Endothelial progenitor cells control remodeling of uterine spiral arteries for the establishment of utero-placental circulation.

Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia.

Maternal vitamin D status and risk of gestational diabetes mellitus in twin pregnancies: a longitudinal twin pregnancies birth cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common complication of pregnancy, with significant short-term and long-term implications for both mothers and their offspring. Previous studies have indicated the potential benefits of vitamin D in reducing the risk of GDM, yet little is known about this association in twin pregnancies. This study aimed to investigate maternal vitamin D status in the second trimester and examine its association with the risk of GDM in twin pregnancies. METHODS: We conducted a prospective cohort study based on data from the Chongqing Longitudinal Twin Study (LoTiS). Peripheral blood serum was collected from the mothers in the second trimester to measure 25(OH)D concentrations. GDM was diagnosed at 23-26 weeks of gestation using a 75-g 2-h oral glucose tolerance test. We used multivariable logistic regression analyses to examine the correlations between vitamin D status and the risk of GDM. RESULTS: Of the total participants, 93 (29.9%) women were diagnosed with GDM. The mean serum 25(OH)D concentration in the second trimester was 31.1 ± 11.2 ng/mL, and the rate of vitamin D insufficiency and deficiency were 23.5% and 18.7%, respectively. Compared to women with a 25(OH)D concentration < 30 ng/mL, those with a 25(OH)D concentration ≥ 30 ng/mL had a significantly lower risk of GDM (RR 0.61; 95% CI: 0.43, 0.86), especially those who were overweight before pregnancy (RR 0.32; 95% CI: 0.16, 0.64). The restricted cubic splines model showed an inverted J-shaped relationship between vitamin D concentrations and GDM risk. CONCLUSIONS: The risk of GDM was significantly reduced in twin pregnant women with vitamin D concentrations ≥ 30 ng/mL in the second trimester. TRIAL REGISTRATION: ChiCTR-OOC-16,008,203. Retrospectively registered on 1 April 2016.

Temperature-dependent excitonic emission characteristics of highly crystallized carbon nitride nanosheets.

Highly-crystallized carbon nitride (HCCN) nanosheets exhibit significant potential for advancements in the field of photoelectric conversion. However, to fully exploit their potential, a thorough understanding of fundamental excitonic photophysical processes is crucial. Here, the temperature-dependent excitonic photoluminescence (PL) of HCCN nanosheets and amorphous polymeric carbon nitride (PCN) is investigated using steady-state and time-resolved PL spectroscopy. The exciton binding energy of HCCN is determined to be 109.26 meV, lower than that of PCN (207.39 meV), which is attributed to the ordered stacking structure of HCCN with a weaker Coulomb interaction between electrons and holes. As the temperature increases, a noticeable reduction in PL lifetime is observed on both the HCCN and PCN, which is ascribed to the thermal activation of carrier trapping by the enhanced electron-phonon coupling effect. The thermal activation energy of HCCN is determined to be 102.9 meV, close to the value of PCN, due to their same band structures. Through wavelength-dependent PL dynamics analysis, we have identified the PL emission of HCCN as deriving from the transitions: σ*-LP, π*-π, and π*-LP, where the π*-LP transition dominants the emission because of the high excited state density of the LP state. These results demonstrate the impact of high-crystallinity on the excitonic emission of HCCN materials, thereby expanding their potential applications in the field of photoelectric conversion. .

Causal relationship between gestational diabetes and preeclampsia: A bidirectional mendelian randomization analysis.

AIMS: The study aimed to explore the potential causal link between gestational diabetes mellitus (GDM) and preeclampsia (PE) using a bidirectional mendelian randomization (MR) analysis. MATERIALS: We conducted a bidirectional MR analysis to investigate the causal relationship between GDM and PE. Data from public genome-wide association studies (GWAS) for GDM and PE were obtained from the FinnGen consortium. Various MR methods were employed, including inverse-variance weighted (IVW), MR-Egger, and sensitivity analyses. Additionally, a knowledge-based approach identified genes underlying this potential connection. RESULTS: The IVW method revealed a lack of significant association between GDM and PE (OR: 1.04, 95 % CI: 0.96-1.14; p = 0.275). Conversely, IVW analysis indicated a causal connection from PE to GDM (OR: 1.14, 95 % CI: 1.06-1.23; p < 0.001). Molecular pathway analysis identified 20 key genes, including ASAP2, central to the PE-GDM relationship. Tissue enrichment analysis showed pertinent gene expression in significant tissues. Moreover, lower ASAP2 expression was detected in PE patients' placentas. CONCLUSIONS: Our bidirectional MR analysis offers evidence supporting a causal link between PE and GDM, elucidating their interconnected pathogenesis. Genetic and knowledge-based insights facilitate a deeper comprehension of these complex pregnancy complications.

