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)

Homeodomain (HDM) proteins encoded by homeobox (HBX) genes represent a large family of transcriptional factors that control differentiation and development in certain cell types. DLX4 is a member of Distal-less (DLX) family of HBX genes. Recent studies have demonstrated that abnormal expression of DLX4 is present in several types of human tumors, such as breast cancer, leukemia and colon cancer. In the present study, we investigated DLX4 mRNA and protein expression in both normal placental tissues and human choriocarcinoma cell lines. Also, using RNA interference (RNAi) technique, we knocked down the expression of DLX4 and examined apoptosis in JEG-3 cells. Our studies demonstrated that DLX4 RNAi inhibited DLX4 mRNA expression and decreased DLX4 protein mass specifically and effectively, potentially enhancing apoptosis. Moreover, we examined expression of caspase-3 and caspase-8, and found that both caspases were increased after DLX4 knockdown. However, DLX4 RNAi did not influence Bax expression in JEG-3 cells. In conclusion, this study suggests that DLX4 may be involved in the survival of human choriocarcinoma cells, which may be mediated by the inhibition of apoptosis. The detailed mechanism needs further investigation.
Placenta
PMID:Inhibition of DLX4 promotes apoptosis in choriocarcinoma cell lines. 1597 50

The uterine endometrium responds to blastocyst implantation with extensive proliferation and differentiation of stromal cells into decidual cells, forming the antimesometrial and mesometrial decidua. These undergo regression by apoptosis but as this process occurs at different time periods suggest that there is spatially dependent temporal control of apoptosis in these specific regions. To elucidate the role of the mitochondrion-dependent signalling pathway in tissue regression, we investigated the spatial and temporal pattern of expression of the Bcl-2 family members in uterine tissues of the implantation site, from the post-implantation period to parturition. Furthermore, the activities of the initiator caspases-8 and -9, and of the executioner caspase-3 were determined. Overall Bax and Bcl-2 were expressed from day 8 till day 19, whilst Bcl-x(L) was extinguished by day 16. In the antimesometrial and in the mesometrial decidua both Bcl-2 and Bax declined from days 10 to 12. In the latter Bcl-2 immunoreactivity decreased till the end of pregnancy, whilst for Bax a constant level remained thereafter. The pattern of variation of enzymatic activities throughout pregnancy for all the enzymes was similar, increasing from days 10 to 14 and decreasing towards the end of pregnancy. The increased levels of active caspase-9 correlated with Bax/Bcl-2 and Bcl-x(L) expression suggesting that the apoptotic mitochondrion-dependent pathway is involved in decidual regression during pregnancy progression.
Placenta 2005 Nov
PMID:Patterns of expression of Bax, Bcl-2 and Bcl-x(L) in the implantation site in rat during pregnancy. 1622 30

We have investigated whether maternal obstructive cholestasis during pregnancy (OCP) causes oxidative stress and apoptosis in rat placenta and whether treatment with ursodeoxycholic acid (UDCA, i.g., 60 microg/100 g b.wt./day, following complete biliary obstruction on day 14 of pregnancy) has protective effects on this organ. In rats with OCP, increased (15-fold) serum bile acid concentrations (BAs) together with signs of placental oxidative stress (lipid peroxidation and protein carbonylation) were found. The latter were partly prevented by UDCA, even though hypercholanemia was not corrected. Some elements of the antioxidant system (total glutathione content, GSH/GSSG ratio and catalase, glutathione peroxidase, and glutathione-S-transferase--but not glutathione reductase--activities) were impaired in placentas from the OCP group. UDCA treatment partly prevented changes in the antioxidant system. OCP induced an increase in Bax-alpha/Bcl-2 mRNA ratio, as determined by real-time quantitative PCR, suggesting enhanced susceptibility to apoptosis activation through the mitochondria-mediated pathway. Accordingly, the activity of caspase-3, but not caspase-8, was increased in OCP placentas, in which DNA-ladder analysis and TUNEL confirmed the existence of apoptosis. UDCA prevented changes in the Bax-alpha/Bcl-2 mRNA ratio and caspase-3 activity. In conclusion, OCP causes oxidative stress and apoptosis in rat placenta, which can be prevented by treatment with UDCA.
Placenta 2006 Jan
PMID:Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. 1631 35

