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)

Activated protein C (APC) is useful in the treatment of sepsis. Ischemia and acidosis, which often accompany sepsis, cause the release of copper from loosely bound sites. We investigated (i) whether physiological concentrations of copper inhibit APC anticoagulant activity and (ii) if any copper-induced APC inhibition is reversible by human serum albumin (HSA) or a high-affinity copper-binding analogue of the human albumin N-terminus, d-Asp-d-Ala-d-His-d-Lys (d-DAHK). APC activity after 30 min of incubation with CuCl2 (10 microM) was decreased 26% below baseline. HSA, both alone and when combined with various ratios of CuCl2, increased APC activity significantly above baseline. d-DAHK alone and 2:1 and 4:1 ratios of d-DAHK:CuCl2 also increased APC activity. APC contained 1.4 microM copper, which helps explain the increased APC activity with HSA and d-DAHK alone. These in vitro results indicate that copper inhibits APC activity and that albumin and d-DAHK reverse the copper-induced APC deactivation.
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PMID:Copper inhibits activated protein C: protective effect of human albumin and an analogue of its high-affinity copper-binding site, d-DAHK. 1182 Jul 75

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, TPL), a low molecular weight stable nitroxyl radical (nitroxide), has been demonstrated in many in vitro and in vivo models to have protective effects against oxidative stress. The beneficial effect of TPL, however, is limited because of its short life-time in tissues. We have previously shown that polynitroxylated macromolecules such as polynitroxyl-human serum albumin (PNA) enable maintaining a sustained concentration of TPL for longer periods in tissues. PNA itself has previously been shown to inhibit ischemia-reperfusion (I/R) injury in the gut and to potentiate the activity of TPL. The aim of the present study was (i) to select an optimum formulation of PNA + TPL for therapeutic applications using in vivo EPR spectroscopy and (ii) to evaluate the efficacy of the PNA + TPL formulation in preventing I/R injury to heart, in an in vivo rat model. Rats were subjected to 45 min occlusion of the left anterior descending (LAD) coronary artery followed by 120 min reperfusion. PNA (100 mg/ml) + TPL (10 mg/ml), human serum albumin (HSA, 100 mg/ml) + TPL (10 mg/ml), or saline were injected 5 min before ischemia (3 ml/kg BW, i.v.) and 5 min before reperfusion (3 ml/kg BW, i.v.), followed by a 4 ml/kg BW infusion over 2 h reperfusion. Myocardial risk and infarct regions were then estimated. The results showed that the infarct volume, expressed as a percentage of the risk region, in the group treated with PNA + TPL was 39.7 +/- 3.1%, which was significantly smaller than for the saline (51.3 +/- 3.5%) or HSA + TPL (48.4 +/- 1.4%) groups. The results demonstrate that the PNA + TPL combination is very effective in reducing myocardial ischemia-reperfusion injury.
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PMID:Polynitroxyl-albumin (PNA) enhances myocardial infarction therapeutic effect of tempol in rat hearts subjected to regional ischemia-reperfusion. 1193 97

This study determined whether insulin at pre- (fasting) and post-prandial concentrations increases coronary blood flow and improves cardiac function after acute ischemia during a situation of myocardial stunning. The experiments were performed using an isolated, erythrocyte perfused, working rat heart model. To the perfusate we added erythrocytes and 1.5% bovine serum albumin to improve clinical relevance. The following protocol was used: 8 min baseline performance assessment, 10 min pre-ischemic treatment, 12 min global ischemia, 20 min post-ischemic treatment and 8 min recovery assessment. Vehicle, 10 mIU l(-1) and 100 mIU l(-1) human insulin were tested (all n=6). No significant vasodilator response to insulin was observed either pre- or post-ischemically. After the 12-min ischemic insult, cardiac function returned dose-dependently to pre-ischemic values (function loss with 100 mIU l(-1) insulin: -0.2+/-0.4% vs. vehicle: 10.7+/-0.8%). This study clearly shows that in our clinically relevant model of moderate ischemia (stunning), insulin is highly cardioprotective at physiological concentrations. This may be explained primarily by higher glucose uptake, improving the myocardial energetic state during ischemia. Therefore, insulin should be considered for use when the myocardium is at acute risk for ischemic incidents.
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PMID:Physiological insulin concentrations protect against ischemia-induced loss of cardiac function in rats. 1206 5

