Placenta最新文献_第7页

Placental angiogenic biomarkers in relation to prenatal bisphenol and phthalate exposure 胎盘血管生成生物标志物与产前双酚和邻苯二甲酸盐暴露有关。

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-26 DOI: 10.1016/j.placenta.2025.11.011

Eleanor A. Medley , Emma Spring , Mia Charifson , Sarah Adelman , Sara Borghi , Yelena Afanasyeva , Eunsil Seok , Mengling Liu , Kurunthachalam Kannan , Shilpi S. Mehta-Lee , Whitney Cowell , Linda G. Kahn

Introduction

Placental development, involving rapid vascularization, is regulated by concentration gradients of numerous growth factors and hormones. Placental growth factor (PlGF) promotes vasculogenesis and angiogenesis in the placenta, while soluble fms-like tyrosine kinase-1 (sFlt-1) inhibits these processes. An elevated ratio of sFlt-1/PlGF in maternal serum is predictive of preeclampsia. Exposure to two classes of ubiquitous endocrine-disrupting chemicals, bisphenols and phthalates, has also been previously linked to preeclampsia development.

Methods

We investigated the relation of urinary concentrations of bisphenols and phthalate metabolites, measured up to three times during pregnancy, with serum concentrations of sFlt-1, PlGF, and their ratio in the New York University Children's Health and Environment Study. Linear mixed models were used to analyze up to three measurements of PlGF and sFlt-1 adjusted for gestational age at the time of serum collection.

Results

We found that higher molar sum concentration of bisphenol A and bisphenol S was associated with lower sFlt-1 (−0.12, 95 % CI: −0.22, −0.03), higher PlGF (0.08, 95 % CI: −0.01, 0.18), and lower sFlt-1/PlGF ratio (−0.12, 95 % CI: −0.21, −0.02). Phthalic acid and metabolites of anti-androgenic and low molecular weight phthalates were similarly associated with higher PlGF and lower sFlt-1/PlGF, but only after 20 weeks of gestation.

Discussion

The unexpected relationship between prenatal bisphenol and phthalate exposure and lower sFlt-1/PlGF warrants further investigation. Our results suggest that the effect of these endocrine-disrupting chemicals on placental health may be more complicated than what is currently understood through these angiogenic biomarkers.

胎盘的发育，包括快速血管形成，受多种生长因子和激素的浓度梯度调节。胎盘生长因子（PlGF）促进胎盘血管生成和血管生成，而可溶性纤维样酪氨酸激酶-1 （sFlt-1）抑制这些过程。母体血清中sFlt-1/PlGF比值升高可预测子痫前期。暴露于两类无处不在的干扰内分泌的化学物质——双酚类物质和邻苯二甲酸盐——也与先兆子痫的发展有关。方法：在纽约大学儿童健康与环境研究中，我们调查了妊娠期间尿中双酚类和邻苯二甲酸酯代谢物浓度与血清sFlt-1、PlGF浓度及其比值的关系。使用线性混合模型分析血清采集时经胎龄调整的PlGF和sFlt-1的三次测量结果。结果：我们发现双酚A和双酚S的摩尔和浓度越高，sFlt-1越低（-0.12,95% CI: -0.22, -0.03）， PlGF越高（0.08,95% CI: -0.01, 0.18）， sFlt-1/PlGF比值越低（-0.12,95% CI: -0.21, -0.02）。邻苯二甲酸及其代谢物抗雄激素和低分子量邻苯二甲酸酯与较高的PlGF和较低的sFlt-1/PlGF相似，但仅在妊娠20周后。讨论：产前双酚和邻苯二甲酸盐暴露与较低的sFlt-1/PlGF之间的意外关系值得进一步研究。我们的研究结果表明，这些干扰内分泌的化学物质对胎盘健康的影响可能比目前通过这些血管生成生物标志物所了解的更为复杂。

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引用次数: 0

GCLM as a novel biomarker for preeclampsia: Integrating bioinformatics and mechanistic validation GCLM作为一种新的子痫前期生物标志物：整合生物信息学和机制验证。

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-24 DOI: 10.1016/j.placenta.2025.11.010

Xiaodan Tan , Xing Chen , Duanfang Zhou , Wenjia Guo , Dan Li , Xiaoli Wang , Jiali Liu , Zhe Peng , Lin Chen

Introduction

Preeclampsia (PE) is a pregnancy-specific disorder associated with hypertension and multi-organ dysfunction, posing serious risks to maternal and fetal health. Early detection remains challenging, highlighting the urgent need to identify reliable molecular biomarkers for improved diagnosis and therapeutic intervention.

Methods

We integrated Gene Expression Omnibus (GEO) datasets (GSE10588, GSE25906, and GSE48424) and identified 671 differentially expressed genes (312 upregulated and 359 downregulated). Weighted Gene Co-expression Network Analysis (WGCNA) identified 165 genes highly correlated with PE, of which 74 overlapped with the DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on these 74 genes. Additionally, 4 machine learning models were applied to prioritize diagnostic biomarkers.

Results

GO analysis revealed enrichment in Wnt signaling, ER-to-Golgi vesicle transport, COPII-coated vesicle components, and ubiquitin-protein transferase activity. KEGG analysis indicated significant involvement in cysteine and methionine metabolism and protein processing in the endoplasmic reticulum. Among the top 20 genes from each machine learning model, Glutamate-cysteine ligase modifier subunit (GCLM) was the only overlapping gene. Its downregulation was validated in clinical samples and PE models. Functional experiments showed that lentiviral GCLM overexpression restored GSH/GPX4 levels, enhanced HUVEC viability, and reduced sFLT-1 secretion.

