Implication of viruses in the etiology of preeclampsia.

Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.

Exploring the role of exosomal MicroRNAs as potential biomarkers in preeclampsia.

The complex pathogenesis of preeclampsia (PE), a significant contributor to maternal and neonatal mortality globally, is poorly understood despite substantial research. This review explores the involvement of exosomal microRNAs (exomiRs) in PE, focusing on their impact on the protein kinase B (AKT)/hypoxia-inducible factor 1-α (HIF1α)/vascular endothelial growth factor (VEGF) signaling pathway as well as endothelial cell proliferation and migration. Specifically, this article amalgamates existing evidence to reveal the pivotal role of exomiRs in regulating mesenchymal stem cell and trophoblast function, placental angiogenesis, the renin-angiotensin system, and nitric oxide production, which may contribute to PE etiology. This review emphasizes the limited knowledge regarding the role of exomiRs in PE while underscoring the potential of exomiRs as non-invasive biomarkers for PE diagnosis, prediction, and treatment. Further, it provides valuable insights into the mechanisms of PE, highlighting exomiRs as key players with clinical implications, warranting further exploration to enhance the current understanding and the development of novel therapeutic interventions.

[Metformin ameliorates PM2.5-induced functional impairment of placental trophoblasts by inhibiting ferroptosis].

OBJECTIVE: To investigate the protective effect of metformin against PM2.5-induced functional impairment of placental trophoblasts and explore the underlying mechanism. METHODS: Sixteen pregnant Kunming mice were randomly assigned into two groups (n=8) for intratracheal instillation of PBS or PM2.5 suspension at 1.5, 7.5, and 12.5 days of gestation. The pregnancy outcome of the mice was observed, and placental zonal structure and vascular density of the labyrinth area were examined with HE staining, followed by detection of ferroptosis-related indexes in the placenta. In cultured human trophoblasts (HTR8/SVneo cells), the effects of PM2.5 exposure and treatment with metformin on cell viability, proliferation, migration, invasion, and tube formation ability were evaluated using CCK8 assay, EDU staining, wound healing assay, Transwell experiment, and tube formation experiment; the cellular expressions of ferroptosis-related proteins were analyzed using ELISA and Western blotting. RESULTS: M2.5 exposure of the mice during pregnancy resulted in significantly decreased weight and number of the fetuses and increased fetal mortality with a reduced placental weight (all P<0.001). PM2.5 exposure also caused obvious impairment of the placental structure and trophoblast ferroptosis. In cultured HTR8/SVneo cells, PM2.5 significantly inhibited proliferation, migration, invasion, and angiogenesis of the cells by causing ferroptosis. Metformin treatment obviously attenuated PM2.5-induced inhibition of proliferation, migration, invasion, and angiogenesis of the cells, and effectively reversed PM2.5-induced ferroptosis in the trophoblasts as shown by significantly increased intracellular GSH level and SOD activity, reduced MDA and Fe2+ levels, and upregulated GPX4 and SLC7A11 protein expression (P<0.05 or 0.01). CONCLUSION: PM2.5 exposure during pregnancy causes adverse pregnancy outcomes and ferroptosis and functional impairment of placental trophoblasts in mice, and metformin can effectively alleviate PM2.5-induced trophoblast impairment.

PPARγ alleviates preeclampsia development by regulating lipid metabolism and ferroptosis.

The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.

Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Eucommia granules activate Wnt/ß-catenin pathway, and improve oxidative stress, inflammation, and endothelial injury in preeclampsia rats.

