FRP-XGBoost: Identification of ferroptosis-related proteins based on multi-view features.

Ferroptosis represents a novel form of programmed cell death. Pan-cancer bioinformatics analysis indicates that identifying and modulating ferroptosis offer innovative approaches for preventing and treating diverse tumor pathologies. However, the precise detection of ferroptosis-related proteins via conventional wet-laboratory techniques remains a formidable challenge, largely due to the constraints of existing methodologies. These traditional approaches are not only labor-intensive but also financially burdensome. Consequently, there is an imperative need for the development of more sophisticated and efficient computational tools to facilitate the detection of these proteins. In this paper, we presented a XGBoost and multi-view features-based machine learning prediction method for predicting ferroptosis-related proteins, which was referred to as FRP-XGBoost. In this study, we explored four types of protein feature extraction methods and evaluated their effectiveness in predicting ferroptosis-related proteins using six of the most commonly used traditional classifiers. To enhance the representational power of the hybrid features, we employed a two-step feature selection technique to identify the optimal subset of features. Subsequently, we constructed a prediction model using the XGBoost algorithm. The FRP-XGBoost achieved an accuracy of 96.74 % in 10-fold cross-validation and a further accuracy of 91.52 % in an independent test. The implementation source code of FRP-XGBoost is available at https://github.com/linli5417/FRP-XGBoost.

Multi-omics reveals the switch role of abnormal methylation in the regulation of decidual macrophages function in recurrent spontaneous abortion.

RSA, recurrent spontaneous abortion, often causes serious physical damage and psychological pressure in reproductive women with unclarified pathogenesis. Abnormal function of decidual cells and aberrant DNA methylation have been reported to cause RSA, but their association remains unclear. Here, we integrated transcriptome, DNA methylome, and scRNA-seq to clarify the regulatory relationship between DNA methylation and decidual cells in RSA. We found that DNA methylation mainly influenced the function of decidual macrophages (DMs), of which four hub genes, HLA-A, HLA-F, SQSTM1/P62, and Interferon regulatory factor 7 (IRF7), related to 22 hypomethylated CpG sites, regulated 16 hub pathways to participate in RSA pathogenesis. In particular, using transcription factor analysis, it is suggested that the upregulation of IRF7 transcription was associated with enhanced recruitment of the transcription factor STAT1 by the hypomethylated promoter region of IRF7. As the current research on DNA methylation of macrophages in the uterine microenvironment of RSA is still blank, our systematic picture of abnormal DNA methylation in regulating DM function provides new insights into the role of DNA methylation in RSA occurrence, which may aid in further prevention and treatment of RSA.

Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity.

Macrophages play a crucial role in shaping the immune state within the tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs toward an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and a high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications.

Hydrogen sulfide inhibits the rupture of fetal membranes throngh anti-aging pathways.

INTRODUCTION: To investigate the relationship between hydrogen sulfide(H2S) and the senescence level of the fetal membranes, and to elucidate how H2S affects the integrity of the fetal membranes. METHODS: The H2S and the senescence levels of fetal membranes, and the expressions of H2S synthase CBS and CSE were detected in the preterm (PT) group and the preterm premature ruptured membranes (pPROM) group. The effects of H2S donors and knockdown of CBS on the senescence level of amniotic epithelial cells, and the expression level of matrix metalloproteinases (MMPs) and epithelial-mesenchymal translation (EMT) were observed. RESULTS: The level of H2S in the fetal membranes in the pPROM group is significantly lower than that in the PT group matched for gestational age. The level of H2S is negatively correlated with the senescence level of fetal membranes. Treatment with H2S donors reduced cell senescence and MMPs expression, but did not affect EMT. CBS siRNA transfection accelerated the senescence of amniotic epithelial cells, and promoted the expression of MMPs and EMT occurrence, but l-cysteine could reverse these effects. DISCUSSION: Our study suggests that H2S, through its anti-aging effect, can influence the expression of MMPs and EMT, thereby contributing to the maintenance of fetal membrane integrity.

Identification of the hub genes in polycystic ovary syndrome based on disease-associated molecule network.

