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)

Apoptosis is an important process in normal animal development as well as in diseases, and inhibitor of apoptosis protein (IAP) is one of the important factors that regulate apoptotic cell death. We found that lipopolysaccharide (LPS) enhances the expression of mRNA and protein of cellular IAP-2 (cIAP2) in human monoblastic U937 cells differentiated by phorbol ester pretreatment. cIAP2 mRNA was not detected in undifferentiated U937 cells. mRNAs of cIAP1 and X-chromosome-linked IAP (XIAP) were expressed constitutively and not affected by LPS in both undifferentiated and differentiated cells. LPS stimulated the expression of cIAP2 mRNA and protein in time- and concentration-dependent manners. LPS enhanced the expression of cIAP2 mRNA and protein in human monocyte-derived macrophages, which was associated with the inhibition of the caspase-3 activation, i.e., decrease in active p17 fragment of caspase-3 with simultaneous accumulation of precursor p20 fragment. We conclude that LPS may inhibit apoptosis of macrophages, at least in part, through the induction of cIAP2.
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PMID:Lipopolysaccharide induces the expression of cellular inhibitor of apoptosis protein-2 in human macrophages. 1111 65

The effect of caspase inhibitors on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 267.4 murine macrophage cells was investigated. Pretreatment of RAW cells with a broad caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), resulted in a striking reduction in LPS-induced NO production. Z-VAD-FMK inhibited LPS-induced NF-kappaB activation. Furthermore, it blocked phosphorylation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) but not that of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinases. Similarly, a caspase 3-specific inhibitor, Z-Asp-Glu-Val-Asp-fluoromethylketone, inhibited NO production, NF-kappaB activation, and JNK/SAPK phosphorylation in LPS-stimulated RAW cells. The attenuated NO production was due to inhibition of the expression of an inducible-type NO synthase (iNOS). The overexpression of the dominant negative mutant of JNK/SAPK and the addition of a JNK/SAPK inhibitor blocked iNOS expression but did not block LPS-induced caspase 3 activation. It was therefore suggested that the inhibition of caspase 3 might abrogate LPS-induced NO production by preventing the activation of NF-kappaB and JNK/SAPK. The caspase family, especially caspase 3, is likely to play an important role in the signal transduction for iNOS-mediated NO production in LPS-stimulated mouse macrophages.
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PMID:Inhibition of caspase 3 abrogates lipopolysaccharide-induced nitric oxide production by preventing activation of NF-kappaB and c-Jun NH2-terminal kinase/stress-activated protein kinase in RAW 264.7 murine macrophage cells. 1117 93

Microglia, the resident immune cells in the brain, play a pivotal role in immune surveillance, host defense, and tissue repair in the CNS. In response to immunological challenges, microglia readily become activated as characterized by morphological changes, expression of surface antigens, and production of immune modulators that impact on neurons to induce neurodegeneration. However, little is known concerning the fate of activated microglia. In the present study, stimulation of cultured rat primary microglia with 1 ng/mL of the inflammagen lipopolysaccharide (LPS) resulted in a maximal activation as measured by the release of tumor necrosis factor alpha (TNF alpha). However, treatment with higher concentrations of LPS resulted in significantly lower quantities of detectable TNF alpha. Further analysis revealed that overactivation of microglia with higher concentrations of LPS (> 1 ng/mL) resulted in a time- and dose-dependent apoptotic death of microglia as defined by DNA strand breaks, surface expression of apoptosis-specific markers (phosphatidylserine), and activation of caspase-3. In contrast, astrocytes were insensitive to LPS-induced cytotoxicity. In light of the importance of microglia and the limited replenishment mechanism, depletion of microglia from the brain may severely hamper its capacity for combating inflammatory challenges and tissue repair. Furthermore, overactivation-induced apoptosis of microglia may be a fundamental self-regulatory mechanism devised to limit bystander killing of vulnerable neurons.
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PMID:Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. 1127 74

