IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-10 DOI: 10.1016/j.placenta.2024.11.004

Farah Deeba , Ricky Hu , Victoria Lessoway , Jefferson Terry , Denise Pugash , Chantal Mayer , Jennifer Hutcheon , Robert Rohling

Introduction

Placenta-mediated diseases are associated with structural changes in the placenta. Quantitative Ultrasound (QUS) imaging measures the acoustic properties of the tissue, which are correlated to the underlying tissue structure. We aimed to develop and validate a diagnostic prediction model using QUS measurements for pre-eclampsia (PE) and small-for-gestational-age (SGA) fetuses/neonates.

Methods

For this prospective case-control study, placentas were collected from a group of women who delivered via cesarean section at BC Women's Hospital, Vancouver, Canada. Ultrasound data were collected and processed to compute three QUS parameters, namely, attenuation coefficient estimate (ACE), integrated backscatter coefficient (IBC), and effective scatterer diameter (ESD) from the placentas. We developed a logistic regression model using QUS parameters as predictors. The primary outcome was the occurrence of SGA and PE.

Results

The dataset consisted of 47 placentas, of which 25 placentas were complicated by SGA/PE. The final placenta-QUS model included quadratic and interaction terms of ACE, IBC, and ESD parameters. The placenta-QUS model was well-calibrated, with a calibration slope of 0.99 (0.57–1.05) and a calibration intercept of 0.003 (−0.02 − 0.22). The model predicted the SGA/PE complicated pregnancies with an apparent Area Under the Receive Operating Characteristic Curve (AUROC) of 0.89 (95 % CI: 0.78–0.98). The optimism-adjusted AUROC was 0.88 (95 % CI: 0.78–0.98).

Discussion

A model for SGA and PE has been developed using QUS measures from the placenta ex vivo. The model showed promising performance in detecting SGA/PE. Future studies will be performed to assess the model performance using QUS measures in utero.

简介胎盘介导的疾病与胎盘的结构变化有关。定量超声（QUS）成像测量组织的声学特性，这些特性与下层组织结构相关。我们的目的是利用 QUS 测量结果开发并验证一个诊断预测模型，用于预测子痫前期（PE）和小于妊娠年龄（SGA）胎儿/新生儿：在这项前瞻性病例对照研究中，收集了加拿大温哥华不列颠哥伦比亚省妇女医院剖宫产产妇的胎盘。我们收集并处理了超声数据，以计算胎盘的三个 QUS 参数，即衰减系数估计值 (ACE)、综合后向散射系数 (IBC) 和有效散射体直径 (ESD)。我们利用 QUS 参数作为预测因子，建立了一个逻辑回归模型。主要结果是发生 SGA 和 PE：数据集包括 47 个胎盘，其中 25 个胎盘并发 SGA/PE。最终的胎盘-QUS模型包括ACE、IBC和ESD参数的二次项和交互项。胎盘-QUS 模型校准良好，校准斜率为 0.99 (0.57-1.05)，校准截距为 0.003 (-0.02 - 0.22)。该模型预测 SGA/PE 并发症妊娠的表观接受操作特征曲线下面积（AUROC）为 0.89（95 % CI：0.78-0.98）。乐观调整后的 AUROC 为 0.88（95 % CI：0.78-0.98）：讨论：利用胎盘体外的 QUS 测量建立了一个 SGA 和 PE 模型。该模型在检测 SGA/PE 方面表现良好。未来的研究将利用宫内 QUS 测量来评估该模型的性能。

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引用次数: 0

Aspartame intake during pregnancy induces placental dysfunction through impaired mitochondrial function and biogenesis modulation 孕期摄入阿斯巴甜会通过线粒体功能受损和生物生成调节诱发胎盘功能障碍。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-08 DOI: 10.1016/j.placenta.2024.11.003

Yang-Ching Chen , Yen-Chia Yeh , Yu-Fang Lin , Shih-Yuan Hsu , Jacus S. Nacis , Jhih-Wei Hsu , Rong-Hong Hsieh

Introduction

Aspartame is a nonnutritive sweetener (NSS), which is widely used in foods and beverages worldwide. The safety of aspartame, a commonly used artificial sweetener, has been debated. Here, we investigated the potential effects and underlying mechanisms of aspartame consumption during pregnancy on placental dysfunction and birth outcomes.

