PLACENTA
·
2024
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IF 3
Caiqun Huang
Introduction T oxoplasma gondii is an opportunistic intracellular parasite that is a major pathogenic factor in miscarriage, especially when it occurs early in pregnancy. We have previously demonstrated that the regulation of forkhead box transcription factor (Foxp3) is associated with abortion in early pregnancy caused by excretory-secretory antigen (ESA) of strain China 1. We aimed to reveal the underlying mechanism of miscarriage caused by ESA. Methods A TLR4 −/− pregnant mouse model was successfully constructed. Pregnant mice at gestational day 5 (G5) were injected with ESA. All animals were sacrificed on G13, pregnancy outcomes were observed, and abortion rates were calculated. Placental status observed by Hematoxylin-eosin staining; gene expression was measured by IHC; flow cytometry analysis was used to determine the number and function of regulatory T cells. In EL4 cells, real-time PCR and Western blot were used to evaluate gene expression and cytokines assay. Results In vivo studies revealed that ESA injection caused 83% abortion in pregnant mice but only 35% abortion in TLR4−/− pregnant mice. In addition, ESA attenuated the number and function of regulatory T cells, further suppressed Foxp3, FOXO1 levels, and upregulated CD127 expression. TLR4 −/− mice partially reversed this inhibitory effect on regulatory T cells. Furthermore, in vitro studies revealed that ESA inhibited TLR4/NF-κB signaling pathway expression and that TLR4 agonists significantly restored the ESA-induced decrease in Foxp3. Discussion These findings suggest that ESA suppresses Foxp3 expression by blocking TLR4/NF-κB signaling, resulting in miscarriage. More importantly, the results indicated that miscarriage caused by ESA is TLR4 dependent.
研究领域:
免疫学
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寄生虫学
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生殖生物学
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DOI
PubMed
高影响因子
MOLECULAR REPRODUCTION AND DEVELOPMENT
·
2025
·Vol. 92
·期 5
·e70029
·
IF 3
Junmei Fan,Junkun Zhang,Xingyu Bi,Pengfei Zhu,Jinbao Wang,Dan Su,Wenjing Shi,Yanling Liu,Huiping Liu,Xueqing Wu
Recurrent pregnancy loss (RPL) is one of obstetrical diseases with no effective therapy methods. Trophoblast cell dysfunction and inflammation induce embryo implantation insufficiency, thereby resulting in RPL. OTU deubiquitinase with linear linkage specificity (OTULIN) plays a role in regulating the immune response and cell death. However, the role of OTULIN in RPL remains unclear. Spontaneous abortion mouse model and lipopolysaccharide-treated HTR-8/SVneo cells were used to investigate the role of OTULIN in RPL. OTULIN expression was downregulated in the labyrinth trophoblast of RPL mice and LPS-treated trophoblast cells. The embryonic reabsorption rate was decreased in OTULIN-overexpressed spontaneous abortion mice, accompanied with the increase in placental/fetus weight ratio. OTULIN overexpression significantly inhibited apoptosis in vivo and in vitro, as evidenced by the decrease in the activity of caspase 3. The expression of pro-inflammatory cytokines was decreased with OTULIN overexpression. Moreover, OTULIN overexpression decreased p-IκBα/IκBα and p-p65/p65 ratio. The nuclear translocation of NF-κB was suppressed via OTULIN overexpression both in vivo and in vitro. Our study suggested that OTULIN deficiency might cause inflammation and trophoblast abnormalities in RPL. The supplementation with OTULIN might alleviate the development of RPL via inhibiting NF-κB mediated inflammation response.
