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)

Homoharringtonine (HHT) is a plant alkaloid with antileukemia activity that is currently being used for treatment of acute, chronic leukemias and MDS. In this study, we show that HHT can induce apoptosis in a variety of human myeloid leukemia cell lines (U937, HL-60, HEL, THP, and K562). U937 and HL60 cells undergo rapid apoptosis on treatment with HHT, as indicated by increased annexin V binding capacity, caspase-3 activation, and cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the expression of bax is upregulated during HHT-induced cell death, whereas the expression of bcl-2 is only slightly decreased. Importantly, treatment of primary leukemic cells, obtained from acute myeloid leukemia patients, resulted in rapid apoptosis. Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia.
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PMID:Homoharringtonine mediates myeloid cell apoptosis via upregulation of pro-apoptotic bax and inducing caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP). 1522 52

Apolipoprotein-E (apoE) is expressed at high levels by macrophages. In addition to its role in lipid transport, macrophage-derived apoE plays an important role in immunoregulation. Previous studies have identified macrophage subpopulations that differ substantially in their ability to synthesize specific cytokines and enzymes, however, potential heterogeneous macrophage apoE expression has not been studied. Here we examined apoE expression in human THP-1 macrophages and monocyte-derived macrophages (MDM). Using immunocytochemistry and flow cytometry methods we reveal a striking heterogeneity in macrophage apoE expression in both cell types. In phorbol-ester-differentiated THP-1 macrophages, 5% of the cells over-expressed apoE at levels more than 50-fold higher than the rest of the population. ApoE over-expressing THP-1 macrophages contained condensed/fragmented nuclei and increased levels of activated caspase-3 indicating induction of apoptosis. In MDM, 3-5% of the cells also highly over-expressed apoE, up to 50-fold higher than the rest of the population; however, this was not associated with obvious nuclear alterations. The apoE over-expressing MDM were larger, more granular, and more autofluorescent than the majority of cells and they contained numerous vesicle-like structures that appeared to be coated by apoE. Flow cytometry experiments indicated that the apoE over-expressing subpopulation of MDM were positive for CD14, CD11b/Mac-1 and CD68. These observations suggest that specific macrophage subpopulations may be important for apoE-mediated immunoregulation and clearly indicate that subpopulation heterogeneity should be taken into account when investigating macrophage apoE expression.
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PMID:Heterogeneous expression of apolipoprotein-E by human macrophages. 1550 Jun 20

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

Salmonella strains are facultative intracellular pathogens that produce marked cytopathology during infection of host cells. Different forms of cytopathic effects have been associated with the virulence systems encoded by the two Salmonella pathogenicity islands (SPI-1 and SPI-2) and the spv locus. We used Salmonella enterica serovar Dublin to investigate the induction of cytopathology during infection of the human macrophage-like cell line THP-1. Analysis of host cells by flow cytometry using a fluorescent terminal deoxynucleotidyltransferase dUTP-biotin nick end labeling (TUNEL) assay revealed that 70% of THP-1 cells showed DNA fragmentation after 4 h of infection, increasing to greater than 90% by 5.5 h. Moreover, the results showed that gentamicin-killed or chloramphenicol-treated bacteria did not induce DNA fragmentation. Serovar Dublin strains with mutations in SPI-1, SPI-2, or spvB induced these cytopathic effects similar to wild-type bacteria. In contrast, a mutation in the phoP regulatory gene abolished DNA fragmentation in the TUNEL assay. Caspase-3 activation was detected during Salmonella infection of THP-1 cells, but caspase-8 and caspase-9 activities were not found. However, inhibition of caspase-3 did not block Salmonella-induced DNA fragmentation. These results identify a previously undetected apoptotic effect in Salmonella-infected cells that is dependent on phoP gene function.
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PMID:Characterization of Salmonella-induced cell death in human macrophage-like THP-1 cells. 1584 88

