Placenta Dysfunction Research Articles

81 Possibilities of the cardiointervalography in the forecasted fetal distress at perinatal losses in anamnesis of mather

Objective: Stressful experiences against the backdrop of perinatal losses (PL) may adversely affect the course of the next pregnancy, promote fetal distress. The structure of causes of perinatal mortality fetal distress is one of the leading places. The aim of the study was to evaluate the possibility cardiointervalography in predicting fetal distress during perinatal history mother. Study design: A study of heart rate variability by cardiointervalography women with PL associated with placenta dysfunction in 16-18 weeks of pregnancy by fetal monitor “Kardiolab Baby Card” (Kharkiv, Ukraine). The study involved 200 pregnant women with PL in the anamnesis (study group) and 100 pregnant women without PL (control group). For assessment of adaptive responses using the parameter activity of regulatory systems (PARS), the calculation is done automatically. Results: Normal adaptive state (PARS = 1-3 points) observed only in 10.0% of pregnant with PL and in the vast majority (61.0%) patients control group (p <0.05), expressed tension of regulatory systems was observed in half pregnant study group against 15.0% of women in the control group (p <0.05). In 22.0% of pregnant women with PL PARS score was 8-10 points, characterized by a failure of adaptation? in the control group similar condition seen in only 3.0% of women (p<0.05). 48 (24.0%) women of the main group diagnosed fetal distress (according to Doppler and cardiotocography): 20 (41.7%) of them - failure of adaptation (PARS = 8-10), while in the absence of fetal distress failure of adaptation found only in 24 (15.8%), i.e. 8-10 points while in the absence of fetal distress failure of adaptation found only in value may be a marker of fetal distress (OR = 3.810 95% CI 1.853-7.832). Conclusions: Evaluation of regulation of the autonomic nervous system in heart rate variability to evaluate adaptation abilities of women and their use as prognostic markers of fetal suffering.

PPARγ Regulates Triclosan Induced Placental Dysfunction.

Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus.

Role of GRK2 in Trophoblast Necroptosis and Spiral Artery Remodeling: Implications for Preeclampsia Pathogenesis.

Impaired invasion of extravillous trophoblasts and severe oxidative stress manifest the poor placentation in preeclampsia, which is life-threatening and more than a hypertensive disease of pregnancy. Previous studies have reported that G protein-coupled receptor kinases (GRKs) play a key role in initiating hypertension and hypertensive renal damage, yet little evidence so far suggests a link between GRKs and preeclampsia-related hypertension. Here, we demonstrate GRK2 expression is significantly downregulated (P < 0.0001) in preeclamptic placentae compared to normotensive controls. Knockdown or inhibition of GRK2 in placentae caused insufficient arterial remodeling and elevated trophoblast necroptosis in vivo. These further induced preeclampsia-like phenotype in mice: hypertension, proteinuria, and elevated pro-angiogenic cytokines. By human extra-villous invasive trophoblast cell line (HTR8/SVneo cells), we revealed the knockdown or inhibition of GRK2 triggered excessive death with typical necroptotic characteristics: nuclear envelope rupture and the activation of RIPK1, RIPK3, and MLKL. Necrostatin-1, an inhibitor of RIPK1, is able to restore the survival of trophoblasts. Together, our findings demonstrated that insufficient GRK2 activity compromises spiral artery remodeling and initiates necrotic events in placentae, thereby leading to preeclampsia. These findings advance our understanding of GRK2 in the pathogenesis of preeclampsia and could shed light on a potential treatment for preeclampsia.

The effect of gestational diabetes on the expression of mitochondrial fusion proteins in placental tissue.

