Preeclampsia Patients Research Articles

Higher Trace Elements and Lower Fatty Acids Levels in Erythrocytes as Predictors of Preeclampsia

BACKGROUND: Preeclampsia is one of the common causes of maternal death in Indonesia. Many studies only focus on the diagnosis and pharmacological treatment of preeclampsia. However, predictors of preeclampsia need to be observed to add more focus on the etiology and prevention of preeclampsia. The imbalances of trace elements and fatty acids play an important role in preeclampsia. Therefore, this study was conducted to evaluate the status of trace elements and fatty acids in preeclampsia patients as predictors of preeclampsia.METHODS: A cross-sectional study was conducted in 3 hospitals, and involving 40 pregnant women classified into severe preeclampsia and normotensive groups. Trace elements and fatty acids were measured in serum and erythrocytes using Inductively Coupled Plasma and Gas Chromatography-Mass Spectrometry. Serum and erythrocytes fatty acid levels' cut-off value, sensitivity, and specificity were analyzed using Receiver Operating Characteristic (ROC) curve and Area Under the Curve (AUC) value.RESULTS: Serum selenium, manganese, and iron levels were significantly different in the preeclampsia group than in the controls (p<0.05). Of all the heavy metals, higher concentrations of cadmium, arsenic, lead, and mercury were found in preeclampsia groups compared to control. Linoleic acid showed the highest predictive value to increase severe preeclampsia with AUC of 0.8. The ratio of high omega-6/omega-3 increases the risk of preeclampsia.CONCLUSION: Selenium, manganese, iron, cadmium, arsenic, lead, and mercury levels are higher in the serum of preeclampsia patients. Almost all erythrocyte fatty acids were significantly higher in the control group compared to preeclampsia. Measurement of trace elements and fatty acids is needed as a predictor of preeclampsia. Erythrocyte fatty acids measurement is considered better than serum.KEYWORDS: trace elements, fatty acids, preeclampsia

Identification of hub genes, diagnostic model, and immune infiltration in preeclampsia by integrated bioinformatics analysis and machine learning

PurposeThis study aimed to identify novel biomarkers for preeclampsia (PE) diagnosis by integrating Weighted Gene Co-expression Network Analysis (WGCNA) with machine learning techniques.Patients and methodsWe obtained the PE dataset GSE25906 from the gene expression omnibus (GEO) database. Analysis of differentially expressed genes (DEGs) and module genes with Limma and Weighted Gene Co-expression Network analysis (WGCNA). Candidate hub genes for PE were identified using machine learning. Subsequently, we used western-blotting (WB) and real-time fluorescence quantitative (qPCR) to verify the expression of F13A1 and SCCPDH in preeclampsia patients. Finally, we estimated the extent of immune cell infiltration in PE samples by employing the CIBERSORT algorithms.ResultsOur findings revealed that F13A1 and SCCPDH were the hub genes of PE. The nomogram and two candidate hub genes had high diagnostic values (AUC: 0.90 and 0.88, respectively). The expression levels of F13A1 and SCCPDH were verified by WB and qPCR. CIBERSORT analysis confirmed that the PE group had a significantly larger proportion of plasma cells and activated dendritic cells and a lower portion of resting memory CD4 + T cells.ConclusionThe study proposes F13A1 and SCCPDH as potential biomarkers for diagnosing PE and points to an improvement in early detection. Integration of WGCNA with machine learning could enhance biomarker discovery in complex conditions like PE and offer a path toward more precise and reliable diagnostic tools.