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

The effect of nitric oxide (NO) on apoptosis in the gastrointestinal mucosa was investigated. Experiments involved long-term exposure of rat gastric mucosal cells in vitro to exogenous NO delivered from the NO, donor S-nitroso-N-acetyl-penicillamine, and the effect of intravenous administration of lipopolysaccharide in vivo, in the presence and absence of the selective inhibitor of inducible NO synthase N-(3-(aminomethyl)benzyl) acetamidine (1400 W). S-nitroso-N-acetyl-penicillamine produced a dose-related inhibition of caspase 3-like activity and DNA fragmentation in isolated gastric mucosal cells. Caspase 3-like activity and DNA fragmentation in gastric, ileal and colonic mucosa were increased both 5 and 24 h after injection of lipopolysaccharide (3 mg/kg, i.v.) to rats in vivo. Administration of 1400 W (5 mg/kg, i.v.) immediately after lipopolysaccharide enhanced caspase 3-like activity and DNA fragmentation above that found with lipopolysaccharide alone. In conclusion, data obtained both in vitro and in vivo suggest that NO exerts an anti-apoptotic effect on rat gastrointestinal mucosal cells.
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PMID:Effect of nitric oxide on apoptotic activity in the rat gastrointestinal tract. 1143 1

Fatty livers are sensitive to lipopolysaccharide (LPS) damage. This study tests the hypothesis that this vulnerability occurs because protective, antiapoptotic mechanisms are not upregulated appropriately. Genetically obese, leptin-deficient ob/ob mice, a model for nonalcoholic fatty liver disease, and their lean litter mates were treated with a small dose of LPS. General measures of liver injury, early (i.e., cytochrome c release) and late (i.e., activation of caspase 3) events that occur during hepatocyte apoptosis, and various aspects of the signal transduction pathways that induce nuclear factor-kappaB (NF-kappaB) and several of its antiapoptotic transcriptional targets (e.g., inducible nitric oxide synthase, bfl-1, and bcl-xL) were compared. Within 0.5-6 h after LPS exposure, cytochrome c begins to accumulate in the cytosol of normal livers, and procaspase 3 cleavage increases. Coincident with these events, kinases (e.g., AKT and Erk-1 and -2) that result in the degradation of inhibitor kappa-B are activated; NF-kappaB activity is induced, and NF-kappaB-regulated gene products accumulate. Throughout this period, there is negligible histological evidence of liver damage, and serum alanine aminotransferase values barely increase over baseline values. Although ob/ob livers have significant histological liver injury and 11-fold greater serum alanine aminotransferase values than those of lean mice by 6 h post-LPS, they exhibit greater activation of AKT and Erk, more profound reductions in inhibitor kappa-B, enhanced activation of NF-kappaB, and greater induction of NF-kappaB-regulated genes. Consistent with this heightened antiapoptotic response, increases in cytochrome c and procaspase 3 cleavage products are inhibited. Together with evidence that ob/ob hepatocytes have a reduced ATP content and undergo increased lysis after in vitro exposure to tumor necrosis factor-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather than because of apoptosis.
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PMID:Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation. 1144 19

We tested the hypothesis that endotoxemia and fasting are associated with increased gut apoptotic activity, gut permeability, and inflammation in a distant organ. Fed or fasted CD-1 mice were studied 6 h after intraperitoneal injection of either saline (sham) or endotoxin (4 mg/kg of 0111:B4 Escherichia coli lipopolysaccharide). We found that endotoxin increased gut caspase-3 and -6 activity by 4.9 +/- 0.6- and 4.5 +/- 0.5-fold, respectively (P < 0.001), and increased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) staining of mucosal cells (P < 0.05). Feeding decreased caspase-3 activity by 40% (P < 0.05) and decreased endotoxin-induced TUNEL staining (P < 0.05). Endotoxin increased gut poly(ADP-ribose) polymerase activity by 15% (P < 0.05). Endotoxin increased gut permeability by 44% (P < 0.05), an effect reduced 36% by feeding (P < 0.05). Similarly, endotoxin increased pulmonary neutrophil infiltration (6.0 +/- 1.0-fold, P < 0.001) and increased lung interleukin (IL)-6 (5.9 +/- 0.1-fold, P < 0.001) and macrophage inflammatory protein (MIP)-2 expression (290 +/- 40-fold, P < 0.001), whereas feeding decreased this effect by 43% for neutrophils, 40% for IL-6 (P < 0.05), and 35% for MIP-2 (P < 0.05). Thus endotoxin increases gut apoptotic activity, gut permeability, and pulmonary inflammation. Enteral feeding may decrease the distant organ inflammation by reducing gut apoptosis, thereby maintaining gut mucosal function during endotoxemia.
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PMID:Enteral feeding decreases gut apoptosis, permeability, and lung inflammation during murine endotoxemia. 1144 38