The mechanisms involved in the apoptotic effect of LCY-2-CHO [9-(2-chlorobenzyl)-9H-carbazole-3-carbaldehyde], a synthetic carbazole derivative identified as an anti-inflammatory compound, were studied. Cell cycle analysis by propidium iodide staining in human THP-1 monocytic leukemia cells showed the ability of LCY-2-CHO to increase cell population in sub-G1 stage with time- and concentration-dependent manners. LCY-2-CHO-mediated cell death was also demonstrated by DNA laddering and was not related to the release of lactate dehydrogenase. Apoptosis in THP-1 cells induced by LCY-2-CHO was accompanied by the Bid cleavage, collapse of mitochondrial transmembrane potential, the release of cytochrome c and the activation of caspase-3. The apoptotic effect of LCY-2-CHO was diminished by the presence of zVEID-fmk (caspase-6 inhibitor), zIETD-fmk (caspase-8 inhibitor), and zVAD-fmk (non-selective caspase inhibitor), but was not altered by several antioxidants, and cathepsin inhibitor. The Bid cleavage and loss of mitochondrial transmembrane potential, but not the cytochrome c release, were reversed by zIETD-fmk. Comparing the cell selectivity of LCY-2-CHO, we found T-cell acute lymphoblastic CEM leukemia cells were sensitive to 1 microM LCY-2-CHO, acute myeloid leukemia HL-60 cells underwent apoptosis at 10 microM, while adherent cancer cells, such as PC3, HT29 and MCF-7, were resistant to 30 microM LCY-2-CHO within 24-h incubation. Taken together in the present study, we demonstrated LCY-2-CHO might be apoptotic for malignant hematopoietic cells but not anchorage-dependent cells. This action is mediated by an intrinsic caspase-dependent apoptotic event involving mitochondria.
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PMID:Cell apoptosis induced by a synthetic carbazole compound LCY-2-CHO is mediated through activation of caspase and mitochondrial pathways. 1589 95

The atherosclerotic plaque is an inflammatory site where macrophage cells are exposed to cytotoxic oxidised low density lipoprotein (oxLDL). Interferon-gamma released from T-cells results in macrophage synthesis of 7,8-dihydroneopterin which has antioxidant and cytoprotective activity. Using the human derived monocyte-like U937 and THP-1 cell lines, we examined whether 7,8-dihydroneopterin could inhibit the cytotoxic effect of oxLDL. In U937 cells, oxLDL caused a dramatic loss of cellular glutathione and caspase independent cell death associated with phosphatidylserine exposure on the plasma membrane. 7,8-Dihydroneopterin completely blocked the cytotoxic effect of oxLDL. In contrast, oxLDL initiated THP-1 cell apoptosis with reduction in cellular thiols, caspase-3 activation and plasma membrane phosphatidylserine exposure. 7,8-Dihydroneopterin was unable to alter these processes or restore the THP-1 cellular thiol content. 7,8-Dihydroneopterin did provide some protection to both THP-1 cells and U937 cells from AAPH derived peroxyl radicals. The preincubation of oxLDL with 7,8-dihydroneopterin did not reduce cytotoxicity, suggesting that 7,8-dihydroneopterin may be acting in U937 cells by scavenging intracellular oxidants generated by the oxLDL. The data show that muM levels of 7,8-dihydroneopterin may prevent oxLDL mediated cellular death within atherosclerotic plaques.
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PMID:OxLDL induced cell death is inhibited by the macrophage synthesised pterin, 7,8-dihydroneopterin, in U937 cells but not THP-1 cells. 1608 8