Methods

Female Sprague Dawley rats were exposed to a low (30 mg/kg) or high (60 mg/kg) dose of aspartame before and during pregnancy; moreover, we assessed placental histopathological structure, oxidative stress markers, and mitochondrial function. In addition, we explored how aspartame affects birth weight in a human maternal–infant cohort.

Results

In animal study revealed that aspartame treatment of female rats for 14 weeks (12 week before pregnancy and 18 days of gestation) causes a significant reduction in the number and weight of fetuses, as well as damage to placental structure. These effects are linked to increased oxidative stress in the placenta, possibly damaging placental trophoblasts, impairing mitochondrial function, and initiating a compensatory mitochondrial biosynthesis mechanism. In the human pregnant cohort revealed that aspartame reduces birth weight considerably.

Discussion

These findings suggested the potential risks associated with aspartame consumption during pregnancy. Therefore, the safety of aspartame, particularly in pregnant individuals, should be reconsidered; specifically, tailored, acceptable daily intake guidelines should be developed for aspartame in different populations.

简介：阿斯巴甜是一种非营养性甜味剂（NSS），在世界各地的食品和饮料中被广泛使用。阿斯巴甜是一种常用的人工甜味剂，其安全性一直备受争议。在此，我们研究了孕期服用阿斯巴甜对胎盘功能障碍和分娩结局的潜在影响及其内在机制：方法：雌性 Sprague Dawley 大鼠在妊娠前和妊娠期间暴露于低剂量（30 毫克/千克）或高剂量（60 毫克/千克）的阿斯巴甜；此外，我们还评估了胎盘组织病理学结构、氧化应激标记物和线粒体功能。此外，我们还在人类母婴队列中探讨了阿斯巴甜对出生体重的影响：动物实验表明，对雌性大鼠进行为期 14 周（孕前 12 周和妊娠 18 天）的阿斯巴甜处理会导致胎儿数量和体重显著下降，并对胎盘结构造成损害。这些影响与胎盘氧化应激增加有关，可能会损害胎盘滋养细胞，损害线粒体功能，并启动线粒体生物合成补偿机制。在人类孕妇队列中发现，阿斯巴甜会大大降低出生体重：讨论：这些研究结果表明，在怀孕期间食用阿斯巴甜具有潜在风险。因此，应重新考虑阿斯巴甜的安全性，特别是对孕妇的安全性；具体而言，应针对不同人群制定有针对性的、可接受的阿斯巴甜每日摄入量指南。

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引用次数: 0

Trophoblast proliferation is higher in female than in male preeclamptic placentas 女性先兆子痫胎盘中滋养细胞的增殖率高于男性。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-08 DOI: 10.1016/j.placenta.2024.10.016

N. Barapatre , L. Hansen , C. Kampfer , T. Rübelmann , C. Schmitz , F. von Koch , H.G. Frank

Introduction

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder with inflammatory complications. There are no known placental histopathological features, which are unique to PE. It is often pooled with the fetal growth restriction (FGR) under a single umbrella pathophysiology, the maternal vascular malperfusion (MVM). The aim of this study is to assess the villous trophoblast and the villous tree quantitatively in PE placentas and to identify morpholgical correlates unique to PE.

Methods

20 PE placentas (10 female and 10 male) and 20 Control placentas (10 female and 10 male) were included in the study. The villous trophoblast and the villous tree were assessed quantitatively by Stereology and 3D Microscopy. For Stereology measurements, the villous tree was classified in contractile and non-contractile parts based on immunohistochemical detection of perivascular myofibroblasts.

Results

The density of proliferative trophoblast nuclei is increased, whereas the density of non-proliferative trophoblast nuclei is decreased in female PE placentas. The male PE placentas do not show this effect. Though no significant difference in the diffusion distance was observed, the non-contractile villi and the fetal vessels inside show a significantly reduced volume in PE placentas. The branching index of the villous tree is lower in PE placentas in general. However, in female PE placentas the deviation is accentuated.

