human myocardium. 1148 70

Arterial ketone index (AKBR) which is the ratio of acetoacetic acid to 3-hydroxybutyric acid in the arterial blood, is believed to reflect the mitochondrial reduction potential of hepatocytes and general energy state of the liver. In the presented paper we challenged this hypothesis by analysing the correlation between AKBR and the results of typical liver blood tests (AspAT, AlAT, LDH, CRP) and biotransforming potential of the liver (cytochromes P450, b5 and their corresponding NADPH and NADH reductases) in the model of ischemia-reperfusion injury of rat liver. The results were compared with histochemical analysis of distribution and activity of SDH, LDH and G-6-Pase, the key marker enzymes of the liver. We have shown that, except in the case of acute phase protein (CRP), a decrease in AKBR correlated well with the increase of the level of indicator enzymes in serum. Histochemical analysis also confirmed that AKBR correlates with the degree of damage to hepatocytes during early stage of reperfusion after 60 min of liver ischemia. In the Spearman test, AKBR was significantly correlated with the changes in cytochrome P450 content and its NADPH reductase activity which indicates a high sensitivity of this test. We conclude that the decrease of AKBR value reflects the impairment of basic energy pathways and detoxicative capability of the liver.
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PMID:Arterial ketone index in assessing liver function and its detoxicative capability after ischemia-reperfusion injury. 1199 3

The intensity of free radical processes and the regulation of NADP-isocitrate dehydrogenase (EC 1.1.1.42; NADP-IDH) activity have been studied in the cytoplasmic fraction of normal and ischemized rat myocardium. Chemiluminescence parameters, such as the light sum (S) of slow flash and the tangent of the kinetic curve slope angle (tanalpha1), which characterize the intensity of free radical processes, were increased in ischemia 2.1- and 20.0-fold, respectively. The slow flash intensity (Imax) was increased 22-fold. The contents of lipid peroxidation products--diene conjugates and malonic dialdehyde--were increased 11.9- and 4.7-fold, respectively, suggesting pronounced oxidative stress. Using homogenous enzyme preparations of NADP-IDH isolated from the normal and experimentally ischemized rat myocardium, a number of catalytic properties of the enzyme were characterized for normal and pathologic conditions. NADP-IDH from the normal and ischemized myocardium had the same electrophoretic mobility and was regulated similarly by Fe2+, Cu2+, Zn2+, and also with succinate and fumarate. However, under normal and pathologic conditions NADP-IDH was different in the affinity for substrates and in the sensitivity to inhibitory effects of hydrogen peroxide, reduced glutathione, and of Ca2+. The degree of synergy in the enzyme inhibition with Fe2+ and H2O2 was less pronounced in ischemia. The inhibitory effect of the reaction product 2-oxoglutarate was higher under normal conditions than in ischemia (the Ki values were 0.22 and 0.75 mM, respectively). The specific features of the NADP-IDH regulation in ischemia are suggested to promote the stimulation of the enzyme functioning during increased level of free radical processes, and this seems to be important for NADPH supplying for the glutathione reductase/glutathione peroxidase antioxidant system of cardiomyocytes.
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PMID:Intensity of free radical processes and regulation of cytoplasmic NADP-isocitrate dehydrogenase in rat cardiomyocytes under normal and ischemic conditions. 1212 79

Oxidative stress is implicated in the pathogenesis of neurodegenerative disorders and brain ischemia, and hydrogen peroxide (H(2)O(2)) plays a central role in the stress. In this study, we have examined the kinetics of H(2)O(2) elimination by PC12 cells as a neuronal model in connection with the enzyme activities supporting the reaction. Similarly to other cell lines previously studied, H(2)O(2) removal kinetics could be divided into two reactions: one apparently following the Michaelis-Menten kinetics (GSH-dependent reaction) and the other following the first-order kinetics (mainly catalyzed by catalase). Based on the enzyme activities in the cell homogenate, it was inferred that glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the GSH- and NADPH-dependent H(2)O(2) elimination by PC12 cells. This is in contrast with fibroblasts and endothelial cells previously examined, in which glutathione reductase (GR) is rate-limiting in the reaction sequence. Treatment of PC12 cells with nerve growth factor increased G6PD activity in the cell homogenate and H(2)O(2) removal activity of the whole cells, with a concomitant increase in the resistance against H(2)O(2) toxicity. These results suggest the importance of G6PD in the antioxidant function of brain and pathogenesis of the oxidative stress-related diseases.
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PMID:Kinetic studies on the hydrogen peroxide elimination by cultured PC12 cells: rate limitation by glucose-6-phosphate dehydrogenase. 1220 36

KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran is a new neuroprotective agent for ischemia-reperfusion damage. The in vitro and in vivo metabolism of KR-31543 in rats has been studied by LC-electrospray mass spectrometry. Rat liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of a metabolite M1. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC-MS/MS analysis with the synthesized authentic standard. Rat CYP3A1 and 3A2 are the major CYP isozymes involved in the formation of M1.
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PMID:Metabolism of a new neuroprotective agent for ischemia-reperfusion damage, KR-31543 in the rat using liquid chromatography/electrospray mass spectrometry. 1243 2

