Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species generated by xanthine oxidase during reperfusion of ischemic liver might in part be responsible for ischemic organ injury. In normothermic ischemia/reperfusion rat model, we investigated whether allopurinol pretreatment improved ischemia-induced mitochondrial dysfunction. Rats were subjected to 60 min of hepatic ischemia and to 1 h and 5 h of reperfusion thereafter. At 18 h and 1 h before ischemia, the animals received 0.25 mL of either saline or allopurinol (50 mg/kg) i.p. In saline-treated ischemic rats, serum aspartate aminotransferase levels increased significantly at 5 h (4685 +/- 310 IU/L) and were significantly reduced with allopurinol pretreatment. Similarly, mitochondrial lipid peroxidation was elevated in the saline-treated ischemic group, but this elevation was prevented by allopurinol. In contrast, mitochondrial glutamate dehydrogenase activity and ketone body ratio decreased in the saline-treated group, but this decrease was also inhibited by allopurinol. Hepatic ATP levels in the saline-treated rats were 42% lower 5 h after reperfusion. However, treatment with allopurinol resulted in significantly higher ATP levels. Allopurinol treatment preserved the concentration of AMP in ischemic liver but inhibited the accumulation of xanthine in reperfused liver. Our findings suggest allopurinol protects against mitochondrial injury, which prevents a mitochondrial oxidant stress and lipid peroxidation and preserves the hepatic energy metabolism.
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PMID:Protective effect of allopurinol on hepatic energy metabolism in ischemic and reperfused rat liver. 1122 Jun 38

1) The oxygen consumption increases during Bufo bufo development in accordance with the two steps which border at the "heart beat" stage. 2) Cytochrome c oxidase activity is not proportional to the oxygen consumption: it is notable and constant in the first step, and it only increases in the second. 3) In the mitochondria of preneural embryos, citrate synthase, NADP+ dependent isocitrate dehydrogenase, and succinate dehydrogenase activities are very low in respect to malate dehydrogenase and glutamate oxaloacetate transaminase activities. The Krebs cycle results lowered at the condensing reaction level with acetyl accumulation when pyruvate is available. The same behavior has been observed in the Xenopus laevis oocytes and differentiated tissues. 4) The presence of a phosphagen system which is different from creatine phosphate and arginine phosphate, supporting ATP level, has been demonstrated in B. bufo embryos. 5) Mitochondria of postneural embryos are able to accomplish a complete Krebs cycle by increasing citrate synthase, and succinate dehydrogenase activities. 6) In all B. bufo development, malate dehydrogenase and glutamate oxaloacetate transaminase constitute a multienzymatic system by which the mitochondria accomplish a decarboxylic amino acid shunt required for the transformation of deutoplasm into protoplasm. This shunt is also operative in the X. laevis oocytes. 7) Through pyruvate production, by oxidative decarboxylation of malate, the NAD(P)+ dependent malic enzyme could carry out a fundamental anaplerotic function in the mitochondria which is specialized in the production of biosynthetic blocks belonging to the embryo in which the carbohydrates metabolism rather than the glycolytic activity is designed for pentose phosphate and glycerol phosphate synthesis for protein and cytomembrane production. 8) Consistent metabolic differences have been highlighted between B. bufo embryos and X. laevis embryos.
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PMID:Physiological differentiation of the mitochondria during Bufo bufo development. 1125 8

