Search Results (182)

Congenital Chagas disease (CCD) is caused when Trypanosoma cruzi crosses the placental barrier during pregnancy and reaches the fetus, which can lead to serious consequences in the developing fetus. Current treatment is carried out with nifurtimox or benznidazole, but their effectiveness is limited, and they cause side effects, requiring the search for new therapeutic strategies. In this sense, many studies have demonstrated the potential of different compounds of the Copaifera genus in the control of parasitic diseases. Here, we aimed to evaluate the effect of oleoresin (OR) and leaf hydroalcoholic extract (LHE) of Copaifera multijuga on Trypanosoma cruzi infection in human villous trophoblast cells (BeWo line) and human placenta explants. Treatment with both compounds reduced invasion, proliferation, and release of trypomastigotes. Furthermore, OR and LHE affected the trypomastigotes and amastigote morphology, compromising their ability to invade and proliferate in BeWo cells, respectively. Also, treatment with OR decreased ROS production in infected BeWo cells, while LHE induced an increase. In addition, both compounds induced pro-inflammatory and anti-inflammatory cytokine production. In human placental explants, both compounds also decreased T. cruzi infection, in addition to inducing the production of pro-inflammatory cytokines. Thus, both OR and LHE of C. multijuga control T. cruzi infection at the human maternal–fetal interface, highlighting the possible therapeutic potential of these compounds for the treatment of CCD. Full article

Background/Objectives: Intrauterine growth restriction (IUGR) is a pathological condition defined by a reduced fetal ability to achieve the genetically expected growth potential during gestation. It affects 5–10% of all pregnancies and it is a leading cause of perinatal morbidity and mortality. During the initial phases of placentation, complex interlinked processes including cell proliferation, differentiation, apoptosis and the invasion of trophoblasts occur. Alterations in the regulation of these processes lead to placental dysfunction. Survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in cell proliferation balance and apoptosis, thus leading to proper placental development. This study aimed to evaluate survivin expression in placentas from IUGR and healthy pregnancies to explore its potential as a biomarker for the early diagnosis, prevention, and treatment of IUGR. Methods: Survivin presence was determined in 153 archival formalin-fixed and paraffin-embedded placental tissues from IUGR (N = 122) and uncomplicated (N = 31) term pregnancies. Tissue microarrays (TMAs) were constructed, and survivin expression was assessed using immunohistochemistry (IHC). Survivin levels were quantified using positive cell proportion (PCP) scores and immunoreactive scores (IRS), with statistical significance determined using mean values, standard deviation (SD), standard error, and Student’s t test in instances of normal distribution, and when this was not the case, the Mann–Whitney test. Chi-square tests, Fisher exact tests, and t-tests (p < 0.05) were used to compare categorical variables. Results: Our results suggested the significantly higher expression of survivin validated with PCP (p < 0.001) and IRS (p < 0.002) in placentas with IUGR compared to placentas from non-complicated term pregnancies. Conclusions: Increased survivin expression in IUGR placentas points to its potential role as a key indicator of placental dysfunction. By signaling early pathological changes, survivin may offer a valuable tool for the early detection of IUGR, potentially allowing for timely clinical interventions that could reduce the risk of serious outcomes, including stillbirth. To fully establish survivin’s clinical value, further research is needed to validate its diagnostic accuracy and to explore its involvement in molecular pathways that may be targeted for therapeutic benefit. Full article

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to major obstetric pathologies, including placenta accreta spectrum, early onset preeclampsia, and fetal growth restriction. Characterization of the normal differentiation processes is, thus, essential for the analysis of these pathologies. Our gene expression analysis, employing purified human CTB and EVT cells, demonstrates a mechanism similar to the epithelial–mesenchymal transition (EMT), which underlies CTB–EVT differentiation. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. A small subgroup of genes undergoes gains of methylation (GOM), associated with differential gene expression (DE). Prominent in this GOM-DE group are genes involved in epithelial–mesenchymal plasticity (EMP). An exemplar is the transcription factor RUNX1, for which we demonstrate a functional role in regulating the migratory and invasive capacities of trophoblast cells. This analysis highlights epigenetically regulated genes acting to underpin the epithelial–mesenchymal plasticity characteristic of human trophoblast differentiation. Identification of these elements provides important information for the obstetric disorders in which these processes are dysregulated. Full article

