2-Methoxyestradiol regulates VEGFR-2 and sFlt-1 expression in human placenta

Lee, D.K.; Nevo, Ori

doi:10.1016/j.placenta.2014.11.013

Cited by 15 publications

(17 citation statements)

References 25 publications

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“…This animal model was not considered in our initial pathogenic data analysis but it is clearly expressed in the integrated pathway and prioritization strategy. In the model 3 (Additional file 5), the COMT gene is quite far connected with VEGF, however, was recently showed that 2-methoxyestradiol has an anti-angiogenic effect connected to KDR and HIF1A probably through a different mechanism not involving sFlt-1 [90]. …”

Section: Discussionmentioning

confidence: 99%

Consensus strategy in genes prioritization and combined bioinformatics analysis for preeclampsia pathogenesis

et al. 2017

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BackgroundPreeclampsia is a multifactorial disease with unknown pathogenesis. Even when recent studies explored this disease using several bioinformatics tools, the main objective was not directed to pathogenesis. Additionally, consensus prioritization was proved to be highly efficient in the recognition of genes-disease association. However, not information is available about the consensus ability to early recognize genes directly involved in pathogenesis. Therefore our aim in this study is to apply several theoretical approaches to explore preeclampsia; specifically those genes directly involved in the pathogenesis.MethodsWe firstly evaluated the consensus between 12 prioritization strategies to early recognize pathogenic genes related to preeclampsia. A communality analysis in the protein-protein interaction network of previously selected genes was done including further enrichment analysis. The enrichment analysis includes metabolic pathways as well as gene ontology. Microarray data was also collected and used in order to confirm our results or as a strategy to weight the previously enriched pathways.ResultsThe consensus prioritized gene list was rationally filtered to 476 genes using several criteria. The communality analysis showed an enrichment of communities connected with VEGF-signaling pathway. This pathway is also enriched considering the microarray data. Our result point to VEGF, FLT1 and KDR as relevant pathogenic genes, as well as those connected with NO metabolism.ConclusionOur results revealed that consensus strategy improve the detection and initial enrichment of pathogenic genes, at least in preeclampsia condition. Moreover the combination of the first percent of the prioritized genes with protein-protein interaction network followed by communality analysis reduces the gene space. This approach actually identifies well known genes related with pathogenesis. However, genes like HSP90, PAK2, CD247 and others included in the first 1% of the prioritized list need to be further explored in preeclampsia pathogenesis through experimental approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0286-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Consensus strategy in genes prioritization and combined bioinformatics analysis for preeclampsia pathogenesis

et al. 2017

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“…Therefore, the regulation of trophoblast differentiation by hypoxia or HIF1α may be complex mechanisms including hypoxic-related factors and cytokines. Increasing evidence indicates that severe hypoxic conditions induce an increase in the level of sEng and sFlt-1 from trophoblast cells, compared with normoxia as a control [9,10,41]. Murphy et al [41] reported that sFlt-1 production from rat placenta under hypoxic condition (1% O 2 ) was significantly increased compared with under 6% O 2 condition used as a control.…”

Section: Discussionmentioning

confidence: 99%

Moderate Hypoxia Down-Regulates Interleukin-6 Secretion and TLR4 Expression in Human Sw.71 Placental Cells

Shirasuna

Shimamura

Seno

et al. 2015

Cell Physiol Biochem

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Background/Aims: The placenta is a vital organ for pregnancy. Many in vitro placental experiments are conducted under 21% O₂; however, O₂ tension could influence cellular functions, including cytokine secretion. We investigated the effects of oxygen tension between moderate hypoxia (5% O₂) and normoxia (21% O₂) by testing the hypothesis that moderate hypoxia regulates cellular phenotypes differently from normoxia in human trophoblast cells. Methods and Results: Sw.71 trophoblast cells were incubated under normoxic or moderately hypoxic conditions. Cells were also treated with lipopolysaccharide (LPS) as a Toll-like receptor 4 (TLR4) ligand inducing inflammation. Interleukin-6 (IL-6) as an inflammatory cytokine was determined, and TLR4, hypoxia-induced factor-1α (HIF1α), and reactive oxygen species (ROS) production were detected. Moderate hypoxia increased HIF1α expression and cell proliferation and acted by two different mechanisms to decrease IL-6 secretion compared with normoxia: it limits the TLR4 expression and ROS production. Treatment with cobalt chloride as an HIF1 activator inhibited IL-6 secretion and TLR4 expression; this effect was reversed on treatment with PX-12 as an HIF1 suppressor. Conclusion: IL-6 secretion, TLR4 expression, and ROS production, classical markers of inflammation, are down-regulated by moderate hypoxia, and HIF1α and ROS have a potential to regulate these responses in human trophoblast cells.

