Placental Protein Research Articles

Alteration in sB7-H4 Serum Levels and Placental Biomarker Expression after Therapeutic Plasma Exchange in Early-Onset Preeclampsia Patients.

Therapeutic plasma exchange (TPE) is a widely used treatment for numerous diseases including pregnancy-related conditions. Our prior study on 20 early-onset preeclampsia patients undergoing TPE revealed a significant extension in pregnancy duration and reduced serum levels of sFlt-1, sFlt-1/PlGF, and sEndoglin. Here, we investigated the impact of TPE on serum sB7-H4, an immunological checkpoint molecule, and placental proteins (Flt-1, Eng, B7-H4, iNOS, TNF-α) in TPE-treated early-onset preeclampsia patients (N = 12, 23 + 2-28 + 5 weeks), conventionally treated counterparts (N = 12, 23 + 5-30 weeks), and gestational age-matched controls (N = 8, 22 + 4-31 + 6 weeks). Immunoblotting, ELISA, and co-immunohistochemistry were used for biomarker analysis, including placental inflammation factors (iNOS, TNF-α). The results showed that TPE extended pregnancy by a median of 6.5 days in this cohort of early-onset preeclampsia. Serum sB7-H4, sFlt-1, and sEndoglin levels decreased, along with reduced expression of their membrane-bound proteins in placental tissue upon TPE treatment. Moreover, TPE-treated patients displayed reduced placental inflammation compared to preeclampsia patients receiving standard-of-care treatment. In conclusion, TPE may improve pregnancy outcomes in early-onset preeclampsia by lowering circulating levels of sB7-H4, sFlt-1, and sEndoglin, as well as reducing placental inflammation. This translational approach holds promise for enhancing placental function and extending gestation in high-risk pregnancies including very preterm PE or HELLP cases.

Maternal Obesity Alters Placental and Umbilical Cord Plasma Oxidative Stress, a Cross-Sectional Study.

Maternal obesity has been shown to impair the oxidative status in the placenta and newborns, potentially leading to adverse pregnancy outcomes and long-term effects on the programming of offspring metabolic status. This study aimed to investigate the impact of maternal obesity on maternal and umbilical cord plasma oxidative status, as well as placental oxidative adaptation. Maternal obesity (n = 20), defined as a pre-pregnancy BMI ≥ 25 kg/m2, and maternal leanness (n = 20), defined as a pre-pregnancy BMI < 23 kg/m2, were the group categories used in this study. Both groups were matched according to gestational age at delivery. Maternal blood, umbilical cord blood, and placental tissue were collected to assess nutritional content (cholesterol, triglyceride, and protein), oxidative stress markers (MDA and protein carbonyl), and antioxidant activity (SOD and catalase). Placental protein expression (SOD2, catalase, UCP2, and Nrf2) was evaluated using Western blot analysis. Catalase activity in maternal plasma significantly increased in the maternal obesity group (p = 0.0200), with a trend toward increased MDA and protein carbonyl levels. In umbilical cord plasma, triglyceride, protein carbonyl, and catalase activity were significantly elevated in the maternal obesity group compared with the lean controls (p = 0.0482, 0.0291, and 0.0347, respectively). Placental protein expression analysis revealed significantly decreased SOD2 (p = 0.0011) and catalase (p < 0.0001), along with Nrf2 downregulation (p < 0.0001). An increase in mitochondrial antioxidant UCP2 expression was observed (p = 0.0117). The neonatal protein carbonyl levels positively correlated with placental protein carbonyl (r = 0.7405, p < 0.0001) and negatively correlated with maternal catalase activity (r = -0.4332, p = 0.0052). This study thus provides evidence that maternal obesity is associated with placental and fetal oxidative stress, alongside a concurrent increase in placental antioxidant UCP2 expression.

