Pathogenetic role of a number of factors in the development and progression of preeclampsia with varying severity in pregnant women.

Context Preeclampsia is a common pregnancy complication, posing significant risks to both the mother and fetus. Predicting and determining the risks of this disease is crucial. Aims This research aims to understand the pathogenetic role of several factors in the development and progression of preeclampsia, particularly in relation to its severity in pregnant patients. Methods The study included 60 pregnant women diagnosed with either mild or severe preeclampsia and 40 healthy pregnant women for comparison. Blood plasma was analysed using biochemical methods, and blood microcirculation parameters were determined to identify homeostatic abnormalities in early preeclampsia. Key results A molecular genetic study revealed the frequency of the endothelial nitric oxide gene eNOSC774T . Homeostatic abnormalities were statistically correlated with polymorphic genotypes of the eNOSC774T gene. Conclusions The research found a correlation between the T774T eNOS genotype mutation and the severity of preeclampsia, alongside significant homeostasis abnormalities in patients. Implications The T774T mutant genotype of the eNOS gene and higher levels of lipid peroxidation products are strongly linked to the severity and progression of preeclampsia. This highlights a significant connection between genetic predisposition and biochemical abnormalities in the disease's development.

Exploration of the molecular characteristics and potential clinical significance of shared immune-related genes between preterm preeclampsia and term preeclampsia.

BACKGROUND: Preeclampsia is a severe obstetric disorder that significantly affects the maternal and neonatal peri-partum safety and long-term quality of life. However, there is limited research exploring the common mechanisms and potential clinical significance between early-onset preeclampsia and full-term preeclampsia from an immunological perspective. METHODS: In this study, data analysis was conducted. Initially, immune-related co-expressed genes involving both subtypes of preeclampsia were identified through Weighted Gene Co-expression Network Analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were further employed to investigate the shared pathways regulated by immune-related genes. Binary logistic regression identified co-expressed genes with diagnostic value for preeclampsia, and a diagnostic model was constructed. Gene Set Enrichment Analysis (GSEA) predicted the potential biological functions of the selected genes. Lasso and Cox regression analyses identified genes closely associated with gestational duration, and a risk score model was established. A 4-gene feature, immune-related gene model for predicting the risk of preterm birth in preeclamptic pregnant women, was developed and validated through qPCR experiments. Immune cell infiltration analysis determined differences in immune cell infiltration between the two subtypes of preeclampsia. RESULTS: This study identified 4 immune-related co-expressed genes (CXCR6, PIK3CB, IL1RAP, and OSMR). Additionally, diagnostic and preterm birth risk prediction models for preeclampsia were constructed based on these genes. GSEA analysis suggested the involvement of these genes in the regulation of galactose metabolism, notch signaling pathway, and RIG-I like receptor signaling pathway. Immune pathway analysis indicated that the activation of T cell co-inhibition could be a potential intervention target for immunotherapy in early-onset preeclampsia. CONCLUSION: Our study provides promising insights into immunotherapy and mechanistic research for preeclampsia, discovering novel diagnostic and intervention biomarkers, and offering personalized diagnostic tools for preeclampsia.

Overexpression of long noncoding RNA DUXAP8 inhibits ER-phagy through activating AKT/mTOR signaling and contributes to preeclampsia.

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.

A New Look at Immunogenetics of Pregnancy: Maternal Major Histocompatibility Complex Class I Educates Uterine Natural Killer Cells.