Gestational diabetes mellitus (GDM) poses a risk factor for fetal mortality and morbidity by directly affecting the placenta and fetus. Mitochondria are dynamic organelles that play a key role in energy production and conversion in placental tissue. Mitochondrial fusion and fission proteins are important in terms of providing mitochondrial dynamics, the adaptation of the cell to different conditions, and maintaining the metabolic stability of the cells. Although GDM shares many features with Type 2 diabetes mellitus (T2DM), different effects of these conditions on the mother and the child suggest that GDM may have specific pathological effects on placental cells. The aim of this study is to investigate the expression of mitochondrial dynamics, and mitochondrial protein folding markers in placentas from GDM patients and women with pre-existing diabetes mellitus. Placentas were properly collected from women, who had pre-existing diabetes (Pre-DM), from women with gestational diabetes mellitus (GDM) and from healthy (non-diabetic) pregnant women. Levels of mitochondrial fusion markers were determined in these placentas by real time quantitative PCR and Western blot experiments. mRNA expressions and protein levels of mitochondrial fusion markers, mitofusin 1, mitofusin 2 (MFN1 and MFN2) and optical atrophy 1 (OPA1) proteins were found to be significantly lower in both Pre-DM placentas and those with GDM compared to healthy (non-diabetic) control group. Likewise, proteins involved in mitochondrial protein folding were also found to be significantly reduced compared to control group. Diabetes during pregnancy leads to processes that correlate with mitochondria dysfunction in placenta. Our results showed that mitochondrial fusion markers significantly decrease in placental tissue of women with GDM, compared to the healthy non-diabetic women. The decrease in mitochondrial fusion markers was more severe during GDM compared to the Pre-DM. Our results suggest that there may be differences in the pathophysiology of these conditions.

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

Epigenetic processes during preeclampsia and effects on fetal development and chronic health.

Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring.

Early neonatal period of newborns from mothers with sexually transmitted infections in the case history

The objective: to analyze the perinatal consequences of childbirth and the early neonatal period of the newborns from mothers with sexually transmitted infections in the case history. Materials and methods. In order to meet the objective, we examined 80 pregnant women on the basis of the Kyiv City Center of Reproductive and Perinatal Medicine (the clinical base of the Department of Obstetrics, Gynecology and Reproductology of Shupyk National Healthcare University of Ukraine) for the period of 2020–2021. There were two groups: group I – 50 pregnant women with STIs in the case history and group II – a control group – 30 practically healthy pregnant women with a successful reproductive history and uncomplicated course of the present pregnancy. Clinical and statistical analysis of perinatal consequences of childbirth and early neonatal period in newborns from these women was conducted. Results. The analysis of perinatal consequences of childbirth from women with sexually transmitted infections in the case history showed a high frequency of intranatal asphyxia of varying severity – 19 children (38.0%), severe – 2 children (4.0%). The early neonatal period disease incidence of infants born from the women in this group is 38 (38.0%; p&lt;0.05) cases against 13.3% in the control group. The frequency of detection of fetal growth retardation syndrome in women patients of group I significantly increased compared to women from the control group - up to 10.0% (p&lt;0.05 by criterion χ2). The fetal growth retardation syndrome occurred in women of group I, due to the placenta dysfunction, which was caused by the primary deterioration of uteroplacental hemodynamics and microthrombosis in the placenta. At the same time, early FGR (up to 32 weeks) was detected in women of group I – 80.0% of cases. It can be assumed that the development of FGR syndrome coincides with the manifestation of the underlying sexually transmitted disease during gestation. Manifestations of intrauterine infection were observed in newborns from women from group I in 18.0% of cases, which was statistically significant compared to the control (p&lt;0.05 by criterion χ2). Among this category of newborns, inflammatory processes of the skin (44.4%), urinary tract infections (33.3%), and pneumonia (22.2%) were most of ten observed. Conclusions. The study confirms and suggests that the presence sexually transmitted infection in the case history adversely affects perinatal outcomes. This had a negative effect on the newborn with the realization in the form of asphyxia, decreased weight growth, CNS damage, conjugative jaundice, intrauterine infection and its implementation in the early neonatal period. Ensuring quality care for this category of newborns requires special attention of neonatologists to predict neonatal complications of intrauterine infection.

