Preeclampsia (PE) is a severe pregnancy complication with unclear molecular mechanisms. Our research investigated the effect of UNC5C-AS1 on human umbilical vein endothelial cell (HUVEC) function in PE. UNC5C-AS1 was downregulated in PE placentas. Upregulating UNC5C-AS1 promoted HUVEC migration, invasion, tube formation, and the expression of vascular permeability factors, while UNC5C-AS1 silencing exhibited an opposite effect. UNC5C-AS1 directly targeted the miR148a3p/EMP1 axis. MiR-148a-3p was up-regulated and EMP1 was downregulated in PE. The regulatory effects of UNC5C-AS1 overexpression on HUVEC functions were reversed by miR-148a-3p mimics, and this reversal was subsequently rescued by EMP1 upregulation. UNC5C-AS1 overexpression ameliorated tissue damage in the PE mouse model. UNC5C-AS1 alleviated the PE-associated injury and modulated HUVEC function by targeting miR-148a-3p/EMP1 axis.

INTRODUCTION:Preeclampsia (PE), known for its association with oxidative stress, can lead to impaired endothelial function. Although melatonin, as an antioxidant, has been used for treating PE, the specific mechanism underlying its therapeutic effect remains ambiguous. The aim of this study is to investigate the correlation between melatonin and PE, and explore the mechanism by which melatonin enhances endothelial cell function in PE. MATERIAL AND METHODS:Serum melatonin levels were quantified by enzyme-linked immunoassay (ELISA), whereas the expression levels of melatonin receptor and sirtuin 7 (SIRT7) in the placental tissues were assessed via western blotting (WB) in both normal and preeclamptic pregnant women. The impact of melatonin on hypoxia-reoxygenation (H/R)-treated wild-type and SIRT7-knockdown human umbilical vein endothelial cells (HUVECs) was evaluated, along with the modulation of SIRT7 expression and the Protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway. RESULTS:We observed a reduction in melatonin levels in patients with PE as well as decreased expression of melatonin receptor type 1A (MTNR-1A) and SIRT7 within placenta. Melatonin restored the migration and tube formation abilities and the expression level of SIRT7 in a PE cell model of HUVECs, while this restorative function was abolished upon SIRT7 knockdown. Furthermore, the AKT/mTOR signaling pathway was suppressed following H/R treatment, a phenomenon that was also observed upon SIRT7 knockdown. Conversely, melatonin administration activated the AKT/mTOR signaling pathway. CONCLUSIONS:Our results indicate a potential correlation between melatonin and the incidence of PE. Melatonin alleviates preeclampsia-related endothelial dysfunction, and this effect is associated with SIRT7 and the AKT/mTOR pathway.

Preterm birth (PTB), defined as delivery between 28 and 37 weeks of gestation, is a leading cause of global neonatal mortality. Its pathogenesis is primarily driven by oxidative stress and inflammation, synergistically inducing calcium ion influx into uterine smooth muscle cells, triggering aberrant contractions and PTB. Current therapies primarily offer only symptom suppression without addressing the underlying etiology, highlighting an urgent need for targeted interventions. Herein, we develop TPT, a multi-bioactive, amphiphilic conjugate, which is synthesized through stepwise covalent conjugation of hydrophilic polyethylene glycol, a superoxide dismutase mimetic, and a hydrogen peroxide-scavenging/anti-inflammatory generating unit onto a molecular skeleton. TPT can self-assemble into a multifunctional nanotherapy (designated as TPT NP). In both in vitro and in vivo lipopolysaccharide-induced PTB models, TPT NP treatment significantly mitigates oxidative/inflammatory cascades, reduces calcium influx and apoptosis in uterine smooth muscle cells, and suppresses myometrial contractions, thereby effectively delaying PTB. Mechanistically, TPT NP restores redox homeostasis in lipopolysaccharide-induced PTB by reducing oxidative damage products and bolstering endogenous antioxidant defenses, while concurrently improving uteroplacental hemodynamics and attenuating uterine hypercontractility. Critically, in vivo evaluations demonstrate excellent safety profiles of TPT NP, with no adverse effects on maternal health and offspring development, underscoring its significant clinical translational potential.

