BIOLOGY OF REPRODUCTION
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2025
·
IF 3
Zhang Yingying,Zhang Eryun,Li Ling,Ren Yongwei,Zhang Jinqiu,Zheng Qiutong,Sun Minya,Zhao Shaojie,Cui Yugui,Gu Ying,Xu Zhice
The risk of multiple placental thrombosis is significantly elevated in preeclampsia, and the vascular endothelium plays a vital role in coagulation processes through the secretion of Integrin alpha 2b, von Willebrand factor, and tissue factor. However, the underlying pathological mechanisms remain unclear. In this study, placental blood vessels were collected from both preeclampsia and normal pregnancies. Protein levels of Integrin alpha 2b were found to be up-regulated in preeclampsia samples compared to controls, indicating enhanced coagulation function in preeclampsia placental tissue. Additionally, higher cholesterol levels of plasma and lower AlkB homolog 1 expression in placental blood vessels of preeclampsia were found, overall DNA N6-methyldeoxyadenosine levels were up-regulated. Interestingly, the DNA N6-methyldeoxyadenosine level at the Integrin alpha 2b promoter was decreased. Cholesterol overload experiments in human umbilical vein endothelial cells demonstrated that cholesterol regulates the protein expression of AlkB homolog 1 and Integrin alpha 2b in a concentration-dependent manner. Furthermore, Integrin alpha 2b protein expression was increased following AlkB homolog 1 knockout, but no changes were observed when cholesterol was incubated with AlkB homolog 1 knockout cells. These findings provide critical insights into the roles of cholesterol levels, AlkB homolog 1, and Integrin alpha 2b in coagulation function within placental blood vessels. This information may contribute to further investigations of potential therapeutic targets and early prevention strategies for placental thrombosis in preeclampsia.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
Human Cell
·
2022
·Vol. 35
·期 5
·1440-1452
·
IF 4.374
Song Guiyu,Jin Feng
Preeclampsia (PE) is a pregnancy-associated disease, which is the major cause of mortality on maternity and perinatal infants. It is hypothesized that PE is a consequence of the dysfunction of the trophoblast cells. Pleckstrin homology-like domain, family A, member 2 (PHLDA2) was shown to inhibit the proliferation, migration, and invasion of trophoblast cells in our previous studies. However, the mechanism by which PHLDA2 affects trophoblast cell function has not been clarified. In the current study, co-immunoprecipitation (Co-IP) with mass spectroscopy analysis was used to explore the proteins that interacted with PHLDA2. A total of 291 candidate proteins were found to be associated with PHLDA2. The interaction between PHLDA2 and Rho guanine nucleotide dissociation inhibitor (RhoGDI) 1 was identified by Co-IP and immunofluorescence staining. Western blot analysis indicated that overexpression of PHLDA2 resulted in upregulation of the RhoGDI1 protein levels, which were stabilized in the presence of cycloheximide. Similarly, overexpression of RhoGDI1 promoted PHLDA2 expression and its stability. Furthermore, pull-down and Co-IP results indicated that PHLDA2 repressed the activity of Rho guanosine triphosphate hydrolase family proteins by regulating RhoGDI1 expression. In addition, RhoGDI1 expression was upregulated in the placental tissues of patients with PE. The effects of the suppression of PHLDA2 expression on proliferation, migration, and invasion of trophoblast cells were partly abrogated following knockdown of RhoGDI1. Taken together, the data indicated that RhoGDI1 mediated regulation of PHLDA2 on the biological behavior of trophoblast cells and may participate in the pathophysiology of PE.
