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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We investigated whether tumor necrosis factor (TNF) and caspase-3 activity are involved in the induction of hepatocellular apoptosis in D-galactosamine (D-GalN)-induced hepatotoxicity in mice. Acute hepatotoxicity was induced by the intraperitoneal injection of D-GalN into female BALB/c mice. D-GalN (0.75-3.0 g/kg) increased the serum glutamate pyruvate transaminase (s-GPT) activity and the percentage of liver DNA fragmentation, an indicator of hepatotoxicity, after 48 h, in a dose-dependent manner. Furthermore, after D-GalN (3.0 g/kg) administration, increased liver DNA fragmentation was detected biochemically at 24 h, then increased s-GPT activity accompanied by increased liver DNA fragmentation was observed after 48 h. The serum TNF (s-TNF) level and the TNF mRNA expression in the liver after D-GalN (3.0 g/kg, i.p.) administration were examined by an ELISA kit and reverse transcription polymerase chain reaction (RT-PCR), respectively, to investigate the relation between the s-GPT activity and liver DNA fragmentation. The s-TNF level and TNF mRNA expression in the liver after D-GalN (3.0 g/kg) administration were detected earlier than liver DNA fragmentation, then increased with time. However, there was almost no association of caspase-3 activity with the increase in liver DNA fragmentation. Increases in the s-TNF level, TNF mRNA expression and the percentage of DNA fragmentation in the liver and s-GPT activity were inhibited by dexamethasone (Dex; 0.4-2.5 mg/kg, i.p.) in a dose-dependent manner. Based on these findings, it was considered that the intracellular apoptosis signal in D-GalN-induced hepatotoxicity in mice did not depend on caspase-3 activity, and that other signals mediated by TNF may be involved.
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PMID:D-galactosamine-induced mouse hepatic apoptosis: possible involvement with tumor necrosis factor, but not with caspase-3 activity. 1054 70

Aminoguanidine is an inhibitor of inducible nitric oxide synthase (iNOS) and is of potential clinical usefulness. Treatment of mice with anti-Fas antibodies (150 microg/kg, i.v.) induced elevation of plasma alanine aminotransferase activity at 4 h and this elevation was inhibited by pretreatment of mice with aminoguanidine (3, 10 and 30 mg/kg, i.p.). The anti-Fas antibody-induced elevation of caspase-3 activity was inhibited by aminoguanidine (30 mg/kg, i.p.), but the addition of aminoguanidine to the cytosol up to 10(-4) M did not inhibit the caspase-3 activity in vitro. Thus, aminoguanidine prevents anti-Fas antibody-induced hepatitis by affecting the apoptotic pathway upstream of caspase-3 activation.
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PMID:Inhibition of anti-Fas antibody-induced hepatitis by aminoguanidine in mice. 1097 30

Lymphocytes can kill target cells including hepatocytes during various inflammatory diseases by Fas receptor-mediated apoptosis. Caspase-8 is activated at the receptor level, thereby initiating the processing of downstream effector caspases. The aim of this study was to investigate the time course of caspase-8 activation and to evaluate the efficacy of the caspase-8 inhibitor IETD-CHO in a model of Fas-induced apoptosis in vivo. C3Heb/FeJ mice were treated with the anti-Fas antibody Jo-2 (0.6 mg/kg). Western blot analysis demonstrated increased cytochrome c in the cytosol (20 min), which was followed by the progressive activation of caspase-3, -9 (40-120 min), and caspase-8 (120 min). At 90 and 120 min, extensive hemorrhage was observed, indicating damage to sinusoidal lining cells. In addition, high plasma ALT levels (997 +/- 316 U/L) and histological evaluation indicated severe parenchymal cell injury. Parenchymal and nonparenchymal cells showed a similar increase in caspase-3 activity and DNA fragmentation. Treatment with IETD-CHO (10 mg/kg) attenuated the increase in caspase-3 activity and DNA fragmentation by 80-90% and completely prevented hemorrhage and parenchymal cell damage. IETD-CHO also prevented the early release of mitochondrial cytochrome c and the processing of caspase-3, -8, and -9. Thus, our data support the hypothesis that Fas-mediated apoptosis is dependent on caspase-8 activation in hepatocytes and nonparenchymal cells. However, the bulk of procaspase-8 is processed late, suggesting that only a small amount of procaspase-8 may actually be activated at the Fas receptor. This initial signal may be amplified by further activation of caspase-8 by effector caspases, i.e., after mitochondrial activation. Caspase-8 is a promising therapeutic target for inhibition of Fas-mediated apoptosis.
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PMID:Protection against Fas receptor-mediated apoptosis in hepatocytes and nonparenchymal cells by a caspase-8 inhibitor in vivo: evidence for a postmitochondrial processing of caspase-8. 1105 47