Revealing the key genes involved in polycystic ovary syndrome (PCOS) and elucidating its pathogenic mechanism is of extreme importance for the development of targeted clinical therapy for PCOS. Investigating disease by integrating several associated and interacting molecules in biological systems will make it possible to discover new pathogenic genes. In this study, an integrative disease-associated molecule network, combining protein-protein interactions and protein-metabolites interactions (PPMI) network was constructed based on the PCOS-associated genes and metabolites systematically collected. This new PPMI strategy identified several potential PCOS-associated genes, which have unreported in previous publications. Moreover, the systematic analysis of five benchmarks data sets indicated the DERL1 was identified as downregulated in PCOS granulosa cell and has good classification performance between PCOS patients and healthy controls. CCR2 and DVL3 were upregulated in PCOS adipose tissues and have good classification performance. The expression of novel gene FXR2 identified in this study is significantly increased in ovarian granulosa cells of PCOS patients compared with controls via quantitative analysis. Our study uncovers substantial differences in the PCOS-specific tissue and provides a plethora of information on dysregulated genes and metabolites that are linked to PCOS. This knowledgebase could have the potential to benefit the scientific and clinical community. In sum, the identification of novel gene associated with PCOS provides valuable insights into the underlying molecular mechanisms of PCOS and could potentially lead to the development of new diagnostic and therapeutic strategies.

CCL21/CCR7 Axis Contributes to Trophoblastic Cell Migration and Invasion in Preeclampsia by Affecting the Epithelial Mesenchymal Transition via the ERK1/2 Signaling Pathway.

Preeclampsia (PE) is a pregnancy-related disorder that is a leading cause of maternal death. The failure of spiral artery remodeling due to insufficient trophoblast migration and invasion is critical in the pathogenesis of PE. Recently, the CC motif chemokine ligand 21 (CCL21) has been widely linked to cancer cell invasion and migration. However, their potential mechanisms are still unknown. In this study, we found that CCL21 expression was significantly lower in the PE group than that in the control group. In vitro experiments revealed that recombinant CCL21 could promote trophoblast cell epithelial-to-mesenchymal transitions (EMTs) and improve migration and invasion. Furthermore, an inhibitor of the ERK1/2 signaling pathway inhibited the CCL21-induced EMT process. Finally, a PE mouse model was established using the NOS inhibitor L-NAME, and we obtained similar results, with downregulated CCL21 and EMT biomarkers and upregulated CCR7. Taken together, these findings suggest that the CCL21/CCR7 axis influences EMT by activating the ERK1/2 signaling pathway, thereby affecting trophoblast cell migration and invasion, which may play a crucial role in the pathogenesis of PE.

CPT1A modulates PI3K/Akt/mTOR pathway to promote preeclampsia.

INTRODUCTION: Preeclampsia (PE) refers to a syndrome of new-onset hypertension with multisystem involvement and damage after 20 weeks of gestation. Defective placentation due to dysregulated behaviors of trophoblast cells is considered a predominant cause of PE. METHODS: Immunofluorescence (if) and Western blot were used to detect the expression and localization of Carnitine palmitoyltransferase 1A (CPT1A) in placenta. CPT1A protein was overexpressed/knocked down in HTR8/SVneo cells by lentiviral/siRNA interference method. CCK-8 Assay, Western blot, flow cytometry, Wound healing and Transwell assay were used to detect the functional impact of CPT1A on HTR8/SVneo cells. Transcriptomics and bioinformatics analysis were used to predict the possible pathway of CPT1A participating in PE. RESULTS: CPT1A was upregulated in preeclamptic placentas when compared with normal controls. The abnormal expression of CPT1A in HTR8/SVneo cells is associated with the invasion and migration of HTR8/SVneo cells but is not related to the proliferation, cycle, and apoptosis of HTR8/SVneo cells. The results of Transcriptomic and Western blots suggest that phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway are activated in the si-CPT1A-1796 group. Compared with the si-NC group, the epithelial-mesenchymal transition (EMT) process of HTR8/SVneo cells in the si-CPT1A- 1796 group was significantly enhanced. DISCUSSION: CPT1A may participate in the pathogenesis of PE by inhibiting the EMT process of HTR8/SVneo cells through the PI3K/AKT/mTOR signaling axis. Thus, the newly unveiled novel function of CPT1A in PE via the PI3K/Akt/mTOR pathway provides a novel insight into the pathogenesis of PE.

