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)

Reperfusion injury can cause liver dysfunction after cold storage and warm ischemia. Recently it has been suggested that more than 50% of hepatocytes and sinusoidal endothelial cells (SEC) are undergoing apoptosis during the first 24 hours of reperfusion. The aim of our study was to quantify apoptotic and necrotic hepatocytes and apoptotic SEC after 60 or 120 minutes of warm, partial no-flow ischemia and 0 to 24 hours reperfusion in male SD rats. Apoptotic cells were identified by TUNEL assay in combination with morphological criteria. After 60 minutes of ischemia and 1 hour of reperfusion there was a significant increase of apoptotic hepatocytes (0.7 +/- 0.1% vs. 0.3 +/- 0.1% in controls) and SEC (1.5 +/- 0.6% vs. 0.3 +/- 0.1% in controls). The number of apoptotic SEC and hepatocytes was not different from controls at 6 hours or 24 hours of reperfusion. In contrast, the number of necrotic hepatocytes was quantified as 12 +/- 2% at 1 hour, 34 +/- 6% at 6 hours, and 57 +/- 11% at 24 hours. These results correlated with the increase in plasma ALT levels at these time points. Longer (120 min) ischemia times did not affect the number of apoptotic cells but increased hepatocellular necrosis to 58 +/- 4% at 6 hours reperfusion. No significant increase in caspase-3 activity and processing was detectable in any of these livers. Moreover, the caspase inhibitor Z-Asp-cmk (2 mg/kg IV) had no significant effect on reperfusion injury. Our results suggest that only a small minority of SEC and hepatocytes undergo apoptosis after 60 to 120 minutes of warm ischemia followed by 0 to 24 hours of reperfusion. Oncotic necrosis appears to be the principal mechanism of cell death for both cell types.
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PMID:Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis? 1139 50

The effects of imperatorin and its synthetic derivative, Y355, on anti-Fas antibody-induced mice hepatitis were studied. Pretreatment of mice by intraperitoneal administration of imperatorine or Y355 at 30 mg/kg inhibited more than 80% of the anti-Fas antibody (150 microg/kg, i.v.)-induced elevation of plasma alanine aminotransferase activity. Furthermore, oral administration of imperatorin or Y355 at 100 mg/kg also had an inhibitory effect on anti-Fas antibody-induced hepatitis. Both compounds inhibited anti-Fas antibody (250 microg/kg)-induced caspase-1 and caspase-3 activities. The present results showed the inhibition of anti-Fas antibody-induced hepatitis by imperatorin and Y355, which might be a result of inhibition of caspase activities.
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PMID:Inhibition of anti-Fas antibody-induced mice hepatitis by furocoumarin derivatives. 1117 22

We examined the effects of ZNC-2381 (1-(4-aminophenyl)methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo[4,5-b] pyridine-2-one), a new oral hepatoprotective agent, on hepatocellular caspase-3 activity and apoptosis induced by anti-mouse Fas antibody (anti-Fas ab) in mice. Oral ZNC-2381, administered at doses of 10, 30 and 100 mg/kg 1 h before inducing hepatic injury with anti-Fas ab, dose-dependently inhibited the increase in serum alanine aminotransferase (s-ALT) activity 8 h after injection of anti-Fas ab. Increases in DNA fragmentation (nucleosome assay) and caspase-3 activity in the liver 2 h after injection of anti-Fas ab were also inhibited by ZNC-2381 in a dose-dependent manner. As shown by histopathological examination, ZNC-2381 dose-dependently inhibited the appearance of TUNEL-positive apoptotic cells in the liver. Moreover, in studies in vitro, ZNC-2381 (1- 100 micromol/l) concentration-dependently inhibited increases in DNA fragmentation and caspase-3 activity caused by anti-Fas ab in isolated mouse hepatocytes. N- Acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-cho), a caspase-3-specific inhibitor, inhibited hepatocellular apoptosis caused by anti-Fas ab both in vivo and in vitro, as well as the increase in s-ALT activity in vivo. These results demonstrate that orally administered ZNC-2381 inhibits hepatocellular apoptosis induced by anti-Fas ab and presents the progression of hepatic injury. We propose that the mechanism of action of ZNC-2381 may involve blockade of the signal transduction pathway (caspase-3) of apoptosis mediated by anti-Fas ab.
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PMID:Effects of a novel hepatoprotective drug, ZNC-2381, on fas-induced hepatocellular caspase-3 activity and apoptosis in mice. 1117 76