NMF typing and machine learning algorithm-based exploration of preeclampsia-related mechanisms on ferroptosis signature genes

BackgroundGlobally, pre-eclampsia (PE) poses a major threat to the health and survival of pregnant women and fetuses, contributing significantly to morbidity and mortality. Recent studies suggest a pathological link between PE and ferroptosis. We aim to utilize non-negative matrix factorization (NMF) clustering and machine learning algorithms to pinpoint disease-specific genes related to the process of ferroptosis in PE and investigate likely underlying biochemistry mechanisms.MethodsThe acquisition of four microarray datasets from the Gene Expression Omnibus (GEO) repository, the integration of these datasets, and the elimination of batch effects formed the core procedure. Genes related to ferroptosis in PE (DE-FRG) were identified. NMF clustering was performed on DE-FRG for unsupervised analysis, generating a heatmap for clustering validation via principal component analysis. Immunocyte infiltration differences between different subtypes were compared to elucidate the impact of ferroptosis on immune infiltration in the placental tissue of PE patients. The application of weighted gene co-expression network analysis (WGCNA) revealed important module genes linked to sample subtypes and disease status. The screening of PE feature genes involved employing SVM, RF, GLM, and XGB machine learning algorithms, and their predictive performance was validated using various analyses and an external dataset. The iRegulon tool was utilized to predict upstream transcription factors associated with ferroptosis feature genes, from which differentially expressed transcription factors were screened to construct a "Transcription Factor—FRG—ferroptosis" regulatory network. Finally, in vitro (cultured cells) and in vivo (rat) models were utilized to evaluate the regulatory mechanisms of ferroptosis in normal and PE placental tissues.ResultsDifferential analysis of the four merged GEO datasets identified 41 DE-FRGs. NMF clustering based on DE-FRGs revealed two PE subtypes. Immunocyte infiltration analysis indicated significant differences in immune levels between these subtypes. Further WGCNA analysis identified module genes associated with PE and these two subtypes. Subsequently, we developed an integrated machine learning model incorporating five FRGs and validated its predictive efficacy using various analyses and an external validation dataset. Finally, based on the transcription factor ARID3A and ferroptosis feature genes EPHB3 and PAPPA2, we constructed a "Transcription Factor—FRG—ferroptosis" regulatory network, with in vitro and in vivo experiments confirming that ARID3A promotes the progression of PE and ferroptosis by activating the expression of EPHB3 and PAPPA2.ConclusionThis analytical journey illuminated a critical regulatory nexus in PE, underscoring the central influence of ARID3A on PE through ferroptosis-mediated pathways.Graphical Ferroptosis in Preeclampsia: ARID3A regulates ferroptosis by upregulating EPHB3 and PAPPA2, exacerbating oxidative stress in placental cells.Machine Learning Insights: Integration of bioinformatics and machine learning identified ferroptosis-related genes and their subtypes in preeclampsia.Immune Microenvironment Alterations: Ferroptosis-driven immune infiltration heterogeneity contributes to the progression of preeclampsia.Therapeutic Potential: Targeting the ARID3A-EPHB3/PAPPA2 axis could offer novel interventions for managing preeclampsia.

Evaluation of vascular peroxidase 1, humanin, MOTS-c and miR-200c expression levels in untreated preeclampsia patients.

The objective of this study was to evaluate the levels of Vascular Peroxidase 1 (VPO1), humanin, and MOTS-c in relation to miR-200c expression in untreated preeclamptic pregnancies, and to compare these findings with endoglin levels. In this study, blood samples were collected from preeclamptic patients presenting to the clinic prior to the initiation of treatment. The levels of endoglin, VPO1, humanin, and MOTS-c were measured using enzyme-linked immunosorbent assay (ELISA), while miR-200c expression was quantified using reverse transcription polymerase chain reaction (RT-PCR). Receiver operating characteristic (ROC) analysis was performed to assess diagnostic accuracy. Statistical significance was determined at p < 0.05. The levels of endoglin, VPO1, and miR-200c were found to be significantly elevated in the preeclampsia group compared to the control group (p < 0.05), whereas MOTS-c levels were significantly reduced (p < 0.05). No significant difference was observed in humanin levels between the two groups. A positive correlation was identified between endoglin levels and VPO1 (r = 0.943, p < 0.001), humanin (r = 0.421, p < 0.01), and uric acid (r = 0.314, p = 0.02) in the preeclamptic group. Our findings suggest that the elevation of VPO1 and miR-200c levels, along with the reduction of humanin and MOTS-c levels, may contribute to the increased endoglin levels and subsequent endothelial dysfunction observed in preeclampsia. These changes may be associated with the pathogenesis and severity of the disease.