[Glucose Metabolism-Derived Nicotinamide Adenine Dinucleotide Phosphate in Late-Onset Preeclampsia Placenta Tissue and Its Correlation with Oxidative Stress].

Objective: To study the changes in the expression of nicotinamide adenine dinucleotide phosphate (NADPH), a glucose metabolism-derived antioxidant, in late-onset preeclampsia (LOPE) placenta tissue and the correlation with oxidative stress. Methods: A total of 13 normal pregnant women and 13 pregnant women with LOPE who were hospitalized in the Obstetrics Department, the First Affiliated Hospital of Chongqing Medical University and who underwent elective cesarean section between November 2020 and October 2021 were included in the study. Placenta tissues were collected from the subjects. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was done to determine the ROS levels in the placenta tissues of the LOPE group and the normal control group. Spectrophotometric analysis was conducted to determine the levels of NADPH, glutathione (GSH), and glucose, and the expressions and activities of glucose-6-phosphate dehydrogenase (G6PD) and phospho-gluconate dehydrogenase (PGD), key rate-limiting enzymes of the pentose phosphate pathway (PPP), in the placenta tissues of the LOPE group and the normal control group. Western blot was done to determine changes in the protein expressions of phosphofructokinase 1 (PFK1), a key rate-limiting enzyme of the glycolytic pathway, G6PD, and PGD in the placenta tissues from the two groups. Results: ROS levels in the placenta tissue of the LOPE group were significantly higher than those of the control group ( P<0.05). The levels of NADPH and GSH, two antioxidants, and glucose in the LOPE placenta were significantly higher than those of the control group ( P<0.05). The expression of PFK1 was significantly elevated in the LOPE group ( P<0.05). However, there were no significant differences in the activities and protein expression of G6PD and PGD between the two groups. Conclusion: Glucose metabolism reprogramming takes place in LOPE placenta tissue, which may be one of the causes of the abnormal elevation of NADPH and GSH.

TOP2A deficit-induced abnormal decidualization leads to recurrent implantation failure via the NF-κB signaling pathway.

BACKGROUND: Successful implantation is a complex process that is influenced by embryo quality, endometrial receptivity, immune factors, and the specific type of in vitro fertilization protocol used. DNA topoisomerase IIα (TOP2A) is a well-known protein involved in cell proliferation; however, its expression and effect on the endometrium in recurrent implantation failure (RIF) have not been fully elucidated. METHODS: The human endometrial tissues of healthy controls and patients with RIF were collected. A proteomic analysis was performed to evaluate the differentially expressed proteins between the RIF group and the fertile control group. The expression patterns of TOP2A in the human preimplantation endometrium of the patients with RIF were determined by immunohistochemical staining, Western blotting and qRT-PCR. TOP2A knockdown (sh-TOP2A) T-HESCs were generated using lentiviruses. The expression of TOP2A in T-HESCs was manipulated to investigate its role in decidualization. The TOP2A-related changes in decidualization were screened by mRNA sequencing in decidualized TOP2A knockdown and control T-HESCs and then confirmed by Western blotting and immunofluorescence staining. TOP2A-deficient mice were generated by injection of TOP2A-interfering adenovirus on GD2.5 and GD3.5. RESULTS: We performed a proteomic analysis of endometrial tissues to investigate the potential pathogenesis of RIF by comparing the patients with RIF and the matched controls and found that TOP2A might be a key protein in RIF. TOP2A is ubiquitously expressed in both stromal and glandular epithelial cells of the endometrium. The data indicate that TOP2A expression is significantly lower in the mid-secretory endometrium of women with RIF. TOP2A expression was downregulated under stimulation by 8-bromo-cAMP and MPA. Ablation of TOP2A resulted in upregulated expression of decidual biomarkers and morphological changes in the cells. Mechanistic analysis revealed that TOP2A regulates the NF-κB signaling pathway in decidualized T-HESCs. The TOP2A-deficient mice exhibited lower fetal weights. CONCLUSIONS: Our findings revealed that abnormal expression of TOP2A affects decidualization and changes the "window of implantation", leading to RIF. TOP2A participates in the processes of decidualization and embryo implantation, functioning at least in part through the NF-κB pathway. Regulating the expression of TOP2A in the endometrium may become a new strategy for the prevention and treatment of RIF.

