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)

The hepatoprotective effects of chalcone derivatives were evaluated in D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced fulminant hepatic failure in mouse. Thirteen chalcone derivatives were synthesized for study and their hepatoprotective effects were evaluated by assessing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in serum. Chalcone preparations were injected into mice at 12 h and 1 h before intraperitoneal injection of D-GalN/LPS. After abdominal administration, changes in AST and ALT between the control and treated groups were observed. Ten of the synthesized chalcone derivatives exhibited inhibitory effects on D-GalN/LPS-induced levels of AST and ALT in mice. Compounds 2, 3, 8, 9, and 12 markedly reduced serum AST and ALT at 8 h, inhibited hepatocyte necrosis and showed significant hepatoprotective activities. The activity of compound 3 was compared with the bifendate (DDB) through oral administration. Compound 3 showed much higher inhibitory effects than bifendate for decreasing AST and ALT activity. The results indicate that compound 3 has strong hepatoprotective activity through suppression of tumor necrosis factor-alpha (TNF-alpha) preduction, reduction of the histological change in the liver, and attenuated of hepatocyte apoptosis confirmed by DNA fragmentation assay.
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PMID:Protective effects of chalcone derivatives for acute liver injury in mice. 1574 13

In this study, we investigated the interaction between lipopolysaccharide (LPS) and lead (Pb) and the involvement of tumor necrosis factor-alpha (TNF-alpha) and oxidative stress in Pb-plus-LPS (Pb/LPS)-induced liver damage in rats. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), TNF-alpha, nitric oxide (NO), and lipid peroxidation (LPO) were determined in rats treated with Pb and/or LPS. Pb ranging from 0 to 15 mg/kg dose dependently increased AST, ALT, NO, or LPO in LPS-treated rats. Pretreatment with iNOS inhibitor 1400W reduced NO, LPO, TNF-alpha, AST, and ALT in Pb/LPS-treated rats. Thus, Pb increased LPS-induced liver damage, which might be associated with increased NO-initiated oxidative stress and TNF-alpha in rats.
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PMID:Coexposure of lead- and lipopolysaccharide-induced liver injury in rats: involvement of nitric oxide-initiated oxidative stress and TNF-alpha. 1580 60

Mercury is a widespread metal in the environment and consequently large populations are currently exposed to low levels of mercury. Endotoxin, a component of the Gram-negative bacteria, promotes inflammatory responses. We recently reported that mercury modulates the production of nitric oxide and various inflammatory cytokines induced by endotoxin in a macrophage cell line (Nitric Oxide 2002, 7:67). The present study was designed to determine the impact of mercury on endotoxin-induced inflammatory cytokine expression and corresponding signal transduction in mouse liver. Male BALB/c mice were exposed continuously to 0, 0.3, 1.5, 7.5, or 37.5 ppm of mercury in drinking water for 14 days and at the end of the treatment period lipopolysaccharide (LPS, 0.5 mg/kg) was injected intraperitoneally 2 hr prior to euthanasia. The doses of mercury and LPS did not cause hepatotoxicity as indicated by unaltered circulating alanine aminotransferase and aspartate aminotransferase levels. Mercury decreased liver glutathione (GSH) and with LPS additively decreased GSH. Mercury activated p38 mitogen-activated protein kinase (MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. In contrast, mercury alone had no effect on activation of extracellular signal-regulated kinase (ERK) but inhibited LPS-induced ERK activation. Mercury increased the expression of tumor necrosis factor alpha (TNFalpha) and further potentiated LPS-induced TNFalpha expression. Mercury did not affect LPS-induced interleukin (IL)-1beta expression but decreased LPS-induced IL-6 expression. Results indicated that low levels of mercury augment LPS-induced TNFalpha expression by altering GSH and p38 MAPK. Mercury modulates LPS-induced p38 and ERK activation and downstream TNFalpha and IL-6 expression in mouse liver.
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PMID:Mercury alters endotoxin-induced inflammatory cytokine expression in liver: differential roles of p38 and extracellular signal-regulated mitogen-activated protein kinases. 1580 65

