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:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to determine whether hemorrhage altered the caspase-3 activity and the ATP levels in rat lung and ileum tissues and determine whether resuscitation with lactated Ringer solution (LR) or whole blood (WB) reversed these changes. Male Sprague-Dawley rats were briefly anesthetized with isoflurane, and their mean arterial blood pressure was reduced from 110 to 40 mmHg by bleeding. The bled rat was then resuscitated with LR or autologous WB to bring mean arterial blood pressure back to 80 mmHg. Lung and ileum tissues were removed at the end of hemorrhage or at the end of the resuscitation period for specified bioassays. Hemorrhage increased cellular caspase-3 activity in the lung and the ileum. After the hemorrhaged rats received LR or WB, caspase-3 activity returned to the basal level in the lung and ileum, respectively. Likewise, hemorrhage decreased cellular ATP levels in lung and ileum. After LR or WB resuscitation, the cellular ATP level returned to the basal level only in the lung resuscitated with LR. The increased caspase-3 activity was associated with the increased expression of caspase-3 mRNA, which also returned to normal levels after either resuscitation. Similarly, hemorrhage increased the expression of inducible nitric oxide synthase and Kruppel-like factor 6 and decreased expression of Kruppel-like factor 4. Subsequent LR resuscitation normalized the expression of these genes in the lung tissue. Our results demonstrate that resuscitation with LR can reverse the expression of genes and their products that are thought to contribute to hemorrhage-induced lung injury.
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PMID:Resuscitation with lactated Ringer solution limits the expression of molecular events associated with lung injury after hemorrhage. 1548 61

The enteric pathogens Shigella dysenteriae serotype 1 and Shiga toxin-producing Escherichia coli share the property of expressing the structurally and functionally related cytotoxins that comprise the Shiga toxin (Stx) family. Stx-producing bacteria are causative agents of bloody diarrheal diseases that may progress to life threatening complications involving the destruction of blood vessels in the kidneys and the central nervous system (CNS). The precise mechanisms of toxin transport across the gut epithelial barrier, and the role of innate immunity in the development of systemic complications, remain to be fully characterized. Earlier studies suggested that Stxs and lipopolysaccharides (LPS) induce the expression of proinflammatory cytokines from differentiated (macrophage-like) THP-1 cells. These cytokines may exacerbate vascular damage by up-regulating the expression of toxin receptors on endothelial cells. Purified Stxs have also been shown to induce apoptosis of epithelial and endothelial cells in vitro, but a comparative evaluation of Stx-induced apoptosis of monocytes and macrophages has not been reported. We used FACS, TUNEL, and DNA laddering analyses to show that Shiga toxin-1 (Stx1) and LPS induce apoptosis in undifferentiated and differentiated THP-1 cells, although the kinetics and extent of apoptosis induction differ between monocytic and macrophage-like cells. Stx1-induced apoptosis is A-subunit-dependent. Stx1 and LPS trigger DNA fragmentation and caspase-3 activation, as evidenced by the cleavage of poly(ADP-ribose) polymerase (PARP). Induction of apoptosis in response to Stx1 and/or LPS treatment occurs without the widespread transcriptional activation of apoptosis-related genes. Finally, we present a model of the role of macrophages and monocytes in the pathogenesis of disease caused by Stxs.
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PMID:Comparative evaluation of apoptosis induced by Shiga toxin 1 and/or lipopolysaccharides in human monocytic and macrophage-like cells. 1574 8

Daidzein (D), a soy isoflavone, is almost completely metabolized in the gut and liver. This biotransformation converts D to more water-soluble products and may affect its biological activity. The ability of daidzein metabolites to modulate 17beta-estradiol (E2)-sensitive gene transcription, cell growth, and a proapoptotic cascade was determined in human cancer cells devoid of any estrogen receptor (ER) and rendered E2 sensitive after transfection with ERbeta. The data show that D and some but not all of its metabolites 1) induce promoter activity, 2) reduce proliferation, 3) promote p38/mitogen-activated protein kinase (MAPK) phosphorylation, and 4) activate a proapoptotic cascade involving the cleavage of caspase-3 and its substrate poly(ADP-ribose)polymerase (PARP) in human cancer cells in an ERbeta-dependent manner. Pretreatment of cells with ICI 182,780, a pure antiestrogen, completely prevented the actions of D and its metabolites. These findings highlight the important and complex influence of metabolic transformation on key physiological effects of isoflavones and demonstrate the need to take biotransformation into account when assessing the potential health benefits of consuming soy isoflavones.
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PMID:Daidzein-sulfate metabolites affect transcriptional and antiproliferative activities of estrogen receptor-beta in cultured human cancer cells. 1625 31