8624 Maternal ZIKV Infection Causes Oxidative Damage in Placenta of Both Female and Male Mice

Abstract Disclosure: V.M. Nascimento: None. I.S. Andrade: None. C.B. Andrade: None. R.S. Alves: None. R.P. Sousa: None. A.C. Valim: None. L.S. Dias: None. K.N. Fontes: None. I.F. Miranda: None. S.A. Coelho: None. L.B. Arruda: None. R.S. Fortunato: None. T.M. Ortiga-Carvalho: None. The placenta is a maternal-fetal organ with nutritional, exchanging, hormonal and protecting functions that are vital for fetal growth and development during gestation. However, these functions can be disturbed by vertically transmitted pathogens such as Zika virus (ZIKV). In 2015, ZIKV was responsible for an increasing number of newborns with congenital abnormalities in Brazil, known as Congenital Zika Syndrome (CZS). Nonetheless, the extension of ZIKV infection in the placenta, leading to CZS, is still unclear. It is known that ZIKV causes oxidative stress in trophoblasts. However, no one has ever studied placental oxidative stress caused by ZIKV infection in vivo. Here, we investigated whether maternal ZIKV infection could cause sex-specific oxidative stress in murine placenta. At gestational day (GD)12.5, pregnant mice (C57BL/6; 8-12 weeks old) were infected with ZIKV-BRPE243 (5x107 PFU; ZIKV group, n=22) or Mock (supernatants of noninfected C6/36 cells; control group, n=28). At GD18.5, c-section was performed and maternal spleens, placentas, fetuses and fetal brains were collected. We measured placental carbonylated protein levels (n=7), by 2D OxyBlot, nitrotyrosine residues (n=5), by immunohistochemistry, reduced thiol content (n=9), total superoxide dismutase (SOD; n=9) and total glutathione peroxidase (GPx; n=9) activities, by spectrophotometry. Data were analyzed by unpaired Student’s t test and Two-Way ANOVA with Tukey’s post test and represented as mean±SEM. ZIKV infection increased maternal spleen weight (p&amp;lt;0.0001) and decreased both female (p=0.0429) and male (p=0.0171) placental weight. Although placental weights were affected by the infection, female and male fetal weight and fetal crown-rump length were not changed. Conversely, maternal ZIKV infection increased only female fetal brain weight (p=0.0028). Moreover, we found that ZIKV infection increased nitrotyrosine residues in the placental labyrinth region of both female (p&amp;lt;0.0001) and male (p=0.0007) fetuses. Meanwhile, nitrotyrosine residues were increased by the infection only in the placental junctional zone of female fetuses (p=0.0131). Although ZIKV increased this oxidative damage biomarker, placental carbonylated protein levels were not changed by the infection in both sexes. Also, reduced thiol content and total SOD and GPx activities were not affected. Together, our data show that maternal ZIKV infection caused oxidative stress in both placental regions of female and male fetuses, as we saw that ZIKV increased oxidative damage, although antioxidant defenses were not changed by the infection, at least at term (GD18.5). ZIKV infection may have disturbed placental growth, as we found that placental weight was decreased in both sexes. Moreover, we believe that the increase in the female fetal brain weight could be a suggestive feature of cerebral edema or hydrocephalus. Presentation: 6/2/2024

8624 Maternal ZIKV Infection Causes Oxidative Damage in Placenta of Both Female and Male Mice

Abstract Disclosure: V.M. Nascimento: None. I.S. Andrade: None. C.B. Andrade: None. R.S. Alves: None. R.P. Sousa: None. A.C. Valim: None. L.S. Dias: None. K.N. Fontes: None. I.F. Miranda: None. S.A. Coelho: None. L.B. Arruda: None. R.S. Fortunato: None. T.M. Ortiga-Carvalho: None. The placenta is a maternal-fetal organ with nutritional, exchanging, hormonal and protecting functions that are vital for fetal growth and development during gestation. However, these functions can be disturbed by vertically transmitted pathogens such as Zika virus (ZIKV). In 2015, ZIKV was responsible for an increasing number of newborns with congenital abnormalities in Brazil, known as Congenital Zika Syndrome (CZS). Nonetheless, the extension of ZIKV infection in the placenta, leading to CZS, is still unclear. It is known that ZIKV causes oxidative stress in trophoblasts. However, no one has ever studied placental oxidative stress caused by ZIKV infection in vivo. Here, we investigated whether maternal ZIKV infection could cause sex-specific oxidative stress in murine placenta. At gestational day (GD)12.5, pregnant mice (C57BL/6; 8-12 weeks old) were infected with ZIKV-BRPE243 (5x107 PFU; ZIKV group, n=22) or Mock (supernatants of noninfected C6/36 cells; control group, n=28). At GD18.5, c-section was performed and maternal spleens, placentas, fetuses and fetal brains were collected. We measured placental carbonylated protein levels (n=7), by 2D OxyBlot, nitrotyrosine residues (n=5), by immunohistochemistry, reduced thiol content (n=9), total superoxide dismutase (SOD; n=9) and total glutathione peroxidase (GPx; n=9) activities, by spectrophotometry. Data were analyzed by unpaired Student’s t test and Two-Way ANOVA with Tukey’s post test and represented as mean±SEM. ZIKV infection increased maternal spleen weight (p&amp;lt;0.0001) and decreased both female (p=0.0429) and male (p=0.0171) placental weight. Although placental weights were affected by the infection, female and male fetal weight and fetal crown-rump length were not changed. Conversely, maternal ZIKV infection increased only female fetal brain weight (p=0.0028). Moreover, we found that ZIKV infection increased nitrotyrosine residues in the placental labyrinth region of both female (p&amp;lt;0.0001) and male (p=0.0007) fetuses. Meanwhile, nitrotyrosine residues were increased by the infection only in the placental junctional zone of female fetuses (p=0.0131). Although ZIKV increased this oxidative damage biomarker, placental carbonylated protein levels were not changed by the infection in both sexes. Also, reduced thiol content and total SOD and GPx activities were not affected. Together, our data show that maternal ZIKV infection caused oxidative stress in both placental regions of female and male fetuses, as we saw that ZIKV increased oxidative damage, although antioxidant defenses were not changed by the infection, at least at term (GD18.5). ZIKV infection may have disturbed placental growth, as we found that placental weight was decreased in both sexes. Moreover, we believe that the increase in the female fetal brain weight could be a suggestive feature of cerebral edema or hydrocephalus. Presentation: 6/2/2024