研究领域:
妇产科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2022
·Vol. 24
·期 1
·1-11
·
IF 2.751
Lingyun Zhang,Shan Zhang,Fangrong Chen
Proteasome 26S subunit, non-ATPase 14 (PSMD14) expression has been previously reported to be reduced in patients with pre-eclampsia (PE). The present study investigated the interaction network associated with the role of PSMD14 in PE. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to determine the transfection efficacy following plasmid-based gene transfer of PSMD14 into HTR-8/SVneo cells. Cell proliferation was measured using an MTT assay and 5-ethynyl-2'-deoxyuridine staining. The expression of proliferation-related proteins, including Ki67 and PCNA, was determined using western blotting. Wound healing and Transwell assays were performed to measure cell invasion and migration, whilst the expression of migration-related proteins, including MMP2 and MMP9, was measured using western blotting. The angiogenesis of HUVECs following treatment with the HTR-8/SVneo cell culture supernatant was examined using tube formation assay. Following overexpression of Hes-related family BHLH transcription factor with YRPW motif 1 (HEY1) by transfection of pcDNA3.1 expression vector containing full-length human HEY1 or knockdown by transfection of shRNA plasmids targeting HEY1, the expression of HEY1 and PSMD14 was detected using RT-qPCR and western blotting. The potential interaction between HEY1 and the PSMD14 promoter was examined using dual-luciferase reporter and chromatin immunoprecipitation assays. PSMD14 overexpression was found to promote the proliferation, invasion, migration of HTR-8/SVneo cells and the angiogenesis of HUVECs following treatment with the HTR-8/SVneo cell culture supernatant, accompanied by enhanced expression of proliferation and migration-related proteins. Furthermore, the transcription factor HEY1 activated the expression of PSMD14. Knocking down HEY1 expression partially reversed the promoting effects of PSMD14 overexpression on the proliferation, invasion, migration, angiogenesis, proliferation and migration-related protein expression in trophoblasts. In conclusion, HEY1-activated PSMD14 promoted trophoblast proliferation, invasion and angiogenesis. Therefore, HEY1 and PSMD14 can be potential targets for PE treatment.
研究领域:
分子生物学
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细胞生物学
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妇产科学
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妇科
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DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
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2025
·Vol. 30
·期 1
·26345
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IF 3.1
Yixiao Wang,Xiaohong Ji,Hengmei Shi,Sicong Liu,Hong Yu
Background:Pre-eclampsia (PE) is a gestational disorder that significantly endangers maternal and fetal health. Transfer ribonucleic acid (tRNA)-derived small RNAs (tsRNAs) are important in the progression and diagnosis of various diseases. However, their role in the development of PE is unclear. Consequently, we detected the expression profiles of tsRNAs in the plasma of patients with PE as well as those in the plasma of the healthy control group, and a multiplicity of experiments were conducted with the aim of clarifying their roles in the occurrence and development of PE and the feasibility of serving as predictive biomarkers for this disorder.Methods:High-throughput sequencing of tsRNA in plasma from PE cases was performed to evaluate its potential as a diagnostic or therapeutic biomarker. The function of tsRNA in trophoblasts was explored using the HTR-8/SVneo cell line. Plasma from pregnant women with suspected PE was analyzed to assess the potential of tsRNA to act as a predictive marker of PE.Results:High-throughput sequencing of tsRNA was performed on plasma from pregnant women with PE and from healthy pregnant controls. Analysis revealed a significant reduction in the level of tRNA-derived stress-inducing RNA (tiRNA)-Gln-CTG in the plasma (p < 0.001) and placenta (p < 0.001) of pregnant women with PE, suggesting its potential involvement in the development of this condition. tiRNA-Gln-CTG was identified in the cytoplasm and nucleus of HTR-8/SVneo cells. In vitro experiments revealed that tiRNA-Gln-CTG influences the proliferation, cycling, migration, and invasion of HTR-8/SVneo cells, possibly by targeting the 3′UTR region of thrombospondin-2 messenger ribonucleic acid (mRNA) for degradation. Extracellular vesicle (EV) carriers may mediate the level of tiRNA-Gln-CTG in the circulation. Y-box binding protein-1 (YBX1) may be involved in loading tiRNA-Gln-CTG into EVs. The sensitivity of low tiRNA-Gln-CTG levels for predicting the onset of PE in suspected cases was 91.7% within 1 week of delivery, 85.7% within 4 weeks of delivery, and 89.3% before delivery, with corresponding specificities of 84.5%, 79.2%, and 73.4%, respectively.Conclusions:tiRNA-Gln-CTG significantly influences trophoblast function and is associated with the development of PE. It can serve as an effective biomarker for predicting PE progression within one week of delivery in women with suspected PE.