Melatonin, a Potential Therapeutic Agent for Preeclampsia, Reduces the Extrusion of Toxic Extracellular Vesicles from Preeclamptic Placentae.

Preeclampsia, characterised by maternal endothelial cell activation, is triggered by toxic factors, such as placental extracellular vesicles (EVs) from a dysfunctional placenta. The increased oxidative stress seen in the preeclamptic placenta links to endoplasmic reticulum (ER) stress. The ER regulates protein folding and trafficking. When the ER is stressed, proteins are misfolded, and misfolded proteins are toxic. Misfolded proteins can be exported from cells, via EVs which target to other cells where the misfolded proteins may also be toxic. Melatonin is a hormone and antioxidant produced by the pineal gland and placenta. Levels of melatonin are reduced in preeclampsia. In this study we investigated whether melatonin treatment can change the nature of placental EVs that are released from a preeclamptic placenta. EVs were collected from preeclamptic (n = 6) and normotensive (n = 6) placental explants cultured in the presence or absence of melatonin for 18 h. Misfolded proteins were measured using a fluorescent compound, Thioflavin-T (ThT). Endothelial cells were exposed to placental EVs overnight. Endothelial cell activation was measured by the quantification of cell-surface ICAM-1 using a cell-based ELISA. EVs from preeclamptic placentae carried significantly (p < 0.001) more misfolded proteins than normotensive controls. Incubating preeclamptic placental explants in the presence of melatonin (1 µM and 10 µM) significantly (p < 0.001) reduced the misfolded proteins carried by EVs. Culturing endothelial cells in the presence of preeclamptic EVs significantly increased the expression of ICAM-1. This increased ICAM-1 expression was significantly reduced when the endothelial cells were exposed to preeclamptic EVs cultured in the presence of melatonin. This study demonstrates that melatonin reduces the amount of misfolded proteins carried by EVs from preeclamptic placentae and reduces the ability of these EVs to activate endothelial cells. Our study provides further preclinical support for the use of melatonin as a treatment for preeclampsia.

Strategies for intra-amniotic administration of fetal therapy in a rabbit model of intrauterine growth restriction.

Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.

Maternal Hyperglycemia Induces Changes in Gene Expression and Morphology in Mouse Placentas.

Pregestational diabetes complicates one million pregnancies in the United States and is associated with placental dysfunction. Placental dysfunction can manifest as stillbirth, spontaneous abortions, fetal growth restriction, and preeclampsia in the mother. However, the underlying mechanisms of placental dysfunction are not well understood. We hypothesize that maternal hyperglycemia disrupts cellular processes important for normal vascular development and function. Hyperglycemia, defined as a non-fasting glucose concentration of >250 mg/dL was induced in eight-week-old female CD1 mice by injecting a one-time intraperitoneal dose of 150mg/kg streptozotocin. Control mice received an equal volume of normal saline. Hyperglycemic and control females were mated with CD-1 males. At Embryonic Day 17.5, the pregnant mice were euthanized. Sixty-eight placentas were harvested from the six euglycemic dams and twenty-six placentas were harvested from three hyperglycemic dams. RNA was extracted from homogenized placental tissue (N=12/group; 2-4 placentas per litter of each group). Total RNA was prepared and sequenced. Differentially expressed genes that were >2-fold change was considered significant. Placentas (9-20/group) were fixed in paraffin wax and sectioned at 6 μm. Cross-sectional areas of placental zones were evaluated using slides stained for hematoxylin and eosin, glycogen, collagen, proliferation and apoptosis. Quantification of staining intensity and percent positive nuclei was done using Leica Image Hub Data software. Data were compared between the control and experimental group using t-tests. Values of p < 0.05 were considered to be statistically significant. The average maternal blood glucose concentrations for control and diabetic dams were 112+/-24 and 473+/-47 respectively (p<0.0001). A higher rate of resorptions was noted in the hyperglycemia exposed placentas compared to euglycemic exposed placentas (24% vs 7%; p=0.04). A total of 24 RNA libraries (12/group) were prepared. Placentas from hyperglycemic pregnancies exhibited 1374 differentially expressed genes (DEGs). The 10 most significantly differentially expressed genes are Filip 1, Prom 2, Fam 78a, Pde4d, Pou3f1, Kcnk5, Dusp4, Cxcr4, Slc6a4 and D430019H16Rik. Their corresponding biologic functions are related to chemotaxis, ossification, cellular and vascular development. Histologically, we found that hyperglycemia exposed placentas demonstrated increased proliferation, apoptosis, and glycogen content and decreased collagen deposition. There was a higher rate of resorptions in the pregnancies of hyperglycemic dams. Pregestational diabetes resulted in significant changes in placental morphology, including increased glycogen content in the spongiotrophoblast, decreased collagen deposition, increased apoptosis and proliferation in the junction zone. Maternal diabetes causes widespread disruption in multiple cellular processes important for normal vascular development and sets the platform for placenta dysfunction.

