查看更多>>摘要：Introduction: Fetal growth and development depend on metabolic energy from placental mitochondria. However, the impact of placental mitochondria on the occurrence of macrosomia remains unclear. We aimed to explore the association between macrosomia without gestational diabetes mellitus (non-GDM) and changes in placental mitochondrial DNA (mtDNA) copy number and methylation. Methods: Fifty-four newborns with macrosomia and 54 normal birthweight controls were enrolled in this study. Placental mtDNA copy number and mRNA expression of nuclear genes related to mitochondrial replication or ATP synthesis-related genes were measured by real-time quantitative polymerase chain reaction (qPCR). Methylation levels of the non-coding regulatory region D-loop and ATP synthesis-related genes were detected by targeted bisulfite sequencing. Results: Newborns with macrosomia had lower placental mtDNA copy number and higher methylation rates of the CpG15 site in the D-loop region (D-CpG15) and CpG6 site in the cytochrome C oxidase III (COX3) gene (COX3-CpG6) than normal birth weight newborns. After adjusting for potential covariates (gestational age, prepregnancy BMI, and infant sex), decreased placental mtDNA copy number (adjusted odds ratio [aOR] = 2.09, 95% confidence interval [CI] 1.03-4.25), elevated methylation rate of D-CpG15 (aOR = 2.06, 95% CI 1.03-4.09) and COX3-CpG6 (aOR = 2.13, 95% CI 1.08-4.20) remained significantly associated with a higher risk of macrosomia. Discussion: Reduced mtDNA copy number and increased methylation levels of specific loci at mtDNA would increase the risk of macrosomia. However, the detailed molecular mechanism needs further identification.
查看更多>>摘要：Introduction: Intravoxel Incoherent Motion (IVIM) MRI is a non-invasive, in vivo techniques which can assess placental perfusion quantitatively, and be useful for evaluating placental microcirculation. Our primary aim was to investigate whether fetal growth restriction (FGR) pregnancies have different placental perfusion and diffusion compared with normal pregnancies using IVIM. A secondary aim was to investigate correlations between placental IVIM parameters and gestational age in normal pregnancy. Methods: This study population included 17 FGR pregnancies and 36 normal pregnancies between 28 + 3 to 38 + 0 weeks. All women underwent a MRI examination including an IVIM sequence with 9 b-values on a 3.0 T MRI system. The standard diffusion coefficeint (D), pseudodiffusion (D*) and perfusion fraction (f) were calculated. Results: Placental f was significantly lower in the FGR group than that in the normal group (33.96 +/- 2.62(%) vs 38.48 +/- 5.31(%), p = 0.002). Placental D and D* in two groups showed no statistical significance (P > 0.05). Placental f moderately increased with increasing gestational age in normal pregnancies (r = 0.411, p = 0.013), and there existed a negative correlation between D values and gestational age (r = -0.390, p = 0.019). Discussion: The f values are able to distinguish FGR from normal pregnancies. It can be uses as a feasible index to evaluate placenta perfusion. Gestational age-associated changes in placental IVIM parameters likely reveal trajectories of microvascular perfusion fraction and diffusion characteristics in the normal developing placenta.
查看更多>>摘要：Introduction: This study aims to examine the association between the presence and size of a vein-to-vein (VV) anastomosis and birth weight discordance relative to placental discordance in monochorionic diamniotic twin pregnancies. Methods: Placentas of two previous prospective studies were included in this retrospective analysis. After injection with color dye, we measured the placental surface of each twin and VV, artery-to-artery (AA), and artery to-vein (AV) anastomoses on a digital photograph. We calculated the birth weight ratio (BWR), placental ratio (PR), and birth weight ratio/placenta ratio (BWR/PR), as well as total AV size and net AV transfusion. Placental characteristics were compared between placentas with and without VV anastomoses. We performed univariate analyses to assess the following predictors for BWR/PR: VV size, AA size, total AV size, and net AV transfusion. Multivariate analysis was then performed, including the variables significant in univariate analysis. Results: We analyzed 247 placentas: 58 (23%) with VV anastomoses and 189 without (77%). The BWR and PR were higher in the group with VV. In contrast, BWR/PR was lower in the group with VV anastomoses than in those without. The size of AA anastomoses was larger in placentas with VV anastomoses than in those without. In univariate analysis, VV size and AA size were significantly associated with BWR/PR. However, in multivariate regression, only VV size remained significantly associated with the BWR/PR. Discussion: VV anastomoses are associated with a decreased birth weight discordance relative to the placental sharing discordance, independent of the AA anastomoses.
