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)

We conducted a series of in vivo experiments to clarify the hepatoprotective activity of green tea against lipopolysaccharide (LPS) + D-galactosamine (GalN)-induced liver injury and to elucidate the mechanism by which green tea exerts its effect in 7-wk-old male Wistar rats. Liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities. Green tea extract significantly suppressed LPS + GalN-induced liver injury when added to the diet (30 or 35 g/kg) and fed to rats for 14 d or when force-fed alone (0.4-1.2 g/kg body) 1.5 h before the injection of drugs. Although all five of the fractions extracted from green tea extract with different organic solvents had significant suppressive effects, the caffeine-containing fraction exhibited the strongest effect, suggesting that the protective effect of green tea against LPS + GalN-induced liver injury is attributable mainly to caffeine. Authentic caffeine also significantly suppressed LPS + GalN-induced liver injury when added to the diet (2 g/kg) and fed to rats for 14 d. Dietary green tea suppressed LPS + GalN-induced apoptosis of liver cells, as assessed by DNA fragmentation. However, dietary green tea did not suppress LPS-induced enhancement of plasma concentration of tumor necrosis factor (TNF)-alpha, the cytokine that is thought to play a pivotal role in the pathogenesis of LPS-induced liver injury, although it significantly suppressed plasma concentrations of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10 and interferon (IFN)-gamma. TNF-alpha + GalN-induced liver injury and apoptosis were also suppressed by dietary green tea. In contrast, dietary caffeine significantly suppressed LPS-induced enhancement not only of plasma IL-1beta, IL-6, IL-10 and IFN-gamma concentrations, but also of TNF-alpha concentration. The results suggest that green tea might suppress LPS + GalN-induced liver injury mainly through the inhibition of TNF-alpha-induced apoptosis of hepatocytes, rather than through the suppression of TNF-alpha production, although the suppressed production of TNF-alpha may be associated with the hepatoprotective effect of caffeine.
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PMID:Green tea suppresses lipopolysaccharide-induced liver injury in d-galactosamine-sensitized rats. 1134 Jan 16

The effects of 1,8-cineole on D-galactosamine/lipopolysaccharide (GalN/LPS)-induced shock model of liver injury was investigated in mice. The co-administration of GalN (700 mg kg(-1), i.p.) and LPS (5 microg kg(-1), i.p.) greatly elevated serum concentrations of tumour necrosis factor-alpha (TNF-alpha), alanine aminotransferase and aspartate aminotransferase, and induced massive hepatic necrosis and lethality in 100% of control mice. Pretreatment with 1,8-cineole (400 mg kg(-1), p.o.) and dexamethasone (1 mg kg(-1), s.c.), 60 min before GalN/LPS, offered complete protection (100%) against the lethal shock and acute elevation in serum TNF-alpha and serum transaminases. Hepatic necrosis induced by GalN/LPS was also greatly reduced by both 1,8-cineole and dexamethasone treatment. The results indicate that 1,8-cineole protects mice against GalN/LPS-induced liver injury through the inhibition of TNF-alpha production, and suggest that 1,8-cineole may be a promising agent to combat septic-shock-associated pathologies.
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PMID:1,8-cineole protects against liver failure in an in-vivo murine model of endotoxemic shock. 1134 67

Sustained upregulation of inducible nitric oxide (NO) synthase in the liver after endotoxin [lipopolysaccharide (LPS)] challenge may result in hepatocellular injury. We hypothesized that administration of a NO scavenger, NOX, may attenuate LPS-induced hepatocellular injury. Sprague-Dawley rats received NOX or saline via subcutaneous osmotic pumps, followed 18 h later by LPS challenge. Hepatocellular injury was assessed using biochemical assays, light, and transmission electron microscopy (TEM). Interleukin (IL)-6 mRNA was measured by RT-PCR. Tumor necrosis factor (TNF)-alpha protein expression was determined by immunohistochemistry. NOX significantly reduced serum levels of ornithine carbamoyltransferase and aspartate aminotransferase. TNF-alpha and IL-6 expression were increased in the livers of saline-treated but not NOX-treated rats. Although there was no difference between groups by light microscopy, TEM revealed obliteration of the space of Disse in saline-treated but not in NOX-treated animals. Electron paramagnetic resonance showed the characteristic mononitrosyl complex in NOX-treated rats. We conclude that NOX reduces hepatocellular injury after endotoxemia. NOX may be useful in the management of hepatic dysfunction secondary to sepsis or other diseases associated with excessive NO production.
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PMID:Scavenging nitric oxide reduces hepatocellular injury after endotoxin challenge. 1140 70