Oxidative stress triggered by septic insult may be the major cause of multiple organ dysfunction syndrome (MODS) in intensive unit care patients. The inducible form of heme oxygenase-1 (HO-1) can be induced by cytokines, lipopolysaccharide, and reactive oxygen species during sepsis. These facts raise the question of whether the expression of HO-1 in leukocytes can indicate the level of oxidative stress of multiple organs in sepsis. Clinical peritonitis was simulated in an animal model by cecal ligation and puncture (CLP). The level of oxidative stress was examined by plasma lipid peroxidation (LPO). Liver function was analyzed by plasma aspartate aminotransferase, alanine aminotransferase, total bilirubin, and direct bilirubin. Lung function was evaluated by severity of edema. Renal function was measured by blood urea nitrogen and creatinine. The correlation between early HO-1 induction and LPO level or organ functional indicators of the same rat at late sepsis was analyzed by linear regression. The results showed that the protein content of HO-1 increased at 9 h after CLP, whereas expression of HO-1 mRNA in leukocytes was significantly increased (P < 0.01) at 6 h after CLP. Plasma level of LPO and the indices of hepatic, pulmonary, and renal function were significantly increased at 18 h after CLP. Moreover, highly negative correlations were observed between HO-1 mRNA expression at 6 h after CLP and level of LPO or severity of hepatic/renal dysfunction at 18 h after CLP. These results suggest that early HO-1 mRNA expression in leukocytes may represent oxidative stress and may predict the severity of liver and renal dysfunction during sepsis.
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PMID:Early expression of heme oxygenase-1 in leukocytes correlates negatively with oxidative stress and predicts hepatic and renal dysfunction at late stage of sepsis. 1583 14

The effect of a crude extract of the aerial parts of Artemisia vulgaris (Av.Cr) was investigated against D-galactosamine (D-GalN) and lipopolysaccharide (LPS) induced hepatitis in mice. Co-administration of D-GalN (700 mg[sol ]kg) and LPS (1 microg[sol ]kg) significantly (p < 0.05) raised the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in mice in the toxin group compared with the values in the control group. Pre-treatment of mice with different doses of Av.Cr (150-600 mg[sol ]kg) significantly (p < 0.05) reduced the toxin-induced rise in plasma ALT and AST. The hepatoprotective effect was further verified by histopathology of the liver, which showed improved architecture, absence of parenchyma congestion, decreased cellular swelling and apoptotic cells, compared with the findings in the toxin group of animals. These findings scientifically validated the traditional use of Artemisia vulgaris for various liver disorders.
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PMID:Hepatoprotective activity of aqueous-methanol extract of Artemisia vulgaris. 1585 91

Gender is known to play a role in the bioavailability, metabolism, and lethality of many toxic substances. This study was conducted to investigate the influence of gender on cocaine hepatotoxicity (CH) and lipopolysaccharide (LPS) potentiation of CH. Male and female CF-1 mice were orally administered 20 mg/kg body weight cocaine hydrochloride once daily for 7 days. Four hours after the last cocaine administration, the mice were administered 12 x 10(6) EU LPS (or equal volume of sterile saline) intraperitoneally. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were evaluated as indices of liver injury. Blood and liver glutathione (GSH), glutathione reductase (GRx), and catalase (CAT) activities were also determined to investigate the extent of oxidative stress induced by the treatments. Serum ALT and AST concentrations were elevated in all males receiving cocaine alone or cocaine + LPS. Furthermore, blood GSH and CAT were decreased and GRx activity was elevated in these same animals. Histological analysis revealed a high degree of hepatic focal necrosis in the male cocaine group, and severe hemorrhagic necrosis in the male cocaine + LPS group. Unlike males, females showed no damage resulting from cocaine or cocaine + LPS exposure, whereas testosterone-supplemented ovariectomized females displayed histological and biochemical profiles statistically similar to males. The results demonstrate that the extent of CH or LPS-potentiated CH is influenced by gender and sex hormones, particularly testosterone.
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PMID:Influence of gender on cocaine hepatotoxicity in CF-1 mice. 1598 39

Lead (Pb) increases lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), lipid peroxidation (LPO), and liver damage. In this study, we investigated the role of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) and the causal relationships between TNF-alpha, NO, and LPO in Pb-increased LPS-induced liver damage in rats. Treatment with PKC and p42/44 MAPK inhibitors significantly reduced Pb + LPS-induced NO, TNF-alpha, LPO, and liver damage, which was revealed by elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Pb + LPS coexposure significantly increased phosphorylation of p42/44 MAPK and TNF-alpha expression in peripheral blood cells; however, exposure to Pb + LPS did not induce TNF-alpha, NO, or LPO production and p42/44 MAPK activation in the liver. Pentoxifylline, a TNF-alpha inhibitor, also reduced liver damage but did not alter NO or LPO in Pb + LPS-treated rats. Thus, Pb increased LPS-induced liver damage through PKC and p42/44 MAPK modulation of TNF-alpha and oxidative stress, but modulation of TNF-alpha did not affect NO or LPO in rats.
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PMID:Modulation of tumor necrosis factor-alpha and oxidative stress through protein kinase C and P42/44 mitogen-activated protein kinase in lead increases lipopolysaccharide-induced liver damage in rats. 1604 92