Our incomplete knowledge of maternal-fetal interface (MFI) physiology impedes a better understanding of the pathological mechanisms leading to pregnancy complications, such as pre-eclampsia and fetal growth restriction. At the MFI, uterine natural killer (uNK) cells do not attack fetal cells but engage in crosstalk with both fetal and maternal cells to support feto-placental development. However, mother and fetus are genetically half-mismatched and certain combinations of variable immune genes-human leukocyte antigens (HLAs) and killer-cell immunoglobulin-like receptor (KIR), indeed, the most variable gene sets in the genome-associate with pregnancy outcomes, suggesting that these interactions regulate uNK cell function. How do these interactions influence the physiology and pathology at the MFI? Uterine NK cell function is regulated by both maternal and fetal Major Histocompatibility Complex (MHC); however, evidence for fetal cells educating uNK cells is lacking, and new evidence shows that maternal rather than fetal MHC class I molecules educate uNK cells. Furthermore, uNK cell education works through self-recognition by the ancient and conserved NKG2A receptor. Pregnant mice lacking this receptor produce normal litter sizes, but a significant portion of the offspring have low birthweight and abnormal brain development. Evidence from a genome-wide association study of over 150,000 human pregnancies validates the finding because women whose NKG2A receptor is genetically determined to engage their own MHC class I molecules are exposed to lower risk of developing pre-eclampsia, suggesting that maternal uNK cell education is a pre-requisite for a healthy pregnancy and, likely, for healthy offspring too.

Knocking down macrophages Caspase-6 through HMGB1 coordinates macrophage trophoblast crosstalk to suppress ferroptosis and alleviate preeclampsia.

OBJECTIVE: Caspase-6 is an important regulatory factor in innate immunity, inflammasome activation, and host defense, but its role in preeclampsia (PE) is unknown. This study aims to investigate the mechanism of Caspase-6 in the interaction between PE rats and macrophage-trophoblast cells, in order to provide a new theoretical basis for the treatment of PE. METHODS: Co-cultures of THP-1 cells and HTR8/SVneo cells were employed to investigate the HMGB1 signaling in macrophages (transfection with si-Caspase-6) and HTR8/SVneo cells. The PE rat model was constructed by using the reduced uterine perfusion pressure (RUPP) surgery to explore the therapeutic effects of bone marrow-derived macrophages (BMDM) transfected with si-Caspase-6 in PE rats. ELISA, Western blot, immunofluorescence, etc., were employed to characterize the expression of ferroptosis-related markers. RESULTS: Caspase-6 expression was significantly increased in CD14+ macrophages in the placental tissue of PE rats. Overexpression of Caspase-6 in THP-1 cells induced ferroptosis of HTR8/SVneo cells, but this process was blocked by anti-HMGB1 neutralizing antibody. Knockdown of Caspase-6 in macrophages could alleviate ferroptosis of HTR8/SVneo cells and restore its basic characteristics. Knockdown of Caspase-6 in BMDM downregulated ferroptosis in placental tissue of PE rats through HMGB1, thereby improving the disease phenotype in rats. CONCLUSION: Knocking down Caspase-6 in BMDM regulated the crosstalk between macrophages and HTR8/SVneo cells through HMGB1, inhibiting HTR8/SVneo cell ferroptosis, thereby improving adverse pregnancy outcomes of PE.

LINC01410 accelerates the invasion of trophoblast cells by modulating METTL3/Fas.

BACKGROUND: Insufficient trophoblast invasion, culminating in suboptimal uterine spiral artery remodeling, is pinpointed as a pivotal contributor to preeclampsia (PE) development. LINC01410 has been documented to be increased in various neoplasms, and is significantly associated with the invasive capabilities of tumor cells. Nonetheless, its function and the mechanisms in the pathogenesis of PE require further investigation. METHODS AND RESULTS: LINC01410 and methyltransferase-like 3 (METTL3) were ectopically expressed in HTR-8/Svneo cells via lentiviral transduction. Subsequently, the cells' invasive capabilities and apoptosis rates were evaluated employing Transwell assays and flow cytometry, respectively. The interplay between LINC01410 and METTL3, alongside the m6A methylation of FAS, was probed through RNA immunoprecipitation (RIP). Additionally, the association between FAS and METTL3 was elucidated via Coimmunoprecipitation (Co-IP) assays. The protein level of NF-κB, BAX, and BCL-2 in LINC01410-overexpressing cells was detected by Western blot. Our findings revealed that LINC01410 elevation increased the invasive ability of HTR-8/Svneo cells, directly impacting METTL3 then leading to its reduced expression. Conversely, heightened METTL3 expression mitigated invasiveness while enhancing apoptosis in these cells. Moreover, METTL3's interaction with FAS led to increased FAS expression, subject to m6A methylation. A surge in LINC01410 markedly decreased both mRNA and protein levels of FAS. Furthermore, LINC01410 overexpression significantly reduced NF-κB and BAX protein levels while augmenting BCL-2. CONCLUSIONS: Upregulation of LINC01410 expression promotes trophoblast cell invasion by inhibiting FAS levels through modified m6A alteration and suppressing the NF-κB pathway. These findings underscore the pivotal role of LINC01410 in regulating trophoblast cell invasion and propose it as a promising therapeutic strategy for preventing or alleviating PE. This offers valuable insights for the clinical treatment of PE, for which definitive targeted therapy methods are currently lacking.

