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OBJECTIVE: Caspase-6 is an important regulatory factor in innate immunity, inflammasome activation, and host defense, but its role in preeclampsia (PE) is unknown. This study aims to investigate the mechanism of Caspase-6 in the interaction between PE rats and macrophage-trophoblast cells, in order to provide a new theoretical basis for the treatment of PE. METHODS: Co-cultures of THP-1 cells and HTR8/SVneo cells were employed to investigate the HMGB1 signaling in macrophages (transfection with si-Caspase-6) and HTR8/SVneo cells. The PE rat model was constructed by using the reduced uterine perfusion pressure (RUPP) surgery to explore the therapeutic effects of bone marrow-derived macrophages (BMDM) transfected with si-Caspase-6 in PE rats. ELISA, Western blot, immunofluorescence, etc., were employed to characterize the expression of ferroptosis-related markers. RESULTS: Caspase-6 expression was significantly increased in CD14+ macrophages in the placental tissue of PE rats. Overexpression of Caspase-6 in THP-1 cells induced ferroptosis of HTR8/SVneo cells, but this process was blocked by anti-HMGB1 neutralizing antibody. Knockdown of Caspase-6 in macrophages could alleviate ferroptosis of HTR8/SVneo cells and restore its basic characteristics. Knockdown of Caspase-6 in BMDM downregulated ferroptosis in placental tissue of PE rats through HMGB1, thereby improving the disease phenotype in rats. CONCLUSION: Knocking down Caspase-6 in BMDM regulated the crosstalk between macrophages and HTR8/SVneo cells through HMGB1, inhibiting HTR8/SVneo cell ferroptosis, thereby improving adverse pregnancy outcomes of PE.
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The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.
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Ferroptosis , Preeclampsia , Humanos , Femenino , Embarazo , Ratas , Animales , Rosiglitazona/farmacología , Rosiglitazona/metabolismo , PPAR gamma/metabolismo , Metabolismo de los Lípidos , Placenta/metabolismo , Preeclampsia/tratamiento farmacológico , Preeclampsia/prevención & control , Preeclampsia/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Hipoxia/metabolismo , LípidosRESUMEN
As a common hypertensive complication of pregnancy, preeclampsia (PE) remains one of the leading causes of maternal and fetal with high morbidity and mortality worldwide. Much research has identified the vital functions of insulin-like growth factor 1 (IGF-1) in PE treatment. However, the combined roles and molecular mechanism of IGF-1 and microRNAs (miRNAs) underlying PE remain unclear. Therefore, we first measured the expression of IGF-1, zinc finger E-box binding homeobox 1 (ZEB1) and microRNA-183 (miR-183) expression in the placenta tissues of patients with PE by Western blot analysis and RT-qPCR. Interactions among IGF-1, ZEB1 and miR-183 were assessed by Western blot analysis, ChIP-PCR and dual-luciferase reporter gene assay. The effect of IGF-1 on the biological characteristics of trophoblast cells was investigated by CCK-8, colony formation assay and in vitro angiogenesis experiments after cells were transfected with si-IGF-1. Finally, a mouse eclampsia model induced by knockdown of IGF-1 was established to confirm the in vitro effect of IGF-1 on PE. We found that IGF-1, ZEB1 and miR-183 were highly expressed in the placental tissues of patients with PE. The knockdown of IGF-1 resulted in reduced proliferation and invasion of trophoblast cells and was accompanied by inhibited angiogenesis. ZEB1 was positively regulated by IGF-1 via ERK/MAPK pathway, which in turn inhibited miR-153 expression by binding to the miR-183 promoter. The in vitro experiments further confirmed that IGF-1 knockdown could induce PE. To sum up, IGF-1 knockdown elevated expression of miR-183 by downregulating ZEB1, thereby promoting deterioration of PE.