Reactive Oxygen Species are Essential for Placental Angiogenesis During Early Gestation.

Background: Preeclampsia (PE) is associated with insufficient placental perfusion attributed to maldevelopment of the placental vasculature. Reactive oxygen species (ROS) are implicated in angiogenesis, but their regulatory effects and mechanisms in placental vascular development remain unclear. Methods: Placental oxidative stress was determined throughout gestation by measuring 4-hydroxynonenal (4HNE) and malondialdehyde (MDA). The antioxidant MitoQ was administered to pregnant mice from GDs 7.5 to 11.5; placental morphology and angiogenesis pathways were examined on GDs 11.5 and 18.5. Moreover, we established a mouse mFlt-1-induced PE model and assessed blood pressure, urine protein levels, and placental vascular development on GDs 11.5 and 18.5. Human umbilical vein endothelial cells (HUVECs) were treated with various H2O2 concentrations to evaluate cell viability, intracellular ROS levels, and tube formation capability. MitoQ, an AKT inhibitor and an ERK1/2 inhibitor were applied to validate the ROS-mediated mechanism regulating placental angiogenesis. Results: First-trimester placentas presented significantly higher MDA and 4HNE levels. MitoQ significantly reduced the blood vessel density and angiogenesis pathway activity in the placenta on GDs 11.5 and 18.5. Serum sFlt-1 levels were elevated, and we observed poor placental angiogenesis and PE-like symptoms in cases with mFlt-1 overexpression. Moderate H2O2 treatment promoted HUVEC proliferation and angiogenesis, whereas these improvements were abolished by MitoQ, AKT inhibitor, or ERK1/2 inhibitor treatment. Conclusions: Moderate ROS levels are essential for placental angiogenesis; diminishing ROS with potent antioxidants during placentation decreases placental angiogenesis and increases PE risk. Therefore, antioxidant therapy should be considered carefully for normal pregnant women during early gestation.

Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs.

Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.

Alterations in Fetal Doppler Parameters Before and Twenty-Four Hours After Radiofrequency Ablation for Twin Reversed Arterial Perfusion Sequence.

Objective: To evaluate alterations in the fetal Doppler parameters of pump fetuses before and 24 h after radiofrequency ablation surgery for twin reversed arterial perfusion sequence (TRAPs). Methods: This is a retrospective study of 28 pump fetuses in TRAPs and 28 normal control twins between 2016 and 2021. The fetal Doppler parameters, including the umbilical artery pulsatility index (UA-PI), middle cerebral artery peak systolic velocity (MCA-PSV), middle cerebral artery pulsatility index (MCA-PI), and cerebroplacental ratio (CPR), of the controls, and pump fetuses before and 24 h after surgery were compared. Results: An increasing trend and a further increase in the MCA-PSV, MCA-PI, MCA-PSV Z score, and MCA-PI Z score after surgery were observed in pump fetuses with gestational age (GA) ≥20 weeks; however, such changes were not observed in those with a GA of <20 weeks. The UA-PI and CPR before and after surgery were not different between control and pump fetuses, whether the GA was ≥20 or <20 weeks. Conclusion: In the middle second trimester, the pump fetus might suffer from high cardiac output rather than hypoxemia before surgery and congestive heart failure, or hemodilutional anemia after surgery. This may provide some theoretical evidence in favor of early intervention, rather than waiting for a more advanced GA, to avoid unnecessary hemodynamic alterations.

Comprehensive Metabolomic Profiling of Cord Blood and Placental Tissue in Surviving Monochorionic Twins Complicated by Twin-Twin Transfusion Syndrome With or Without Fetoscopic Laser Coagulation Surgery: A Retrospective Cohort Study.