Rheumatoid arthritis and adverse pregnancy outcomes: a bidirectional two-sample mendelian randomization study.

BACKGROUND: There is growing evidence of bidirectional associations between rheumatoid arthritis and adverse pregnancy outcomes (APOs) in observational studies, but little is known about the causal direction of these associations. Therefore, we explored the potential causal relationships between rheumatoid arthritis and APOs using a bidirectional two-sample Mendelian randomization (MR) in European and Asian populations. METHODS: We conducted a bidirectional two-sample Mendelian randomization analysis using available summary statistics from released genome-wide association studies. Summary statistics for instrument-outcome associations were retrieved from two separate databases for rheumatoid arthritis and adverse pregnancy outcomes, respectively. The inverse-variance weighted method was used as the primary MR analysis, and cML-MA-BIC was used as the supplementary analysis. MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran Q statistic method were implemented as sensitivity analyses approach to ensure the robustness of the results. RESULTS: Our study showed that a higher risk of rheumatoid arthritis in the European population was associated with gestational hypertension (OR: 1.04, 95%CI: 1.02-1.06), pre-eclampsia (OR: 1.06, 95%CI: 1.01-1.11), fetal growth restriction (OR: 1.08, 95%CI: 1.04-1.12), preterm delivery (OR:1.04, 95%CI: 1.01-1.07). Furthermore, we found no evidence that APOs had causal effects on rheumatoid arthritis in the reverse MR analysis. No association between rheumatoid arthritis and APOs was found in East Asian population. There was no heterogeneity or horizontal pleiotropy. CONCLUSIONS: This MR analysis provides the positive causal association from rheumatoid arthritis to gestational hypertension, pre-eclampsia, fetal growth restriction and preterm delivery genetically. It highlights the importance of more intensive prenatal care and early intervention among pregnant women with rheumatoid arthritis to prevent potential adverse obstetric outcomes.

The effect of RNLS gene polymorphisms on preeclampsia susceptibility: a meta-analysis study.

Aim: The authors designed a meta-analysis to find a comprehensive result of the impact of RNLS polymorphisms on preeclampsia (PE) susceptibility. Methods: The online databases PubMed, Scopus, and Google Scholar were employed for the purpose of literature search. Data analysis was conducted using STATA (ver. 12.0) and MetaGenyo web tool. Results: The findings showed that the RNLS rs10887800 polymorphism could increase risk of PE in allelic, codominant heterozygous and dominant genetic models. In addition, the analysis indicated that the RNLS rs2576178 polymorphism was associated with higher risk of PE in allelic, codominant homozygous, dominant, and recessive models. Conclusion: The findings of meta-analysis showed that the RNLS rs10887800 and rs2576178 polymorphisms could increase risk of PE in several genetic models.

[Box: see text].

[Relationship between maternal and fetal ERAP-1 gene polymorphism and pre-eclampsia].