Conclusion

In PE, the villous trophoblast shows a sexually dimorphic alteration in the density of proliferative and non-proliferative nuclei, which is inherently different from FGR.

简介子痫前期（PE）是一种伴有炎症并发症的妊娠高血压疾病。目前尚未发现子痫前期特有的胎盘组织病理学特征。它通常与胎儿生长受限（FGR）一起被归结为一种病理生理学，即母体血管灌注不良（MVM）。本研究旨在定量评估 PE 胎盘中的绒毛滋养层和绒毛树，并确定 PE 胎盘特有的形态学相关性。通过立体学和三维显微镜对绒毛滋养细胞和绒毛树进行定量评估。在进行立体学测量时，根据血管周围肌成纤维细胞的免疫组化检测结果，将绒毛树分为收缩和非收缩两部分：结果：女性PE胎盘中增殖滋养细胞核的密度增加，而非增殖滋养细胞核的密度降低。男性 PE 胎盘则没有这种影响。虽然在弥散距离上没有观察到明显差异，但在 PE 胎盘中，非收缩绒毛和胎儿血管的体积明显减少。一般来说，PE 胎盘中绒毛树的分支指数较低。结论：结论：在PE胎盘中，绒毛滋养细胞增殖核和非增殖核的密度显示出性别上的双态性变化，这与FGR有本质区别。

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引用次数: 0

Methylation aberrations in partner spermatozoa and impaired expression of imprinted genes in the placentae of early-onset preeclampsia 早发型子痫前期胎盘中伴侣精子的甲基化畸变和印记基因的表达受损。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-06 DOI: 10.1016/j.placenta.2024.10.068

Sweta Nair , Kushaan Khambata , Himangi Warke , Vandana Bansal , Anushree Patil , Zakiya Ansari , Nafisa H. Balasinor

Introduction

Disturbed paternal epigenetic status of imprinted genes has been observed in infertility and recurrent spontaneous abortions. Shallow placentation has been associated with early-onset preeclampsia. Hence, the present study aimed to investigate the methylation patterns of imprinted genes involved in placental development, in the spermatozoa of partners of women experiencing preeclampsia.

Methods

The study involved recruitment of couples into preeclampsia (n = 14) and control (n = 25) groups. Methylation analysis of imprinted gene differentially methylated regions (DMRs) and LINE1 repetitive element was carried out by pyrosequencing in the spermatozoa and placental villi. Global 5 mC levels in the spermatozoa were measured through ELISA. Expression of imprinted genes was quantified in the placental villi by real time qPCR. Association of birth weight with DNA methylation and gene expression was assessed.

Results

KvDMR, PEG3 DMR, PEG10 DMR and DLK1-GTL2 IG-DMR were differentially methylated in the spermatozoa and placental villi of preeclampsia group. Global 5 mC content and LINE1 methylation levels did not differ between the spermatozoa of the two groups. Increased transcript levels of PEG3, IGF2, DLK1, PHLDA2 and CDKN1C were observed in the preeclamptic placental villi. Birth weight showed significant association with KvDMR, PEG10 DMR, DLK1-GTL2 IG-DMR and LINE1 methylation levels in the spermatozoa. DLK1 expression levels showed a negative association with birth weight.

Discussion

The study highlighted the paternal contribution to early-onset preeclampsia, in the form of disrupted sperm DNA methylation patterns at imprinted gene loci. These loci, after further evaluation in future studies, could serve as sperm-based preeclampsia predictive markers, for couples planning pregnancy.