METTL3 promotes trophoblast ferroptosis in preeclampsia by stabilizing the ACSL4 m6A modification.

This study aims to explore the role of methyltransferase-like 3 (METTL3) modulation of ferroptosis in the pathogenesis of trophoblast-mediated preeclampsia. The expression of METTL3 and acyl-CoA synthetase long chain family member 4 (ACSL4) was measured in clinical placental tissues and trophoblasts using qPCR and Western blot techniques. The effects of METTL3 on the symptoms of preeclampsia were also validated in rat models. METTL3 and ACSL4 were upregulated in placental tissues from patients with preeclampsia and in hypoxia-induced trophoblasts. METTL3 silencing increased the migration and invasion of trophoblasts cultured under hypoxic conditions. Knockdown of METTL3 increased cell viability and suppressed ferroptosis in hypoxia-stimulated trophoblasts. Hypoxia increased the level of m6A in cells, whereas silencing METTL3 partially reversed this change. Silencing METTL3 resulted in a decrease in m6A modification of ACSL4 mRNA, which led to a reduction in ACSL4 mRNA stability. ACSL4 upregulation partially reversed the effects of METTL3 silencing on cell viability, migration, invasion, and ferroptosis in hypoxia-stimulated trophoblasts. Inhibition of METTL3 in preeclampsia rats decreased blood pressure, urine protein levels, fetal survival rate, and ACSL4-mediated ferroptosis. METTL3 elevates ferroptosis to inhibit the migration and invasion of trophoblasts and in vivo preeclampsia symptoms by catalyzing the m6A modification of ACSL4 mRNA.

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).

A multi-tissue metabolome atlas of primate pregnancy.

Pregnancy induces dramatic metabolic changes in females; yet, the intricacies of this metabolic reprogramming remain poorly understood, especially in primates. Using cynomolgus monkeys, we constructed a comprehensive multi-tissue metabolome atlas, analyzing 273 samples from 23 maternal tissues during pregnancy. We discovered a decline in metabolic coupling between tissues as pregnancy progressed. Core metabolic pathways that were rewired during primate pregnancy included steroidogenesis, fatty acid metabolism, and arachidonic acid metabolism. Our atlas revealed 91 pregnancy-adaptive metabolites changing consistently across 23 tissues, whose roles we verified in human cell models and patient samples. Corticosterone and palmitoyl-carnitine regulated placental maturation and maternal tissue progenitors, respectively, with implications for maternal preeclampsia, diabetes, cardiac hypertrophy, and muscle and liver regeneration. Moreover, we found that corticosterone deficiency induced preeclampsia-like inflammation, indicating the atlas's potential clinical value. Overall, our multi-tissue metabolome atlas serves as a framework for elucidating the role of metabolic regulation in female health during pregnancy.

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.

Association of Paternal Age Alone and Combined with Maternal Age with Perinatal Outcomes: A Prospective Multicenter Cohort Study in China.