Acute hepatic failure was induced experimentally in rats by intraperitoneal injection of 2.5 mL kg(-1) carbon tetrachloride (CCl4), and the effects on the expression and function of P-glycoprotein in the liver, kidney and brain were evaluated. The CCl4 injection significantly increased the indicators of hepatic function (glutamate oxaloacetate transaminase, glutamate pyruvate transaminase), but not of renal function (blood urea nitrogen, glomerular filtration rate). In rats with acute hepatic failure, the hepatic P-glycoprotein concentration increased 1.5-fold and the ATP concentration decreased to approximately 40% that in control rats. In contrast, P-glycoprotein concentrations in the kidney and brain and ATP concentrations in the kidney remained unchanged. The in-vivo P-glycoprotein function in these tissues was suppressed as evaluated by biliary and renal secretory clearances and brain distribution of rhodamine 123, a P-glycoprotein substrate. These findings suggest that factors other than P-glycoprotein concentration are involved in the systemic suppression of P-glycoprotein function in diseased rats. In Caco-2 cells, plasma collected from CCl4-treated rats exhibited a greater inhibitory effect on P-glycoprotein-mediated transport of rhodamine 123 than that from control rats, suggesting the accumulation of an endogenous P-glycoprotein substrate/inhibitor in the plasma of diseased rats. In fact, the plasma concentration of corticosterone, an endogenous P-glycoprotein substrate, increased 2-fold in CCl4-treated rats compared with control rats. It was demonstrated that P-glycoprotein function is systemically suppressed in rats with CCl4-induced acute hepatic failure, not only in the target organ (liver), but also in other organs (kidney and brain), although the P-glycoprotein concentration remained unchanged in the kidney and brain, and increased in the liver. In the systemic suppression of the P-glycoprotein function in the diseased state, the alteration of plasma concentrations or components of endogenous P-glycoprotein-related compounds, such as corticosterone, would likely be involved.
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PMID:Expression and function of P-glycoprotein in rats with carbon tetrachloride-induced acute hepatic failure. 1142 64

We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg/kg/day by intramuscular injection) or solvent alone, and subjected to the ischemia--reperfusion process. Another group served as the sham-operated controls. Ischemia--reperfusion induced huge alterations of hepatocyte functions, namely, a decrease in ATP content and bile flow, and membrane leakage of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). These effects were associated with alterations in mitochondrial functions characterized by (1) a decrease in ATP synthesis, (2) a decrease in NAD(P)H levels and mitochondrial membrane potential, and (3) an increase in mitochondrial swelling reflecting the generation of permeability transition. Pretreatment of rats with S-15176 alleviated these deleterious ischemia--reperfusion effects at both the cellular and mitochondrial levels in a dose-dependent manner. The protection of mitochondrial functions was almost complete at a dosage of 10 mg/kg/day. In addition, in vitro, S-15176 totally abolished the swelling of isolated mitochondria induced by a calcium overload with an IC(50) value of 10 microM. These data demonstrate that S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion and suggest that this protective effect could be related to the inhibition of the mitochondrial permeability transition.
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PMID:Attenuation of liver normothermic ischemia--reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative. 1144 61

Pyruvate has been shown to benefit cellular energy metabolism and to reduce free radical formation. Concerning gastrointestinal side effects of orally administered sodium pyruvate, in this pilot study we investigated the therapeutic effectiveness of sodium pyruvate infusions in patients with alcoholic liver disease (ALD). Fifteen patients with ALD received sodium pyruvate infusions for: (1) 10 days (54-86.4 g pyruvate daily, 150-180 mg/min., 6-8 h); and (2) 15 days (50-54 g daily, 100 mg/min., 6 h). Sodium pyruvate treatment resulted in significantly decreased serum AST (p<0.03), ALT (p<0.03), AP (p<0.004), GGT (p<0.05), and total bilirubin (p<0.04). Improvement of liver function was also evident from the significantly decreased Combined Clinical and Laboratory Index (from 6.50+/-0.71, to 3.92+/-0.84, p<0.001), and Liver Damage Score (from 3.83+/-0.71 to 2.75+/-0.58, p<0.01). The two therapy schedules used showed similar results. Unchanged serum pyruvate, lactate, and glucose confirmed the good utilization of pyruvate. Tolerance of sodium pyruvate treatment was very good in 26.09% and good in 68.94% of the observations. Our results showed good therapeutic effectiveness and good tolerance of sodium pyruvate infusions in patients with ALD. This is possibly due to the rapid gain of ATP and GTP, required to redress defective cells, and to antioxidant action of pyruvate.
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PMID:Sodium pyruvate infusions in patients with alcoholic liver disease. Preliminary report. 1168 47

