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)

The two apoptosis receptors of mammalian cells, i.e. the 55 kDa TNF receptor (TNF-R1) and CD95 (Fas/APO1) are activated independently of each other, however, their signaling involves a variety of ICE-related proteases [I]. We used a cell-permeable inhibitor of ICE-like protease activity to examine in vivo whether post-receptor signaling of TNF and CD95 are fully independent processes. Mice pretreated with the inhibitor, Z-VAD-fluoromethylketone (FMK) were dose-dependently protected from liver injury caused by CD95 activation as determined by plasma alanine aminotransferase and also from hepatocyte apoptosis assessed by DNA fragmentation (ID50 = 0.1 mg/kg). A dose of 10 mg/kg protected mice also from liver injury induced by TNF-alpha. Similar results were found when apoptosis was initiated via TNF-alpha or via CD95 in primary murine hepatocytes (IC50 = 1.5 nM) or in various human cell lines. In addition to prevention, an arrest of cell death by Z-VAD-FMK was demonstrated in vivo and in vitro after stimulation of apoptosis receptors. These findings show in vitro and in vivo in mammals that CD95 and the TNF-alpha receptor share a distal proteolytic apoptosis signal.
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PMID:ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-alpha. 909 74

The Fas receptor (APO-1/CD95) is expressed on hepatocytes and is thought to be important in triggering apoptosis after ligation by the Fas ligand carried on cytotoxic T cells. Recent evidence has shown that several splice variants of Fas exist, the major one of which (FasTMDel) may produce a soluble protein which can modulate apoptosis by interacting with ligand. There are no data on the expression of splice variants of Fas in liver disease. RNA was extracted from needle biopsies from 13 patients with hepatitis C virus (HCV) infection and six normal liver samples. By reverse transcriptase polymerase chain reaction (RT-PCR) FasTMDel expression was demonstrated at the mRNA level, in both normal and HCV-infected liver. Quantitative PCR demonstrated an increase in Fas transcript relative to FasTMDel in HCV infection. This difference is due to an induction of Fas, with FasTMDel remaining at constant levels in the two groups. If translated into protein, liver cells may express more Fas and thus be susceptible to apoptosis inducible by ligand-bearing cytotoxic T cells. These findings suggest that mechanisms exist to regulate the differential splicing of Fas and FasTMDel dependent on the cell's environment. The degree of alteration in the levels of Fas relative to FasTMDel occurred independently of the ALT levels and histological grading of the HCV-infected cases. However, an association was noted between increasing Fas:FasTMDel ratio and log viral load in the liver, measured by competitive PCR.
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PMID:Alteration in mRNA levels of Fas splice variants in hepatitis C-infected liver. 942 85

Endotoxin (ET) induces neutrophil sequestration in hepatic sinusoids, the activation of proinflammatory transcription factors (nuclear factor KB [NF-kappaB]) with up-regulation of adhesion molecules on sinusoidal endothelial cells and hepatocytes. However, if galactosamine (Gal) is co-administered with ET, neutrophils transmigrate and attack parenchymal cells. This suggests that a signal from parenchymal cells triggers neutrophil transmigration. In this study, we tested the hypothesis that parenchymal cell apoptosis may induce neutrophil transendothelial migration in the Gal/ET model. Treatment of C3Heb/FeJ mice with 700 mg/kg Gal and 100 microg/kg ET induced tumor necrosis factor alpha (TNF-alpha) formation (13.25 +/- 0.75 ng/mL) and hepatic NF-kappaB activation at 90 minutes; the generation of the C-X-C chemokine KC (2.86 +/- 0.30 ng/mL at 5 hours); sinusoidal neutrophil sequestration (380 +/- 21 polymorphonuclear leukocytes/50 high-power fields) and apoptosis (925% +/- 29% increase of DNA fragmentation; and a 45-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells) at 6 hours, followed by transmigration of neutrophils and development of substantial necrosis (38% +/- 3% of hepatocytes; alanine transaminase [ALT]: 1,500 +/- 300 U/L) at 7 hours. Administration of uridine (1,000 mg/kg) did not reduce plasma levels of TNF-alpha and KC, NF-kappaB activation, or polymorphonuclear leukocyte sequestration, but attenuated apoptosis by 90% to 94%. In these livers, neutrophils did not transmigrate and liver injury was prevented (necrosis: < 5%; ALT: 40 +/- 3 U/L). However, massive apoptosis and liver injury initiated by the anti-Fas antibody, Jo2, did not recruit neutrophils into the liver. We conclude that excessive parenchymal cell apoptosis represents an important signal for transmigration of primed neutrophils sequestered in sinusoids during endotoxemia in vivo. However, apoptosis per se does not cause neutrophil sequestration in the liver vasculature.
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PMID:Parenchymal cell apoptosis as a signal for sinusoidal sequestration and transendothelial migration of neutrophils in murine models of endotoxin and Fas-antibody-induced liver injury. 973 84

