Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine models have shown that IL-18 has antiangiogenic and antitumor effects, but little is known about IL-18 production in human tumors. We investigated IL-18 expression in clinically localized prostate cancers by immunohistochemistry and showed that 75% of the prostate cancers studied (27/36 cases) presented with tumor cells producing IL-18. Prostate tumor cell lines PC-3, DU 145 and LNCaP synthesized the immature form of IL-18 (p24). IFN-gamma produced in prostate cancers induced caspase-1 mRNA and IL-18 secretion of tumor cell lines, which was inhibited by the cell-permeable Tyr-Val-Ala-Asp-aldehyde caspase-1 inhibitor (YVAD-CHO). Interestingly, IFN-alpha also induced IL-18 secretion of the poorly differentiated cell line PC-3. PC-3 and DU 145, but not the well-differentiated cell line LNCaP, expressed IL-18R alpha (IL-1Rrp) protein and transcripts for IL-18R beta (AcPL). Exogenous IL-18 increased mitochondrial activity of both cell lines evaluated by the tetrazolium (MTT) assay but did not influence their proliferation. This indicated that prostate tumor cells could secrete IL-18 in response to IFN-gamma in the tumor microenvironment and that IL-18 could act as a autocrine/paracrine factor for the tumor. In the cohort of patients studied, IL-18 expression in prostate cancers (with up to 10% of tumor cells stained) was associated with a favorable outcome and equally predictive as pathologic stage on multivariate analysis (log rank test, p = 0.02). Tumor IL-18 production is a novel physiopathologic feature of prostate cancer and appears to be a favorable event in the course of the disease. Modulation of IL-18 production by interferons could have a beneficial clinical effect, which deserves further investigation.
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PMID:IL-18 is produced by prostate cancer cells and secreted in response to interferons. 1291 59

N-Tosyl-L-phenylalanyl chloromethyl ketone (TPCK), a chymotrypsin-like serine protease inhibitor, affected apoptosis in human monocytic THP.1 cells differently dependent on both the concentration used and the apoptotic stimulus. TPCK (50 - 75 microM) induced both biochemical and ultrastructural changes characteristic of apoptosis, including proteolysis of poly (ADP-ribose) polymerase (PARP) and lamins together with formation of large kilobase pair fragments of DNA, particularly of 30 - 50 and 200 - 300 kilobase pairs in length but without internucleosomal cleavage of DNA. The induction of apoptosis by TPCK also involved the processing of CPP32 and Mch 3 to their catalytically active subunits. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK), an ICE-like protease inhibitor, completely prevented all the biochemical and morphological changes induced by TPCK demonstrating the involvement of ICE-like proteases in the execution phase of apoptosis. Lower concentrations of TPCK (5 - 20 microM) prevented internucleosomal cleavage of DNA induced by other apoptotic stimuli. TPCK (10 microM) inhibited cell death induced by etoposide but potentiated that induced by cycloheximide demonstrating that it differentially affected apoptosis in THP.1 cells dependent on the stimulus used. These results are consistent with at least three distinct TPCK targets, one being important for cell survival, the second in facilitating internucleosomal cleavage of DNA and the third in the modulation of apoptosis induced by different apoptotic stimuli.
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PMID:Apoptosis in human monocytic THP.1 cells involves several distinct targets of N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK). 1455 72

The mechanisms of ultraviolet-B (UV-B)-induced apoptosis and the role of p38 mitogen-activated protein kinase (MAPK) were investigated in murine peritoneal macrophages. Exposure of murine peritoneal macrophages to UV-B irradiation induced rapid apoptosis concurrent with DNA fragmentation and activation of caspase-3 but did not activate caspase-1. UV-B irradiation (100 mJ/cm2) also induced expression of phospho-p38 and -c-Jun N-terminal kinase (JNK) MAPK; however, no significant expression of phospho-p42/44 was observed 120 min after exposure. Pretreatment of macrophages with a p38 MAPK inhibitor, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190), and a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-CHO, suppressed UV-B irradiation-induced apoptosis as observed by DNA laddering and DNA fragmentation estimation quantitatively. Pretreatment with caspase-1 inhibitor, N-acetyl-Tyr-Val-Ala-Asp-CHO, had no effect. UV-B-induced caspase-3 activation resulted in the cleavage of poly-(ADP-ribose) polymerase (PARP), which was inhibited by the caspase-3 inhibitor. SB202190 pretreatment also prevented activation of caspase-3 and the cleavage of PARP. However, the caspase-3 and -1 inhibitors did not affect UV-B-induced expression of phospho-p38 and -JNK. These results suggest that activation of p38 MAPK upstream of caspases might play an important role in the apoptotic process of macrophages exposed to UV-B irradiation.
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PMID:Role of p38 mitogen-activated protein kinase and caspases in UV-B-induced apoptosis of murine peritoneal macrophages. 1497 15