Objective: To investigate the relationship between the polymorphism of endoplasmic reticulum aminopeptidase 1 (ERAP-1) gene and the occurrence of pre-eclampsia (PE). Methods: A case-control study was conducted in Beijing Obstetrics and Gynecology Hospital from October 2018 to October 2021. A total of 51 PE pregnant women with onset gestational age<34 weeks were selected as the PE group, and 48 normal pregnant women during the same period were selected as the control group. Venous blood samples were collected from the pregnant women before delivery and umbilical cord within 5 minutes after delivery. Single nucleotide polymorphisms (SNP) of ERAP-1 gene in the pregnant women and their fetus were detected by next-generation sequencing. Univariate analysis and multivariate logistic regression analysis were used to analyze all the SNP loci and alleles detected in the two groups, and the significant SNP were screened. Results: (1) A total of 13 target SNP loci of maternal ERAP-1 gene were selected by univariate analysis. Among them, the frequency distribution of genotypes at 96096828, 96121524, 96121715, 96122260 and 96122281 showed statistically significant differences between PE group and control group (all P<0.05). Multivariate logistic regression analysis showed that the risk of PE in pregnant women with TC genotype at locus 96121524 was 2.002 times higher than those with TT genotype (95%CI: 0.687-5.831, P=0.020). (2) A total of 4 target SNP loci of ERAP-1 gene in fetal were selected by univariate analysis, and there was no statistical significance in gene polymorphism of the 4 loci between PE group and control group (all P>0.05). Multivariate logistic regression analysis showed that the risk of PE in fetus with genotype AA at locus 96121406 was 0.236 times that of fetus with genotype GG (95%CI: 0.055-1.025, P=0.016). Conclusion: ERAP-1 gene with TC genotype at 96121524 in the mother and GG genotype at 96121406 in the fetus might be related to the incidence of PE.

Upregulation of Siglec-6 induces mitochondrial dysfunction by promoting GPR20 expression in early-onset preeclampsia.

BACKGROUND: Preeclampsia, especially early-onset preeclampsia (EO-PE), is a pregnancy complication that has serious consequences for the health of both the mother and the fetus. Although abnormal placentation due to mitochondrial dysfunction is speculated to contribute to the development of EO-PE, the underlying mechanisms have yet to be fully elucidated. METHODS: The expression and localization of Siglec-6 in the placenta from normal pregnancies, preterm birth and EO-PE patients were examined by RT-qPCR, Western blot and IHC. Transwell assays were performed to evaluate the effect of Siglec-6 on trophoblast cell migration and invasion. Seahorse experiments were conducted to assess the impact of disrupting Siglec-6 expression on mitochondrial function. Co-IP assay was used to examine the interaction of Siglec-6 with SHP1/SHP2. RNA-seq was employed to investigate the mechanism by which Siglec-6 inhibits mitochondrial function in trophoblast cells. RESULTS: The expression of Siglec-6 in extravillous trophoblasts is increased in placental tissues from EO-PE patients. Siglec-6 inhibits trophoblast cell migration and invasion and impairs mitochondrial function. Mechanismly, Siglec-6 inhibits the activation of NF-κB by recruiting SHP1/SHP2, leading to increased expression of GPR20. Notably, the importance of GPR20 function downstream of Siglec-6 in trophoblasts is supported by the observation that GPR20 downregulation rescues defects caused by Siglec-6 overexpression. Finally, overexpression of Siglec-6 in the placenta induces a preeclampsia-like phenotype in a pregnant mouse model. CONCLUSIONS: This study indicates that the regulatory pathway Siglec-6/GPR20 has a crucial role in regulating trophoblast mitochondrial function, and we suggest that Siglec-6 and GPR20 could serve as potential markers and targets for the clinical diagnosis and therapy of EO-PE.

The role of the Chitinase 3-Like 1 (CHI3L1) genes in the preeclampsia pathophysiology.

OBJECTIVE: The aim of this study was to investigate the relationship between Chitinase 3-Like 1 gene polymorphisms and the occurrence of preeclampsia in a selected cohort of pregnant women. METHODS: A total of 75 pregnant women participated in the study, 35 of whom were diagnosed with preeclampsia, while 40 served as healthy controls. The preeclamptic group was subdivided based on severity. Real-time polymerase chain reaction was employed to analyze the serum samples for variations in Chitinase 3-Like 1 gene polymorphisms. RESULTS: The rs880633 polymorphism was found to be significantly more frequent in the control group (80%) compared with the overall preeclamptic group (60%) (p<0.05). In the severity-based subgroups, rs880633 appeared in 57.1% of non-severe and 61.9% of severe preeclamptics. Contrarily, the heterozygous form of rs7515776 polymorphism showed a significantly higher prevalence in the preeclamptic cohort (p<0.05), without distinctions in severity subgroups. CONCLUSION: The study suggests that the rs880633 polymorphism may serve a protective role against the development of preeclampsia, whereas the rs7515776 polymorphism may be associated with an elevated risk. Further research is warranted to elucidate the clinical implications of these findings.