Bisphenol S and Epidermal Growth Factor Receptor Signaling in Human Placental Cytotrophoblasts.

Background:Bisphenol S (BPS) is an endocrine-disrupting chemical and the second most abundant bisphenol detected in humans. In vivo BPS exposure leads to reduced binucleate cell number in the ovine placenta. Binucleate cells form by cellular fusion, similar to the human placental syncytiotrophoblast layer. Given that human placental syncytialization can be stimulated through epidermal growth factor (EGF), we hypothesized that BPS would reduce human cytotrophoblast syncytialization through disruption of EGF receptor (EGFR) signaling.Objective:We tested whether BPS interferes EGFR signaling and disrupts human cytotrophoblast syncytialization.Methods:We first tested BPS competition for EGFR using an EGF/EGFR AlphaLISA assay. Using human primary term cytotrophoblast cells (hCTBs) and MDA-MD-231 cells, a breast cancer cell line with high EGFR expression, we evaluated EGFR downstream signaling and tested whether BPS could inhibit the EGF response by blocking EGFR activation. We also evaluated functional end points of EGFR signaling, including EGF endocytosis, cell proliferation, and syncytialization.Results:BPS blocked EGF binding in a dose-dependent manner and reduced EGF-mediated phosphorylated EGFR in both cell types. We further confirmed that BPS acted as an EGFR antagonist as shown by a reduction in EGF internalization in both hCTBs and MDA-MD-231 cells. Finally, we demonstrated that BPS interfered with EGF-mediated cell processes, such as cell proliferation in MDA-MD-231 cells and syncytialization in hCTBs. EGF-mediated, but not spontaneous, hCTB syncytialization was fully blocked by BPS (), a dose within urinary BPS concentrations detected in humans.Conclusions:Given the role of EGFR in trophoblast proliferation and differentiation during placental development, this study suggests that exposures to BPS at environmentally relevant concentrations may result in placenta dysfunction, affecting fetal growth and development. https://doi.org/10.1289/EHP7297