A-313 Use of the Preeclampsia Ratio in the Prognosis of Preterm Delivery and Adverse Outcomes

Abstract Background Preeclampsia (PE) is a hypertensive disorder of pregnancy that is characterized by high blood pressure and end-organ dysfunction with or without proteinuria after 20 weeks gestation. PE occurs in 6-8% of pregnancies and contributes to significant fetal, neonatal, and maternal morbidity and mortality. The ratio of two angiogenic placental proteins, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), are used in the management of PE. The purpose of this study was to evaluate use of the sFlt-1/PlGF ratio (PE ratio) generated using the ADVIA Centaur® and Atellica® IM sFlt-1 assay and the ADVIA Centaur and Atellica IM PlGF assays in the prognosis of preterm delivery and adverse outcomes in women presenting with signs and symptoms of PE. Methods A total of 654 females with singleton pregnancies between gestational weeks 20+0 days and 35+6 days and who had signs and symptoms of PE, but without severe features of PE were enrolled at 24 collection sites and followed prospectively for two weeks. Serum samples were collected at enrollment and adverse outcomes that included preterm delivery were prospectively collected within the two weeks after enrollment. Serum samples from approximately half of the population (n=316) were tested in singlicate using the sFlt-1 and PlGF assays on the ADVIA Centaur system in a derivation study that determined the optimal cutoff of the PE ratio in relation to adverse outcome. The remaining serum samples (n=338) were subsequently tested on the ADVIA Centaur system in a cut-off validation study that evaluated the clinical performance (sensitivity [SE], specificity [SP], positive predictive value [PPV], negative predictive value [NPV]) of the PE ratio at the derived cutoff in relation to adverse outcome. Method comparison studies were performed between the ADVIA Centaur versus the Roche Elecsys sFlt-1 and PlGF assays (n=255) and the ADVIA Centaur versus the Atellica IM sFlt-1 and PlGF assays (n=316). Results The rate of maternal adverse outcomes within two weeks was similar in the derivation study (32.3%) and validation study (28.1%). Using a receiver operating characteristic (ROC) curve analysis with the derivation cohort, a derived cutoff of 38 showed optimal clinical performance of the PE ratio in relation to adverse outcome (SE=72.5%, SP=94.7%, PPV=84.6%, NPV=89.5%). Similar clinical performance results of the PE ratio at the cutoff of 38 in relation to adverse outcome were found with the verification cohort (SE=88.42%, SP=87.65%, PPV=73.68%, NPV=95.09%). Weighted Deming regression analysis demonstrated equivalency between the Centaur, Roche, and Atellica PE ratios with correlation coefficients (r) of 0.9242 (Centaur vs Roche) and 0.995 (Centaur vs Atellica). Conclusions Measurement of sFlt-1 and PlGF to determine PE ratio can be performed on either the ADVIA Centaur or Atellica Analyzer and can be used to identify women presenting with PE or signs and symptoms of PE who are at high risk of experiencing an adverse event in the subsequent two weeks. Not available for sale in the U.S.A. The products/features mentioned herein are not commercially available in all countries. Their future availability cannot be guaranteed.

Does placental VEGF-A protein expression predict early neurological outcome of neonates from FGR complicated pregnancies?