We tested the hypothesis that the expression levels of p53 and the pro-apoptotic mediators from the Bcl-2 family are higher in cytotrophoblasts, when compared to cultures with abundant syncytiotrophoblasts. Cytotrophoblasts isolated from normal term human placentas were cultured in Dulbecco's Modified Eagle medium (DMEM) for 24 h, when the cytotrophoblast phenotype predominates, in DMEM for 72 h, when the syncytiotrophoblast phenotype predominates, or in Ham's-Waymouth medium or DMEM with 1.5% dimethylsulfoxide, each of which maintains the cytotrophoblast phenotype through 72 h of culture. Apoptosis was assessed by detection of cleavage products of poly-ADP-ribose polymerase, by expression of cleaved cytokeratin 18 intermediate filaments, and by assessment of caspase-3 activity. Independent of time in culture, cytotrophoblasts showed higher levels of apoptosis compared to syncytiotrophoblasts. Cytotrophoblasts also expressed a 2-fold higher level of p53, a 2-fold lower level of 60 kDa Mdm-2 protein, a 2-fold higher level of Bak, but no differences in the expression of 90 kDa Mdm-2, Bcl-2, Bcl-X(L), Mcl-1, Bax, Bad, and Bad phosphorylated at the serine(112), serine(136), or serine(155) sites, compared to the syncytiotrophoblasts. Using co-immunoprecipitation, we demonstrated a greater degree of Bak-p53 interaction in cytotrophoblasts than in syncytiotrophoblasts. We also detected Bak-Mcl-1 interaction that was no different between the two phenotypes. Among the proteins studied, enhanced p53 activity, differential Bak expression, and Bak-p53 interactions may contribute to the higher level of constitutive apoptosis in cultures of cytotrophoblasts compared to syncytiotrophoblasts.
Placenta
PMID:Enhanced basal apoptosis in cultured term human cytotrophoblasts is associated with a higher expression and physical interaction of p53 and Bak. 1637 85

This study investigated the cytotoxic effect of zinc-citrate compound (CIZAR) on choriocarcinoma cell lines. Primary cultured normal trophoblast cells (NPT), human tumorigenic poorly differentiated trophoblast cell line (HT), and choriocarcinoma cell line (BeWo) were exposed to different concentrations of CIZAR and cultured at different times. Cell viability was determined by CCK-8 assay. The effects on cell cycle progression, population distribution and apoptotic incidence were determined by flow cytometry. The appearance of apoptosis was confirmed by DNA laddering and DAPI staining. The quantitative analysis of telomerase was measured by TRAPeze telomerase detection kit. The molecular mechanism of CIZAR-induced apoptosis was examined with Western blot analysis and colorimetric caspase-3 activity assay. In in vitro condition, CIZAR had a selective cytotoxic effect on choriocarcinoma cell line in dose- and time-dependent patterns. Flow cytometric analysis, DNA laddering, and DAPI staining indicated that BeWo cells only have been induced apoptosis by CIZAR. Shortening of telomere was also observed only in BeWo cells. Results also displayed that CIZAR-induced apoptosis involves the up-regulation of p21(WAF1) and Bax protein and down-regulation of Bcl-2 which were accompanied by the activation of caspase-3. Taken together, our results suggest that CIZAR is an apoptotic inducer in malignant trophoblast cells (BeWo).
Placenta 2007 Jan
PMID:Cytotoxic effect of zinc-citrate compound on choriocarcinoma cell lines. 1650 48