Ecteinascidin-743 (ET-743) is a novel marine-derived anticancer drug with clinical activity in soft tissue sarcoma and ovarian cancer. Reversible transaminitis and subclinical cholangitis have frequently been described in patients who receive ET-743. To facilitate understanding of this adverse effect and help design suitable therapeutic rescue strategies, we characterized the hepatic effects of ET-743 in rats. Female rats received ET-743 (single dose, 40 microg/kg) i.v., and liver changes were assessed from 6 h up to 3 months after dosing by histopathology, immunohistochemistry, electron microscopy, hepatic and plasma biochemistry, and DNA microarray analysis. At 24 h posttreatment and beyond, livers displayed degeneration and patchy focal necrosis of bile duct epithelial cells associated with mild inflammation followed by fibrosis. Sporadic and focal zones of hepatic necrosis and hemorrhage were observed from day 2 onward, although the majority of hepatocytes appeared normal as judged by electron microscopy. Pathological alterations persisted up to 3 months after dosing. Plasma levels of total bilirubin were elevated up to 7-fold over those in untreated rats from day 2 onward and returned to control values by day 24. Activities of alkaline phosphatase and aspartate aminotransferase in plasma were elevated for 2 and 3 months, respectively. Activities of the hepatic microsomal drug-metabolizing enzymes cytochrome P-450 A1/2, CYP2E1, and CYP3A2 were decreased. DNA microarray analysis of livers from ET-743-treated animals showed a dramatic increase in the expression of ATP binding cassette transport genes Abcb1a and Abcb1b, which impart resistance to anticancer drugs, and of Cdc2a and Ccnd1, the rodent homologues of human cell cycle genes CDC2 and cyclin D1, respectively. The cell cycle gene expression changes mirrored ET-743-induced increases in liver weight and Ki-67 labeling of liver nuclei. The results suggest that the toxicity exerted by ET-743 in the rat liver is a consequence of biliary rather than hepatocellular damage and that it is accompanied by a wave of mitogenic activity, which may be driven by the transcriptional increase in Cdc2a expression.
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PMID:Hepatobiliary damage and changes in hepatic gene expression caused by the antitumor drug ecteinascidin-743 (ET-743) in the female rat. 1215 27

The hepatotoxicity of the novel cyclic dipeptide cyclo(Trp-Pro), which has shown potential usage in various pharmacological fields, had not been assessed. Further studies on the isomers of this cyclic dipeptide (cyclo(L-Trp-L-Pro), cyclo-(L-Trp-D-Pro), cyclo(D-Trp-L-Pro) and cyclo(D-Trp-D-Pro)) revealed further biological activities. The assessment of hepatotoxicity of these isomers was thus warranted. In vitro screens were performed on primary isolated rat hepatocytes, the Chang liver and N-2-alpha cell lines. In vivo screening involved the assessment of serum levels of lactate dehydrogenase, aspartate transaminase, ATP, Ca2+ and albumin after intraperitoneal injection over a 1 and 5 day period in the rat model. Liver samples were also obtained for the assessment of lipid peroxidation. It was found that only cyclo(D-Trp-L-Pro) was hepato-specific in its action, while the other isomers were not. The greatest effect on any biochemical or physiological parameter was noted after 5 days. LDH secretion was greatly increased in the presence of cyclo(L-Trp-L-Pro) and cyclo-(L-Trp-D-Pro) (p < 0.05). Significantly increased levels of lipid peroxidation were observed in all the isomer-treated samples (p < 0.05), while Ca2+ concentrations were decreased at day 5. Decreased protein synthesis was noted in the presence of all the isomers at day 1. These results indicate the potential harm involved in the administration of the isomers, which may limit their potential usage in the treatment of various diseases.
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PMID:Hepatotoxicity of the isomers of cyclo(Trp-Pro). 1236 54