Fetal hypoxia due to placental dysfunction is thehallmark of fetal growth restriction (FGR). Preferential perfusion of the brain (brain-sparing effect), as a part of physiological placental cardiovascular compensatory mechanisms to hypoxia, in FGR was reported. Therefore, the correlation between vascular endothelial growth factor A (VEGF-A) protein expression in the FGR placentas and newborns' early neurological outcome was examined. This study included 50 women with FGR complicated pregnancies and 30 uneventful pregnancies. Fetal hemodynamic parameters, neonatal acid-base status after delivery, placental pathohistology and VEGF-A expression were followed. Early neonatal morphological brain evaluation by ultrasound and functional evaluation of neurological status by Amiel- Tison Neurological Assessment at Term (ATNAT) were performed. VEGF-A protein expression level was significantly higher in the FGR placentas than normal term placentas (Fisher-Freeman-Halton's test, p≤0.001). No statistically significant correlation between placental VEGF-A expression and different prenatal and postnatal parameters was noticed. Whereas the alteration of an early neurological status assessed by ATNAT was found in 58 % of FGR newborns, morphological brain changes evaluated by UZV was noticed in 48 % of cases. No association between the level of placental VEGF-A expression and the early neurological deficits was found. As far as we know this is the first study of a possible connection between VEGF-A protein expression in the FGR placentas and neonates' early neurological outcomes. The lack of correlation between the FGR placental VEGF-A expression and neonates' neurological outcome could indicate that optimal early neurodevelopment may take place due to compensatory mechanism not related to placental VEGF-A expression.

ITRAQ Based Proteomics Reveals the Potential Mechanism of Placental Injury Induced by Prenatal Stress.

Maternal stress experienced during prenatal development is recognized as a significant risk factor for neurodevelopmental and neuropsychiatric disorders across the offspring's lifespan. The placental barrier serves a crucial function in safeguarding the fetus from detrimental exposures during gestation. However, previous investigations have not yet comprehensively elucidated the extensive connections between prenatal stress and the expression of placental proteins. In this study, we used iTRAQ-based quantitative proteomics to elucidate the placental adaptive mechanisms of pregnant rats in response to fear-induced stress. Our results showed that during pregnancy, exposure to fear-induced stress led to a pathological hypercoagulable state in the mother's body. Placental circulation was also disrupted, significantly reducing placental efficiency and blood oxygen saturation in newborn rats. Proteomic analyses showed that most of the DEPs were annotated to the PI3K-Akt and ECM-receptor interaction signaling pathway. In addition, the expressions of CDC37, HSP90β, AKT, p-AKT and p-mTOR were down-regulated significantly in the placenta. Our results demonstrated that prenatal fear-induced stress led to inhibition of the cellular signal transduction of placental PI3K/AKT/mTOR, which affected biological processes such as rRNA processing, translation, protein folding, protein stability, and oxygen transport in the placenta. These abnormalities in biological functions could potentially damage the barrier function of the placenta and thereby result in abnormal development in the offspring.

Adiponectin and Leptin during Pregnancy: A Systematic Review of Their Association with Pregnancy Disorders, Fetal Growth and Placental Function

During pregnancy, the adipokines leptin and adiponectin can affect placental nutrient transport and inflammatory pathways, potentially leading to altered fetal growth and pregnancy complications including gestational diabetes mellitus (GDM) and preeclampsia (PE). The aim of this systematic review is to gather and analyze research on maternal circulating leptin and adiponectin levels and their relationship to adverse pregnancy and birth outcomes. Additionally, it seeks to determine whether these hormones are linked to alterations in placental transporters and cell signaling pathways. PubMed and MEDLINE were systematically searched to include studies published between 2012 and 2022. All primary data studies reporting serum adiponectin and/or leptin, placental mRNA and protein levels of related transporters, and adverse birth outcomes were eligible. The current systematic review encompasses a total of 14 articles. Abnormal serum maternal leptin and adiponectin levels were associated with changes in fetal growth and placental cellular signaling and nutrient transporters. A majority of studies associated elevated maternal leptin and reduced adiponectin with fetal overgrowth, although this relationship was not consistent and may be complicated when other pathologies are present. The effects of maternal leptin and adiponectin on fetal growth may be driven by placental adaptation in nutrient transporters and mitochondria. Future studies should determine if the placental effects of leptin and adiponectin that have been found in models have mechanistic roles in human pregnancy.

