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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen free radicals have been shown to be implicated in ischemic tissue injury, and free radical-induced reactions may also play an important role in the pathophysiology of circulatory shock. The present study was designed to investigate the potential use of ascorbic acid as an exogenous antioxidant on the liver's recovery from hemorrhagic shock in situ. Rats (fasted overnight) were subjected to 60 min of hemorrhagic shock (HS) (mean arterial pressure = 40 mmHg) under pentobarbital anesthesia, followed by retransfusion of the shed blood. One-half of the animals (n = 6) were injected with 10 mg/kg of ascorbic acid prior to induction of shock, while untreated animals (n = 6) received the same volume of saline solution. in untreated animals, systemic plasma levels of malondialdehyde rose from 1.07 +/- .08 during normotension (NT) to 1.36 +/- .18* 60 min after resuscitation (RS), documenting oxygen free radical-induced lipid peroxidation. Accordingly, plasma levels of alanine aminotransferase (16.5 +/- 2.5; 34.9 +/- 12.3*; 105.8 +/- 68.7* U/L; NT/HS/RS) and ammonia (127 +/- 40; 532 +/- 160*; 304 +/- 244* micrograms/dL) rose significantly during the experiment. Hepatic ATP content of the liver fell from 4.8 +/- .83 to .56 +/- .27* after HS and recovered partially to 2.7 +/- 1.6* mumol/g after RS. Leukocyte infiltration in the liver, indicated by tissue levels of myeloperoxidase, remained constant during HS but rose during RS (37.9 +/- 18.5; 38.6 +/- 16.4; 81.4 +/- 30.7*, arbitrary units), thus documenting an inflammatory reaction after HS. In the ascorbic acid group, plasma levels of malondialdehyde were comparable to those of untreated animals after RS, as were enzyme concentrations and ammonia. No differences were observed with regard to the tissue concentrations of ATP or myeloperoxidase. Mean arterial blood pressure as well as liver tissue perfusion, as measured by Laser Doppler flowmetry, did not show significant differences between the groups. It was concluded that, although an effect of oxygen free radicals on liver tissue could be found during and after HS, treatment with ascorbic acid alone, in our model, failed to ameliorate the recovery of the animals upon resuscitation (values are mean +/- SD; *, p < .05 vs. NT; one-way ANOVA).
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PMID:No evidence for a protective effect of ascorbic acid on free radical generation and liver injury after hemorrhagic shock in rats. 872 88