PURPOSE: Pre-eclampsia (PE) is a pregnancy-related complication. Eucommia is effective in the treatment of hypertensive disorders in pregnancy, but the specific effects and possible mechanisms of Eucommia granules (EG) in PE remain unknown. The aim of this study was to investigate the effects and possible mechanisms of EG in PE rats. METHODS: Pregnant Sprague Dawley rats were divided into five groups (n = 6): the control group, the model group, the low-dose group, the medium-dose group, and the high-dose group of EG. The PE model was established by subcutaneous injection of levonitroarginine methyl ester. Saline was given to the blank and model groups, and the Eucommia granules were given by gavage to the remaining groups. Blood pressure and urinary protein were detected. The body length and weight of the pups and the weight of the placenta were recorded. Superoxide dismutase (SOD) activity and levels of malondialdehyde (MDA), placental growth factor (PIGF), and soluble vascular endothelial growth factor receptor-1 (sFIt-1) were measured in the placenta. Pathological changes were observed by hematoxylin-eosin staining. Wnt/ß-catenin pathway-related protein expression was detected using Western blot. RESULTS: Compared with the model group, the PE rats treated with EG had lower blood pressure and urinary protein. The length and weight of the pups and placental weight were increased. Inflammation and necrosis in the placental tissue was improved. SOD level increased, MDA content and sFIt-1/PIGF ratio decreased, and Wnt/ß-catenin pathway-related protein expression level increased. Moreover, the results of EG on PE rats increased with higher doses of EG. CONCLUSIONS: EG may activate the Wnt/ß-catenin pathway and inhibit oxidative stress, inflammation, and vascular endothelial injury in PE rats, thereby improving the perinatal prognosis of preeclamptic rats. EG may inhibit oxidative stress, inflammation, and vascular endothelial injury through activation of the Wnt/ß-catenin pathway in preeclampsia rats, thereby improving perinatal outcomes in PE rats.

Pregnancy-Specific Beta-1-Glycoprotein 1 Increases HTR-8/SVneo Cell Migration through the Orai1/Akt Signaling Pathway.

The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on Orai1-mediated store-operated calcium entry (SOCE) and the Akt signaling pathway in human trophoblast cell migration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the level of PSG1 in the serum of pregnant women with EOPE. The effects of PSG1 on trophoblast proliferation and migration were examined using cell counting kit-8 (CCK8) and wound healing experiments, respectively. The expression levels of Orai1, Akt, and phosphorylated Akt (p-Akt) were determined through Western blotting. The results confirmed that the serum PSG1 levels were lower in EOPE women than in healthy pregnant women. The PSG1 treatment upregulated the protein expression of Orai1 and p-Akt. The selective inhibitor of Orai1 (MRS1845) weakened the migration-promoting effect mediated by PSG1 via suppressing the Akt signaling pathway. Our findings revealed one of the mechanisms possibly involved in EOPE pathophysiology, which was that downregulated PSG1 may reduce the Orai1/Akt signaling pathway, thereby inhibiting trophoblast migration. PSG1 may serve as a potential target for the treatment and diagnosis of EOPE.

Analysis of changes in high-mobility group box 1, receptor for advanced glycation endproducts, and T helper 17/regulatory T balance in severe preeclampsia with acute heart failure.

We measured the levels of High-Mobility Group Box 1 (HMGB1), Receptor for Advanced Glycation Endproducts (RAGE), T Helper 17 cells (Th17), Regulatory T cells (Treg), and related cytokines in the peripheral blood of patients with severe preeclampsia (SPE) complicated with acute heart failure (AHF) to explore the expression changes in these indicators. In total, 96 patients with SPE admitted to Gansu Provincial Maternity and Child-care Hospital between June 2020 and June 2022 were included in the study. The patients were divided into SPE+AHF (40 patients) and SPE (56 patients) groups based on whether they suffered from AHF. Additionally, 56 healthy pregnant women who either received prenatal examinations or were admitted to our hospital for delivery during the same period were selected as the healthy control group. An enzyme-linked immunosorbent assay was performed to detect the expression levels of HMGB1, RAGE, interleukin (IL)-17, IL-6, transforming growth factor ß (TGF-ß), IL-10, and NT-proBNP in plasma. Flow cytometry was employed to determine the percentages of Th17 and Treg cells. Compared to the healthy control group, the SPE+AHF and SPE groups had higher plasma levels of HMGB1 and RAGE expression, higher Th17 percentage and Th17/Treg ratio, and lower Treg percentage. Compared to the SPE group, the SPE+AHF group had higher plasma levels of HMGB1 and RAGE expression, higher Th17 percentage and Th17/Treg ratio, and lower Treg percentage (P < .05). In patients with SPE with AHF, plasma HMGB1 was positively correlated with RAGE, Th17, Th17/Treg, IL-17, and IL-6 and was negatively correlated with TGF-ß and IL-10 (P < .05). Our findings revealed that patients with SPE with AHF had elevated levels of HMGB1 and RAGE while exhibiting Th17/Treg immune imbalance, suggesting that the abnormal expression of these indicators may be involved in the pathogenesis of SPE with AHF.