Necrotizing enterocolitis (NEC) is a devastating inflammatory condition of the gut that occurs in premature infants. Ischemia-reperfusion gut injury with production of reactive oxygen species (ROS) is thought to contribute to NEC; the exact cellular mechanisms involved are largely unknown. The purpose of this study was to determine the intracellular signaling transduction pathways involved in oxidative stress-induced intestinal epithelial cell apoptosis. H2O2 treatment resulted in rat intestinal epithelial cell apoptosis in a dose- and time-dependent manner; the caspase inhibitor, zVAD-fmk, blocked this response. Western blotting was performed to determine phosphorylation of kinases and ELISA was used to assess DNA fragmentation, as a measure of apoptosis. A rapid increase in phosphorylation of extracellular signal-related kinase (ERK)1/2, c-Jun N-terminal kinase (JNK)1/2, and Akt was noted. Inhibition of ERK and JNK decreased H2O2-induced apoptosis. Additionally, inhibition of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) attenuated and enhanced H2O2-mediated apoptosis and mitochondrial membrane potential decrease, respectively. Furthermore, activation of PKC reduced the Akt phosphorylation, whereas inhibition of PKC attenuated H2O2-mediated activation of caspase-3 and enhanced the H2O2-induced Akt phosphorylation. This study shows that activation of multiple signaling transduction pathways occurs during oxidative stress-induced intestinal epithelial cell injury. In contrast to ERK, JNK, and PKC, PI3-K/Akt may play an important role as a protective cellular signaling pathway during this process.
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PMID:Signal transduction pathways involved in oxidative stress-induced intestinal epithelial cell apoptosis. 1630 92

Gut epithelial apoptosis is involved in the pathophysiology of multiple diseases. This study characterized intestinal apoptosis in three mechanistically distinct injuries with different kinetics of cell death. FVB/N mice were subjected to gamma radiation, Pseudomonas aeruginosa pneumonia or injection of monoclonal anti-CD3 antibody and sacrificed 4, 12, or 24 hours post-injury (n=10/time point). Apoptosis was quantified in the jejunum by hematoxylin and eosin (H&E), active caspase-3, terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling (TUNEL), in situ oligoligation reaction (ISOL,) cytokeratin 18, and annexin V staining. Reproducible results were obtained only for H&E, active caspase-3, TUNEL and ISOL, which were quantified and compared against each other for each injury at each time point. Kinetics of injury were different with early apoptosis highest following radiation, late apoptosis highest following anti CD3, and more consistent levels following pneumonia. ISOL was the most consistent stain and was always statistically indistinguishable from at least 2 stains. In contrast, active caspase-3 demonstrated lower levels of apoptosis, while the TUNEL assay had higher levels of apoptosis in the most severely injured intestine regardless of mechanism of injury. H&E was a statistical outlier more commonly than any other stain. This suggests that regardless of mechanism or kinetics of injury, ISOL correlates to other quantification methods of detecting gut epithelial apoptosis more than any other method studied and compares favorably to other commonly accepted techniques of quantifying apoptosis in a large intestinal cross sectional by balancing sensitivity and specificity across a range of times and levels of death.
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PMID:Epithelial apoptosis in mechanistically distinct methods of injury in the murine small intestine. 1735 92

Bacterial modulation of phagocyte cell death is an emerging theme in pathogenesis. Here we describe the systemic destruction of macrophages and neutrophils by the Gram-negative Photobacterium damselae ssp. piscicida (Phdp) in fish pasteurellosis, a deadly systemic infection. Following experimental inoculation, Phdp spreads by bacteraemia and colonizes the organs, producing a septicaemic infection, and secretes the apoptogenic exotoxin AIP56 which is systemically disseminated. In experimental and natural pasteurellosis, destruction of macrophages and neutrophils by secondary necrosis following caspase-3-associated apoptosis was seen predominantly in the spleen, head kidney and gut lamina propria. Identical phagocyte destruction occurred after injection of rAIP56, but not of heat-inactivated rAIP56, or AIP56-negative Phdp strains, indicating that AIP56 is responsible for phagocyte destruction occurring in pasteurellosis. Active caspase-3 and active neutrophil elastase are present in the blood in advanced infection, indicating that phagocyte lysis by secondary necrosis is accompanied by release of tissue-damaging molecules. The AIP56-induced lysis of phagocytes represents a very efficient, self-amplifying etiopathogenic mechanism, because it results in two effects that operate in concert against the host, namely, evasion of the pathogen from a crucial defence mechanism through the destruction of both professional phagocytes, and release of tissue-damaging molecules. The induction by a bacterial exotoxin of in vivo systemic lysis of both professional phagocytes by secondary necrosis, now described for the first time, may represent an overlooked etiopathogenic mechanism operating in other infections of vertebrates.
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PMID:Systemic macrophage and neutrophil destruction by secondary necrosis induced by a bacterial exotoxin in a Gram-negative septicaemia. 1738 31