This study was undertaken to examine, electrophysiologically and immunohistochemically, the effect of endotoxin on the guinea pig cochlea. A bacterial endotoxin (lipopolysaccharide, LPS, 5 mg/ml, 0.2 ml) was injected into the middle ear trans-tympanically. The electrocochleograms were continuously recorded from before to 48 h after the injection with an electrode inserted into the facial canal. Then, the animals were sacrificed by intracardiac perfusion of a fixative, temporal bones were removed and immunohistochemically stained for single-stranded DNA (ssDNA) and caspase 3 (CPP32). ssDNA was detected at 48 h in the stria vascularis and spiral ligament. CPP32 was observed in the stria vascularis, the spiral ligament and the organ of Corti. The threshold of the compound action potential increased significantly at 48 h in the LPS group. These results suggest that the activation of CPP32 and fragmentation of DNA are involved in the dysfunction of the cochlea observed under inflammatory conditions.
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PMID:Detection of apoptotic change in the lipopolysaccharide (LPS)-treated cochlea of guinea pigs. 1150 43

Liver resident NK1.1+ T cells are supposed to play a pivotal role in the onset of inflammatory liver injury in experimental mouse models such as concanavalin A (Con A)-induced hepatitis. These cells, expressing the adhesion receptor, CD44, are largely depleted from the liver by a single intravenous injection of low-molecular-weight fragments of hyaluronic acid (LMW-HA). Here, we report that LMW-HA pretreatment protected mice from liver injury in several models of T-cell- and macrophage-dependent, tumor necrosis factor alpha (TNF-alpha)-mediated inflammatory liver injury, i.e., from liver injury induced by either Con A or Pseudomonas exotoxin A (PEA) or PEA/lipopolysaccharide (LPS). Interestingly, apart from inhibition of cellular adhesion, pretreatment of mice with LMW-HA was also capable of preventing hepatocellular apoptosis and activation of caspase-3 induced by direct administration of recombinant murine (rmu) TNF-alpha to D-galactosamine (GalN)-sensitized mice. LMW-HA-induced hepatoprotection could be neutralized by pretreatment with the nuclear factor-kappaB (NF-kappaB) inhibitor, pyrrolidine dithiocarbamate (PDTC), demonstrating the involvement of NF-kappaB in the observed protective mechanism. Indeed, injection of LMW-HA rapidly induced the production of TNF-alpha by Kupffer cells and the translocation of NF-kappaB into hepatocellular nuclei. Both LMW-HA-induced TNF-alpha production and NF-kappaB translocation were blocked by pretreatment with PDTC. Our findings provide evidence for an unknown mechanism of LMW-HA-dependent protection from inflammatory liver disease, i.e., induction of TNF-alpha- and NF-kappaB-dependent cytoprotective proteins within the target parenchymal liver cells.
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PMID:Low-molecular-weight hyaluronic acid induces nuclear factor-kappaB-dependent resistance against tumor necrosis factor alpha-mediated liver injury in mice. 1152 40

Caspase-11 plays a crucial role in both inflammation and apoptosis. Caspase-11 not only activates caspase-1, that is required for the maturation of proinflammatory cytokines such as interleukin (IL)-1 and IL-18, but also activates caspase-3, leading to cellular apoptosis under pathological conditions. Here, we cloned the rat homolog of caspase-11, and investigated its inducibility by inflammatory stimuli and signal transduction pathways involved. Deduced amino acid sequence of rat caspase-11 showed 88.7% similarity to mouse caspase-11, and in vitro translation of rat caspase-11 cDNA yielded approximately a 43 kDa polypeptide, which was in agreement with predicted protein size generated from full-length rat caspase-11 cDNA. The expression of caspase-11 was strongly induced at both mRNA and protein levels by inflammatory stimuli such as lipopolysaccharide (LPS), interferon-gamma, and tumor necrosis factor-alpha in C6 rat glial cells as well as primary astrocytes. LPS induced activation of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) in C6 cells. However, SB203580 (specific inhibitor of p38 kinase), but not PD98059 (specific inhibitor of ERK kinase), inhibited LPS induction of caspase-11, indicating that induction of caspase-11 by LPS in astrocytes was mediated through the p38 MAPK pathway. Inflammatory induction of caspase-11 in astrocytes may play an important role in both inflammatory responses involving these cells and auto-regulatory apoptosis of activated astrocytes in inflammatory sites.
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PMID:Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway. 1168 90


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