Maternal and paternal age at birth is increasing globally. Maternal age may affect perinatal outcomes, but the effect of paternal age and its joint effect with maternal age are not well established. This prospective, multicenter, cohort analysis used data from the University Hospital Advanced Age Pregnant Cohort Study in China from 2016 to 2021, to investigate the separate association of paternal age and joint association of paternal and maternal age with adverse perinatal outcomes. Of 16,114 singleton deliveries, mean paternal and maternal age (± SD) was 38.0 ± 5.3 years and 36.0 ± 4.1 years. In unadjusted analyses, older paternal age was associated with increased risks of gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy, preeclampsia, placenta accreta spectrum disorders, placenta previa, cesarean delivery (CD), and postpartum hemorrhage, preterm birth (PTB), large-for-gestational-age, macrosomia, and congenital anomaly, except for small-for-gestational-age. In multivariable analyses, the associations turned to null for most outcomes, and attenuated but still significant for GDM, CD, PTB, and macrosomia. As compare to paternal age of < 30 years, the risks in older paternal age groups increased by 31-45% for GDM, 17-33% for CD, 32-36% for PTB, and 28-31% for macrosomia. The predicted probabilities of GDM, placenta previa, and CD increased rapidly with paternal age up to thresholds of 36.4-40.3 years, and then plateaued or decelerated. The risks of GDM, CD, and PTB were much greater for pregnancies with younger paternal and older maternal age, despite no statistical interaction between the associations related to paternal and maternal age. Our findings support the advocation that paternal age, besides maternal age, should be considered during preconception counseling.Trial Registration NCT03220750, Registered July 18, 2017-Retrospectively registered, https://classic.clinicaltrials.gov/ct2/show/NCT03220750 .

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.

Incidence, risk factors and maternal outcomes of unsuspected placenta accreta spectrum disorders: a retrospective cohort study.

BACKGROUND: To identify incidence and underlying risk factors for unsuspected placenta accreta spectrum (PAS) and compare the maternal outcomes between suspected and unsuspected cases in three large academic referral centers. METHODS: A retrospective cohort study was conducted in three university-based tertiary referral centers from Jan 1st, 2013, to Dec 31st, 2022. All cases of PAS confirmed by pathology were included in the study. Unsuspected PAS cases were diagnosed at the time of delivery, while suspected cases served as the control group. Potential risk factors were compared between the two groups. Multivariable regression model was also performed to identify risk factors. Maternal outcomes were also evaluated. RESULTS: A total of 339 pathology-confirmed PAS cases were included in the study out of 415,470 deliveries, of which 35.4% (n = 120) were unsuspected cases. Unsuspected PAS cases were 7.9 times more likely to have a history of intrauterine adhesions (adjusted odds ratio [aOR] 7.93; 95% confidence interval [CI] 2.35-26.81), 7.0 times more likely to have a history of clinically confirmed PAS (aOR, 6.99; 95% CI 2.85-17.18), 6.3 times more likely to have a posterior placenta (aOR, 6.30; 95% CI 3.48-11.40), and 3.4 times more likely to have a history of placenta previa (aOR, 3.41; 95% CI 1.18-9.82). On the other hand, cases with gravidity > 3, placenta previa, and/or a history of previous cesarean delivery were more likely to be diagnosed antenatally (aOR 0.40, 0.19, 0.36; 95% CI 0.22-0.74, 0.09-0.40, 0.19-0.70). Although the suspected PAS group had a higher proportion of invasive cases and abdominal and pelvic organ injuries (74.4% vs. 25.8%, p < 0.001; 6.8% vs. 1.7%, p = 0.037), the maternal outcomes were more favorable in the sPAS group, with a lower median volume of 24-hour blood loss and blood product transfusion (estimated blood loss in 24 h, 1000 [800-2000] vs. 2000 [1400-2400], p < 0.001; RBC unit transfusion, 0 [0-800] vs. 800 [600-1000], p < 0.001; fresh-frozen plasma transfusion, 0 [0-450] vs. 600 [400-800], p < 0.001). CONCLUSIONS: Our findings indicate that 35% of patients with PAS were unsuspected prior to delivery. Factors associated with PAS being unsuspected prior to delivery include a history of intrauterine adhesions, a history of clinically confirmed PAS, a posterior placenta, and a history of placenta previa. Additionally, gravidity > 3, a history of previous cesarean delivery, and placenta previa increase the likelihood of antenatal diagnosis.

Potential impact on using aspirin as the primary prevention of adverse pregnancy outcomes in twins conceived using ART.

With the development of assisted reproductive technology, the number of twin pregnancies is increasing year by year. Given the increased risk of pregnancy complications associated with twin pregnancies, and the fact that these babies are rare and difficult to obtain through assisted reproductive technology, clinicians urgently require finding effective and safe drugs to improve pregnancy outcomes. Low-dose aspirin can not only promote placental blood supply, but also effectively anti-inflammatory. Whether Low-dose aspirin can effectively reduce the risk of pregnancy complications in this special group needs to be clarified. We therefore retrospectively analyzed 665 twin pregnancies from assisted reproduction technology, grouped according to aspirin use, and followed pregnancy outcomes to assess bleeding risk. Low-dose aspirin was found to be effective in preventing preeclampsia without a significant risk of bleeding. However, aspirin does not prevent specific complication in twin pregnancies and seems to have a better preventive effect only when the mother is under 30, which should alarm clinicians should not blindly using aspirin in this particular group.