Preeclampsia and STOX1 (storkhead-box protein 1): Molecular evaluation of STOX1 in preeclampsia.

Preeclampsia (PE) is clinically defined as a part of pregnancy characterized by hypertension and multiple organ failure. PE is broadly categorized into two types: "placental" and "maternal". Placental PE is associated with fetal growth restriction and adverse maternal and neonatal outcomes. STOX1 (Storkhead box 1), a transcription factor, discovered through a complete transcript analysis of the PE susceptibility locus of 70,000 bp on chromosome 10q22.1. So far, studies investigating the relationship between STOX1 and PE have focused on STOX1 overexpression, STOX1 isoform imbalance, and STOX1 variations that could have clinical consequence. Initially, the Y153H variation of STOX was associated with the placental form of PE. Additionally, studies focusing on the maternal and fetal interface have shown that NODAL and STOX1 variations play a role together in the unsuccessful remodeling of the spiral arteries. Research specifically addressing the overexpression of STOX1 has shown that its disruption of cellular hemoastasis, leading to impaired hypoxia response, disruption of the cellular antioxidant system, and nitroso/redox imbalance. Furthermore, functional studies have been conducted showing that the imbalance between STOX1 isoforms contributes to the pathogenesis of placental PE. Research indicates that STOX1B competes with STOX1A and that the overexpression of STOX1B reverses cellular changes that STOX1A induces to the pathogenesis of PE. In this review, we aimed at elucidating the relationship between STOX1 and PE as well as function of STOX1. In conclusion, based on a comprehensive literature review, numerous studies support the role of STOX1 in the pathogenesis of PE.

Genetic predictors of blood pressure traits are associated with preeclampsia.

Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University's BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (ORDBP = 1.10, 95% CI 1.02-1.17, p = 7.68 × 10-3; ORSBP = 1.16, 95% CI 1.09-1.23, p = 2.23 × 10-6; ORPP = 1.14, 95% CI 1.07-1.27, p = 9.86 × 10-5). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.

Circulating extracellular vesicular microRNA signatures in early gestation show an association with subsequent clinical features of pre-eclampsia.

In a prospective cohort of subjects who subsequently developed preeclampsia (PE, n = 14) versus remaining healthy (NORM, n = 12), early gestation circulating extracellular vesicles (EVs) containing a panel of microRNA signatures were characterized and their biological networks of targets deciphered. Multiple microRNAs of which some arose from the placenta (19MC and 14MC) demonstrated changes in association with advancing gestation, while others expressed were pathognomonic of the subsequent development of characteristic clinical features of PE which set in as a late-onset subtype. This panel of miRNAs demonstrated a predictability with an area under the curve of 0.96 using leave-one-out cross-validation training in a logistic regression model with elastic-net regularization and precautions against overfitting. In addition, this panel of miRNAs, some of which were previously detected in either placental tissue or as maternal cell-free non-coding transcripts, lent further validation to our EV studies and the observed association with PE. Further, the identified biological networks of targets of these detected miRNAs revealed biological functions related to vascular remodeling, cellular proliferation, growth, VEGF, EGF and the PIP3/Akt signaling pathways, all mediating key cellular functions. We conclude that we have demonstrated a proof-of-principle by detecting a panel of EV packaged miRNAs in the maternal circulation early in gestation with possibilities of biological function in the placenta and other maternal tissues, along with the probability of predicting the subsequent clinical appearance of PE, particularly the late-onset subtype.

Association of Perinatal Cardiovascular Features with Angiotensin System Expressions in Maternal Preeclampsia.