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-expressing cells. A matrix metalloproteinase-like enzyme cleaves the membrane-bound FasL to produce the soluble FasL (sFasL). Since FasL has been reported to play a pivotal role in the development of hepatitis, we evaluated clinical significance of serum sFasL in acute liver injury including acute self-limited and fulminant hepatitis. Serum sFasL in 19 patients including 12 with acute self-limited hepatitis and 7 with fulminant hepatitis was measured by an enzyme-linked immunosorbent assay (ELISA). The clinical data consisted of 18 indices including age, sex, liver function tests, hepatocyte growth factor (HGF), outcome and sFasL. Serum sFasL in fulminant hepatitis is 0.06+/-0.01 ng/ml, being identical to that in acute self-limited hepatitis, Serum sFasL is positively correlated with AST and ALT (p<0.0001 and p<0.0001). The factors associated with outcome of the patients were HGF, albumin, prothrombin time, platelet count, cholinesterase and leukocyte count in this order. Serum sFasL serves as an indicator of liver injury in acute self-limited and fulminant hepatitis.
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PMID:Clinical significance of serum soluble Fas ligand in patients with acute self-limited and fulminant hepatitis. 975 39

Experimental hepatitis induced by tumor necrosis factor in D-(+)-galactosamine-sensitized mice or by an agonistic anti-Fas antibody in normal mice is accompanied by dramatic apoptosis of hepatocytes. Apoptosis is the final result of activation of a cascade of caspases. We used caspase-1-/- mice, generated by gene targeting, to study the role of this protease in TNF- and anti-Fas-induced lethal hepatitis. We found that mutant mice exhibited the typical caspase-1-/- phenotype, since they resisted to a lethal injection of LPS and released no interleukin-1beta in the circulation, in contrast to wild-type littermates. When caspase-1-/- mice were challenged with different doses of tumor necrosis factor/D-(+)-galactosamine or with anti-Fas, no increased survival was observed compared with control mice. Furthermore, apoptosis in the livers of these mice and serum levels of alanine aminotransferase were not reduced. These data indicate that caspase-1 deficiency does not lead to reduced apoptosis in these models, either because caspase-1 is irrelevant in this model or because of functional redundancy.
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PMID:Caspase-1 is not involved in experimental hepatitis in mouse. 1006 84

