Obstetrics and gynecology research最新文献

Introduction: Neuronal apoptosis and consequent inhibition of autophagy, with loss of synaptic connections are central events in the genesis of fetal alcohol spectrum disorders (FASD). However, studies of molecular mechanisms of autophagy in human fetal brain are limited. Recently, prenatal exposure to EtOH was associated with reduced miRNA-9 levels in fetal brain-derived exosomes (FB- Es) isolated from maternal plasma, which correlated with small eyes, an anatomical hallmark of fetal alcohol syndrome (FAS). Since miR-9 targets several genes that regulate synaptic plasticity, EtOH-induced inhibition of miR-9 could potentially result in dysregulation of genes involved in synaptogenesis/plasticity.

Methods: Rats were fed a 6.7% EtOH liquid diet from E16 to birth. Human studies: Fetal brain tissues from elective pregnancy terminations were collected at 9-23 weeks gestational age (GA; n=20 EtOH-exposed and 20 GA- and fetal sex-matched unexposed controls). EtOH consumption was assessed by questionnaire (adapted from NIAAA PASS). Expressions of 84 genes in a synaptic plasticity microarray were assessed in human fetal brain samples, verified by qRT-PCR, and for some mRNAs, copy number was determined in FB-Es by droplet digital PCR. Protein expression was measured in brain by qWestern blot assays or with a MAP kinase microarray. Exosomal protein levels were measured by ELISA.

Results: Levels of pro-apoptotic caspase-3 and Bax were significantly increased in the brains of EtOH-exposed rat pups, while early expressions of anti-apoptotic Bcl2 and biphasic Bag3 were inhibited. Phosphorylation of GSK3β was increased, and during Bag3 inhibition, the GSK3β target β-catenin also was increased. EtOH-exposed P8 and P15 rats showed motor abnormalities during low Bag3 expression. EtOH exposure reduced expression of synaptophysin and synapsin. In most synaptic plasticity pathways, levels of mRNAs were reduced. Several immediate-early genes were upregulated, but SYNPO, which is involved late in synaptic plasticity was downregulated 78%. Genes involved in Long Term Potentiation (LTP) and long-term depression (LTD) were downregulated, but the neurotoxic cytokine TNF⍺ was upregulated.

Conclusions: Prenatal exposure to EtOH was associated with reduced expression of autophagy genes in the fetal brains of rats and humans. Inhibition of Bag3 correlated with upregulation of GSK3β and its downstream targets, suggesting dysregulation of β-catenin signaling. Synaptic proteins, including those implicated in LTP and LTD also were inhibited by EtOH. The results in FB-E mirrored those in brain tissue. Reduced expression of miR-9 target synaptic genes in FB-Es might serve as novel biomarkers to predict FASD.

Introduction: An estimated 20% of women consume alcohol during pregnancy, and 10% of women receive antidepressants during their pregnancy. Women with depression are more likely to use alcohol (EtOH) in early pregnancy and are more likely to have a child with one of the fetal alcohol spectrum disorders (FASD). Previously, we provided evidence in rat neurons in vitro that DING phosphatase (p38SJ, a member of the DINGGG family of proteins that has neuroprotective effects under conditions of cellular stress) was neuroprotective against EtOH-mediated toxicity. Now, we examine the effects of DING, alone or in combination with EtOH and serotonergic (5-HT) pathway molecules and drugs, on EtOH-mediated neurotoxicity in human fetal tissues in vitro.

Methods: Human fetal brain tissue was collected between 9 and 23 weeks' gestation. Primary neurons and neurospheres were prepared from a 16-week fetal brain. Exposures to EtOH and SSRI were assessed by detailed questionnaires. Neurotoxicity/apoptosis was assessed in synaptosome extracts with the Caspase-Glo 3/7 assay and a neurotoxicity microarray. Developmental expressions of DING, serotonin transporter (SERT), and 5-HT1A receptor (5HT1A) protein levels were quantified in the brain, placenta, synaptosomes, serum, and "fetal brain-derived exosomes" (FB-Es) by quantitative western blotting and digital droplet PCR.