Objectives: To investigate metabolomic perturbations caused by twin-twin transfusion syndrome, metabolic changes associated with fetoscopic laser coagulation in both placental tissue and cord plasma, and to investigate differential metabolites pertinent to varying fetal outcomes, including hemodynamic status, birth weight, and cardiac function, of live-born babies. Methods: Placental tissue and cord plasma samples from normal term or uncomplicated preterm-born monochorionic twins and those complicated by twin-twin transfusion syndrome treated with or without fetoscopic laser coagulation were analyzed by high-performance liquid chromatography metabolomic profiling. Sixteen comparisons of different co-twin groups were performed. Partial least squares-discriminant analysis, metabolic pathway analysis, biomarker analysis, and Spearman's correlation analysis were conducted based on differential metabolites used to determine potential biomarkers in different comparisons and metabolites that are pertinent to neonatal birth weight and left ventricular ejection fraction. Results: These metabolomic investigations showed that the cord plasma metabolome has a better performance in discriminating fetuses among different hemodynamic groups than placental tissue. The metabolic alteration of twin-twin transfusion syndrome in these two types of samples centers on fatty acid and lipid metabolism. The fetoscopic laser coagulation procedure improves the metabolomic change brought by this syndrome, making the metabolomes of the treated group less distinguishable from those of the control and preterm birth groups. Certain compounds, especially lipids and lipid-like molecules, are noted to be potential biomarkers of this morbid disease and pertinent to neonatal birth weight and ejection fraction. Conclusions: Fetoscopic laser coagulation can ameliorate the metabolomic alteration caused by twin-twin transfusion syndrome in placental tissue and cord plasma, which are involved mainly in fatty acid and lipid-like molecule metabolism. Certain lipids and lipid-like molecules are helpful in differentiating co-twins of different hemodynamic statuses and are significantly correlated with neonatal birth weight or ejection fraction.

Investigation and Validation of Molecular Characteristics of Endometrium in Recurrent Miscarriage and Unexplained Infertility from a Transcriptomic Perspective.

Recurrent miscarriage (RM) and unexplained infertility (UI) are gordian knots in reproductive medicine, which are troubling many patients, doctors, and researchers. Although these two diseases of early pregnancy have a significant impact on human reproductive health, little is known about the specific mechanisms, which caused treatment difficulties. This study focused on the molecular signatures underlying the pathological phenotypes of two diseases, with the hope of using statistical methods to identify the significant core genes. An unbiased Weighted Correlation Network Analysis (WGCNA) algorithm was used for endometrial transcriptome data analysis and the disease-related gene modules were screened out. Through enrichment analysis of the candidate genes, we found similarities between both diseases and shared enrichment of immune-related pathways. Therefore, we used immune algorithms to assess the infiltration of immune cells and found abnormal increases of CD8+T cells and neutrophils. In order to explore the molecular profile behind the immunophenotypic changes, we used the SVM algorithm and LASSO regression to identify the core genes with diagnostic capacity in both diseases and discussed their significance of immune disorders in the endometrium. In the end, the satisfactory diagnostic ability of these core genes was verified in the broader group. Our results demonstrated the presence of immune disorders in non-pregnancy tissues of RM and UI, and identified the core molecules of this phenotype, and discuss mechanisms. This provides exploratory evidence for the in-depth understanding of the mechanism of RM and UI and may provide potential targets for their future treatment.

The effects of gestational diabetes mellitus with maternal age between 35 and 40 years on the metabolite profiles of plasma and urine.

BACKGROUND: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance in pregnancy and without a history of diabetes mellitus. While there are limited metabolomic studies involving advanced maternal age in China, we aim to investigate the metabolomic profiling of plasma and urine in pregnancies complicated with GDM aged at 35-40 years at early and late gestation. METHODS: Twenty normal and 20 GDM pregnant participants (≥ 35 years old) were enlisted from the Complex Lipids in Mothers and Babies (CLIMB) study. Maternal plasma and urine collected at the first and third trimester were detected using gas chromatography-mass spectrometry (GC-MS). RESULTS: One hundred sixty-five metabolites and 192 metabolites were found in plasma and urine respectively. Urine metabolomic profiles were incapable to distinguish GDM from controls, in comparison, there were 14 and 39 significantly different plasma metabolites between the two groups in first and third trimester respectively. Especially, by integrating seven metabolites including cysteine, malonic acid, alanine, 11,14-eicosadienoic acid, stearic acid, arachidic acid, and 2-methyloctadecanoic acid using multivariant receiver operating characteristic models, we were capable of discriminating GDM from normal pregnancies with an area under curve of 0.928 at first trimester. CONCLUSION: This study explores metabolomic profiles between GDM and normal pregnancies at the age of 35-40 years longitudinally. Several compounds have the potential to be biomarkers to predict GDM with advanced maternal age. Moreover, the discordant metabolome profiles between the two groups could be useful to understand the etiology of GDM with advanced maternal age.