Conclusion

Our study identifies GCLM as a potential biomarker and therapeutic target for PE, offering new insight into its molecular pathogenesis and suggesting clinical relevance for diagnosis and intervention.

子痫前期（PE）是一种与高血压和多器官功能障碍相关的妊娠特异性疾病，对孕产妇和胎儿健康构成严重风险。早期检测仍然具有挑战性，迫切需要确定可靠的分子生物标志物，以改善诊断和治疗干预。方法：整合GEO数据集（GSE10588、GSE25906和GSE48424），鉴定出671个差异表达基因（312个上调，359个下调）。加权基因共表达网络分析（WGCNA）鉴定出165个与PE高度相关的基因，其中74个与deg重叠。对这74个基因进行了基因本体（GO）和京都基因基因组百科全书（KEGG）富集分析。此外，应用4种机器学习模型对诊断性生物标志物进行优先排序。结果：氧化石墨烯分析显示Wnt信号、er到高尔基囊泡运输、copii包被囊泡成分和泛素蛋白转移酶活性富集。KEGG分析表明，在内质网的半胱氨酸和蛋氨酸代谢和蛋白质加工显著参与。在每个机器学习模型的前20个基因中，谷氨酸-半胱氨酸连接酶修饰子亚基（GCLM）是唯一重叠的基因。其下调在临床样本和PE模型中得到验证。功能实验表明，慢病毒GCLM过表达可恢复GSH/GPX4水平，增强HUVEC活力，减少sFLT-1分泌。结论：本研究确定GCLM是PE的潜在生物标志物和治疗靶点，为PE的分子发病机制提供了新的认识，并为PE的诊断和干预提供了临床意义。

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引用次数: 0

Impaired placental vascular remodeling and persistent uNK cells in the RUPP model: A time-dependent perspective RUPP模型中受损的胎盘血管重构和持续的uNK细胞：一个时间依赖的视角

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-21 DOI: 10.1016/j.placenta.2025.11.008

C.M. van Kammen , F.M. Al Darwish , G.J. Strijkers , B.F. Coolen , L.K. Alles , M.M. Faas , R. Schiffelers , A.T. Lely , F. Terstappen

Background

Placental insufficiency underlies major obstetric complications such as preeclampsia and fetal growth restriction (FGR). The reduced uterine perfusion pressure (RUPP) model is widely used to mimic PE and FGR; however, its impact on placental structure, immune cell regulation, and vascular remodeling in the mesometrial triangle remains poorly examined. This study investigates these processes to clarify the model's relevance for human placenta dysfunction pathology.

Methods

Maternal, fetal, and placental parameters were assessed in pregnant rats at gestational day (GD) 14, 16, 18, and 19, comparing normal pregnant and RUPP groups. Placental morphology was assessed using hematoxylin and eosin staining. Within the mesometrial triangle, uterine natural killer (uNK) cell distribution was evaluated using ANK61 staining, while trophoblast invasion and spiral artery remodeling were assessed by pan-cytokeratin and α-SMA staining, respectively.

Results

Placental macrostructural architecture was preserved in RUPP. However, uNK cell migration from the mesometrial triangle was impaired, with higher ANK61-positive cell presence persisting at GD19. This was accompanied by a reduction in trophoblast invasion depth. Spiral artery remodeling was impaired in RUPP placentas, with a greater proportion of unremodeled vessels and fewer highly remodeled arteries by GD19.

Conclusion

While gross placental structure remains intact in the RUPP model, the key functional adaptations uNK cell migration, trophoblast invasion, and vascular remodeling, are impaired. These findings support the RUPP as a relevant model to study the pathophysiological mechanisms of placental insufficiency. Future research should focus on temporal molecular profiling to elucidate the mechanisms behind impaired uNK cell retention and shallow trophoblast invasion.

背景：胎盘功能不全是主要产科并发症的基础，如先兆子痫和胎儿生长受限（FGR）。子宫灌注压降低（RUPP）模型被广泛用于模拟PE和FGR；然而，其对胎盘结构、免疫细胞调节和系膜三角血管重塑的影响仍未得到充分研究。本研究探讨了这些过程，以阐明该模型与人类胎盘功能障碍病理的相关性。方法在妊娠第14、16、18、19天对妊娠大鼠进行母、胎、胎盘参数测定，并与正常妊娠组和RUPP组进行比较。采用苏木精和伊红染色评估胎盘形态。在子宫系膜三角内，采用ANK61染色评价子宫自然杀伤细胞（natural killer, uNK）的分布，采用泛细胞角蛋白染色和α-SMA染色分别评价滋养细胞侵袭和螺旋动脉重构。结果RUPP术后胎盘宏观结构得以保留。然而，从中轴线三角形的uNK细胞迁移受到损害，在GD19时，较高的ank61阳性细胞持续存在。这伴随着滋养层浸润深度的减少。RUPP胎盘的螺旋动脉重塑受损，GD19显示未重塑血管比例更高，高度重塑动脉比例更低。结论在RUPP模型中，胎盘大体结构保持完整，但细胞迁移、滋养细胞侵袭和血管重构等关键功能受到损害。这些发现支持RUPP作为研究胎盘功能不全病理生理机制的相关模型。未来的研究应该集中在时间分子分析上，以阐明uNK细胞保留受损和浅滋养层侵袭背后的机制。