Protective role of complement factor H against the development of preeclampsia.

Pregnancy is an immunologically regulated, complex process. A tightly controlled complement system plays a crucial role in the successful establishment of pregnancy and parturition. Complement inhibitors at the feto-maternal interface are likely to prevent inappropriate complement activation to protect the fetus. In the present study, we aimed to understand the role of Factor H (FH), a negative regulator of complement activation, in normal pregnancy and in a model of pathological pregnancy, i.e. preeclampsia (PE). The distribution and expression of FH was investigated in placental tissues, various placental cells, and in the sera of healthy (CTRL) or PE pregnant women via immunohistochemistry, RT-qPCR, ELISA, and Western blot. Our results showed a differential expression of FH among the placental cell types, decidual stromal cells (DSCs), decidual endothelial cells (DECs), and extravillous trophoblasts (EVTs). Interestingly, FH was found to be considerably less expressed in the placental tissues of PE patients compared to normal placental tissue both at mRNA and protein levels. Similar results were obtained by measuring circulating FH levels in the sera of third trimester CTRL and PE mothers. Syncytiotrophoblast microvesicles, isolated from the placental tissues of PE and CTRL women, downregulated FH expression by DECs. The present study appears to suggest that FH is ubiquitously present in the normal placenta and plays a homeostatic role during pregnancy.

Placental and Renal Pathways Underlying Pre-Eclampsia.

Pre-eclampsia is a serious complication of pregnancy characterized by a state of multiorgan hypertensive disorders, with or without proteinuria and possible multiorgan dysfunction. Chronic kidney disease is an established risk factor for the development of pre-eclampsia, as angiogenic homeostasis is altered and the maternal circulation is already hypertensive. Facing pre-eclampsia in the context of chronic kidney disease is a challenging emergency for both the mother and the fetus. The clinical features and the management of this multi-organ disorder are clearly defined in the modern literature but the underlying pathophysiologic mechanisms remain not fully elucidated. Understanding the pathophysiology that mediates the onset of pre-eclampsia itself and in synergy with chronic kidney disease is fundamental for developing prompt prevention strategies, treatment planning, and patient counseling. This review aims to summarize the main molecular mechanisms involved in the process of pre-eclampsia, with a particular focus on the role of the kidneys and hormonal pathways related to renal function in normal pregnancy and pre-eclamptic syndromes.

Nox2 inhibition reduces trophoblast ferroptosis in preeclampsia via the STAT3/GPX4 pathway.

AIMS: Ferroptosis, a novel mode of cell death characterized by lipid peroxidation and oxidative stress, plays an important role in the pathogenesis of preeclampsia (PE). The aim of this study is to determine the role of Nox2 in the ferroptosis of trophoblast cells, along with the underlying mechanisms. METHODS: The mRNA and protein levels of Nox2, STAT3, and GPX4 in placental tissues and trophoblast cells were respectively detected by qRT-PCR and western blot analysis. CCK8, transwell invasion and tube formation assays were used to evaluate the function of trophoblast cells. Ferroptosis was evaluated using flow cytometry and the lipid peroxidation assay. Glycolysis and mitochondrial respiration were investigated by detecting the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) using Seahorse extracellular flux technology. The t-test or one-way ANOVA was used for statistical analysis. KEY FINDINGS: Nox2 was up-regulated while STAT3 and GPX4 were down-regulated in PE placental tissues. Nox2 knockdown inhibited ferroptosis in trophoblast cells, which was shown by enhanced proliferation and invasion, decreased ROS and lipid peroxide levels, and reduced glycolysis and mitochondrial dysfunction. Nox2 negatively correlated with MVD in PE placentas, and Nox2 knockdown restored ferroptosis-inhibited tube formation. Nox2 could interact with STAT3. Inhibiting Nox2 restored ferroptosis-induced alterations in the mRNA and protein levels of STAT3 and GPX4. SIGNIFICANCE: Nox2 may trigger ferroptosis through the STAT3/GPX4 pathway, subsequently leading to regulation of mitochondrial respiration, transition of glycolysis, and inhibition of placental angiogenesis. Therefore, targeted inhibition of Nox2 is expected to become a new therapeutic target for PE.