D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor alpha (TNF-alpha) plays a pivotal role. We examined the effects of etoposide on GalN/LPS-induced fulminant hepatic failure. Mice were given an intraperitoneal dose of GalN (800 microg/g body weight)/LPS (100 ng/g body weight) with and without intraperitoneal etoposide (10 microg/g body weight) treatment. Liver injury was assessed biochemically and histologically. TNF-alpha levels in the serum, and apoptosis of hepatocytes and CPP32/caspase-3 in the liver, were determined. GalN/LPS treatment caused lethal liver injury in 87% of animals (13 of 15). The effect was associated with significant increases in TNF-alpha and alanine transaminase (ALT) levels in serum, the number of apoptotic hepatocytes, CPP32/caspase-3 activity, and TNF receptor 1 (TNFR1) mRNA expression in the liver. Etoposide (10 microg/g body weight) was given 3 times (at 50, 26, and 4 hours before GalN/LPS administration). Treatment of GalN/LPS-treated mice with etoposide reduced apoptosis of hepatocytes, resulting in reduction of lethality (13% [2 of 15]), while another topoisomerase II inhibitor, IRCF-193, showed no significant effect. The antilethal effect of etoposide was also confirmed in GalN/TNF-alpha-induced fulminant hepatic failure. Etoposide treatment reduced CPP32/caspase-3 activity in the liver, although it did not alter the serum TNF-alpha levels or hepatic TNFR1 mRNA expressions. In addition, etoposide treatment enhanced the mRNA and protein expression of Bcl-xL, an antiapoptotic molecule in the liver. The present findings suggest that etoposide prevents endotoxin-induced lethal liver injury by up-regulation of Bcl-xL, and that etoposide could be useful for the treatment of TNF-alpha-mediated liver diseases.
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PMID:Etoposide prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure resulting in reduction of lethality. 1139 33

Excessive apoptosis has been implicated in a number of acute and chronic human diseases. The activation of caspases has been shown to be critical for the apoptotic process. The objective of this investigation was to evaluate the beneficial effects and mechanism of action of the caspase-8 inhibitor IETD-CHO and the caspase-3 inhibitor DEVD-CHO against tumor necrosis factor (TNF)-induced hepatocellular apoptosis in vivo and compare these results to effects of the same inhibitors against Fas-induced apoptosis. Treatment of C3Heb/FeJ mice with 700 mg/kg galactosamine/100 microg/kg endotoxin induced parenchymal apoptosis (indicated by caspase-3 activation and morphology) and severe liver injury (indicated by the increase in plasma alanine aminotransferase activities and histology) at 7 h. Treatment with IETD-CHO or DEVD-CHO (10 mg/kg at 3, 4.5, and 5.5 h) significantly attenuated caspase-3 activation and liver injury. Western analysis showed that DEVD-CHO had no effect while IETD-CHO substantially reduced procaspase-3 and procaspase-9 processing. On the other hand, caspase-3 activation and liver injury by the anti-Fas antibody Jo-2 was completely prevented by a single dose of DEVD-CHO and, as previously shown, by IETD-CHO at 90 min. Both inhibitors prevented procaspase-3 and procaspase-9 processing. Thus, there are fundamental differences in the efficacy of caspase inhibitors in these two models. We conclude that Fas may rely exclusively on caspase-8 activation and mitochondria to activate caspase-3, which can process more procaspase-8 and thus propagate the amplification of the apoptotic signal. TNF can activate a similar signaling pathway. However, alternative signaling mechanisms seem to exist, which can compensate if the main pathway is blocked.
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PMID:Differential protection with inhibitors of caspase-8 and caspase-3 in murine models of tumor necrosis factor and Fas receptor-mediated hepatocellular apoptosis. 1155 23

