IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

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

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

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

Feto-placental vascular structure and in silico haemodynamics: Of mice, rats, and human 胎盘血管结构和硅血流动力学：小鼠、大鼠和人类。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-28 DOI: 10.1016/j.placenta.2024.10.020

Introduction

The complex arborization of the feto-placental vasculature is crucial for optimal fetal nutrition, waste exchange and ultimately, development. Ethical and experimental limitations constrain research into the human placenta, hence experimental animal models such as mice and rats, are crucial to understand placental function. It is unclear how well the mouse and rat feto-placental vascular structure emulates human. Moreover, the implications of differences in vascular structure, especially in arborization, for placental function remain unclear.

Methods

We use micro-computed tomography imaging, high frequency Doppler ultrasound and computational fluid dynamics to characterize feto-placental vasculature structure and haemodynamics in mice, rats, and human.

Results

Our data suggest that despite structural differences between rat and mouse placenta, haemodynamics are similar and that both hold applicability to investigating feto-placental structure and function. We show that human cotyledons demonstrate vascularity-dependent haemodynamic behaviour (including flow deceleration and oxygen exchange) similar to rodents and can be analysed in the same spectrum as rodents. Finally, we show strong structure-function relationships when interspecies datasets are combined; notably, we demonstrate that surrogate measures such as vascularity, can be used to estimate placental oxygen exchange function.

Discussion

Pre-clinical placental research utilising rat and mouse placentae to understand the impact of feto-placental arborization on placental function and fetal development can inform the human context.

引言胎儿-胎盘血管的复杂分支对胎儿的最佳营养、废物交换和最终发育至关重要。伦理和实验方面的限制制约了对人类胎盘的研究，因此小鼠和大鼠等实验动物模型对了解胎盘功能至关重要。目前还不清楚小鼠和大鼠胎盘血管结构与人类胎盘血管结构的相似程度。此外，血管结构的差异，尤其是动脉化对胎盘功能的影响仍不清楚：方法：我们利用微型计算机断层扫描成像、高频多普勒超声波和计算流体动力学来描述小鼠、大鼠和人类的胎盘血管结构和血流动力学特征：结果：我们的数据表明，尽管大鼠和小鼠胎盘的结构不同，但血流动力学相似，都适用于研究胎盘结构和功能。我们的研究表明，人类子叶表现出与啮齿类动物相似的血管依赖性血流动力学行为（包括血流减速和氧气交换），并能以与啮齿类动物相同的频谱进行分析。最后，我们展示了将不同物种间的数据集结合在一起时的强大结构-功能关系；特别是，我们展示了血管等替代措施可用于估计胎盘的氧交换功能：讨论：临床前胎盘研究利用大鼠和小鼠胎盘来了解胎盘轴化对胎盘功能和胎儿发育的影响，可以为人类胎盘研究提供参考。

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引用次数: 0

Methylation and expression of imprinted genes in circulating extracellular vesicles from women experiencing early onset preeclampsia 早发型子痫前期妇女循环细胞外囊泡中印记基因的甲基化和表达。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-24 DOI: 10.1016/j.placenta.2024.10.019

Introduction

Preeclampsia (PE) is a pregnancy complication marked by high blood pressure, posing risk to maternal and fetal health. "Genomic imprinting", an epigenetic phenomenon regulated by DNA methylation at Differently Methylated Regions (DMR's), influences placental development. Research on circulating extracellular vesicles (EVs) in PE suggests them as potential source for early biomarkers, but methylation status of EV-DNA in Preeclampsia is not reported yet.

Methods

This study examines the methylation and expression profile of imprinted genes - PEG10, PEG3, MEST, and DLK1 in circulating EVs of 1^st and 3^rd trimester control and early onset preeclampsia (EOPE) pregnant women (n = 15) using pyrosequencing and qRT-PCR respectively.

