Gene/Protein Disease Symptom Drug Enzyme Compound
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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 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

The syncytiotrophoblast contains aggregates of nuclei termed syncytial knots. Increased numbers of syncytial knots have been reported in placentae of pregnancies complicated by pre-eclampsia and fetal growth restriction (FGR). As oxidative stress has been implicated in the pathophysiology of these disorders, we hypothesised that the formation of syncytial knots may be induced by exposure to hypoxia, hyperoxia or reactive oxygen species (ROS). We assessed both the number and morphology of syncytial knots induced by culture in hypoxia, hyperoxia and with ROS. We also investigated whether the presence of syncytial knots in normal tissue was associated with a down-regulation of anti-apoptotic proteins Bcl-2, Mdm2, XIAP and survivin. Using our measurement system we describe an increased number of syncytial knots when tissue is cultured in hypoxia, hyperoxia or in the presence of ROS. The morphology of these syncytial knots was similar to those seen in vitro, although the nuclei from cultured placental explants were morphologically more homogenous, had fewer nuclear pores, and a higher heterochromatin:euchromatin ratio. Despite the apoptotic appearances of nuclei we did not detect a loss of anti-apoptotic proteins in the region of syncytial knots. We conclude that the increased number of syncytial knots in placentae from pregnancies complicated by pre-eclampsia and FGR can be replicated in vitro by ROS or hypoxia, supporting their involvement in the pathogenesis of these conditions.
Placenta 2007 Apr
PMID:Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species. 1714 Jun 57

Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with aberrant cell turnover, including increased apoptosis, in placental villous trophoblast. The increased apoptosis is associated with exaggerated expression of p53, which promotes cell cycle arrest or apoptosis via downstream proteins such as p21 or Bax. These changes in apoptosis and p53 expression are purported to result from exposure to altered oxygen tension. Using a model of villous trophoblast turnover, we examined the effect of 20%, 6% and 1% ambient oxygen (O(2)) on apoptosis, necrosis, proliferation and expression of p53 and related regulators of cell turnover, compared to both fresh tissue. Altered O(2) tension exerted an effect on cell turnover in cultured term villous tissue: cytotrophoblast proliferation was increased by culture in 20% O(2) and reduced in 1% O(2) (median proliferative index: fresh tissue=0.32%, 20% O(2)=0.9%, 6% O(2)=0.28%, 1% O(2)=0.07%). Apoptosis was increased in all culture environments, but was significantly enhanced by culture in 1% O(2) (median apoptotic index: fresh tissue=0.64%, 20% O(2)=2.96%, 6% O(2)=3.81%, 1% O(2)=9.2%). Necrotic cell death was also increased by culture in 1% O(2) compared to 6% and 20% O(2). The expression of p53, p21 and Mdm2 in both cytotrophoblast and stromal cells was increased following culture in 1% O(2). There was no alteration in the expression of Bax or Bcl-2. This study provides evidence that p53 is elevated in trophoblast following exposure to hypoxia. The potential role of the p53-pathway in the control of cell turnover in villous trophoblast and the regulation of p53 by altered O(2) tension merits further investigation.
Placenta 2008 Feb
PMID:Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. 1815 42

Maternal diabetes affects the development of the offspring by altering the uterine environment. We aimed to investigate the extent to which the blood flow (measured as Tissue Perfusion Units; TPU) to implantation sites and the expression of developmentally important genes in the offspring are affected by maternal diabetes. We measured mRNA levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), Bcl-2 associated X protein (Bax), B-cell lymphoma protein (Bcl-2), tumor suppressor protein-53 (p53), paired box protein-3 (Pax-3) and vascular endothelial growth factor-A (Vegf-A). Moreover, we studied the effect on uterine blood flow (TPU) and the expression of the genes exerted by embryonic maldevelopment (malformation or resorption). Streptozotocin induced diabetic (D) and non-diabetic (N) pregnant rats were used in the study. Blood flow (TPU) to implantation sites was measured by a laser Doppler flow meter, and gene expression was analyzed by RT-PCR. Maternal diabetes caused increased blood flow (TPU) to implantation sites compared with normal pregnancy. Furthermore, implantation sites of D rats containing malformed offspring showed impaired growth and decreased blood flow (TPU) compared with their littermates at all gestational days. Resorbed offspring from both N and D rats displayed increased blood flow (TPU) compared with their non-resorbed littermates. Moreover, we found that maternal diabetes causes decreased expression of genes involved in the oxidative stress defense system (CuZnSOD in non-malformed D11 embryos, MnSOD at all gestational time points, ECSOD and Gpx-1 at GD11-GD15, CAT and Gpx-2 at GD15), decreased expression of Pax-3 at GD11, and increased expression of Vegf-A at all gestational time points. We conclude that both maternal metabolism and embryonic developmental state affect the blood flow (TPU) to the implantation site. Maternal diabetes causes decreased expression of anti-oxidative enzymes and enhanced angiogenesis in the offspring in rats.
Placenta 2008 May
PMID:Altered uterine perfusion is involved in fetal outcome of diabetic rats. 1838 70