Bacterial endotoxin (lipopolysaccharide; LPS) augments the hepatotoxicity of a number of xenobiotics including allyl alcohol. The mechanism for this effect is known to involve the inflammatory response elicited by LPS. Upregulation of cyclooxygenase-2 (COX-2) and production of eicosanoids are important aspects of inflammation, therefore studies were undertaken to investigate the role of COX-2 in LPS-induced enhancement of liver injury from allyl alcohol. Rats were pretreated (iv) with a noninjurious dose of LPS or sterile saline vehicle and 2 h later were treated (ip) with a noninjurious dose of allyl alcohol or saline vehicle. COX-2 mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and liver injury was assessed from activities in serum of alanine and aspartate aminotransferases (ALT and AST, respectively) and from histology. Liver injury was observed only in rats cotreated with LPS and allyl alcohol. Serum ALT activity was increased by 4 h after administration of LPS and continued to increase through 8 h. COX-2 mRNA was detectable at low levels in livers from rats receiving only the vehicles at any time up to 8 h. Expression of COX-2 mRNA was increased by 30 min after administration of LPS and remained elevated through 6 h. Allyl alcohol treatment alone caused an increase in COX-2 mRNA at 4 h (2 h after allyl alcohol) that lasted less than 2 h. In livers from rats cotreated with LPS and allyl alcohol, levels of COX-2 mRNA were greater than levels seen with either LPS or allyl alcohol alone. The increased expression of COX-2 mRNA was accompanied by an increase in the concentration of prostaglandin (PG) D(2) in plasma. Plasma PGD(2) concentration was increased to a greater extent in rats treated with LPS plus allyl alcohol compared to allyl alcohol or LPS alone. Pretreatment with the COX-2 selective inhibitor, NS-398, abolished the increase in plasma PGD(2) and reduced the increase in ALT and AST activities observed in rats cotreated with LPS and allyl alcohol. NS-398 did not affect liver injury from allyl alcohol alone administered at a larger, hepatotoxic dose. In addition, ibuprofen, a nonselective inhibitor of cyclooxygenases, did not protect against liver injury from LPS plus allyl alcohol. In isolated hepatocytes PGD(2), but not PGE(2), reduced the concentration of allyl alcohol required to cause half-maximal cytotoxicity. These results suggest that products of COX-2 play a role in the augmentation of allyl alcohol-induced liver injury by LPS.
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PMID:Involvement of cyclooxygenase-2 in the potentiation of allyl alcohol-induced liver injury by bacterial lipopolysaccharide. 1144 26

Tumour necrosis factor (TNF) is a major mediator in septic shock and several inflammatory diseases such as hepatitis. Galactosamine (GalN) sensitises experimental animals for TNF and the combination TNF/GalN leads to a lethal inflammatory hepatitis. We describe that a single injection of lipopolysaccharide (LPS), interleukin-1 (IL-1) or TNF can desensitise against the lethality induced by TNF/GalN, but also against changes in metabolic parameters such as hypothermia and transaminase release, in a dose responsive way. We also describe the desensitising capacity of a component present in Mouse Liver Extract (MLE). The MLE desensitises mice against the effects of TNF/GalN in a dose responsive way. The activity of the MLE is heat labile and does not involve LPS, TNF, IL-1 or TNF soluble receptors. We describe partial and complete purification of the factor. Partially pure material protects mice against all changes induced by TNF/GalN. The protection is dose dependent and heat labile and also possible in endotoxin-hyporesponsive C3H/HeJ mice. The pure material protects against lethality, hypothermia and AST release and it appears as a heat labile protein of relative molecular weight of 70 kDa probably with a break down product of 35 kDa.
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PMID:Detection, characterisation and purification of a murine liver factor capable of desensitising towards the lethal activity of tumour necrosis factor. 1150 80