导言：在不孕症和复发性自然流产中观察到父系印记基因的表观遗传状态受到干扰。浅胎盘与早发子痫前期相关。因此，本研究旨在调查子痫前期妇女伴侣精子中参与胎盘发育的印记基因的甲基化模式：研究将夫妇分为子痫前期组（14 人）和对照组（25 人）。通过对精子和胎盘绒毛进行热测序，对印记基因差异甲基化区（DMRs）和LINE1重复元件进行甲基化分析。通过酶联免疫吸附法测定了精子中5 mC的总体水平。通过实时 qPCR 对胎盘绒毛中印记基因的表达进行了量化。评估了出生体重与 DNA 甲基化和基因表达的关系：结果：子痫前期组精子和胎盘绒毛中的KvDMR、PEG3 DMR、PEG10 DMR和DLK1-GTL2 IG-DMR存在不同程度的甲基化。两组精子的5 mC含量和LINE1甲基化水平没有差异。在子痫前期胎盘绒毛中观察到 PEG3、IGF2、DLK1、PHLDA2 和 CDKN1C 的转录水平升高。出生体重与精子中的 KvDMR、PEG10 DMR、DLK1-GTL2 IG-DMR 和 LINE1 甲基化水平有明显关联。DLK1表达水平与出生体重呈负相关：该研究强调了父方对早发性子痫前期的贡献，其表现形式为精子DNA甲基化模式在印记基因位点的紊乱。这些基因位点在未来的研究中得到进一步评估后，可作为基于精子的子痫前期预测标记，供计划怀孕的夫妇使用。

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引用次数: 0

BMP5 promotes trophoblast functions upon N-glycosylation via the BMP5-SMAD1/5 signaling pathway in preeclampsia 在子痫前期，BMP5通过BMP5-SMAD1/5信号通路的N-糖基化促进滋养层功能。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-05 DOI: 10.1016/j.placenta.2024.11.002

Hao Wang , Ningning Fan , Xinyuan Cui , Ru Xie , Ying Tang , Aline M. Thomas , Shen Li , Jian V. Zhang , Shuai Liu , Huamin Qin

Introduction

Preeclampsia (PE) is one of the most common pregnancy-related complications worldwide and currently lacks an effective treatment. While trophoblast cell dysfunction has been identified as the fundamental cause of PE, the underlying mechanisms remain unclear. Bone morphogenetic protein 5 (BMP5) is a secreted glycoprotein highly expressed in the placenta that is involved in cell proliferation, migration, and invasion. However, the role and mechanism of BMP5 glycosylation of trophoblast cell function remain unclear.

Methods

The expression of BMP5 and N-glycosylation in preeclamptic placental tissues was investigated. We predicted and validated the N-glycosylation sites of BMP5. Additionally, we evaluated the effect of BMP5 N-glycosylation on the proliferation, migration, invasion, and angiogenesis of human immortalized trophoblastic HTR-8/SVneo cells. Furthermore, the role of N-glycosylated BMP5 in activating the BMP5-SMAD1/5 signaling pathway and regulating trophoblastic cell functions was explored.

Results

Our study reveals that PHA-E + L (recognizing branching N-glycans) reactive N-glycans and BMP5 expression levels are lower in preeclamptic villous tissues compared to normal placental tissues. Additionally, we demonstrated that BMP5 is an N-glycosylation-modified protein. Furthermore, N-glycosylated BMP5 promoted the functional trophoblastic cells (HTR-8/SVneo). We also revealed that N-glycosylation of BMP5 regulates multiple cell functions through the BMP5-SMAD1/5 signaling pathway.

Conclusion

N-glycosylated BMP5 promotes trophoblast cell proliferation, migration, invasion, and angiogenesis. This study provides mechanistic insight as to how N-glycosylation of BMP5 in trophoblast cells can contribute to the pathogenesis of preeclampsia and provides a new basis for its diagnosis and treatment.

