Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that vitamin K2 (VK2) has a potent apoptosis inducing activity toward various types of primary cultured leukemia cells including acute myelogenous leukemia arising from myelodysplastic syndromes (MDS). We established a novel cell line, designated MDS-KZ, from a patient with MDS in blastic transformation, and further investigated the effects of VK2 using this novel cell line. MDS-KZ shows complex chromosomal anomaly including -4, 5q-, -7, 13q+, 20q-, consistent with that seen in the original patient. Culture of MDS-KZ cells in RPMI1640 medium containing 10% FBS lead to steady but very slow proliferation with a doubling time of 14 days. However, the cellular growth rate was significantly accelerated in the presence of various growth factors such as granulocyte colony-stimulating factor, stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, and thrombopoietin. Most of the cultured cells show the morphological features of myeloblasts. They are positive for CD7, CD33, CD34, CD45, CD117, and HLA-DR. However, about 10% of the cells are more mature metamyelocytes and neutrophils with various dysplastic characteristics such as pseudo-Pelger nuclear anomaly and hypersegmentation, suggesting a potential for differentiation in this cell line. As previously reported for cultured primary leukemia cells, exposure to VK2, but not to VK1, resulted in induction of apoptosis of MDS-KZ cells in a dose-dependent manner (IC50: 5 microM). In addition, VK2 treatment induced down-regulation of BCL-2 and up-regulation of BAX protein expression with concomitant activation of caspase-3 (CPP32). A tetrapeptide functioning as antagonist of caspase-3, Ac-DEVD-H, suppressed the VK2-induced inhibition of cell growth, suggesting that caspase-3 is, at least in part, involved in VK2-induced apoptosis. These observations suggest that the MDS-KZ cell line can serve as a model for the study of the molecular mechanisms of VK2-induced apoptosis.
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PMID:Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation. 1048 91

Helicobacter pylori LPS activates a homolog of gp91(phox), NADPH oxidase 1 (Nox1), in guinea pig gastric mucosal cells cultured in 10% FBS-containing medium. RT-PCR and Northern hybridization demonstrated that H. pylori LPS stimulated expression of Nox1 and a novel p47(phox) homolog (Noxo1) mRNAs with a peak at 4 h, followed by upregulation of superoxide anion (O2-) generation. Pretreatment with 10 mg/ml of a nonabsorbable antigastric ulcer drug, ecabet sodium (ecabet), completely blocked these two mRNA expressions and the upregulation of O2- production. Under low (0.1%)-FBS conditions, H. pylori LPS predominantly caused apoptosis of the cells. Ecabet completely blocked the LPS-triggered phosphorylation of transforming growth factor-beta-activated kinase 1 (TAK1) and TAK1-binding protein 1, activation of caspase 8, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase 3, and appearance of apoptotic cells. In contrast, ecabet had no effect on ethanol- or etoposide-initiated apoptosis. The ecabet-pretreated cells exhibited the responsiveness to H. pylori LPS, similarly as untreated control cells did, when ecabet was removed by washing before the addition of H. pylori LPS. Incubation of H. pylori LPS with ecabet eliminated the toxic effects of the LPS, and nondenatured polyacrylamide gel electrophoresis indicated the formation of higher molecular mass complexes between H. pylori LPS and ecabet, suggesting that ecabet may interact with H. pylori LPS and block the activation of Toll-like receptor 4 (TLR4). Our results suggest that ecabet may suppress TLR4-mediated inflammation or accelerated apoptosis caused H. pylori infection.
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PMID:Ecabet sodium inhibits Helicobacter pylori lipopolysaccharide-induced activation of NADPH oxidase 1 or apoptosis of guinea pig gastric mucosal cells. 1545 21

To produce erythropoietin (EPO), Chinese hamster ovary (CHO) cells were first cultured in a medium containing FBS (growth medium) and then in a serum-free medium containing sodium butyrate (production medium). Sodium butyrate increases recombinant protein production, but also induces apoptosis, which reduces cell viability and productivity. In a previous study, we found that silkworm hemolymph (SH), an insect serum, inhibits the apoptosis of insect and mammalian cells. To overcome sodium butyrate-induced apoptosis, we added SH to growth medium. This pretreatment with SH inhibited the sodium butyrate-induced apoptosis of CHO cells and consequently increased their longevity and their ability to produce EPO. As a result, the volumetric productivity of EPO was increased five-fold. SH was found to inhibit cytochrome c release from mitochondria into the cytosol, and prevented the activation of caspase-3 and other subsequent caspase reactions.
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PMID:Beneficial effect of silkworm hemolymph on a CHO cell system: Inhibition of apoptosis and increase of EPO production. 1594 45