Maternal hypertensive condition alters adipose tissue function and blood pressure sensitivity in offspring.

Preeclampsia (PE) is characterized by hypertension, proteinuria, and fetal growth restriction during pregnancy, suggesting that the preeclamptic intrauterine environment may affect the growth and health of the offspring. This study aimed to how maternal hypertension affects male offspring growth, focusing on lipid metabolism and blood pressure in mice. Female mice were infused with angiotensin II (Ang II) on gestational day 12. Dysregulation and accumulation of lipid were observed in the placenta of Ang II-induced maternal hypertensive dams, associating with fetal growth restriction. Ang II-offspring showed lower birth weight than in the control-offspring. Isolated and differentiated adipocyte from neonatal mice of Ang II-dams showed higher Pparγ mRNA expression compared with the control group. Lower body weight tendency had continued in Ang II-offspring during long period, body weight of Ang II-offspring caught up the control-offspring at 16 weeks of age. The adipose tissue of Ang II-offspring in adult also showed higher Pparγ mRNA expression with the accumulation of neutrophils and inflammatory monocytes than in those control. In addition, Ang II-offspring had higher basal blood pressure and higher sensitivity to hypertensive stimuli than in the control-offspring. Taken together, maternal hypertension induced by Ang II changes placental function, causing a lower birth weight. These changes in the intrauterine environment may affect adipocyte function and blood pressure of offspring after growth.

High level 27-HC impairs trophoblast cell invasion and migration via LXR in pre-eclampsia.

INTRODUCTION: To explore the potential impact of 27-hydroxycholesterol (27-HC) on trophoblast cell function in pre-eclampsia. RESULTS: The levels of 27-HC and the expression of CYP27A1 are upregulated in clinical samples of PE. Furthermore, high concentrations of 27-HC can inhibit the invasion and migration ability of trophoblast cells in vitro, and this inhibitory effect is weakened after LXR silencing. In HTR8/SVneo cells treated with 27-HC, the expression of ABCA1/ABCG1 are increased. Finally, we established a mouse model of PE using l-NAME (N-Nitro-l-Arginine Methyl Ester). We found an increase in the levels of 27-HC in the peripheral blood serum of the PE mouse model, and an upregulation of CYP27A1 and LXR expressions in the placenta of the PE mouse model. CONCLUSION: 27-HC inhibits the invasion and migration ability of trophoblast cells by activating the LXR signaling pathway, which is involved in the pathogenesis of Pre-eclampsia(PE).

Expression of the immune checkpoint molecules CD226 and TIGIT in preeclampsia patients.

BACKGROUND: Imbalanced immune responses are involved in developing preeclampsia (PE). We wish to explore the expression and potential changes of immune checkpoint molecules TIGIT, CD226 and CD155 in PE patients. METHODS: The expression of the immune checkpoint molecules TIGIT, CD226 and CD155 in different lymphocyte subpopulations was determined by flow cytometry in 24 patients with PE and compared to 24 healthy pregnant women of the same gestational age as the controls.​Serum CD155 was detected by ELISA in the patients with PE compared to controls. RESULTS: The percentages of CD4+ and CD8+ T lymphocytes in the peripheral blood of PE patients were not significantly different from those of the controls, whereas the regulatory T cells (Tregs) in PE patients were significantly lower than those in controls (6.43 ± 1.77% vs. 7.48 ± 1.71%, P = 0.0420). The expression of TIGIT and CD226 showed different percentages on CD4+ T cells, CD8+ T cells and Treg cells. However, the difference in the percentages of TIGIT, CD226 on these T cells between the two groups was not statistically significant. The level of CD155 in peripheral serum of PE patients was 6.64 ± 1.79 ng/ml, which was not significantly different from that in the control group 5.61 ± 1.77 ng/ml, P = 0.0505. The present results demonstrate that TIGIT, CD226 and CD155 are not present at altered immune conditions in the peripheral blood of patients with PE, compared with normal pregnant women. CONCLUSION: The immune checkpoint molecules TIGIT, CD226 and CD155 are not abnormally expressed in PE patients.

IL-33 supplementation improves uterine artery resistance and maternal hypertension in response to placental ischemia.