Our aim was to study the antioxidant and immunomodulatory effect of silibinin and vitamin E on the early postoperative course in rats that had undergone a partial hepatectomy (PHX). Male Wistar rats that were treated with silibinin (50 mg/b.w.kg i.p.) and/or vitamin E (500 mg/b.w.kg p.o.) were randomised to undergo 70% PHX. At 72 h after operation, Concanavalin A (Con-A) induced lymphocyte proliferation, and lipopolysaccharide (LPS) induced interleukin-1 (IL-1) mitogenicity and tumour necrosis factor-alpha (TNF-alpha) cytotoxicity were measured in the spleen. In addition, total free radical scavenger capacity of the liver was analysed. In PHX animals, Con-A induced lymphocyte proliferation was significantly decreased, and both LPS induced IL-1 and TNF-alpha activity were significantly increased as compared to Sham treated animals. Treatment with silibinin and vitamin E synergistically restored both lymphocyte proliferation (P<0.01) and cytokine activity (P<0.001) in PHX animals. In addition, silibinin and vitamin E synergistically (P<0.001) restored total hepatic free radical scavenger capacity as well as serum levels of AST and gammaGT, that were all markedly decreased in PHX animals. Our results suggest that preoperative treatment with silibinin and/or vitamin E modulates the cellular immunoresponse and restores impaired liver function following PHX, presumably through their antioxidant capacity. This may explain their beneficial effects on the postoperative course of liver repair.
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PMID:Effect of silibinin and vitamin E on restoration of cellular immune response after partial hepatectomy. 1153 68

A coffee extract significantly suppressed lipopolysaccharide (LPS)-induced hepatitis in D-galactosamine-sensitized rats, as assessed by the plasma alanine and aspartate aminotransferase activities, when it was added to the diet (30 g/kg) and fed to rats for 14 days. Its effect was as strong as that of a green tea extract. The coffee extract suppressed LPS-induced hepatitis when singly force-fed (1.2 g/kg) 1.5 h prior to the injection of the drugs, whereas a decaffeinated coffee extract had no significant effect. The hepatoprotective effect of caffeine was stronger than that of theobromine. These results indicate that coffee can protect animals from LPS-induced hepatitis, and that the effect of coffee might be mainly due to caffeine.
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PMID:Suppressive effect of coffee on lipopolysaccharide-induced hepatitis in D-galactosamine-sensitized rats. 1157 46

We evaluated the efficacy of ONO-4819, a newly developed agonist of a prostaglandin receptor subtype (EP4), on experimental model of acute liver injury in rats. Acute liver injury was induced by simultaneous intraperitoneal (i.p.) administration of D-galactosamine (GalN, 1 g/kg body weight) and lipopolysaccharide (LPS, 100 mg/kg body weight). The rats received a single intraperitoneal injection of ONO-4819 (0.2 mg/kg body weight) or physiological saline immediately after GalN/LPS administration. Submassive hepatic necrosis with marked elevation of serum total bilirubin, serum aspartate aminotransferase and serum alanine aminotransferase levels developed 24 h after GalN/LPS administration. The administration of ONO-4819 significantly inhibited the development of submassive hepatic necrosis and inhibited the elevation in levels of biochemical markers that indicate liver function. In addition, the apoptotic index of hepatocytes assessed by the TUNEL method was significantly lower in rats treated with ONO-4819 than in the control. Although serum levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-8 (IL-8) were markedly elevated after GalN/LPS administration, ONO-4819 significantly inhibited the elevation of those of TNF-alpha and IFN-gamma but not that of IL-8. The beneficial effect of ONO-4819 for acute liver injury was similar at doses of 0.1, 0.05 and 0.01 mg/kg body weight. These results suggest that the EP4 agonist, ONO-4819, may have a protective effect against experimental liver injury in rats through the suppression of inflammatory cytokines.
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PMID:A novel prostaglandin E receptor subtype agonist, 0N0-4819, attenuates acute experimental liver injury in rats. 1167 10

