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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigates the extent of apoptosis in complete hydatidiform mole (CHM), using an in situ 3'-end DNA labelling (TUNEL) technique on formalin-fixed and paraffin-embedded sections. The sections were also immunostained with antibodies to p53, Bax and Bcl-2 proteins. In 10 normal placenta cases and 15 CHM cases, the apoptotic index was <1 and 2-4 per cent, respectively. The labelled trophoblastic cells possessed pyknotic nuclei and densely eosinophilic cytoplasm which corresponded well to the so-called apoptotic bodies by light and electron microscopy. The p53 positive reaction was restricted to the nuclei of cytotrophoblasts and intermediate trophoblasts, while the syncytiotrophoblasts showed only rare immunolocalization. Strong p53 expression was seen most often in cytotrophoblasts of CHM (>30 per cent of nuclei) which also showed a higher apoptosis index, while cytotrophoblasts in normal placentae were weakly and focally labelled (<10 per cent of nuclei). There were statistical differences between normal and CHM cases (P<0.05). Bcl-2 accumulation, on the other hand, was observed predominantly in syncytiotrophoblasts of normal placentae, and cytotrophoblasts and intermediate trophoblasts did not express Bcl-2 in all cases. Interestingly, syncytiotrophoblasts were found to be negative for Bax protein and positive in cytotrophoblast, which is consistent with the function of the protein in conveying increased apoptosis susceptibility to this cell population. The results show that the level of apoptosis correlates with the histological type of the gestational trophoblasts, and apoptosis index is higher in cytotrophoblasts in CHM. The fact that p53 quantitative expression and an increase in the Bax/Bcl-2 ratio were also observed in CHM suggested that they may contribute partly to the high level of apoptosis.
Placenta
PMID:p53, Bax and Bcl-2 expression, and apoptosis in gestational trophoblast of complete hydatidiform mole. 969 56

The inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and immune interferon gamma (IFN-gamma) stimulate villous cytotrophoblast apoptosis while epidermal growth factor (EGF) protects. We hypothesize that TNF-alpha, IFN-gamma and EGF regulate apoptosis in part by modulating cellular expression levels of the anti-death gene bcl-2. While Bcl-2 is reported to be strongly expressed in villous syncytiotrophoblasts, it is not known whether the protein is expressed in cultured villous cytotrophoblasts (CT) and, if so, whether it is functional. We show by Northern blot analysis that bcl-2 mRNA is expressed in cultured CT and by immunoblot analysis that the protein is strongly expressed in highly purified first trimester and term villous cytotrophoblasts. The expression levels of Bcl-2 protein were the same in first trimester and term cytotrophoblasts. Culture with TNF-alpha/IFN-gamma and EGF did not alter expression of either Bcl-2 protein or of the pro-apoptotic Bcl-2 family member Bak. Double label flow cytometric analysis that measured apoptosis and Bcl-2 content simultaneously showed that cells expressing low levels of Bcl-2 underwent TNF-alpha/IFN-gamma-induced apoptosis at a higher frequency than cells expressing lower levels. We conclude that Bcl-2 is expressed in cytotrophoblasts, that its expression is constitutive and that modulation of its expression levels does not mediate cytokine and growth factor regulation of apoptosis in these cells.
Placenta
PMID:The role of Bcl-2 expression in EGF inhibition of TNF-alpha/IFN-gamma-induced villous trophoblast apoptosis. 1041 7

Apoptosis, the morphology of cell suicide, may result from programmed cell death or may be a response to exogenous stimuli. Apoptosis can be induced in cultured trophoblast and can be identified in the trophoblast of placental villi. The trophoblast regulates maternal-fetal gas, nutrient and waste product exchange; therefore, the presence of apoptosis in this key cellular interface highlights the importance of understanding what controls apoptosis in the placenta. In this review, we describe the signal transduction pathways that trigger apoptosis in other systems, identify key genetic controls for the process and outline the final common pathway which effects execution in cells committed to suicide. Multiplicity, redundancy and cross talk among pathways characterize the surface membrane signals and exogenous stimuli that trigger apoptosis in other cells. As each step in the apoptotic process is discussed, we describe what is known about the step in human placental villi. Recent studies suggest that a further understanding of receptor-mediated signalling pathways, the Bcl-2 regulators and the caspases and substrates involved in placental apoptosis will surely provide insights into both normal placental development and the placental dysfunction associated with some abnormal pregnancies.
Placenta 2000 Jan
PMID:To be, or not to be, that is the question. Apoptosis in human trophoblast. 1069 45

Telomerase activity (TA) and apoptosis were analysed in placenta with and without intrauterine growth retardation (IUGR). Thirty-one specimens were taken from chorionic villi in the first trimester (Group A), 32 placenta specimens were obtained from cases without IUGR in second and third trimester (Group B) and 12 specimens of placenta tissue were obtained from cases of asymmetric IUGR between 26 and 39 weeks of gestation (Group C). TA was analysed by the Telomeric Repeat Amplification Protocol (TRAP) and in situ TRAP assay. Apoptotic changes were assessed by immunohistochemical staining using Bcl-2 monoclonal antibody and by terminal transferase-mediated in situ end-labelling (TUNEL). TA was detected in 29 of the 31 (93.5 per cent) chorionic villi (Group A) and in 20 of the 32 (62.5 per cent) placenta without IUGR (Group B), whereas weak TA was observed in the placenta of all 12 asymmetric IUGR cases (Group C). Significantly higher Bcl-2 immunoreactivity was observed in trophoblastic cells of Group A (85.9+/-4.2 per cent) and Group B (72.8+/-7.2 per cent) than Group C (54.84+/-4.83 per cent), while TUNEL positive cells were identified at a significantly higher frequency in the trophoblastic cells of Group C (9.7+/-7.4 per cent) than Group A (1.1+/-1.9 per cent) or Group B (2.9+/-3.7 per cent).
Placenta
PMID:Telomerase activity and apoptosis as indicators of ageing in placenta with and without intrauterine growth retardation. 1094 Jan 99

