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)

Ag stimulation of CD8+ lymphocytes in vivo results in their migration to various tissues as well as the activation of a cytolytic program involving perforin, TNF-alpha, and Fas ligand. The liver is one of the main sites for infiltration by activated CD8+ T cells, and this is followed by the death of hepatocytes. The contribution of the various cytolytic components to this process is unclear. Hepatocyte damage by CD8+ T cells was studied using the MHC class I-restricted OVA-specific TCR transgenic mouse (OT-1) to examine the contribution of Fas to hepatocyte death. Activated CD8+ T cells from both OT-1 and Fas-deficient OT-1lpr mice migrated to the liver in similar numbers after OVA administration, but only in OT-1 mice was there evidence of significant hepatocyte damage histologically and by elevation of serum aspartate transaminase. These differences were not the result of inefficient induction of cytolytic activity in OT-1lpr liver T cells, since they were as cytolytic in vitro as OT-1 liver T cells. This was supported by findings of similar high levels of message for perforin, TNF-alpha, and Fas ligand in liver lymphocytes from both mice. These findings demonstrate that following Ag activation, infiltrating liver CD8+ T lymphocytes induce hepatocyte damage in a Fas-dependent manner.
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PMID:Liver damage by infiltrating CD8+ T cells is Fas dependent. 1171 37

AIM:To study the effect of hepatocyte apoptosis and necrosis induced by TNF-alpha on the pathogenesis of acute severe hepatitis (ASH).METHODS:The model of ASH was prepared in D-galactosamine (GalN) sensitized BALB/c mice by injection of either endotoxin (ET) or tumor necrosis factor-alpha(TNF-alpha. Morphological changes of apoptotic hepatocytes were studied by both light and electron microscope and in site end labeling method (ISEL). Molecular biological changes of DNA ladder were observed by electrophoresis of extract from liver tissues. Biochemical changes were measured by alanine aminotransferase (ALT), aspartic aminotransferase (AST) and TNF-alpha. The relation between apoptosis and necrosis was evaluated simultaneously.RESULTS:The sequence of hepatocyte apoptosis, necrosis, and final death from ASH was observed both in GalN/ET and GalN/TNF-alpha group. Apoptosis was prominent at 3.5h and 6h after injection of inducer, while necrosis became dominant at 9h after challenge. The appearance of apoptosis was earlier in GalN/TNF-alpha group than that in GalN/ET group. Pretreatment of mice with antiTNF IgG1 may completely prevent the liver injury induced by GalN/ET.CONCLUSION:TNF-alpha can cause liver amage by inducing hepatic apoptosis and necrosis in mice with endotoxemia.
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PMID:Effect of hepatocyte apoptosis induced by TNF-alpha on acute severe hepatitis in mouse models. 1181 75

During 2000, four cases of fatal Lassa fever were imported from Africa to Europe. In two patients, consecutive serum samples were available for monitoring of virus load and cytokine levels in addition to standard laboratory data. Both patients had non-specific early clinical symptoms including high fever. Patient 1 developed multi-organ failure and died of hemorrhagic shock on day 15 of illness, while patient 2 died of respiratory failure due to aspiration without hemorrhage on day 16. Ribavirin was administered to both patients beginning only on day 11. High serum aspartate aminotransferase and lactate dehydrogenase (LDH) levels were remarkable in both patients. Patient 1 had an initial virus load of 10(6) S RNA copies/ml as measured by real-time RT-PCR. Viremia increased steadily and reached a plateau of approximately 10(8)-10(9) copies/ml 4 days before death, while IFN-gamma and TNF-alpha rose to extremely high levels only shortly before death. In contrast, in patient 2 the virus load decreased from 10(7) to 10(6) copies/ml during the late stage of illness which was paralleled by a decrease in the IFN-gamma and TNF-alpha levels. The IL-10 level increased when specific IgM and IgG appeared. These data suggest that a high virus load and high levels of pro-inflammatory cytokines in the late stage of Lassa fever play an important role in the pathogenesis of hemorrhage, multi-organ failure, and shock in Lassa fever.
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PMID:Monitoring of clinical and laboratory data in two cases of imported Lassa fever. 1182 74

The effects of betaine or taurine on hepatotoxicity induced by lipopolysaccharide (LPS) were examined in adult male SD rats. Rats were provided with drinking water containing either 1% betaine or taurine for 2 weeks prior to challenge with LPS (5 mg/kg, iv). Supplementation with betaine or taurine protected the animals from induction of LPS hepatotoxicity as measured by changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities and total bilirubin levels in serum, and hepatic glutathione contents. LPS challenge increased serum TNF-alpha and nitrate/nitrite in rats, which were reduced by betaine or taurine intake. Taurine depletion induced by supply of drinking water containing 3% beta-alanine for 7 days did not enhance the LPS-induced hepatic damage or the decrease in hepatic glutathione level. The results indicate that intake of betaine or taurine attenuates the LPS-induced hepatotoxicity resulting from activation of Kupffer cells.
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PMID:Attenuation of bacterial lipopolysaccharide-induced hepatotoxicity by betaine or taurine in rats. 1189 13