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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PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2025
·
IF 4
Li Ji,Anqi Deng,Huiying Chen,Shuangyan Guo,Pingyu Wang,Ruiyi Zhang,Wenyang Chen,Taotao Fan,Lijuan Jiang,Bing Shen
Introduction BaoTaiyin (BTY) is a traditional Chinese medicine decoction. It has been used to treat recurrent miscarriage (RM). However, there are no comprehensive systematic studies to identify the chemical compositions of BTY and molecular mechanisms on RM. Finding the chemical components of BTY and clarifying the underlying processes in the treatment of RM were the goals of the study. Methods We used ultra-high-performance liquid chromatography coupled with triple quadruple time-of-flight tandem mass spectrometry to analyze the chemical components of BTY, network analysis to predict the pharmacological effects of the identified active ingredients, and cell experiments to identify potential molecular mechanisms. Results We found 12 active ingredients among 61 components identified in BTY. These identified activities were linked to regulatory effects on 127 key signaling pathways, targeting 107 proteins. Through network analysis, we determined that insulin-like growth factor 1 receptor, matrix metalloproteinases, PI3K, and STAT3 may be the core targets of BTY’s therapeutic effects on RM. We further explored this mechanism to find that aqueous extracts of BTY significantly enhanced IGFBP2 and CaMKK2 expression and trophoblast proliferation, whereas inhibitors of IGF1R/PI3K/AKT pathway or CaMKK2 blocked the effect of BTY on trophoblast proliferation. In addition, IGFBP2 siRNA suppressed BTY-induced CaMKK2 expression. Caffeic acid, as one of components of BTY, increased intracellular Ca 2+ concentration and proliferation in trophoblast. Conclusion Our research showed that BTY may have therapeutic benefits on RM through multiple targets and pathways, such as the IGF1R/PI3K/AKT and Ca 2+ /calmodulin signaling pathways.
研究领域:
中药学
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分子生物学
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生殖医学
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PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
·
2023
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IF 2.8
Yanli Song,Dongjie He,Shaoqi Shi,Tianwei Cui,Hui Zhang,Xianmin Zhao,Tingting Ni,Huidongzi Xiao,Aiwu Wei
BackgroundWomen with antiphospholipid syndrome (APS) or antiphospholipid antibodies (aPLs) are at high risk for obstetric complications, including recurrent pregnancy loss (RPL). However, effective treatments for RPL are lacking.ObjectiveThis study aimed to reveal the function and underlying mechanism of hyperoside (Hyp) in RPL associated with antiphospholipid antibodies (aCLs).MethodsThe pregnant rats (N = 24) were divided randomly into four groups: normal human-IgG (NH-IgG); aCL-pregnancy loss (aCL-PL); aCL-PL + Hyp (40 mg/kg/day); aCL-PL + low molecular weight heparin (LMWH, 525 μg/kg/day). HTR‐8 cells were treated with 80 μg/mL aCL to establish the cell models of miscarriage.ResultsIn pregnant rats, aCL-IgG injection raised the abortion rate of embryos, while Hyp treatment inhibited the effects. Additionally, Hyp inhibited the platelet activation and uteroplacental insufficiency caused by aCL. In vivo and in vitro experiments further suggested that Hyp suppressed aCL-induced inflammation and apoptosis by downregulating NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-related factors and decreasing apoptotic rates. After aCL administration, Hyp therapy downregulated the expression of purinergic ligand-gated ion channel 7 (P2X7), which is reported to induce cytokine release and apoptosis. Furthermore, we found that the treatment of 3′-O-(4-Benzoyl) benzoyl-ATP (BzATP, an agonist of the P2X7 receptor) reversed the inhibitory effects of Hyp on cell function.ConclusionsHyp exerts protective effects on aCL-induced pregnancy loss by preventing platelet activation-mediated P2X7/NLRP3 pathway. Therefore, Hyp may provide a feasible pharmaceutical strategy for the treatment of RPL.
研究领域:
妇产科学
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免疫学
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药理学
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PubMed
高影响因子
Journal of Biomedical Nanotechnology
·
2022
·Vol. 18
·期 5
·1449-1459
·
IF 3.641
Lu Lidan,Cai Ximei,Guo Luqin,Ji Hongjian,Ren Jiajie,Ni Haiyan,Feng Xiaoling
We prepared a quercitrin nano micellar delivery system in this study to evaluate its oral bioavailability. The optimal formulation of quercetin nano micelles was determined through an orthogonal test. Characteristics (size of particles-SOP, morphology, efficiency of encapsulation-EE
and stability) and the therapeutic property of quercitrin nano micelles on unexplained recurrent abortion (URSA) were evaluated. The SOP of quercitrin nano micelles was 111.88±3.70 nm with an EE of 95.66±0.57. A substantially increased release rate of quercetin from the micellar
system was observed in different dissolution media comparable to that of quercitrin. Also, through quercitrin micelles, the oral bioavailability of quercetin was increased by 15.45-fold compared to quercitrin solution. Significantly, quercetin could reduce the levels of LDH and SOD as well
as increase the level of MDA in serum restricted HTR-8/SVneo cells. Western blotting (WB) experiments showed that quercitrin had a protective effect on H2O2 induced oxidative stress injury of a human placental trophoblast HTR8-SVneo cell line. The developed nano micelles
are a potential carrier that could enhance the aqueous solubility, oral in vivo availability and potential therapeutic abortion effect of quercitrin.