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引用次数: 0

Adipokine visfatin as a response of an efficient placenta to key pregnancy risk factors 脂肪因子visfatin作为有效胎盘对关键妊娠危险因素的反应。

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-17 DOI: 10.1016/j.placenta.2025.11.007

Aleksandra Stangret , Anna Wnuk , Zbigniew Lewandowski , Marta Chołuj , Marta Skoda , Dariusz Szukiewicz , Włodzimierz Sawicki , Krzysztof Cendrowski

Introduction

Visfatin is a multifunctional adipokine, primarily produced by visceral fat but also expressed in the placenta, where it may contribute to pregnancy regulation. Obesity, advanced maternal age are associated with oxidative stress and inflammation, increasing the risk of pregnancy complications. Understanding placental adaptations to these factors is essential for improving maternal and fetal health outcomes. This study aimed to evaluate the relationship between placental visfatin levels, maternal pre-pregnancy body weight status, age, 3-nitrotyrosine (3-NT) - a biomarker of nitrative stress, to explore potential links between these factors and placental function in an uncomplicated pregnancy.

Methods

This retrospective cohort study analyzed placental tissues collected from 39 parturients immediately after birth. ELISA assays measured term placental visfatin and 3-NT levels. Maternal parameters, including BMI, gestational weight gain, gestational age, and pregnancy-related comorbidities, were recorded. Pearson correlation and multivariate regression analyses were performed to assess associations between visfatin levels, BMI, age, and oxidative stress markers.

Results

Visfatin concentrations were significantly higher in women with pre-pregnancy obesity (p < 0.042). Visfatin correlated with 3-NT levels (r = 0.46; p < 0.003) and maternal age (r = 0.35; p < 0.030). In women ≤35 years, visfatin correlated positively with BMI, independent of gestational age and weight at term (r = 0.42; p < 0.031).

Conclusions

Elevated visfatin concentration in an effectively functioning term placenta may result from maternal pre-pregnancy obesity, maternal age, oxidative and nitrative stress (3-NT). This supports the idea that in physiological pregnancy visfatin contributes to placental processes that sustain and maintain healthy pregnancy outcomes in women with pregnancy risk factors.

Visfatin是一种多功能脂肪因子，主要由内脏脂肪产生，但也在胎盘中表达，可能参与妊娠调节。肥胖、高龄产妇与氧化应激和炎症有关，增加了妊娠并发症的风险。了解胎盘对这些因素的适应对于改善孕产妇和胎儿的健康结果至关重要。本研究旨在评估胎盘visfatin水平、孕妇孕前体重状况、年龄、3-硝基酪氨酸（3-NT）（一种营养应激的生物标志物）之间的关系，探讨这些因素与无并发症妊娠胎盘功能之间的潜在联系。方法：本回顾性队列研究分析了39例分娩后立即收集的胎盘组织。ELISA法测定足月胎盘visfatin和3-NT水平。记录母体参数，包括体重指数、妊娠体重增加、胎龄和妊娠相关合并症。采用Pearson相关和多变量回归分析来评估脂肪素水平、BMI、年龄和氧化应激标志物之间的关系。结论：有效功能足月胎盘内内脂素浓度升高可能与孕妇孕前肥胖、孕妇年龄、氧化应激和硝化应激（3-NT）有关。这支持了这样一种观点，即在生理妊娠中，visfatin有助于维持和维持具有妊娠危险因素的妇女健康妊娠结局的胎盘过程。

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引用次数: 0

miR-196a-5p suppresses the MAPK/ERK pathway by targeting HOXA7 to regulate the proliferation and apoptosis of placental trophoblasts in gestational diabetes miR-196a-5p通过靶向HOXA7抑制MAPK/ERK通路，调控妊娠糖尿病胎盘滋养细胞的增殖和凋亡

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-17 DOI: 10.1016/j.placenta.2025.11.006

Jianhua Li , Xinping Xie , Lin Lu , Bei Gan , Jianying Yan

Introduction

Gestational diabetes mellitus (GDM) disrupts placental trophoblast function through hyperglycemia-induced apoptosis and impaired proliferation. Non-coding RNAs, particularly miR-196a-5p, are implicated in GDM pathogenesis, but their mechanistic roles remain unclear. HOXA7, a homeobox transcription factor, and the MAPK/ERK pathway are critical in cellular regulation, however, their interplay in GDM is unexplored.

Methods

Clinical samples (blood and placental tissues) from GDM patients and controls were analyzed via miRNA-seq, qRT-PCR, and Western blot. Bioinformatics (TargetScan, miRDB, miRWalk) identified miR-196a-5p targets. Functional validation used HTR8-Svneo trophoblasts under high-glucose (25 mM) conditions, with miR-196a-5p mimics/inhibitors and HOXA7 overexpression and two key functional rescue assays: co-treatment with a miR-196a-5p mimic and HOXA7 overexpression, and co-treatment with a mimic and a MEK activator, including CCK-8, Transwell, flow cytometry, and dual-luciferase reporter analysis. miR-196a-5p was upregulated in GDM patients and directly targeted HOXA7 via three conserved 3′UTR binding sites.

