KLF6 negatively regulates HIF-1α in extravillous trophoblasts under hypoxia.

Introduction: HIF-1α, the master regulator of hypoxia cellular response, is stabilized under low oxygen levels and degraded in the presence of oxygen but its transcription, translation, and degradation are tightly regulated by numerous pathways. KLF6 is a transcription factor involved in proliferation, differentiation, and apoptosis in several cell systems. Under hypoxia it is upregulated in a HIF-1α-dependent manner in extravillous trophoblasts.

Krüppel-like factor 6 involvement in the endoplasmic reticulum homeostasis of extravillous trophoblasts.

Introduction: Trophoblast homeostasis and differentiation require a proper endoplasmic reticulum (ER) function. The Krüppel-like factor-6 (KLF6) transcription factor modulates trophoblast migration, differentiation, and reactive oxygen species (ROS) production. Since ROS may impact on ER homeostasis, we assessed whether downregulation of KLF6 altered the unfolded protein response (UPR) and cellular process associated with ER homeostasis.

Downregulation of krüppel-like factor 6 expression modulates extravillous trophoblast cell behavior by increasing reactive oxygen species.

Introduction: Placental extravillous trophoblasts play a crucial role in the establishment of a healthy pregnancy. Reactive oxygen species (ROS) may contribute to their differentiation and function as mediators in signaling processes or might cause oxidative stress resulting in trophoblast dysfunction. The krüppel-like transcription factor 6 (KLF6) regulates many genes involved in essential cell processes where ROS are also involved.

Krüppel-like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta.

Trophoblast cell differentiation is of paramount importance for successful pregnancy. Krüppel-like factor 6 (KLF6), a transcription factor with diverse roles in cell physiology and tumor biology, is required for trophoblast differentiation through the syncytial pathway. Herein, we demonstrate that extravillous trophoblast (EVT) cell migration and mesenchymal phenotype are increased upon KLF6 downregulation or the expression of a deletion mutant lacking its transcriptional regulatory domain (KΔac).

Krüppel-like factor 6 (KLF6) requires its amino terminal domain to promote villous trophoblast cell fusion.

Introduction: Villous cytotrophoblast (vCTB) cells fuse to generate and maintain the syncytiotrophoblast layer required for placental development and function. Krüppel-like factor 6 (KLF6) is a ubiquitous transcription factor with an N-terminal acidic transactivation domain and a C-terminal zinc finger DNA-binding domain. KLF6 is highly expressed in placenta, and it is required for proper placental development.

Role of the lipid transport protein StarD7 in mitochondrial dynamics.

Mitochondria are dynamic organelles crucial for cell function and survival implicated in oxidative energy production whose central functions are tightly controlled by lipids. StarD7 is a lipid transport protein involved in the phosphatidylcholine (PC) delivery to mitochondria. Previous studies have shown that StarD7 knockdown induces alterations in mitochondria and endoplasmic reticulum (ER) with a reduction in PC content, however whether StarD7 modulates mitochondrial dynamics remains unexplored.

Dual-responsive nanogels based on oligo(ethylene glycol) methacrylates and acidic co-monomers.

Ethylene glycol-based nanogels (NGs) have demonstrated their potential for the development of next-generation formulations for biomedical applications due to their interesting properties. In this work, monodispersed NGs based on oligo(ethylene glycol) methacrylates (OEG) were synthesized through free radical precipitation/dispersion polymerization assisted by ultrasonication. Di(ethylene glycol)methyl ether methacrylate (DEGMA) and oligo(ethylene glycol) methacrylate (OEGMA; Mn 475 g mol-1) were used as the main monomers, acrylic acid (AA) or itaconic acid (IA) as co-monomers (OEG-co-AA and OEG-co-IA, respectively) and tetraethylene glycol dimethacrylate (TEGDMA) as crosslinker.

Effect of Chlorpyrifos on human extravillous-like trophoblast cells.

An increased risk of pregnancy disorders has been reported in women and animal models exposed to organophosphate pesticides. However, less information is available on impacts to human placental function. Here, we addressed the impact of chlorpyrifos (CPF) on extravillous cytotrophoblasts (evCTB) employing HTR8/SVneo cells as an in vitro model.

Hexosamine pathway regulates StarD7 expression in JEG-3 cells.

StarD7 is a lipid binding protein involved in the delivery of phosphatidylcholine to the mitochondria whose promoter is activated by Wnt/β-catenin signaling. Although the majority of glucose enters glycolysis, ~ 2-5% of it can be metabolized via the hexosamine biosynthetic pathway (HBP). Considering that HBP has been implicated in the regulation of β-catenin we explored if changes in glucose levels modulate StarD7 expression by the HBP in trophoblast cells.

Chlorpyrifos induces endoplasmic reticulum stress in JEG-3 cells.

Chlorpyrifos (CPF) is an organophosphorous pesticide widely used in agricultural, industrial, and household applications. We have previously shown that JEG-3 cells are able to attenuate the oxidative stress induced by CPF through the adaptive activation of the Nrf2/ARE pathway. Considering that there is a relationship between oxidative stress and endoplasmic reticulum stress (ER), herein we investigated whether CPF also induces ER stress in JEG-3 cells.

Suppression of StarD7 promotes endoplasmic reticulum stress and induces ROS production.

StarD7 is an intracellular lipid transport protein identified as up-regulated in the choriocarcinoma JEG-3 cell line. StarD7 facilitates the delivery of phosphatidylcholine (PC) to the mitochondria, and StarD7 knockdown causes a reduction in phospholipid synthesis. Since inhibition of PC synthesis may lead to endoplasmic reticulum (ER) stress we hypothesized that StarD7 may be involved in maintaining cell homeostasis.