To clarify the physiological importance of the tryptophan catabolizing enzyme, indoleamine 2,3-dioxygenase, in human pregnancy, we have studied how the expression of this enzyme controls extravillous cytotrophoblast invasion into the decidua. We have generated an Ishikawa cell line stably transfected with a plasmid encoding indoleamine 2,3-dioxygenase under the control of a tetracycline inducible promoter. Using this Ishikawa cell line and extravillous cytotrophoblast cell line, HTR-8/SVneo, we developed a quantitative in vitro trophoblast invasion assay. When trophoblast cells were cultured on a layer of Ishikawa cells expressing indoleamine 2,3-dioxygenase, tryptophan degradation was enhanced and trophoblast cell invasion was suppressed. These findings suggest that indoleamine 2,3-dioxygenase expressed in the decidua may play a role in regulating trophoblast invasion. Full article

Placenta accreta spectrum (PAS) refers to a group of abnormal placental attachments in which the placenta adheres too deeply to the uterine wall, with varying degrees of invasion classified as accreta, increta, or percreta. Increased rates of uterine surgeries, advanced maternal age, and cesarean deliveries have all contributed to an increase in the incidence of PAS. Complications associated with PAS can lead to severe intrapartum or postpartum hemorrhage, hysterectomy, and significant maternal morbidity, making early diagnosis and management crucial for improving outcomes. Understanding the epidemiology and risk factors of PAS is crucial for developing early detection protocols and preventive strategies. Localized data, particularly from Bahrain, can inform targeted care approaches and optimize resource allocation, ultimately leading to improved clinical guidelines, enhanced patient education, and better healthcare outcomes for affected women. There are growing concerns about the impact of PAS on maternal health and healthcare resources in Bahrain, similar to trends observed in other regions. To improve patient education and management strategies, it is essential to comprehend the regional patterns, characteristics, and outcomes associated with PAS. However, the absence of comprehensive data specific to Bahrain hinders effective clinical decision-making and policy development. Addressing this gap is imperative for advancing maternal healthcare in the region. Full article

Background: Preeclampsia (PE) is a pregnancy-specific disorder and a leading cause of maternal and fetal morbidity and mortality. Impaired trophoblast invasion is a hallmark of PE, and alternative splicing (AS) is crucial for trophoblast differentiation and placental development. However, the exact mechanisms of AS in PE remain poorly understood. Methods: To elucidate AS-mediated regulatory pathways in PE, a total of 38 fresh-frozen placental samples, including 13 pre-eclampsia samples and 25 normal control samples, were collected from Renmin Hospital of Wuhan University between 1 February and 30 July 2022. We performed transcriptome sequencing of seven PE and seven normal placentas to identify differentially spliced events. After quality control and adapter trimming, raw sequencing reads were aligned to the human reference genome using STAR. Differential exon usage was analyzed using DEXSeq (version 1.36.0), and exons with an adjusted p-value < 0.05 and a fold change greater than 2 or less than 0.5 were considered significantly differentially spliced. Functional assays, including CCK8, colony formation, and cell cycle analyses, were conducted to assess trophoblast proliferation, whereas wound healing and Transwell assays were used to evaluate trophoblast migration and invasion using the HTR-8/SVneo cell line. RNA immunoprecipitation sequencing (RIP-seq) and RNA stability assays were employed to investigate mRNA interactions and stability. Results: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) emerged as a key RNA-binding protein associated with alternative splicing regulation, intersecting both AS-related candidate genes and known splicing factors, although it is not a classical splicing factor itself. IGF2BP3 overexpression markedly enhanced HTR-8/SVneo trophoblast proliferation, migration, and invasion while suppressing ROS activation. RNA-seq, RIP-seq, and RNA stability assays revealed that IGF2BP3 directly interacts with and enhances the stability of PDE3A mRNA. Functional rescue experiments confirmed that PDE3A knockdown partially abrogated IGF2BP3-mediated trophoblast progression. Furthermore, miR-196a-5p was identified as a negative regulator of IGF2BP3 via miRNA inhibitor/mimic transfection, qRT-PCR, and functional assays, confirming that miR-196a-5p overexpression downregulates IGF2BP3, thereby impairing trophoblast migration and proliferation. Notably, restoring IGF2BP3 expression reversed these inhibitory effects. Conclusions: Our findings reveal a previously unrecognized regulatory axis in PE in which miR-196a-5p suppresses IGF2BP3 expression, leading to PDE3A mRNA destabilization and impaired trophoblast function. This study offers mechanistic insights into PE pathogenesis and identifies IGF2BP3 as a potential therapeutic target. Full article