Results

Hyperglycemia suppressed MAPK/ERK phosphorylation, reducing trophoblast proliferation, migration, and invasion while increasing apoptosis. miR-196a-5p-mimic exacerbated these effects, whereas inhibitors or HOXA7 overexpression restored MAPK/ERK activity and cellular functions. Crucially, rescue experiments confirmed that HOXA7 is a necessary mediator for miR-196a-5p′s effects and that activating the MAPK/ERK pathway downstream is sufficient to reverse the induced dysfunction. miR-196a-5p suppresses the MAPK/ERK pathway by specifically regulating HOXA7, thereby reducing proliferation and increasing apoptosis of placental trophoblasts.

Discussion

This study demonstrated that miR-196a-5p with higher expression in GDM suppresses the HOXA7/MAPK/ERK axis to inhibit placental trophoblasts proliferation and promote its apoptosis.

妊娠期糖尿病（GDM）通过高血糖诱导的胎盘滋养细胞凋亡和增殖受损来破坏胎盘滋养细胞功能。非编码rna，特别是miR-196a-5p，与GDM的发病机制有关，但其机制作用尚不清楚。同源盒转录因子HOXA7和MAPK/ERK通路在细胞调控中至关重要，然而，它们在GDM中的相互作用尚未被探索。方法采用miRNA-seq、qRT-PCR和Western blot对GDM患者和对照组的临床样本（血液和胎盘组织）进行分析。生物信息学（TargetScan, miRDB, miRWalk）鉴定出miR-196a-5p靶点。功能验证使用高糖（25 mM）条件下的HTR8-Svneo滋养细胞，miR-196a-5p模拟物/抑制剂和HOXA7过表达，以及两个关键的功能恢复试验：与miR-196a-5p模拟物和HOXA7过表达共同处理，与模拟物和MEK激活物共同处理，包括CCK-8， Transwell，流式细胞术和双荧光素酶报告分析。miR-196a-5p在GDM患者中上调，并通过三个保守的3'UTR结合位点直接靶向HOXA7。结果低血糖抑制MAPK/ERK磷酸化，减少滋养细胞增殖、迁移和侵袭，增加细胞凋亡。miR-196a-5p-mimic加剧了这些影响，而抑制剂或HOXA7过表达恢复了MAPK/ERK活性和细胞功能。至关重要的是，救援实验证实HOXA7是miR-196a-5p作用的必要介质，激活下游的MAPK/ERK通路足以逆转诱导的功能障碍。miR-196a-5p通过特异性调节HOXA7抑制MAPK/ERK通路，从而减少胎盘滋养细胞的增殖，增加胎盘滋养细胞的凋亡。本研究表明，在GDM中高表达的miR-196a-5p通过抑制HOXA7/MAPK/ERK轴抑制胎盘滋养细胞增殖，促进其凋亡。

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引用次数: 0

Immune and vascular dysregulation at the maternal–fetal interface in oocyte donation triplet pregnancies: unraveling mechanisms of failed immune tolerance 卵母细胞捐献三胞胎妊娠中母胎界面的免疫和血管失调：揭示免疫耐受失败的机制

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-11 DOI: 10.1016/j.placenta.2025.11.001

Eva Manuela Pena-Burgos , María De La Calle , Jose Juan Pozo-Kreilinger , Cecilia García-Díaz , Rebeca Rodríguez Pena , Ángel Vázquez Martín , Rita María Regojo-Zapata

Introduction

Oocyte donation (OD) pregnancies present the highest level of fetal allogenicity, potentially triggering immune dysregulation at the maternal–fetal interface. Triplet pregnancies represent an extreme physiological challenge, yet the immune and vascular adaptations in OD triplets remain poorly understood. This study evaluated immunovascular profiles in triplet pregnancies conceived via OD compared with non-OD and spontaneous conceptions, exploring mechanisms of maladaptation related to high fetal allogenicity.

Methods

We conducted a retrospective case–control study of 115 triplet placentas: 29 conceived by OD and 86 by spontaneous conception, artificial insemination, or assisted reproductive technology without OD. Decidua basalis, chorionic villi, and fetal membranes were assessed by immunohistochemistry for immune and vascular markers. Quantitative immunoreactivity scores, qualitative expression patterns, and vascular morphology were compared between groups.

Results

OD placentas showed reduced CD163⁺ regulatory macrophages, increased CD68⁺, CD14⁺ macrophages, CD56⁺ NK cells, and HLA-DR⁺ immune cells, moderate PD-L1 expression, scanty CD4⁺ regulatory T cells, and only scattered CD8⁺ T cells in decidua basalis. Vascular alterations in OD placentas included muscularized maternal vessels (29.9 %), perivascular immune infiltration, endothelial activation (WT1⁺, CD15⁺), and absence of VEGF expression. C4d deposition on villous basal membranes was more frequent in OD placentas, indicating complement activation.

Discussion

OD triplet pregnancies exhibit a distinct immunovascular phenotype compatible with a graft-versus-host-like process. Regulatory immune cell depletion, enrichment of antigen-presenting cells, and vascular maladaptation suggest chronic immune dysregulation, contributing to placental insufficiency and adverse outcomes. These findings highlight the need for closer monitoring and may inform targeted interventions in highly allogeneic pregnancies.