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Factor I del Crecimiento Similar a la Insulina , MicroARNs , Preeclampsia , Animales , Femenino , Humanos , Ratones , Embarazo , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Genes Homeobox , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Placenta/metabolismo , Preeclampsia/genética , Preeclampsia/metabolismo , Regulación hacia Arriba/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Dedos de ZincRESUMEN
This study investigated the implication of monitoring hypertensive disorders in pregnancy (HDP) to prevent preeclampsia (PE) in pregnant women of advanced maternal age. Between January 2016 and April 2021, 262 consecutive pregnant women aged ≥40 years were recruited. Extensive monitoring of hypertensive disorders in pregnancy, including blood hypercoagulability screening and subsequent interventions, was performed in 129 pregnant women in our university hospital. The remaining 133 patients from other centres, who did not receive antenatal maternal pregnancy screening and preventive intervention during the same period, constituted the non-intervention group enabling comparison to mimic a trial. The incidences of hypertensive disorders, mild and severe PE, eclampsia, and chronic hypertension complicated by PE in the intervention group were significantly lower than in the non-intervention group (10.08 versus 20.30%, 8.52 versus 18.80%, 7.75 versus 21.05%, 0 versus 3.01%, and 3.86 versus 15.04%, respectively; P < 0.05). Premature birth, low birth weight, and foetal loss were significantly rarer in the intervention group than in the non-intervention group (6.98 versus 24.81%, 7.75 versus 21.80%, and 0.78 versus 14.29% respectively; P < 0.001). The comparison of MP with routine blood coagulation biochemical examination found that the MP detection system of Beijing Yes Medical Devices Co., Ltd., had similar sensitivity as thromboelastogram. Still, it was significantly better than the routine biochemical indicators (P < 0.01). Based on MP parameters, early anticoagulant treatment with low-molecular-weight heparin or low-dose aspirin in pregnant women with hypercoagulability can effectively prevent the occurrence of PE and significantly improve the prognosis of both mothers and infants.
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INTRODUCTION: Recently, ferroptosis has been reported to be closely related to preeclampsia (PE). However, the mechanisms associated with ferroptosis in PE have been poorly studied. METHODS: A PE rat model was established via reduced uterine perfusion pressure (RUPP) surgery. A Ferroptosis inhibitor was used to treat the model rats. Blood pressure, urine protein, sFlt-1, GSH, GSH-PX, MDA, total Fe, Fe (II), and Fe (â ¢) levels were detected. Placenta morphological changes and fetal survival rate were observed and counted, respectively. miRNA sequencing and bioinformatical analysis were conducted to establish the ferroptosis-related interaction network of miRNAs-mRNAs in PE. After hypoxia treatment, cells were silenced glutamic-oxaloacetic transaminase1 (GOT1) or overexpressed miR-2115-3p/GOT1. Cellular proliferation, invasion, and reactive oxygen species (ROS) were determined. The ferroptosis-related factors levels (ACSL4, TfR1, GPX4, SCL7A11, GSH, GSH-PX, Fe (II), and MDA) were quantified. RESULTS: In vivo, ferrostatin-1 attenuated ferroptosis in the PE models, significantly increasing fetal survivability. The miR-2115-3p/GOT1 pathway was screened for possible association with abnormal ferroptosis in PE. miR-2115-3p was discovered to interact with the mRNA of GOT1. Inhibition of GOT1 and overexpression of miR-2115-3p reversed the decrease in cell proliferation capacity, GSH, GSH-PX, and GPX4 levels, and the increase in ROS, ACSL4, TfR1, MDA, total Fe, and Fe (II) levels induced by hypoxia. However, simultaneous overexpression of miR-2115-3p and GOT1 reversed the above results of overexpression of miR-2115-3p. DISCUSSION: miR-2115-3p might interact with the GOT1 mRNA to downregulate its expression, further inhibiting the hypoxia-promoted ferroptosis in a PE model.
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Ferroptosis , MicroARNs , Preeclampsia , Humanos , Embarazo , Femenino , Ratas , Animales , Preeclampsia/genética , Preeclampsia/metabolismo , Aspartato Aminotransferasas , Ferroptosis/genética , Especies Reactivas de Oxígeno , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero , HipoxiaRESUMEN
The etiology of fetal hydrocephalus is complex, and the outcome of fetal neurodevelopment after birth is also different. The purpose of this study is to conduct anti-infection of hydrocephalus fetuses with non-specific infection, and observe their neurodevelopment after birth, so as to provide clinical basis for further guidance and management of fetal hydrocephalus. Eighteen single pregnant women with fetal hydrocephalus confirmed by intrapartum ultrasonography in the Second Xiangya Hospital between July 1, 2019, and December 1, 2020, were included. Pelvis MRI, NITP, amniotic fluid/umbilical cord blood puncture, infection index, TORCH, and other examinations were completed during pregnancy. If the patient's infection index is elevated, the second-generation cephalosporin will be used for anti-infection therapy, and the development of fetal hydrocephalus, growth, and neurodevelopment after birth will be observed. Fetal hydrocephalus subsided in 3 cases (25%, 95% CI [0%, 53.7%]) remained stable in 6 cases (50%, 95% CI [16.8%, 83.2%]), progressed in 2 cases (16.7%, 95% CI [0%, 41.4%]), and terminated pregnancy in 1 case (8.7% [0%, 26.7%]). Of the 6 untreated patients, pregnancy was terminated in 3 (50%), hydrocephalus remained stable in 2 (33.3%), and spontaneous resolution in 1 case (16.7%). Fourteen patients delivered successfully, including 11 children with no obvious abnormalities in growth and development, 1 with mild growth retardation and 2 with moderate growth retardation. Anti-infective therapy in the case of non-specific infection or maternal infection can partially prevent the progression of hydrocephalus.