We hypothesized that fibrin enhances apoptosis and modulates differentiation of trophoblast in vitro. Cytotrophoblasts isolated from normal term human placentas were cultured < or =72 h in DMEM-10%-FBS on a fibrin matrix in standard or hypoxic conditions. Trophoblasts were cultured on plastic (control), type I collagen (matrix control), or dishes with fibrinogen, fibrin degradation products (FDP), thrombin, plasma fibronectin or cellular fibronectin. Apoptosis was determined by western analysis of the cleavage products of poly-ADP-ribose polymerase and cytokeratin 18 and caspase 3 activity. Cell cycle regulation was quantified by expression of proliferating cell nuclear antigen (PCNA) and p27 protein. Differentiation was determined by media level of hCG and hPL. Compared to the two controls, fibrin matrix had no effect on trophoblast apoptosis or total cell death in standard conditions. Neither fibrin nor collagen altered expression of PCNA or p27. In contrast, fibrin significantly increased the secretion of both hCG and hPL. Fibrin, but not FDP, thrombin or fibronectins, promoted hormonal differentiation. Fibrin limited the impact of a < or =8h of hypoxia on trophoblast hormone release but did not avert the effects of 24h of low oxygen and did not alter apoptosis in hypoxic trophoblast. We conclude that fibrin provides an environment conducive for trophoblast re-epithelialization of the surface of villi, where injury is marked by fibrin deposition.
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PMID:Fibrin enhances differentiation, but not apoptosis, and limits hypoxic injury of cultured term human trophoblasts. 1595 63

Adenosine triphosphate (ATP) has been shown to induce programmed cell death in various systems. However, little is known about the effect of ATP on human granulosa-luteal cells (hGLCs). The present study was designed to examine the effect of ATP on the activation of the caspase signaling pathway and its role in inducing programmed cell death. Human GLCs were collected from patients undergoing in vitro fertilization programs, and then were cultured in FBS-supplemented DMEM for 3 days prior to our studies. To examine the dose-response relationship, hGLCs were treated with increasing concentrations of ATP (10 microM, 100 microM, 1 mM or 10 mM) for 24 hours. For time-course experiments, hGLCs were treated with 10 mM ATP for 6, 12, or 24 hours. Western blot analysis was performed using antibodies against the pro- and active forms of caspase-3, -9, or PARP. To quantify the induction of apoptosis, DNA fragmentation was measured using the cell death detection enzyme-linked immunosorbent assay. To examine the effect of human chorionic gonadotropin (hCG) in protecting cells from apoptosis, hGLCs were treated with 10 IU hCG in the presence of 10 mM ATP for 12 hours. It was demonstrated that ATP was capable of inducing DNA fragmentation in a dose- and time-dependent manner. Furthermore, Western blot analysis, which detected the pro- and active forms of caspase-3, or PARP, demonstrated that ATP activated the caspase-signaling pathway, leading to the proteolytic conversion of pro-caspase-3 to active caspase-3, and the subsequent cleavage of the caspase substrate PARP. Based on our observation, caspase-9 was not triggered by ATP. Interestingly, hCG attenuated the effect of ATP in activating the caspase signaling pathway. To our knowledge, this is the first demonstration of the ATP-induced activation of the caspase signaling pathway in the human ovary. These results support the notion that the caspase-signaling pathway is involved in mediating ATP actions in the human ovary.
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PMID:Adenosine triphosphate induces activation of caspase-3 in apoptosis of human granulosa-luteal cells. 1600 27