Idiosyncratic liver injury occurs in a small fraction of people on certain drug regimens. The cause of idiosyncratic hepatotoxicity is not known; however, it has been proposed that environmental factors such as concurrent inflammation initiated by bacterial lipopolysaccharide (LPS) increase an individual's susceptibility to drug toxicity. Ranitidine (RAN), a histamine-2 receptor antagonist, causes idiosyncratic liver injury in humans. In a previous report, idiosyncrasy-like liver toxicity was created in rats by cotreating them with LPS and RAN. In the present study, the ability of metabonomic techniques to distinguish animals cotreated with LPS and RAN from those treated with each agent individually was investigated. Rats were treated with LPS or its vehicle and with RAN or its vehicle, and urine was collected for nuclear magnetic resonance (NMR)- and mass spectroscopy-based metabonomic analyses. Blood and liver samples were also collected to compare metabonomic results with clinical chemistry and histopathology. NMR metabonomic analysis indicated changes in the pattern of metabolites consistent with liver damage that occurred only in the LPS/RAN cotreated group. Principal component analysis of urine spectra by either NMR or mass spectroscopy produced a clear separation of the rats treated with LPS/RAN from the other three groups. Clinical chemistry (serum alanine aminotransferase and aspartate aminotransferase activities) and histopathology corroborated these results. These findings support the potential use of a noninvasive metabonomic approach to identify drug candidates with potential to cause idiosyncratic liver toxicity with inflammagen coexposure.
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PMID:Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide. 1605 Dec 91

To examine the role of histamine H1 and H2 receptors in the regulation of lipopolysaccharide (LPS)-induced liver injury, a combination of D-galactosamine and LPS (GalN/LPS) was administered to histamine H1 receptor knockout (H1-R KO) and H2 receptor knockout (H2-R KO) mice. The numbers of necrotic and apoptotic hepatocytes in the liver, as well as the levels of serum aspartate transaminase (AST) and alanine transaminase (ALT), were increased significantly by GalN/LPS treatment compared to the appropriate controls. Pretreatment with histamine ameliorated the GalN/LPS-induced necrotic and apoptotic changes in the hepatocytes and inhibited the elevation of serum AST and ALT levels. Histamine attenuated the GalN/LPS-induced increases in the levels of TNF-alpha, but augmented those of IL-10 both in the liver and serum. Histamine inhibited the GalN/LPS-induced caspase-3 activity in the liver. Furthermore, these effects of histamine were completely or partially attenuated in H2-R KO mice, but not in H1-R KO mice. Peritoneal macrophages from H2-R KO mice exhibited blunted changes in the effects of histamine on LPS-induced TNF-alpha and IL-10 production in vitro compared to the wild-type (WT) controls. In summary, the present findings suggest that the histamine H2-R-TNF-alpha and -IL-10 pathways play protective roles in endotoxin-induced hepatic injury.
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PMID:The role of histamine H1 receptor and H2 receptor in LPS-induced liver injury. 1605 91

Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg(-1) intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg(-1) i.v.) or DL-propargylglycine (PAG, 10-100 mg kg(-1) i.v.), an inhibitor of the H2S-synthesizing enzyme cystathionine-gamma-lyase (CSE). PAG was administered either 30 min prior to or 60 min after the induction of endotoxemia. Endotoxemia resulted in circulatory failure (hypotension and tachycardia) and an increase in serum levels of alanine aminotransferase and aspartate aminotransferase (markers for hepatic injury), lipase (indicator of pancreatic injury) and creatine kinase (indicator of neuromuscular injury). In the liver, endotoxemia induced a significant increase in the myeloperoxidase (MPO) activity, and in the expression and activity of the H2S-synthesizing enzymes CSE and cystathionine-beta-synthase. Administration of PAG either prior to or after the injection of LPS dose-dependently reduced the hepatocellular, pancreatic and neuromuscular injury caused by endotoxemia, but not the circulatory failure. Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H2S and in the liver. These findings support the view that an enhanced formation of H2S contributes to the pathophysiology of the organ injury in endotoxemia. We propose that inhibition of H2S synthesis may be a useful therapeutic strategy against the organ injury associated with sepsis and shock.
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PMID:Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia. 1610 May 27


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