We investigated the mechanism of 3-morpholinosyndnomine (SIN-1) neurotoxicity in nearly pure neuronal cultures. In a simple saline solution, SIN-1 neurotoxicity was found to be mediated by peroxynitrite and independent of glutamate receptor activation [Y. Zhang & P.A. Rosenberg (2002) Eur. J. Neurosci, 16, 1015-1024]. To further study the mechanism of peroxynitrite toxicity to neurons we investigated the role of caspases and poly (ADP-ribose) polymerase (PARP) in this model system. Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-cmk), a specific caspase-1 inhibitor, completely blocked neurotoxicity as well as ATP depletion induced by SIN-1. However, a caspase-3 inhibitor and a pan-caspase inhibitor were both without effect. These results suggested that the protection of Ac-YVAD-cmk might not be due to its inhibition of caspase-1. Indeed, Western blot analysis and assay of caspase activity indicated that caspase activation was not involved in SIN-1 toxicity. Ac-YVAD-cmk also completely blocked in vitro protein nitration induced by SIN-1 or peroxynitrite, suggesting that Ac-YVAD-cmk may interact with peroxynitrite directly. Similarly, although activation of PARP is thought to be a major cause of peroxynitrite-induced ATP depletion, and two PARP inhibitors, 1,5-dihydroxyisoquinoline (DHQ) and 3-aminobenzamide (3-AB), completely prevented ATP depletion and neurotoxicity induced by SIN-1, SIN-1 did not increase poly (ADP-ribosyl)ation and PARP activity. Furthermore, DHQ and 3-AB completely prevented in vitro protein nitration induced by peroxynitrite, indicating that DHQ and 3-AB directly interact with peroxynitrite. Taken together, these results suggest that in the model system used here peroxynitrite neurotoxicity is independent of caspase and PARP activation, and therefore implicate a novel mechanism.
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PMID:Caspase-1 and poly (ADP-ribose) polymerase inhibitors may protect against peroxynitrite-induced neurotoxicity independent of their enzyme inhibitor activity. 1537 93

The potential significance of bovine ephemeral fever virus (BEFV)-induced apoptosis and involved viral molecules was fully unknown. In the present study, evidence is provided demonstrating that bovine ephemeral fever virus induces apoptosis in several cell lines. Five types of assays for apoptosis were used in examining BEFV-infected cells. (1) Assay for DNA fragmentation, (2) nuclear staining with acridine orange, (3) ELISA detection of cytoplasmic histone-associated DNA fragment, (4) terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labelling (TUNEL) assay of BEFV-infected cells, (5) observation of blebbing of the plasma membrane and the formation of apoptotic bodies of apoptic cells by scanning electron microscope. The level of lactate dehydrogenase (LDH) in BEFV-infected cells was increased significantly after 20-25 h post-infection. Caspases-2, -3, -4, -6, -8, -9, and -10 were activated in BEFV-infected BHK-21 cells. To determine further whether BEFV-induced apoptosis was caspase-dependent, the effect of the tripeptide pan-ICE (caspase) inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone on the inhibition of apoptosis in BEFV-infected BHK-21 cells, was investigated. Apoptosis could be blocked by the caspase inhibitor (Z-VAD-fmk), indicating that BEFV induces caspase-dependent apoptosis in cultured cells.
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PMID:Apoptosis induced by bovine ephemeral fever virus. 1554 40

