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

Interleukin-1beta (IL-1beta) is a proinflammatory cytokine that is synthesized as an inactive precursor molecule that must be proteolytically processed to generate the biologically active form. Maturation of the precursor is primarily performed by caspase-1, an intracellular cysteine protease; however, processing by other proteases has been described. Meprins are cell surface and secreted metalloproteases expressed by renal and intestinal brush-border membranes, leukocytes, and cancer cells. In this study we show that purified recombinant meprin B can process the interleukin-1beta precursor to a biologically active form. Amino-terminal sequencing and mass spectrometry analysis of the product of digestion by activated meprin B determined that proteolytic cleavage resulted in an additional six amino acids relative to the site utilized by caspase-1. The biological activity of the meprin B-cleaved cytokine was confirmed by measuring the proliferative response of helper T-cells. These results suggest that meprin may play an important role in activation of this proinflammatory cytokine in various pathophysiological conditions.
Cytokine 2005 Sep 07
PMID:Generation of biologically active interleukin-1beta by meprin B. 1609 9

Caspases are intracellular cysteine proteases that mediate cell death and inflammation. Caspase-3 is a major mediator of both apoptotic and necrotic cell death. Caspase-1 mediates inflammation though the activation of the cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18). Increases in both caspase-1 and -3 have been described in ischemic injury to various organs including brain, heart and kidney. Both pharmacological inhibitors and genetic approaches have been used to inhibit caspases in vivo. Pancaspase inhibitors protect against ischemic injury in brain, heart and kidney. Pancaspase inhibition also reduces cold preservation injury due to apoptosis in liver endothelial cells and prolongs animal survival after orthotopic liver transplantation. Caspase-1 inhibition or caspase-1 deficiency protects against ischemic injury in brain, heart and kidney models of ischemia. Specifically, impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. This review focuses on studies of caspase-1 and pancaspase inhibition in ischemic injury to brain, heart and kidney. In addition, the studies of pancaspase inhibition in cold ischemic injury and organ preservation will be reviewed. The therapeutic potential of caspase inhibition in ischemic injury will be discussed.
Curr Drug Targets Immune Endocr Metabol Disord 2005 Sep
PMID:Caspases as drug targets in ischemic organ injury. 1617 88

On-site production of hydrogen and carbon nanofibers by thermocatalytic decomposition (TCD) of mineral oil waste (MWO) is analyzed. An experimental study carried out at lab scale to estimate the yields that can be expected from TCD of the MWO collected in the Aragon area is presented. Based on these results, mass and energy balance have been carried out to have a preliminary estimation on the products that could be obtained by processing the 10 000 tonnes/year of MWO that can be collected in the Aragon region. The process would consist of four steps: (1) drying, (2) vaporization, (3) primary decomposition, and (4) catalytic decomposition. After drying and vaporization, MWO is converted in step 3 into fuel grade carbon and a gas mixture that mainly contains hydrogen and methane. Methane is partially converted in step 4 into hydrogen and a carbon material that contains carbon nanofibers which could be used to manufacture utilities with high added value. The 10 000 tonnes/year of MWO would yield 705 t/y of H2, 4962 t/y of fuel grade carbon, and 1016 t/y of pure carbon. The mixture obtained (71% H2: 23% CH4) could be used as a hydrogen source to obtain pure hydrogen or hydrogen-natural gas mixtures to fuel a captive fleet of public urban vehicles powered by fuel cells or dedicated ICE, respectively.
Environ Sci Technol 2005 Sep 01
PMID:On-site production of hydrogen from mineral waste oils by thermocatalytic decomposition: an Aragon case study. 1619 Feb 51

We present retrospectively our experience in the use of high-dose chemotherapy and haematopoietic stem cell support (HSCS) for refractory gestational trophoblastic neoplasia (GTN) in the largest series so far reported. In all, 11 patients have been treated at three Trophoblast Centres between 1993 and 2004. The conditioning regimens comprised either Carbop-EC-T (carboplatin, etoposide, cyclophosphamide, paclitaxel and prednisolone) or CEM (carboplatin, etoposide and melphalan) or ICE (ifosfamide, carboplatin, etoposide). Two patients had complete human chorionic gonadotrophin responses, one for 4 and the other for 12 months. Three patients had partial tumour marker responses for 1-2 months. High-dose chemotherapy and HSCS for GTN is still unproven. Further studies are needed, perhaps in high-risk patients who fail their first salvage treatment.
Br J Cancer 2005 Sep 19
PMID:High-dose chemotherapy and peripheral blood stem cell support in refractory gestational trophoblastic neoplasia. 1622 7

Chondrosarcoma is a difficult musculoskeletal tumor to treat. Surgical treatment leads to severe disability, with high rates of local recurrence and life threat. No adjuvant therapy is effective in differentiated chondrosarcomas. Bisphosphonates (BPs) are a class of molecules which is effective in malignant bone diseases. The aim of the present study was to determine the effects of zoledronic acid (ZOL) on chondrosarcoma tumor progression. ZOL was tested in vivo (s.c. 100 microg/kg, twice a week) in a rat chondrosarcoma model and in vitro (10(-7)-10(-4) M) on cells derived from this model. Two types of animal models were assessed, the first simulated development after intralesional curettage, the second nonoperative development of the tumor. Cell proliferation, caspase-1, -3 activities and cell cycle analysis were studied. The results revealed that ZOL slows down primary tumor development, tumor progression after intralesional curretage and increases overall survival. ZOL inhibits cell proliferation and increases cell death, with no significant variation of caspase-1 and -3 activities and cell cycle profiles. The present study demonstrates for the first time that in addition to surgery, the therapy of chondrosarcoma with BPs might be beneficial. Because of these first results, new therapeutic approaches of chondrosarcoma must be considered, mainly for low grade chondrosarcoma when disabling operation is planned and when only intralesional resection can be undertaken.
Int J Cancer 2006 Sep 01
PMID:Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival. 1657 Feb 73