Placental oxidative stress has been implicated in many complications of human pregnancy, including preterm delivery and preeclampsia. It is now appreciated that reactive oxygen species can induce a spectrum of changes, ranging from homeostatic induction of enzymes to apoptotic cell death. Little is known regarding the occurrence of placental oxidative stress in other species. We investigated markers of oxidative stress in the labyrinthine (LZ) and junctional (JZ) zones of the murine placenta across gestational age, and correlated these with expression of the cyclooxygenase enzymes COX-1 and COX-2, and apoptosis. We tested a causal link between the two by subjecting placental explants to hypoxia-reoxygenation (H/R) in vitro, a known stimulus for generation of oxidative stress. Western blotting demonstrated significant increases in the concentrations of hydroxynonenal (HNE), COX-1 and COX-2 with gestational age. Dual-labelling demonstrated co-localisation of HNE, and COX-1 and COX-2 within the trophoblast of the LZ, and glycogen cells of the JZ. An apoptotic index based on TUNEL-positivity demonstrated an increase with gestational age, and dual-labelling showed co-localisation of TUNEL labelling with HNE and active caspase-3 within the trophoblast of the LZ. H/R significantly increased oxidative stress, induction of COX-1 and COX-2, and the apoptotic index. Co-localisation demonstrated the increases in COX to be within the trophoblast of the LZ, and in particular the glycogen cells of the JZ. Apoptosis was restricted to the LZ. We speculate that the induction of COX enzymes is a physiological response to oxidative stress, and may play a role in initiating or augmenting parturition. Generation of oxidative stress may also play a role in influencing the growth trajectory of the placenta, and its component cell types. The mouse may provide an experimental genetic model in which to investigate these phenomena.
Placenta 2007 Jul
PMID:Oxidative stress and the induction of cyclooxygenase enzymes and apoptosis in the murine placenta. 1722 4

Decreased placental oxygenation and increased oxidative stress are implicated in the development of preeclampsia. Oxidative stress arises from imbalance between pro-versus anti-oxidants and can lead to biological oxidation and apoptosis. Because pregnant women living at high altitude (3100 m, HA) have lowered arterial PO2 and an increased incidence of preeclampsia, we hypothesized that HA placentas would have decreased anti-oxidant enzyme activity, increased oxidative stress (lipid peroxidation, protein oxidation and nitration) and greater trophoblast apoptosis than low-altitude (LA) placentas. We measured enzymatic activities, lipid and protein oxidation and co-factor concentrations by spectrophotometric techniques and ELISA in 12 LA and 18 HA placentas. Immunohistochemistry (IHC) was used to evaluate nitrated proteins and specific markers of apoptosis (activated caspase 3 and M30). Superoxide dismutase activity was marginally lower (p=0.05), while glutathione peroxidase activity (p<0.05), thioredoxin concentrations (p<0.005) and thioredoxin reductase activity p<0.01 were all reduced in HA placentas. Decreased anti-oxidant activity was not associated with increased oxidative stress: lipid peroxide content and protein carbonyl formation were lower at HA (p<0.01). We found greater nitrotyrosine residues in the syncytiotrophoblast at 3100 m (p<0.05), but apoptosis did not differ between altitudes. Our data suggest that hypoxia does not increase placental oxidative stress in vivo. Nitrative stress may be a consequence of hypoxia but does not appear to contribute to increased apoptosis. Lowered placental concentrations of anti-oxidants may contribute to the susceptibility of women living at HA to the development of preeclampsia, but are unlikely to be etiological.
Placenta
PMID:Chronic hypoxia in vivo reduces placental oxidative stress. 1729 68