卵母细胞捐赠（OD）妊娠表现出最高水平的胎儿异体性，可能引发母胎界面的免疫失调。三胞胎妊娠是一种极端的生理挑战，然而对OD三胞胎的免疫和血管适应仍然知之甚少。本研究评估了外胎妊娠与非外胎妊娠和自然妊娠三胞胎的免疫血管状况，探讨了与胎儿高异体性相关的适应不良机制。方法：对115例三胞胎胎盘进行回顾性病例对照研究，其中29例为体外受精，86例为自然受孕、人工授精或非体外受精辅助生殖技术。基底蜕膜、绒毛膜绒毛和胎膜采用免疫组化检测免疫和血管标志物。比较各组间定量免疫反应性评分、定性表达模式和血管形态。结果：OD胎盘CD163+调节性巨噬细胞减少，CD68+、CD14+巨噬细胞、CD56+ NK细胞、HLA-DR+免疫细胞增多，PD-L1表达中等，CD4+调节性T细胞稀少，基底蜕膜仅有零散CD8+ T细胞。OD胎盘的血管改变包括母血管肌肉化（29.9%）、血管周围免疫浸润、内皮细胞激活（WT1+、CD15+）和VEGF表达缺失。C4d在绒毛基膜上的沉积在OD胎盘中更为频繁，表明补体活化。讨论：OD三胞胎妊娠表现出独特的免疫血管表型，与移植物抗宿主样过程相容。调节性免疫细胞耗竭、抗原呈递细胞富集和血管失调提示慢性免疫失调，导致胎盘功能不全和不良后果。这些发现强调了密切监测的必要性，并可能为高度异体妊娠的针对性干预提供信息。

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引用次数: 0

Adenosine promotes trophoblast proliferation without inducing differentiation or apoptosis 腺苷促进滋养细胞增殖，但不诱导分化或凋亡

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-07 DOI: 10.1016/j.placenta.2025.11.005

Mohammed N.H. Ali, Mariia Adler, Magdalena Novotna, Viktor Gala, Cilia Abad, Frantisek Staud, Lukas Cerveny

Objective

Adenosine and other nucleosides are essential regulators of cellular processes, but their specific roles in trophoblast growth and regulation remain incompletely defined. This study investigated the effects of purine and pyrimidine nucleosides on trophoblast proliferation, and further examined whether adenosine influences apoptosis, differentiation, or the expression of its receptors, transporters, and metabolizing enzymes.

Methods

Nucleoside-induced proliferation was assessed by measuring metabolic activity, DNA synthesis, total DNA content, and MKI-67 expression in BeWo and JEG-3 cell lines, and by PCNA protein levels in placental explants. Adenosine was further evaluated for its effects on apoptosis, cytotrophoblast differentiation, and gene expression. Apoptosis was assessed via caspase-3 and -8 activity, differentiation by human chorionic gonadotropin (hCG) secretion and ERVW-1 expression, and gene regulation by qPCR analysis of adenosine receptors, nucleoside transporters, and metabolizing enzymes.

Results

All nucleosides promoted proliferation in BeWo and JEG-3 cells, as indicated by increased metabolic activity, DNA synthesis, and total DNA content. For adenosine, MKI-67 expression analysis further confirmed its pro-proliferative effect. In placental explants, only adenosine significantly increased PCNA levels. Furthermore, adenosine did not affect caspase activity, hCG secretion, ERVW-1 expression, or the gene and protein expression of adenosine receptors, transporters, and metabolizing enzymes.

Conclusions

Nucleosides, particularly adenosine, promote trophoblast proliferation. Adenosine has no additional effects on differentiation, apoptosis, or transcriptional changes in genes regulating its signaling or metabolism. Given adenosine's diverse biological roles beyond proliferation, further research is warranted to explore its broader impact on placental function and adaptation, especially under pathological conditions.

目的腺苷和其他核苷是细胞过程的重要调节因子，但它们在滋养细胞生长和调节中的具体作用尚未完全确定。本研究探讨了嘌呤和嘧啶核苷对滋养细胞增殖的影响，并进一步研究了腺苷是否影响细胞凋亡、分化或其受体、转运体和代谢酶的表达。方法通过测定BeWo和JEG-3细胞系的代谢活性、DNA合成、总DNA含量、MKI-67表达以及胎盘外植体PCNA蛋白水平来评价核苷诱导的增殖。进一步评估腺苷对细胞凋亡、细胞滋养细胞分化和基因表达的影响。通过caspase-3和-8活性，人绒毛膜促性腺激素（hCG）分泌和ERVW-1表达的分化，以及通过qPCR分析腺苷受体、核苷转运体和代谢酶的基因调控来评估细胞凋亡。结果所有核苷均能促进BeWo和JEG-3细胞的增殖，增加代谢活性、DNA合成和总DNA含量。对于腺苷，MKI-67表达分析进一步证实了其促增殖作用。在胎盘外植体中，只有腺苷能显著提高PCNA水平。此外，腺苷不影响caspase活性、hCG分泌、ERVW-1表达，也不影响腺苷受体、转运体和代谢酶的基因和蛋白表达。结论核苷类物质，尤其是腺苷，对滋养细胞增殖有促进作用。腺苷对调节其信号传导或代谢的基因的分化、凋亡或转录变化没有额外的影响。鉴于腺苷在增殖之外的多种生物学作用，有必要进一步研究其对胎盘功能和适应的更广泛影响，特别是在病理条件下。

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引用次数: 0

Association between MRI-derived early second trimester placental physiology and birth weight percentiles in pregnancies without ischemic placenta disease (IPD) 无缺血性胎盘疾病（IPD）妊娠中，mri衍生的妊娠中期早期胎盘生理与出生体重百分位数之间的关系

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-06 DOI: 10.1016/j.placenta.2025.11.003

Raymi O. Ramirez , Jennifer J. Kim , Precious Ann Fortes , Carla Janzen , Peggy Sullivan , Sherin U. Devaskar , Kyunghyun Sung

Introduction

This study investigated whether placental structure and function, measured using multiparametric MRI (mpMRI) in early second trimester, are associated with birth weight percentiles. We focused on pregnancies without ischemic placental disease (IPD), excluding cases with preeclampsia, fetal growth restriction (FGR), small for gestational age (SGA), or placental abruption. Clinical and pathological moderators were also examined.