1. We have investigated the effects of (i) several guanidines on the activity of the inducible isoform of nitric oxide (NO) synthase (iNOS) in murine cultured macrophages and rat aortic vascular smooth muscle cells (RASM); and (ii) 1-amino-2-hydroxy-guanidine, the most potent inhibitor of iNOS activity discovered, on haemodynamics, multiple organ (liver, renal, and pancreas) dysfunction and iNOS activity in rats with endotoxic shock. 2. The synthesized guanidine analogues caused concentration-dependent inhibitions of the increase in nitrite formation caused by lipopolysaccaride (LPS, 1 microgram ml-1) in J774.2 macrophages and RASM cells with the following rank order of potency: 1-amino-2-hydroxy-guanidine > 1-amino-2-methyl-guanidine > 1-amino-1-methyl-guanidine > 1-amino-1,2-dimethyl-guanidine. Interestingly, 1-amino-2-hydroxy-guanidine (IC50: J774.2, 68 microM; RASM, 114 microM) was more potent in inhibiting nitrite formation caused by LPS than NG-methyl-L-arginine, but less potent than aminoethyl-isothiourea. 3. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 115 +/- 4 mmHg (time 0) to 98 +/- 5 mmHg at 2 h (P < 0.05, n = 10) and 69 +/- 5 mmHg at 6 h (P < 0.05, n = 10). The pressor effect of noradrenaline (NA, 1 mg kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine (10 mg kg-1, i.v. plus 10 mg kg-1 h-1 starting at 2 h after LPS) prevented the delayed hypotension and vascular hyporeactivity seen in LPS-rats. However, 1-amino-2-hydroxy-guanidine had no effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 4. Endotoxaemia for 6 h caused a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT) and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine significantly attenuated the liver dysfunction caused by LPS (P < 0.05, n = 10). Injection of LPS also caused a rapid (almost maximal at 2 h) increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by 1-amino-2-hydroxy-guanidine (P > 0.05; n = 10). Endotoxaemia also caused a dysfunction of pancreas (rise in serum levels of lipase) as well as a metabolic acidosis (falls in PCO2, HCO3 and base excess). Both pancreatic dysfunction and metabolic acidosis were largely attenuated by treatment of LPS-rats with 1-amino-2-hydroxy-guanidine. In rats infused with saline rather than LPS, 1-amino-2-hydroxy-guanidine had no effect on liver, renal or pancreatic function (n = 4). 5. Endotoxaemia for 6 h resulted in a rise in the serum levels of nitrite (11.0 +/- 0.8 microM, P < 0.01, n = 10), which was significantly reduced by 1-amino-2-hydroxy-guanidine (6.5 +/- 0.7 microM, P < 0.05, n = 10). Endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with 1-amino-2-hydroxy-guanidine. In addition, endotoxaemia for 6 h resulted in a significant increase in myeloperoxidase activity (MPO), an indicator of neutrophil infiltration, in the liver. Treatment of LPS-rats with 1-amino-2-hydroxy-guanidine did not affect the rise in MPO-activity in the liver caused by endotoxin. 6. Thus, 1-amino-2-hydroxy-guanidine is a potent inhibitor of iNOS activity in macrophages or RASM in culture as well as in rats with endotoxic shock. Inhibition of iNOS activity with 1-amino-2-hydroxy-guanidine prevents the delayed circulatory failure and attenuates the dysfunction of liver, and pancreas, as well as the metabolic acidosis caused by endotoxaemia.
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PMID:Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. 873 25

Tissue injury is a common occurrence in multiple organ failure, a possible clinical complication of Gram-negative bacterial sepsis. Gram-negative bacteria, in part through lipopolysaccharide (LPS), tumor necrosis factor, and other cytokines, activate neutrophils to increase oxygen consumption and produce reactive oxygen species (ROS). ROS have been suggested to play a critical role in the pathogenesis of multiple organ failure. Accordingly, we hypothesized that the susceptibility of tissues to ROS can be reduced by augmenting the antioxidant status of the affected tissues. Rats were challenged intravenously with LPS (Escherichia coli: 0111:B4) at a dose of 1 mg/kg body weight, and 0, 2, 4, or 6 h later were treated intravenously with plain liposomes or alpha-tocopherol liposomes (20 mg alpha-tocopherol/kg body weight); treated rats were then killed 24 h after LPS challenge. Animals challenged with LPS were extensively damaged in the liver, as evidenced by an increase in plasma alanine aminotransferase and aspartate aminotransferase activities, and also in the lung, as indicated by a decrease in pulmonary angiotensin-converting enzyme and alkaline phosphatase activities. The injection of LPS also resulted in increased myeloperoxidase activities in the two organs, suggestive of activation of the inflammatory response. Within the pulmonary and hepatic organs of LPS-challenged animals, the involvement of oxidative stress mechanisms was evident, because a significant decrease in reduced glutathione and an increase in lipid peroxidation were observed. In contrast, the administration of alpha-tocopherol liposomes in the post-LPS-challenge period resulted in a significant alleviation of both lung and liver injuries, evidenced by a general reversal of the altered biochemical indices toward normal among treated animals. The therapeutic effect was found to be greater when liposomal alpha-tocopherol treatment was given earlier during the development of injury. Plain liposomes administered immediately after LPS injection also protected hepatic and pulmonary tissues from injuries. However, unlike alpha-tocopherol liposomes, plain liposomes did not confer any beneficial effect when administered at later timepoints post-LPS injection. These data suggest that alpha-tocopherol, administered in a liposomal form, may serve as a potentially effective pharmacological agent in the treatment of LPS-induced tissue injuries.
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PMID:Treatment of LPS-induced tissue injury: role of liposomal antioxidants. 882 99

