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)

HIV-1 Tat, in addition to its critical role in viral transcription, is secreted from infected cells and can act as a proto-cytokine. We studied the effects of HIV-1 Tat in primary human microvascular endothelial cells of lung origin and found that it caused apoptosis. This apoptosis occurred without induction of either Fas or TNF, known mediators of programmed cell death. Tat, like Fas ligand, induced cleavage of chromatin structure, as evidenced by changes in DNA laddering, incorporation of fluorescein into the nicked chromosomal DNA (TUNEL assay), and mono- or oligonucleosomes. Furthermore, Tat treatment caused cleavage of poly(A/DP)-ribose polymerase, a substrate of caspases. Caspase-3, but not caspase-9, was activated following treatment of primary human microvascular endothelial cells of lung origin with either Tat or anti-Fas agonist Ab (anti-Fas). Inhibition of caspase-3 activity markedly reduced apoptosis. Although Fas-mediated apoptosis involved changes in Bcl-2, Bax, and Bad regulatory proteins, such alterations were not observed with Tat. Taken together, these data demonstrate that HIV-1 Tat is able to activate apoptosis in microvascular endothelium by a mechanism distinct from TNF secretion or the Fas pathway.
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PMID:HIV-1 Tat induces microvascular endothelial apoptosis through caspase activation. 1150 21

Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other organs. Aspirin triggers the production of 15-epimers during cell-cell interaction in a cytokine-primed milieu, and aspirin-triggered 15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) may contribute to the bioactivity profile of this prototype nonsteroidal anti-inflammatory drug in vivo. We determined the effect of LXA(4), 15-(R/S)-methyl-11,12-dehydro-LXA(4) methyl ester (15-(R/S)-methyl-LXA(4)), and stable analogs of LXA(4) on TNF-alpha-stimulated neutrophil-enterocyte interaction in vitro and TNF-alpha-stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human colonic mucosa ex vivo. LXA(4), 15-(R/S)-epi-LXA(4), and 16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA(4) methyl ester (16-phenoxy-LXA(4)) inhibited TNF-alpha-stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA(4)potently attenuated TNF-alpha-stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-alpha induced disruption of mucosa architecture and enhanced colonocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(R/S)-methyl-LXA(4) attenuated TNF-alpha-stimulated colonocyte apoptosis and protected the mucosa against TNF-alpha-induced mucosal damage. In aggregate, our data demonstrate that lipoxins and aspirin-triggered 15-epi-LXA(4) are potent antagonists of TNF-alpha-mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-alpha-triggered chemokine release and colonocyte apoptosis, and are protective against TNF-alpha-induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxygenase-derived eicosanoids and suggest new therapeutic approaches for the treatment of inflammatory bowel disease.
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PMID:Lipoxin A(4) and aspirin-triggered 15-epi-lipoxin A(4) antagonize TNF-alpha-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-alpha-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo. 1150 22

One of the consequences of cytokine-orchestrated inflammation after CNS trauma is apoptosis. Our hypothesis is that cell death in the spinal cord after injury results in part from increased synthesis and release of IL-1beta. Using a ribonuclease protection assay, we demonstrated that there is increased transient expression of IL-1beta mRNA and, by using IL-1beta protein ELISA assay, that there are increased IL-1beta protein levels in the contused rat spinal cord, initially localized to the impact region of the spinal cord (segment T8). Using an ELISA cell death assay, we showed that there is apoptosis in the spinal cord 72 h after injury, a finding that was confirmed by measuring caspase-3 activity, which also significantly increased at the site of injury 72 h after trauma. Treatment of the contused spinal cord at the site of injury with the IL-1 receptor antagonist (rmIL-lra, 750 ng/mL) for 72 h using an osmotic minipump completely abolished the increases in contusion-induced apoptosis and caspase-3 activity.
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PMID:IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. 1156 5

The inhibitor-of-apoptosis protein survivin is expressed in most cancers and leukemias and during fetal development, but not in most normal adult tissues. Survivin expression was analyzed in umbilical cord blood (UCB) and adult bone marrow CD34(+) cells and in the factor-dependent MO7e cell line; also investigated was whether survivin expression was regulated by hematopoietic growth factors. Survivin messsenger RNA (mRNA) and protein were expressed in fresh UCB and marrow CD34(+) cells. The combination of thrombopoietin, Flt3 ligand, and stem cell factor upregulated survivin expression in CD34(+) cells within 24 hours; survivin expression was cell-cycle related and highest during G2/M, whereas growth-factor withdrawal resulted in decreased survivin expression. Cell-cycle fractionation of UCB CD34(+) with Hoechst-33342/pyronin-Y demonstrated that survivin message was undetectable in freshly isolated G0 cells, but present in G1 cells. After cytokine stimulation, survivin mRNA and protein expression were observed in both G0 and G1 CD34(+) cells as well as in cells that had progressed to S and G2/M phase, indicating that survivin expression is regulated in all phases of the cell cycle. This contrasts with the expression of survivin predominantly during G2/M in cancer cells. In CD34(+) cells and MO7e cells, growth factor-mediated upregulation of survivin was associated with inhibition of apoptosis, and downregulation of survivin was coincident with increased apoptosis. Furthermore, an inverse correlation between survivin and active caspase-3 was observed in CD34(+) cells. These findings demonstrate that survivin is not a cancer-specific antiapoptotic protein and plays a regulatory role in normal adult hematopoiesis.
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PMID:Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis. 1156 95