A successful pathogen manipulates its host for its own benefit. After ingestion, on reaching the intestine Salmonella encounters the resident tissue macrophages. Rather than being destroyed by these professional phagocytes after internalization, Salmonella survives intracellularly. Invasive Salmonella has been reported to induce apoptosis of macrophages as a part of its infection process, which may allow it to avoid detection by the innate immune system. However, the induction of apoptosis under different host environments, including the anaerobic stress encountered by the pathogen in the gut, remains to be examined. The present study is aimed at investigating the apoptotic potential of S. enterica serovar Typhi (S. typhi) grown under anaerobic conditions simulating the in vivo situation encountered by the pathogen. Apoptotic cell death was determined by assessment of nucleosomal DNA and flow cytometric analysis. Evaluation of the data revealed that anaerobically grown S. typhi could induce apoptosis in significantly more number of macrophages compared to the bacterial cells grown under aerobic conditions. A significantly enhanced generation of reactive nitrogen intermediates and caspase-3 activity during macrophage apoptosis induced by anaerobic S. typhi correlated with the increased generation of tumour necrosis factor-alpha, interleukin (IL)-1alpha and IL-6. The results indicate that reactive nitrogen intermediates and monokines induce caspase-3 mediated apoptosis of macrophages by S. typhi under anaerobic conditions. These findings may be relevant for clearer understanding of the Salmonella-macrophage interactions and may be of clinical importance in the development of preventive intervention against the infection.
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PMID:Reactive nitrogen intermediates and monokines induce caspase-3 mediated macrophage apoptosis by anaerobically stressed Salmonella typhi. 1788 27

Cholecystokinin (CCK) is a gut-brain peptide has been described to be able to induce mitosis according to recent studies. Additionally, conflicting data has been published on whether tumours of the central and peripheral nervous system in general, and gliomas in particular, express CCK receptors. In the present in vitro study we employed reverse transcription followed by the polymerase chain reaction (RT-PCR) to investigate whether mRNA for CCK-A and CCK-B receptors as well as CCK peptide itself is present in primary human gliomas and the U-87 MG GBM cell line. The data show that 14/14 (100%) of the primary gliomas exhibited mRNA expression for the CCK peptide gene and the B receptor including the U-87 MG cells, whereas, only 2/14 (14%) showed presence of the CCK-A receptor. The presence of CCK receptors together with CCK peptide expression itself suggests presence of an autocrine loop controlling glioma cell growth. In support of this conclusion, a neutralizing antibody against the CCK peptide exhibited a dose dependent inhibition of cell growth whereas, antagonists to CCK caused a dose depend inhibition of exogenous stimulated glioma cell growth in vitro, via the CCK-B receptor which is PKC activated. Assessment of apoptosis and proteasome activity were undertaken and we report that treatment with CCK antagonists decreased proteasome and increased caspase-3 activity. These data indicate that CCK peptide and CCK-B are abundant in human gliomas and they act to stimulate cell growth in an autocrine manner, primarily via the high affinity CCK-B receptor, which was blocked by antagonists to CCK, perhaps via apoptosis.
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PMID:Cholecystokinin (CCK) and CCK receptor expression by human gliomas: Evidence for an autocrine/paracrine stimulatory loop. 1842 48

We employed transgenic mice overexpressing betacellulin (BTC) to study its effects in the gut. BTC stimulated crypt cell proliferation and markedly increased intestinal size, while the crypt-villus architecture was preserved. Introduction of a dominant negative epidermal growth factor receptor (EGFR) completely abolished the intestinal hyperplasia. BTC increased polyp multiplicity but did not change the mean size or the histological quality of intestinal polyps in Apc(+/Min) mice. Analysis of intact and cleaved caspase-3 levels indicated that BTC has anti-apoptotic effects in the intestinal epithelium. We conclude that increased BTC levels support the survival of nascent adenomas in Apc(+/Min) mice, resulting in a larger total polyp number at later stages.
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PMID:Betacellulin stimulates growth of the mouse intestinal epithelium and increases adenoma multiplicity in Apc+/Min mice. 1865 77

Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabelling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabelling for activated caspase-3, terminal dUTP nucleotide end labelling and by ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double-labelled tissue sections. They were identified in all layers of the colonic muscle. In the muscularis propria 1.5 +/- 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 +/- 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is a continuing process in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.
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PMID:Apoptotic cell death of human interstitial cells of Cajal. 1879 96


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