Multiple organ dysfunction syndrome (MODS) is mediated by complex mechanisms in which interactions between activated leukocytes and endothelial cells play a central role. ICAM-1 (intercellular adhesion molecule-1) mediates firm adhesion and transendothelial migration of activated leukocytes from postcapillary venules into the tissue. The present study evaluated the ICAM-1 expression in various organs after 40 min of intestinal ischemia and 1, 3, 6, 12 h of reperfusion (I/R) in the rat, using a dual monoclonal antibody technique (n = 36). Endothelial barrier permeability, using the vascular leakage of radiolabeled human serum albumin was also assessed (n = 12). Neutrophil sequestration in the lungs was quantitated by myeloperoxidase activity and plasma protease inhibitor levels were measured with electroimmunoassay. Significant regional differences were found in ICAM-1 expression between organs, both constitutively and after I/R-injury. The highest constitutive levels were observed in the liver and lungs, followed by the kidneys. The constitutive ICAM-1 expression in the intestines and in the heart was about 1/20 compared with that found in the liver and lungs. The brain and muscle had levels of about 1/150 of that in the liver and lungs. After intestinal I/R, significant increases (17-45%) were found in the lungs, intestines, brain, heart, and muscle. Albumin leakage index (ALI) in all examined organs and myeloperoxidase activity in the lungs increased after I/R-injury. Serum levels of albumin and most protease inhibitors decreased significantly after I/R challenge. Intestinal I/R results in an increase of systemic ICAM-1 expression with marked organ variability. The upregulation of ICAM-1 could represent a crucial step in the adherence- and migration process of activated leukocytes and potentially in the development of tissue injury.
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PMID:The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression, endothelial barrier function, neutrophil tissue influx, and protease inhibitor levels in rats. 1209 41

MgATP substantially inhibited 1-alkyl-sn-glycero-3-phosphate (AGP) acetyltransferase found in neuronal nuclei. Other nucleotides and the ATP analogue AMP-PNP did not show a comparable inhibition. MgATP inhibition decreased in the presence of bovine serum albumin or the fatty acyl CoA synthetase inhibitor, Triacsin C. MgATP inhibition increased when nuclei were preincubated in 50 mM Tris-HCl (pH 7.4)/1 mM MgCl(2) at 37 degrees C, and preincubations elevated levels of nuclear free fatty acid. Exogenous free fatty acid, added to the acetylation incubations, increased the inhibition seen in the presence of MgATP. Oleoyl CoA, in the absence of MgATP, also inhibited AGP acetylation. These results suggested that MgATP supported the conversion of nuclear free fatty acids to fatty acyl CoA. Fatty acyl CoA may directly inhibit nuclear AGP acetyltransferase, but inhibition brought about by MgATP was competitive for the AGP substrate, suggesting an inhibitor close in structure to AGP. 1-Hexadecyl-2-arachidonoyl-sn-glycero-3-phosphate was identified as a competitive inhibitor for AGP in the acetylation reaction. Neuronal nuclei can convert AGP to 1-alkyl-2-acyl-sn-glycero-3-phosphate (AAcylGP), a reaction dependent upon MgATP and the presence of acetyl CoA or free CoA. This nuclear acylation was increased by free fatty acid addition and was seen using oleoyl CoA in the absence of MgATP. Nuclear AAcylGP formation was inhibited by bovine serum albumin and by Triacsin C. Thus, nuclear AGP acetyltransferase may be regulated by AGP acyltransferase activity and the availability of MgATP, a nucleotide that is rapidly lost during brain ischemia.
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PMID:MgATP may depress de novo neuronal nuclear PAF generation by promoting the formation of alkylacylglycerophosphate, an inhibitor of alkylglycerophosphate acetyltransferase. 1245 14