Results

In 1^st trimester, PEG3 was significantly hypermethylated, whereas no significant methylation changes were noted in PEG10 and MEST in EOPE. In 3^rd trimester, significant hypomethylation in PEG10, PEG3 and IGDMR was observed whereas significant hypermethyaltion noted in MEST. mRNA expression of PEG10, PEG3 and DLK1 was not affected in circulating EVs of 1^st trimester EOPE. However, in 3^rd trimester significant increased expression in PEG10, PEG3 and DLK1 noted. MEST expression was reduced in 3^rd trimester EOPE. No correlation was observed between average DNA methylation and gene expression in PEG10 and PEG3 in 1^st trimester. However, in 3^rd trimester, significant negative correlation was noted in PEG10 (r = −0.426, p = 0.04), PEG3 (r = −0.496, p = 0.01), MEST (r = −0.398, p = 0.03) and DLK1 (r = −0.403, p = 0.03).

Discussion

The results of our study strengthen the potential of circulating EVs from maternal serum as non-invasive indicators of placental pathophysiology, including preeclampsia.

导言子痫前期（PE）是一种以高血压为特征的妊娠并发症，对母体和胎儿的健康构成威胁。"基因组印记 "是一种由不同甲基化区域（DMR）的 DNA 甲基化调控的表观遗传现象，影响着胎盘的发育。对 PE 中循环细胞外囊泡（EVs）的研究表明，它们是早期生物标志物的潜在来源，但子痫前期 EV-DNA 的甲基化状态尚未见报道：本研究采用热测序法和 qRT-PCR 法分别检测了第一和第三孕期对照组和早发子痫前期（EOPE）孕妇（n = 15）循环 EV 中印记基因 PEG10、PEG3、MEST 和 DLK1 的甲基化和表达谱：结果：在妊娠头三个月，PEG3 发生了明显的高甲基化，而在 EOPE 中，PEG10 和 MEST 没有发生明显的甲基化变化。在妊娠三个月时，PEG10、PEG3 和 IGDMR 发生了明显的低甲基化，而 MEST 则发生了明显的高甲基化。在妊娠三个月的 EOPE 循环 EV 中，PEG10、PEG3 和 DLK1 的 mRNA 表达未受影响。然而，在怀孕三个月时，PEG10、PEG3 和 DLK1 的表达明显增加。在妊娠三个月的 EOPE 中，MEST 的表达减少。在妊娠头三个月，PEG10 和 PEG3 的平均 DNA 甲基化与基因表达之间没有相关性。然而，在妊娠第 3 个月，PEG10（r = -0.426，p = 0.04）、PEG3（r = -0.496，p = 0.01）、MEST（r = -0.398，p = 0.03）和 DLK1（r = -0.403，p = 0.03）的基因表达呈显著负相关：讨论：我们的研究结果增强了母体血清中的循环EV作为胎盘病理生理学（包括子痫前期）非侵入性指标的潜力。

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引用次数: 0

MiR-142-5p mediated Nrf2 dysregulation in gestational diabetes mellitus and its impact on placental angiogenesis 妊娠期糖尿病中 MiR-142-5p 介导的 Nrf2 失调及其对胎盘血管生成的影响

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-24 DOI: 10.1016/j.placenta.2024.10.021

Introduction

Gestational diabetes mellitus (GDM) presents significant risks during pregnancy, including adverse perinatal outcomes and placental dysfunction. Impaired angiogenesis, involving crucial factors like Vascular Endothelial Growth Factor (VEGF), contributes to these complications. The Nrf2/Keap1 pathway, crucial for vascular redox homeostasis, has been linked to GDM-associated angiogenesis dysregulation.

Methods

This study aimed to investigate the molecular mechanisms underlying placental Nrf2 regulation, focusing on angiomiRs, key regulators of angiogenesis in GDM. Computational analysis identified miR-142-5p targeting Nrf2 mRNA. Expression levels of miR-142-5p were assessed in GDM placenta and correlated with Nrf2 expression. Experimental validation utilized human trophoblastic cell lines (BeWo) exposed to hyperglycemic conditions, assessing the effects of anti-miR-142 transfection on Nrf2 expression and angiogenic marker levels.

Results

miR-142-5p expression was significantly downregulated in GDM placenta, correlating positively with Nrf2 expression. In BeWo cells exposed to hyperglycemia, anti-miR-142 transfection notably increased Nrf2 expression alongside angiogenic marker levels, confirming the computational predictions.

