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)

IL-13 has been shown to exert potent anti-inflammatory properties. In this study, we elucidated the functional role of endogenous IL-13 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies demonstrated that the level of IL-13 increased in tissues including liver, lung, and kidney, whereas no considerable increase was found in either peritoneal fluid or serum after CLP. Immunohistochemically, IL-13-positive cells were Kupffer cells in liver, alveolar macrophages in lung, and epithelial cells of urinary tubules in kidney. IL-13 blockade with anti-IL-13 Abs significantly decreased the survival rate of mice after CLP from 53% to 14% on day 7 compared with control. To determine the potential mechanisms whereby IL-13 exerted a protective role in this model, the effects of anti-IL-13 Abs on both local and systemic inflammation were investigated. Administration of anti-IL-13 Abs did not alter the leukocyte infiltration and bacterial load in the peritoneum after CLP but dramatically increased the neutrophil influx in tissues after CLP, an effect that was accompanied by significant increases in the serum levels of aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine. Tissue injury caused by IL-13 blockade was associated with increases in mRNA and the protein levels of CXC chemokines macrophage inflammatory protein-2 and KC as well as the CC chemokine macrophage inflammatory protein-1alpha and the proinflammatory cytokine TNF-alpha. Collectively, these results suggest that endogenous IL-13 protected mice from CLP-induced lethality by modulating inflammatory responses via suppression of overzealous production of inflammatory cytokines/chemokines in tissues.
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PMID:Expression and contribution of endogenous IL-13 in an experimental model of sepsis. 1067 15

This study determined whether free radical formation by the liver, tumor necrosis factor (TNF)-alpha production by isolated Kupffer cells, and plasma endotoxin are affected by dietary saturated fat. Rats were fed enteral ethanol and corn oil (E-CO) or medium-chain triglycerides (E-MCT) and control rats received corn oil (C-CO) or medium-chain triglycerides (C-MCT) for 2 wk. E-CO rats developed moderate fatty infiltration and slight inflammation; however, E-MCT prevented liver injury. Serum aspartate aminotransferase levels, gut permeability, and plasma endotoxin doubled with E-CO but were blunted approximately 50% with E-MCT. In Kupffer cells from E-CO rats, intracellular calcium was elevated by lipopolysaccharide (LPS) in a dose-dependent manner. In cells from E-MCT rats, increases were blunted by approximately 40-50% at all concentrations of LPS. The LPS-induced increase in TNF-alpha production by Kupffer cells was dose dependent and was blunted by 40% by MCT. E-CO increased radical adducts and was reduced approximately 50% by MCT. MCT prevent early alcohol-induced liver injury, in part, by inhibition of free radical formation and TNF-alpha production by inhibition of endotoxin-mediated activation of Kupffer cells.
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PMID:Medium-chain triglycerides inhibit free radical formation and TNF-alpha production in rats given enteral ethanol. 1071 67

The purpose of this study was to determine whether early alcohol-induced liver injury (ALI) in females is associated with changes in CD14 on Kupffer cells, activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat control or ethanol-containing diets for 4 wk using the intragastric enteral protocol. Physiological parameters were similar in both genders. Ethanol was increased as tolerance developed with higher blood levels than previously observed, resulting in a fourfold increase in aspartate aminotransferase (males 389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more rapidly and was nearly twofold greater and endotoxin levels were significantly higher in females after ethanol. Also, expression of CD14 on Kupffer cells was 1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear extracts and TNF-alpha mRNA expression were threefold greater in females. These data are consistent with the hypothesis that elevated endotoxin after ethanol triggers more activation of Kupffer cells via enhanced CD14 expression in females. NF-kappaB is activated in this process, leading to increases in TNF-alpha mRNA expression in the liver and more severe liver injury in females. It is concluded that gender differences in ALI are dependent on endotoxin and a signaling cascade leading to TNF-alpha.
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PMID:Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha. 1076 20

Tumor necrosis factor (TNF)-alpha and Fas ligand (FasL) are trimeric proteins that induce apoptosis through similar caspase-dependent pathways. Hepatocytes are particularly sensitive to inflammation-induced programmed cell death, although the contribution of TNF-alpha and/or FasL to this injury response is still unclear. Here, we report that D-galactosamine and lipopolysaccharide-induced liver injury in C57BL/6 mice is associated with increased hepatic expression of both TNF-alpha and FasL mRNA. Pretreatment of mice with a TNF-binding protein improved survival, reduced plasma aspartate aminotransferase concentrations, and attenuated the apoptotic liver injury, as determined histologically and by in situ 3' OH end labeling of fragmented nuclear DNA. In contrast, pretreatment of mice with a murine-soluble Fas fusion protein (Fasfp) had only minimal effect on survival, and apoptotic liver injury was either unaffected or exacerbated depending on the dose of Fasfp employed. Similarly, mice with a spontaneous mutation in FasL (B6Smn.C3H-Fasl(gld) derived from C57BL/6) were equally sensitive to D-galactosamine/lipopolysaccharide-induced shock. We conclude that the shock and apoptotic liver injury after D-galactosamine/lipopolysaccharide treatment are due primarily to TNF-alpha release, whereas increased FasL expression appears to contribute little to the mortality and hepatic injury.
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PMID:Lipopolysaccharide and D-galactosamine-induced hepatic injury is mediated by TNF-alpha and not by Fas ligand. 1080 Dec 87