Cats are different from dogs, and many questions remain open concerning the establishment of pregnancy. In cats, as in dogs, no feto-maternal signaling leading to establishment of pregnancy is known. But as opposed to dogs, the placenta is a source of steroid hormones and corticotropin-releasing hormone (CRH). Scarce information is available on physiological mechanisms at the uterine level during early gestation; more studies are needed on lymphocyte subsets, feto-maternal crosstalk and other mechanisms leading to local immunosuppression, allograft acceptance and embryo nidation and invasion. Recent studies investigate the function of extracellular vesicles (EVs); however, there is no study on embryo- or endometrium-derived EV. During pregnancy, anti-Müllerian hormone (AMH) serum concentrations were found to be higher than in non-pregnant cats, and a recent study found that supraphysiological levels may lead to pregnancy loss; the function of AMH during pregnancy warrants investigation. Most information is available on corpus luteum development and function, showing some similarities to dogs. Some information on maintenance of feline pregnancy was obtained by ovariectomy (OE) or the use of endocrine disruptors, showing that OE does not lead to pregnancy loss in all cases, especially when performed after day 35; the variable effect is still not fully understood. Antiprogesterone, dopamine agonists and prostaglandins were used in different dosages and treatment schemes and showed variable effect during the second half of gestation, highlighting progesterone and prolactin as key hormones for the maintenance of gestation. Some events during early gestation are comparable with the canine species, even though they appear earlier, like the entrance of the zygote into the uterus and implantation; however, significant differences are present concerning the histomorphology of the placenta and, in a few cases, even the gross morphology as in some cats, where the zonary placenta does not completely surround the fetus. Sonographical monitoring of feline pregnancy requires knowledge of species-specific developmental steps and the differential appearance of fetal and maternal structures in comparison with dogs. Full article

Background/Objectives: Marinobufagenin (MBG) is a biomarker that is found to be high in pre-eclampsia (preE), and thus is relevant in the pathogenesis of obstetric complications. MBG is thought to possibly be implicated in harmful signaling within cytotrophoblasts (CTBs) of the placenta. In this study, we evaluated how anti-MBG human monoclonal antibody can alter cellular signaling in CTBs and in a rat model of preE. Methods: CTB cell proliferation, migration, and invasion as a result of MBG, both with and without anti-MBG present, were monitored via cell-based studies. Pro-angiogenic and anti-angiogenic factors in response to MBG with and without antibody were measured. Finally, we evaluated the lead anti-MBG antibody in comparison with the parent murine antibody in a rat model of preE. Results: CTB cells exposed to ≥1 nM MBG showed decreased (p < 0.05) proliferation, migration, and invasion, decreased secretion of VEGF and PIGF, and increased secretion of sFlt-1 and sEng. Pretreatment with anti-MBG significantly (p < 0.05) attenuated MBG-induced CTB dysfunction and modulation of VEGF, PIGF, sFlt-1, and sEng expression. In the rat model, anti-MBG treatment normalized blood pressure, reduced proteinuria, and eliminated fetal effects. Conclusions: MBG is a potential causative agent for preE, as it causes dysfunction in CTBs due to anti-angiogenic milieu. Our study suggests that anti-MBG antibody binds to MBG, neutralizing it and preventing downstream signaling in vitro. In a rat model of preE, treatment with anti-MBG antibody was effective at normalizing blood pressure, kidney function, and fetal birth weights. These data suggest that a human monoclonal antibody with high specificity and affinity for MBG has potential as a therapeutic agent for preE. Full article

