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)

The hepatoprotective effects of misoprostol, a PGE1 analog, against ischemia-reperfusion liver injury were studied using a rat partial liver ischemia model. Serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels were determined as biochemical indices of injury. Hepatic cell necrosis was assessed histologically using tetranitroblue tetrazolium (TNBT) and hematoxylin and eosin (H&E) staining. With placebo treatment, 90 min of partial hepatic ischemia followed by 24 hr of reperfusion resulted in increased levels of serum OCT (760 +/- 521 IU/liter) and ALT (4327 +/- 1982 IU/liter), while extensive hepatic necrosis was evident by TNBT and H&E staining. Treatment with two doses of 25 micrograms misoprostol/kg body weight at 1 min before ischemia and 1 min before reperfusion significantly reduced the serum levels of OCT and ALT (207 +/- 189 IU/liter, P less than 0.01 and 2075 +/- 1217 IU/liter, P less than 0.01, respectively) and hepatic necrosis. When a single dose of misoprostol was administered 1 min before reperfusion, similar protective effects were observed. However, when the treatment of misoprostol was delayed to 1 min after reperfusion, significantly less hepatoprotection was seen. Misoprostol exerted no hepatoprotection at all when it was administered at 5 min or later after reperfusion. These results demonstrate that misoprostol partially protects the liver against ischemia-reperfusion injury in the rat. The observation that the protective effect of misoprostol occurs only within the first minute of reperfusion suggests that its mechanism of action involves an early event in reperfusion injury, such as modifying the effects of reactive oxygen metabolites.
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PMID:Misoprostol hepatoprotection against ischemia-reperfusion-induced liver injury in the rat. 149 53

The thiol redox status of intracellular and extracellular compartments is critical in the determination of protein structure, regulation of enzyme activity, and control of transcription factor activity and binding. Thiol antioxidants act through a variety of mechanisms, including (1) as components of the general thiol/disulfide redox buffer, (2) as metal chelators, (3) as radical quenchers, (4) as substrates for specific redox reactions (GSH), and (5) as specific reductants of individual protein disulfate bonds (thioredoxin). The composition and redox status of the available thiols in a given compartment is highly variable and must play a part in determining the metabolic activity of each compartment. It is generally beneficial to increase the availability of specific antioxidants under conditions of oxidant stress. Cells have devised a number of mechanisms to promote increased intracellular levels of thiols such as GSH and thioredoxin in response to a wide variety of stresses. Exogenous thiols have been used successfully to increase cell and tissue thiol levels in cell cultures, in animal models, and in humans. Increased levels of GSH and other thiols have been associated with increased tolerance to oxidant stresses in all of these systems and in some cases, with disease prevention or treatment in humans. A wide variety of thiol-related compounds have been used for these purposes. These include thiols such as GSH and its derivatives, cysteine and NAC, dithiols such as lipoic acid, which is reduced to the thiol form intracellularly, and "prothiol" compounds such as OTC, which are enzymatically converted to free thiols within the cell. In choosing a thiol for a specific function (e.g., protection of lung from oxidant exposure or protection of organs from ischemia reperfusion injury), the global effects must also be considered. For example, large increases in free thiols in the circulation are associated with toxic effects. These effects may be the result of thiyl radical-mediated reactions but could also be due to destabilizing effects of increases in thiol/disulfide ratios in the plasma, which normally is in a more oxidized state than intracellular compartments. Changes in the thiol redox gradient across cells could also adversely affect any transport or cell signaling processes, which are dependent on formation and rupture of disulfide linkages in membrane proteins. Therapeutic thiol administration has been shown to have great potential, and its efficacy should be increased by selecting compounds and methods of delivery that will minimize perturbations in the thiol status of regions external to the targeted areas.
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PMID:Thiol-based antioxidants. 1084 51

Because end-organ injury can occur with reperfusion following hemorrhage or ischemia, we hypothesized that aggressive intravenous fluid resuscitation would aggravate tissue injury in a fixed-volume model of hemorrhagic shock. Unanesthetized chronically prepared male rats were hemorrhaged 33-36 mL/kg for 2.5 h. Then Lactated Ringers Solution (3x hemorrhage volume) was infused over 5 min (FAST), 20 min (MEDIUM), 180 min (SLOW), or not at all (NO RESUS). Plasma ornithine carbamoyltransferase (OCT), lactate, and creatinine were measured as indices of hepatocellular injury, anaerobic metabolism, and renal function, respectively. At 1 h post-resuscitation (PR), MAP was greater after SLOW and MEDIUM treatment (tx) than after other txs (P < 0.05). OCT increased earliest after FAST tx to values greater than those after other txs from 30 min to 24 h PR (P < 0.01). Plasma lactate was elevated immediately before resuscitation in all groups (P < 0.01) and returned to baseline at 3 h PR after SLOW tx compared to 5 h PR after FAST tx (P < 0.05). Creatinine at 5 h PR was less in the groups treated with intravenous fluid compared to the NO RESUS group, P < 0.05. Survival at 72 h was reduced in the FAST (57%) and NO RESUS (58%) groups compared to the SLOW (87%) and MEDIUM (85%) groups (P < 0.05). Thus, overly aggressive fluid tx accelerates hepatocellular injury, is no better than lesser rates of resuscitation at correcting plasma lactate and preserving renal function, and provides no overall survival benefit.
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PMID:Detrimental effects of rapid fluid resuscitation on hepatocellular function and survival after hemorrhagic shock. 1235 25

Oxygen-regulated protein 150 (ORP150) is an inducible endoplasmic reticulum (ER) chaperone molecule that is upregulated after numerous cellular insults and has a cytoprotective role in renal, neural, and cardiac models of ischemia-reperfusion injury. ORP150 also has been shown to play a role in cellular Ca(2+) homeostasis, and in turn, regulating calpain activity. In this study, we identified ORP150 in whole rat renal cortical mitochondria and matrix fractions, demonstrated the targeting of an ORP150-GFP construct to the mitochondria of NIH-3T3 cells, and showed that the NH(2)-terminal 13 amino acids of ORP150 are sufficient for this translocation. ORP150 expression was found to be regulated by the anti-C/enhancer-binding protein homologous protein (CHOP)/GADD153 transcription factor and ORP150 levels increased in the mitochondria and ER of COS-7 cells after diverse stresses, including hypoxia, serum starvation, prolyl hydroxylase inhibition with dimethyloxaloylglycine, and exposure to tunicamycin, ethidium, bromide, and 2-deoxyglucose. Induction of the mitochondrial specific stress response in COS-7 cells through expression of an ornithine transcarbamylase mutant (Delta OTC) increased mitochondrial ORP150 levels and mitochondrial calpain activity. To determine whether mitochondrial ORP150 and mitochondrial calpain 10 interact, rat cortical mitochondria exposed to Ca(2+) resulted in ORP150 cleavage in a calpain inhibitor-dependent manner, revealing that ORP150 is a substrate and may be regulated by calpain 10. These data reveal a novel cellular localization for ORP150 and that mitochondrial ORP150 is upregulated by CHOP/GADD153 in response to mitochondrial and ER stress. Our data also reveal that ORP150 is a substrate for mitochondrial calpain 10.
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PMID:Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress. 1809 45