Supporting the Characterization of Preeclampsia Patients Through Descriptive and Clustering Analysis

One of the most common causes of maternal death during pregnancy is preeclampsia. A deeper understanding of the patient’s features can aid in the hospital’s clinical care distribution. However, at the IESS Los Ceibos Hospital, these types of studies have not been carried out for preeclampsia. Therefore, in this work, we describe the application of descriptive and clustering analysis to characterize preeclamptic patients. Preeclamptic patients treated at the IESS Los Ceibos Hospital in Guayaquil comprised the dataset used in this study. Descriptive and clustering analysis allowed us to find that severe preeclampsia (O141) is the most common diagnosis when preeclamptic patients arrive at the hospitalization unit, representing 79.5% of the cases. Moreover, women whose maternal age falls between 26 and 35 years have the highest prevalence of preeclampsia, representing 55.4% of the cases. Finally, adult patients in their late 30s or older are often diagnosed with severe preeclampsia (O141) and often require many hours of hospital care during the first two visits. These findings will help to generate care and prevention policies, such as the use of a low dose of aspirin, in these age groups to avoid the complications that preeclampsia can cause.

Enhanced capture of preeclampsia-derived extracellular vesicles from maternal plasma by monocytes and T lymphocytes.

Released from trophoblast and other fetal cells, placental extracellular vesicles (EVs) reach the maternal peripheral blood and modulate immune responses. Increased EVs in plasma of preeclampsia (PE) patients indicate their involvement in the etiology of this condition. This study addresses the uptake of plasma EVs by peripheral blood mononuclear cells (PBMCs) and explores the underlying internalization mechanisms. Plasma EVs were isolated from women with normotensive pregnancy (EVNP) and those with PE (EVPE), and characterized by cryo-transmission electron microscopy, nanoparticle tracking analysis, Western blotting, flow cytometry, and micro bicinchoninic acid assay (micro-BCA). To investigate whether the origin of PBMCs affects uptake, samples from males, pregnant women, and non-pregnant women were included. Primary PBMCs and macrophages derived from the human leukemia monocytic cell line THP-1 were incubated with PKH-stained EVs, and uptake was assessed by flow cytometry and confocal microscopy. Key molecules involved in monocyte differentiation and macrophage function were evaluated in EV-treated cells using LEGENDplex™ assay and real-time polymerase chain reaction (RT-PCR). Independent of the PBMC source, EVs were mostly captured by monocytes and in a lower proportion by T lymphocytes. Capture of EVPE was higher than of EVNP in primary T lymphocytes, monocytes, and THP-1-derived macrophages. After inhibition by Wortmannin and Cytochalasin D, EV internalization by THP-1-derived macrophages was significantly inhibited but not completely abolished. No defined polarization profile of treated THP-1-derived macrophages could be identified. These findings provide evidence of EV modifications in PE, which enhance their uptake by monocytes and other immune cells, mainly through phagocytosis and endocytosis.

The role of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in determining the severity of pre-eclampsia in antenatal women: A case control study

Pre-eclampsia (PE) remains a significant global health concern, affecting 2-8% of pregnancies and contributing to maternal and perinatal morbidity and mortality. Characterized by hypertension and proteinuria after 20 weeks of gestation, PE often involves systemic inflammation and endothelial dysfunction. Its exact etiology is multifactorial, involving immune dysregulation and vascular abnormalities. Early identification of high-risk pregnant women is crucial to mitigate adverse outcomes. In India, PE affects 8-10% of pregnancies.Inflammatory markers such as the Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) have emerged as potential indicators of systemic inflammation. Elevated NLR and PLR levels in PE suggest a role in the disorder's pathophysiology, reflecting immune responses to placental ischemia and pro-inflammatory cytokine release.This study aims to compare NLR and PLR levels between PE patients and normotensive pregnant women, evaluate their association with PE severity, and discuss their potential as predictive biomarkers. A case-control study was conducted with 84 participants, following eligibility criteria via convenient sampling. Demographic characteristics, obstetric history, and CBC-derived biomarkers were assessed.Among 84 pregnant women, 42 had preeclampsia (PE) and 42 were normotensive. The PE group had significantly higher Neutrophil-to-Lymphocyte Ratios (5.11 ± 2.88 vs. 2.74 ± 0.78) and Platelet-to-Lymphocyte Ratios (108 ± 46.7 vs. 85.4 ± 29.4) compared to controls. PE incidence peaked between 34-38 weeks. Higher PLR and NLR values were linked to severe PE. ANC booking was lower in the PE group. Obesity trends were not statistically significant.Significant associations were found between elevated NLR and PLR and PE severity, highlighting their potential clinical utility.Our findings indicate NLR and PLR as valuable biomarkers for predicting and managing PE. Integration of these markers into routine prenatal care could enhance clinical management and improve maternal and fetal outcomes.