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) has been found to protect a variety of epithelial and cancer cell types against cytotoxicity and apoptosis induced by DNA damage, but the specific apoptotic signaling events and the levels at which they are blocked by HGF/SF have not been identified. We found that treatment of MDA-MB-453 human breast cancer cells with adriamycin (also known as doxorubicin, a DNA topoisomerase IIalpha inhibitor) induced a series of time-dependent events, including the mitochondrial release of cytochrome c and apoptosis-inducing factor, mitochondrial membrane depolarization, activation of a set of caspases (caspase-9, -3, -7, -2, and -8), cleavage of poly(ADP-ribose) polymerase (PARP), and up-regulation of expression of the Fas ligand. All of these events were blocked by preincubation of the cells with HGF/SF. In contrast, the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone blocked some of these events (e.g. caspase-3 activation and PARP cleavage) but did not block cytochrome c release or mitochondrial depolarization. These findings suggest that HGF/SF functions, in part, upstream of the mitochondria to block mitochondrial apoptosis signaling, prevent activation of multiple caspases, and protect breast cancer cells against apoptosis.
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PMID:Hepatocyte growth factor/scatter factor blocks the mitochondrial pathway of apoptosis signaling in breast cancer cells. 1157 Dec 97

The cytotoxin-associated gene (cagA) and vacuolating cytotoxin (Vac) production have been reported to be major virulence factors of Helicobacter pylori. However, there have been some disputes regarding the correlation between these virulence factors and clinical outcomes. We evaluated whether the cagA-positive genotype and Vac production might be correlated with various gastroduodenal diseases in Korea and whether this correlation could be due to differences in proinflammatory cytokine gene expression and apoptosis of gastric epithelial cells in vitro. The presence of the cagA gene was examined by the polymerase chain reaction (PCR), and Vac production was detected using the bacterial culture supernatant and HeLa cells after H. pylori was isolated from Korean patients. Gastric epithelial cells were infected with cagA+Vac+, cagA+Vac-, or cagA-Vac- strains, after which cytokine gene expression was evaluated, using quantitative reverse transcription (RT)-PCR. Apoptosis and caspase-3 activation were measured in H. pylori-infected gastric epithelial cells. There was no significant correlation between the presence of these virulence factors in H. pylori isolates and peptic ulcer or gastric cancer. Upregulation of cytokine gene expression, including that of interleukin (IL)-1alpha, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemotactic protein (MCP)-1, as well as apoptosis and caspase-3 activation, were similar in infections with cagA-positive and cagA-negative strains, but were not correlated with the production of Vac. These results suggest that the lack of correlation between virulence factors of isolated H. pylori strains and serious gastroduodenal disease entities in Korea may be due to the similar capacity for proinflammatory cytokine gene expression and apoptosis caused by infection with each of the H. pylori strains.
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PMID:Virulence factors of Helicobacter pylori in Korean isolates do not influence proinflammatory cytokine gene expression and apoptosis in human gastric epithelial cells, nor do these factors influence the clinical outcome. 1157 34

Crocus sativus L. is used in Chinese traditional medicine to treat some disorders of the central nervous system. Crocin is an ethanol-extractable component of Crocus sativus L.; it is reported to prevent ethanol-induced impairment of learning and memory in mice. In this study, we demonstrate that crocin suppresses the effect of tumor necrosis factor (TNF)-alpha on neuronally differentiated PC-12 cells. PC-12 cells dead from exposure to TNF-alpha show apoptotic morphological changes and DNA fragmentation. These hallmark features of cell death did not appear in cells treated in the co-presence of 10 microM crocin. Moreover, crocin suppressed the TNF-alpha-induced expression of Bcl-Xs and LICE mRNAs and simultaneously restored the cytokine-induced reduction of Bcl-X(L) mRNA expression. The modulating effects of crocin on the expression of Bcl-2 family proteins led to a marked reduction of a TNF-alpha-induced release of cytochrome c from the mitochondria. Crocin also blocked the cytochrome c-induced activation of caspase-3. To learn how crocin exhibits these anti-apoptotic actions in PC-12 cells, we tested the effect of crocin on PC-12 cell death induced by daunorubicin. We found that crocin inhibited the effect of daunorubicin as well. Our findings suggest that crocin inhibits neuronal cell death induced by both internal and external apoptotic stimuli.
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PMID:Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells. 1172 92