Results: Increasing the levels of activated DING, either by addition to culture media or by intracellular overexpression, was associated with increased cell survival. Developmental expressions of DING, in the presence of EtOH- or SSRI-exposure, were investigated in brain and placenta tissues. While 5HT1A, 5-hydroxytryptamine serotonin receptor 1A (5-HT1A) was strongly inhibited under EtOH stress conditions (>10-fold), DING was not only able to reverse the negative effects of stress, as measured by the synaptic plasticity array, but also upregulated the 5-HT receptor (5-fold compared to untreated control) upon treatment of neurons.

Conclusions: Maternal EtOH use is associated with decreased 5-HT receptor and DING protein expression in the fetal brain and with increased neuronal apoptosis. Combined exposure to EtOH and SSRIs may have greater toxic effects than either one alone. DING reversed the toxic effects of EtOH on serotonin receptors in neurons and neurospheres. These findings provide potential mechanisms for the neuroprotective effects of DING, which might suggest neuroprotective approaches to preventing fetal alcohol spectrum disorders (FASD).

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with adverse maternal and fetal outcomes. While placental dysfunction is implicated in PE pathogenesis, the impact of PE on placental lipid metabolism and its potential sexual dimorphism remains poorly understood.

Methods: We conducted a comprehensive analysis of term placentas from PE and normotensive pregnancies with male and female fetuses. Lipid profiles were quantified using mass spectrometry, and mRNA expression of genes involved in fatty acid oxidation, esterification, and transport was assessed using qPCR.

Results: Placentas from PE pregnancies exhibited elevated lipid levels, with male placentas showing a more pronounced increase in triacylglycerols, cholesteryl esters, and free cholesterol compared to female placentas. Gene expression analysis revealed sexually dimorphic alterations, with male PE placentas exhibiting upregulation of genes involved in fatty acid uptake, oxidation, and esterification, while female PE placentas showed a more complex response with both upregulation and downregulation of certain genes. Notably, peroxisomal fatty acid oxidation was upregulated in male PE placentas but suppressed in female PE placentas.

Conclusions: Our findings reveal sexually dimorphic alterations in placental lipid metabolism in PE, suggesting that male placentas may be more vulnerable to lipotoxicity. These insights may have implications for understanding the pathogenesis of PE and developing sex-specific interventions to improve maternal and fetal outcomes.

Background: Macrophages play a key role in all environmental conditions surrounding pregnancy. Coating of autologous red blood cells (RBCs) with polyclonal antibodies to Rh(D) antigen may result in an immunomodulation and improved outcome in Rh(D) positive women with recurrent pregnancy loss (RPL).

Methods: A total of 60 Rh(D) positive women (age 23 to 45 years) with a history of RPL and ineffective treatment with low molecular weight heparin (LMWH) and/or aspirin were included in this retrospective study. In addition to this treatment, Anti-D (300 μg) was given subcutaneously to each woman either prior to pregnancy and/or two times within 12 weeks of gestation.

Results: Treatment with Anti-D in non-responders to heparin/aspirin resulted in successful pregnancies in 67% of all cases. The remaining women had only aborts (23%) or did not become pregnant (10%). None of the treated women has developed anemia due to this treatment or any other significant adverse reaction. The rate of successful pregnancies does not appear to be influenced by the administration of: Anti-D prior to pregnancy, age, thrombophilia or previous alive births.

Conclusion: The improved outcome following the administration of Anti-D in women with RPL might be explained by immune modulations induced by different immune reactions including polarization of decidual macrophages. The results obtained in this study clearly indicate that Anti-D is safe and highly effective in treatment of Rh(D) positive women with RPL. However, further studies are required to support our results and to find out the optimal dose and timing of Anti-D administration.