简介子痫前期（PE）是全球最常见的妊娠相关并发症之一，目前缺乏有效的治疗方法。虽然滋养层细胞功能障碍已被确定为子痫前期的根本原因，但其潜在机制仍不清楚。骨形态发生蛋白 5（BMP5）是一种在胎盘中高度表达的分泌性糖蛋白，参与细胞增殖、迁移和侵袭。然而，BMP5糖基化对滋养层细胞功能的作用和机制仍不清楚：方法：研究了BMP5和N-糖基化在先兆子痫胎盘组织中的表达。我们预测并验证了 BMP5 的 N-糖基化位点。此外，我们还评估了 BMP5 N-糖基化对人永生滋养细胞 HTR-8/SVneo 的增殖、迁移、侵袭和血管生成的影响。此外，还探讨了N-糖基化的BMP5在激活BMP5-SMAD1/5信号通路和调控滋养细胞功能中的作用：结果：我们的研究发现，与正常胎盘组织相比，子痫前期绒毛组织中PHA-E + L（识别分支N-糖）活性N-糖和BMP5的表达水平较低。此外，我们还证实 BMP5 是一种 N-糖基化修饰蛋白。此外，N-糖基化的 BMP5 对功能性滋养细胞（HTR-8/SVneo）有促进作用。我们还发现，BMP5的N-糖基化通过BMP5-SMAD1/5信号通路调节多种细胞功能：结论：N-糖基化的 BMP5 可促进滋养层细胞的增殖、迁移、侵袭和血管生成。这项研究从机理上揭示了滋养层细胞中 BMP5 的 N-糖基化如何导致子痫前期的发病机制，并为子痫前期的诊断和治疗提供了新的依据。

{"title":"BMP5 promotes trophoblast functions upon N-glycosylation via the BMP5-SMAD1/5 signaling pathway in preeclampsia","authors":"Hao Wang , Ningning Fan , Xinyuan Cui , Ru Xie , Ying Tang , Aline M. Thomas , Shen Li , Jian V. Zhang , Shuai Liu , Huamin Qin","doi":"10.1016/j.placenta.2024.11.002","DOIUrl":"10.1016/j.placenta.2024.11.002","url":null,"abstract":"<div><h3>Introduction</h3><div>Preeclampsia (PE) is one of the most common pregnancy-related complications worldwide and currently lacks an effective treatment. While trophoblast cell dysfunction has been identified as the fundamental cause of PE, the underlying mechanisms remain unclear. Bone morphogenetic protein 5 (BMP5) is a secreted glycoprotein highly expressed in the placenta that is involved in cell proliferation, migration, and invasion. However, the role and mechanism of BMP5 glycosylation of trophoblast cell function remain unclear.</div></div><div><h3>Methods</h3><div>The expression of BMP5 and N-glycosylation in preeclamptic placental tissues was investigated. We predicted and validated the N-glycosylation sites of BMP5. Additionally, we evaluated the effect of BMP5 N-glycosylation on the proliferation, migration, invasion, and angiogenesis of human immortalized trophoblastic HTR-8/SVneo cells. Furthermore, the role of N-glycosylated BMP5 in activating the BMP5-SMAD1/5 signaling pathway and regulating trophoblastic cell functions was explored.</div></div><div><h3>Results</h3><div>Our study reveals that PHA-E + L (recognizing branching N-glycans) reactive N-glycans and BMP5 expression levels are lower in preeclamptic villous tissues compared to normal placental tissues. Additionally, we demonstrated that BMP5 is an N-glycosylation-modified protein. Furthermore, N-glycosylated BMP5 promoted the functional trophoblastic cells (HTR-8/SVneo). We also revealed that N-glycosylation of BMP5 regulates multiple cell functions through the BMP5-SMAD1/5 signaling pathway.</div></div><div><h3>Conclusion</h3><div>N-glycosylated BMP5 promotes trophoblast cell proliferation, migration, invasion, and angiogenesis. This study provides mechanistic insight as to how N-glycosylation of BMP5 in trophoblast cells can contribute to the pathogenesis of preeclampsia and provides a new basis for its diagnosis and treatment.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":"158 ","pages":"Pages 240-252"},"PeriodicalIF":3.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142626681","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

Corrigendum to “Unveiling placental development in circadian rhythm-disrupted mice: A photo-acoustic imaging study on unstained tissue” [Placenta 158 (2024) 57-61] 昼夜节律紊乱小鼠胎盘发育揭秘：未染色组织的光声成像研究" [Placenta 158 (2024) 57-61]

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-04 DOI: 10.1016/j.placenta.2024.10.066

M.N. Cizmeciyan , N.I. Bektas , N. Derin , T. Denizaltı , A. Khoshzaban , M.B. Unlu , C. Celik-Ozenci