The mechanism of liver cell injury induced by an overdose of the analgesic acetaminophen (AAP) remains controversial. Recently, it was hypothesized that a significant number of hepatocytes die by apoptosis. Since caspases have been implicated as critical signal and effector proteases in apoptosis, we investigated their potential role in the pathophysiology of AAP-induced liver injury. Male C3Heb/FeJ mice were fasted overnight and then treated with 500 mg/kg AAP. Liver injury became apparent at 4 h and was more severe at 6 h (plasma ALT activities: 4110 +/- 320 U/liter; centrilobular necrosis). DNA fragmentation increased parallel to the increase of plasma ALT values. At 6 h there was a 420% increase of DNA fragmentation and a 74-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells located predominantly around central veins. However, the activity of the proapoptotic caspase-3 was not increased at any time after AAP. In contrast, injection of the anti-Fas antibody Jo-2 (positive control) caused a 28-fold increase of caspase-3 activity and severe DNA fragmentation before significant ALT release. Treatment with the caspase inhibitor ZVAD-CHF2 had no effect on AAP toxicity but completely prevented Jo-mediated apoptosis. In contrast, Jo-induced caspase activation and apoptosis could be inhibited by AAP treatment in a time- and dose-dependent manner. We conclude that AAP-induced DNA fragmentation does not involve caspases, suggesting a direct activation of endonucleases through elevated Ca2+ levels. In addition, electrophilic metabolites of AAP may inactivate caspases or their activation pathway. This indicates that AAP metabolism has the potential to inhibit signal transduction mechanisms of receptor-mediated apoptosis.
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PMID:Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice. 1022 10

The effect of cyclosporine A (CsA) on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibody (250 microg/kg) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 hr. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with CsA (10, 30 and 100 mg/kg) in a dose-dependent manner. Anti-Fas antibody administration elevated CPP32-like protease activity at 3 hr in mouse liver, and this elevation of CPP32-like activity was inhibited by treatment with CsA. The present results show that CsA treatment inhibits the anti-Fas antibody-induced apoptotic process of hepatitis, at least in part, by affecting a reaction upstream of CPP32-like protease activation.
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PMID:The protective effect of cyclosporine A on anti-Fas antibody-induced hepatitis in mice. 1036 89

The well known discrepancy between cytotoxic T lymphocyte (CTL) infiltration in the liver and disease biological activity, as assessed by alanine aminotransferase (ALT) levels, during the course of chronic hepatitis C virus (HCV) infection, suggests the possible failure of cytotoxic mechanisms devoted to virus clearance. To further investigate the biological events involved in CTL-mediated lysis, i.e. B7/CD28 costimulatory and Fas/Fas-ligand pathways, the CD80 and CD95 antigen expression in liver tissue specimens from chronically HCV-infected patients was evaluated. The results were analysed in relation to serum ALT values and the histological activity (HAI) of liver disease. The data provide evidence for a strong and comparable hepatocyte CD80 and C95 structure expression in chronically HCV-infected livers. CD80- and CD95-carrying liver cells were more frequently distributed at the periportal region of the hepatic lobule, above all near piecemeal necrosis areas, among infiltrating CTL. On the other hand, a negative correlation was found between liver tissue expression of both antigens and serum ALT activity. The relationship with HAI was not statistically significant. The results imply that HCV infection triggers CD80 and CD95 molecule expression on hepatocytes. Further studies are required to clarify the relevance of such a finding in the context of virus-host interactions.
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PMID:Liver tissue expression of CD80 and CD95 antigens in chronic hepatitis C: relationship with biological and histological disease activities. 1041 66

Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.
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PMID:Nitric oxide ameliorates actinomycin D/endotoxin-induced apoptotic liver failure in mice. 1042 31

The effect of pentoxifylline on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibodies (250 microg/kg, i.v.) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 h. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with pentoxifylline at the doses of 10 and 100 mg/kg (i.p.). Anti-Fas antibody administration also elevated the CPP32-like protease activity in the liver at 3 h. Although pentoxifylline at 100 mg/kg, i.p., inhibited the anti-Fas antibody-induced elevation of plasma ALT, this treatment did not significantly inhibit the anti-Fas antibody-induced elevation of CPP32-like activity. The present results clearly showed that treatment with pentoxifylline inhibited anti-Fas antibody-induced hepatitis, at least in part, by affecting a reaction downstream of CPP32-like protease activation.
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PMID:Pentoxifylline inhibits anti-Fas antibody-induced hepatitis by affecting downstream of CPP32-like activity in mice. 1056 69


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