研究领域:
药剂学
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生殖医学
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分子生物学
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高影响因子
Immunity Inflammation and Disease
·
2023
·Vol. 11
·期 5
·e879
·
IF 3.2
Xiuping Zhang,Yuanjing Hu,Zhiping Zhang,Xueluo Zhang,Lixia Liang,Xiangrong Cui,Yuanxia Wu,Fen Hu,Xueqing Wu
Introduction Approximately 50% of cases with recurrent spontaneous abortion (RSA) have unexplained etiology. Aberrant expression of transmembrane and ubiquitin-like domain containing 1 (TMUB1) is closely related to a series of diseases, including RSA. However, the function and underlying mechanism of TMUB1 in the occurrence of RSA has not been described. Methods TMUB1 expression was detected in the placental villous tissues of 30 women with normal miscarriages and 12 women with RSA. The pregnant mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce abortion. Human chorionic trophoblast cells were treated with LPS. Pathological analysis of placental tissues was performed by hematoxylin and eosin staining. Results TMUB1 was highly expressed in the placental villous tissues of RSA patients compared to the patients who underwent induced abortions. After LPS administration, the mice exhibited high embryo absorption and pathological alterations, as well as presented an increase in inflammation and apoptosis (the etiology of RSA induction) in placental tissues. Moreover, the upregulated expression of TMUB1 was also found in placental tissues of LPS-induced mice, and further investigation showed that TMUB1 deficiency blocked embryo loss as well as inhibited apoptotic rate and inflammation after LPS activation. Furthermore, we found that the loss of TMUB1 suppressed the phosphorylation of IkappaB kinase (IKK) α/β and attenuated cytoplasmic-nuclear translocation of nuclear factor-κB (NF-κB) p65 in LPS-induced cells. Conclusion Our results indicate that TMUB1 may involve in the modulation of apoptosis and NF-κB pathway-mediated inflammation in RSA. Therefore, TMUB1 may develop as a potential biomarker for RSA treatment.
研究领域:
妇产科学
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分子生物学
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免疫学
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病理学
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Di Lei,Tingting Chen,Cuifang Fan,Qingzhen Xie
Benz[a]anthracene (BaA), a hazardous polycyclic aromatic hydrocarbon classified by the EPA, is a probable reproductive toxicant. Epidemiological studies suggest that BaA exposure may be a risk factor for recurrent miscarriage (RM). However, the underlying mechanisms are not well understood. This study identified DEC1 as a key gene through RNA-seq and single-cell RNA sequencing analysis. DEC1 expression was found to be downregulated in villous tissues from women with RM and in primary extravillous trophoblasts (EVTs) exposed to BaA. BaA suppressed DEC1 expression by promoting abnormal methylation patterns. Further analysis revealed that ARHGAP5 is a direct target of DEC1 in EVTs, where DEC1 inhibits trophoblast invasion by directly regulating ARHGAP5 transcription. Additionally, BaA destabilized matrix metalloproteinase 2 (MMP2) by activating the aryl hydrocarbon receptor (AhR) and promoting E3 ubiquitin ligase MID1-mediated degradation. In a mouse model, BaA induced miscarriage by modulating the DEC1/ARHGAP5 and MID1/MMP2 axes. Notably, BaA-induced miscarriage in mice was prevented by DEC1 overexpression or MID1 knockdown. These findings indicate that BaA exposure leads to miscarriage by suppressing the DEC1/ARHGAP5 pathway and enhancing the MID1/MMP2 pathway in human EVTs.