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“…Similarly, cells were treated with a prolyl-4-Hydroxylase inhibitor, dimethyloxaloylglycine (DMOG; 1 mM) for 24 hours to stabilise HIF-1α levels. 27 In each case, the exposure period was sufficient to cause visible changes in cell morphology and a reduction in cell viability to < 50 % of controls as measured by the MTT assay. In all cases, cells were also exposed to increasing concentrations of BPA (0, 0.09, 0.9, and 9.0 µM) with consecutive media changes performed every 24 hours.…”

Section: Serum Starvation / Glutathione Depletion / Hif-1α α α α Elevmentioning

confidence: 96%

“…This transcription factor can be chemically stabilised using DMOG to increase endogenous HIF-1 α levels mimicking the molecular change that occurs in hypoxia. 27 Investigations were conducted to establish if BPA could influence cell viability induced by DMOG. Treatment of BeWo cells with DMOG (1 mM) for 24 hours resulted in a substantial increase in HIF-1α (> 2000%) expression (Fig 3A), reminiscent of hypoxic conditions, and a reduction in cell viability to 15.9 % of controls ( Fig 3C).…”

Section: Bpa Reduces Cell Death In Stress-induced Paradigmsmentioning

confidence: 99%

Bisphenol A Increases BeWo Trophoblast Survival in Stress-Induced Paradigms through Regulation of Oxidative Stress and Apoptosis

Ponniah

Billett

Girolamo

2015

Chem. Res. Toxicol.

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Bisphenol A (BPA) is ubiquitous in the environment and is reported to be present at high concentrations in placental tissue, where its presence raises concerns over its potential to disrupt placental function. This report investigates how BPA interferes with the survival of human choriocarcinoma BeWo cells (a model of placental trophoblasts) under stress-induced paradigms reminiscent of pathways activated in placental development. These include conditions that promote oxidative stress (glutathione depletion) and apoptosis (serum withdrawal) or mimic hypoxia (HIF-1α accumulation via dimethyloxalylglycine treatment). Treatment of BeWo cells with BPA during stress-induced paradigms led to a consistent and significant increase in cell viability, with a concomitant increase in glutathione levels and a reduction in apoptosis. Assessment of the antioxidant capacity of BPA revealed its ability to quench reactive oxygen species and reduce the levels generated during glutathione and serum depletion. BPA was also able to reduce the activation of the antioxidant response element (ARE) through mediation of its activators, nuclear factor erythroid related factor family members (Nrf's). Indeed, the expression and nuclear translocation of Nrf2 (an important ARE activator) were impaired by BPA, while Nrf1 and Nrf3 expression levels were increased. Furthermore, BPA increased the levels of the anti-apoptotic proteins (Bcl-2 and Hsp70) and decreased HIF-1α levels during stress-induced conditions. Together, these results indicate that BPA inhibits trophoblast cell death under conditions of cellular stress. This could have implications on placental trophoblasts during development.

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2-Methoxyestradiol regulates VEGFR-2 and sFlt-1 expression in human placenta

Cited by 15 publications

References 25 publications

Consensus strategy in genes prioritization and combined bioinformatics analysis for preeclampsia pathogenesis

Consensus strategy in genes prioritization and combined bioinformatics analysis for preeclampsia pathogenesis

Moderate Hypoxia Down-Regulates Interleukin-6 Secretion and TLR4 Expression in Human Sw.71 Placental Cells

Bisphenol A Increases BeWo Trophoblast Survival in Stress-Induced Paradigms through Regulation of Oxidative Stress and Apoptosis

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