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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

INTRODUCTION: Heme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron. Under situations of oxidative stress, heat stress, ischemia/reperfusion injury or endotoxemia, HO-1 has been shown to be induced and to elicit a protective effect. The mechanism of how this protective effect is executed is unknown. RESULTS: HO-1 induction with cobalt protoporphorin (Co-PP) dose-dependently protected against apoptotic cell death as well as neutrophil-mediated oncosis in the galactosamine/endotoxin (Gal/ET) shock model. Induction of HO-1 with Co-PP dose-dependently protected against neutrophil-mediated oncosis as indicated by attenuated ALT release and TNF-mediated apoptotic cell death as indicated by reduced caspase-3 activation. HO-1 induction did not attenuate Gal/ET-induced TNF-alpha formation. Furthermore, a similar protective effect with the high dose of Co-PP was observed when animals were treated with Gal/TNF-alpha. CONCLUSIONS: HO-1 induction attenuates apoptosis and neutrophil-mediated oncosis in the Gal/ET shock model. However, the protective effect is not due to the reduction of TNF-alpha release or the attenuation of neutrophil accumulation in the liver sinusoids.
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PMID:Heme oxygenase-1 induction in hepatocytes and non-parenchymal cells protects against liver injury during endotoxemia. 1496 Jan 94

Osteopontin (OPN) plays a pivotal role in various immune responses and inflammatory diseases. OPN is expressed in various granulomatous diseases; however, the cellular and molecular role of OPN in these diseases is not well known. We analyzed the role of OPN in a beta-glucan-induced hepatic granuloma model. First, we found that neither OPN deficiency nor overexpression of OPN affected the number and the size of hepatic granulomas at day 7, indicating that OPN is not involved in the formation of hepatic granulomas at the early stages. Importantly, OPN did not influence the liver tissue damage as defined by alanine aminotransferase and aspartate aminotransferase levels at early stages. Second, OPN deficiency resulted in the reduction of IL-12 and IFN-gamma production at early stages. Third, at late stages, OPN deficiency resulted in a decrease in the number and size of hepatic granulomas, and a reduction of liver tissue injury. This was due to the reduction of the cellular recruitment including macrophages, CD4 T cells and dendritic cells into the liver, and the reduction of tumor necrosis factor (TNF)-alpha production in the liver. In contrast, overexpression of OPN resulted in the persistence of granuloma formation. These data suggest that OPN affects the persistence of hepatic granuloma formation. Our results indicate that OPN up-regulates the production of IL-12 and IFN-gamma within the granulomas at early stages, and OPN has an additional role in the regulation of cellular recruitment and TNF-alpha production at late stages that determine the severity of liver tissue injury.
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PMID:Osteopontin affects the persistence of beta-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms. 1497 21

Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-gamma and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-gamma and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-alpha, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.
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PMID:Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis. 1500 60

The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 cytokine that plays an important role in several fibroinflammatory diseases. We examined the role of OPN in the development of experimental NASH. A/J mice were fed MCD or control diet for up to 12 wk, and serum alanine aminotransferase (ALT), liver histology, oxidative stress, and the expressions of OPN, TNF-alpha, and collagen I were assessed at various time points. MCD diet-fed mice developed hepatic steatosis starting after 1 wk and inflammation by 2 wk; serum ALT increased from day 3. Hepatic collagen I mRNA expression increased during 1-4 wk, and fibrosis appeared at 8 wk. OPN protein expression was markedly increased on day 1 of MCD diet and persisted up to 8 wk, whereas OPN mRNA expression was increased at week 4. TNF-alpha expression was increased from day 3 to 2 wk, and evidence of oxidative stress did not appear until 8 wk. Increased expression of OPN was predominantly localized in hepatocytes. Hepatocytes in culture also produced OPN, which was stimulated by transforming growth factor-beta and TNF-alpha. Moreover, MCD diet-induced increases in serum ALT levels, hepatic inflammation, and fibrosis were markedly reduced in OPN(-/-) mice when compared with OPN(+/+) mice. In conclusion, our results demonstrate an upregulation of OPN expression early in the development of steatohepatitis and suggest an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH.
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PMID:Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. 1504 74

1. The aim of this study was to investigate the effect of Trolox on hepatic microsomal cytochrome P450 (CYP) activity and gene expression during ischemia and reperfusion (I/R). 2. Rats were subjected to 60 min of hepatic ischemia, and 5 h (acute phase) and 24 h (subacute phase) of reperfusion. Rats were treated intravenously with Trolox (2.5 mg kg(-1)) or vehicle, 5 min before reperfusion. 3. The serum alanine aminotransferase level and lipid peroxidation were increased as a result of I/R. These increases were attenuated by Trolox. Reduced glutathione concentration decreased in I/R group, and this decrease was inhibited by Trolox. 4. Both total hepatic CYP content and NADPH-cytochrome P450 reductase activity decreased after I/R, which were restored by Trolox. 5. CYP1A1 activity and its protein level decreased 24 h after reperfusion; decreases which were prevented by Trolox. Both the activity and mRNA expression of CYP1A2 decreased 24 h after reperfusion. The decrease in CYP1A2 mRNA was prevented by Trolox. CYP2B1 activity and mRNA expression decreased 5 h after reperfusion. The decrease in CYP2B1 activity was prevented by Trolox. In contrast, the CYP2E1 activity and its protein level increased 5 h after reperfusion and this increase was prevented by Trolox. 6. The expression of TNF-alpha and iNOS mRNAs increased after I/R. Trolox inhibited increase in iNOS mRNA expression. 7. Trolox ameliorates hepatic drug-metabolizing dysfunction, as indicated by abnormalities in CYP isoforms during I/R, and this protection is likely due to the scavenging of reactive oxygen species.
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PMID:Effects of Trolox on the activity and gene expression of cytochrome P450 in hepatic ischemia/reperfusion. 1505 25