Conservative management versus cesarean hysterectomy in patients with placenta increta or percreta.

OBJECTIVE: To compare conservative management and cesarean hysterectomy in patients with placenta increta or percreta. MATERIALS AND METHODS: In this multicenter retrospective study, we recorded data on 2219 patients with placenta increta or percreta from 20 tertiary care centers in China from 1 January 2011 to 31 December 2015. Propensity score analysis was used to control for baseline characteristics. We divided patients into conservative management (C) and hysterectomy (H) groups. The primary outcome was operative/postoperative maternal morbidity; secondary outcomes were maternal-neonatal outcomes. RESULTS: In total, 17.9% (398/2219) of patients had placenta increta and percreta; 82.1% (1821/2219) of the patients were in group C. After propensity score matching, 140 pairs of patients from the two groups underwent one-to-one matching. Group C showed less average blood loss within 24 h of surgery (1518 ± 1275 vs. 4309 ± 2550 ml in group H, p<.001). There were more patients with blood loss >1000 ml in group H than in group C (93.6% [131/140] vs. 61.4% [86/140], p<.001). More patients received blood transfusions in group H than in group C (p=.014). There was no significant difference between the groups in terms of bladder injury, postoperative anemia, fever, and disseminated intravascular coagulation. Neonatal outcomes in the two groups were similar. CONCLUSION: Either conservative management or hysterectomy should be considered after thorough evaluation and detailed discussion of risks and benefits. A balance between bleeding control and fertility can be achieved.

Elevated Serum SFRP5 Levels During Preeclampsia and Its Potential Association with Trophoblast Dysfunction via Wnt/ß-Catenin Suppression.

Preeclampsia (PE) is a life-threatening pregnancy complication associated with diminished trophoblast migration and invasion. Wnt signalling is one of the most important regulators of placentation. Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that may inhibit Wnt signalling. In this study, we aimed to investigate the relationship between SFRP5 and PE and its effect on trophoblast function, as well as the underlying signalling pathways. SFRP5 levels in the serum and placental tissues were detected using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. To evaluate the effect of SFRP5 on Wnt signalling, the human trophoblast cell line HTR8/SVneo was treated with recombinant human SFRP5 and Dickkopf-related protein 1 (Dkk-1, canonical Wnt inhibitor) proteins and lithium chloride (LiCl, canonical Wnt agonist). The migration and invasion ability of HTR8/SVneo cells was evaluated using wound-healing and Matrigel Transwell assays. The activities of multiple matrix metalloproteinases (MMP)-2/9 were detected using gelatin zymography. Expression of glycogen synthase kinase-3 beta (GSK3ß) and ß-catenin proteins was investigated using western blotting. The serum SFRP5 levels were elevated in patients with PE, but SFRP5 expression was not detected in the placental tissues. Furthermore, SFRP5 inhibited the migration and invasion of HTR8/SVneo cells in vitro, increased GSK3ß, and decreased ß-catenin expression and MMP-2/9 activity in HTR8/SVneo cells. In conclusion, this study suggests that SFRP5 inhibits trophoblast migration and invasion potentially via the inhibition of Wnt/ß-catenin signalling, which might be involved in the development of PE. However, the primary cause of the increased SFRP5 levels needs to be investigated.

The clinical evaluation of preoperative abdominal aortic balloon occlusion for patients with placenta increta or percreta.