Gestational diabetes mellitus (GDM) represents a prevalent pregnancy complication with long-term health implications for offspring. While metabolic outcomes have been extensively studied, sex-specific effects on neurodevelopment remain poorly understood. Here we investigated the sex-dependent impact of maternal GDM on offspring brain development and behavior using a high-fat diet and low-dose streptozotocin induced mouse model. We found that adult female offspring exposed to maternal GDM exhibited depressive-like behaviors and sustained impairments in hippocampal neurogenesis across multiple developmental stages (embryonic, weaning and adult), characterized by reduced neural stem cell proliferation and altered differentiation. By contrast, male offspring displayed substantial metabolic dysfunction but no sustained neurogenic deficits beyond the embryonic period. Metabolomic analysis revealed persistent downregulation of myo-inositol in female offspring hippocampus, associated with disruptions in neurogenic signaling pathways. In vitro experiments with female-derived neural stem cells confirmed that hyperglycemic conditions directly impaired proliferation and differentiation, partly through oxidative stress mechanisms. These findings establish a sex-specific vulnerability to GDM-induced neurodevelopmental alterations and identify myo-inositol metabolism as a potential therapeutic target for preventing long-term neuropsychiatric consequences in female offspring.Maternal GDM induces sex-specific effects on offspring neurodevelopment, with females exhibiting persistent hippocampal neurogenesis deficits and depressive-like behaviors, while males show neurogenic resilience. The identification of myo-inositol depletion and oxidative stress as potential contributors to female-specific neurogenic impairments provides new insights into sex-specific vulnerability to maternal metabolic disturbances and suggests potential targets for intervention. HFD, High fat diet; STZ, Streptozotocin; GCL, Granule cell layer; SGZ, Subgranular zone; NSCs, Neural stem cells. Figure created with BioRender.com.

The precise balance between human trophoblast stem cells (hTSCs) self-renewal and differentiation into syncytiotrophoblasts (STBs) is essential for proper placental development. While the transcriptional and signaling networks regulating this process have been extensively studied, the contribution of protein homeostasis remains poorly understood. Here, we identify FBXO22, the substrate recognition subunit of the SCF E3 ubiquitin ligase complex, as a key regulator of trophoblast fate. We found that FBXO22 was enriched in the nuclei of cytotrophoblasts (CTBs) and levels were reduced markedly in early placental villi from patients with recurrent pregnancy loss (RPL). Experimental loss of FBXO22 compromised hTSC stemness and led to aberrant premature differentiation toward STBs. Mechanistically, FBXO22 selectively ubiquitinates and destabilizes the CoREST complex, thereby coordinating with HDAC1 and LSD1 to regulate histone modifications, including H3K27 acetylation (H3K27ac) and H3K9 dimethylation (H3K9me2). Disruption of this nuclear ubiquitination pathway perturbs the balance between proliferation and differentiation, ultimately impairing placental development. Our findings uncover a previously unrecognized nuclear role of FBXO22 in maintaining cellular homeostasis, linking ubiquitin-mediated protein degradation to trophoblast fate determination and providing new insights into the molecular pathology underlying early pregnancy loss.

INTRODUCTION:Previous studies suggest a link between Basal Metabolic Rate (BMR) and obstetrical disorders; however, causality remains unclear. We investigated the causal effects of BMR on 14 obstetric disorders and evaluated the potential mediating effects of blood metabolites in these relationships. METHODS:Using Genome-Wide Association Study (GWAS) summary data, we conducted both univariate and multivariable Mendelian Randomization (MVMR) analyses. The primary causal inference was based on Inverse Variance Weighted (IVW), MR-Egger, weighted median, and sensitivity analyses (Cochran's Q, MR-PRESSO). Mediation analysis was employed to quantify the proportion of effects operating through metabolite-regulated pathways. RESULTS:BMR was inversely associated with hyperemesis gravidarum (OR=0.73, 95%CI: 0.59-0.90, P=0.008), Intrahepatic Cholestasis of Pregnancy (ICP) (OR=0.67, 95%CI: 0.56-0.80, P<0.001), poor fetal growth (OR=0.80, 95%CI:0.71-0.90, P=0.001), and preterm delivery (OR=0.78, 95%CI:0.70-0.87, P<0.001). MVMR identified elevated BMR and mannose levels as protective against ICP, with BMR showing a positive correlation with mannose. Mediation analysis revealed that BMR reduced ICP risk partly through increased mannose (OR = 1.38, 95% CI: 1.19-1.59, P = 2.03 × 10-5), accounting for 29.93% of the effect. DISCUSSION:Elevated BMR significantly reduced risks of intrahepatic cholestasis (HR=0.67), fetal distress (HR=0.80), and preterm birth (HR=0.78), mediated partly by mannose levels. Mendelian randomization established causality, linking metabolic adaptation to improved pregnancy outcomes. However, these findings, based on European genetic data, limit generalizability, and unmeasured confounders may persist despite MR methods. CONCLUSION:Higher BMR may lower risks of hyperemesis gravidarum, ICP, poor fetal growth, and preterm delivery. Mannose mediates the protective effect of BMR on ICP, highlighting potential metabolic pathways for intervention.