Discussion

Our findings highlight the pivotal role of miRNAs in GDM-associated impaired angiogenesis by modulating Nrf2 expression. Understanding these molecular mechanisms provides insights into potential therapeutic targets for improving pregnancy outcomes in GDM cases.

导言：妊娠期糖尿病（GDM）在妊娠期间具有重大风险，包括不利的围产期结局和胎盘功能障碍。血管生成受损，血管内皮生长因子（VEGF）等关键因子参与其中，是导致这些并发症的原因之一。Nrf2/Keap1通路对血管氧化还原平衡至关重要，它与GDM相关的血管生成失调有关：本研究旨在研究胎盘Nrf2调控的分子机制，重点关注GDM中血管生成的关键调控因子--angiomiRs。计算分析发现了靶向 Nrf2 mRNA 的 miR-142-5p。评估了 miR-142-5p 在 GDM 胎盘中的表达水平，并将其与 Nrf2 的表达相关联。实验验证利用暴露于高血糖条件下的人类滋养细胞系（BeWo），评估抗 miR-142 转染对 Nrf2 表达和血管生成标志物水平的影响。在暴露于高血糖的 BeWo 细胞中，抗 miR-142 转染明显增加了 Nrf2 表达和血管生成标志物水平，证实了计算预测：我们的研究结果凸显了 miRNA 通过调节 Nrf2 表达在 GDM 相关血管生成障碍中的关键作用。通过了解这些分子机制，我们可以深入了解改善 GDM 妊娠结局的潜在治疗靶点。

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引用次数: 0

Placental volume at gestational week 27 and subsequent fetal growth: An observational study 孕 27 周胎盘容积与胎儿后续生长：一项观察性研究。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-24 DOI: 10.1016/j.placenta.2024.10.022

Objectives

To study if placental volume and placental to fetal ratio at gestational week (GW) 27 correlate with subsequent fetal growth. We also investigated whether the 1/3 smallest and 1/3 largest fetuses have different growth potential depending on placental volume.

Methods

Placental and fetal volume was measured by magnetic resonance imaging (MRI) at GW 27 and 37 in 86 singleton pregnancies. Placental to fetal ratio was calculated as placental volume/fetal volume. Growth was calculated as [(fetal volume at GW 37 – fetal volume at GW 27)/number of days between the MRI examinations]. To explore whether a higher placental volume affected growth of small and large fetuses differently, we performed separate analyses of the 1/3 smallest and 1/3 largest fetuses with placental volume under and above the median at GW 27.

Results

We found a positive correlation of both placental volume and placental to fetal ratio at GW 27 with average growth velocity, r = 0.51 (p < 0.001) and r = 0.33 (p = 0.002) respectively. The correlation between fetal volume at GW 27 and average growth velocity was r = 0.48 (p < 0.001). The small fetuses had significantly lower average growth velocity if the placental volume was low compared to if the placental volume was high, 22 (SD 3) cm³/day versus 25 (SD 3) cm³/day, p = 0.02. Among the large fetuses, placental volume did not significantly affect growth.

Conclusions

Placental volume and placental to fetal ratio at GW 27 were positively correlated with subsequent fetal growth. Possibly, placental size is an indicator of fetal growth potential, especially among small fetuses.

研究目的研究胎盘体积和胎盘与胎儿在孕周（GW）27时的比例是否与随后的胎儿生长相关。我们还研究了1/3最小胎儿和1/3最大胎儿是否因胎盘体积不同而具有不同的生长潜力：方法：通过磁共振成像（MRI）测量了 86 例单胎妊娠在第 27 和 37 周的胎盘和胎儿体积。胎盘与胎儿的比率按胎盘体积/胎儿体积计算。胎儿生长速度的计算公式为[（第37孕期的胎儿体积-第27孕期的胎儿体积）/磁共振成像检查的间隔天数]。为了探究胎盘体积增大是否会对小胎儿和大胎儿的生长产生不同影响，我们分别对胎盘体积低于和高于 GW 27 中位数的 1/3 最小胎儿和 1/3 最大胎儿进行了分析：我们发现，胎盘体积和胎盘与胎儿比率与平均生长速度呈正相关，r = 0.51（p 3/天对 25（SD 3）立方厘米/天，p = 0.02）。在巨大胎儿中，胎盘容积对生长没有显著影响：结论：胎盘体积和胎盘与胎儿的比率与胎儿随后的生长呈正相关。结论：胎盘体积和胎盘与胎儿比值与胎儿随后的生长呈正相关，胎盘大小可能是胎儿（尤其是小胎儿）生长潜力的指标。