Isolated mongrel hearts were preserved for 6 h at 5 degrees C followed by normothermic reperfusion for 2 h. The dogs were divided into three groups; K+-cardioplegic solution alone, group C, n = 7; K+-cardioplegic solution with lidocaine 200 mg/l, group L, n = 7; and K+-cardioplegic solution with betamethasone 250 mg/l and lidocaine 200 mg/l, group B + L, n = 7. Ventricular fibrillation occurred early during reperfusion in all dogs in group C, in one of seven in group L, and in two of seven dogs in group B + L. The serum MB fraction of creatinine kinase (MB-CK), mitochondrial aspartate aminotransferase (m-AAT) and calcium overload were suppressed to a greater extent in both groups L and B + L during reperfusion compared to group C. Myocardial ATP, total adenine nucleotide, and creatine phosphate did not differ between the three groups at the end of reperfusion. Myocardial ADP and AMP declined significantly during reperfusion in group C, however, they remained unchanged in group B + L and increased in group L which showed significantly higher levels compared to group C. Left ventricular functional recovery during reperfusion was consistently better in both group L and B + L compared to group C. These results suggested that membrane stabilization prevents myocardial damage from hypothermia and cardioplegia and provides better myocardial viability and functional recovery in donor heart preservation.
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PMID:The significant role of membrane stabilization in hypothermic cardioplegic cardiac preservation in a canine experimental model. 1462 34

The most common parameters used to evaluate sperm quality are motility rate and duration and fertilization ability. In this study, chemical and biochemical parameters of sea bass (Dicentrarchus labrax) sperm were investigated to find an alternative method for evaluating sperm fertilization ability before and after cryopreservation. The biochemical and chemical analyses were performed with fresh and frozen-thawed sperm and seminal plasma. To cryopreserve sperm, 250-microl straws were used. Fertilization ability was evaluated by inseminating eggs (obtained from hormonally stimulated females) with fresh and cryopreserved sperm. The results revealed a linear relationship (P < 0.05) between semen fertilization capacity and some seminal plasma (beta-D-glucuronidase activity, potassium concentration) and sperm (ATP concentration, aspartate aminotransferase activity) parameters. Variations in semen fertilization rate could be best described by two multiple regression models: one including the sperm parameters and another including the seminal plasma parameters. For practical application, the use of simple regression models is of value. Fertilization rate in both fresh and cryopreserved sperm was reliably predicted by determining the ATP concentration or the beta-D-glucuronidase activity or both.
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PMID:Adenosine triphosphate concentration and beta-D-glucuronidase activity as indicators of sea bass semen quality. 1496 Apr 78

Hepatotoxic effect of (+)usnic acid, the active constituent of Usnea siamensis Wainio was studied in rats, isolated rat hepatocytes and isolated rat liver mitochondria. In rats, after treatment with high dose of (+)usnic acid (200 mg/kg per day, i.p.) for 5 days, there was no significant change in serum transaminase activity (serum AST, ALT) while the electron micrographs showed apparent morphological damage of mitochondria and endoplasmic reticulum. (+)Usnic acid at high dose (1 mM) as well as carbon tetrachloride (CCl4, the reference hepatotoxin) induced loss of cell membrane integrity in isolated rat hepatocytes by increasing the release of cellular transaminases (AST, ALT). Increase in lipid peroxidation, decrease in glutathione (GSH) content and increase in aniline hydroxylase activity (CYP 2E1) were also found. Combination of (+)usnic acid and CCl4 showed the additive results. (+)Usnic acid (0.15-6 microM) possessed uncoupling activity in isolated rat liver mitochondria. It stimulated respiration by mitochondria respiring with glutamate plus malate or succinate as substrates and activated ATPase activity. Increasing concentration of (+)usnic acid (>6 microM) exhibited loss of respiratory control and ATP synthesis. In conclusion, hepatotoxic effect of high dose (+)usnic acid may involve its reactive metabolite(s), causing loss of integrity of membrane like structures, resulting in destruction of mitochondrial respiration and oxidative phosphorylation.
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PMID:Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. 1501 5


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