Preeclampsia (PE) is a pregnancy-specific syndrome driven by placental dysfunction, and premature placental senescence has increasingly been implicated in its pathogenesis. However, the upstream regulatory mechanisms remain poorly understood. Here, we found that placental SIRT1 expression was reduced in PE and was accompanied by senescence-associated features. In trophoblasts, SIRT1 knockdown enhanced senescence and senescence-associated secretory phenotype (SASP) release, while impairing proliferative capacity, migration, and invasion, whereas pharmacological activation of SIRT1 attenuated placental senescence and ameliorated PE-like manifestations in vivo. Mechanistically, iron chelation alleviated senescence, whereas senolytic intervention partially restored iron homeostasis, supporting a self-reinforcing interaction between iron dyshomeostasis and senescence. Collectively, these findings identify the SIRT1-p53 axis as an upstream regulator linking iron dyshomeostasis to placental senescence, support the existence of a ferro-aging-like pathogenic program in diseased placentas, and provide new insights into the molecular basis of placental dysfunction in PE.

Placentation is a complicated process critical for maternal–fetal exchange of nutrients and gases that includes stepwise vasculogenesis and angiogenesis. Wnt inhibitory factor I (WIFI) is a secreted Wnt antagonist that acts as a tumor-suppressor gene by antagonizing angiogenesis and proliferation and inducing apoptosis. The purpose of this study was to investigate the function of WIFI on placental angiogenesis in human umbilical vein endothelial cells (HUVECs) under hypoxic conditions. We found that WIFI was diversely expressed in placental vascular endothelial cells at different points during gestation and was weaker in the early placenta than in the term placenta. We validated the antiangiogenesis role of WIFI by inhibiting proliferation, tube formation and migration, and inducing apoptosis of endothelial cells through antagonizing Wnt/β-catenin signaling pathway. We also identified that hypoxic conditions similar to the early placenta inhibited the expression of WIFI and reversed the antiangiogenesis of WIFI in HUVECs. In conclusion, our present study supported the hypothesis that WIFI is crucial as a negative regulator of the functions of endothelial cells in angiogenesis and that hypoxia plays an important role in controlling WIFI expression and angiogenesis. We also demonstrated that Wnt/β-catenin signaling pathway was activated in correspondence with the suppression of WIFI in the angiogenesis of endothelial cells under hypoxic conditions. Keywords hypoxia, angiogenesis, Wnt inhibitory factor I, human umbilical vein endothelial cells

Cervical incompetence occurs when the cervix fails to maintain its normal morphology and function during second-trimester, leading to recurrent second-trimester miscarriages or preterm births. To standardize and guide the clinical diagnosis and treatment of cervical insufficiency in China, the Perinatal Medicine Branch of the Chinese Medical Association and the Obstetrics Group of the Chinese Society of Obstetrics and Gynecology developed this consensus by referencing related research evidence and so on. This consensus provides evidence-based analysis and recommendations on key clinical issues including the diagnosis of cervical incompetence, indications for cervical cerclage, surgical techniques, timing of intervention, perioperative management, and adjunctive therapies, offering evidence-based guidance for obstetric clinical practice.Practice guideline registration:International Practice Guidelines Registry and Transparency Platform (PREPARE-2024CN1155)