Reactive oxygen species such as nitric oxide (NO) and/or superoxide have been proposed as mediators in the pathogenesis of reperfusion injury and acute endotoxemia. The purpose of this study was to examine the role of NO in a model of hepatic ischemia-reperfusion with endotoxemia (I/R + LPS). Rats subjected to 30 min of partial hepatic ischemia followed by reperfusion and LPS (Salmonella enteritidis, 1 mg/kg, i.v.,) administration, exhibited a marked, time-dependent increase in plasma alanine aminotransferase (ALT) levels compared to sham controls. An abrupt increase in liver nitrite/nitrate levels was also observed in I/R + LPS rats in association with the increases in plasma ALT. Although liver NO production in I/R + LPS rats increased with time, exacerbation of liver damage was not evident. Administration of L-NAME decreased NO production in plasma and liver but did not affect the liver damage in rats subjected to I/R + LPS. Superoxide levels in livers from I/R + LPS rats increased by threefold after 90 min reperfusion as compared to sham controls but dropped to control levels after 4 hr. There was a significant increase in neutrophils in liver lobes subjected to ischemia-reperfusion and LPS compared to sham controls and to non-ischemic lobes which received LPS. The number of neutrophils in the liver increased further in rats given L-NAME. These results suggest that the progressive injury seen in livers of I/R + LPS rats was possibly due to NO interaction with superoxide forming another reactive oxygen species such as peroxynitrite. However, inhibition of NO synthesis did not ameliorate liver damage, possibly because of an increase in tissue accumulation of activated polymorphonuclear leukocytes (PMN). Lung NO production increased in I/R + LPS rats after 4 hr reperfusion compared to sham controls. Prior administration of L-NAME did not prevent a significant rise in pulmonary NO generation (P < 0.05 at 90 min and 4 hr, compared to sham controls). This unexpected rise of pulmonary NO in the L-NAME treated group of rats was associated with a tendency for increased PMN accumulation (based on myeloperoxidase data) and superoxide generation. The results suggest that endogenous NO protected against excessive neutrophil infiltration in the lung in this model of hepatic ischemia-reperfusion and endotoxemia, and the use of L-NAME, a nonselective NOS inhibitor, may aggravate lung injury.
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PMID:Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia. 884 95

Tumor necrosis factor-alpha (TNF) is known to be released after partial hepatectomy. Furthermore, TNF triggers the release of chemotactic cytokines, such as epithelial neutrophil activating protein (ENA-78), which are important for neutrophil chemotaxis, activation, and propagation of the inflammatory response. We now postulate that ENA-78 may play a role the hepatic inflammatory response that occurs following partial hepatectomy. Rats were subjected to 70% hepatectomy or sham laparotomy and were killed in a time-dependent manner. Hepatic neutrophil influx, as assessed by myeloperoxidase (MPO) levels, serum alanine aminotransferase (ALT), and hepatic TNF and ENA-78 levels, as measured by ELISA, were evaluated at 1, 6, and 12 h following operation. MPO levels became significantly elevated within 6 h of hepatectomy and remained elevated at 12 h. Serum ALT became significantly elevated within 1 h of hepatectomy and continued to rise at 12 h. Hepatic TNF and ENA-78 were also increased significantly after hepatectomy. Next, rats undergoing 70% hepatectomy were treated with neutralizing anti-ENA-78 serum; this resulted in a significant decrease in hepatic MPO and serum ALT, suggesting less hepatic injury. To determine whether ENA-78 release was induced by TNF is this model, rats were treated with neutralizing anti-TNF serum and hepatic ENA-78 levels measured 6 h posthepatectomy. ENA-78 levels were significantly decreased in the animals receiving the anti-TNF serum, suggesting that ENA-78 is released in response to TNF in this model. These data suggest that TNF triggers the release of ENA-78 following 70% hepatectomy and that ENA-78 contributes to the hepatic neutrophil influx and liver injury following 70% hepatectomy.
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PMID:Hepatic inflammation following 70% hepatectomy may be related to up-regulation of epithelial neutrophil activating protein-78. 896 89