Excessive hypercholesterolemia in pregnancy induces sex-specific differences in the placental unfolded protein response

Excessive hypercholesterolemia in pregnancy induces sex-specific differences in the placental unfolded protein response

Placental Origins of Preeclampsia: Insights from Multi-Omic Studies.

Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality worldwide, with the placenta playing a central role in disease pathophysiology. This review synthesizes recent advancements in understanding the molecular mechanisms underlying PE, focusing on placental genes, proteins, and genetic variants identified through multi-omic approaches. Transcriptomic studies in bulk placental tissue have identified many dysregulated genes in the PE placenta, including the PE signature gene, Fms-like tyrosine kinase 1 (FLT1). Emerging single-cell level transcriptomic data have revealed key cell types and molecular signatures implicated in placental dysfunction and PE. However, the considerable variability among studies underscores the need for standardized methodologies and larger sample sizes to enhance the reproducibility of results. Proteomic profiling of PE placentas has identified numerous PE-associated proteins, offering insights into potential biomarkers and pathways implicated in PE pathogenesis. Despite significant progress, challenges such as inconsistencies in study findings and lack of validation persist. Recent fetal genome-wide association studies have identified multiple genetic loci associated with PE, with ongoing efforts to elucidate their impact on placental gene expression and function. Future directions include the integration of multi-omic data, validation of findings in diverse PE populations and clinical subtypes, and the development of analytical approaches and experimental models to study the complex interplay of placental and maternal factors in PE etiology. These insights hold promise for improving risk prediction, diagnosis, and management of PE, ultimately reducing its burden on maternal and neonatal health.

Placental Protein 13: Vasomodulatory Effects on Human Uterine Arteries and Potential Implications for Preeclampsia.

Placental protein 13 (PP13) exhibits a plasma concentration that increases gradually during normal gestation, a process that is disrupted in preeclampsia, which is characterized by elevated vascular resistance, reduced utero-placental blood flow, and intrauterine growth restriction. This study investigated PP13's role in vascular tone regulation and its molecular mechanisms. Uterine and subcutaneous arteries, isolated from both pregnant and non-pregnant women, were precontracted with the thromboxane analogue U46619 and exposed to PP13 using pressurized myography. The molecular mechanisms were further investigated, using specific inhibitors for nitric oxide synthase (L-NAME+LNNA at 10-4 M) and guanylate cyclase (ODQ at 10-5 M). The results showed that PP13 induced vasodilation in uterine arteries, but not in subcutaneous arteries. Additionally, PP13 counteracted U46619-induced vasoconstriction, which is particularly pronounced in pregnancy. Further investigation revealed that PP13's mechanism of action is dependent on the activation of the nitric oxide-cGMP pathway. This study provides novel insights into the vasomodulatory effects of PP13 on human uterine arteries, underscoring its potential role in regulating utero-placental blood flow. These findings suggest that PP13 may be a promising candidate for improving utero-placental blood flow in conditions such as preeclampsia. Further research and clinical studies are warranted to validate PP13's efficacy and safety as a therapeutic agent for managing preeclampsia.

Dietary sodium sulphate supplementation during mid-to-late gestation improves placental angiogenesis, bile acid metabolism, and serum amino acid concentrations of sows

Sulphate plays a vital role in the growth and development of the foetus. Sodium sulphate (Na2SO4) is utilised as a dietary protein nutrient factor and helps replenish sulphur elements in livestock and poultry. Therefore, this study aimed to investigate the effects of Na2SO4 supplementation in mid to late pregnancy on bile acid metabolism, amino acid metabolism, placental vascular development and antioxidant capacity of sows. At day 1 of gestation (G1), a total of twenty-six primiparous sows were carefully chosen and randomised into two groups: (1) control group, (2) Na2SO4 group (1.40 g/kg). Blood samples and placentas from sows were collected to measure biochemistry parameters, antioxidant indexes, placental vascular density, and indicators related to bile acid metabolism and amino acid concentrations, respectively. We found that dietary supplementation with Na2SO4 had a tendency for a reduction of incidence of stillborn at farrowing. Further observation showed that sows supplemented with Na2SO4 had decreased total bile acid level in cord blood, and increased placental gene expression of sulphotransferase and organic anion transport peptide. Na2SO4 supplementation increased catalase and total superoxide dismutase activity in cord blood, decreased placental malondialdehyde content, and enhanced placental protein expression of Sirtuin 1. Moreover, Na2SO4 consumption resulted in increased vascular density of placental stroma and elevated amino acid levels in sows and cord blood. Furthermore, maternal Na2SO4 consumption reduced serum urea concentrations of sows and umbilical cord blood at G114. In addition, dietary supplementation with Na2SO4 activated the protein expression of the placental mechanistic target of rapamycin complex 1. Collectively, these findings indicated that maternal supplementation with Na2SO4 during mid-to-late gestation elevated foetal survival via improving placental angiogenesis, bile acid metabolism and amino acid utilisation.