A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.
Bioorg Med Chem Lett 2006 Sep 15
PMID:Synthesis and evaluation of thiazepines as interleukin-1beta converting enzyme (ICE) inhibitors. 1687 Apr 41

Caspase-5 is a caspase-1-like protease with pro-apoptotic and pro-inflammatory activities. Here we have identified a novel exon at the 5'-end of the human caspase-5 gene. This novel exon was present in six alternatively spliced caspase-5 mRNA variants expressed in human peripheral blood mononuclear cells (PBMC) and encoded the previously unknown amino-terminus of caspase-5. The genomic region upstream of this exon contained sequence elements homologous to those of the caspase-11 promoter in the mouse, and transcription of caspase-5 was upregulated by lipopolysaccharide (LPS) in a caspase-11-like manner in human PBMC in vivo. Taken together, our findings call for a revision of the structure of caspase-5 at the genomic level as well as at the mRNA and protein levels.
Biochem Biophys Res Commun 2006 Sep 22
PMID:Identification of a novel exon encoding the amino-terminus of the predominant caspase-5 variants. 1689 18

Elite populations of farm animals under genetic selection are often maintained in high hygiene conditions, yet the commercial populations may be raised in, and are expected to perform well in, environments of varied hygiene levels. This presents special challenges to genetically improve those traits for which genotype by environment interactions are important. Twelve immune-related genes were studied for associations with general mortality and other performance traits in 3 elite commercial broiler chicken lines raised in high and low hygiene environments. The genes were toll-like receptor 4, MD-2 (accessory' protein of TLR4), interferon-gamma, transforming growth factor-beta3, inducible nitric oxide synthase, macrophage migration inhibitory factor, interleukin-2, caspase-1, inhibitor of apoptosis protein-1, tumor necrosis factor-related apoptosis-inducing ligand, chicken B-cell marker, and bone morphogenetic protein-7. From a total of 56 identified single-nucleotide polymorphisms (SNP) in 12 genes, 14 SNP that had moderate allelic frequencies in at least 2 of the 3 lines were typed in about 100 progeny-tested sires from each of 3 elite commercial broiler chicken lines using restriction fragment length polymorphism techniques and then used in association analysis. The traits measured on the progeny (total progeny = 145,467) were: mortality from hatching to 14 d and from 14 to 40 d of age, BW at 7 and 40 d of age, feed conversion, ultrasound breast depth, percentage of breast, eviscerated carcass weight, twisted legs or evident tibial dyschondroplasia, x-ray-inspection-based subclinical or incipient development of tibial dyschondroplasia, curly or crooked toes or bowed legs, oxygen content of blood, and female's antibody titer to infectious bursal disease virus at 27 wk. Association analyses were conducted with allele and haplotype substitution effect models using progeny mean data adjusted for fixed and mate effects as sire trait records. Ten of the 12 genes had SNP associations with at least 1 trait. Most detected effects were with mortality and growth traits. Most gene-SNP trait associations varied by genetic line or with environment. These results indicate that associations of candidate genes with important broiler traits can be identified in multiple environments, and they offer a potential for the implementation of marker-assisted selection for traits expressed in the environment in which the commercial broiler needs to perform. The effects of these immune-related candidate genes, however, are complex and affected by genetic background and environment.
Poult Sci 2006 Sep
PMID:Association of twelve immune-related genes with performance of three broiler lines in two different hygiene environments. 1697 41

Cysteine proteases are crucial regulatory enzymes in human physiology and disease. Inhibitors are usually designed with reactive electrophiles to covalently bond to the catalytic cysteinyl sulfur, and consequently they also indiscriminately interact with biological thiolates and other nucleophiles, leading to toxic side effects in vivo. Here we describe an alternative to using reactive electrophiles, demonstrating the use of a much less reactive azidomethylene substituent (-CH2-N3) that confers potent inhibition of cysteine proteases. This new approach resulted in potent, reversible, competitive inhibitors of caspase-1 (IC50 < 10 nM), with significant advantages over aldehydes such as high stability in vitro to thiols (10 mM dithiothreitol (pH 7.2), 20 mM glutathione (pH 7.2, 9, 11)) and aqueous media, as well as some highly desirable druglike features. It was also demonstrated that azides can be incorporated into inhibitors of other caspases (e.g. 3, 8) and cathepsins (e.g. K, S, B), indicating the versatility of this valuable new approach to cysteine protease inhibition.
J Am Chem Soc 2006 Sep 27
PMID:Organic azide inhibitors of cysteine proteases. 1698 72

Caspase-1 promotes both the maturation of proinflammatory cytokines and apoptosis in cells infected by certain pathogens. Work by now reveals a surprising new function for caspase-1: the stimulation of membrane biogenesis to repair damage caused by bacterial pore-forming toxins. Thus, caspase-1 may promote host cell survival as a means of resistance to pathogenic bacteria.
Cell 2006 Sep 22
PMID:Caspase-1 builds a new barrier to infection. 1699 Jan 37


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