INVESTIGATION OF SFLT-1 AND VEGF EXPRESSION IN NORMOTENSIVE AND PREECLAMPTIC PLACENTA. AN IMMUNOHISTOCHEMICAL STUDY

Objectives: The pathogenesis of preeclampsia is still not clear, but endothelial dysfunction believed to be one of the most encountered problems during placenta development in preeclamptic patients. Both vascular endothelial growth factor (VEGF) and its antagonist, soluble Fms-Like tyrosine kinase-1 (sFlt-1), have roles in vascular function. In this study, we have investigated immunohistochemical expression of VEGF and sFlt-1 in term placenta of normotensive and preeclampsia patients. Methods: Totally twenty term placentas were obtained from pregnant women of which 10 preeclampsia patient and 10 normotensive. Placentas were dissected and tissue samples were subjected to routine tissue processing protocol, then embedded in paraffin blocks. Serial sections were obtained from paraffin blocks and stained with H&amp;amp;E and PAS for routine histopathology. VEGF and sFlt-1 immunohistochemistry was performed to the sections. Results: When compared to control group, severe pathological changes were observed in preeclamptic placentas. Increase in number of syncytial knots and intervillous bridges, hemorrhage in interstitium, dilatation and congestion in villous capillaries, increase in fibrin accumulation in villus stroma, and increase in thickening of basement membrane were very clear. VEGF expression was significantly higher in normotensive placentas compared to preeclamptic. On the other hand, sFlt-1 expression was significantly increased in preeclamptic placentas. Conclusions: When the VEGF and sFlt-1 expression was considered, higher expression of sFlt-1 at preeclampsia, but decrease in VEGF expression, might be related to endothelial dysfunction in preeclampsia. Overall, this study demonstrates, imbalance between VEGF and sFlt-1 is one of the major reason of endothelial dysfunction in preeclamptic placenta.

Mitochondrial dysfunction in placental trophoblast cells experiencing gestational diabetes mellitus.

Mitochondrial dysfunction is known to occur in diabetic phenotypes including type 1 and 2 diabetes mellitus. The incidence of gestational diabetes mellitus (GDM) is increasing and defined as the onset of a diabetic phenotype during pregnancy. The role of placental mitochondria in the aetiology of GDM remains unclear and is an emerging area of research. Differing mitochondrial morphologies within the placenta may influence the pathogenesis of the disorder. This study observed mitochondrial dysfunction in GDM placenta when assessing whole tissue. Upon further investigation into mitochondrial isolates from the cytotrophoblast and syncytiotrophoblast, mitochondrial dysfunction appears exaggerated in syncytiotrophoblast. Assessing mitochondrial populations individually enabled the determination of differences between cell lineages of the placenta and established varying levels of mitochondrial dysfunction in GDM, in some instances establishing significance in pathways previously inconclusive or confounded when assessing whole tissue. This research lays the foundation for future work into mitochondrial dysfunction in the placenta and the role it may play in the aetiology of GDM. Mitochondrial dysfunction has been associated with diabetic phenotypes, yet the involvement of placental mitochondria in gestational diabetes mellitus (GDM) remains inconclusive. This is in part complicated by the different mitochondrial subpopulations present in the two major trophoblast cell lineages of the placenta. To better elucidate the role of mitochondria in this pathology, this study examined key aspects of mitochondrial function in placentas from healthy pregnancies and those complicated by GDM in both whole tissue and isolated mitochondria. Mitochondrial content, citrate synthase activity, reactive oxygen species production and gene expression regulating metabolic, hormonal and antioxidant control was examined in placental tissue, before examining functional differences between mitochondrial isolates from cytotrophoblast (Cyto-Mito) and syncytiotrophoblast (Syncytio-Mito). Our study observed evidence of mitochondrial dysfunction across multiple pathways when assessing whole placental tissue from GDM pregnancies compared with healthy controls. Furthermore, by examining isolated mitochondria from the cytotrophoblast and syncytiotrophoblast cell lineages of the placenta we established that although both mitochondrial populations were dysfunctional, they were differentially impacted. These data highlight the need to consider changes in mitochondrial subpopulations at the feto-maternal interface when studying pregnancy pathologies.

One Step Closer to a Cure for Preeclampsia?

One Step Closer to a Cure for Preeclampsia?