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.

Chinese experts' consensus guideline on preimplantation genetic testing of monogenic disorders.

Recent developments in molecular biological technologies and genetic diagnostic methods, accompanying with updates of relevant terminologies, have enabled the improvements of new strategies of preimplantation genetic testing for monogenic (single gene) disorders (PGT-M) to prevent the transmission of inherited diseases. However, there has been much in the way of published consensus on PGT-M. To properly regulate the application of PGT-M, Chinese experts in reproductive medicine and genetics have jointly developed this consensus statement. The consensus includes indications for patient selection, genetic and reproductive counseling, informed consent, diagnostic strategies, report generation, interpretation of results and patient follow-ups. This consensus statement serves to assist in establishment of evidence-based clinical and laboratory practices for PGT-M.

Elevated expression of glycolytic genes as a prominent feature of early-onset preeclampsia: insights from integrative transcriptomic analysis.

Introduction: Preeclampsia (PE), a notable pregnancy-related disorder, leads to 40,000+ maternal deaths yearly. Recent research shows PE divides into early-onset (EOPE) and late-onset (LOPE) subtypes, each with distinct clinical features and outcomes. However, the molecular characteristics of various subtypes are currently subject to debate and are not consistent. Methods: We integrated transcriptomic expression data from a total of 372 placental samples across 8 publicly available databases via combat algorithm. Then, a variety of strategies including Random Forest Recursive Feature Elimination (RF-RFE), differential analysis, oposSOM, and Weighted Correlation Network Analysis were employed to identify the characteristic genes of the EOPE and LOPE subtypes. Finally, we conducted in vitro experiments on the key gene HK2 in HTR8/SVneo cells to explore its function. Results: Our results revealed a complex classification of PE placental samples, wherein EOPE manifests as a highly homogeneous sample group characterized by hypoxia and HIF1A activation. Among the core features is the upregulation of glycolysis-related genes, particularly HK2, in the placenta-an observation corroborated by independent validation data and single-cell data. Building on the pronounced correlation between HK2 and EOPE, we conducted in vitro experiments to assess the potential functional impact of HK2 on trophoblast cells. Additionally, the LOPE samples exhibit strong heterogeneity and lack distinct features, suggesting a complex molecular makeup for this subtype. Unsupervised clustering analysis indicates that LOPE likely comprises at least two distinct subtypes, linked to cell-environment interaction and cytokine and protein modification functionalities. Discussion: In summary, these findings elucidate potential mechanistic differences between the two PE subtypes, lend support to the hypothesis of classifying PE based on gestational weeks, and emphasize the potential significant role of glycolysis-related genes, especially HK2 in EOPE.

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.

Different subtypes of gestational diabetes mellitus are associated with distinct perinatal outcomes in twin pregnancies.

AIMS: To determine whether different gestational diabetes mellitus (GDM) subtypes are associated with distinct perinatal outcomes in twin pregnancies. MATERIALS: This retrospective cohort study enrolled women with twin pregnancies who gave birth at a tertiary hospital between January 2017 and December 2022. GDM was diagnosed by the IADPSG diagnostic criteria. Three subtypes of GDM were defined as only abnormal fasting glucose (OAFG) values, only abnormal post-load glucose (OAPG) values and abnormal combined fasting and post-load glucose (ACFPG) values. Logistic regression or generalized estimation equation models were used to test the correlation of subtypes of GDM and perinatal outcomes. RESULTS: GDM with OAPG had a slightly higher risk for preterm delivery (PTD) at <37 gestational weeks (aOR 1.22, 95 %CI 1.01-1.47) and neonatalintensivecareunit (NICU) admission (aOR 1.31, 95 %CI 1.09-1.57). GDM with ACFPG were associated with PTD at <37 gestational weeks (aOR 1.42, 95 %CI 1.06-1.89) and PTD at <34 gestational weeks (aOR 1.65, 95 % CI 1.14-2.39). GDM with OAFG had a lower risk of being small-for-gestational age (SGA) (aOR 0.48, 95 % CI 0.26-0.92). CONCLUSIONS: Different subtypes of GDM are associated with distinct perinatal outcomes. Only abnormal fasting glucose levels may be responsible for reduced the risk of SGA neonates.