Development and validation of a nomogram for predicting postpartum hemorrhage in women with preeclampsia: A retrospective case-control study.

This retrospective case-control study aimed to develop a nomogram for predicting postpartum hemorrhage in women with preeclampsia. This study was carried out at the Fujian Maternity and Child Health Hospital, involving 542 preeclampsia patients who underwent vaginal deliveries. The participants were split into 2 groups: a training cohort (85%, n = 460) and a validation cohort (15%, n = 82). Least absolute shrinkage and selection operator regression was applied to pinpoint relevant risk factors by selecting appropriate candidate variables. Subsequently, multivariate logistic regression analysis was conducted on the training set, leading to the creation of a nomogram as a visual risk prediction tool. The model's performance was tested and verified internally and externally by examining receiver operating characteristic curves and calibration curves. The correlation heatmap revealed collinearity among variables, necessitating the use of least absolute shrinkage and selection operator regression to select 4 candidate variables. Multivariate logistic regression analysis identified significant associations with the following outcomes: white blood cell count (odds ratio [OR]: 2.485, 95% confidence interval [CI]: 1.483-4.166), third stage of labor (OR: 1.382, 95% CI: 1.182-1.616), anemia (OR: 9.588, 95% CI: 4.022-22.854), and labor analgesia (OR: 0.187, 95% CI: 0.073-0.477). These variables were utilized to construct the nomogram. The receiver operating characteristic curves demonstrated good predictive performance (area under the curve train = 0.867, area under the curve test = 0.882), and the calibration curve yielded a C-index of 0.867. The nomogram created in this study has good sensitivity and specificity to assess risk and support clinical decision-making for postpartum hemorrhage in women with preeclampsia.

Biochemical investigation of FOXP3 genetic polymorphism and its association with biochemical parameters in pre-eclampsia patients.

This study addresses the pivotal question of the association between FOXP3 gene polymorphism and pre-eclampsia (PE), employing the Tetra ARMS PCR method for analysis. PE, a multifaceted disorder marked by hypertension and organ dysfunction during pregnancy, led to an exploration of FOXP3 due to its integral role in immune regulation and its implication in various autoimmune and inflammatory disorders. The primary objective was to discern the relationship between FOXP3 gene polymorphism (rs2232365) and the risk of PE. Recruiting 200 PE patients and 100 healthy pregnant women as controls, genomic DNA was extracted from peripheral blood samples, and FOXP3 promoter region polymorphism was meticulously examined using the Tetra ARMS PCR method. The results revealed significant differences in FOXP3 gene polymorphism between PE patients and healthy controls. Specifically, certain alleles and genotypes were more frequent in PE patients, suggesting a potential genetic predisposition to this disorder. Our findings showed that rs2232365 A/G variant was found to be associated with PE under the overdominance model [OR=1.89, CI 95%= 0.99-3.60, P<0.05]. The heterozygous genotype (A/G) of FOXP3 (rs2232365) was associated with increasing the level of clinical and biochemical markers in mild and severe PE patients when compared to controls. Thus, the FOXP3 (rs2232365) A/G variant can be considered a substantial risk factor for PE.

Discover overlooked complications after preeclampsia from three real-world medical record datasets of over 100,000 pregnancies.