O(2)-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), a liver-selective nitric oxide (NO)-donating prodrug, is metabolized by hepatic enzymes to release NO within the liver. This study was undertaken to examine the effects of V-PYRRO/NO on D-galactosamine/lipopolysaccharide (GlaN/LPS)-induced liver injury in mice. Mice were given injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after GlaN/LPS (700 mg/30 microg/kg, i.p.). V-PYRRO/NO administration dramatically reduced GlaN/LPS-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase activity and improved pathology. To examine the mechanisms of the protection, cDNA microarray was performed to profile the gene expression pattern in livers of mice treated with GlaN/LPS, GlaN/LPS plus V-PYRRO/NO, or controls. V-PYRRO/NO administration greatly ameliorated GlaN/LPS-induced alterations in the expression of genes encoding the stress response, DNA damage/repair response, and drug-metabolizing enzymes in accordance with hepatoprotection. Gel shift assay and Western blot analysis supported microarray results, showing that V-PYRRO/NO suppressed GlaN/LPS-induced activation of nuclear factor-kappaB and GlaN/LPS-induced increases in caspase-1, caspase-8, tumor necrosis factor receptor 1 (TNFR1)-associated death domain, and TNF-related apoptosis-inducing ligand. Immunohistochemical analysis further revealed that GlaN/LPS-induced activation of TNFR1, caspase-3, and hepatocellular apoptosis was ameliorated by V-PYRRO/NO treatment. GlaN/LPS-induced elevation of hepatic caspase-3 activity was diminished by V-PYRRO/NO treatment. In addition, V-PYRRO/NO alone suppressed the basal expression of genes encoding inducible NO synthase and TNF-alpha-related components, as revealed by mouse 1.2 array. In summary, this study demonstrates that the liver-selective NO donor, V-PYRRO/NO, is effective in blocking GlaN/LPS-induced hepatotoxicity in mice, and that this protection appears to involve, at least in part, the suppression of the TNF-alpha-mediated cell death pathways.
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PMID:O(2)-Vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate protection against D-galactosamine/endotoxin-induced hepatotoxicity in mice: genomic analysis using microarrays. 1175 92

M50054, 2,2'-methylenebis (1,3-cyclohexanedione), was identified as a novel inhibitor of apoptosis (programmed cell death) using an in vitro cell death assay system induced in human Fas-expressing WC8 cells by soluble human Fas ligand. Furthermore, M50054 inhibited the apoptotic cell death of U937, a human monocytic leukemic cell line, induced by anticancer agents such as etoposide; it was also confirmed that M50054 inhibited apoptotic features such as DNA fragmentation and phosphatidylserine exposure in these cells. These anti-apoptotic effects were attributable to inhibition of caspase-3 activation. Additionally, M50054 significantly inhibited anti-Fas-antibody-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase. Alopecia (hair loss) symptoms were also significantly improved with topical treatment with M50054. In conclusion, M50054 inhibits apoptosis induced by a variety of stimuli via inhibition of caspase-3 activation, and may thus be effective for hepatitis and chemotherapy-induced alopecia.
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PMID:Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia. 1175 32

Acute administration of cadmium results in hepatotoxicity. Recent reports indicate that Kupffer cells, the resident macrophages of the liver, participate in the manifestation of chemical-induced hepatotoxicity. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that is a major product of Kupffer cells and mediates the hepatotoxic effects of lipopolysaccharide (LPS). It has been speculated that cadmium also may exert its hepatotoxicity via the production of TNF-alpha by the Kupffer cells. Therefore, this study was undertaken to determine whether mice deficient in TNF-alpha are resistant to Cd-induced hepatotoxicity. TNF-alpha-null (TNF-KO) and wild-type (WT) mice were dosed ip with saline, LPS (0.1 mg/kg)/Gln (d-galactosamine, 700 mg/kg), or CdCl2 (2.2, 2.8, 3.4, and 3.9 mg Cd/kg). Serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities were quantified to assess liver injury. Caspase-3 activity was quantified to assess hepatocellular apoptosis. LPS/Gln treatment increased ALT (17-fold) and SDH (21-fold) in WT mice. In contrast, LPS/Gln-treatment did not significantly increase ALT or SDH in TNF-KO mice. LPS/Gln-treatment caused a 7.8-fold increase in caspase-3 activity in WT mice but did not increase caspase-3 in TNF-KO mice. Cadmium caused a dose-dependent increase in liver injury in both WT and TNF-KO mice. However, the liver injury produced by Cd in the TNF-KO mice was not different from that in WT at any dose. No significant increase in caspase-3 activity was detected in any of the Cd-treated mice. These data indicate that, in contrast to LPS/Gln-induced hepatotoxicity, TNF-alpha does not appear to mediate Cd-induced hepatotoxicity.
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PMID:Tumor necrosis factor-alpha-null mice are not resistant to cadmium chloride-induced hepatotoxicity. 1190 45