查看更多>>摘要：Introduction: Recurrent miscarriage (RM), refers to two or more consecutive spontaneous miscarriage in a pregnant woman. RM is caused by many factors, and microRNAs play an important role in the development and pathology of RM. In the present study, we investigated the function of miR-187 in the pathogenesis of RM and its effects on human trophoblast cells. Methods: The localization of miR-187 in the human placenta in early pregnancy was determined by in situ hybridization. QRT-PCR was used to detect the expression of miR-187 in villi of normal early pregnancy induced abortion group and recurrent spontaneous miscarriage group. Then, HTR8/SVneo cells were used to investigated the effect of miR-187 on BCL6 expression and biological activity of trophoblasts. Results: We found that the expression of miR-187 in villi of RM group was higher than that of normal abortion group and miR-187 inhibited the proliferation, migration, and invasion of HTR8 cells. We also found that miR187 promoted apoptosis, inhibited EMT, and inhibited the PI3K/AKT pathway in HTR8 cells. In addition, we also found that BCL6 is a direct target of miR-187 and is negatively regulated by miR-187. In addition, BCL6 reversed the inhibitory effects of miR-187 on HTR8/SVneo cells. These data demonstrate that miR-187-induced repression of PI3K/AKT signaling is mediated by BCL6 in HTR8 cells. Disscussion: MiR-187 inhibits the proliferation, migration, and invasion of trophoblasts through a mechanism that involves regulation of BCL6.
查看更多>>摘要：Introduction: Gestational diabetes mellitus (GDM) is associated with many adverse outcomes of pregnancy, especially macrosomia. The aim of our study was to verify whether high glucose concentrations change the methylation levels of the insulin-like growth factor-2 (IGF-2)/H19 gene promoters to increase the expression of IGF-2, a key gene in fetal growth regulation. Methods: HTR8/SVneo cells were used to establish a cell model of intrauterine hyperglycemia in pregnant women with GDM. The RNA expression levels of the IGF-2/H19 genes and the methylation levels of the IGF-2/H19 gene promoter regions were measured. Methylated and unmethylated IGF-2/H19 gene promoter plasmids were transfected into HTR8/SVneo cells. Results: Among the five groups of cells, the RNA levels of IGF-2 and H19 were lowest in the 5-mM (physiological blood glucose level) group, which was statistically significant (all P < 0.05). Compared with those in the 5-mM group, two cytosine-phosphate-guanine (CpG) sites in the promoter region of the IGF-2 gene and twelve CpG sites in the promoter region of the H19 gene had statistically significant changes in methylation levels (all P < 0.05). Additionally, luciferase activity was significantly higher in cells transfected with the methylated H19 gene promoter plasmid than in control cells transfected with the unmethylated plasmid (P < 0.01), while the methylated IGF-2 gene promoter plasmid produced lower luciferase activity than the unmethylated plasmid (P < 0.01). Discussion: High glucose concentrations may increase IGF-2/H19 expression by changing the methylation levels of the IGF-2 and H19 gene promoters.
查看更多>>摘要：Introduction: Preeclampsia (PE) is a pregnancy-specific multisystemic syndrome. This study aimed to investigate the associations between angiotensinogen (AGT), methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF) polymorphisms, and PE in the Han Chinese population. Methods: We genotyped 26 single-nucleotide polymorphisms (SNP) in three genes by using QuantStudioTM 12 K Flex Real-Time PCR technology in 168 patients with PE and 204 healthy pregnant control subjects. The associations of tested polymorphisms with PE were analyzed at allele, genotype, and haplotype levels. Results: A common coding variant in MTHFR, rs2274976, was significantly associated with increased risk of PE in both allelic and genotype models (P < 0.05). The heterozygous genotypes of rs699 (G/A vs G/G) in AGT gene and rs3025035 (C/T vs C/C) in VEGF gene showed weak associations with increased PE risk, whereas the mutant homozygous genotype of rs3024987 (TT vs C/C) and the heterozygous genotype of rs3025039 (C/T vs C/C) in VEGF gene displayed weak associations with decreased PE risk (P < 0.05). Discussion: However, these weak associations lost significance after multiple testing correction. The results indicated that rs2274976 in MTHFR gene may contribute to the increased risk of PE in pregnant women. AGT and VEGF gene polymorphisms may not play a significant role in PE development.