Placental Protein 13 and Syncytiotrophoblast Basement Membrane Ultrastructures in Preeclampsia.

Background and Objectives: Preeclampsia has been linked to an inflammatory response that may be brought on by endothelial cell dysfunction. This paper investigates the pathomechanism of syncytiotrophoblast basement membrane (STBM) damage and Placental Protein 13 (PP13) release, which may have a role in systemic endothelial dysfunction in preeclampsia. Materials and Methods: This comparative cross-sectional study involves 54 preeclampsia patients (27 early-onset preeclampsia and 27 late-onset preeclampsia) and 27 pregnant women with normal blood pressure. An enzyme-linked immunosorbent assay was performed to evaluate maternal blood levels of PP13. Following birth, a portion of the placenta was collected for transmission electron microscope (TEM) and immunohistochemical (IHC) analysis. The data were analyzed using STATA version 15. Results: PP13 expression in the placental syncytiotrophoblast was significantly lower in the early-onset preeclampsia, compared to late-onset preeclampsia and normotensive pregnancy, group (p < 0.001). In contrast, serum PP13 levels were found to be the highest in the early-onset preeclampsia group, although no significant difference were found in mean maternal serum levels of PP13 between the three groups. The decreased PP13 expression in placental syncytiotrophoblast can be attributed to the greater extent of damage in the STBM in early-onset preeclampsia that leads to the release of a larger amount of PP13 into maternal circulation. The hypothesis aligns with the TEM analysis results. Preeclamptic pregnancies showed placental syncytiotrophoblast aponeurosis, whereas normotensive pregnancies did not. Placental lesions and STBM shedding were found to be more pronounced in early-onset preeclampsia compared to late-onset preeclampsia. Conclusions: PP13 and STBM damage may play a role in systemic endothelial dysfunction in preeclampsia.

Методологія профілактики великих акушерських синдромів

Aim - to develop a method of prevention of major obstetric syndromes (MOS) from the standpoint of a single genesis determined by morphofunctional disorders in the fetoplacental system (FPS), with an assessment of effectiveness by methodological standards of evidence-based medicine Materials and methods. The group I - 32 pregnant women, prevention of MOS was carried out with low doses of acetylsalicylic acid (ASA) at 100-150 mg per os once a day, from 12 to 36 weeks of pregnancy; the group II - 31 pregnant women, who from 6 to 16 weeks were treated prophylactically with progesterone according to the scheme: 200 mg 1 time per day per vagina every day; the group III - 36 pregnant women who received prophylactic monotherapy, consisting of taking magnesium in combination with vitamin B6 for three courses of 6 weeks each; the group IV - 56 pregnant women who refused any preventive measures; the control group (CG) - 50 healthy pregnant women. Тhe effectiveness of prophylactic therapy was evaluated by dynamic examination of the pregnant groups of the study, which included the determination of the following indicators: placental alpha microglobulin (PAMG); placental growth factor; placental protein (PAPP-A), blood leukocyte elevation index, allergy index, concentration of magnesium in blood serum. To objectify the effectiveness of the developed method, the standards of evidence-based medicine were applied. Statistical processing of research results was carried out using standard Microsoft Excel 5.0 and Statistical 6.0 programs. Results. In pregnant women of the group IV, the level of the fibronectin (521±17 μg/ml) increased by an average of 17%, compared to patients of the groups I-III (355±12 μg/ml, 361±13 μg/ml, 368±16 μg/ml; p&lt;0.05), which led to a subsequent increase in the frequency of spontaneous premature births in patients of the group IV; the level of PAMG exceeds the value in the CG by 7.7 times in the group IV; in the group III by 1.7 times, and in pregnant women of groups I and II, it was 25.2±3.8 ng/ml and 26.4±4.2 ng/ml, respectively, against 177±18 ng/ml in group IV (p&lt;0.05). The concentration of the PAPP-A was reduced from the early stages of pregnancy in all studied groups - 6.9±1.8 mg/l, 8.8±1.9 mg/l, 9.2±2.1 mg/l, 7.5±1.6 mg/l (according to the groups I-IV) versus 15.7±2.5 mg/l in the CG (р&lt;0.05). When using the magnesium drug (III group), there are differences with the group IV in most indicators. Conclusions. Methods for the prevention of a complicated course in the high-risk groups for the development of vasculitis when studying personalized and predictive value, which made it possible to divide them in order from more effective to less effective: the method with the appointment of low doses of ASA was in the first place; on the II - prophylactic appointment of micronized vaginal progesterone; on the III - the use of magnesium. The research was conducted according to principles of Declaration of Helsinki. Protocol of research was proved by local ethical committee, mentioned in institution’s work. A informed sonsennt was collected in order to carry out the research. The author is stating no conflict of interests is declared.