研究领域:
生殖毒理学
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分子生物学
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细胞生物学
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表观遗传学
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动物模型
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高影响因子
JOURNAL OF MOLECULAR HISTOLOGY
·
2025
·Vol. 56
·期 2
·1-11
·
IF 2.2
Zhang Xiuping,Wang Shimin,Liang Lixia,Hu Fen,Zhang Xueluo,Cui Xiangrong,Zhang Zhiping,Wu Xueqing
Recurrent spontaneous abortion (RSA) brings tremendous difficulties to clinical treatment and prognosis. Pre-B-cell leukemia homeobox 1 (PBX1), as a functional transcription factor, involves in the regulation of cell apoptosis and proliferation. However, the underlying mechanism of PBX1 in RSA treatment has not been explored. We established a lipopolysaccharide (LPS)-induced abortion model and detected PBX1 expression with real-time PCR, western blot and immunohistochemistry. The PBX1-overexpressed adenovirus (AV-oePBX1) was infected into trophoblast cells treated with LPS to define the function of PBX1 on cell apoptosis, inflammation and NF-κB pathway. A luciferase reporter assay was conducted to validate the transcription regulation of PBX1 on transmembrane and ubiquitin like domain containing 1 (TMUB1). Compared to women with normal abortion, PBX1 was downregulated in the placental villous tissues of RSA patients. The placental tissues of LPS-treated mice also manifested notably reduction of PBX1 at mRNA and protein levels. PBX1 overexpression alleviated inflammation and apoptosis of trophoblast cells. Substantially, PBX1 was negatively correlated with TMUB1, which was highly expressed in RSA patients and LPS-treated mice. Moreover, PBX1 bound to TMUB1 promoter and inhibited its transcription. Interestingly, exogenous TMUB1 abolished the effects of PBX1 on apoptosis, inflammation, and NF-κB signal pathway. In total, PBX1 attenuated cell apoptosis and inflammation, and suppressed NF‐κB signal pathway induced by LPS through downregulating TMUB1 transcription. Therefore, PBX1 may be developed as a novel target for clinical treatment of RSA.
研究领域:
妇产科学
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分子生物学
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转化医学
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PubMed
高影响因子
PLACENTA
·
2025
·
IF 2.5
Caiqun Huang,E Fen Cheng,Jinping Ni,Ying Lyu
Introduction Unexplained recurrent spontaneous abortion (URSA) involves multifactorial etiologies, with regulatory T cells (Tregs) playing a pivotal role in maintaining immune tolerance during pregnancy. Baicalein, a flavonoid from Scutellaria baicalensis, exhibits anti-inflammatory and immunomodulatory properties. This study evaluates baicalein's therapeutic potential in mitigating URSA via the TLR4/NF-κB signaling pathway. Methods A URSA mouse model was used, and baicalein was administered intraperitoneally. Pregnancy outcomes, abortion rates, and placental morphology were assessed on gestational day 14 (G14). Treg cells were quantified via flow cytometry, and gene/protein expression levels were analyzed by immunohistochemistry, Western blotting, and real-time PCR. In vitro experiments on ihESCs further investigated the role of the TLR4/NF-κB pathway. Results Baicalein reduced abortion rates from 33.3 % in URSA mice to 21.6 % (low dose) and 14.8 % (high dose), improved embryonic development by altering placental structure and decidual morphology, and reduced inflammation at the maternal-fetal interface. It expanded Treg cells and enhanced the expression of IGFBP-1 and PRL, markers of endometrial decidualization, and decreased TLR4, p-P65, and P65 expression. In vitro, baicalein's effects were abrogated by TLR4 inhibition, confirming pathway specificity. Discussion Baicalein improved pregnancy outcomes by enhancing Treg function and promoting decidualization via TLR4/NF-κB pathway inhibition. These findings highlight baicalein's potential as a therapeutic agent for URSA.
研究领域:
生殖医学
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免疫学
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药理学
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PubMed
高影响因子
Genes & Genomics
·
2022
·Vol. 44
·期 11
·1385-1397
·
IF 2.164
Zhang Xueluo,Chen Yanhua,Wang Xianping,Zhang Zhiping,Wang Jun,Shen Yan,Hu Yuanjing,Wu Xueqing
Background Trophoblasts are the most important parts of the placenta in early pregnancy. Trophoblast cell dysfunction can induce embryo implantation insufficiency, thereby resulting in multiple diseases, including recurrent spontaneous abortion (RSA). A previous study indicates higher nerve injury-induced protein 1 (NINJ1) RNA levels in the villi tissues of RSA patients. Objective This study aimed to investigate the effect of NINJ1 on trophoblast behaviors and pregnancy loss. Methods Fresh villi tissues were obtained from with RSA patients and patients with artificial selective abortion for personal reasons, and NINJ1 expression in these tissues was detected. Extravillous trophoblast cell line HTR-8/SVneo was transfected with small-interfering RNA targeting NINJ1 or NINJ1 overexpression vector to perform loss-/gain-of-function experiments. Spontaneous abortion (SA) was induced by mating CBA/J females with DBA/2 males and the pregnant females were intraperitoneally injected with adenovirus vector carrying NINJ1 short hairpin RNA. Results NINJ1 mRNA and protein levels were higher in the villi tissues of RSA patients than those of artificial selective abortion patients. NINJ1 knockdown promoted trophoblast cell proliferation, migration and invasion but inhibited cell apoptosis. Moreover, conditioned medium from NINJ1-depleted trophoblasts promoted the angiogenesis of human umbilical vein endothelial cells. NINJ1 knockdown also promoted activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway in trophoblasts, and STAT3 inhibitor reversed NINJ1 knockdown-induced effects on trophoblast behaviors. Furthermore, pregnancy loss was attenuated by NINJ1 inhibition. Conclusion NINJ1 contributes to the development of SA and triggers trophoblast cell dysfunction through inhibiting the STAT3 pathway. 