Although apoptosis is prominent in placental cells in pregnancy complications such as preeclampsia, the cause is unknown. We surmised that hypoxia-reoxygenation (HR) is the mechanism and hypothesized that mitochondrial oxidants and Bcl-2 proteins cause HR-induced placental apoptosis. Our goal was studying expression of five Bcl-2 proteins--Bcl-2, Bcl-xL, Bax, Bak, Bad--and testing effects of diazoxide and cyclosporine A on oxidative stress and apoptosis in villous tissues subjected to HR. Term human placentas were obtained from normal pregnancies following elective caesarean deliveries. Villous tissues were subjected to "repetitive HR" (one hour at 2% O(2) then one hour at 8% O(2), alternatively, for a total of 6h) or "prolonged HR" (3h at 2% O(2) then 3h of 8% O(2)). Samples maintained at 2% and 8% O(2) served as hypoxic and normoxic controls, respectively. Prolonged HR caused the most severe villous apoptotic changes, increased the expression of Bax and Bak mRNA and protein and reduced the expression of Bcl-2 mRNA. Pre-administration of diazoxide and cyclosporine A reduced TUNEL-positive nuclei and levels of nitrotyrosine and 4-hydroxy-2-nonenol after prolonged HR. Thus, duration of hypoxia and reoxygenation is important in determining severity of HR-induced apoptosis in placenta. These apoptotic changes are closely associated with Bax and Bak effects and oxidative stress in mitochondria.
Placenta 2008 Jul
PMID:Bax, Bak and mitochondrial oxidants are involved in hypoxia-reoxygenation-induced apoptosis in human placenta. 1847 57

Bcl-2 family members are important regulators of cell fate in normal organ development and in disease status. Pro- and anti-apoptotic members of this family function through a complex network of homo- and hetero-dimers to determine whether a cell lives or dies. Members of the Bcl-2 family are classically recognized for their role in apoptosis, yet emerging evidence has highlighted their importance in the regulation of cell cycle. Cellular proliferation, differentiation and death accompany early placental development of the trophoblast lineage. We have recently reported on the expression and function of two Bcl-2 family members in normal placental development, namely the pro-apoptotic Mtd/Bok, and its anti-apoptotic partner Mcl-1 and have found that their expression is upregulated by low oxygen, a key mediator of trophoblast cell proliferation in early placentation. Interestingly, we have also reported that the expression of the Mtd/Mcl-1 system is altered in preeclampsia, a placental pathology associated with a status of oxidative stress and typically characterized by an immature proliferative trophoblast phenotype and excessive trophoblast cell death. In this pathology levels of pro-apototic Mtd-L and Mtd-P are increased and anti-apoptotic Mcl-1 is cleaved in to a pro-apoptotic isoform. Disruption in Mtd/Mcl-1 expression seen in preeclampsia may contribute to both the increased apoptosis and hyperproliferative nature of this disorder.
Placenta 2009 Mar
PMID:IFPA Trophoblast Research Award Lecture: the dynamic role of Bcl-2 family members in trophoblast cell fate. 1909 1

Human chorionic gonadotropin (hCG) is one of the earliest signals secreted by the implanting embryo. In addition to its well-known luteotropic function in early pregnancy, hCG also acts directly on decidualizing endometrium. Recently, we demonstrated that recombinant hCG (rhCG) prevented apoptosis in decidualizing human endometrial stromal cells (HESCs) exposed to oxidative stress. Two hCG preparations are widely used clinically: rhCG, produced by recombinant DNA technology, and urinay hCG (uhCG), extracted from urine of post-menopausal women. However, an analysis of the direct effects of rhCG and uhCG on the decidual phenotype of HESCs has not yet been done. In this study, we investigated the effects of uhCG and rhCG on the morphological and functional profiles of decidualizing HESCs. We demonstrate that neither rhCG nor uhCG alter the morphological appearance of the decidual HESC cultures, although rhCG but not uhCG attenuated prolactin expression, a major decidual marker protein. Moreover, rhCG, but not uhCG, protected decidualizing HESCs from oxidative cell death, mediated at least in part by two major mechanisms. First, rhCG, but not uhCG, enhances the expression of manganese superoxide dismutase, a cardinal enzyme in the cellular defense against oxidative damage. Second, rhCG signaling selectively limits activation of the apoptotic machinery in decidualizing HESCs by enhancing Bcl-2 expression whereas uhCG induces the expression of Fas ligand. Our results suggest that rhCG might be a preferable agent to protect the maternal decidua against oxidative damage in pregnancy, especially at the time of implantation and beyond.
Placenta 2011 Aug
PMID:Differential effects of urinary and recombinant chorionic gonadotropin on oxidative stress responses in decidualizing human endometrial stromal cells. 2164 41


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