引用次数: 0

Placental extracellular vesicles promoted cervical tumour tissue undergoing death 胎盘细胞外囊泡促进了宫颈肿瘤组织的死亡。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-02 DOI: 10.1016/j.placenta.2024.10.069

Lin Wang , Jinqiu Zhang , Angang Sun , Yongxiang Yin , Ye Shen , Dengxin Zhang , Qi Chen , Min Zhao

Background

Cervical cancer is a leading cause of death in developing countries. Although the placenta is a tumor-like organ, the placental development, including invasive function, is well controlled. One mechanism is that extracellular vesicles (EVs) released from the placenta contribute to this regulation. Placental EVs carry functional proteins and regulatory RNAs. Our previous study reported that placental EVs inhibited ovarian cancer growth in vitro and in vivo.

Methods

Whether the inhibitory effect induced by placental EVs also applies to cervical cancer, a non-endocrine-related cancer, in this study, we first co-cultured the cervical tumour tissues with placental explants.

Results

Co-culturing cervical tumour tissues (n = 7) with placental explants showed necrotic signs and increased levels of senescence-associated proteins and death-associated miRNAs, including miRNA-143-3p, miRNA-519a-5p and miRNA-199a-3p in tumour tissues. Additionally, treatment of HeLa cells with placental EVs reduced the viability of HeLa cells and inhibited the ability of invasion and migration of HeLa cells. Increased levels of senescence-associated proteins and reduced levels of proliferative proteins may contribute to the inhibitory effects in HeLa cells.

Discussion

placental EVs are involved in regulating placental development, and the delivery of cargo significantly impacts the functions of target cells. This study found that factors released from placental explants, likely placental EVs, had anti-tumour effects on the cervical tumour by inhibiting cervical cancer cell viability, invasion, and migration. Cargo in placental EVs, such as cellular death-associated miRNAs, may contribute to the inhibitory effects on cervical tumour.

背景：宫颈癌是发展中国家的主要死因。虽然胎盘是一个肿瘤样器官，但胎盘的发育，包括侵袭功能，都得到了很好的控制。一种机制是胎盘释放的细胞外囊泡 (EVs) 有助于这种调控。胎盘EVs携带功能性蛋白质和调控RNA。我们之前的研究报告称，胎盘 EVs 可抑制卵巢癌在体外和体内的生长：胎盘EVs的抑制作用是否也适用于宫颈癌这种与内分泌无关的癌症，在本研究中，我们首先将宫颈肿瘤组织与胎盘外植体共培养：结果：宫颈肿瘤组织（n = 7）与胎盘外植体共培养后，肿瘤组织出现坏死迹象，衰老相关蛋白和死亡相关 miRNA 水平升高，包括 miRNA-143-3p、miRNA-519a-5p 和 miRNA-199a-3p。此外，用胎盘 EVs 处理 HeLa 细胞可降低 HeLa 细胞的活力，抑制 HeLa 细胞的侵袭和迁移能力。讨论：胎盘 EVs 参与了胎盘发育的调控，货物的运送会对靶细胞的功能产生重大影响。本研究发现，胎盘外植体释放的因子（可能是胎盘EVs）通过抑制宫颈癌细胞的活力、侵袭和迁移，对宫颈肿瘤具有抗肿瘤作用。胎盘EVs中的载体，如细胞死亡相关的miRNAs，可能有助于对宫颈肿瘤的抑制作用。

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引用次数: 0

Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia 在子痫前期小鼠模型中，妊娠中晚期注射瘦素可诱导胎盘线粒体和内质网折叠蛋白反应。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-11-02 DOI: 10.1016/j.placenta.2024.11.001

Jessica L. Faulkner , Mayumi Takano , Safia Ogbi , Wen Tong , Masahiko Nakata , Desmond Moronge , Tereza Cindrova-Davies , Dino A. Giussani

Introduction

Preeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown.

Methods

In the current study we measured the expression of proteins involved in the endoplasmic reticulum (UPR^er) and mitochondrial (UPR^mt) unfolded protein responses in placentas of wild-type sham normal pregnant and leptin-infused preeclamptic mice.