Apoptosis is critical in placental development, and its dysregulation is linked to pregnancy complications such as intrauterine growth restriction (IUGR) and preeclampsia (PE). Environmental exposures, particularly secondhand smoke (SHS) and e-cigarettes (eCigs), may contribute to placental dysfunction through apoptotic pathways. This study examined the effects of SHS and eCig exposure on placental apoptosis and growth-regulatory proteins in a murine model. C57BL/6 pregnant mice were exposed to SHS or eCigs at two critical gestational time points: early trophoblast invasion (E12.5 to E18.5) and established invasion (E14.5 to E18.5). Placental tissues were collected and analyzed for pro-apoptotic and anti-apoptotic markers, heat shock proteins, insulin-like growth factor-binding proteins (IGFBPs), and growth regulators. SHS exposure increased pro-apoptotic markers (BAD, Fas/FasL) and decreased mitochondrial function markers (cytochrome c), indicating compromised cellular survival. Both SHS and eCig exposure reduced anti-apoptotic markers (BCL-2, HSP27, survivin) and growth regulators (IGF-1, IGFBPs). SHS and eCig exposure create a pro-apoptotic environment in the placenta, potentially impairing fetal development through altered apoptotic and growth-regulatory pathways. These findings underscore the risks of environmental exposures during pregnancy, highlighting the need for strategies to minimize maternal exposure to SHS and eCigs. Full article

Preeclampsia (PE) is a multifactorial hypertensive disorder that typically manifests after the twentieth week of pregnancy, significantly impacting perinatal mortality and neonatal morbidity. Its development is influenced by immunological components, systemic inflammation, and genetic factors, with placental malfunction playing a crucial role. While many aspects of its pathophysiology have been elucidated, its key mechanisms remain incompletely understood. MicroRNAs (miRNAs), small noncoding RNA molecules that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in PE. Dysregulated miRNAs have been identified in pregnant PE patients, highlighting their role in disease onset. Placenta-specific miRNAs, such as miR-210 and miR-155, influence inflammation, endothelial function, and hypoxia responses, which are closely associated with PE development. These miRNAs play a crucial role in regulating trophoblast invasion, angiogenesis, and immune modulation, further linking their dysregulation to the pathophysiology of PE. This review aims to provide a comprehensive overview of the role of miRNAs in PE, focusing on their potential as diagnostic biomarkers and therapeutic targets. By integrating recent advancements in molecular research, we explore their implications in clinical practice, particularly in risk assessment, early detection, and novel treatment strategies. Full article

Placental samples for RNA extraction are collected via non-recovery (euthanasia) or invasive (surgery) methods in small ruminants, such as sheep. Alternatively, delivered placentas could be used, but the feasibility of obtaining high-quality RNA from this tissue is unknown in sheep. We aimed to evaluate the possibility of extracting RNA from naturally delivered ovine placenta, comparing two preservation methods. Twenty-seven single-pregnant sheep were monitored 24/7 from gestational day 140 to parturition. Tissue was collected after placental delivery, preserved using snap frozen (SF, n = 27) and RNAlater^® (LTR, n = 27) techniques, and processed for RNA extraction using a commercial kit. RNA concentration (ng/µL), A260/280, and RNA quality number (RQN) were measured. Concentration was higher (p < 0.001) in LTR (70.39 ± 6.3) than in SF (49.77 ± 10.5), A260/280 was higher (p = 0.045) in SF (2.06 ± 0.01) than in LTR (2.03 ± 0.01), and RQN was higher (p < 0.0001) in SF (6.81 ± 0.24) than in LTR (2.84 ± 0.24) samples. Timing of placental delivery did not affect the evaluated indicators. Results indicate that extracting high-quality RNA from delivered placentas preserved via the snap-frozen technique is possible, supporting a method that aligns with the refinement principle of animals used in research. Full article

Placenta accreta spectrum (PAS) involves abnormal placental attachment and can lead to severe complications such as postpartum hemorrhage and hysterectomy. Ultrasound is the main tool used to screen for PAS due to its non-invasive nature and convenience, although its accuracy depends on the skill of the operator. Magnetic Resonance Imaging has emerged as a supplementary tool, especially for complex cases or posterior placentas, providing more accurate anatomical detail and enabling the invasion depth and location to be assessed. This review summarizes recent advances in prenatal imaging for PAS, aiming to improve diagnostic accuracy and guide future research. Full article