Acacetin (5,7-dihydrocy-4'-methoxy flavone), which is a flavonoid compound, possesses anti-peroxidative and anti-inflammatory effects. The effects of acacetin on cell viability in human gastric carcinoma AGS cells were investigated. This study demonstrated that acacetin was able to inhibit cell proliferation and induce apoptosis in a concentration- and time-dependent manner. Acacetin-induced cell death was characterized with changes in nuclear morphology, DNA fragmentation, and cell morphology. The molecular mechanism of acacetin-induced apoptosis was also investigated. Treatment with acacetin caused induction of caspase-3 activity in a time-dependent manner, but not caspase-1 activity, and induced the degradation of DNA fragmentation factor (DFF-45) and poly(ADP-riobse) polymerase. Cell death was completely prevented by a pancaspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone. Furthermore, treatment with acacetin caused a rapid loss of mitochondrial transmembrane potential, stimulation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. Antioxidants such as N-acetylcysteine and catalase, but not superoxide dismutase, allopurinol, or pyrrolidine dithiocarbamate, significantly inhibited acacetin-induced cell death. In addition, it was found that acacetin promoted the up-regulation of Fas and FasL prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement of a Fas-mediated pathway in acacetin-induced apoptosis. On the other hand, the results showed that acacetin-induced apoptosis was accompanied by up-regulation of Bax and p53, down-regulation of Bcl-2, and cleavage of Bad. Taken together, these results suggest that ROS production and a certain intimate link might exist between receptor- and mitochondria-mediated death signalings that committed to acacetin-induced apoptosis in AGS cells. The induction of apoptosis by acacetin may provide a pivotal mechanism for its cancer chemopreventive action.
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PMID:Acacetin induces apoptosis in human gastric carcinoma cells accompanied by activation of caspase cascades and production of reactive oxygen species. 1568 11

Metacaspases in plants, fungi, and protozoa constitute new members of a conserved superfamily of caspase-related proteases. A yeast caspase-1 protein (Yca1p), which is the single metacaspase in Saccharomyces cerevisiae, was shown to mediate apoptosis triggered by oxidative stress or aging in yeast. To examine whether plant metacaspase genes are functionally related to YCA1, we carried out analyses of AtMCP1b and AtMCP2b, representing the two subtypes of the Arabidopsis metacaspase family, utilizing yeast strains with wild-type and the disrupted YCA1 gene (yca1Delta). Inducible expression of AtMCP1b and AtMCP2b significantly promoted yeast apoptosis-like cell death of both the wild-type and yca1Delta strains, relative to the vector controls, during oxidative stress and early aging process. Mutational analysis of the two AtMCPs revealed that their cell-death-inducing activities depend on their catalytic center cysteine residues as well as caspase-like processing. In addition, the phenotype induced by the expression of two AtMCPs was effectively prevented when the cells were pretreated with a broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone. These results suggest that the two subtypes of Arabidopsis metacaspases are functionally related to Yca1p with caspase-like characteristics. However, we found that bacterial and yeast extracts containing AtMCP1b, AtMCP2b, or Yca1p exhibit arginine/lysine-specific endopeptidase activities but cannot cleave caspase-specific substrates. Together, the results strongly implicate that expression of metacaspases could result in the activation of downstream protease(s) with caspase-like activities that are required to mediate cell death activation via oxidative stress in yeast. Metacaspases from higher plants may serve similar functions.
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PMID:Two Arabidopsis metacaspases AtMCP1b and AtMCP2b are arginine/lysine-specific cysteine proteases and activate apoptosis-like cell death in yeast. 1569 45