研究领域:
妇产科学
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分子生物学
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临床医学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Xuan Zhang,Lei Sun
Preeclampsia (PE) is a complex disease of pregnancy, and an important cause of this disease is insufficient trophoblast invasion and migration. However, the underlying mechanism of PE remains largely unknown. Here, transcriptome sequencing analysis found the high expression of hepatocyte nuclear factor 4 alpha (HNF4A) in PE placentas. Meanwhile, we found that HNF4A expression was up-regulated in the placentas of PE patients. Thus, we assumed that HNF4A might be involved in PE progression. To validate our hypothesis, l -arginine methyl ester ( l -NAME) or lipopolysaccharide (LPS)-treated rats were used to mimic the pathological status of PE in vivo . Consistently, HTR8/SVneo cells were treated with hypoxia/reoxygenation (H/R) or LPS to simulate PE progression in vitro . The results observed an increase in elevated urine protein levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which indicated that the PE-like rat model was successfully established. Meanwhile, the expression of pro-inflammatory cytokines interleukin (IL)-6 and IL-1β was increased in PE placentas. HTR8/SVneo cells were used to further explore the underlying mechanism of PE in vitro . H/R conditions up-regulated the acetylation level of HNF4A. Further analysis showed that HNF4A overexpression inhibited trophoblast invasion and migration, while HNF4A knockdown promoted the progression. Additionally, inhibiting HNF4A was found to reduce the levels of IL-6 and IL-1β secretion in HTR8/SVneo cells following H/R or LPS exposure. Conclusively, these findings suggest that inhibiting HNF4A suppresses inflammation whilst promoting trophoblast invasion and migration in PE, providing a promising target for the treatment of PE.
研究领域:
妇产科学
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分子生物学
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病理生理学
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PubMed
高影响因子
Communications Biology
·
2025
·Vol. 8
·期 1
·1-15
·
IF 5.1
Wang Yue,Wang Yang,Tong Fei,Gao Qianqian,Li Baoxuan,Zhao Yan
Preeclampsia is one of the most common pregnancy disorders, and characterized by insufficient trophoblast invasion and placental inflammation. Our RNA sequencing results showed that OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) was downregulated in placenta from preeclampsia patients, compared with the healthy control. Clinical and experimental data demonstrated that OTUB2 was expressed in macrophages. Gain- and loss-of-function experiments revealed that OTUB2 overexpression blocked M1 polarization of macrophages, and attenuated macrophages-induced apoptosis, and impaired migration and invasion of trophoblasts. Moreover, OTUB2 alleviated LPS-induced preeclampsia-like symptoms in rats, including hypertension, proteinuria, inflammation in placenta and insufficient infiltration of trophoblasts. Additionally, OTUB2 mediated deubiquitination of nuclear receptor subfamily 4 group A member 1 (NR4A1) and suppressed its degradation, and the Cys51 is crucial for catalytic activity of OTUB2. The effects of OTUB2 were partially reversed by shNR4A1. In conclusion, OTUB2 suppressed macrophage M1 polarization, macrophages-induced trophoblast damage, and restrained experimental preeclampsia in rodents by mediating deubiquitination of NR4A1. These findings may provide novel insight for clinical prevention and diagnosis of preeclampsia.
研究领域:
生殖医学
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免疫学
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分子生物学
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病理学
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药理学
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DOI
PubMed
高影响因子
ANNALS OF MEDICINE
·
2023
·
IF 4.4
Zhengwen Xu,Youran Li,Ying Liu,Shengmin Liu,Lin Zhang,Jing Wang,Shaofei Su,Lin Liu,Lanlan Meng,Hongyuan Zhu,Jingru Sun,Lijun Shao,Lin Li,Yanhong Zhai,Guanghui Li,Zheng Cao
Background As folates are essential for embryonic development and growth, it is necessary to accurately determine the levels of folates in plasma and red blood cells (RBCs) for clinical intervention. The aims of this study were to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitation of folates in plasma and RBCs and to examine the association between plasma and RBC folate concentrations and gestational diabetes mellitus (GDM), gestational hypertension (GH) and preeclampsia (PE).Methods With the in-house developed LC-MS/MS, a retrospective cross-sectional study was conducted. The healthy pregnant women of first- (n = 147), second- (n = 84) and third-trimester (n = 141) or the women diagnosed with GDM (n = 84), GH (n = 58) or PE (n = 23), that were aged between 22 and 46 years old and registered at our institute, were subjected for measurement of folic acid (FA) and 5-methyltetrahydrofolate (5-MTHF), followed by appropriate statistical association analysis.Results The assay for simultaneous quantitation of FA and 5-MTHF in plasma and RBCs was linear, stable, with imprecision less than 15% and recoveries within ±10%. The lower limits of quantification for FA and 5-MTHF measurement in whole blood were 0.57 and 1.09 nmol/L, and in plasma were 0.5 and 1 nmol/L, respectively. In the association analysis, the patients with lower RBC folate level (<906 nmol/L) presented higher risks of PE development (OR 4.861 [95% CI 1.411–16.505]) by logistic regression and restricted cubic spline (RCS) regression in a nonlinear fashion. In addition, higher level of plasma folates in pregnancy was significantly associated with GH risk but may be protective for the development of GDM.Conclusions The in-house developed LC-MS/MS method for folates and metabolites in plasma or RBC showed satisfactory analytical performance for clinical application. Further, the levels of folates and metabolites were diversely associated with GDM, GH and PE development.