We studied the effects of cyclosporin A (CsA) administration 1) on the properties of the permeability transition pore (PTP) in mitochondria isolated from the liver and 2) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of Escherichia coli (LPS) plus D-galactosamine (D-GalN) in rats. CsA exerted a marked PTP inhibition ex vivo, with an effect that peaked between 2 and 9 h of drug treatment and decayed with an apparent half-time of about 13 h. Administration of LPS plus D-GalN to naive rats caused the expected increased serum levels of tumor necrosis factor (TNF)-alpha, liver inflammation with BID cleavage, activation of caspase 3, appearance of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive nuclei, and release of alanine aminotransferase and aspartate aminotransferase into the bloodstream. Treatment with CsA before or within 5 h of the administration of LPS plus D-GalN protected rats from hepatotoxicity despite the normal increase of serum TNF-alpha and BID cleavage. These results indicate that CsA prevents the hepatotoxic effects of TNF-alpha by blocking the mitochondrial proapoptotic pathway through inhibition of the PTP and provides a viable strategy for the treatment of liver diseases that depend on increased production and/or liver sensitization to TNF-alpha.
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PMID:Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor-alpha. 1520 Dec 76

Ginsan, a polysaccharide isolated from Panax ginseng, has been shown to be a potent immunomodulator, producing a variety of cytokines such as TNF-alpha, IL-1, IL-2, IL-6, IL-12, IFN-gamma and GM-CSF, and stimulating lymphoid cells to proliferate. In the present study, we analyzed some immune functions 1st-5th days after ginsan i.p. injection, including the level of non-protein thiols (NPSH) as antioxidants, heme oxygenase (HO) activity as a marker of oxidative stress, zoxazolamine-induced paralysis time and level of hepatic cytochrome P-450 (CYP450) as indices of drug metabolism system, and activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and albumin level as indicators of hepatotoxicity. Ginsan in the dose of 100 mg/kg caused marked elevation (1.7 to approximately 2 fold) of HO activity, decrease of total CYP450 level (by 20-34%), and prolongation of zoxazolamine-induced paralysis time (by 65-70%), and showed some differences between male and female mice. Ginsan treatment did not seem to cause hepatic injury, since serum AST, ALT, and ALP activities and levels of total bilirubin and albumin were not changed.
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PMID:Effects of polysaccharide ginsan from Panax ginseng on liver function. 1520 59

Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction of reducing sugars with primary amino groups of proteins (Maillard reaction). They accumulate in various tissues in the course of aging. Because AGEs induce protein cross-links and oxidative stress (radicals) within cells and tissues, they have been implicated in the development of many degenerative diseases. Binding of AGEs to receptors like RAGE induces the release of profibrotic cytokines, such as TGF-beta or proinflammatory cytokines, such as TNF-alpha or IL-6. AGE inhibitors or breakers, such as aminoguanidine or ALT-711, inhibit the age-induced heart hypertrophy or stiffness of the large arteries. On the other hand, little is known about the physiological role of RAGE as the receptor of AGEs. Investigations about the expression of RAGE in lung tissue and lung tumors may give a hint for such a role.
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PMID:RAGE: a new pleiotropic antagonistic gene? 1524 20

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. Leptin-deficient obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum alanine aminotransferase levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-alpha, TGF-beta, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.
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PMID:Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. 1525 62

Background: Rebound hepatitis is a potentially life-threatening complication of withdrawal from immunosuppressive therapy in patients with chronic Hepatitis B viral (HBV) infections. Objectives: To document the incidence of rebound hepatitis and determine whether the hepatitis is associated with serologic evidence of immunological rebound or the appearance of specific mutations in the HBV genome. Methods: Serum cytokines (IL-6, IL-10, TNF-alpha and INF-gamma) were documented by enzyme linked immunoassays and previously described HBV mutants (surface, core, pre-core and basal core promoter) by signal probe hybridization analysis in chronic HBV carriers treated with either 6 weeks of prednisone followed by 6 weeks of acyclovir (PR/AC, n = 20) or placebo/placebo (PL/PL, n = 20). Results: Rebound hepatitis (serum ALT > 2X baseline) occurred in 6/20 (30%) PR/AC patients versus 2/20 (10%) PL/PL recipients (P = 0.24). Serum cytokine levels were similar in those who developed rebound hepatitis compared to those who did not. HBV mutants were absent prior to and during treatment but developed in the follow-up period in three patients. All three patients were PR/AC recipients and in each case, the HBV mutation was in the basal core promoter gene. In two of the three patients, the mutant appeared just prior to the onset of rebound hepatitis while in the third, rebound hepatitis did not occur. Conclusions: The results of this study indicate an association exists between some cases of rebound hepatitis and the development of HBV mutants.
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PMID:Rebound hepatitis following withdrawal of immunosuppressive therapy in patients with chronic Hepatitis B viral infections. 1534 68


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