{"title":"Placental volume at gestational week 27 and subsequent fetal growth: An observational study","authors":"","doi":"10.1016/j.placenta.2024.10.022","DOIUrl":"10.1016/j.placenta.2024.10.022","url":null,"abstract":"<div><h3>Objectives</h3><div>To study if placental volume and placental to fetal ratio at gestational week (GW) 27 correlate with subsequent fetal growth. We also investigated whether the 1/3 smallest and 1/3 largest fetuses have different growth potential depending on placental volume.</div></div><div><h3>Methods</h3><div>Placental and fetal volume was measured by magnetic resonance imaging (MRI) at GW 27 and 37 in 86 singleton pregnancies. Placental to fetal ratio was calculated as placental volume/fetal volume. Growth was calculated as [(fetal volume at GW 37 – fetal volume at GW 27)/number of days between the MRI examinations]. To explore whether a higher placental volume affected growth of small and large fetuses differently, we performed separate analyses of the 1/3 smallest and 1/3 largest fetuses with placental volume under and above the median at GW 27.</div></div><div><h3>Results</h3><div>We found a positive correlation of both placental volume and placental to fetal ratio at GW 27 with average growth velocity, r = 0.51 (p < 0.001) and r = 0.33 (p = 0.002) respectively. The correlation between fetal volume at GW 27 and average growth velocity was r = 0.48 (p < 0.001). The small fetuses had significantly lower average growth velocity if the placental volume was low compared to if the placental volume was high, 22 (SD 3) cm<sup>3</sup>/day versus 25 (SD 3) cm<sup>3</sup>/day, p = 0.02. Among the large fetuses, placental volume did not significantly affect growth.</div></div><div><h3>Conclusions</h3><div>Placental volume and placental to fetal ratio at GW 27 were positively correlated with subsequent fetal growth. Possibly, placental size is an indicator of fetal growth potential, especially among small fetuses.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564700","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

Endothelin-1 potentiated constriction in preeclampsia placental veins: Role of ETAR/ETBR/CaV1.2/CALD1 内皮素-1可促进子痫前期胎盘静脉收缩：ETAR/ETBR/CaV1.2/CALD1的作用。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-24 DOI: 10.1016/j.placenta.2024.10.011

Background

Placenta plays a vital role in preeclampsia. The present study investigated the role of endothelin-1 (ET-1) and its receptors in preeclampsia placenta.

Method

Placenta samples were collected from normal and preeclampsia pregnancies, with one single fetus. Placental chorionic plate vessel tone was measured with DMT using vasoactive agents with or without antagonists. Role of L-type voltage-dependent calcium channels (CaV1.2) in single smooth muscle cell was detected using whole-cell patch clamp. PCR, Western blot, and ELISA was used to detect molecule expressions. Placental vessel explants and human umbilical vein smooth muscle cell (HUVSMC) were exposed to ET-1 treatment with or without antagonists. Human umbilical vein endothelial cell (HUVEC) and pregnant sheep was exposed to hypoxic condition, simulating preeclampsia.

Results

ET-1 and IRL1620 mediated stronger contractions in preeclampsia placental veins, despite unchanged ETAR and decreased ETBR expression. Comparing with control, there was higher ET-1 in umbilical plasma, maternal plasma, and placental vessels from preeclampsia. In utero hypoxia increased plasma ET-1 in fetal lambs and ewes. Hypoxia promoted ET-1 production in HUVEC. Role and expression of CaV1.2 was decreased in preeclampsia placental vessels, while high-molecular-weight caldesmon (CALD1), the marker of contractile phenotype of smooth muscle cells, was significantly increased. ET-1 treatment increased CALD1 in placental explants and in HUVSMC via ETAR/ETBR.