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Hidrocefalia , Ultrasonografía Prenatal , Niño , Femenino , Feto , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/terapia , Embarazo , Diagnóstico Prenatal , Estudios ProspectivosRESUMEN
Recent studies suggest that pregnancy may not be absolutely contraindicated in women with moderate pulmonary hypertension. We aimed to evaluate the long-term outcomes of pregnant women with pulmonary hypertension diagnosed by echocardiography in our clinical department. Pregnant women with pulmonary hypertension, diagnosed by a pulmonary systolic arterial pressure > 30 mmHg via echocardiography, who were admitted in our department for termination of pregnancy or delivery between 2004 and 2016 were included in this retrospective cohort study. Demographic characteristics, clinical histories, perinatal outcomes, and follow-up outcomes after discharge were reported. The primary outcome was survival of the pregnant women after discharge. A total of 88 pregnant women with pulmonary hypertension were included in this cohort study. The women were categorized into severe and moderate pulmonary hypertension groups according to their pulmonary systolic arterial pressure at admission. Women with severe pulmonary hypertension were significantly more likely to have deteriorated cardiac function and higher incidence of neonatal complications during the perinatal periods (p < 0.05). During a median follow-up of 26 months, the mortality rate was significantly higher in women with severe pulmonary hypertension (p < 0.05). However, the accumulated survival rate was >90% for women with moderate pulmonary hypertension within the follow-up period. Multivariate Cox regression analyses showed that poor cardiac function before pregnancy, irregular antenatal care, and hyperuricemia were independent mortality risk factors for women with pulmonary hypertension after discharge. In conclusion, the long-term survival of pregnant women with moderate pulmonary hypertension diagnosed by echocardiography was considered acceptable in this cohort. Our findings suggest that pregnancy might not be absolutely contraindicated in women with moderate pulmonary hypertension.
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Preeclampsia (PE) is a hypertensive disorder of uncertain etiology that is the leading cause of maternal and fetal morbidity or mortality. The dysregulation of microRNAs (miRNAs) has been highlighted as a potential factor involved in the development of PE. Therefore, our study investigated a novel miRNA, miRNA 183 (miR-183), and its underlying association with PE. Expression of miR-183, forkhead box P1 (FOXP1), and G protein subunit gamma 7 (GNG7) in placental tissues of patients with PE was determined. Gain- and loss-of-function experiments were conducted to explore modulatory effects of miR-183, FOXP1, and GNG7 on the viability, invasion, and angiogenesis of trophoblast cells in PE. Finally, we undertook in vivo studies to explore effects of FOXP1 in the PE model. The results revealed suppressed expression of FOXP1 and significant elevations in miR-183 and GNG7 expression in placental tissues of PE patients. FOXP1 was observed to promote proliferation, invasion, and angiogenesis in human chorionic trophoblastic cells. miR-183 resulted in depletion of FOXP1 expression, while FOXP1 was capable of restraining GNG7 expression and promoting the mTOR pathway. The findings confirmed the effects of FOXP1 on PE. In conclusion, miR-183 exhibits an inhibitory role in PE through suppression of FOXP1 and upregulation of GNG7.