A novel regulator of human villous trophoblast fusion: the Krüppel-like factor 6.

Cell-cell fusion is an essential event during life. Throughout human pregnancy, the syncytiotrophoblast (STB) layer of the placenta is formed by continuous fusion of the underlying villous cytotrophoblasts, thus maintaining placental functionality. Defects in this process are associated with pathologies like pre-eclampsia and intrauterine growth restriction.

The Lipid Transfer Protein StarD7: Structure, Function, and Regulation.

The steroidogenic acute regulatory (StAR) protein-related lipid transfer (START) domain proteins constitute a family of evolutionarily conserved and widely expressed proteins that have been implicated in lipid transport, metabolism, and signaling. The 15 well-characterized mammalian START domain-containing proteins are grouped into six subfamilies. The START domain containing 7 mRNA encodes StarD7, a member of the StarD2/phosphatidylcholine transfer protein (PCTP) subfamily, which was first identified as a gene overexpressed in a choriocarcinoma cell line.

The role of pregnancy-specific glycoprotein 1a (PSG1a) in regulating the innate and adaptive immune response.

Among several explanations for the acceptance of the fetus, the one that suggests that the maternal immune system is suppressed or modified has been the subject of many studies. Thus, it has been proposed that the cells of innate immune system might be able to distinguish the pregnant from the non-pregnant state producing a signal, the so-called signal P. We have previously proposed that pregnancy-specific glycoprotein 1a (PSG1a), a representative member of the main glycoprotein family secreted by placental trophoblast, may modulate the activation of antigen-presenting cells promoting the T-cell shift of the maternal cell immunity toward a less harmful phenotype.

PSG gene expression is up-regulated by lysine acetylation involving histone and nonhistone proteins.

Background: Lysine acetylation is an important post-translational modification that plays a central role in eukaryotic transcriptional activation by modifying chromatin and transcription-related factors. Human pregnancy-specific glycoproteins (PSG) are the major secreted placental proteins expressed by the syncytiotrophoblast at the end of pregnancy and represent early markers of cytotrophoblast differentiation. Low PSG levels are associated with complicated pregnancies, thus highlighting the importance of studying the mechanisms that control their expression.

StarD7 knockdown modulates ABCG2 expression, cell migration, proliferation, and differentiation of human choriocarcinoma JEG-3 cells.

Background: StAR-related lipid transfer domain containing 7 (StarD7) is a member of the START-domain protein family whose function still remains unclear. Our data from an explorative microarray assay performed with mRNAs from StarD7 siRNA-transfected JEG-3 cells indicated that ABCG2 (ATP-binding cassette sub-family G member 2) was one of the most abundantly downregulated mRNAs.

Methodology/principal Findings: Here, we have confirmed that knocking down StarD7 mRNA lead to a decrease in the xenobiotic/lipid transporter ABCG2 at both the mRNA and protein levels (-26.

Chlorpyrifos modifies the expression of genes involved in human placental function.

The effects of organophosphate pesticides on human placenta remain poorly investigated although an increased risk of pregnancy alterations has been reported in women chronically exposed to these pesticides. Here, we have addressed whether chlorpyrifos (CPF) modifies the expression of genes relevant for placental function. Human placental JEG-3 cells were exposed to increasing CPF concentrations up to 100 μM for 24 and 48 h and cell viability, mRNA, protein and hormone levels were analyzed.

Krüppel-like factor 6 expression changes during trophoblast syncytialization and transactivates ßhCG and PSG placental genes.

Background: Krüppel-like factor-6 (KLF6) is a widely expressed member of the Sp1/KLF family of transcriptional regulators involved in differentiation, cell cycle control and proliferation in several cell systems. Even though the highest expression level of KLF6 has been detected in human and mice placenta, its function in trophoblast physiology is still unknown.

Methodology/principal Findings: Herein, we explored KLF6 expression and sub-cellular distribution in human trophoblast cells differentiating into the syncytial pathway, and its role in the regulation of genes associated with placental development and pregnancy maintenance.

StarD7 gene expression in trophoblast cells: contribution of SF-1 and Wnt-beta-catenin signaling.

Steroidogenic acute regulatory protein-related lipid transfer domain containing 7 (StarD7) is a poorly characterized member of the steroidogenic acute regulatory protein-related lipid transfer proteins, up-regulated in JEG-3 cells, involved in intracellular transport and metabolism of lipids. Previous studies dealing with the mechanisms underlying the human StarD7 gene expression led us to define the cis-acting regulatory sequences in the StarD7 promoter using as a model JEG-3 cells. These include a functional T cell-specific transcription factor 4 (TCF4) site involved in Wnt-β-catenin signaling.

Structural organization of the mitochondrial DNA control region in Aedes aegypti.

The complete A+T - rich region of Aedes aegypti mitochondrial DNA has been cloned and sequenced. In Argentinean populations of the species, a polymorphism in the length of the amplified fragment was observed. Nucleotide sequence comparison of the shortest and longest A+T - rich amplified fragments detected revealed the presence of 2 types of tandemly repeated blocks.

Activation of the human pregnancy-specific glycoprotein PSG-5 promoter by KLF4 and Sp1.

Pregnancy-specific glycoproteins (PSGs) are major placental proteins thought to be essential for the maintenance of gestation. Little is known about the regulation of expression of the 11 genes encoding these proteins. It was previously demonstrated that Krüppel-like factor 6 (KLF6) and specific-protein 1 (Sp1) bind to conserved sequence within the PSG-5 gene promoter.