TP508 is a 23-amino acid peptide derived from human prothrombin that increases cartilage matrix production and reduces alkaline phosphatase activity without changing chondrocyte proliferation. This study tested the hypothesis that TP508 acts by blocking the onset of apoptosis associated with hypertrophy. Rat costochondral resting zone chondrocytes and human auricular chondrocytes were cultured in DMEM containing 50microM ascorbic acid and 10% FBS. Apoptosis was induced by treatment of confluent cultures with chelerythrine, tamoxifen, or inorganic phosphate (Pi) for 24h. One half of the cultures received TP508 (0, 0.7, or 7microg/ml). Apoptosis was assessed as a function of DNA fragmentation ([3H]-thymidine labeled DNA fragments), TUNEL staining, and cell viability using the MTT assay, as well as by assessing the Bcl-2/Bax mRNA and protein ratios and caspase-3 activity. The universal NO synthase inhibitor l-NMMA was used to assess the effect of NO production on chondrocyte apoptosis and specific NO synthase subspecies were identified using iNOS inhibitor 1400W and nNOS inhibitor vinyl-l-NIO, as well as l-NAME, which inhibits both iNOS and eNOS. Finally, we assessed if TP508 would block NO production induced by the apoptogens. Chelerythrine, tamoxifen and Pi-induced apoptosis and this was reversed by TP508. All apoptogens increased NO production and this was reduced by TP508. TP508 reduced NO levels to the same extent as 1400W but not to the same extent as l-NAME, suggesting that its effects are mediated primarily by iNOS. In addition, TP508 reduced the effect of chelerythrine to the same extent as 1400W and l-NAME, again indicating that it acts via inhibition of an iNOS pathway. TP508 also regulated Bcl-2/Bax mRNA in a time and dose-dependent manner. The Bcl-2/Bax mRNA ratio was 0.11 in the absence of TP508 at 1h and 4.95 at 7microg/ml TP508; by 3h the ratio was approximately 1 in both groups. The Bcl-2/Bax protein ratio also increased by 63% at 1h. TP508 did not affect caspase-3 activity. TP508 also caused a dose-dependent increase in protein kinase C (PKC) activity within 9min that was maximal at 270min. These results show that TP508 prevents apoptosis in growth plate chondrocytes via inhibition of iNOS-dependent NO and suggest a possible role for PKC in the mechanism.
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PMID:Thrombin peptide TP508 prevents nitric oxide mediated apoptosis in chondrocytes in the endochondral developmental pathway. 1802 91

Geranylgeranoic acid (GGA) and 2,3-dihydrogeranylgeranoic acid (2,3-diGGA) are geranylgeraniol-derived metabolites (Kodaira et al. (2002) J Biochem 132: 327-334). In the present study, we examined the effects of these acids on HL-60 cells. The cells were differentiated into neutrophils by GGA stimulation like retinoic acid stimulation. In the case of cells stimulated with 2,3-diGGA, neutrophils were not detected, but the formation of lipid droplets was induced. On the other hand, when the cells were cultured in the presence of 0.1% FBS instead of 10% FBS, apoptotic cells were induced not only by GGA stimulation but also with 2,3-diGGA. In the latter case, when the cells were cultured in the co-presence of a caspase-3 inhibitor (Ac-DMQD-CHO), the lipid droplets formation was observed in the cells. These results suggest that GGA and 2,3-diGGA are extremely different from each other with respect to their effects on HL-60 cells.
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PMID:Formation of lipid droplets induced by 2,3-dihydrogeranylgeranoic acid distinct from geranylgeranoic acid. 1806 7

The cell growth is controlled by the interaction of survival and cell growth arrest pathways as well as apoptosis mechanisms which determine the outcome of cell faith as proliferation or apoptosis. In this study, we have studied the activity of survival pathways, i.e., Akt and ERK1/2 with regard to XIAP (inhibitor of apoptosis) in serum starved and stimulated conditions. The HEK-293 cells were cultured in RPMI + 10% FBS. The cells were serum starved by switching to medium with 1% FBS for 24 h and serum stimulated by changing the medium to 10% FBS following serum starvation. The expression of p-Akt, p-ERK, Akt, ERK and XIAP was studied in various time points using western blot. The apoptosis was evaluated by DNA condensation using Hoechst 33258 and Caspase-3 assay. In serum starved condition expression of p-Akt and XIAP is very low. Serum stimulation increases p-Akt and p-ERK within 5 min and sustains a high level for 30 min. The expression of total Akt and ERK1/2 has not changed significantly for 24 h. XIAP expression starts at 6 h after serum stimulation, reaches to maximum level at 12 h and decreases to baseline within 24 h. Furthermore, serum starvation for 24 h does not induced apoptosis and DNA condensation. Taken together, the results indicate that serum activates Akt and ERK pathways earlier than XIAP expression. Furthermore, XIAP expression is low in serum starvation unlike p-ERK which suggests a survival role for ERK in serums starvation. The expression pattern of XIAP indicates induction by Akt and/or ERK activation which requires further studies.
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PMID:The time course of Akt and ERK activation on XIAP expression in HEK 293 cell line. 1964 22