Methods

In this prospective single-center cohort, 199 participants were recruited between 2017 and 2019. Placental MRI was performed at two gestational age (GA) windows: 14–16 weeks (w) and 19–24w. Placental volume, perfusion, and oxygenation were quantified and standardized to 16w for the first imaging timepoint and 20w for the second imaging timepoint. After excluding IPD cases, linear mixed-effects models were used to explore retrospective associations between MRI metrics and birth weight percentiles, adjusting for clinical and histopathological variables.

Results

Early second trimester mpMRI showed significant associations between placental volume (positive association) and perfusion (negative association) as early as 16w GA to birthweight percentiles (p < 0.05). The nonlinear three-way interaction between the change of mpMRI parameters between 16w and 20w GA (

Δ

w GA) was consistently positively associated to birth weight percentiles regardless of clinical and pathological factors (p < 0.05).

Discussion

Early second trimester mpMRI markers (volume and perfusion) at 16w and 20w GA are associated with birth weight outcomes, suggesting utility in early pregnancy monitoring. The three-way interaction between the mpMRI markers may serve as a composite marker for identifying variation in fetal growth trajectories.

前言：本研究探讨了在妊娠中期早期使用多参数MRI （mpMRI）测量胎盘结构和功能是否与出生体重百分位数相关。我们的研究重点是没有缺血性胎盘疾病（IPD）的妊娠，排除先兆子痫、胎儿生长受限（FGR）、小胎龄（SGA）或胎盘早剥的病例。还检查了临床和病理调节因子。方法：在这个前瞻性单中心队列中，在2017年至2019年期间招募了199名参与者。在14-16周(w)和19-24周（GA）两个胎龄窗口进行胎盘MRI检查。对胎盘体积、灌注和氧合进行量化和标准化，第一个成像时间点为16w，第二个成像时间点为20w。在排除IPD病例后，采用线性混合效应模型，在调整临床和组织病理学变量的情况下，探讨MRI指标与出生体重百分位数之间的回顾性关联。结果：早在妊娠中期中期，mpMRI就显示胎盘体积（正相关）和灌注（负相关）与出生体重百分位数之间存在显著关联(p)。讨论：妊娠中期早期mpMRI标志物（体积和灌注）在妊娠中期中期16w和20w与出生体重结局相关，提示在妊娠早期监测中的应用。mpMRI标记之间的三方相互作用可以作为识别胎儿生长轨迹变化的复合标记。

{"title":"Association between MRI-derived early second trimester placental physiology and birth weight percentiles in pregnancies without ischemic placenta disease (IPD)","authors":"Raymi O. Ramirez , Jennifer J. Kim , Precious Ann Fortes , Carla Janzen , Peggy Sullivan , Sherin U. Devaskar , Kyunghyun Sung","doi":"10.1016/j.placenta.2025.11.003","DOIUrl":"10.1016/j.placenta.2025.11.003","url":null,"abstract":"<div><h3>Introduction</h3><div>This study investigated whether placental structure and function, measured using multiparametric MRI (mpMRI) in early second trimester, are associated with birth weight percentiles. We focused on pregnancies without ischemic placental disease (IPD), excluding cases with preeclampsia, fetal growth restriction (FGR), small for gestational age (SGA), or placental abruption. Clinical and pathological moderators were also examined.</div></div><div><h3>Methods</h3><div>In this prospective single-center cohort, 199 participants were recruited between 2017 and 2019. Placental MRI was performed at two gestational age (GA) windows: 14–16 weeks (w) and 19–24w. Placental volume, perfusion, and oxygenation were quantified and standardized to 16w for the first imaging timepoint and 20w for the second imaging timepoint. After excluding IPD cases, linear mixed-effects models were used to explore retrospective associations between MRI metrics and birth weight percentiles, adjusting for clinical and histopathological variables.</div></div><div><h3>Results</h3><div>Early second trimester mpMRI showed significant associations between placental volume (positive association) and perfusion (negative association) as early as 16w GA to birthweight percentiles (p < 0.05). The nonlinear three-way interaction between the change of mpMRI parameters between 16w and 20w GA (<span><math><mrow><mo>Δ</mo></mrow></math></span> w GA) was consistently positively associated to birth weight percentiles regardless of clinical and pathological factors (p < 0.05).</div></div><div><h3>Discussion</h3><div>Early second trimester mpMRI markers (volume and perfusion) at 16w and 20w GA are associated with birth weight outcomes, suggesting utility in early pregnancy monitoring. The three-way interaction between the mpMRI markers may serve as a composite marker for identifying variation in fetal growth trajectories.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"172 ","pages":"Pages 120-130"},"PeriodicalIF":2.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Determination of residue aspirin and its bioactive metabolites in human placenta: Application to high-risk to preeclampsia women received prophylactic low-dose aspirin. 人胎盘中残留阿司匹林及其生物活性代谢物的测定：预防性低剂量阿司匹林在高危子痫前期妇女中的应用

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-06 DOI: 10.1016/j.placenta.2025.11.004

Kenean Getaneh Tlaye, So Pui Kin, Gashaw Garedew Woldeamanuel, Bo Wah Leung, Liona C Poon, Chi Chiu Wang

Introduction: The human placenta plays central role in preeclampsia (PE) pathogenesis and may modulate the effectiveness of prophylactic low-dose aspirin (LDA). In this study, we optimized and validated LC-MS/MS method to quantify the residual acetylsalicylic acid (ASA), salicylic acid (SA), and gentisic acid (GA) in the placenta of LDA exposed women.