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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PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Xinhang Meng,Minfeng Shi,Jinfeng Qian,Yujie Luo,Liyuan Cui,Dajin Li,Songcun Wang
The establishment of placentation and maternal-fetal tolerance are important determinants of a successful pregnancy. Tacrolimus, also known as FK506, is a calcineurin inhibitor that has often been used for pregnant women after solid organ transplantation. Previous therapeutic interventions have shown the benefits of using the immuno-suppressive agent FK506 in improving clinical pregnancy and live birth rates and reducing the risk of spontaneous miscarriage. However, the mechanism(s) by which FK506 is involved in these processes have not been fully elucidated. To further characterize its function in early pregnancy, we explored the effect of FK506 on the human-derived first trimester extravillous trophoblast cells (HTR8/SVneo cells) and found that FK506 promoted invasion, tube formation and proliferation, but inhibited apoptosis of HTR8/SVneo cells. Based on the integrated metabolomics and transcriptomics analyses, the present study provided the cellular and molecular cues evidently showing that FK506 had positive effects on the placentation and maternal-fetal tolerance through modulating FASN-CEACAM1 pathway. The spontaneous-abortion-prone model gave further evidence that FK506 exerted a protective effect on pregnancy by regulating the FASN-CEACAM1 axis. These findings might provide a new fundamental mechanism and promising potential of low-dose FK506 in preventing pregnancy loss.
研究领域:
妇产科学
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免疫学
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生殖生物学
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分子生物学
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PubMed
高影响因子
Theranostics
·
2022
·
IF 11.6
Liling Wang,Huan Wang,Jing Luo,Ting Xie,Gil Mor,Aihua Liao
Rationale: Recurrent pregnancy loss (RPL) is a distressing disorder that seriously affects the physical and psychological health of women. RPL is also a sentinel risk marker for future obstetric complications and warrants in-depth investigation. Abnormal polarization and functions of decidual macrophages are associated with RPL; however, the underlying mechanisms remain poorly understood. Methods: Decorin expression, localization, and content in the decidua of women with normal pregnancy (NP) and those with RPL were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, immunofluorescence, and enzyme-linked immunosorbent assay. The profiles of decidual macrophage subsets were determined using flow cytometry and immunofluorescence in both groups. The correlation between decorin content and the proportion of decidual macrophage subsets in the decidua of early NP women was determined using Pearson analysis. The effects of decorin on the polarization and functions of macrophages were assessed in an in-vitro model of Raw264.7 cells via flow cytometry, western blotting, and RT-qPCR. Moreover, the mitochondrial metabolism in Raw264.7 cells under decorin administration was measured via flow cytometry, western blotting, and immunofluorescence. Thirty-three pregnant mice were included in the in vivo model and underwent different treatments. The embryo abortion rate, macrophage phenotype in the spleen and uteri, and placental development were evaluated using flow cytometry and hematoxylin-eosin staining. Results: Decorin, derived from decidual stromal cells, was highly expressed in the decidua of women with RPL. A positive correlation between decorin content and the proportion of M1-like macrophages was also observed in the decidua of early NP women. In vitro studies showed that decorin treatment inhibited macrophage polarization to M2-like subsets and boosted the inflammatory response, which was related to enhanced anaerobic glycolysis, increased mitochondrial membrane potential and intracellular reactive oxygen species levels, reduced mitochondrial mass, and activation of the myeloid differentiation primary response 88-nuclear factor-κB signaling pathway. Adoptive transfer of decorin-treated bone marrow-derived macrophages in pregnant C57BL/6 mice increased the embryo absorption, accompanied by impaired fetal vascularization. Conclusions: Decidual stromal cell-derived decorin can polarize decidual macrophages toward the M1 phenotype by regulating mitochondrial metabolism, resulting in the occurrence of RPL.
研究领域:
妇产科学
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免疫学
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细胞生物学
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生殖医学
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PubMed
高影响因子
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