Preeclampsia poses a significant threat to women's long-term health. However, what diseases are affected and at what level they are affected by PE needs a thorough investigation. To conduct the first large-scale, non-hypothesis-driven study using EHR data from multiple medical centers to comprehensively explore adverse health outcomes after preeclampsia. Retrospective multi-cohort case-control study. We analyzed 3,592 preeclampsia patients and 23,040 non-preeclampsia controls from the University of Michigan Healthcare System. We externally validated the findings using UK Biobank data (443 cases, 14,870 controls) and Cedar Sinai data(2755 cases, 60,305 controls). We showed that six complications are significantly affected by PE. We demonstrate the effect of race as well as preeclampsia severity on these complications. PE significantly increases the risk of later hypertension, uncomplicated and complicated diabetes, renal failure and obesity, after careful confounder adjustment. We also identified that hypothyroidism risks are significantly reduced in PE patients, particularly among African Americans. Severe PE affects hypertension, renal failure, uncomplicated diabetes and obesity more than mild PE, as expected. Caucasians are affected more negatively than African Americans by PE on future hypertension, uncomplicated and complicated diabetes and obesity. This study fills a gap in the comprehensive assessment of preeclampsia's long-term effects using large-scale EHR data and rigorous statistical methods. Our findings emphasize the need for extended monitoring and tailored interventions for women with a history of preeclampsia, by considering pre-existing conditions, preeclampsia severity, and racial differences.

SIRT6 mitigates oxidative stress and RSL3-induced ferroptosis in HTR-8/SVneo cells

Dysregulation in placental trophoblast cells frequently results in oxidative stress, culminating in pregnancy-related complications. While iron is essential for fetal development, cellular ferroptosis due to elevated iron levels might mediate the emergence of preeclampsia (PE), presenting significant risks during gestation. We found abnormally activated oxidative stress and increased iron concentration in the placental tissues of PE patients. Subsequently, we treated placental trophoblasts with hydrogen peroxide and RSL3 to induce oxidative stress and ferroptosis models. The results revealed that SIRT6 overexpression activates the Nrf2/HO-1 pathway, restores the oxidative imbalance of the cells, and protects the cells from ferroptosis. Meanwhile, activation of the Nrf2/HO-1 pathway alone showed similar results. Thus, we posit that SIRT6, via the Nrf2/HO-1 pathway, alleviates cellular oxidative stress and diminishes ferroptosis, offering a novel therapeutic avenue for PE.

Miro2 sulfhydration by CBS/H2S promotes human trophoblast invasion and migration via regulating mitochondria dynamics

Insufficient cytotrophoblast (CTB) migration and invasion into the maternal myometrium leads to pregnancy related complications like Intra-uterus Growth Restriction (IUGR), and pre-eclampsia (PE). We previously found that hydrogen sulfide (H2S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H2S levels were lower in PE patients’ plasma; H2S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H2S donor, 1 µM) promoted CBS/H2S translocation onto mitochondria, preserved mitochondria functions, enhanced cell invasion and migration. CBS knockdown hindered the above functions which were rescued by GYY4137, indicating the vital roles of CBS/H2S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2C185/C504) were highly sulfhydrated by H2S. Knockdown Miro2 or double mutation of Miro2C185/C504 to serine fragmented mitochondria, and inhibited cell invasion and migration which can’t be rescued by H2S. The present study showed that human cytotrophoblast receives low dose H2S regulation; CBS/H2S sustained mitochondria functions via Miro2C185/C504 sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.

Linking EDC-laden food consumption and modern lifestyle habits with preeclampsia: A non-animal approach to identifying early diagnostic biomarkers through biochemical alterations