The vector of modern obstetrics is aimed at finding ways to predict various placenta-associated complications, including those associated with neuronal dysfunction on in fetal growth restriction (FGR). The technology of fetal neuronal exosome (FNE) isolation from the maternal bloodstream opens up unique opportunities for detecting early signs of fetal brain damage. Using this method, FNEs were isolated from the blood of pregnant women with and without early-onset FGR, and the expression of a number of proteins in their composition was assessed (Western blotting). Significant changes in the level of proteins involved in neurogenesis (pro-BDNF (brain-derived neurotrophic factor), pro-NGF (nerve growth factor), TAG1/Contactin2) and presynaptic transmission (Synapsin 1, Synaptophysin) were revealed. The preliminary data on the expression of FNE proteins that perform post-translational modifications—sumoylation (SUMO 1, UBC9) and neddylation (NEDD8, UBC12)—were obtained. A relationship was established between altered protein expression and neonatal outcomes in newborns with growth restriction. Our study opens up new possibilities for non-invasive prenatal monitoring of fetal neurodevelopment disorders and possibilities of their correction in placenta-associated diseases. Full article

Background: Disruptions in epigenetic mechanisms regulating placentation, particularly imbalances in the levels of small non-coding RNAs, contribute to various pregnancy complications, including preeclampsia (PE) and placenta accreta spectrum (PAS). Given that abnormal trophoblast differentiation, invasiveness, and angiogenesis—reduced in PE and excessive in PAS—are central to the pathogenesis of these conditions, this study aimed to identify universal circulating piRNAs and their targets. Methods: Small RNA deep sequencing, quantitative reverse transcription combined with real-time polymerase chain reaction, magnetic bead-based multiplex immunoassay, ELISA, and Western blotting were employed to quantify circulating piRNAs and proteins in the blood serum of pregnant women during the 11th–14th weeks of gestation. Results: Statistically significant negative correlations were identified between PE- and PAS-associated piRNAs (hsa_piR_019122, hsa_piR_020497, hsa_piR_019949, and piR_019675) and several molecules, including Endoglin, IL-18, VEGF-A, VEGF-C, Angiopoietin-2, sFASL, HB-EGF, TGFα, and Clusterin. These molecules are involved in processes such as angiogenesis, inflammation, the epithelial–mesenchymal transition, cell proliferation, adhesion, and apoptosis. A first-trimester pregnancy screening algorithm was developed using logistic regression models based on Clusterin concentration and the levels of hsa_piR_020497, hsa_piR_019949, piR_019675, and hsa_piR_019122. Conclusions: The proposed screening tool for early pregnancy monitoring may enable the prediction of PE or PAS in the first trimester, allowing timely interventions to reduce maternal and perinatal morbidity and mortality. Full article

Background: Placenta accreta spectrum (PAS) refers to abnormal placental attachment, categorized into placenta accreta, increta, and percreta, with varying severity. The incidence of PAS has risen alongside the increasing rate of caesarean sections. PAS is a significant cause of maternal complications, including bleeding, hysterectomies of necessity and intestinal or urinary surgical complications, and of foetal complications, preterm birth or foetal anaemia. Early diagnosis is crucial for its management and for improving its outcomes. Materials and Methods: This retrospective study, conducted at the County Emergency Clinical Hospital “Saint Andrew the Apostle”, Constanța, analysed cases of placenta praevia and PAS from 2018 to 2022. Data were collected from observation sheets and operative protocols, involving 13,841 patients. Placenta praevia and PAS were diagnosed using ultrasound and MRI and confirmed by histopathology. Results: Among the 13,841 deliveries, 25 cases of placenta praevia (0.82% incidence) and 17 cases of PAS (0.57% incidence) were identified. Ultrasound demonstrated 88% sensitivity, and MRI 94% sensitivity for PAS detection. Of the 17 PAS cases, 11 were diagnosed as placenta accreta, 3 were diagnosed as placenta increta, and 3 as placenta percreta, with all percreta cases involving bladder invasion. Hysterectomy was the standard surgical treatment. Discussion: The risk factors for PAS included previous caesarean sections (94.1% of PAS cases), smoking, and uterine fibroids. The study confirmed the importance of early imaging and the involvement of a multidisciplinary team in managing PAS, particularly in complex cases with bladder involvement. Caesarean section followed by hysterectomy was the preferred surgical approach. Conclusions: Smoking, uterine scars, and uterine fibroids are significant risk factors for placenta praevia with pathological adhesion. Ultrasound and MRI are highly accurate in diagnosing PAS, with histopathology providing definitive confirmation. Multidisciplinary care is essential in managing complex cases, ensuring optimal maternal and foetal outcomes. The surgical treatment involves caesarean section and hysterectomy, with additional interventions for bladder invasion in percreta cases. Full article