The present study was designed to examine the in vivo effect of ebselen on reperfusion injury to the liver. Lipid peroxidation and glutathione (GSH) levels of the reperfused liver tissue, as well as hepatocellular damage (serum GOT, GPT, LDH, and histology) were examined. The production of thiobarbituric acid-reactive substance did not increase in the 60-min-reperfused liver tissue in the ebselen group. Ebselen completely suppressed the increase in lipid hydroperoxide production in the reperfused liver tissue. After the tissue GSH level was reduced by buthionine sulphoximine, ebselen failed to suppress the lipid peroxidation of the reperfused liver tissue. Serum levels of GOT, GPT, and LDH, histological analysis, and the tissue level of GSH clearly showed that ebselen protects the reperfused liver tissue, both structurally and functionally. We conclude that ebselen's primary effect on ischemia-reperfusion injury may be due to a GSH-peroxidase-like effect and/or the inhibitory effect of leukocyte infiltration.
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PMID:Ebselen, a novel anti-oxidant compound, protects the rat liver from ischemia-reperfusion injury. 908 92

When activated, inflammatory cells such as polymorphonuclear leukocytes (PMNs) can damage isolated hepatocytes in vitro. These studies were performed to determine if flutamide activates PMNs. Flutamide (Eulexin) is an orally active, nonsteroidal antiandrogen that can cause liver injury associated with inflammation. Activation of PMNs was assessed from the production of superoxide anion and the release of myeloperoxidase in the presence or absence of flutamide and phorbol myristate acetate (PMA) or f-methionyl-leucyl-phenylalanine (fmlp). In addition, hepatocytes were cocultured with PMNs stimulated with PMA or fmlp in the presence or absence of flutamide, and cytotoxicity to hepatocytes was evaluated from the release of alanine aminotransferase into the medium. Flutamide alone did not stimulate the generation of superoxide anion by PMNs but potentiated its production in response to PMA. At lower concentrations of flutamide (i.e. 25 microM), there was a tendency toward increased release of myeloperoxidase, whereas at higher concentrations (i.e. 75-100 microM) flutamide inhibited degranulation in response to fmlp. In coculture with hepatocytes, PMNs exposed to either flutamide, fmlp, or PMA alone caused a significant increase in release of alanine aminotransferase. Hepatocellular toxicity caused by PMNs incubated with flutamide and PMA was additive and was not affected by the addition of superoxide dismutase and catalase. Flutamide had no significant effect on fmlp-induced injury in cocultures. These data indicate that flutamide alters the activation of PMNs by subsequent stimuli in vitro. In addition, in the presence of flutamide, minor PMN-mediated injury to isolated hepatocytes was observed.
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PMID:Alteration by flutamide of neutrophil response to stimulation. Implications for tissue injury. 917 23

The phenotypes of infiltrating lymphocytes in liver with chronic hepatitis C, including changes associated with interferon (IFN) treatment, were characterized. Specimens obtained from 22 patients treated with IFN were examined using avidin-biotin-peroxidase immunohistochemistry. In areas of lobular and periportal inflammation, most lymphocytes were CD8+ T cells of the CD45RO+ (memory) subset. The centres of lymphoid follicles were occupied by CD20+ B cells and a few CD4+ T cells which were CD45RA+ (naive subset). Follicular centres were surrounded mainly with CD4+ T cells. CD8+ T cells, mostly CD45RO+, were scattered through the mantle zones of follicles and extended around them. No significant changes in CD45RA+ lobular infiltrates accompanied IFN treatment. On the other hand, the number of CD45RO+ lobular infiltrates decreased after IFN treatment in complete responders (P < 0.01). Moreover, there were significant correlations between CD45RO+ cell counts and serum alanine aminotransferase concentrations, CD45RO+ cell counts and the liver histologic grade and CD45RO+ cell counts and CD8+ cell counts. These results suggest that CD8+ memory T cells participate in hepatocyte injury in chronic hepatitis C, and that a decrease of CD8+ memory T cells correlates with the decreased liver inflammation with IFN treatment.
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PMID:Naive and memory T cell infiltrates in chronic hepatitis C: phenotypic changes with interferon treatment. 921 25