This study demonstrates that intraperitoneal injections of DHA (all cis 4,7,10,13,16,19 docosahexaenoic acid C22: n-3) bound to bovine serum albumin ameliorate murine acute renal failure (ARF) induced by temporary occlusion of the renal artery. Three micromoles of DHA decreased serum creatinine (Scr) from 2.3 mg/dl to 1.1 mg/dl 24 h after reperfusion (n = 15; P < 0.05). Scr of the treated animals were significantly lower than controls throughout a 7-d time course. Although lower doses of DHA were less effective, higher doses were not more effective. Ribonuclease (RNase) protection assays showed that ischemia increased mRNA abundance for TNF-alpha and inducible nitric oxide synthase (iNOS) at 24 h. This increase was prevented by DHA administration. Because TNF-alpha and iNOS contribute to renal ischemic injury, their inhibition may contribute to DHA's salutary effect. In addition, the data may have therapeutic implications, because the DHA improves ARF even when administered at 4 h after reperfusion.
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PMID:Docosahexaenoic acid ameliorates murine ischemic acute renal failure and prevents increases in mRNA abundance for both TNF-alpha and inducible nitric oxide synthase. 1253 39

An altered metabolism of endothelial cell-derived nitric oxide has been implicated in the microvascular dysfunction associated with ischemia/reperfusion. The objective of this study was to examine whether S-nitroso human serum albumin, a novel nitric oxide-donor, improves flap viability and whether it influences edema formation after prolonged ischemia when administered prior to and in the initial phase of reperfusion. Denervated epigastric island skin flaps were elevated in 30 male Sprague Dawley rats, rendered ischemic for 8 hours, subsequently reperfused and further observed for either 3 hours (acute) or 7 days (chronic). In the sham rats (n = 6), skin flaps were elevated only. Starting 1 hour prior to reperfusion, S-nitroso human serum albumin (n = 12) or human serum albumin (n = 12) as placebo was infused systemically for 2 hours. In the chronic model, flap necrosis as well as viable flap size was evaluated after 7 days of reperfusion in six rats per group, comparing to sham rats. In the acute model, edema formation was evaluated after 3 hours of reperfusion in six rats per group. Administration of S-nitroso human serum albumin significantly decreased flap necrosis from 18.1 +/- 15.6% in the human serum albumin group to 2.1 +/- 1.5% in the S-nitroso human serum albumin group, which was similar to the sham group (2.5 +/- 4.2%). Viable flap size (sham 13.4 +/- 1.6 cm2) was also significantly improved in the S-nitroso human serum albumin group (10.1 +/- 1 cm2) versus the human serum albumin group (7.0 +/- 2.2 cm2). There was no significant difference between the groups regarding postischemic edema formation. These results show that administration of S-nitroso human serum albumin prior to and in the initial phase of reperfusion significantly improves flap viability after 7 days but does not influence early observable edema formation. These findings support the role of nitric oxide as an important mediator in the protection against skin flap ischemia/reperfusion injury.
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PMID:Protective effect of a novel NO-donor on ischemia/reperfusion injury in a rat epigastric flap model. 1258 21

A time-resolved imaging method for visualizing L-glutamate release in mammalian brain slices is proposed by using an enzyme membrane combined with a difference-image analysis. The enzyme membrane is composed of L-glutamate oxidase and horseradish peroxidase incorporated into a bovine serum albumin matrix. L-Glutamate triggers an enzyme-coupling reaction to convert a redox substrate (DA-64) to Bindschedler's Green, which gives a green color signal. The difference-image analysis is based on calculating slopes of a signal versus time (t) plot in the time range from (t - 40 s) to (t + 40 s) for visualizing L-glutamate release in terms of its flux (in mol min(-1) cm(-2)). The method was applied to a time-resolved imaging of hippocampal distribution of ischemia-induced L-glutamate release in mouse brain slices. The image of L-glutamate distribution showed that the level and time courses of L-glutamate fluxes were neuronal region-dependent. The maximum flux of L-glutamate at CA1 was observed at 7.7 min after ischemia. The flux at 7.7 min increased in the order of CA1 approximately CA3 > DG. The time course of the L-glutamate flux in the CA1 region was biphasic and that in the DG region was modestly biphasic. In the CA3 region, such biphasic release of L-glutamate was not seen. The ischemia-induced L-glutamate flux was accelerated when Mg2+ was omitted from an extracellular solution. The present enzyme membrane-based approach provides a useful method for visualizing distribution of L-glutamate release in the brain slices during ischemia.
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PMID:Imaging of L-glutamate fluxes in mouse brain slices based on an enzyme-based membrane combined with a difference-image analysis. 1457 43