Results

The data show that mid-late gestation leptin infusion induced activation of indices of placental UPR^er and UPR^mt, while reducing placental repair mechanisms to UPR^mt in preeclamptic mice. Mid-late gestation infusion with leptin upregulated markers of placental oxidative stress, reduced the placental expression levels of mitochondrial electron transport chain complexes I and II and increased the expression of placental endothelin-1 (ET-1) in preeclamptic mice. The leptin-induced activation of several placental UPR^mt markers as well as ET-1 levels correlated with fetal growth restriction and impaired maternal endothelial function in preeclamptic mice.

Discussion

Collectively, these data indicate that elevated levels of leptin in mid-late pregnancy in mice promote placental stress responses, akin to those in pregnant women with preeclampsia.

导言：先兆子痫患者，包括瘦人和肥胖者，都会出现瘦素水平升高，这与母体内皮功能障碍和胎儿不良结局（如生长受限）的发生有关，从而导致出生体重不足。最近对怀孕小鼠的研究表明，妊娠中晚期注射瘦素可诱发子痫前期的临床特征，包括母体血压升高、母体内皮功能障碍和胎儿生长受限。然而，瘦素是否会引发胎盘应激反应，从而导致与子痫前期一样的不良胎儿结局，目前尚不清楚：在本研究中，我们测量了野生型假正常妊娠小鼠和注入瘦素的子痫前期小鼠胎盘中参与内质网（UPRer）和线粒体（UPRmt）未折叠蛋白反应的蛋白质的表达：数据显示，妊娠中晚期输注瘦素可诱导激活胎盘UPRer和UPRmt指数，同时降低子痫前期小鼠胎盘对UPRmt的修复机制。妊娠中晚期输注瘦素可上调胎盘氧化应激指标，降低胎盘线粒体电子传递链复合物I和II的表达水平，并增加子痫前期小鼠胎盘内皮素-1（ET-1）的表达。瘦素诱导的胎盘UPRmt标记物和ET-1水平的激活与胎儿生长受限和先兆子痫小鼠母体内皮功能受损相关：总之，这些数据表明，小鼠妊娠中晚期瘦素水平升高会促进胎盘应激反应，这与子痫前期孕妇的应激反应类似。

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引用次数: 0

Placental methylation and pro-inflammatory protein levels in cord blood 胎盘甲基化和脐带血中的促炎蛋白水平。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-30 DOI: 10.1016/j.placenta.2024.10.067

Sanne D. van Otterdijk , Alexandra M. Binder , Karin B. Michels

Introduction

The neonates’ inflammatory response may in part be shaped during development by the placental epigenome, but evidence is scarce. We investigated the association between placental DNA methylation and pro-inflammatory proteins in cord blood.

Methods

A total of 249 mother-child dyads from the Harvard Epigenetic Birth Cohort were included in this study. Genome-wide methylation in placental DNA was assessed using the Illumina Human Methylation 450 Bead Chip array and verified by pyrosequencing. Cord blood inflammation markers assessed were interleukin-6, interleukin-8 and tumor necrosis factor α, intercellular adhesion molecule 1, serum amyloid A, and C-reactive protein.

Results

We identified differential placental DNA methylation of three loci in the HIVEP3 gene shore region that were associated with TNFα protein levels in cord blood. TNFα levels were associated with mode of delivery, gestational age and birth order. Three other loci located in the open sea region of the BCL11B gene were associated with SAA protein levels in cord blood. SAA levels were associated with birthweight, gestational age, and infant sex.

Conclusions

Our results suggest a potential role for HIVEP3 and BCL11B placental DNA methylation in the acute immune response of the neonate. These immune markers were correlated with several mother and child characteristics.