The role of NF-kappaB, the rapid-response transcription factor for multiple genes, in cold ischemia-reperfusion (I/R) injury was examined after syngeneic transplantation of liver grafts. Lewis rat recipients were killed 1-48 h after reperfusion of three different liver grafts: 1) uninfected control, 2) infected ex vivo with control adenoviral vector (AdEGFP), and 3) infected ex vivo with AdIkappaB. In uninfected control livers, NF-kappaB was activated biphasically at 1-3 and 12 h after reperfusion with aspartate transaminase (AST) levels of 4,244 +/- 691 IU/l. The first peak of NF-kappaB activation associated with an increase of mRNA for TNF-alpha, IL-1beta, and IL-10. AdEGFP transfection resulted in similar outcomes. Interestingly, AdIkappaB-transfected liver grafts suffered more severe I/R injury (AST >9,000 IU/l). Transfected IkappaB was detected in transplanted livers as early as 6 h, and this correlated with the abrogation of the second, but not the first, peak of NF-kappaB activation at 12-48 h and increased apoptosis. Thus inhibition of the second wave of NF-kappaB activation in IkappaB-transfected livers resulted in an increase of liver injury, suggesting that NF-kappaB may have a dual role during liver I/R injury.
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PMID:Role of NF-kappaB on liver cold ischemia-reperfusion injury. 1238 32

The objective was to study toxin-induced effects on physiological parameters in the rabbit and whether these parameters show dose-response and co-variation after administration of a recombinant fusion protein between staphylococcal enterotoxin (SE) and the Fab fragment of an antibody. Rabbits are very sensitive to SE toxins and the cardiovascular and immune effects are similar to those observed in septic shock in man. The test compound, r-C242 Fab-SEA, was administered intravenously to anaesthetised New Zealand white rabbits at doses in the range of 0.00005-50 microg/kg. All rabbits were checked for titres of anti-SEA antibodies before entering the experiment, since they could neutralise the effect of the test compound. Heart rate, blood pressure and body temperature were continuously monitored before and during 6 h after dosing. Immediately before the start of administration and 3 and 6 h during the experiment, blood gases (pO(2) and pCO(2)), pH, haematology, clinical chemistry, cytokine response (TNF-alpha) and trace elements (Mn, Cu, Zn, Se, Ag, Cd, Hg and Pb) were measured. No mortality occurred, but at 50 microg/kg severe adverse clinical signs developed. The decrease in blood pressure was weakly dose-related. Heart rate, ECG, body temperature, pCO(2) and pH were not affected by the treatment. pO(2) tended to increase as a function of time, but not in relation to dose. WBC and PLT decreased dose dependently. TNF-alpha was not affected by the treatment. The major effects on clinical chemistry were a dose-dependent increase in AST and creatinine. Potassium and urea showed dose dependent increases, mainly at higher doses, though these changes were of less value for drug selection purposes. Trace element changes were observed, including an increase in Mn and a decrease of Zn at all doses. The Cu/Zn ratio decreased below normal at low doses, whereas at high doses in which adverse effects developed, it increased above normal. Post mortem examination revealed minimal to moderate dose-related granulocytic infiltrate in the lungs. The present study showed dose-response and co-variation between several changes in cardiovascular, haematology, clinical chemistry and trace element parameters during the initial phase of toxin-induced effects preceding a possible lethal endpoint and associated patho-physiological changes.
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PMID:Effects of a superantigen-antibody recombinant fusion protein (r-C242 Fab-SEA) on toxicological responses in the anaesthetised rabbit. 1250 54

The role of high mobility group-1 protein (HMG-1) in LPS- and TNF-alpha-induced lethal shock in galactosamine (GalN)-sensitized mice was investigated. No detectable HMG-1 levels were observed by immunoblotting analysis in plasma from untreated or GalN-sensitized BALB/c mice 5 h after LPS injection, although significant levels of HMG-1 were detected in plasma 6 h after the challenge. All GalN-sensitized BALB/c but not BALB/lps(d) mice succumbed by 6 h after LPS injection. When GalN-sensitized mice were injected with TNF-alpha, the presence of HMG-1 was seen at 5.5 h in plasma of BALB/c mice and at 6 h in BALB/lps(d) mice, although almost all GalN-sensitized BALB/c mice died by 6 h after challenge. The time-dependent phenomenon correlated with elevated serum aspartate aminotransferase (AST) levels and the appearance of apoptotic cells in livers. Administration of pooled plasma, equivalent to approximately 200 microg recombinant murine HMG-1, taken from mice on the verge of near death, did not result in induction of lethal shock in GalN-sensitized mice. Taken together with the late appearance of HMG-1 in moribund mice, these data suggest that HMG-1 does not decisively contribute to lethality in the GalN sensitization model.
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PMID:Does high mobility group 1 protein function as a late mediator for LPS- or TNF-induced shock in galactosamine-sensitized mice? 1253 98