Endothelial cell function can be influenced by nutrition, especially dietary FA and antioxidants. One class of dietary FA that is found in meat and dairy products derived from ruminant animals is conjugated linoleic acids (CLA). We have examined the effects of several CLA isomers on endothelial cell proliferation. 9t,11t-CLA was the only isomer that inhibited bovine aortic endothelial cell (BAEC) [3H]methylthymidine incorporation (I50 = 35 microM), and this antiproliferative effect was time-dependent. A small decrease (20%) in cell number was observed only at the highest concentration (60 microM) tested. The 9c,11t-, 9c,11c-, 10t 12c-, and 11c,13t-CLA isomers did not exhibit any antiproliferative effects over a 5-60 microM concentration range. alpha-Tocopherol and BHT decreased BAEC proliferation, but pretreatment of cells with either of these antioxidants substantially attenuated the antiproliferative effect of 9t,11 t-CLA. No difference in lipid peroxidation, as measured by the thiobarbituric acid assay for malondialdehyde, was observed on treatment of endothelial cells with either 9t,11 t- or 9c,11 t-CLA. However, a 43% increase in caspase-3 activity was observed after incubating BAEC with 9t,11 t-CLA, suggesting that the antiproliferative effect of this isomer is partially due to an apoptotic pathway. In contrast to the above results with normal endothelial cells, these five CLA isomers all inhibited proliferation of the human leukemic cell line THP-1, with the 9t,11 t isomer again being the most (I50 = 60 microM) effective. These results confirm that different CLA isomers have different inhibitory potencies on the proliferation of normal and leukemic cells.
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PMID:9-trans, 11-trans-CLA: antiproliferative and proapoptotic effects on bovine endothelial cells. 1645 22

Tomoregulin-1, a type-I transmembrane protein with two follistatin modules, a unique epidermal growth factor (EGF) domain and a short, highly conserved cytoplasmic tail, was studied. A number of hematopoietic cell lines (L1210, CEM, Jurkat, U937, K562, JY, THP-1 and T2) express tomoregulin-1 endogenously. In these cells, apoptosis was induced by an antiserum (C29) and purified IgG against the follistatin modules, but not by antisera against the EGF-domain or the cytoplasmic tail. Furthermore, C29 induced apoptosis in tomoregulin-1-, but not in mock-transfected cells. Apoptosis was monitored through genomic DNA fragmentation, annexin-V staining and caspase-3 activation. Treatment of the cells with C29 in the presence of H89 (a SerlThr kinase inhibitor) or 8'-bromo-cyclicAMP revealed that apoptosis was mediated by a cAMP-dependent Ser/Thr kinase. Moreover, C29 increased [cAMP]i over 5-fold. Together, these data suggest that the C29 antiserum against tomoregulin-1 induces apoptosis of hematopoietic cells.
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PMID:Induction of apoptosis in hematopoietic cells with an antibody against tomoregulin-1. 1647 15

Honokiol, a compound extracted from Chinese medicinal herb Magnolia officinalis, has several biological effects. However, its protective effects against endothelial injury remain unclarified. In this study, we examined whether honokiol prevented oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial dysfunction. Incubation of oxLDL with honokiol (2.5-20 microM) inhibited copper-induced oxidative modification as demonstrated by diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Expression of adhesion molecules (ICAM, VCAM and E-selectin) and endothelial NO synthase (eNOS) affected by oxLDL was investigated by flow cytometry and Western blot. We also measured the production of reactive oxygen species (ROS) using the fluorescent probe 2',7'-dichlorofluorescein acetoxymethyl ester (DCF-AM). Furthermore, several apoptotic phenomena including increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase-3 were also investigated. Apoptotic cell death was characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. The results showed that honokiol prevented the copper-induced oxidative modification of LDL. Honokiol also ameliorated the oxLDL-diminished eNOS protein expression and reduced the oxLDL-induced adhesion molecules and the adherence of THP-1 cells to HUVECs. Furthermore, honokiol attenuated the oxLDL-induced cytotoxicity, apoptotic features, ROS generation, intracellular calcium accumulation and the subsequent mitochondrial membrane potential collapse, cytochrome c release and activation of caspase-3. Our results suggest that honokiol may have clinical implications in the prevention of atherosclerotic vascular disease.
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PMID:Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells. 1658 Jun 56

Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8- and 2.6-fold decrease in cell proliferation, respectively) (P<0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8- and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (P<0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 microg ml(-1) VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 microg ml(-1) VP-16 (P<0.001). VP-16 enhanced the release of IL-1beta and TNF-alpha from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (P<0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.
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PMID:Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells. 1704 52


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