OBJECTIVE: To evaluate the efficacy and safety of abdominal aortic balloon for pregnant women with placenta increta or percreta (PIP). METHODS: Retrospective analysis of the parameters containing estimated blood loss, red cell suspension (RCS) transfusion volume, hysterectomy, surgery time, postoperative hospital days, neonatal status and complications between the two groups. RESULTS: The patients with preoperative abdominal aortic balloon occlusion (AABO) had significant reduction in blood loss volume, red cell suspension transfusion volume and plasma transfusion volume compared to patients without balloon. Similarly, the surgery time and hysterectomy were obviously reduced in the AABO group. However, there were no difference in the Apgar scores and neonatal complications between the two groups, indicating that the abdominal aortic balloon has little adverse effect on the newborns. CONCLUSION: AABO plays dramatic roles on reducing blood loss volume and blood transfusion volume and it is also a safe and effective technology providing new insight into the therapy of patient with PIP. SYNOPSIS: Preoperative abdominal aortic balloon occlusion (AABO), as a new intravascular interventional therapy, is safe and effective in patients with placenta increta or percreta.

Impaired Sphingosine-1-Phosphate Synthesis Induces Preeclampsia by Deactivating Trophoblastic YAP (Yes-Associated Protein) Through S1PR2 (Sphingosine-1-Phosphate Receptor-2)-Induced Actin Polymerizations.

Incomplete spiral artery remodeling, caused by impaired extravillous trophoblast invasion, is a fundamental pathogenic process associated with malplacentation and the development of preeclampsia. Nevertheless, the mechanisms controlling this regulation of trophoblast invasion are largely unknown. We report that sphingosine-1-phosphate synthesis and expression is abundant in healthy trophoblast, whereas in pregnancies complicated by preeclampsia the placentae are associated with reduced sphingosine-1-phosphate and lower SPHK1 (sphingosine kinase 1) expression and activity. In vivo inhibition of sphingosine kinase 1 activity during placentation in pregnant mice led to decreased placental sphingosine-1-phosphate production and defective placentation, resulting in a preeclampsia phenotype. Moreover, sphingosine-1-phosphate increased HTR8/SVneo (immortalized human trophoblst cells) cell invasion in a Hippo-signaling-dependent transcriptional coactivator YAP (Yes-associated protein) dependent manner, which is activated by S1PR2 (sphingosine-1-phosphate receptor-2) and downstream RhoA (Ras homolog gene family, member A)/ROCK (Rho-associated protein kinase) induced actin polymerization. Mutation-based YAP-5SA (S61A, S109A, S127A, S164A, S381A) demonstrated that sphingosine-1-phosphate activation of YAP could be either dependent or independent of Hippo signaling. Together, these findings suggest a novel pathogenic pathway of preeclampsia via disrupted sphingosine-1-phosphate metabolism and signaling-induced, interrupted actin dynamics and YAP deactivation; this may lead to potential novel intervention targets for the prevention and management of preeclampsia.

Elabela: Negative Regulation of Ferroptosis in Trophoblasts via the Ferritinophagy Pathway Implicated in the Pathogenesis of Preeclampsia.

Preeclampsia is a leading contributor to increased maternal morbidity and mortality in the perinatal period. Increasing evidence demonstrates that ferroptosis is an essential mechanism for the pathogenesis of preeclampsia. Elabela is a novel small-molecule polypeptide, mainly expressed in embryonic and transplacental tissues, with an ability to promote cell proliferation and invasion. However, its specific regulatory mechanism in preeclampsia has not been completely elucidated. In this study, we first reveal an increased grade of ferroptosis accompanied by a downregulation of the expression of Elabela in preeclampsia placentas. We then confirm the presence of a ferroptosis phenotype in the placenta of the mouse PE-like model, and Elabela can reduce ferroptosis in the placenta and improve adverse pregnancy outcomes. Furthermore, we demonstrate that targeting Elabela alleviates the cellular dysfunction mediated by Erastin promoting increased lipid peroxidation in vitro. Subsequent mechanistic studies suggest that Elabela increases FTH1 levels by inhibiting the ferritinophagy pathway, and consequently chelates the intracellular labile iron pool and eventually arrests ferroptosis. In conclusion, Elabela deficiency exacerbates ferroptosis in the placenta, which is among the potential mechanisms in the pathogenesis of preeclampsia. Targeting the Elabela-ferritinophagy-ferroptosis signaling axis provides a new therapeutic intervention strategy to alleviate preeclampsia.