In this study, we investigated whether Bone Morphogenetic Protein-2 (BMP-2) could modulate dedifferentiation, apoptosis and proliferation capacity in the normal and OA cultured chondrocytes. The articular chondrocytes from normal (n = 4) and OA (n = 4) cartilages were harvested separately. The chondrocytes were cultured in monolayer in the presence of 100 ng mL(-1) BMP-2 and 1% FBS as a test group and 1% FBS alone as a control group. Then, the chondrocytes were harvested and assessed for morphology with invert microscopy, proliferation by using MTT-assay and apoptosis with caspase-3 immunocytochemistry. The results indicated that the normal and the most OA chondrocytes showed round and polygonal appearance with chondrocyte-like morphology in BMP-2 treated groups after 6 days. The MTT proliferation test didn't show significant difference between test and control groups. The OA cells showed proliferation rate higher than the normal cells and significant difference in the presence of BMP-2 was observed (p<0.05). Positive immunostaining of caspase-3 in test and control groups was 1 and 20% in normal and 30 and 43% in OA groups, respectively. The percentage of apoptosis was reduced in the presence of BMP-2. In conclusion, it appears that BMP-2 involves in suppression of dedifferentiation and apoptosis processes of cultured human chondrocytes.
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PMID:Effect of bone morphogenetic protein-2 on normal and osteoarthritic human articular chondrocytes. 1994 54

Even though there have been some investigations into cellular responses induced by ultrafine titanium dioxide (TiO(2)) in vitro, the relationship between cellular responses and secondary particle size is still not clear. In this study, a stable and uniform TiO(2)-cell culture-medium dispersion was prepared, and cellular responses prompted by "ultrafine secondary particles" were examined. The TiO(2)-DMEM-FBS dispersion included secondary particles in which the secondary particle size was 100 nm or less. In the present study, a "secondary particle" was defined as a complex aggregate of TiO(2) primary particles, proteins from FBS and other medium components. Secondary particle size did not influence the cell viability. The TiO(2)-DMEM-FBS dispersion introduced to the human keratinocyte HaCaT cells caused weak intracellular oxidative stress and apoptosis. The cellular influence of ultrafine TiO(2)in vitro is caused by the following mechanisms: (1) Secondary particles are formed. Ultrafine TiO(2) particles dispersed in medium immediately form secondary particles with proteins and salts. (2) "Ultrafine" secondary particles are taken up by the cells. The secondary particles reach the cells by diffusion and/or sedimentation and are taken up by the cells, through endocytosis. (3) Intracellular reactive oxygen species (ROS) level increases. Internalized secondary particles induce an increase in intracellular reactive oxygen species levels, although the secondary particles do not break up in the cell. In the case of ultrafine TiO(2), the increase of the intracellular ROS level was minimal. Moreover, the antioxidation system of cells such as glutathione was working. (4) Apoptotic cell death is induced. An accumulation of oxidative stress activates the apoptotic pathway (such as the caspase-3) and subsequently induces apoptotic cell death. After 24h of exposure to TiO(2), the percentage of apoptotic cells was only 6-7%. As a result, although the ultrafine TiO(2) particles induce some cellular responses, these cellular responses to ultrafine TiO(2) are weaker than those of other cytotoxic ultrafine metal oxide particles, such as nickel oxide.
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PMID:Cellular responses by stable and uniform ultrafine titanium dioxide particles in culture-medium dispersions when secondary particle size was 100 nm or less. 2054 99


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