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized that IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 µg/kg/day) into normal pregnant (NP) and RUPP rats from gestation day 14 to 19. We found that IL-33 supplementation in RUPP rats reduces maternal blood pressure and improves the uterine artery resistance index (UARI). In addition to physiological improvements, we found decreased circulating and placental cytolytic Natural Killer cells (cNKs) and decreased circulating, placental, and renal TH17s in IL-33-treated RUPP rats. cNK cell cytotoxic activity also decreased in IL-33-supplemented RUPP rats. Furthermore, renal ROS and placental preproendothelin-1 (PPET-1) decreased in RUPP rats treated with IL-33. These findings demonstrate a role for IL-33 in controlling vascular function and maternal BP during pregnancy by decreasing inflammation, renal ROS, and PPET-1 expression. These data suggest that IL-33 may have therapeutic potential in managing PE.NEW & NOTEWORTHY Though decreased IL-33 signaling has been clinically associated with PE, the mechanisms linking this signaling pathway to overall disease pathophysiology are not well understood. This study provides compelling evidence that mechanistically links reduced IL-33 with the inflammatory response and vascular dysfunction observed in response to placental ischemia, such as in PE. Data presented in this study submit the IL-33 signaling pathway as a possible therapeutic target for the treatment of PE.

Altered release of thrombomodulin and HMGB1 in the placenta complicated with preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe pregnancy complication due to placental dysfunction. Thrombomodulin (TM), a glycoprotein expressed on the trophoblast cell membrane, plays an organ-protective role in the placenta by regulating coagulation and inflammation. TM-mediated regulation of High Mobility Group Box1(HMGB1) is an essential mechanism that contributes to placental homeostasis and prevents pregnancy complications in mice. Here, we aimed to clarify the role of placental TM and HMGB1 in the pathophysiology of human PE. METHODS AND RESULTS: In this study, maternal blood serum and placental tissue were obtained from 72 PE patients and 110 normal controls. Soluble TM(sTM) and HMGB1 levels in the maternal serum were assessed. The placental TM and HMGB1 expression levels were evaluated using immunohistochemistry and qPCR. Serum sTM and HMGB1 levels gradually increased with gestational age in normal pregnancies; however, both circulating sTM and HMGB1 levels were significantly higher in the PE group. Serum HMGB1/sTM ratio was elevated in PE patients compared to that in normal controls, which correlated positively with the clinical severity of PE. The immunohistochemistry analysis revealed the loss of TM and the increase in extranuclear HMGB1. TM mRNA expression was diminished in PE placentas, which negatively correlated with soluble fms-like tyrosine kinase-1 (sFlt-1) expression. DISCUSSION: The increase in circulating sTM and HMGB1 could be attributed to the enhanced placental TM shedding in PE patients. The molecular events mediated by the imbalance in the placental TM and HMGB1 levels could be an underlying feature of PE; maternal serum HMGB1/sTM ratio could reflect this status.

Progesterone modulates TNF receptors expression by Jurkat cells cultured with plasma from pregnant women with preeclampsia.

Pregnant women with preeclampsia (PE) present a shift in the immune response to an inflammatory profile. This deviation could be due to the interaction of tumor necrosis factor (TNF) with TNFR1 and TNFR2 receptors, besides the failure in modulation of inflammation regulatory mechanisms. This study evaluated the effects of progesterone on the expression of TNFR1 and TNFR2 by Jurkat cells after stimulation with plasma from PE and normotensive (NT) pregnant women. Jurkat cells were cultured with or without progesterone in a medium containing 20% (v/v) plasma from PE or NT women. The expression of TNF receptors was evaluated by flow cytometry. The concentration of soluble forms of TNF receptors and cytokines was determined in culture supernatant and plasma by ELISA. The plasma of PE women showed significantly higher concentrations of sTNFR1 and TNF and lower concentrations of sTNFR2 compared to the NT group. TNFR1 receptor expression was increased in Jurkat cells, while TNFR2 was decreased after culture with PE plasma when compared with Jurkat cells cultured with progesterone and plasma from NT women. The concentration of sTNFR1, TNF, and IL-10 in the culture supernatant of Jurkat cells was increased after culture with PE plasma, while the sTNFR2 receptor was decreased when compared to the NT group. Results demonstrate that in preeclamptic women a systemic inflammation occurs with an increase of inflammatory molecules, and progesterone may have a modulating effect on the expression of TNF receptors, shifting Jurkat cells towards an anti-inflammatory profile with greater expression of TNFR2.