We hypothesized and investigated whether prenatal exposure to preeclampsia (PE) would simultaneously affect perinatal cardiovascular features and angiotensin system expressions. This prospective study was composed of mother-neonate dyads with (n = 49) and without maternal preeclampsia (n = 48) in a single tertiary medical center. The neonates exposed to PE had significantly larger relative sizes for the left and right coronary arteries and a higher cord plasma level of aminopeptidase-N, which positively correlated with the maternal diastolic blood pressures and determined the relative sizes of the left and right coronary arteries, whereas the encoding aminopeptidase-N (ANPEP) mRNA level in the PE cord blood leukocytes was significantly decreased, positively correlated with the neonatal systolic blood pressures (SBPs), and negatively correlated with the cord plasma-induced endothelial vascular cell adhesion molecule-1 mRNA levels. The PE cord plasma significantly induced higher endothelial mRNA levels of angiotensin II type 1 receptor (AT1R) and AT4R, whereas in the umbilical arteries, the protein expressions of AT2R and AT4R were significantly decreased in the PE group. The endothelial AT1R mRNA level positively determined the maternal SBPs, and the AT4R mRNA level positively determined the neonatal chamber size and cardiac output. In conclusion, PE may influence perinatal angiotensin system and cardiovascular manifestations of neonates across placentae. Intriguing correlations between these two warrant further mechanistic investigation.

A hidden proteome encoded by circRNAs in human placentas: Implications for uncovering preeclampsia pathogenesis.

BACKGROUND: CircRNA-encoded proteins (CEPs) are emerging as new players in health and disease, and function as baits for the common partners of their cognate linear-spliced RNA encoded proteins (LEPs). However, their prevalence across human tissues and biological roles remain largely unexplored. The placenta is an ideal model for identifying CEPs due to its considerable protein diversity that is required to sustain fetal development during pregnancy. The aim of this study was to evaluate circRNA translation in the human placenta, and the potential roles of the CEPs in placental development and dysfunction. METHODS: Multiomics approaches, including RNA sequencing, ribosome profiling, and LC-MS/MS analysis, were utilised to identify novel translational events of circRNAs in human placentas. Bioinformatics methods and the protein bait hypothesis were employed to evaluate the roles of these newly discovered CEPs in placentation and associated disorders. The pathogenic role of a recently identified CEP circPRKCB119aa in preeclampsia was investigated through qRT-PCR, Western blotting, immunofluorescence imaging and phenotypic analyses. RESULTS: We found that 528 placental circRNAs bound to ribosomes with active translational elongation, and 139 were translated to proteins. The CEPs showed considerable structural homology with their cognate LEPs, but are more stable, hydrophobic and have a lower molecular-weight than the latter, all of which are conducive to their function as baits. On this basis, CEPs are deduced to be closely involved in placental function. Furthermore, we focused on a novel CEP circPRKCB119aa, and illuminated its pathogenic role in preeclampsia; it enhanced trophoblast autophagy by acting as a bait to inhibit phosphorylation of the cognate linear isoform PKCß. CONCLUSIONS: We discovered a hidden circRNA-encoded proteome in the human placenta, which offers new insights into the mechanisms underlying placental development, as well as placental disorders such as preeclampsia. Key points A hidden circRNA-encoded proteome in the human placenta was extensively identified and systematically characterised. The circRNA-encoded proteins (CEPs) are potentially related to placental development and associated disorders. A novel conserved CEP circPRKCB119aa enhanced trophoblast autophagy by inhibiting phosphorylation of its cognate linear-spliced isoform protein kinase C (PKC) ß in preeclampsia.

[Association of the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene with preeclampsia among Chinese women].