Elevated maternal androgen is associated with dysfunctional placenta and lipid disorder in newborns of mothers with polycystic ovary syndrome

To investigate the placental morphology alterations and identify the clinical characteristics of women with polycystic ovary syndrome (PCOS) and their newborns. Pregnant women with PCOS (n = 12) and pregnant women without PCOS (n = 11) were recruited. Then, the placenta, maternal blood and cord blood were collected after delivery. Clinical observational study. Not applicable. In the present study, pregnant women with PCOS and healthy pregnant women were recruited from the clinic of the Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, China, between February 2015 and October2015. None. A proteomic analysis was performed on the placenta in women with PCOS and healthy women. The maternal testosterone, androstenedione, dehydroepiandrosterone sulfate, free androgen index, cholesterol, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I levels were significantly higher in the PCOS group than in the control group, and the offspring in the PCOS group had higher dehydroepiandrosterone sulfate, high-density lipoprotein, and cholesterol levels, when compared with the control group. The placenta in the PCOS group demonstrated infarction, calcification, and a greater intervillous space, when compared with the control group. A higher level of estrogen receptor-β protein was observed in the placenta of women with PCOS, when compared with women without PCOS. A total of 258 proteins in the placenta were identified to be significantly different, when the PCOS and control groups were compared, and fibronectin 1 exhibited the closest relationship with other differential proteins. The overexposure to hyperandrogenism and hyperlipidemia affects the functions of the placenta, which are associated with the development of metabolic disorders in newborns.

The role of hepatic sinusoidal obstruction in the pathogenesis of the hepatic involvement in HELLP syndrome: Exploring the literature.

This study aims to determine, based on existing data, whether the mechanism resulting in liver dysfunction in HELLP syndrome resembles that in Sinusoidal Obstruction Syndrome (SOS). HELLP syndrome is a serious pregnancy disorder with high maternal and perinatal morbidity and mortality rates. Because of poor insight in its pathophysiology, particularly that of the liver involvement, clinical management is limited to symptomatic treatment, often followed by termination of pregnancy. SOS is a rare, potentially life-threatening complication of radio and/ or chemotherapy in the preparation of hematopoietic cell transplantation. The etiology of liver dysfunction in SOS is - unlike that in HELLP syndrome - better-understood and seems to be initiated by direct toxic damage and demise of endothelial cells, causing hepatic sinusoidal obstruction and ischemia. We searched Pubmed, Embase and Cochrane for reports on the etiology of HELLP and SOS. This yielded 73 articles, with 14 additional reports from the references listed in these articles. The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction. The placenta releases, besides anti-angiogenetic factors, also necrotic debris and cell-free DNA, a mixture that not only induces systemic endothelial dysfunction as in preeclampsia, but also a systemic inflammatory response. The latter aggravates the endothelio-toxic effects in the systemic cardiovascular bed, amplifying the already increased pro-thrombotic conditions. Particularly in microcirculations with extremely low shear forces, such as in the hepatic sinusoids, this will facilitate microthrombi formation and fibrin deposition eventually resulting in obstruction of the sinusoids similar as in SOS. The latter causes ischemic damage and progressive demise of hepatocytes. The available information supports the concept that the liver damage in HELLP and SOS results from sinusoidal ischemia, presumably resulting from partially overlapping pathophysiological mechanisms.

Transcriptome-wide analysis of the SCNT bovine abnormal placenta during mid- to late gestation

The dysfunction of placenta is common in somatic cell nuclear transfer (SCNT) cloned cattle and would cause aberrant fetal development and even abortion, which occurred with highest rate at the mid- to late gestation. However, the mechanism of abnormal placentas was unclear. To analyze the transcriptome-wide characteristics of abnormal placentas in SCNT cloned cattle, the mRNA, lncRNA and miRNA of placental cotyledon tissue at day 180 after gestation were sequenced. A total of 19,055 mRNAs, 30,141 lncRNAs and 684 miRNAs were identified. Compared with control group, 362 mRNAs, 1,272 lncRNAs and nine miRNAs (six known and three novel miRNAs) were differentially expressed (fold change ≥ 2 and P-value < 0.05). The differentially expressed genes were functionally enriched in urea and ions transmembrane transport, which indicated that the maternal-fetal interactions were disturbed in impaired placentas. Furthermore, the competing endogenous RNAs (ceRNAs) networks were identified to illustrate their roles in abnormal placental morphology. The present research would be helpful to discover the mechanism of late gestational abnormality of SCNT cattle by provides important genomic information and insights.