Preeclampsia (PE), a pregnancy complication characterized by new-onset hypertension with or without proteinuria and/or end-organ damage, and it may be influenced by exposure to endocrine-disrupting chemicals present in processed foods and modern lifestyles. This study explores the potential link using a non-animal approach to identify early diagnostic biomarkers for preeclampsia. Seventy pregnant women aged 21–41 years participated, and completed questionnaires assessing socio-demographic factors, Suboptimal Health Status Questionnaire scores for fatigue, digestive, cardiovascular, immune, and mental health issues, and exposure to endocrine-disrupting chemicals from processed food consumption and daily product use. Peripheral blood samples were analyzed for hormone profiles, complete blood count, and liver function tests (LFT). Statistical analysis revealed that mothers above 27 years old, with a Body Mass Index exceeding 32.59 Kg/m2, and a Mean Arterial Pressure of 108.5 mmHg exhibited a potential obesogenic effect on preeclampsia development. Socio-demographic factors like, lower economic class, housewife status, primiparous pregnancy, non-graduate education, and rural residence were significantly associated with results. Analysis of biochemical parameters revealed that serum creatinine, blood urea, total protein, platelet count, blood urea nitrogen, bilirubin profile, LFT profile, and thyroid profile showed potential detrimental effects on kidney, liver, muscle, and thyroid function in preeclampsia patients. Notably, PC, serum urea, bilirubin, total protein, serum glutamic-oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), and thyroid stimulating hormone (TSH) levels were significantly associated with preeclampsia in individuals reporting higher exposure to endocrine disrupting chemicals (EDCs). Minor biochemical alterations were also observed with dairy product consumption. SHS-25 analysis indicated a significant increase in fatigue, and digestive, cardiovascular, immune, and mental health-related issues in patients. Probably, biochemical alterations due to EDC exposure from processed foods and modern lifestyle habits contribute to organ dysfunction in preeclampsia. Identifying these potential biomarkers may pave the way for the development of non-invasive, early diagnostic tools for improved preeclampsia management. This research emphasizes the importance of non-animal testing methods for assessing EDC-related health risks in pregnancy and contributes to the advancement of early PE diagnosis strategies.

CHARACTERISTICS AND MATERNAL-PERINATAL OUTCOMES IN WOMEN WITH SEVERE PREECLAMPSIA AT SUMBER WARAS HOSPITAL

Preeclampsia is a cause of high maternal and fetal morbidity and mortality in developing countries. According to the Indonesian Health Profile, in 2021, hypertension in pregnancy is the second most common cause of maternal death in Jakarta with 22 cases out of 152 deaths. This study aims to determine the characteristics and maternal and perinatal outcomes of severe preeclampsia patients at Sumber Waras Hospital. This study was conducted in a descriptive qualitative observational manner with a cross-sectional approach using secondary data from medical records of patients with severe preeclampsia. The number of samples in this study was 85 pregnant women using a total sampling method on all pregnant women with severe preeclampsia who gave birth at Sumber Waras Hospital in the period January 2022 - December 2023. In this study, it was found that the majority of mothers with severe preeclampsia were aged 18-35 years. (63.5%), BMI in the second-degree obesity category (43.5%), multiparous parity status (64.7%), and term gestational age (76.5%). Maternal outcomes that occurred included eclampsia (14.1%), HELLP syndrome (2.4%), visual impairment (10.6%), and pulmonary edema (1.2%). The majority of perinatal outcomes had live babies (98.8%), no asphyxia (88.2%), and babies with normal weight (78.8%). Severe preeclampsia at Sumber Waras Hospital occurs more often in pregnant women aged 18-35 years, with a second-degree obesity BMI, multiparous, and term. Meanwhile, the outcomes that occurred were eclampsia, HELLP syndrome, visual disturbances, pulmonary edema, live babies, babies without asphyxia, and normal-weight babies. Keywords: Severe Preeclampsia., Characteristics., Outcomes

Research progress of exosomes in pathogenesis and treatment of preeclampsia.

Preeclampsia (PE) is a critical and severe disease in obstetrics, which seriously affects maternal and neonatal life safety and long-term prognosis. However, the etiology and pathogenesis of PE are complex, and no unified conclusion has been reached. The types and number of exosomes and their transport substances in PE patients changed. The study of exosomes in PE patients helps clarify the etiology, diagnosis, effective treatment, accurate monitoring, and prognosis. The published articles were reviewed. Exosomes may affect endothelial and vascular production and function, participate in maternal-fetal immune regulation, and transport substances such as miRNAs, lncRNAs, and proteins involved in the development of PE. Detection of the contents of exosomes can help in the early diagnosis of PE, and can help to improve PE by inhibiting the action of exosomes or preventing their binding to target organs. Exosomes may be involved in the development of PE, and exosomes can be used as markers for predicting the onset of PE and tracking the disease process and determining the prognosis, and exosomes have great potential in the treatment of PE.