Relationships between BMI and breast cancer risk have been widely reported in previous Mendelian randomization (MR) studies, but the underlying molecular mechanisms remain unclear. We conducted this comprehensive two-sample MR to investigate the mediating role of 8 circulating biomarkers linking genetically predicted BMI to breast cancer risk both individually and simultaneously. A total of 281 BMI-associated single-nucleotide polymorphisms (SNPs) were used to estimate the associations of BMI with biomarker levels and breast cancer susceptibility. Instruments involving 8 364 SNPs were used to proxy 8 circulating biomarkers related to adipocytokine imbalance, chronic low-grade inflammation and insulin/insulin-like growth factor (IGF) axis dysregulation. Two-step MR mediation analyses were conducted to evaluate the indirect effects of a single biomarker in the relationship between genetically predicted BMI and breast cancer risk, and stepwise MR mediation analyses were employed to identify potential pathways involving multiple mediators. Genetically predicted BMI was positively correlated with genetically predicted circulating leptin (LEP), insulin (INS), and C-reactive protein (CRP) levels, with β values ranging from 0.166 to 0.453, and negatively correlated with IGF-1 levels (β=−0.118), whereas no statistically significant associations were found for adiponectin, resistin, soluble leptin receptor or insulin-like growth factor binding protein-3 levels. Two-step MR mediation analyses showed that in the association between genetically predicted BMI and breast cancer susceptibility (OR: 0.894; 95

Metabolic disturbances of decidual macrophages (dMφs) may contribute to the pathology of miscarriage, yet the underlying mechanisms remain poorly defined. Here, we document upregulated tryptophan metabolic pathway in dMφs from women with unexplained recurrent pregnancy loss (URPL), with increased kynurenine (KYN) levels in the decidua and elevated aryl hydrocarbon receptor (AHR) expression in dMφs. Excessive activation of the KYN-AHR axis compromises both mitochondrial and lysosomal integrity. This impairment facilitates the leakage of mtDNA into the cytoplasm and subsequent release into the extracellular space, thereby activating the cGAS-STING signaling cascade. Mechanistically, AHR directly binds to the xenobiotic response element within the CISH promoter region, promoting its transcription. The upregulation of CISH promotes the ubiquitination and degradation of ATP6V1A, disrupting lysosomal acidification and exacerbating mtDNA release. In vivo, excessive administration of KYN in pregnant mice increases the rate of embryo resorption, whereas pharmacological inhibition of AHR partially attenuates cGAS-STING pathway activation in dMφs and ameliorates fetal loss in an abortion-prone mouse model. Collectively, our findings describe a pivotal role for the AHR/CISH/ATP6V1A axis in orchestrating immune dysfunction within the decidua that may contribute to URPL, which sheds new light on the potential pathogenesis of URPL and paves the way for improving pregnancy outcomes.

Background: Klotho is an anti aging protein implicated in oxidative stress regulation, endothelial protection, placental senescence, and fetal growth. Its role in placenta related pregnancy complications remains unclear. To systematically review the evidence on Klotho in placenta related pregnancy complications and to quantitatively synthesize eligible studies. Methods: This systematic review and meta-analysis was reported in accordance with the PRISMA 2020 statement. Of 54 records identified, 9 studies were included in the systematic review and 7 in the meta-analysis. Study quality was assessed using a structured tool for non randomized studies. Random-effects models with Hartung-Knapp adjustment were used to calculate pooled standardized mean differences as Hedges' g with 95% confidence intervals (CIs). Results: Most included studies suggested reduced Klotho expression in placenta related pathological pregnancies. Meta-analysis showed significantly lower serum Klotho levels in pregnancies complicated by intrauterine growth restriction, fetal growth restriction, and small for gestational age (Hedges'g = -1.07, 95% CI: -1.34 to -0.80) and in pregnancies with adverse fetal outcomes (Hedges'g = -1.13, 95% CI: -1.29 to -0.97). Placental Klotho levels were also significantly reduced in pregnancy complications (Hedges'g = -1.35, 95% CI: -1.80 to -0.90). By contrast, pooled associations for serum Klotho in preeclampsia and overall pregnancy complications were not statistically significant due to substantial heterogeneity. Conclusions: Reduced Klotho is consistently associated with placental dysfunction, particularly in pregnancies with fetal growth impairment and adverse fetal outcomes. Placental Klotho appears to provide a more stable signal than circulating Klotho.