To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10/IL-4- and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-gamma, TNF-alpha, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity. In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a 10-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection.
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PMID:IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. 1084 96

Although cells of the innate inflammatory response, such as macrophages and neutrophils, have been extensively studied in the arena of Gram-negative bacterial pneumonia, a role for T cells remains unknown. To study the role of specific T cell populations in bacterial pneumonia, mice deleted of their TCR beta- and/or delta-chain were intratracheally inoculated with Klebsiella pneumoniae. Gamma delta T cell knockout mice displayed increased mortality at both early and late time points. In contrast, mice specifically lacking only alpha beta-T cells were no more susceptible than wild-type mice. Pulmonary bacterial clearance in gamma delta-T cell knockout mice was unimpaired. Interestingly, these mice displayed increased peripheral blood dissemination. Rapid up-regulation of IFN-gamma and TNF-alpha gene expression, critical during bacterial infections, was markedly impaired in lung and liver tissue from gamma delta-T cell-deficient mice 24 h postinfection. The increased peripheral blood bacterial dissemination correlated with impaired hepatic bacterial clearance following pulmonary infection and increased hepatic injury as measured by plasma aspartate aminotransferase activity. Combined, these data suggest that mice lacking gamma delta-T cells have an impaired ability to resolve disseminated bacterial infections subsequent to the initial pulmonary infection. These data indicate that gamma delta-T cells comprise a critical component of the acute inflammatory response toward extracellular Gram-negative bacterial infections and are vital for the early production of the proinflammatory cytokines IFN-gamma and TNF-alpha.
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PMID:Gamma delta-T cells are critical for survival and early proinflammatory cytokine gene expression during murine Klebsiella pneumonia. 1094 93

To clarify the relationship between coffee and fitness, we investigated the effect of coffee on weight gain and total cholesterol as well as production of cytokines and activities of GOT (aspartate aminotransferase; EC 2.6.1.1.) and GPT (alanine aminotransferase; EC 2.6.1.2.) as injected lipopolysaccharides. Forty-eight male Wistar rats were divided into three dietary groups (n=16), which were fed a stock diet (control group), the diet supplemented with freeze-dried coffee of 6.2 g/kg (0.62% coffee group), and the diet supplemented with freeze-dried coffee of 13.6 g/kg (1.36% coffee group). It was confirmed by HPLC analysis that the serum caffeine concentrations in both coffee groups became significantly higher in 140 days after the start of feeding. No significant differences in body weight and serum cholesterol were found between the coffee groups and control group, though the coffee groups tended to be somewhat high at cholesterol level. Activities of serum GOT and GPT increased at 2 h after LPS injection, but in the coffee groups were significantly suppressed (p<0.05). However, the coffee feeding could not suppress the increases of serum cytokine (TNF-alpha and IL-6) levels. These results suggest that coffee may serve as a preventive against liver injury.
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PMID:Coffee and fitness-coffee suppresses lipopolysaccharide-induced liver injury in rats. 1122 4

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

Administration of Con A induces severe injury to hepatocytes in mice and is considered to be a model for human hepatitis. In the current study, we investigated the role of CD44 in Con A-induced hepatitis. Intravenous administration of Con A (20 mg/kg) caused 100% mortality in C57BL/6 CD44-knockout (KO) mice, although it was not lethal in C57BL/6 CD44 wild-type (WT) mice. Administration of lower doses of Con A (12 mg/kg body weight) into CD44 WT mice induced hepatitis as evident from increased plasma aspartate aminotransferase levels accompanied by active infiltration of mononuclear cells and neutrophils, and significant induction of apoptosis in the liver. Interestingly, CD44 KO mice injected with similar doses of Con A exhibited more severe acute suppurative hepatitis. Transfer of spleen cells from Con A-injected CD44 KO mice into CD44 WT mice induced higher levels of hepatitis when compared with transfer of similar cells from CD44 WT mice into CD44 WT mice. The increased hepatitis seen in CD44 KO mice was accompanied by increased production of cytokines such as TNF-alpha, IL-2 and IFN-gamma, but not Fas or Fas ligand. The increased susceptibility of CD44 KO mice to hepatitis correlated with the observation that T cells from CD44 KO mice were more resistant to activation-induced cell death when compared with the CD44 WT mice. Together, these data demonstrate that activated T cells use CD44 to undergo apoptosis, and dysregulation in this pathway could lead to increased pathogenesis in a number of diseases, including hepatitis.
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PMID:CD44-deficient mice exhibit enhanced hepatitis after concanavalin A injection: evidence for involvement of CD44 in activation-induced cell death. 1134 3

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


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