Conclusion

The present study firstly demonstrated ET-1 induced greater contraction in preeclampsia placental chorionic plate veins via ETAR/ETBR, instead of via weaker CaV1.2. In utero hypoxia promoted plasma ET-1 in fetal lambs and ewe, similar to that in preeclampsia. ET-1, binding with ETAR/ETBR increased CALD1, which was associated with stronger contraction in preeclampsia. The data provided important information in preeclampsia onset.

背景：胎盘在子痫前期中起着至关重要的作用。本研究探讨了内皮素-1（ET-1）及其受体在子痫前期胎盘中的作用：方法：从正常妊娠和子痫前期妊娠的一个胎儿中采集胎盘样本。用DMT测量胎盘绒毛膜板血管张力，使用血管活性剂或不使用拮抗剂。使用全细胞膜片钳检测单个平滑肌细胞中 L 型电压依赖性钙通道（CaV1.2）的作用。使用 PCR、Western 印迹和 ELISA 检测分子表达。将胎盘血管外植体和人脐静脉平滑肌细胞（HUVSMC）暴露于含有或不含拮抗剂的 ET-1 处理中。将人脐静脉内皮细胞（HUVEC）和怀孕绵羊置于缺氧条件下，模拟子痫前期：结果：ET-1和IRL1620在子痫前期胎盘静脉中介导了更强的收缩，尽管ETAR表达不变，ETBR表达减少。与对照组相比，子痫前期脐血、母体血浆和胎盘血管中的ET-1含量更高。宫内缺氧会增加胎羔和母羊血浆中的 ET-1。缺氧促进了 HUVEC 中 ET-1 的产生。子痫前期胎盘血管中CaV1.2的作用和表达减少，而平滑肌细胞收缩表型的标志物高分子量钙粘蛋白（CALD1）显著增加。ET-1通过ETAR/ETBR增加了胎盘外植体和HUVSMC中的CALD1：本研究首次证明了ET-1通过ETAR/ETBR而不是通过较弱的CaV1.2诱导子痫前期胎盘绒毛膜板静脉产生更大的收缩。宫内缺氧会促进胎儿羔羊和母羊血浆中的 ET-1，这与子痫前期的情况相似。ET-1与ETAR/ETBR结合会增加CALD1，而CALD1与子痫前期更强的收缩有关。这些数据为子痫前期的发病提供了重要信息。

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引用次数: 0

Placenta-associated biomarkers and pregnancy outcome in HPA-1a alloimmunization: A prospective cohort study 胎盘相关生物标志物与 HPA-1a 同种免疫的妊娠结局：前瞻性队列研究

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-24 DOI: 10.1016/j.placenta.2024.10.014

Introduction

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from parental incompatibility in human platelet antigens (HPA) and subsequent maternal sensitization. The HPA-1a epitope is also expressed on placental tissue. Chronic placental inflammation and lower birth weight is observed more often in HPA-1a alloimmunized pregnancies, suggesting a placental component in the pathophysiology of FNAIT. Today, prediction of FNAIT severity is limited. The aim of the study was to investigate whether dysregulated maternal angiogenic proteins are associated with neonatal outcome in HPA-1a alloimmunized pregnancies.

Material and methods

Eighty-seven HPA-1a negative pregnant women were identified from a large prospective screening study in Poland (PREVFNAIT) including 43 HPA-1a immunized and 44 non-immunized controls. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were measured in maternal plasma from 2nd and 3rd trimester by enzyme-linked immunosorbent assay and levels/ratios were compared between study groups, using uni- and multivariable analyses. Main outcome measures were either classic FNAIT-related (severe thrombocytopenia, petechia, intracranial hemorrhage), placenta-related (small for gestational age) or a composite variable combining them all.