Down-Regulation of CPEB4 Alleviates Preeclampsia through the Inhibition of Ferroptosis by PFKFB3.

Gestational diabetes mellitus (GDM) complicated with preeclampsia can lead to polyhydramnios, ketosis. Herein, we explored that CPEB4 in cancer progression of preeclampsia and its underlying mechanism. All the serum samples were collected from patients with preeclampsia. These was the induction of CPEB4 in patients with preeclampsia. The serum of CPEB4 mRNA expression was positive correlation with Proteinuria, systolic blood pressure and diastolic blood pressure in patients. The serum of CPEB4 mRNA expression was also negative correlation with body weight of infant in patients. The serum of CPEB4 mRNA expression also was negative correlation with GPX4 level and GSH activity level in patients. The serum of CPEB4 mRNA expression was positive correlation with iron content in patients. CPEB4 gene inhibited trophoblast cell proliferation. CPEB4 gene promoted trophoblast cell ferroptosis by mitochondrial damage. CPEB4 gene induced PFKFB3 expression by the inhibition of PFKFB3 Ubiquitination. PFKFB3 inhibitor reduced the effects of CPEB4 on cell proliferation and ferroptosis of trophoblast cell. Taken together, the CPEB4 promoted trophoblast cell ferroptosis through mitochondrial damage by the induction of PFKFB3 expression, CPEB4 as an represents a potential therapeutic strategy for the treatment of preeclampsia or various types of GDM.

Protein Misfolding in Pregnancy: Current Insights, Potential Mechanisms, and Implications for the Pathogenesis of Preeclampsia.

Protein misfolding disorders are a group of diseases characterized by supra-physiologic accumulation and aggregation of pathogenic proteoforms resulting from improper protein folding and/or insufficiency in clearance mechanisms. Although these processes have been historically linked to neurodegenerative disorders, such as Alzheimer's disease, evidence linking protein misfolding to other pathologies continues to emerge. Indeed, the deposition of toxic protein aggregates in the form of oligomers or large amyloid fibrils has been linked to type 2 diabetes, various types of cancer, and, in more recent years, to preeclampsia, a life-threatening pregnancy-specific disorder. While extensive physiological mechanisms are in place to maintain proteostasis, processes, such as aging, genetic factors, or environmental stress in the form of hypoxia, nutrient deprivation or xenobiotic exposures can induce failure in these systems. As such, pregnancy, a natural physical state that already places the maternal body under significant physiological stress, creates an environment with a lower threshold for aberrant aggregation. In this review, we set out to discuss current evidence of protein misfolding in pregnancy and potential mechanisms supporting a key role for this process in preeclampsia pathogenesis. Improving our understanding of this emerging pathophysiological process in preeclampsia can lead to vital discoveries that can be harnessed to create better diagnoses and treatment modalities for the disorder.

Circulating miRNAs and Preeclampsia: From Implantation to Epigenetics.

In this review, we comprehensively present the literature on circulating microRNAs (miRNAs) associated with preeclampsia, a pregnancy-specific disease considered the primary reason for maternal and fetal mortality and morbidity. miRNAs are single-stranded non-coding RNAs, 20-24 nt long, which control mRNA expression. Changes in miRNA expression can induce a variation in the relative mRNA level and influence cellular homeostasis, and the strong presence of miRNAs in all body fluids has made them useful biomarkers of several diseases. Preeclampsia is a multifactorial disease, but the etiopathogenesis remains unclear. The functions of trophoblasts, including differentiation, proliferation, migration, invasion and apoptosis, are essential for a successful pregnancy. During the early stages of placental development, trophoblasts are strictly regulated by several molecular pathways; however, an imbalance in these molecular pathways can lead to severe placental lesions and pregnancy complications. We then discuss the role of miRNAs in trophoblast invasion and in the pathogenesis, diagnosis and prediction of preeclampsia. We also discuss the potential role of miRNAs from an epigenetic perspective with possible future therapeutic implications.