Acetaminophen (AAP) overdose can cause severe liver injury and liver failure in experimental animals and humans. Recently, several authors proposed that apoptosis might be a major mechanism of cell death after AAP treatment. To address this controversial issue, we evaluated a detailed time course of liver injury after AAP (300 mg/kg) in fasted C3Heb/FeJ mice. Apoptotic hepatocytes were quantified in H&E-stained liver sections using morphologic criteria (cell shrinkage, chromatin condensation and margination, and apoptotic bodies). The number of apoptotic hepatocytes remained at baseline (0.2 +/- 0.1 cells/10 high-power fields [HPF]) up to 2 h after AAP administration. However, between 3 and 24 h, apoptotic cell death increased significantly, e.g., 6.3 +/- 0.8 cells/10 HPF at 6 h. Despite the increase in the number of hepatocytes meeting the morphological criteria of apoptosis, this cell fraction remained well below 1% of all parenchymal cells. No evidence for caspase-3 processing or increase in enzyme activity was detected at any time. These results were compared to the overall percent of necrotic cells in liver sections. Confluent areas of centrilobular necrosis were estimated to involve 40-60% of all hepatocytes between 3 and 24 h after AAP administration. These numbers correlated with the increase in plasma alanine aminotransferase activities, which reached a peak level of 5900 +/- 1350 U/l at 24 h. A similar result was obtained with higher doses of AAP and with the use of fed animals. Thus, oncotic necrosis and not apoptosis is the principal mechanism of liver-cell death after AAP overdose in vivo.
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PMID:Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? 1201 92

Reactive oxygen species (ROS) can directly induce or enhance tumor necrosis factor (TNF)-mediated apoptosis in a number of different cell lines. To test the relevance of intracellular ROS in modulating apoptotic signaling in vivo, we evaluated hepatocellular apoptosis mediated by the TNF or Fas receptor in wild-type and glutathione peroxidase-1 (Gpx1-/-)-deficient mice (129SV/B6 background). Apoptosis developed in livers of wild-type animals 4-6 h after intraperitoneal administration of 700 mg/kg galactosamine/100 micro g/kg endotoxin. Apoptosis was indicated by processing of procaspases-3 (assessed by western blotting), a fivefold increase in caspase-3 activity (DEVD-AMC as substrate), and a 44-fold increase in DNA fragmentation (ELISA). The time course and magnitude of apoptosis were the same in Gpx1-/- mice. In contrast, Gpx1-/- mice had higher plasma alanine aminotransferase (ALT) levels and more severe hemorrhage compared to wild-type animals at 6 h. Treatment of wild-type mice with the anti-Fas antibody Jo-2 (0.6 mg/kg i.v.) resulted in processing of procaspase-3 and a sevenfold increase in caspase-3 activity in both wild-type and Gpx1-/- mice. However, higher plasma ALT values in Gpx1-/- mice at 3 h may reflect a trend to develop more rapidly secondary necrosis. These data suggest that, under our experimental conditions, intracellular ROS did not modulate the death receptor-initiated apoptotic signaling cascade in hepatocytes. As Gpx1 is located in the cytosol and in mitochondria, which are the main cellular compartments involved in apoptotic signaling, our findings indicate that the oxidant stress in vivo was insufficient to modulate these signaling pathways. However, Gpx1 deficiency enhances the susceptibility for secondary necrosis or neutrophil-induced cell injury.
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PMID:Reactive oxygen as modulator of TNF and fas receptor-mediated apoptosis in vivo: studies with glutathione peroxidase-deficient mice. 1247 May


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