Results

There were no significant differences in plasma concentrations of sFlt-1, PlGF, sEng nor sFlt-1/PlGF ratio when comparing immunized and non-immunized pregnancies. Among HPA-1a alloimmunized pregnancies, increasing levels of the sFlt-1 protein in 3rd trimester were significantly associated with lower neonatal platelet count (multivariable linear regression, p = 0.024). Increased sFlt-1 and sFlt-1/PlGF ratio in 3rd trimester were significantly associated with higher odds of a composite adverse neonatal outcome in alloimmunized pregnancies (multivariable logistic regression, p = 0.029 and p = 0.019, respectively).

Conclusion

An anti-angiogenic profile in HPA-1a alloimmunized mothers is associated with a composite adverse neonatal outcome. This suggests that sFlt-1 and the sFlt-1/PlGF ratio may assist in predelivery risk stratification and clinical management decisions for FNAIT.

导言胎儿和新生儿同种免疫血小板减少症（FNAIT）是由于父母的人类血小板抗原（HPA）不相容以及随后的母体致敏造成的。HPA-1a 表位也在胎盘组织上表达。在 HPA-1a 同种免疫妊娠中更常观察到慢性胎盘炎症和较低的出生体重，这表明 FNAIT 的病理生理学中存在胎盘成分。目前，对 FNAIT 严重程度的预测还很有限。该研究旨在探讨母体血管生成蛋白失调是否与 HPA-1a 同种免疫妊娠的新生儿结局有关。材料和方法从波兰的一项大型前瞻性筛查研究（PREVFNAIT）中确定了 87 名 HPA-1a 阴性孕妇，其中包括 43 名 HPA-1a 免疫对照和 44 名非免疫对照。通过酶联免疫吸附法测定了怀孕第二和第三季度母体血浆中的胎盘生长因子（PlGF）、可溶性瘤样酪氨酸激酶-1（sFlt-1）和可溶性内胚叶素（sEng），并使用单变量和多变量分析比较了研究组之间的水平/比率。主要结果指标为典型的 FNAIT 相关（严重血小板减少、瘀斑、颅内出血）、胎盘相关（胎龄小）或综合所有指标的复合变量。结果免疫妊娠与非免疫妊娠的血浆中 sFlt-1、PlGF、sEng 或 sFlt-1/PlGF 比值无显著差异。在HPA-1a同种免疫妊娠中，怀孕三个月时sFlt-1蛋白水平的升高与新生儿血小板计数的降低显著相关（多变量线性回归，p = 0.024）。结论 HPA-1a 同种免疫母亲的抗血管生成特征与新生儿综合不良结局相关。这表明，sFlt-1 和 sFlt-1/PlGF 比值可能有助于对 FNAIT 进行分娩前风险分层和临床管理决策。

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引用次数: 0

In vivo placental gene modulation via sonoporation. 通过超声波进行体内胎盘基因调控。

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-23 DOI: 10.1016/j.placenta.2024.10.015

Lance G A Nunes, Fredrick J Rosario, Johann Urschitz

Placental dysregulation frequently results in pregnancy complications that impact fetal well-being and potentially predispose the infant to diseases later in life. Thus, efforts to understand the molecular mechanisms underlying placental disorders are crucial to aid the development of effective treatments to restore placental function. Currently, the most common methods used for trophoblast-specific gene modulation in the laboratory are transgenic animals and lentiviral trophectoderm transduction. The generation of transgenic animal lines is costly and requires a considerable amount of time to generate and maintain, while the integration preference of lentiviruses, actively transcribed genes, may result in genotoxicity. Therefore, there is much interest in the development of non-viral in vivo transfection techniques for use in both research and clinical settings. Herein, we describe a non-viral, minimally invasive method for in vivo placental gene modulation through sonoporation, an ultrasound-mediated transfection technique wherein the application of ultrasound on target tissues is used to direct the uptake of DNA vectors. In this method, plasmids are bound to lipid microbubbles, which are then injected into the maternal bloodstream and ultimately delivered to the placenta when subjected to low-frequency ultrasound. Syncytiotrophoblasts are directly exposed to maternal blood and, therefore highly accessible to therapeutic agents in the maternal circulation. This technique can be used to modulate gene expression and, subsequently, the function of the placenta, circumventing the requirement to generate transgenic animals. Sonoporation also offers a safer alternative to existing viral techniques, making it not only an advantageous research tool but also a potentially adaptable technique in clinical settings.