Value of Maternal Renal Function Indicators in Predicting Small for Gestational Age Infants in Patient with Severe Preeclampsia

Background: Severe preeclampsia poses significant health risks to both pregnant patients and their newborns. Our goal was to explore the association between serum renal function related indicators in pregnant patients with severe preeclampsia and the occurrence of small for gestational age (SGA) infants, as well as to further identify independent risk factors for SGA based on these indicators. Methods: This was a retrospective case-control study. We evaluated the renal function indicators of 127 severe preeclampsia pregnant patients and 127 normal pregnant patients antenatally who delivered in Shijiazhuang Fourth Hospital from January 2022 to December 2022. Mann-Whitney U test and Chi-square test were used to compare the differences in clinical data between two groups. Spearman correlation analysis was used to determine the correlation between renal function indicators and newborn weight in severe preeclampsia pregnant patients. Receiver operating characteristic (ROC) curve was used to determine the optimal critical values of the above indicators, and multivariate logistic regression analysis was used to determine the independent risk factors for severe preeclampsia combined with SGA. Results: Blood urea nitrogen (BUN), serum creatinine (SCr) and serum uric acid (SUA) in severe preeclampsia patients with SGA were higher than severe preeclampsia without SGA (p &lt; 0.05 vs. all groups). In the severe preeclampsia group, these indicators were significantly negatively correlated with birth weight (p &lt; 0.001 vs. all groups), whereas no correlation was observed in the control group. In the severe preeclampsia group, a ROC analysis was performed based on whether the infants were small for gestational age, and the indicators were divided into two groups according to the optimal cut-off value. After adjusting for confounding factors, elevated BUN (≥4.9 mmol/L) served as an independent risk factor for severe preeclampsia patients with SGA (odds ratio (OR) = 4.336, 95% confidence interval (95% CI): 1.781–10.552, p = 0.001), and the corresponding area under the curve was 0.661 (0.572, 0.743). Conclusions: Serum renal function indicators in pregnant patients with severe preeclampsia were significantly associated with the occurrence of small for gestational age (SGA) infants. Moreover, elevated maternal BUN levels (≥4.9 mmol/L) prior to delivery may indicate the occurrence of SGA. However, we also acknowledge that the predictive power of this single marker is limited.

The Deubiquitinating Enzyme USP4 Promotes Trophoblast Dysfunction by Stabilizing RYBP.

Previous studies have suggested that impaired spiral artery remodeling, placental dysfunction, and insufficient trophoblast infiltration are the etiology and pathogenesis of Preeclampsia (PE). Ring 1 and YY1 binding protein (RYBP) has been reported to be associated with trophoblast dysfunction. However, the molecular mechanism of RYBP involved in trophoblasts in the pathogenesis of PE is poorly defined. RYBP and Ubiquitin-specific peptidase 4 (USP4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). RYBP, USP4, p-PI3K, PI3K, p-AKT, and AKT protein levels were measured using western blot assay. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay. RYBP and USP4 expression were upregulated in placental tissues from PE patients. By using JEG-3 and HTR-8/SVneo trophoblast cells, RYBP overexpression or USP4 upregulation could hinder cell viability, proliferation, invasion, migration, and promote apoptosis. Mechanistically, USP4 could trigger the deubiquitination of RYBP and prevent its degradation. In addition, USP4 repressed the PI3K/AKT signaling pathway by regulating RYBP. In total, Decreased USP4-mediated ubiquitination results in an adverse impact on trophoblast function by enhancing RYBP expression, providing a novel therapeutic target for PE.

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.

Elevated 12,13-diHOME level in maternal and umbilical cord blood complicated with preeclampsia.