Preeclampsia (PE) is a pregnancy disorder characterized by placental maladaptation and maternal hypertension, with oxidative stress and lipid peroxidation as central features. Here we identify 2,4-dienoyl-CoA reductase 1 (DECR1), the rate-limiting enzyme in the auxiliary β-oxidation of unsaturated fatty acids, as a key regulator of trophoblast lipid redox balance. DECR1 expression is reduced in placentas from patients with late-onset preeclampsia (LOPE) and an L-NAME-induced PE mouse models. Genetic or pharmacological inhibition of DECR1 increases PUFA-rich lipid accumulation, enhances lipid peroxidation, and induces mitochondrial dysfunction, leading to loss of membrane potential, reactive oxygen species buildup, ATP depletion, and impaired trophoblast migration and invasion. In vivo, DECR1 inhibition causes hypertension, renal injury, fetal growth restriction, and defective placental vascular remodeling. Mechanistically, DECR1 loss disrupts mitochondrial quality control by suppressing mitocytosis, effects that are reversed by radical-trapping agents or mitochondria-targeted antioxidants. Liproxstatin-1 treatment restores maternal, fetal, and placental homeostasis. These findings define a DECR1-lipid peroxidation-mitochondria axis that maintains trophoblast function and placental adaptation, highlighting DECR1 as a potential therapeutic target for PE.

Prenatal exposure to environmental chemicals poses risks to fetal growth, yet most epidemiological studies have examined single chemical classes in isolation, leaving the broader multi-class maternal-fetal exposure landscape inadequately characterized. In addition, fetal exposure is typically inferred from cord blood concentrations, which conflates maternal body burden with transplacental transfer (TPT), obscuring the independent contribution of placental transport. We conducted a prospective cohort study screening 300 xenobiotics spanning multiple chemical classes, including PFAS, phthalate metabolites, environmental phenols/parabens, and pesticide- or industrial-related chemicals, across maternal serum and paired cord blood to define the core maternal-fetal exposome. Nineteen priority pollutants were detected at frequencies of ≥ 70% across all three biological matrices, including maternal serum, larger-twin cord blood, and smaller-twin cord blood, with PFAS representing the predominant chemical class. TPT varied substantially across compounds and differed nominally between co-twins for MBP. In linear mixed-effects models, higher TPT indices of MMP (β =  - 15.14; 95% CI: -27.66 to - 2.62), MBP (β =  - 11.61; 95% CI: -22.17 to - 1.05), and PFTrDA (β =  - 34.60; 95% CI: -67.91 to - 1.30) were nominally associated with lower birth weight. For PFTrDA, these associations were detected only when exposure was characterized by TPT, whereas corresponding cord blood concentrations were not significantly associated with fetal growth outcomes. These findings characterize a multi-class maternal-fetal exposome in twin pregnancies and provide exploratory evidence that TPT may constitute a complementary dimension of prenatal chemical exposure relevant to fetal growth.

BACKGROUND:Preeclampsia, a life-threatening hypertensive disorder of pregnancy, has been linked to iron dysregulation, though mechanistic insights remain limited. METHODS:We integrated clinical data, a reduced uterine perfusion pressure mouse model, in vitro trophoblast cell experiments, and placental organoids derived from patients with preeclampsia. Iron metabolism was assessed via mass spectrometry, quantitative polymerase chain reaction, Peris' Prussian blue staining and immunohistochemistry. Ferroptosis markers and iron transporters were analyzed. Interventions included the iron chelator deferoxamine, antioxidant MitoQ, ferroptosis inhibitor Fer-1 (ferrostatin-1), and the apoptosis inhibitor Z-VAD. RESULTS:Patients with preeclampsia exhibited elevated hemoglobin, ferritin, and serum iron levels from the second trimester, alongside placental iron overload. Single-cell/nucleus RNA sequencing revealed dysregulated iron transporters (TFRC↑, DMT1↑, FPN↓) in preeclampsia trophoblasts. Iron overload induced ferroptosis and apoptosis in trophoblasts, evidenced by increased lipid peroxidation (4HNE↑, Gpx4↓), ROS, Tunnel staining positive and cell death, while suppressing PlGF and progesterone secretion. Both deferoxamine and MitoQ rescued these effects in vitro (similar to Ferr-1) and in preeclampsia-derived organoids. The reduced uterine perfusion pressure model confirmed the preservation of iron dyshomeostasis and ferroptosis in preeclamptic placentas, while oral administration of MitoQ was found to reduce 4-hydroxynonenal and malondialdehyde expression in placenta. CONCLUSIONS:Our findings reveal that iron overload and subsequent ferroptosis contribute to placental damage in preeclampsia, suggesting that iron metabolism dysregulation is a critical feature of the disease. This highlights the need to reevaluate iron supplementation protocols in high-risk pregnancies and to consider individualized iron management strategies that balance maternal-fetal iron requirements while minimizing oxidative stress.