Preeclampsia can be lethal to both mother and baby. The prominent symptoms of this syndrome are hypertension, proteinuria and oedema, resulting from an exaggerated aseptic systemic inflammatory response, triggered by placental factors shed into the maternal circulation. Syncytiotrophoblast microparticles (STBM) are one possible factor, shed when the placenta is exposed to stressors such as hypoxia/reperfusion. These can disrupt mitochondria, triggering apoptosis and necrosis, placental pathologies which are increased in preeclampsia. We tested the effects of antioxidant vitamins C (50 microM) and E (50 microM) on trophoblast in culture, using term villous cytotrophoblast preparations. Following Percoll gradient centrifugation and MHC class I expressing cell depletion of placenta digests, syncytial fragments were removed using anti-placental alkaline phosphatase antibody. This yielded cytotrophoblasts of consistently high purity. EGF (10 ng/ml) stimulated syncytialisation and hCG and progesterone production. However, mitochondrial induced apoptosis (MIA) was evident 96h post-isolation, as mitochondrial membrane potential loss and caspase 9 and caspase 3 activation. ROCK-1 cleavage and syncytiotrophoblast particle shedding increased concurrently with apoptosis induction. Vitamins blocked MIA and syncytiotrophoblast particle shedding and significantly increased hCG (p<0.005) and progesterone (p<0.02) concentrations in culture supernatants, reflecting the increased survival rates. Although more cells survived in culture, syncytialisation rate (%) was significantly reduced (p<0.005). We conclude that vitamins C and E can significantly reduce mitochondrial damage generated following syncytialisation in vitro. However, further work is required to determine whether antioxidant vitamins interfere with normal fusion processes.
Placenta 2008 Aug
PMID:Vitamins C and E inhibit apoptosis of cultured human term placenta trophoblast. 1865 32

Anandamide (AEA) belongs to an emerging class of lipid mediators collectively termed "endocannabinoids". This endogenously synthesized compound has been implicated in multiple processes, mainly related to the regulation of cell growth/death. During pregnancy endometrial fibroblast-like stromal cells proliferate and differentiate into decidual cells, forming the decidua. After reaching its maximum development, the decidua undergoes regression, which appears to be associated with apoptosis. In order to study the role of this endocannabinoid in this process, the effects of AEA upon cell viability and cell death in primary rat decidual cell cultures was investigated. The results obtained demonstrated that AEA induces cell death, in a dose-dependent manner which is associated with morphological alterations, such as nuclear condensation, DNA fragmentation and upregulation of caspase-3/7 activities. Moreover, these effects were attenuated by AM251, a selective antagonist for the cannabinoid receptor CB1. High concentrations induced a dramatic effect in cell viability and morphology, though methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor completely reversed the cytotoxic effect. These findings suggest that AEA in the uterine environment may play an important role in regulating apoptosis through CB1 and thereby modulate decidual stability and regression during pregnancy. However, it cannot be discarded the hypothesis that AEA, in high concentrations, represent a deleterious factor during this complex process.
Placenta 2009 Aug
PMID:Anandamide-induced cell death: dual effects in primary rat decidual cell cultures. 1956 Aug 19

The placenta has a pivotal role, shuttling nutrients to the developing fetus and producing hormones essential to pregnancy. Maternal food restriction (MFR) during pregnancy results in growth restricted newborns, a consequence attributed primarily to maternal nutrient supply. We hypothesized that MFR further compromises fetal growth by decreased placental growth or increased placental apoptosis. We determined the potential pathway (Fas-Fas-ligand; Fas-FasL) of placental apoptosis in MFR pregnancies. We assessed the two morphologically and functionally distinct zones (basal and labyrinth) at embryonic age 20 (E20) in ad libitum fed controls (AdLib) and 50% MFR placentas. We studied fetuses and placentas from both proximal and mid-horn positions to evaluate any differential impact by MFR. Placenta apoptosis was quantified using terminal dUTP nick-end labeling (TUNEL) assay and the data were compared to immunodetection of cleaved caspase-3, Fas and FasL followed by Western blot quantification of Fas, FasL, caspase-8 and -3, tBID, and poly-ADP-ribose polymerase (PARP). MFR reduced maternal, fetal and placental basal and labyrinth weights. The results suggest that the increased apoptosis may be mediated, in part, via Fas pathway and the defective placental development in the MFR may be a major contributor to the decreased fetal growth.
Placenta 2009 Sep
PMID:Increased placental apoptosis in maternal food restricted gestations: role of the Fas pathway. 1961 44


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