Manganese porphyrin-based treatment improves fetal-placental development and protects against oxidative damage and NLRP3 inflammasome activation in a rat maternal hypothyroidism model

Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP]5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1β, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.

Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes

AbstractIntravitreal anti–vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti–placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0–12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Association between maternal iron status and the risk of pre-eclampsia: a case-control study.

This study aimed to assess the associations of maternal iron status and placental iron transport proteins expression with the risk of pre-eclampsia (PE) in Chinese pregnant women. A total of 94 subjects with PE and 112 healthy pregnant women were enrolled. Fasting blood samples were collected to detect maternal iron status. The placenta samples were collected at delivery to detect the mRNA and protein expression of divalent metal transporter 1 (DMT1) and ferroportin-1 (FPN1). Logistic analysis was used to explore the associations of maternal iron status with PE risk. The associations of placental iron transport proteins with maternal iron status were explored. After adjusting for covariates, dietary total iron, non-heme iron intake and serum hepcidin were negatively associated with PE, with adjusted ORs (95%CIs) were 0.40 (0.17, 0.91), 0.42 (0.18, 0.94) and 0.02 (0.002, 0.13) for the highest versus lowest tertile, respectively. For the highest tertile versus lowest tertile, serum iron (4.08 (1.58, 10.57)) and ferritin (5.61 (2.36, 13.31)) were positively associated with PE. The mRNA expressions and protein levels of DMT1 and FPN1 in placenta were up-regulated in the PE group (p < 0.05). The mRNA expressions of DMT1 and FPN1 in placenta showed a negative correlation with the serum hepcidin (r = -0.71, p < 0.001; r = -0.49, p < 0.05). In conclusion, the maternal iron status were closely associated with PE risk, placental DMT1 and FPN1 were upregulated in PE which may be a promising target for the prevention of PE.

Differential proteomics of circulating extracellular vesicles of placental origin isolated from women with early-onset preeclampsia reveal aberrant innate immune and hemostasis processes.

Early-onset preeclampsia (EOPE) is a severe gestational hypertensive disorder with significant feto-maternal morbidity and mortality due to uteroplacental insufficiency. Circulating extracellular vesicles of placental origin (EV-P) are known to be involved in the pathophysiology of EOPE and might serve as an ideal reservoir for its specific biomarkers. Therefore, we aimed to characterize and perform comparative proteomics of circulating EV-P from healthy pregnant and EOPE women before delivery. The EV-P from both groups were isolated using immunoaffinity and were characterized using transmission electron microscopy, dynamic light scattering, nanoparticle tracking analysis, and immunoblotting. Following IgG albumin depletion, the pooled proteins that were isolated from EV-P of both groups were subjected to quantitative TMT proteomics. Circulating term EV-P isolated from both groups revealed ∼150nm spherical vesicles containing CD9 and CD63 along with placental PLAP and HLA-G proteins. Additionally, the concentration of EOPE-derived EV-P was significantly increased. A total of 208 proteins were identified, with 26 among them being differentially abundant in EV-P of EOPE women. This study linked the pathophysiology of EOPE to 19 known and seven novel proteins associated with innate immune responses such as complement and TLR signaling along with hemostasis and oxygen homeostasis. The theory suggesting circulating EVs of placental origin could mimic molecular information from the parent organ-"the placenta"-is strengthened by this study. The findings pave the way for possible discovery of novel prognostic and predictive biomarkers as well as provide insight into the mechanisms driving the pathogenesis of EOPE.