Gamma-interferon (IFN-gamma) a cytokine produced by CD4+ T helper type 1 cells, CD8+ T cells and natural killer (NK) cells, plays a central role in the development of humoral and cell-mediated immunity. IFN-gamma participates in the maturation and differentiation of B cells, but it has been previously reported that IFN-gamma may inhibit the early stages of B cell activation. We report that the inhibition of the B lymphoma cell WEHI-279-proliferation induced by IFN-gamma, involves the induction of typical features of apoptosis (nuclear chromatin condensation and fragmentation, cell shrinkage, phosphatidyl-serine (PS) exposure and mitochondrial membrane potential (delta psim) loss). IFN-gamma-mediated B cell apoptosis was decreased by the addition of the T helper type 2 cytokine, IL-4. WEHI-279 cells express CD95 and undergo apoptosis after treatment with either an agonistic anti-CD95 Ab or with a soluble recombinant CD95L. However, incubation with CD95-Fc or TRAIL-R1-Fc fusion proteins, did not prevent IFN-gamma-mediated apoptosis, suggesting that IFN-gamma-mediated apoptosis occurs independently of CD95/CD95L and TRAIL-R/TRAIL interactions. IFN-gamma-mediated apoptosis is associated with caspase-3 activation that can be prevented by the addition of the broad caspase inhibitor zVAD-fmk. These data indicate that IFN-gamma may play a major role in the regulation of B cell apoptosis, and suggest the involvement of an alternative pathway which is independent of the death receptors.
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PMID:Gamma-interferon induces apoptosis of the B lymphoma WEHI-279 cell line through a CD95/CD95L-independent mechanism. 1178 Nov 85

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to attenuate proliferation of vascular smooth muscle cells (VSMCs) by mechanisms independent of lipid reduction. In the current study, we investigated the effect of lipophilic and hydrophilic statins (fluvastatin and pravastatin) on apoptosis in unstimulated or cytokine-stimulated VSMCs. The presence of apoptosis in rat VSMCs was evaluated by electrophoresis of DNA fragments and 4'6'-diamidine-2'-phenylindole staining and quantified by flow cytometry. Fluvastatin but not pravastatin enhanced apoptosis in interleukin-1beta-stimulated VSMCs. The proapoptotic effect of fluvastatin was fully reversed by mevalonate and geranylgeranyl-pyrophosphate, and partially by farnesyl-pyrophosphate, but not by squalene. Inhibition of the extracellular signal-regulated protein kinase (ERK1/2) pathway significantly increased fluvastatin-enhanced apoptosis, whereas inhibition of the p38-mitogen-activated protein kinase (MAPK) pathway significantly prevented this increase. However, fluvastatin showed no effect on the activity of ERK1/2 and p38-MAPK. Furthermore, fluvastatin-induced apoptosis was inhibited by YVAD-FMK (a caspase-1/interleukin-1beta-converting enzyme-like protease inhibitor) and DEVD-FMK (a caspase-3/CPP32 inhibitor), indicating involvement of an important segment in the apoptosis signaling pathway. These findings suggest that fluvastatin enhances apoptosis in cytokine-stimulated VSMCs and that protein prenylation, MAPK (ERK1/2 and p38-MAPK), and caspases are critically involved in the pathways of fluvastatin-enhanced apoptosis.
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PMID:Fluvastatin enhances apoptosis in cytokine-stimulated vascular smooth muscle cells. 1179 Oct 17

Due to the dominating roles that caspases play in the apoptotic cascade, their activities appear to be a primary factor in the death pathway (apoptosis versus oncosis/necrosis) decision. In murine FL5.12 proB lymphocytes, the cellular consequences of acrolein treatment included a lack of typical apoptotic features in preference to oncosis/necrosis. Oncosis/necrosis was apparent by detection of a reduction in intracellular ATP concentration, increased plasma membrane leakage (measured by LDH release and flow cytometric detection of propidium iodide uptake) and morphological criteria. Analysis of acrolein-treated cell lysates or recombinant caspase enzymes showed overall dose-dependent decreases in caspase-3, -8 and -9 activities. In addition to acrolein's effect on intracellular caspases, it was also able to alter caspase-dependent apoptosis induced by secondary treatment with etoposide or following cytokine withdrawal. Acrolein at doses > or =20 microM circumvented etoposide or interleukin-3 withdrawal induced apoptosis. When acrolein was combined with mechlorethamine, another alkylating agent not dependent on caspases for its cell death signaling, necrosis was increased in a dose-dependent manner. Overall, these data suggest that caspase inhibition plays an important role in the cell death pathway decision, particularly with treatments dependent on the caspase cascade to induce apoptosis.
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PMID:Acrolein-induced cell death: a caspase-influenced decision between apoptosis and oncosis/necrosis. 1180 30


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