Oltipraz is a cancer chemopreventive agent active against a wide variety of chemical carcinogens. In spite of the intense chemoprevention and toxicology studies on oltipraz, no information is available on its antifibrotic efficacy. In the present study, the effects of oltipraz on dimethylnitrosamine (DMN)-induced liver fibrogenesis were assessed in rats. As part of mechanistic studies, the expression of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) was monitored. Treatment of rats with DMN (10 microl/kg body weight, i.p., three times per week for 4 weeks) resulted in marked increases in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (gamma-GT) activities. DMN also caused an increase in the plasma bilirubin content, whereas total plasma protein and albumin levels were rather decreased. Oltipraz (50 mg/kg body weight, p.o., three times per week for 4 weeks) inhibited the increases in plasma ALT, AST, gamma-GT and bilirubin by DMN. DMN increased liver fibrosis as histopathologically assessed by Van Gieson's staining and Masson's trichrome staining (fibrosis score, 3.7; Knodell score, 16), which was reduced by oltipraz treatment (fibrosis score, 2.5; Knodell score, 8.0). Reverse transcription-polymerase chain reaction analysis revealed that oltipraz inhibited an increase in the TGF-beta1 mRNA by DMN. Oltipraz was also active in reducing the production of plasma TNF-alpha by DMN or lipopolysaccharide (LPS), which would contribute to its cytoprotective effect. These results demonstrated that oltipraz inhibited hepatocyte injury and impairment of liver function induced by DMN, and reduces DMN-induced liver fibrosis possibly through suppression of TGF-beta1 and TNF-alpha production.
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PMID:Inhibition of dimethylnitrosamine-induced liver fibrosis by [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] (oltipraz) in rats: suppression of transforming growth factor-beta1 and tumor necrosis factor-alpha expression. 1180 29

Idiosyncratic reactions occur in a small fraction (typically <5%) of the population taking therapeutic drugs. Chlorpromazine (CPZ) is a phenothiazine, antipsychotic drug that has caused several idiosyncratic responses during its therapeutic use. Clinical evidence suggests that conditions associated with inflammation are risk factors for the appearance of these responses. Accordingly, we tested the hypothesis that an inflammatory stimulus, bacterial lipopolysaccharide (LPS), renders animals susceptible to CPZ-induced idiosyncratic reactions seen in humans. Male Sprague-Dawley rats (200-250 g) were fasted for 24 h. A small dose of LPS (7.4 x 10(6) EU/kg from Escherichia coli) or its vehicle (saline) was administered by tail vein 2 h before an intraperitoneal injection of CPZ (70 mg/kg) or its vehicle (saline). Cholestasis and hepatocellular necrosis were evaluated as increased concentrations of serum bile acids and bilirubin and increased activities of alkaline phosphatase, gamma-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase. With the exception of bile acids, these serum markers were elevated in animals treated with LPS/CPZ. Histopathological lesions in liver sections were consistent with these findings. Elevated serum creatine kinase activity, which is associated with human idiosyncratic responses to phenothiazines, was also found in animals treated with LPS/CPZ, but not with either LPS or CPZ alone. These results raise the possibility that concurrent, modest inflammation may underlie susceptibility of individuals to certain idiosyncratic reactions and may form the basis for an animal model with which to understand and predict drug idiosyncrasy.
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PMID:Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy? 1180 5


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