Background:There is insufficient evidence to determine whether the risk factors and pregnancy outcomes associated with gestational diabetes mellitus (GDM) in twin pregnancies vary by chorionicity. Materials:A retrospective cohort study was conducted among twin pregnancies. GDM was diagnosed using the IADPSG diagnostic criteria. Logistic regression and generalized estimation equation (GEE) models were used to identify the risk factors of GDM and its impact on pregnancy outcomes, stratified by monochorionic (MC) and dichorionic (DC) pregnancies. Results:Advanced maternal age (MC: aOR 2.18, 95% CI 1.25-3.81 and DC: aOR 1.32, 95% CI 1.06-1.67) and preexisting hypertension (MC: aOR 2.69, 95% CI 1.04-9.36 and DC: aOR 1.70, 95% CI 1.12-2.59) were risk factors for GDM regardless of chorionicity. Overweight (aOR 1.65, 95% CI 1.26-1.98), obesity (aOR 2.31, 95% CI 1.43-3.74), multiparity (aOR 1.43, 95% CI 1.10-1.88), assisted reproductive technology (ART) use (aOR 1.75, 95% CI 1.36-2.26), and polycystic ovary syndrome (PCOS) (aOR 1.98, 95% CI 1.37-4.12) were risk factors for GDM only in DC pregnancies. GDM was only associated with an increased risk of preeclampsia in MC pregnancies (aOR 1.29, 95% CI 1.04-2.26). GDM was associated with an increased risk of preterm delivery (PTD) at < 37 (aOR 1.13, 95% CI 1.05-1.34) and < 34 gestational weeks (aOR 1.15, 95% CI 1.07-1.75) in DC pregnancies. Conclusion:The risk factors and pregnancy outcomes associated with GDM in twin pregnancies vary by chorionicity.

Early antenatal corticosteroids (ACS) are widely recommended for women at risk of preterm delivery to prevent neonatal death and neurocognitive impairment, yet inconsistent evidence has reported its impact on bronchopulmonary dysplasia (BPD). We aimed to systematically investigate risks of BPD as well as other major neonatal adverse outcomes among preterm infants. This meta-analysis searched PubMed, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL Plus, PsycInfo (OvidSP), and ClinicalTrials.gov from 1st January 1990 to 31st March 2026. Four reviewers independently screened records, extracted data, and assessed risk of bias using Cochrane tools for randomized clinical trials (RCTs) and the Newcastle-Ottawa Scale for cohort studies. Exposures was the administration of early ACS prior to preterm delivery. The primary outcome was a composite of neonatal death or BPD, and BPD alone among survivors. Secondary outcomes included composites of neonatal death or retinopathy of prematurity (ROP) and neonatal death or neurodevelopmental impairment (NDI), alongside incidences of chorioamnionitis, respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL). Pooled risk ratios (RRs) with 95

Dysglycaemia and periodontal inflammation frequently co-occur during pregnancy, but the microbial mechanisms linking these conditions and their potential for intervention remain incompletely understood. Here, we establish prospective pregnancy cohorts including more than 2500 volunteers and longitudinally profile oral microbiome dynamics in 534 pregnant women. We show that gestational diabetes mellitus (GDM) is associated with a progressive shift from Streptococcus-dominated oral microbiota to Prevotella/Porphyromonas-enriched dysbiosis. In mouse and cellular models, this dysbiotic oral microbiota induces periodontal inflammation, systemic IL-17 and IL-1β responses, suppression of glucagon-like peptide-1 and insulin, and exacerbation of hyperglycemia. Conversely, oral microbiota remodeling through transplantation of Streptococcus-dominated bacteria attenuates periodontal inflammation, restores glucagon-like peptide-1 and insulin levels, and improves glycaemic status in mice. Salivary metabolomics identifies docosahexaenoic acid (DHA) depletion in GDM, and in vitro assays show selective suppression of dysbiosis-associated oral pathogens by DHA. We therefore test topical gingival DHA in a double-blind randomized controlled trial of 40 pregnant women with GDM (ChiCTR2400080741), with probing depth and fasting blood glucose as primary endpoints and gingival index, attachment loss and plaque index as secondary endpoints. Daily gingival DHA application for six weeks improves probing depth and attenuates fasting glucose increase compared with placebo, with median fasting glucose changes from baseline of 0.10 versus 0.27 mmol/L. Together, these findings identify oral dysbiosis as a microbial driver of periodontal and glycaemic deterioration during pregnancy and support oral microbiome modulation as a potential adjunctive strategy for pregnancy care, although the clinical findings remain preliminary and require validation in larger trials with broader glycaemic endpoints.