Adenosine triphosphate (ATP)-MgCl(2) attenuates ischemia-reperfusion (I-R)-induced lung injury in rats. A previous study indirectly suggests that Mg(2+)-dependent ecto-ATPases on the surface of leukocytes are responsible for the hydrolysis of ATP-MgCl(2) to adenosine, which then contributes to the protective effect of ATP-MgCl(2). This study investigated the role of leukocytes in I-R injury and the protective effect of ATP-MgCl(2) in our buffer-perfused isolated rat lung model. After isolating the lung blood flow of adult male Sprague-Dawley rats, the lungs were perfused through the pulmonary artery cannula with a physiologic salt solution containing human serum albumin. The protective effect of ATP-MgCl(2) pretreatment with or without leukocytes was investigated. Capillary permeability (K(fc)), lung weight gain (LWG), lung wet weight/body weight ratio (LW/BW), lung lavage protein concentration (LPC) and pulmonary artery pressure (PAP) were measured. I-R produced a significant increase in K(fc), LWG, LW/BW, LPC, and PAP. The increases in these indices were significantly attenuated by pretreatment with ATP-MgCl(2) (1 x 10(-6)M) together with leukocytes (2.9 x 10(6)/ml in the perfusate) but not with ATP-MgCl(2) alone. Our data suggest that I-R-induced acute lung injury is not dependent on circulating leukocytes. Pretreatment with ATP-MgCl(2) plus leukocytes but not ATP-MgCl(2) alone had protective effects against I-R lung injury. Whether these findings occur in vivo could not be determined in this study. In our isolated lung red blood cell-free perfusate system, the protective effect of ATP-MgCl(2) requires the presence of leukocytes.
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PMID:The protective effect of adenosine triphosphate-MgCl2 on ischemia-reperfusion lung injury is leukocyte dependent. 1463 Nov 11

Our aim was to determine whether cytokine mRNA expression is induced by experimental manipulation including artificial perfusate or ischemia-reperfusion (I/R) in an isolated, perfused rat lung model. Constant pulmonary flow [Krebs-Henseleit solution supplemented with low-endotoxin (LE) or standard (ST) bovine serum albumin 4%, 0.04 ml/g body wt] and ventilation were maintained throughout. Right and left pulmonary arteries were isolated, and the left pulmonary artery was occluded for 60 min and then reperfused for 30 min. Analysis of tumor necrosis factor-alpha, IL-1 beta, IL-6, IL-10, and IFN-gamma mRNA expression by RT-PCR and evaluation of vascular permeability by bronchoalveolar lavage (BAL) fluid albumin content were conducted separately in right and left lung. Both LE and ST groups (each 12 rats) showed increases in vascular permeability by I/R (BAL fluid albumin content: 5.53 +/- 1.55 vs. 15.63 +/- 8.87 and 4.76 +/- 2.71 vs. 16.72 +/- 4.85 mg.ml BAL fluid-1.g lung dry wt-1, mean +/- SD; right vs. left lung in LE and ST groups, P < 0.05 between right and left). Cytokine mRNA expression was significantly higher in the I/R lung than in the control lung in the LE group, whereas it was higher in the control lung in the ST group (P < 0.05). mRNAs of not only proinflammatory but also anti-inflammatory cytokines were expressed in I/R lung, which are expected to aggravate I/R injury. The reversed pattern of cytokine mRNA expression in the ST group was possibly due to the longer perfusion of control lung with perfusate containing endotoxin, which caused no lung damage without I/R.
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PMID:Cytokine mRNA expression in unilateral ischemic-reperfused rat lung with salt solution supplemented with low-endotoxin or standard bovine serum albumin. 1465 1


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