Preeclampsia (PE) is a condition in pregnancy characterized by hypertension and proteinuria, thus leading to severe complications for both mother and fetus, including fetal growth restriction (FGR). However, there are still unclear aspects regarding the pathogenesis, prevention, and treatments. This study aimed to elucidate the characteristics of lipid metabolism in maternal and umbilical cord plasma complicated with PE using liquid chromatography-mass spectrometry (LC-MS). The study included singleton pregnant women at Osaka Metropolitan University Hospital from March 2023 to February 2024. PE was diagnosed based on new-onset hypertension after 20 weeks of gestation and other symptoms such as proteinuria and organ dysfunction. FGR was defined by ultrasound measurements below -1.5 standard deviation (SD). Plasma samples were collected from maternal and umbilical cord blood within 24 hours before delivery. Lipid metabolites were comprehensively analyzed using LC-MS, and the lipokine 12,13-diHOME, identified as elevated in the comprehensive analysis, was quantified. Immunohistochemistry was conducted on placental samples to assess soluble epoxide hydrolase (sEH) expression. The study involved 31 participants, with 20 in the control group and 11 in the PE group. A comprehensive analysis of maternal plasma samples identified a significant increase in 12,13-diHOME levels in the PE group compared to the control group. Quantification of 12,13-diHOME showed a significant increase in maternal plasma, umbilical venous plasma, and umbilical arterial plasma in the PE group compared to the control group (p = 0.007, p = 0.008, p = 0.005). PE with FGR showed significantly higher 12,13-diHOME concentrations in the umbilical arterial/venous ratio compared to the PE without FGR group (p = 0.03). Negative correlations were observed between 12,13-diHOME levels and birth weight in the PE group. Immunohistochemistry did not show significant differences in the sEH expression between the groups. This study demonstrated that 12,13-diHOME levels were significantly elevated in maternal and umbilical cord blood in PE patients, particularly in PE with FGR. Elevated 12,13-diHOME may reflect the progression of placental ischemia due to PE pathogenesis. This lipid metabolite could serve as a marker for the severity of preeclampsia, thus providing new insights into perinatal lipidomics and the potential role of 12,13-diHOME in PE.

DOCK1 deficiency drives placental trophoblast cell dysfunction by influencing inflammation and oxidative stress, hallmarks of preeclampsia.

Preeclampsia (PE) is a globally prevalent obstetric disorder, pathologically characterized by abnormal placental development. Dysfunctions of angiogenesis, vasculogenesis and spiral artery remodeling are demonstrated to be involved in PE pathogenesis; however, the underlying mechanisms remain largely unknown. Here, we investigated the role of the dedicator of cytokinesis 1 (DOCK1), crucial molecule in various cellular processes, in PE progression using HTR-8 cells derived from first-trimester placental extravillous trophoblasts. Our analysis revealed an aberrant DOCK1 expression in the placental villi of PE patients and its impact on essential cellular functions for vascular network formation. A deficiency of DOCK1 in HTR-8 cells impaired the vascular network formation, exacerbated the expression of anti-angiogenic factor ENG, and reduced VEGF levels. Moreover, DOCK1 knockout amplified apoptosis, as indicated by an altered BCL2: BAX ratio and enhanced levels of cleaved PARP. DOCK1 depletion also boosted NF-κB activation and pro-inflammatory cytokine production (IL-6 and TNF-α). Furthermore, the mice treated with DOCK1 inhibitor, TBOPP, exhibited PE-like symptoms. These findings highlight the multifaceted roles of DOCK1 in the pathophysiology of PE, demonstrating that its deficiency can lead to placental dysfunction by orchestrating inflammatory responses and oxidative stress. These insights emphasize the pathogenic role of DOCK1 in PE development and suggest potential treatment strategies that require further exploration. In the graphical abstract, a split image of placental villi contrasts the effects of normal and reduced DOCK1 expression on preeclampsia. The left side illustrates adequate DOCK1 levels supporting healthy trophoblast function and effective spiral artery remodeling. The right side highlights the consequences of DOCK1 deficiency, leading to trophoblast dysfunction and impaired spiral artery remodeling, accompanied by angiogenic imbalance, increased inflammation, oxidative stress, and apoptosis, contributing to placental dysfunction and the development of preeclampsia.