The CXCR3 chemokine receptor, a member of the CXCR family, has been linked to a pathological role in autoimmune disease, inflammatory disease, allograft rejection, and ischemia. In the kidney, expression of the CXCR3 receptor and its ligands is up-regulated in states of glomerulonephritis and in allograft rejection, but little is known about the expression and functional role the CXCR3 receptor might play. Here, we study the function of the CXCR3 chemokine receptor in an immortalized human proximal tubular cell line (IHKE-1). Stimulation of the CXCR3 receptor by its selective agonist monokine induced by IFN-gamma leads via a Ca(2+)-dependent mechanism to an up-regulation of early growth response gene (EGR)-1. Overexpression of EGR-1 induces down-regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase and stimulates the generation of reactive oxygen species (ROS) via the NADH/NADPH-oxidase system. EGR-1 overexpression or treatment with monokine induced by IFN-gamma resulted in a ROS-dependent inhibition of basolateral Na(+)/K(+)-ATPase activity, compromising sodium transport in these cells. Thus, activation of the CXCR3 receptor in proximal tubular cells might disturb natriuresis during inflammatory and ischemic kidney disease via EGR-1-mediated imbalance of ROS.
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PMID:Up-regulation of early growth response gene-1 via the CXCR3 receptor induces reactive oxygen species and inhibits Na+/K+-ATPase activity in an immortalized human proximal tubule cell line. 1251 59

Histochemical analysis of NADPH-diaphorase (NADPH-d) activity was performed on segments of the lumbar spinal cord in rabbit after 7 days pretreatment with the Ginkgo biloba extract Tanakan, and 30 min of ischemia followed by 24 h of reperfusion. In sections of the L5 segment of the spinal cord of untreated controls, NADPH-d-positive neurons were identified in the dorsal horns, in the pericentral region and occasionally in the ventral horns. The rabbits were completely paraplegic after 30 min of ischemia and 24 h of reperfusion. High NADPH-d activity was found in the wall of blood vessels in sections of the L5 segment and the numbers of NADPH-d-positive neurons in all sites was moderately elevated. After 7 days of Tanakan pretreatment, 30 min of ischemia and 24 h of reperfusion, the animals did not show paraplegia. Only a light tremor of the hind limbs was observed. NADPH-d activity in blood vessels and neurons was similar to that in controls. In the dorsal horns, NADPH-d positivity in neurons and fibres was increased. Our results indicate that Tanakan can scavenge free radicals produced during ischemia/reperfusion and may reduce reperfusion damage.
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PMID:NADPH-diaphorase activity in the spinal cord after ischemic injury and the effects of pretreatment with Ginkgo biloba extract (EGb 761). 1255 15

The aim of this study was to quantify the expression of E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vascular endothelial cells (HUVECs) exposed to anoxia/reoxygenation (A/R) in the presence or absence of an inflammatory context (0.1 IU/ml tumor necrosis factor-alpha [TNF-alpha]) and to investigate the effects of two different NADPH inhibitors, apocynin and diphenyleneiodonium (DPI), on the expression of the endothelial cell adhesion molecules. Confluent HUVECs were exposed to anoxia for 3 hours (100% N2), followed by a reoxygenation period of 4 hours. TNF-alpha at 0.1 IU/ml was added to the medium either under normoxic conditions for 7 hours (TNF-alpha) or just before the start of anoxia (A/R + TNF-alpha). Levels of E-selectin, VCAM-1, and ICAM-1 were quantified using specific monoclonal antibodies revealed by an alkaline phosphatase-labeled goat F(ab)'2 fragment against mouse IgG antibody and the fluorescent substrate Attophos. Adhesion experiments were also performed using calcein-labeled U937 leukocytes. HUVECs submitted to A/R overexpressed E-selectin but not VCAM-1 or ICAM-1, whereas TNF-alpha at 0.1 IU/ ml increased the expression of all three adhesion molecules. In endothelial cells subjected to A/R in the presence of TNF-alpha, a synergistic increase of E-selectin expression and a synergistic adhesion of U937 cells was noted. The NADPH oxidase inhibitors apocynin and DPI both decreased significantly the U937 adhesion and the E-selectin overexpression on HUVECs submitted to A/R, TNF-alpha, or A/R + TNF-alpha. These results suggest that E-selectin expression is implicated in the leukocyte adhesion to HUVECs caused by A/R in the presence or absence of an inflammatory context. NADPH oxidase appears to participate in the E-selectin overexpression on HUVECs subjected either to A/R and/or TNF-alpha, suggesting a major role of this enzyme in the ischemia/reperfusion syndrome.
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PMID:Effect of NADPH oxidase inhibition on E-selectin expression induced by concomitant anoxia/reoxygenation and TNF-alpha. 1257 57

Mitochondrial Ca(2+) accumulation can induce a sudden increase in the permeability of the inner membrane. This phenomenon is due to the generation of a large nonselective ion channel, termed the permeability transition pore (PTP), which contributes to cellular injury during ischemia and reperfusion. Inhibition of PTP generation constitutes a relevant pharmacological target to protect a cell from death. In this study, we examined the effect of S-15176 ((N-[(3,5-di-tertiobutyl-4-hydroxy-1-thiophenyl)]-3-propyl-N'-(2,3,4-trimethoxybenzyl)piperazine), a novel anti-ischemic agent, on PTP in rat liver mitochondria. S-15176 prevented PTP opening generated by various triggering agents, as attested by the concentration-dependent inhibition of mitochondrial swelling, of mitochondrial membrane potential dissipation and of NADPH oxidation. These effects were associated with an increase in the Ca(2+) loading capacity of mitochondria. S-15176 was a strong inhibitor of lipid peroxidation, but experiments with another trimetazidine derivative devoid of antioxidant activity indicated that this activity was not essential to the inhibitory effect. Binding studies demonstrated that [3H]S-15176 bound to mitochondrial binding sites, especially those localized in the inner membrane. These sites were shared by several well-known inhibitors of PTP opening. These results demonstrate that the mechanism by which S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion involves inhibition of PTP opening and provide evidence that the drug operates through low structural specificity binding sites located in the inner mitochondrial membrane.
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PMID:S-15176 inhibits mitochondrial permeability transition via a mechanism independent of its antioxidant properties. 1274 16


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