Molecular pathways disrupted by gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for mother and baby. An effective therapeutic that can reduce the incidence of GDM and improve long-term maternal and fetal outcomes is a major research priority, crucially important for public health. A lack of knowledge about the underlying pathophysiology of GDM has hampered the development of such therapeutics. What we do know, however, is that maternal insulin resistance, low-grade inflammation and endothelial cell dysfunction are three central features of pregnancies complicated by GDM. Indeed, data generated over the past decade have implicated a number of candidate regulators of insulin resistance, inflammation and endothelial cell dysfunction in placenta, maternal adipose tissue and skeletal muscle. These include nuclear factor-κB (NF-κB), peroxisome proliferator-activated receptors (PPARs), sirtuins (SIRTs), 5' AMP-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK3), PI3K/mTOR, inflammasome and endoplasmic reticulum (ER) stress. In this review, the identification of these as key modulators of GDM will be discussed. The biochemical pathways involved in the formation of these may represent potential sites for intervention that may translate to therapeutic interventions to prevent the development of GDM.

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction.

Key points Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health.A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus.Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR.Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy.Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (K mf) of 14C‐glutamine and 14C‐glutamate (glutamine K mf and glutamate K mf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamine K mf and glutamate K mf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamine K mf remained elevated whereas glutamate K mf was similar between groups. In summary, we provide evidence that glutamine K mf and glutamate K mf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

MORPHOLOGICAL RESEARCH OF PLACENTA IN WOMEN WITH PRETERM LABOR

Preterm labor is one of the most current problems of modern medicine. Preterm labor is defined as the birth of a child in the gestation period less than 37 full weeks of gestation and is the second most common cause (after congenital anomalies) of neonatal mortality [3]. The highest percentage of morbidity and mortality occurs in children born to gestational age less than 32 weeks, although the proportion of these newborns is 16 % of all preterm infants [4]. Preterm labor is a polyetiology problem that depends on many factors. One of the major problems is the formation of placental dysfunction, which manifests itself by morphofunctional changes in the placenta associated with violation of uterine-placental circulation.&#x0D; The aim of the study – to obtain the peculiarities of placentas’ histological condition in women with burdent anamnesis and preterm labor with different Apgar point scale of newborn.&#x0D; Materials and Methods. A total of 19 placentas of women with preterm labor were observed in Maternal Hospital No. 5 of Odesa, Ukraine. We studed their residence areas, obstetrical and gynacology anamnesis, current pregnancy and labor anamnesis. We exa­mined the ultrasound datas of the newborns, studied their anthropometric, Apgar scale and histology of placentas’ datas. All interviewed women were devided into two groups: less than 35 years old – 12 women of the group 1 and more than 35 years old – 7 women, it was the group 2. The average age of the examined groups was 31.3 years old. Statistical datas processing was carried out by using the Fisher angular transformation. The degree of probability (P) between two comparative values was considered to be statistically valid when P&lt;0.05.&#x0D; The research results showed that all elder women were married, lived in ecoregions of the city, had more often revolved to artificial reproductive technologies, had singleton gestation compared to younger group of patients. Newborns of women afer 35 had better points of Apgar scale and no one had IUGR compared to newborns of the younger women. Signs of placenta dysfynction were detected in placentas of both groups of women.&#x0D; Conclusions. In our investigation the women of different age groups with preterm labor had signs of placenta dysfunction but women after 35 years had better datas of newborn babies according to Apgar scale and absence of IUGR. Probably, it is connected with residency, official marriage and better preconceptional preparation in this group.