In the third trimester of normal pregnancy, the mother tolerates daily shedding of several grams of dying placental trophoblast into the maternal circulation. The balance between apoptotic and necrotic shedding is presently unknown. Since pre-eclampsia is characterized by an altered placental oxygenation and increased trophoblast shedding, we investigated the role of oxygen on the balance of apoptotic versus necrotic trophoblast shedding in vitro. We studied human trophoblast turnover in explanted villi from late first and third trimester placentas in low oxygen (2 per cent) and higher oxygen tensions (6 per cent and 18 per cent) for up to 72h. Trophoblast turnover including apoptosis and necrosis were assessed by histology, immunolocalization of Mib-1 (proliferation marker), Bcl-2 (apoptosis inhibitor), activated caspase 3 (apoptosis promoter), cytokeratin 18 neo-epitope formation (M30 antibody), TUNEL test (DNA degradation), and (3)H-cytidine and(3) H-uridine incorporations. Culture in 2 per cent oxygen increased cytotrophoblast proliferation and syncytiotrophoblast shedding by necrosis. The proteins necessary for execution of apoptosis were mostly retained in the cytotrophoblast due to lack of syncytial fusion. Culture in 6 per cent and 18 per cent oxygen reduced cytotrophoblast proliferation. Syncytial fusion occurred and activity of caspase 3 was found in the syncytiotrophoblast; the latter remained intact demonstrating physiologic turnover, including apoptotic shedding. We conclude that severe placental hypoxia favours necrotic rather than apoptotic shedding of syncytial fragments into the maternal circulation. Since uteroplacental ischaemia is a significant risk factor for pre-eclampsia, these findings may explain the link between reduced uteroplacental blood flow and the systemic clinical manifestations of this disease.
Placenta
PMID:Hypoxia favours necrotic versus apoptotic shedding of placental syncytiotrophoblast into the maternal circulation. 1256 45

Placenta cretas are defined as abnormal adherences or ingrowths of placental tissue, but their pathogenetic mechanism has not been fully explained. During histologic examination of postpartum uteri, we noticed that the number of implantation site intermediate trophoblasts was increased in the placental bed of placenta cretas. To validate our observation and to address the pathogenetic role of implantation site intermediate trophoblasts in placenta cretas, we examined postpartum uteri with placenta cretas (n=34) and noncretas (n=22), obtained from Cesarean or immediate postpartum hysterectomy specimens. Using antibody to CD146, a marker for implantation site intermediate trophoblasts, we found that placenta cretas had significantly thicker layer of implantation site intermediate trophoblasts (2300+/-1200 mum) than noncretas (1500+/-1200 microm, P<0.025). We also observed that the confluent distribution of cells was more frequent in placenta cretas (97%) than noncretas samples (45%, P<0.001), and that the total number of implantation site intermediate trophoblasts within the superficial myometrium of the placental bed was significantly higher in placenta cretas than noncretas. Using antibodies to Ki-67, Bcl-2 and cleaved caspase-3 to determine the proliferative index and apoptotic rates of implantation site intermediate trophoblasts, we found that they were close to zero in both groups and did not differ significantly. These findings suggest that the increased number of implantation site intermediate trophoblasts observed in placenta cretas may be related to the pathogenesis of placental ingrowth, but the mechanism by which the increase in implantation site intermediate trophoblasts causes placenta cretas remains to be clarified.
 ...
PMID:Implantation site intermediate trophoblasts in placenta cretas. 1520 87

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

The onset of preeclampsia is associated with increased maternal insult that could affect placental function. By increasing sodium intake (0.9% or 1.8% NaCl in drinking water) during the last week of gestation in the rat, we developed an animal model that shows many characteristics of preeclampsia such as increased blood pressure, decreased circulatory volume and diminished activity of the renin-angiotensin-aldosterone system. The aim of the present study was to determine in this model whether maternal perturbations in pregnancy lead to placental oxidative stress. Sprague-Dawley pregnant rats receiving salted-water were compared to not-supplemented pregnant rats. Markers of oxidative stress, ensuing cell death, and changes in the production of vasoactive substances (prostanoids: thromboxane, TxB(2); and prostacyclin, PGF(1alpha)) and the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) were measured in the placenta. In tissue from pregnant rats on 1.8% NaCl supplement, 8-iso-PGF(2alpha) levels, TxB(2)/6-keto-PGF(1alpha) ratios, total TNF-alpha RNA expression, as well as the apoptotic index (Bax/Bcl-2 ratio) and endothelial nitric oxide synthase protein expression increase while total glutathione content decreases. These findings demonstrate that maternal insult during gestation induced an imbalance in the oxidative environment in the placenta favouring oxidation. This was accompanied by an increased synthesis of vasoconstrictive substances and TNF-alpha by the placenta as well as the increased rate of placental cell apoptosis.
Placenta 2007 Jan
PMID:Placental oxidative stress in a rat model of preeclampsia. 1646 76


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