Methods: Analytes were extracted from the placenta using acetonitrile with 0.1 % formic acid (v/v). Stable deuterated isotopes i.e., ASA-d4, SA-d4, and GA-d3 were used as an internal standard (IS) for ASA, SA, and GA respectively. The multiple reaction monitoring (MRM) mode with ion transitions of m/z 178.9 → 93.2, 182.9 → 97, 136.9 → 92.9, 140.9 → 96.9, 152.9 → 108.9, and 154.9 → 110.9 were used for ASA, ASA-d4, SA, SA-d4, GA, and GA-d3, respectively.

Results: The developed method was successfully applied to analyze ASA, SA, and GA residuals in the placenta of aspirin responder (R) and non-responder (NR) women who had been taking LDA for PE prevention. Slightly higher yet non-significant increment of ASA and SA was seen in R placenta. Following LDA, ASA and GA were found to be rarely detected and short-lived, while SA was the most abundant and retained in the placenta for an extended duration.

Conclusion: The method allows the determination of ASA, SA, and GA from human placenta. The difference in aspirin responsiveness among women at high risk for PE may be driven by other pharmacokinetic, pharmacodynamic, or pharmacogenomic variabilities, rather than by differences in the placental concentration of ASA.

人胎盘在子痫前期（PE）发病机制中起着核心作用，并可能调节预防性低剂量阿司匹林（LDA）的有效性。本研究优化并验证了LC-MS/MS定量LDA暴露妇女胎盘中残留乙酰水杨酸（ASA）、水杨酸（SA）和龙胆酸（GA）的方法。方法：用含0.1%甲酸（v/v）的乙腈提取胎盘中分析物。使用稳定的氘化同位素ASA-d4、SA-d4和GA-d3分别作为ASA、SA和GA的内标（IS）。ASA、ASA-d4、SA、SA-d4、GA、GA-d3分别采用离子跃迁m/z为178.9→93.2、182.9→97、136.9→92.9、140.9→96.9、152.9→108.9、154.9→110.9的多重反应监测（MRM）模式。结果：所建立的方法成功应用于阿司匹林有反应(R)和无反应（NR）服用LDA预防PE的妇女胎盘中ASA、SA和GA残留量的分析。R胎盘中ASA和SA的升高略高，但不显著。在LDA之后，ASA和GA很少被检测到，寿命也很短，而SA含量最多，在胎盘中保留的时间也很长。结论：本方法可用于测定人胎盘中ASA、SA和GA的含量。在PE高危妇女中，阿司匹林反应性的差异可能是由其他药代动力学、药效学或药物基因组学变异性驱动的，而不是由胎盘ASA浓度的差异驱动的。

{"title":"Determination of residue aspirin and its bioactive metabolites in human placenta: Application to high-risk to preeclampsia women received prophylactic low-dose aspirin.","authors":"Kenean Getaneh Tlaye, So Pui Kin, Gashaw Garedew Woldeamanuel, Bo Wah Leung, Liona C Poon, Chi Chiu Wang","doi":"10.1016/j.placenta.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.placenta.2025.11.004","url":null,"abstract":"<p><strong>Introduction: </strong>The human placenta plays central role in preeclampsia (PE) pathogenesis and may modulate the effectiveness of prophylactic low-dose aspirin (LDA). In this study, we optimized and validated LC-MS/MS method to quantify the residual acetylsalicylic acid (ASA), salicylic acid (SA), and gentisic acid (GA) in the placenta of LDA exposed women.</p><p><strong>Methods: </strong>Analytes were extracted from the placenta using acetonitrile with 0.1 % formic acid (v/v). Stable deuterated isotopes i.e., ASA-d4, SA-d4, and GA-d3 were used as an internal standard (IS) for ASA, SA, and GA respectively. The multiple reaction monitoring (MRM) mode with ion transitions of m/z 178.9 → 93.2, 182.9 → 97, 136.9 → 92.9, 140.9 → 96.9, 152.9 → 108.9, and 154.9 → 110.9 were used for ASA, ASA-d4, SA, SA-d4, GA, and GA-d3, respectively.</p><p><strong>Results: </strong>The developed method was successfully applied to analyze ASA, SA, and GA residuals in the placenta of aspirin responder (R) and non-responder (NR) women who had been taking LDA for PE prevention. Slightly higher yet non-significant increment of ASA and SA was seen in R placenta. Following LDA, ASA and GA were found to be rarely detected and short-lived, while SA was the most abundant and retained in the placenta for an extended duration.</p><p><strong>Conclusion: </strong>The method allows the determination of ASA, SA, and GA from human placenta. The difference in aspirin responsiveness among women at high risk for PE may be driven by other pharmacokinetic, pharmacodynamic, or pharmacogenomic variabilities, rather than by differences in the placental concentration of ASA.</p>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Placental dysfunction and neonatal mortality induced by Salmonella Abortusequi in a murine model of pregestational infection 流产沙门菌在妊娠感染小鼠模型中引起胎盘功能障碍和新生儿死亡