In Utero Overnutrition Influences Placental Nutrient Transport and Fetal Overgrowth

Obesity is defined as a body mass index (BMI) ≥30 kg/m2. Forty-three percent of women of childbearing age are obese, with a greater prevalence noted in Black women. Obesity increases the risk of diabetes (Type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM)). Obesity and diabetes are chronic states of overnutrition and metabolic dysregulation, each associated with an increased risk of macrosomia (large weight for gestational age in offspring). Macrosomia not only increases pregnancy complications but also increases the risk of metabolic disorders throughout the lifespan of the offspring. Fetal growth in utero is mediated by the nutritional environment and nutritional transport across the placenta. Maternal-fetal nutrient transport is primarily mediated by placental transporters for glucose, amino acids, free fatty acids, and cholesterol in the syncytiotrophoblast of the placenta. Yet, the mechanistic pathway driving fetal overgrowth in environments of overnutrition are not well defined. Therefore, we will test the hypothesis that diabetes (T2DM or GDM) exacerbates placental nutrient transport and fetal overgrowth in Black pregnant women with obesity. To evaluate the combined influence of obesity and diabetes (T2DM or GDM) on fetal growth, we evaluated n=100 electronic medical records of Black obese women with and without diabetes (T2DM or GDM) from 2012-2022 at the University of Mississippi Medical Center (UMMC). These women were singleton pregnancies with no additional underlying conditions. Gestational age of offspring and maternal age were similar among all groups. This study was approved by the Institutional Review Board at UMMC (IRB-UMMC-2021-0455). We found that Black obese women with diabetes (n=43) had higher BMIs compared to Black women with obesity alone (n=57) (43.50 ± 4.76 kg/m2 vs. 39.19 ± 3.48 kg/m2) (p&lt;0.05), indicating that obesity increases risk of diabetes in Black pregnant women. Additionally, offspring from Black obese women with diabetes had elevated birthweight compared to offspring from women with obesity alone (3345 ± 614.6 g vs. 3099 ± 465.4 g; p&lt;0.05). Male offspring from Black obese women with diabetes had elevated birthweight (3460 ± 695.8 g) compared to female offspring from Black obese women without diabetes (3068 ± 439.8 g) (p&lt;0.05), suggesting the maternal nutritional environment influences males more than females. Yet, the type of diabetes, T2DM or GDM, did not influence birthweight in offspring from Black obese women (T2DM: 3412 ± 743.5 g vs GDM: 3271 ± 439.7 g). To evaluate the influence of obesity plus diabetes on placental nutrient transport, we measured placental protein expression of glucose transporter-1 (Glut-1), a primary glucose transporter in the placenta, in a separate subset of placental tissue from Black obese women with and without diabetes (IRB-UMMC-2019-0058). Protein expression of Glut-1 was increased in placental tissue from Black women with obesity and diabetes (n=4) compared to Black women with obesity alone (n=4) (20.38 ± 5.87 A.U. vs. 9.41 ± 1.46 A.U.; p&lt;0.05). However, BMI was elevated in the group of women with obesity and diabetes compared to obesity alone (49.565 ± 1.39 kg/m2 vs. 43.44 ± 2.44 kg/m2; p&lt;0.05), again indicating that obesity increases risks of diabetes in Black pregnant women. This study indicates that combined obesity with diabetes during pregnancy is associated with increased birthweight and placental protein expression of Glut-1. Additional studies are warranted to decipher the separate influences of elevated BMI and diabetes on fetal growth, along with the associated placental mechanisms that influence nutrient transport and fetal growth in pregnancies complicated by obesity and diabetes. UMMC Department of OBGYN. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Receptor-recognition and antiviral mechanisms of retrovirus-derived human proteins.

Human syncytin-1 and suppressyn are cellular proteins of retroviral origin involved in cell-cell fusion events to establish the maternal-fetal interface in the placenta. In cell culture, they restrict infections from members of the largest interference group of vertebrate retroviruses, and are regarded as host immunity factors expressed during development. At the core of the syncytin-1 and suppressyn functions are poorly understood mechanisms to recognize a common cellular receptor, the membrane transporter ASCT2. Here, we present cryo-electron microscopy structures of human ASCT2 in complexes with the receptor-binding domains of syncytin-1 and suppressyn. Despite their evolutionary divergence, the two placental proteins occupy similar positions in ASCT2, and are stabilized by the formation of a hybrid β-sheet or 'clamp' with the receptor. Structural predictions of the receptor-binding domains of extant retroviruses indicate overlapping binding interfaces and clamping sites with ASCT2, revealing a competition mechanism between the placental proteins and the retroviruses. Our work uncovers a common ASCT2 recognition mechanism by a large group of endogenous and disease-causing retroviruses, and provides high-resolution views on how placental human proteins exert morphological and immunological functions.