查看更多>>摘要：Introduction: Preeclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. The regular growth, migration and invasion of villous trophoblast cells contribute to placental development. The objective of this study was to investigate the role and mechanism of circular RNA homeodomain interacting protein kinase 3 (circHIPK3) in the biological functions of trophoblast cells. Methods: The expression of circHIPK3, microRNA-346 (miR-346) and potassium channel modulatory factor 1 (KCMF1) mRNA was measured by quantitative real-time PCR (qPCR). Trophoblast cell proliferation, migration/ invasion and cell cycle progression/apoptosis were determined by CCK-8 assay, transwell assay and flow cytometry assay, respectively. The predicted relationship between miR-346 and circHIPK3 or KCMF1 by bioinformatics was confirmed dual-luciferase reporter assay and RIP assay. Results: CircHIPK3 and KCMF1 were downregulated, while miR-346 was upregulated in placenta tissues from PE patients. The forced expression of circHIPK3 promoted trophoblast cell proliferation and migration/invasion but alleviated cell cycle arrest and cell apoptosis. MiR-346 was a target of circHIPK3, and miR-346 restoration reversed the effects of circHIPK3 upregulation. In addition, circHIPK3 acted as miR-346 sponge to modulate KCMF1 expression. KCMF1 downregulation partially repressed trophoblast cell proliferation, migration and invasion that were facilitated by miR-346 inhibition or circHIPK3 upregulation. Discussion: CircHIPK3 contributes to trophoblast cell proliferation, migration and invasion by upregulating KCMF1 via acting as miR-346 sponge.
查看更多>>摘要：Introduction: Junctional adhesion molecule-C (JAM-C) is an important regulator of many physiological processes, ranging from maintenance of tight junction integrity of epithelia to regulation of cell migration, homing and proliferation. Preeclampsia (PE) is a trophoblast-related syndrome with abnormal placentation and insufficient trophoblast invasion. However, the role of JAM-C in normal pregnancy and PE pathogenesis is unknown. Methods: The expression and location of JAM-C in placentas were determined by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The expression of differentiation and invasion markers were detected by qRT-PCR or western blot. The effects of JAM-C on migration and invasion of trophoblasts were examined using wound-healing and invasion assays. Additionally, a mouse model was established by injection of JAM-C-positive adenovirus to explore the effects of JAM-C in vivo. Results: In normal pregnancy, JAM-C was preferentially expressed on cytotrophoblast (CTB) progenitors and progressively decreased when acquiring invasion properties with gestation advance. However, in PE patients, the expression of JAM-C was upregulated in extravillous trophoblasts (EVTs) and syncytiotrophoblasts (SynTs) of placentas. It was also demonstrated that JAM-C suppressed the differentiation of CTBs into EVTs in vitro. Consistently, JAM-C inhibited the migration and invasion capacities of EVTs through GSK3 beta/beta-catenin signaling pathway. Importantly, Ad-JAMC-infected mouse model mimicked the phenotype of human PE. Discussion: JAM-C plays an important role in normal placentation and upregulated JAM-C in placentas contributes to PE development.
Tsai, Bridget W.Lau, SandyPaek, Song YeeWise, Michelle...
4页
查看更多>>摘要：Antiphospholipid antibodies (aPL) are autoantibodies that cause pregnancy disorders by a poorly defined mechanism that involves the placenta. The human placenta is covered by a single multinucleated cell, the syncytiotrophoblast, which extrudes vast numbers of extracellular vesicles (EVs) into the maternal blood. Extracellular vesicles are tiny packages of cellular material used by cells for remote signalling. In normal pregnancy, placental EVs assist maternal adaptations to pregnancy. We have previously shown that aPL alter the cargo of placental EVs, increasing the load of danger signals. These changes in EV cargo may explain how aPL contribute to the increased risk of recurrent miscarriage, preeclampsia and stillbirths observed in aPL-affected pregnancies. An additional possibility, that aPL alters the targeting of placental EVs to maternal organs to cause maternal maladaptation to pregnancy was investigated in this study.
Yap, Yann W.Hannan, Natalie J.Wallace, Euan M.Marshall, Sarah A....
5页
查看更多>>摘要：Nuclear factor erythroid 2-related factor-2 (Nrf2), and the less well characterised proteins Nrf1 and Nrf3, are member of the cap 'n' collar family of transcription factors. Nrf proteins regulate the expression of endogenous antioxidant enzymes and have recently become the targets for various therapeutic treatments. Recently, Nrf proteins have been of particular interest as a target in placental-derived oxidative stress induced pregnancy disorders. Here, we report the presence of Nrf1, Nrf2 and Nrf3 proteins in both human primary trophoblast and human trophoblast choriocarcinoma cell line (BeWo). We also detail the steps taken to successfully silence all Nrf proteins in both human primary trophoblast cells and BeWo via detection of mRNA and protein using quantitative PCR, and SDS-PAGE and Western Blotting respectively.
NSTL
Elsevier