IF 2.5 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2025-11-04 DOI: 10.1016/j.placenta.2025.11.002

Diana M. Betancourt , Mariángeles Noto Llana , Ailín N. Garófalo , Sebastián H. Sarnacki , M. Cristina Cerquetti , Nairobi Hernández Bridón , M. Carolina Pustovrh , Mónica N. Giacomodonato

Introduction

Salmonella Abortusequi is a host-restricted equine pathogen and a major cause of abortion in mares, threatening reproductive health and industry sustainability. This study was aimed to identify factors that adversely affect placental function, contributing to the development of fetal growth restriction (FGR) and neonatal mortality.

Methods

CF1 virgin female mice received a pregestational intragastric dose of Salmonella Abortusequi (10⁸ CFU/mouse). On gestational day 18 (GD18), pregnant females were sacrificed, and maternal tissues and fetoplacental units were collected. In a separate group, pregnancy proceeded to term for neonatal outcome assessment.

Results

Salmonella Abortusequi infection impaired placental morphometry and efficiency, leading to FGR and increased neonatal mortality. Offspring from infected dams had persistently low body weight and 40.3 % mortality rate during the first postnatal week. Molecular detection of the invA gene confirmed bacterial presence in fetoplacental units at GD18 and prolonged persistence in maternal spleen and liver up to 90 days post-inoculation. Infection significantly reduced placental claudin-4 gene and protein expression, suggesting a disruption of placental barrier integrity.

Discussion

This study demonstrates that a pregestational infection with Salmonella Abortusequi can exert long-term consequences not only on placental development and fetal growth, but also on neonatal viability and early postnatal development. Importantly, these findings highlight the potential impact of subclinical maternal infections as contributors to reproductive failure and early-life morbidity.

流产沙门菌是一种宿主受限的马病原体，是导致母马流产的主要原因，威胁着生殖健康和产业的可持续性。本研究旨在确定影响胎盘功能、促进胎儿生长受限（FGR）发展和新生儿死亡率的因素。方法scf1雌性小鼠妊娠期灌胃流产沙门菌（108 CFU/只）。在妊娠第18天（GD18）处死孕妇，收集母体组织和胎胎盘单位。在另一组中，对妊娠至足月进行新生儿结局评估。结果流产沙门菌感染会影响胎盘形态测定和效率，导致FGR和新生儿死亡率升高。感染母鼠的子代体重持续偏低，产后第一周死亡率为40.3%。invA基因的分子检测证实了细菌在GD18时存在于胎儿胎盘单位中，并在接种后90天内在母体脾脏和肝脏中持续存在。感染显著降低胎盘claudin-4基因和蛋白表达，提示胎盘屏障完整性被破坏。本研究表明，妊娠期感染流产沙门氏菌不仅会对胎盘发育和胎儿生长产生长期影响，还会对新生儿生存能力和产后早期发育产生长期影响。重要的是，这些发现强调了亚临床母体感染对生殖失败和早期生命发病率的潜在影响。

{"title":"Placental dysfunction and neonatal mortality induced by Salmonella Abortusequi in a murine model of pregestational infection","authors":"Diana M. Betancourt , Mariángeles Noto Llana , Ailín N. Garófalo , Sebastián H. Sarnacki , M. Cristina Cerquetti , Nairobi Hernández Bridón , M. Carolina Pustovrh , Mónica N. Giacomodonato","doi":"10.1016/j.placenta.2025.11.002","DOIUrl":"10.1016/j.placenta.2025.11.002","url":null,"abstract":"<div><h3>Introduction</h3><div><em>Salmonella</em> Abortusequi is a host-restricted equine pathogen and a major cause of abortion in mares, threatening reproductive health and industry sustainability. This study was aimed to identify factors that adversely affect placental function, contributing to the development of fetal growth restriction (FGR) and neonatal mortality.</div></div><div><h3>Methods</h3><div>CF1 virgin female mice received a pregestational intragastric dose of <em>Salmonella</em> Abortusequi (10<sup>8</sup> CFU/mouse). On gestational day 18 (GD18), pregnant females were sacrificed, and maternal tissues and fetoplacental units were collected. In a separate group, pregnancy proceeded to term for neonatal outcome assessment.</div></div><div><h3>Results</h3><div><em>Salmonella</em> Abortusequi infection impaired placental morphometry and efficiency, leading to FGR and increased neonatal mortality. Offspring from infected dams had persistently low body weight and 40.3 % mortality rate during the first postnatal week. Molecular detection of the <em>invA</em> gene confirmed bacterial presence in fetoplacental units at GD18 and prolonged persistence in maternal spleen and liver up to 90 days post-inoculation. Infection significantly reduced placental claudin-4 gene and protein expression, suggesting a disruption of placental barrier integrity.</div></div><div><h3>Discussion</h3><div>This study demonstrates that a pregestational infection with <em>Salmonella</em> Abortusequi can exert long-term consequences not only on placental development and fetal growth, but also on neonatal viability and early postnatal development. Importantly, these findings highlight the potential impact of subclinical maternal infections as contributors to reproductive failure and early-life morbidity.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"172 ","pages":"Pages 139-149"},"PeriodicalIF":2.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0