Excessive apoptotic cell death is implicated in a growing number of acute and chronic disease states. Caspases are critical for the intracellular signaling pathway leading to apoptosis. The aim of this investigation was to evaluate the efficacy and the mechanism of action of the novel caspase inhibitor CV1013 in a well-characterized model of TNF-induced apoptosis. Administration of 700 mg/kg galactosamine/100 microg/kg endotoxin (Gal/ET) induced hepatocellular apoptosis in C3Heb/FeJ mice as indicated by increased caspase-3 activity (706% above controls) and enhanced DNA fragmentation (3400% above controls) at 6 h. In addition, apoptosis was aggravated by the neutrophil-induced injury at 7 h (ALT activities: 4220 +/- 960 U/L and 48 +/- 4% necrosis). All animals died 8-12 h after Gal/ET treatment from shock and liver failure. A dose of 10 or 1 mg/kg of CV1013 administered three times (3, 4.5, and 5.5 h after Gal/ET) effectively prevented caspase-3 activation and parenchymal cell apoptosis at 6 h as well as the subsequent neutrophil-induced aggravation of the injury at 7 h after Gal/ET treatment. Animals treated with 10 mg/kg CV1013 survived for 24 h without liver injury. CV1013 reduced the processing of caspase-3 and caspase-8. This suggests that CV1013 may have inhibited the small amount of active caspase-8 generated at the receptor level. Because of the multiple amplification loops used to activate the entire caspase cascade, blocking the initial intracellular signal by CV1013 was highly effective in preventing apoptotic cell death. CV1013 has therapeutic potential for disease states with excessive apoptosis.
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PMID:Protection against TNF-induced liver parenchymal cell apoptosis during endotoxemia by a novel caspase inhibitor in mice. 1107 99

Hepatocyte growth factor (HGF) has a potent antiapoptotic effect on hepatocytes in D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated rats. Here, we report that adenovirus mediated HGF gene transfer into liver prevents liver failure and reduces mortality of rats treated with d-GalN/LPS. Fisher 344 rats, which were given intraperitoneal injections of pAxCAHGF 48 h before, were treated with D-GalN/LPS. Serum ALT in the HGF group at 6 and 12 h after D-GalN/LPS was decreased to 1/6 and 1/12 of the control group (P < 0.01, each). Concomitant reduction of apoptotic cells were also observed. The Kaplan-Meier analysis showed that a survival rate in the HGF group was improved, compared to that in the control group (P < 0.05). Caspase-3 activity in the HGF group decreased, compared to that in the control group, especially at 12 h (P < 0.05), although it maintained a high level in the control group. Expression of Bcl-xL and cyclooxygenase-2 (Cox-2) was induced in liver by HGF gene transfer. These data suggest that HGF exerts an antiapoptotic effect through dual induction of Bcl-xL and Cox-2, which suppresses caspase-3 activity.
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PMID:Adenovirus-mediated hepatocyte growth factor gene transfer prevents lethal liver failure in rats. 1109 40

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

Previous studies have shown that caspase inhibitors are effective at protecting against anti-Fas antibody (alpha-Fas)-mediated liver injury/lethality. The purpose of these experiments was to characterize more fully the efficacy of a broad-spectrum, irreversible caspase inhibitor, IDN-1965 (N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid), in this model and the role of caspase inhibition in long-term protection. The ED(50) for IDN-1965 by i.p. administration, based on alanine aminotransferase activities, was 0.14 mg/kg. The caspase inhibitor was also efficacious when administered intravenously and orally (ED(50) values of 0.04 and 1.2 mg/kg, respectively). Histologically, marked reduction in Fas-induced apoptosis with IDN-1965 (1 mg/kg, i.p.) was apparent at 6 h. Also, caspase 3-like activities were decreased in a dose-dependent manner, but the inhibition of caspase activity was transient. Immunohistochemical studies demonstrated that IDN-1965 greatly reduced the activation of caspase 3. In survival studies, a single i.p. treatment of 1 mg/kg IDN-1965 or continuous i.p. infusion via osmotic pumps completely blocked lethality measured up to 7 days after alpha-Fas administration. IDN-1965 was also effective in inhibiting liver injury when administered as long as 3 h after or 1 h before alpha-Fas administration. Lastly, Western blot analysis demonstrated that processing of caspases 3, 6, and 8, as well as Bid (a protein responsible for the release of mitochondrial cytochrome C and amplification of the apoptotic cascade) was inhibited by IDN-1965. In conclusion, the broad-spectrum caspase inhibitor IDN-1965 is markedly effective at inhibiting Fas-mediated apoptosis by multiple routes of administration. The therapeutic potential of caspase inhibitors appears promising for the treatment of apoptosis-mediated liver injury based on potency and postinsult efficacy.
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PMID:Characterization of the caspase inhibitor IDN-1965 in a model of apoptosis-associated liver injury. 1130 74


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