胎盘功能失调经常导致妊娠并发症，影响胎儿的健康，并可能使婴儿日后易患疾病。因此，了解胎盘失调的分子机制对于帮助开发有效的治疗方法以恢复胎盘功能至关重要。目前，实验室中最常用的滋养层特异性基因调控方法是转基因动物和慢病毒滋养层转导。转基因动物品系的生成成本较高，需要大量时间来生成和维持，而慢病毒的整合偏好是主动转录基因，可能会导致基因毒性。因此，开发用于研究和临床的非病毒体内转染技术备受关注。在本文中，我们介绍了一种非病毒、微创的体内胎盘基因调控方法，即超声介导的转染技术，通过在靶组织上应用超声来引导 DNA 载体的吸收。在这种方法中，质粒与脂质微气泡结合，然后注入母体血液，在低频超声的作用下最终输送到胎盘。合胞滋养细胞直接暴露在母体血液中，因此极易接触到母体循环中的治疗药物。这种技术可用于调节基因表达，进而调节胎盘的功能，从而避免了产生转基因动物的要求。与现有的病毒技术相比，声波修复技术还提供了一种更安全的替代技术，使其不仅成为一种有利的研究工具，而且有可能成为一种适用于临床环境的技术。

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引用次数: 0

Puerarin alleviates symptoms of preeclampsia through the repression of trophoblast ferroptosis via the CREB/HO-1 pathway 葛根素通过CREB/HO-1途径抑制滋养细胞铁凋亡，从而缓解子痫前期症状

IF 3 2区医学 Q2 DEVELOPMENTAL BIOLOGY

Placenta

Pub Date : 2024-10-22 DOI: 10.1016/j.placenta.2024.10.013

Introduction

Preeclampsia (PE) is a pregnancy-associated complication characterised by new-onset hypertension and proteinuria. This study explored the therapeutic potential of puerarin (Pue) in PE and investigated the underlying mechanism, with a focus on placental ferroptosis.

Methods

Using an N^G-nitro-L-arginine methyl ester (L-NAME)-induced PE mouse model, we assessed the effects of Pue on PE phenotypes and placental ferroptosis. Antioxidative and anti-ferroptotic effects of Pue were studied in three ferroptotic cell models (hypoxia/reperfusion, cobalt chloride, and erastin). The regulation of Pue on cAMP response element binding protein (CREB) and heme oxygenase-1 (HO-1) was evaluated through gain- and loss-of-function assays. Luciferase assays were used to elucidate the effect of Flag-CREB on Hmox1 promoter fragments. CREB/HO-1 modulation by Pue was validated in mouse placentas with PE.

Results

Pue significantly alleviated maternal hypertension, proteinuria, fetal growth restriction, and placental damage in PE mice. This was associated with an upregulation of the anti-ferroptosis system (glutathione peroxidase 4 [GPX4], cys2/glutamate antiporter [SLC7A11], and glutathione [GSH]) and repression of reactive oxygen species (ROS) and malondialdehyde (MDA) in trophoblasts. Pue reduced HO-1 and CREB, and HO-1 deficiency upregulated GPX4 and SLC7A11. Manipulation of CREB expression led to changes in HO-1/GPX4; whereas, the regulation reversed by Pue administration. Flag-CREB enhanced luciferase activity on the full length Hmox1 promoter (−2000/+78), which contains three CREB1 binding sites (S1–S3). In contrast, no increase in luciferase activity was observed with promoter fragments (−850/+78) and (−550/+78), which contain only the CREB1 binding sites S2 and S3, respectively.

Discussion

Pue ameliorated PE-like symptoms in mice by repressing trophoblast ferroptosis via inhibition of CREB signalling and affecting the Homx1 promoter.