研究领域:
临床医学
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营养学
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分析化学
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DOI
PubMed
高影响因子
Human Cell
·
2024
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IF 3.4
Zhang Ke,Zhang Hailing,Wang Bing,Gao Shanshan,Sun Caiping,Jia Cong,Cui Jinquan
Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE. Graphical abstract
研究领域:
妇产科学
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分子生物学
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细胞生物学
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转录调控
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信号传导
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DOI
PubMed
高影响因子
FASEB JOURNAL
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2025
·Vol. 39
·期 18
·e71060
·
IF 4.2
Hongyu Liu,Yali Deng,Mei Peng,Yanting Nie,Jingfei Chen
The pathogenesis of preeclampsia (PE) involves endoplasmic reticulum stress (ERS) and the subsequent induction of mitophagy. Ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) is a key factor regulating mitophagy, but its role in PE has not been reported. In this study, we aimed to analyze the role of ARIH1 in the pathogenesis of PE. The role of ARIH1 in the pathogenesis of PE was investigated in a PE rat model and in an in vitro hypoxia/reoxygenation (H/R) model using HTR8 trophoblast cells. The study revealed that ARIH1 was upregulated while Mitochondrial fusion protein 2 (MFN2) was downregulated in PE rats and H/R-treated HTR8 cells. Inhibition of ARIH1 reversed the suppressed proliferation and invasion capacities of HTR8 cells under H/R conditions, reduced intracellular reactive oxygen species (ROS) and calcium ions (Ca 2+ ), and modulated the protein expression of LC3II/LC3I, p62, glucose-regulatory protein 78 (GRP78), and C/EBP homologous protein (CHOP). Additionally, mitochondrial membrane potential was improved. Interestingly, treatment with Tunicamycin or Thapsigargin could reverse the inhibitory effects of ARIH1 downregulation on trophoblastic cells by activating endoplasmic reticulum stress (ERS) and mitophagy. Notably, the study identified for the first time that ARIH1 mediates the ubiquitination degradation of MFN2. Inhibition of MFN2 abolished the regulatory effects of ARIH1 downegulation on ERS and mitophagy in trophoblast cells, as well as the associated damage in PE rats. Overall, the findings underscore the crucial role of ARIH1 in regulating mitophagy and ERS through MFN2, highlighting its significance in the pathogenesis of PE. Graphical The mechanism by which ubiquitin ligase ARIH1 promotes the occurrence of preeclampsia through MFN2. Our research found that ARIH1 is an important factor mediating the occurrence and development of PE, as well as mitochondrial autophagy and endoplasmic reticulum stress, and this effect is achieved through MFN2. Mechanistically, it was discovered for the first time that ARIH1 mediated the ubiquitination and degradation of MFN2.
研究领域:
妇产科学
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分子生物学
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细胞生物学
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病理生理学
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围产医学
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信号转导
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产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2025
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IF 3.8
Xiaomin Ye,Peiqu Zhong,Qiongfang Chen,Dongmei Zhou,Jieyu Luo,Youcai Liang,Jiayuan Zhang,Lijian Zhao
The widespread use of perfluorooctanesulfonic acid (PFOS) has raised concerns regarding its potential on pregnant women, particularly in relation to the development of pre-eclampsia (PE). This study investigates the impact of PFOS exposure on the LncRNA/Rnd3 axis in pregnant mice and its association with trophoblast cell functions in PE. Bioinformatics analysis revealed PFOS-related gene alterations in PE, with pathways enriched in apoptotic signaling and cytokine interactions. Experimental findings showed the downregulation of Oip5os1 and Rnd3, along with the upregulation of miR-155, affecting trophoblast behavior. Animal experiments confirmed that PFOS-induced gene expression changes are linked to PE progression. PFOS exposure impairs trophoblast proliferation and migration via the Oip5os1/miR-155/Rnd3 axis, contributing to PE development.