Milk samples were collected from 44 mares (trotters, warm blood horses, quarter horses) during lactation between the 1st and 90th day p.p. at 20 defined days. The activity of the enzymes LDH, gamma-GT, GOT, GPT and lactoperoxidase was investigated. The aim of this study was to find out the changes of these parameters during lactation and whether an influence of race, conception, date of foaling, age and number of lactations existed on the enzyme activities in mare's milk. The following results were obtained: In mare's milk the LDH-activity was highest (xg = 629 x 1.5 +/- 1 U/l) on the 1st day p.p. and showed a marked decrease on the 3rd day p.p. followed by a slight decrease until the 20th day p.p. It remained then at a constant level of about 80 U/l. The lowest activity (xg = 65.2 x 1.51 +/- 1 U/l) was measured on the 76th day p.p. The influence of conception and date of foaling time were statistically significant. The gamma-GT-activity was highest on the 3rd day p.p. (xg = 143.4 x 1.45 +/- 1 U/L) and decreased during lactation. The lowest activity was measured on the 90th day p.p. (xg = 23.2 x 1.51 +/- 1 U/L). The influence of race and conception--time were statistically significant. The GOT-activity of the 1st day p.p. (xg = 38.3 x 1.77 +/- 1 U/L) was higher than in mature milk. After the 3rd day p.p. activities between 15.5 x 1.38 +/- 1 U/l and 11.9 x 1.38 +/- 1 U/L were measured. The GPT-activity was highest on the 1st day p.p. (xg = 37.5 x 1.81 +/- 1 U/L) and decreased on the following days. After the 9th day p.p. activities between 9.1 x 1.37 +/- 1 U/l and 8.5 x 1.32 +/- 1 U/l were found. The influence of age, race, race (time, date of foaling (time and conception (time were significant. No Lactoperoxidase activity could be found in mare's milk. The origin and importance of the mare's milk enzymes are discussed.
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PMID:[Activities of the enzymes LDH, gamma-GT, GOT, GPT and lactoperoxidase in the milk of breeding mares during the course of lactation]. 954 6

Prevention of cellular damage after warm ischemia is of major importance in liver transplantation. In this study, we determined the extent to which lipid peroxides contribute to the pathogenesis of hepatic cell damage induced by transient warm ischemia with subsequent reperfusion. In addition, the function and immunohistochemical features of glutathione peroxidase, a potent physiological lipid peroxide scavenger of the liver, was assessed. Reperfusion following 15 or 30 minutes of warm ischemia resulted in a significant elevation in serum and liver lipid peroxidase (LPO) levels. In addition, necrosis of the hepatic periportal area accompanied with remarkable rises in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. In contrast, 30 min of ischemia without reperfusion caused minimal hepatocellular damage. The adverse changes after ischemia/reperfusion were minimized by pretreatment with superoxide dismutase (SOD). These results indicate that increased lipid peroxidation by production of radicals after reperfusion caused the liver cell damage. After ischemia/reperfusion, liver glutathione peroxidase (GSH-PO) activity was significantly decreased and its location altered in the damaged liver. These findings suggest that GSH-PO contributes significantly to the protection against hepatic reperfusion injuries.
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PMID:Alterations in glutathione peroxidase activity following reperfusion injury to rat liver. 960 29


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