导言：新生儿的炎症反应可能部分是在发育过程中由胎盘表观基因组形成的，但这方面的证据还很少。我们研究了胎盘 DNA 甲基化与脐带血中促炎蛋白之间的关联：本研究共纳入了哈佛表观遗传出生队列中的 249 对母子。使用Illumina人类甲基化450珠芯片阵列评估胎盘DNA的全基因组甲基化，并通过热测序进行验证。评估的脐带血炎症标记物包括白细胞介素-6、白细胞介素-8和肿瘤坏死因子α、细胞间粘附分子1、血清淀粉样蛋白A和C反应蛋白：结果：我们发现HIVEP3基因岸区的三个位点的胎盘DNA甲基化差异与脐带血中的TNFα蛋白水平有关。TNFα水平与分娩方式、胎龄和胎次有关。位于BCL11B基因开放海区的另外三个位点与脐带血中的SAA蛋白水平有关。SAA水平与出生体重、胎龄和婴儿性别有关：我们的研究结果表明，HIVEP3 和 BCL11B 胎盘 DNA 甲基化在新生儿急性免疫反应中的潜在作用。这些免疫标记物与母婴的一些特征相关。

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引用次数: 0

Transcriptomic analysis identified novel biomarker in invasive placenta accreta spectrum 转录组分析确定了侵袭性胎盘早剥谱中的新型生物标志物。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-29 DOI: 10.1016/j.placenta.2024.10.023

Xiaoming Shi , Ling Jin , Xinlu Meng , Xiao Huo , Yan Sun , Lixiang Xue , Yuan Wei , Yuanyuan Wang , Zhongnan Yin , Yangyu Zhao , Lian Chen

Introduction

Placenta accreta spectrum (PAS) disorders pose a grave threat to maternal life due to severe hemorrhage and the heightened risk of peripartum hysterectomy. Consequently, there's a pressing need for circulating biomarkers in clinical settings. MicroRNAs (miRNAs), being stable in peripheral circulation, hold promise as potential biomarkers for PAS.

Methods

This study recruited singleton live pregnancies, including cases of invasive PAS, placenta previa (PP), and controls, across three phases. Initially, RNA-seq of peripheral blood identified 6 miRNAs in the screening phase. Subsequently, in the training and validation phases, miR-23a-5p, along with its target genes ASF1B and CHTF8, were validated using qRT-PCR. The diagnostic value of these markers for PAS and adverse outcomes was evaluated using Receiver Operating Characteristic (ROC) curves.

Results

The results showed miR-23a-5p was down-regulated in PAS, whereas ASF1B and CHTF8 were up-regulated. miR-23a-5p had modest diagnostic efficiency for PAS and adverse outcomes, as the AUC were 0.689 and 0.711 respectively. However, when miR-23a-5p combined with CHTF8, the AUC can improve greatly to 0.869 in PAS diagnosis and 0.856 in prediction of adverse outcomes.

Discussion

We propose the miR-23a-5p plays a role in PAS pathogenesis through regulating cell proliferation, migration, invasion, apoptosis by targeting various genes. This study confirmed its potential value of miR-23a-5p combined with target gene CHTF8 as novel biomarkers for PAS and adverse outcomes.

导言：胎盘早剥（PAS）疾病会导致严重出血，并增加围产期子宫切除术的风险，对产妇生命构成严重威胁。因此，临床上迫切需要循环生物标志物。微RNA（miRNA）在外周循环中稳定，有望成为PAS的潜在生物标志物：本研究招募了单胎活产孕妇，包括侵袭性 PAS、前置胎盘（PP）病例和对照组，共分为三个阶段。最初，在筛选阶段，外周血的 RNA 序列鉴定出了 6 个 miRNA。随后，在训练和验证阶段，利用 qRT-PCR 验证了 miR-23a-5p 及其靶基因 ASF1B 和 CHTF8。利用接收者操作特征曲线（ROC）评估了这些标记物对 PAS 和不良结局的诊断价值：结果显示，miR-23a-5p 在 PAS 中下调，而 ASF1B 和 CHTF8 上调。然而，当miR-23a-5p与CHTF8结合使用时，PAS诊断的AUC可大大提高到0.869，不良预后预测的AUC可提高到0.856：我们认为，miR-23a-5p通过靶向多种基因调控细胞增殖、迁移、侵袭和凋亡，在PAS发病机制中发挥作用。本研究证实了miR-23a-5p与靶基因CHTF8结合作为PAS和不良预后的新型生物标志物的潜在价值。

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