Evidence suggests that IL-1beta is involved in promoting physiological nonrapid eye movement (NREM) sleep. IL-1beta has also been proposed to mediate NREM sleep enhancement induced by bacteria or their components. Mature and biologically active IL-1beta is cleaved from an inactive precursor by a cysteinyl aspartate-specific protease (caspase)-1. This study aimed to test the hypothesis that inhibition in brain of the cleavage of biologically active IL-1beta will reduce in rats both spontaneous NREM sleep and NREM sleep enhancement induced by the peripheral administration of components of the bacterial cell wall. To test this hypothesis, rats were intracerebroventricularly administered the caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD; 3, 30, 300, and 1,500 ng) or were pretreated intracerebroventricularly with YVAD (300 ng) and then intraperitoneally injected with the gram-negative bacterial cell wall component LPS (250 microg/kg). Subsequent sleep-wake behavior was determined by standard polygraphic recordings. YVAD administration at the beginning of the light phase of the light-dark cycle significantly reduced time spontaneously spent in NREM sleep during the first 12 postinjection hours. YVAD pretreatment also completely prevented NREM sleep enhancement induced by peripheral LPS administration at the beginning of the dark phase. These results, in agreement with previous evidence, support the involvement of brain IL-1beta in physiological promotion of NREM sleep and in mediating NREM sleep enhancement induced by peripheral immune challenge.
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PMID:Inhibition of caspase-1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide. 1645 62

Caspase recruitment domains (CARDs) are small helical protein domains that adopt the Greek key fold. For the two CARDs studied to date, RICK-CARD and caspase-1-CARD (CP1-CARD), the proteins unfold by an apparent two-state process at equilibrium. However, the folding kinetics are complex for both proteins and may contain kinetically trapped species on the folding pathway. In the case of RICK-CARD, the time constants of the slow refolding phases are consistent with proline isomerism. RICK-CARD contains three prolines, P47 in turn 3, and P85 and P87. The latter two prolines constitute a nonconserved PxP motif in helix 6. To examine the role of the prolines in the complex folding kinetics of RICK-CARD, we generated seven proline-to-alanine mutants, including three single mutants, three double mutants, and one triple mutant. We examined the spectroscopic properties, equilibrium folding, binding to CP1-CARD, and folding kinetics. The results show that P85 is critical for maintaining the function of the protein and that all mutations decrease the stability. Results from single mixing and sequential mixing stopped-flow studies strongly suggest the presence of parallel folding pathways consisting of at least two unfolded populations. The mutations affect the distribution of the two unfolded species, thereby affecting the population that folds through each channel. The two conformations also are present in the triple mutant, demonstrating that interconversion between them is not due to prolyl isomerism. Overall, the data show that the complex folding pathway, especially formation of kinetically trapped species, is not due to prolyl isomerism.
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PMID:Substitutions of prolines examine their role in kinetic trap formation of the caspase recruitment domain (CARD) of RICK. 1650 Dec 20

The anti-cancer effects and possible mechanisms of the freshwater clam (Corbicula fluminea Muller) and its active compounds (FME) on cell viability in human leukemia HL-60 cells were investigated. This study demonstrated that FME was able to inhibit cell proliferation in a concentration- and time-dependent manner. Treatment with FME caused induction of caspase-2, caspase-3, caspase-6, caspase-8, and caspase-9 activity in a time-dependent manner, but not affect caspase-1 activity; it induced the proteolysis of DNA fragmentation factor (DFF-45) and poly(ADP-ribose) polymerase (PARP). Induction of cell death by FME was completely prevented by a pan-caspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and a caspase-2 inhibitor, Z-Val-Asp-Val-Ala-Asp-FMK (Z-VDVAD-FMK). Furthermore, treatment with FME caused a rapid loss of mitochondrial transmembrane potential, stimulation of generation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and GSH depletion. Anti-oxidants such as N-acetylcysteine, catalase, superoxide dismutase, allopurinol, and pyrrolidine dithiocarbamate, but not diphenylene iodonium, significantly inhibited FME-induced cell death. In addition, the results showed that FME-induced apoptosis was accompanied by up-regulation of Bax and Bad, and down-regulation of Bcl-2 and Bcl-XL. Taken together, induction of apoptosis on HL-60 cells by FME was mainly associated with ROS production, GSH depletion, mitochondrial dysfunction, and caspase activation.
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PMID:Apoptosis-inducing active components from Corbicula fluminea through activation of caspase-2 and production of reactive oxygen species in human leukemia HL-60 cells. 1654 98


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