Endoplasmic reticulum stress impairs trophoblast syncytialization through upregulation of HtrA4 and causes early-onset preeclampsia.

OBJECTIVE: Syncytiotrophoblasts form via mononuclear cytotrophoblast fusion during placentation and play a critical role in maternal-fetal communication. Impaired syncytialization inevitably leads to pregnancy-associated complications, including preeclampsia. Endoplasmic reticulum stress (ERS) is reportedly linked with preeclampsia, but little is known about its association with syncytialization. High temperature requirement factor A4 (HtrA4), a placental-specific protease, is responsible for protein quality control and placental syncytialization. This study aimed to investigate the relationship among HtrA4, ERS, and trophoblast syncytialization in the development of early-onset preeclampsia (EO-PE). METHODS: HtrA4 expression and ERS in preeclamptic placentas and control placentas were analyzed by Western blotting and qRT-PCR. HtrA4 and ERS localization in placentas was determined by immunohistochemistry and immunofluorescence. BeWo cells were used to stimulate the effects of HtrA4 and ERS on syncytialization. RESULTS: HtrA4 expression was upregulated in EO-PE and positively correlated with ERS. HtrA4 activity was increased in preeclampsia. Under normoxia, HtrA4 overexpression in BeWo cells did not alter the ERS level. In addition, treatment with hypoxia/reoxygenation (H/R) or an ERS inducer increased HtrA4 expression. HtrA4 upregulation suppressed the levels of syncytin-2 and ß-HCG in the presence of forskolin (FSK), and this change was exaggerated after ERS activation. In addition, treatment with an ERS inhibitor markedly suppressed FSK-treated cell fusion in a manner related to downregulation of HtrA4 expression. CONCLUSION: Our results suggest that ERS enables syncytialization of placental development by upregulating HtrA4, but that excessive HtrA4 expression and preexisting ERS impair syncytialization and cause EO-PE.

Adipocyte-Derived Exosomal NOX4-Mediated Oxidative Damage Induces Premature Placental Senescence in Obese Pregnancy.

Background: A recent study has reported that maternal obesity is linked to placental oxidative damage and premature senescence. NADPH oxidase 4 (NOX4) is massively expressed in adipose tissue, and its induced reactive oxygen species have been found to contribute to cellular senescence. While, whether, in obese pregnancy, adipose tissue-derived NOX4 is the considerable cause of placental senescence remained elusive. Methods: This study collected term placentas from obese and normal pregnancies and obese pregnant mouse model was constructed by a high fat diet to explore placental senescence. Furthermore, adipocyte-derived exosomes were isolated from primary adipocyte medium of obese and normal pregnancies to examine their effect on placenta functions in vivo and vitro. Results: The placenta from the obese group showed a significant increase in placental oxidative damage and senescence. Exosomes from obese adipocytes contained copies of NOX4, and when cocultured with HTR8/SVneo cells, they induced severe oxidative damage, cellular senescence, and suppressed proliferation and invasion functions when compared with the control group. In vivo, adipocyte-derived NOX4-containing exosomes could induce placental oxidative damage and senescence, ultimately leading to adverse pregnancy outcomes. Conclusion: In obesity, adipose tissue can secrete exosomes containing NOX4 which can be delivered to trophoblast resulting in severe DNA oxidative damage and premature placental senescence, ultimately leading to adverse pregnancy outcomes.

Construction of Conjugated 1,3-Enynes via Pd-Catalyzed Cascade Alkynylation of Aryl Phenol-Tethered Alkynes with Alkynyl Bromides.

An efficient Pd-catalyzed cascade alkynylation of aryl phenol-tethered alkynes with alkynyl bromides is described. This protocol could provide various conjugated 1,3-enynes possessing a polysubstituted spirocyclohexadienone, as well as an all-carbon tetrasubstituted alkene moiety. The products could also undergo ring-expansion and cyclization transformations under different conditions to convert to diverse fused cyclic scaffolds.