OBJECTIVE: To assess the association of -c.108C>T and c.192Q>R polymorphisms of paraoxonase 1 (PON1) gene with preeclampsia (PE) and the influence of genotypes on the metabolic and oxidative stress indexes among Chinese women. METHODS: This case-control study has included 334 patients with PE and 1337 healthy pregnant women. The -c.108C>T and c.192Q>R genotypes were determined by PCR and restriction fragment length polymorphism method. Metabolic and oxidative stress parameters were also analyzed. RESULTS: No statistical difference in the genotypic and allelic frequencies for the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene was found between the PE patients and the healthy controls (P > 0.05). Nevertheless, the 192Q-108T haplotype of these polymorphisms was associated with an increased risk of PE (P = 0.007). Total antioxidant capacity (TAC) and atherosderosis index were higher in patients with the -108TT genotype compared with those with a CT genotype (P < 0.05); whilst total oxidant status was lower in patients with a CT genotype compared with those with a CC genotype (P = 0.036). Malondialdehyde level was higher in patients with a 192RR genotype compared with those with a QQ genotype (P = 0.019). TAC level was higher in patients with a RR genotype compared with those with a QR genotype (P = 0.015). CONCLUSION: The 192Q-108T haplotype of the PON1 gene is associated with the risk for PE. These polymorphisms may be associated with abnormal lipid metabolism and oxidative stress among Chinese PE patients.

Connecting the Dots: Exploring the Interplay Between Preeclampsia and Peripartum Cardiomyopathy.

Preeclampsia and peripartum cardiomyopathy (PPCM) are significant obstetric problems that can arise during or after pregnancy. Both are known to be causes of maternal mortality and morbidity. Several recent studies have suggested a link between preeclampsia and the pathophysiology of PPCM. However, the common thread that connects the two has yet to be thoroughly and fully articulated. Here, we investigate the complex dynamics of preeclampsia and PPCM in this review. Our analysis focuses mainly on inflammatory and immunological responses, endothelial dysfunction as a shared pathway, and potential genetic predisposition to both diseases. To begin, we will look at how excessive inflammatory and immunological responses can lead to clinical symptoms of both illnesses, emphasizing the role of proinflammatory cytokines and immune cells in modifying vascular and tissue responses. Second, we consider endothelial dysfunction to be a crucial point at which endothelial damage and activation contribute to pathogenesis through increased vascular permeability, vascular dysfunction, and thrombus formation. Finally, we examine recent information suggesting genetic predispositions to preeclampsia and PPCM, such as genetic variants in genes involved in the management of blood pressure, the inflammatory response, and heart structural integrity. With this synergistic study, we seek to encourage more research and creative therapy solutions by emphasizing the need for an interdisciplinary approach to understanding and managing the connection between preeclampsia and PPCM.

RNA-binding protein SORBS2 increases human trophoblast cell migration via stabilizing HK2 mRNA in preeclampsia.

In brief: SORBS2, an RNA-binding protein, is identified as a regulator of aerobic glycolysis, which is essential for trophoblast migration and placental development. Reduced SORBS2 expression in preeclampsia may impair trophoblast migration by affecting mRNA stability and glycolysis, suggesting its role in the disease's pathogenesis. Abstract: Insufficient trophoblast migration and impaired uterine spiral artery remodeling are implicated in the pathogenesis of preeclampsia, contributing to inadequate placentation. However, the molecular mechanism underlying this process remains unclear. Aerobic glycolysis, which produces substantial lactate, is crucial for establishing a favorable microenvironment for early uterine preparation and supporting embryo implantation and trophoblast migration. In the present study, we have demonstrated that SORBS2, an RNA-binding protein, regulated aerobic glycolysis and significantly improved trophoblast migration in vitro. Our results showed that SORBS2 expression was significantly reduced in human PE placentas and trophoblasts during hypoxia. Overexpression of SORBS2 enhanced cell proliferation and migration, whereas knockdown of SORBS2 decreased these functions in HTR-8/SVneo cells. Mechanistic studies have demonstrated that SORBS2 directly interacts with the 3' untranslated regions (UTRs) of key glycolysis-related genes, specifically HK2. This interaction results in enhanced stability of HK2 and activation of glycolysis. Moreover, silencing HK2 abrogated the enhancement of proliferation and migration of HTR-8/SVneo cells induced by SORBS2. In conclusion, our findings suggest that the downregulation of SORBS2 may contribute to the pathogenesis of preeclampsia by regulating mRNA stability and inhibiting trophoblast migration during placentation.