导言子痫前期（PE）是一种与妊娠相关的并发症，以新发高血压和蛋白尿为特征。本研究探讨了葛根素（Pue）在子痫中的治疗潜力，并研究了其潜在机制，重点是胎盘铁绒毛膜变性。在三种铁变态反应细胞模型（缺氧/再灌注、氯化钴和麦拉宁）中研究了Pue的抗氧化和抗铁变态反应作用。通过功能增益和功能缺失试验评估了 Pue 对 cAMP 反应元件结合蛋白（CREB）和血红素加氧酶-1（HO-1）的调节作用。荧光素酶试验用于阐明 Flag-CREB 对 Hmox1 启动子片段的影响。结果 Pue 能显著缓解 PE 小鼠的母体高血压、蛋白尿、胎儿生长受限和胎盘损伤。这与上调滋养细胞中的抗铁锈色素沉着系统（谷胱甘肽过氧化物酶 4 [GPX4]、cys2/谷氨酸转运体 [SLC7A11] 和谷胱甘肽 [GSH]）以及抑制活性氧（ROS）和丙二醛（MDA）有关。Pue会降低HO-1和CREB，而HO-1的缺乏会上调GPX4和SLC7A11。操纵 CREB 的表达会导致 HO-1/GPX4 的变化；而服用 Pue 则会逆转这种调节。Flag-CREB 增强了全长 Hmox1 启动子（-2000/+78）上的荧光素酶活性，该启动子包含三个 CREB1 结合位点（S1-S3）。与此相反，启动子片段（-850/+78）和（-550/+78）的荧光素酶活性没有增加，这两个片段分别只包含 CREB1 结合位点 S2 和 S3。

{"title":"Puerarin alleviates symptoms of preeclampsia through the repression of trophoblast ferroptosis via the CREB/HO-1 pathway","authors":"","doi":"10.1016/j.placenta.2024.10.013","DOIUrl":"10.1016/j.placenta.2024.10.013","url":null,"abstract":"<div><h3>Introduction</h3><div>Preeclampsia (PE) is a pregnancy-associated complication characterised by new-onset hypertension and proteinuria. This study explored the therapeutic potential of puerarin (Pue) in PE and investigated the underlying mechanism, with a focus on placental ferroptosis.</div></div><div><h3>Methods</h3><div>Using an N<sup>G</sup>-nitro-L-arginine methyl ester (L-NAME)-induced PE mouse model, we assessed the effects of Pue on PE phenotypes and placental ferroptosis. Antioxidative and anti-ferroptotic effects of Pue were studied in three ferroptotic cell models (hypoxia/reperfusion, cobalt chloride, and erastin). The regulation of Pue on cAMP response element binding protein (CREB) and heme oxygenase-1 (HO-1) was evaluated through gain- and loss-of-function assays. Luciferase assays were used to elucidate the effect of Flag-CREB on <em>Hmox1</em> promoter fragments. CREB/HO-1 modulation by Pue was validated in mouse placentas with PE.</div></div><div><h3>Results</h3><div>Pue significantly alleviated maternal hypertension, proteinuria, fetal growth restriction, and placental damage in PE mice. This was associated with an upregulation of the anti-ferroptosis system (glutathione peroxidase 4 [GPX4], cys2/glutamate antiporter [SLC7A11], and glutathione [GSH]) and repression of reactive oxygen species (ROS) and malondialdehyde (MDA) in trophoblasts. Pue reduced HO-1 and CREB, and HO-1 deficiency upregulated GPX4 and SLC7A11. Manipulation of CREB expression led to changes in HO-1/GPX4; whereas, the regulation reversed by Pue administration. Flag-CREB enhanced luciferase activity on the full length <em>Hmox1</em> promoter (−2000/+78), which contains three CREB1 binding sites (S1–S3). In contrast, no increase in luciferase activity was observed with promoter fragments (−850/+78) and (−550/+78), which contain only the CREB1 binding sites S2 and S3, respectively.</div></div><div><h3>Discussion</h3><div>Pue ameliorated PE-like symptoms in mice by repressing trophoblast ferroptosis via inhibition of CREB signalling and affecting the <em>Homx1</em> promoter.</div></div>","PeriodicalId":20203,"journal":{"name":"Placenta","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527700","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}

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