Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure to small, noninjurious doses of the inflammagen, bacterial endotoxin (lipopolysaccharide, LPS) augments the toxicity of certain hepatotoxicants including aflatoxin B(1) (AFB(1)). Mediators of inflammation, in particular neutrophils (PMNs), are responsible for tissue injury in a variety of animal models. This study was conducted to examine the role of PMNs in the pathogenesis of hepatic injury after AFB(1)/LPS cotreatment. Male, Sprague-Dawley rats (250-350 g) were treated with either 1 mg AFB(1)/kg, ip or its vehicle (0.5% DMSO/saline), and 4 h later with either E. coli LPS (7. 4 x 10(6) EU/kg, iv) or its saline vehicle. Over a course of 6 to 96 h after AFB(1) administration, rats were killed and livers were stained immunohistochemically for PMNs. LPS resulted in an increase in PMN accumulation in the liver that preceded the onset of liver injury. To assess if PMNs contributed to the pathogenesis, an anti-PMN antibody was administered to reduce PMN numbers in blood and liver, and injury was evaluated. Hepatic parenchymal cell injury was evaluated as increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum and from histologic examination of liver sections. Biliary tract alterations were evaluated as increased concentration of serum bile acids and activities of gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), and 5'-nucleotidase (5'-ND) in serum. Neutrophil depletion protected against hepatic parenchymal cell injury caused by AFB(1)/LPS cotreatment but not against markers of biliary tract injury. This suggests that LPS augments AFB(1) hepatotoxicity through two mechanisms: one of which is PMN-dependent, and another that is not.
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PMID:Lipopolysaccharide augments aflatoxin B(1)-induced liver injury through neutrophil-dependent and -independent mechanisms. 1105 57

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

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

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

There has been a widespread impression that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mediate the toxicity of high doses of lipopolysaccharide (LPS, endotoxin) and are key factors in septic shock. However, the clinical efficacy of treatment with antagonists of TNF-alpha and IL-1beta is still controversial, suggesting that mediators other than TNF-alpha and IL-1beta might contribute causally to endotoxin-induced death. Recent studies implicated high mobility group-1 (HMG-1) protein as a late mediator of endotoxin lethality in mice. However, the role of HMG-1 in mediating multiple organ damage-associating trauma has not been studied. This study was designed to investigate changes in HMG-1 gene expression in vital organs, and its potential role in mediating multiple organ damage following major burns. Wistar rats were subjected to a 35 percent full-thickness thermal injury, and randomly divided into three groups as follows: normal controls (n = 7), thermal injury (n = 24), and recombinant bactericidal/permeability-increasing protein (rBPI21) treatment (n = 12). Tissue samples from liver and lungs were collected to measure tissue endotoxin levels and HMG-1 mRNA expression. In addition, blood samples were obtained for measurement of organ function parameters. Our data demonstrated a significant increase in HMG-1 gene expression in tissues at 24 h postburn, which remained markedly elevated up to 72 h after thermal injury (P< 0.05-0.01). Treatment with rBPI21 could significantly decrease tissue HMG-1 mRNA expression in the liver and lung (P < 0.01). In addition, there were high positive correlations between hepatic HMG-1 mRNA and serum aminoleucine transferase (ALT) and aspartate aminotransferase (AST) levels, and also between pulmonary HMG-1 mRNA and myeloperoxidase activities (P < 0.05-0.01). Taken together, these findings indicate that thermal injury per se can markedly enhance HMG-1 gene expression in various organs. Up-regulation of HMG-1 expression may be involved in the pathogenesis of endogenous endotoxin-mediated multiple organ damage secondary to major burns.
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PMID:The significance of changes in high mobility group-1 protein mRNA expression in rats after thermal injury. 1195 36


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