研究领域:
毒理学
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生殖生物学
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分子生物学
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DOI
PubMed
高影响因子
Orphanet Journal of Rare Diseases
·
2021
·Vol. 16
·期 1
·1-13
·
IF 4.123
Shao Yong,Chen Siyu,Li Huan,Tang Qin,Xu Di
Background ICP pregnant women have a unique profile of serum bile acid metabolism, thus the early and accurate identification of ICP patients is beneficial to early appropriate treatment and improvement of pregnancy outcomes. In this study, ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) was used to analyze the 15 types of serum bile acid profiles among patients with ICP in third trimester, patients with cholelithiasis, and patients with hepatitis B virus. The ICP diagnostic model established by partial least squares-discriminant analysis (PLS-DA) was used to screen the differential bile acids for clinical subtypes of ICP. 144 cases of ICP patients were involved in this study, and divided into four subgroups according to serum level of TBA, DBIL, and ALT.Results (1) The differential serum bile acid profiles of ICP group and normal pregnant women were DCA, TDCA, TCA, GDCA and GLCA. (2) The differential serum bile acid profiles of the ICP1 group (ICP with jaundice) and normal pregnant women were TCDCA, TCA, GCA, GCDCA, TUDCA and GUDCA. (3) The differential serum bile acid profiles of the ICP3 group (Hyperchoicemia of pregnancy) and normal pregnant group was GUDCA, LCA, GLCA, UDCA, TUDCA, CDCA, and TLCA (P < 0.05). (4) The differential serum bile acid profiles of ICP4 group (idiopathic aminotransferase abnormality during pregnancy) and normal pregnant group was UDCA, GUDCA, TUDCA, GCA and GLCA (P < 0.05). (5) The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP1 group was significantly higher than normal group, ICP2 group, ICP3 group, and ICP4 group (P < 0.05); The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP2 group, ICP3 group, and ICP4 group was significantly higher than normal group (P < 0.05), but no difference was found among ICP2 group, ICP3 group, and ICP4 group (P > 0.05).Conclusion Maternal serum bile acid profiles are useful to differentiate the four subtypes of ICP. ICP with jaundice could be an important predictor of adverse pregnancy outcomes of ICP.
研究领域:
妇产科学
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代谢组学
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DOI
PubMed
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-12
·
IF 5.2
Liu Sishi,Gao Man,Zhang Xue,Wei Jun,Cui Hong
Preeclampsia (PE) is a common pregnancy disorder characterized by hypertension and proteinuria. Trophoblast behavior severely affect PE progression. Transcription factor Forkhead box protein P2 (FOXP2) was involved in cell migration and invasion, but its role in PE progression remains unknown. Laminin subunit alpha 4 (LAMA4) was predicted as a downstream gene of FOXP2 and related to PE. Thus, we supposed that FOXP2 might regulate PE by regulating LAMA4. We found the decreased FOXP2 expression in patients with PE compared with healthy pregnant women. The rat model of PE was induced by L-NAME oral gavage. FOXP2 overexpression lowered systolic and diastolic blood pressure and restored pathological changes of rats with PE. Trophoblasts under the hypoxia/reoxygenation (H/R) treatment were used to mimic PE in vitro. The results revealed that FOXP2 overexpression inhibited apoptosis but promoted migration, invasion, and angiogenesis of H/R-treated trophoblasts. Dual luciferase and chromatin immunoprecipitation-polymerase chain reaction assays confirmed that FOXP2 transcriptionally upregulated the LAMA4 expression in trophoblasts. LAMA4 knockdown reversed the migration and invasion-promoting role of FOXP2 overexpression in trophoblasts with H/R treatment. Collectively, our findings suggest that the FOXP2/LAMA4 axis regulates PE by suppressing trophoblast apoptosis and promoting its migration, invasion, and angiogenesis.
研究领域:
妇产科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
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