AIMS:Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder in which immune dysregulation has been increasingly implicated. This study aimed to elucidate how interferon-γ (IFN-γ) signaling affects trophoblast function and metabolism and to explore the underlying immunometabolic mechanisms contributing to RPL pathogenesis. MATERIALS AND METHODS:Human trophoblast cells were treated with IFN-γ to assess proliferation, apoptosis, migration, and invasion. Metabolic alterations were analyzed using Seahorse extracellular flux assays, glucose uptake measurements, and metabolomic profiling. Molecular mechanisms were investigated by examining IDO1 expression, kynurenine production, aryl hydrocarbon receptor (AHR) activation, and hypoxia-inducible factor-1α (HIF-1α) signaling. IDO1 expression was further evaluated in chorionic villi from RPL patients and healthy controls. KEY FINDINGS:IFN-γ selectively suppressed trophoblast migration and invasion without affecting proliferation or apoptosis. IFN-γ markedly upregulated IDO1, leading to increased kynurenine accumulation and activation of AHR signaling through nuclear translocation and ARNT dimerization, thereby shifting trophoblasts toward an epithelial-like phenotype. Concurrently, IFN-γ stabilized HIF-1α and enhanced glycolytic flux, glucose uptake, and lactate secretion, accompanied by reduced tricarboxylic acid cycle intermediates. Pharmacological inhibition of glycolysis with 2-DG attenuated IFN-γ-induced IDO1 expression in a dose-dependent manner. Aberrant IDO1 expression was also observed in chorionic villi from RPL patients. SIGNIFICANCE:These findings demonstrate that IFN-γ signaling impairs trophoblast invasion through coordinated activation of the IDO1/kynurenine/AHR axis and metabolic reprogramming, revealing an immunometabolic mechanism that may contribute to the pathogenesis of recurrent pregnancy loss.

BACKGROUND:Increasing evidence suggests that the biological activity of trophoblasts and M1-type macrophages plays a crucial role in recurrent spontaneous abortion. However, detailed mechanistic studies on the intercellular communication between these two cells at the maternal-fetal interface are not clear. METHODS:In this study, extracellular vesicles (EVs) were first isolated from the supernatant of M1 macrophages induced by THP-1 cells (M1-EVs), identified by transmission electron microscopy, exosome immunofluorescence uptake, and western blotting, and characterized by mRNA sequencing to screen for specific target genes by mRNA profiling. CCK8 and western blotting experiments were used to investigate the effects of M1-EVs on trophoblast proliferation and autophagy. Subsequently, target genes MPPED2 and PI3K/AKT signaling pathway were found by bioinformatics analysis of raw mRNA sequencing results. Western blotting and CCK8 experiments were used to reveal the potential mechanisms by which MPPED2 in M1-EVs regulates trophoblast function. RESULTS:M1 macrophages induce inflammatory responses in the mother and fetus, and M1 macrophages inhibit trophoblast autophagy and proliferative capacity by secreting EVs. By mRNA transcriptome sequencing, MPPED2, among others, were identified as the most up-regulated mRNAs in M1-EVs-treated trophoblasts. Further functional experiments indicate that M1 macrophage-derived exosomes may regulate PI3K/AKT pathway activity by transferring MPPED2, leading to reduced autophagy and proliferation activity in trophoblasts. CONCLUSION:Our findings suggest that MPPED2 from exosomes plays an important role in intercellular communication between M1 macrophages and the trophoblast, elucidating a novel mechanism by which M1 macrophages regulate trophoblast function and its role in recurrent spontaneous abortion.