Vibrio vulnificus is the leading cause of death in the United States associated with the consumption of raw seafood, particularly oysters. In epidemiological studies, primary septicemia and inflammation-mediated septic shock caused by V. vulnificus is strongly associated with liver disease, often in the context of chronic alcohol abuse. The present study was undertaken to determine whether clinical biomarkers of liver function or cellular oxidative stress are associated with peripheral blood mononuclear cell inflammatory cytokine responses to V. vulnificus. Levels of interleukin-1 beta (IL-1 beta), IL-6, IL-8, and tumor necrosis factor alpha elicited in response to V. vulnificus and measured in cell supernatants were not associated with the liver biomarkers aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or the AST/ALT ratio. In contrast, reduced glutathione (GSH) levels were associated with the release of all four cytokines (IL-1 beta [R(2) = 0.382; P = 0.006], IL-6 [R(2) = 0.393; P = 0.005], IL-8 [R(2) = 0.487; P = 0.001], and TNF-alpha [R(2) = 0.292; P = 0.021]). Those individuals with below-normal GSH levels produced significantly less proinflammatory cytokines in response to V. vulnificus. We hypothesize that persons with markers for cellular oxidative stress have increased susceptibility to V. vulnificus septicemia.
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PMID:Inflammatory cytokine response to Vibrio vulnificus elicited by peripheral blood mononuclear cells from chronic alcohol users is associated with biomarkers of cellular oxidative stress. 1281 21

Accidental hypothermia is a common companion of trauma/haemorrhage, and several clinical studies have identified reduced body temperature as an independent risk predisposing to increased morbidity and mortality. Accordingly, the majority of trauma care guidelines prescribe early and aggressive rewarming of hypothermic patients. Enzyme reactions are generally downregulated at temperatures below 37 degrees C, including most of those responsible for the inflammatory response. The rationale for adhering to these recommendations uncritically may therefore be questioned. In a rat model of mild hypothermia and haemorrhagic shock we wanted to compare the influence of rapid rewarming with persistently reduced temperature on the synthesis of early inflammatory mediators and organ function. Thirty-four male albino Sprague-Dawley rats were studied. Withdrawal of 2.5 ml blood/100 g body weight was performed over 10 min, with simultaneous reduction of body temperature to 32.5-33.5 degrees C. Seventy-five minutes after initiation of bleeding, two-thirds of the shed blood was retransfused. One group (n=17) was rewarmed to normothermia, the other (n=17) was kept hypothermic. The study was terminated after an observation period of 2 h. At the end of the study the rewarmed animals had a significantly lower mean arterial pressure, higher heart rate, higher synthesis of reactive oxygen species from peritoneal phagocytes, increased circulating levels of nitric oxide, and higher values of the organ markers aspartate aminotransferase and urea. The pro-inflammatory cytokines TNF-alpha and IL-6, the anti-inflammatory cytokine IL-10, the organ markers alanine aminotransferase, alpha-glutathione S-transferase and creatinine, as well as organ injury scores were equal in both groups. Three rewarmed rats died prematurely, versus one hypothermic animal. In conclusion, the results suggest that during the early stages after haemorrhagic shock, rapid rewarming from mild hypothermia may have unfavourable effects both on basic haemodynamic variables, and on the internal inflammatory environment of cells and tissues.
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PMID:Rapid rewarming after mild hypothermia accentuates the inflammatory response after acute volume controlled haemorrhage in spontaneously breathing rats. 1286 16

This study was designed to investigate the role of p38 mitogen-activated protein (MAP) kinase on Kupffer cells (KCs) secretion of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta and hepatic injury following burn trauma. Sprague-Dawley rats were randomized into four groups: (1) sham burn rats given vehicle, (2) sham burn rats given the p38 MAP kinase inhibitor SB203580 (10mg/kg i.v., 15min and 12h after sham burn), (3) rats given a 30% total body surface area (TBSA) full-thickness burn and fluid resuscitation plus vehicle, and (4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at 24h post-burn to examine plasma aspartate transaminase (AST) and alanine transaminase (ALT) and KCs were isolated. The KCs secretion of TNF-alpha and IL-1beta and p38 MAP kinase activity (by Western blot analysis) were also examined. These studies showed by more significant activation of p38 MAP kinase in KCs harvested from burn rats than from shams. Burn trauma resulted in hepatic dysfunction and promoted KCs secretion of TNF-alpha and IL-1beta. SB203580 inhibited p38 MAP kinase activity, reduced KCs secretion of proinflammatory cytokines, and alleviated burn-mediated hepatic dysfunction. These data suggest p38 MAP kinase activation is one important aspect of the signaling event that may mediate the KCs secretion of proinflammatory cytokines TNF-alpha and IL-1beta following burn trauma.
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PMID:Role of p38 mitogen-activated protein kinase in Kupffer cell secretion of the proinflammatory cytokines after burn trauma. 1292 76


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