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Factores de Transcripción Forkhead/biosíntesis , Subunidades gamma de la Proteína de Unión al GTP/biosíntesis , MicroARNs/metabolismo , Preeclampsia/metabolismo , Proteínas Represoras/biosíntesis , Adulto , Animales , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/genética , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Expresión Génica , Humanos , Ratones , MicroARNs/genética , Placenta/metabolismo , Preeclampsia/genética , Preeclampsia/patología , Embarazo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patologíaRESUMEN
Preeclampsia (PE) is a pathological condition that manifests during pregnancy as the occurrence of an abnormal urine protein level and increased blood pressure due to inadequate cytotrophoblast invasion. To elucidate the mechanism underlying PE, the present study primarily focused on the regulatory effects and mechanism of the G protein γ 7 (GNG7) on placental cytotrophoblasts in a rat PE model. Initially, the PE model was established with 45 specific pathogenfree SpragueDawley rats (30 females and 15 males). The expression patterns of GNG7, 4Ebinding protein 1 (4EBP1), phosphoprotein 70 ribosomal protein S6 kinase (p70S6K) and mammalian target of rapamycin (mTOR) were examined in the PE rats. Placental cytotrophoblasts isolated from normal and PE rats were treated with a small interfering RNA against GNG7, mTOR signaling pathway activator (HIV1 Tat) or inhibitor (rapamycin). Following treatment, cell proliferation, differentiation and apoptosis were evaluated, and mTOR signaling pathwayrelated factors (4EBP1, p70S6K and mTOR), cell proliferationrelated factors (vascular endothelial growth factor and transforming growth factorß1), differentiationrelated factors [activator protein2 (AP2)α and AP2γ], and apoptosisrelated factors [Bcell lymphoma 2 (Bcl2) and Bcl2associated X protein] were determined. Finally, soluble fmslike tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) levels were measured via enzymelinked immunosorbent assay. Initially, the mTOR signaling pathway was inactivated in the placental tissues and cytotrophoblasts in the PE rats. Silencing GNG7 reduced the levels of sFlt1 and sEng and activated the mTOR signaling pathway. Silencing of GNG7 or activation of the mTOR signaling pathway enhanced cell proliferation and differentiation, but inhibited the apoptosis of placental cytotrophoblasts in the PE rats. Taken together, the results showed that GNG7 silencing repressed apoptosis and enhanced the proliferation and differentiation of placental cytotrophoblasts in PE rats through activation of the mTOR signaling pathway.
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Diferenciación Celular , Subunidades gamma de la Proteína de Unión al GTP/genética , Silenciador del Gen , Placenta/patología , Preeclampsia/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Trofoblastos/patología , Animales , Apoptosis , Presión Sanguínea , Proteínas Portadoras/metabolismo , Proliferación Celular , Diástole , Modelos Animales de Enfermedad , Endoglina/metabolismo , Femenino , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Fosfoproteínas/metabolismo , Placenta/metabolismo , Preeclampsia/fisiopatología , Preeclampsia/orina , Embarazo , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Sístole , Regulación hacia Arriba , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
AIM: To compare the evaluations of evaluate levator ani muscle injury (LAMI) by tomographic ultrasound imaging (TUI) and multiplanar (MP) ultrasound in patients with pelvic organ prolapse (POP). METHOD: This retrospective analysis studied women who underwent International Continence Society POP quantification examination between October 2015 and June 2016. LAMI was assessed by both TUI and MP ultrasounds. Concordance of these two testing results was analyzed. Their correlations with clinical symptoms were also studied. RESULTS: A total of 135 women were included. All the patients with POP had a minimal LAMI depth ≥ 7 mm. Two examinations, TUI and MP, had satisfactory concordance (k = 0.71, P < 0.01). Depth of LAMI in the coronal plane demonstrated good agreement with TUI scores (r = 0.84; P < 0.01). After controlling for age, BMI, and parity, to have clinically significant POP and POP symptoms, the odds ratios (ORs) for the depth of LAMI in the coronal plane were 1.31 (95% CI 1.19-1.44) and 1.25 (95% CI 1.14-1.36), and for TUI scores were 1.72 (95% CI 1.37-2.17) and 1.63 (95% CI 1.31-2.03). Receiver operating characteristic curve analyses showed a cutoff depth of 7 mm of LAMI yielded a sensitivity of 62% and specificity of 80% for POP symptoms. CONCLUSIONS: TUI and MP had satisfactory concordance in detecting LAMI and correlated with clinical symptoms of POP.
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Diafragma Pélvico/diagnóstico por imagen , Diafragma Pélvico/lesiones , Prolapso de Órgano Pélvico/fisiopatología , Ultrasonografía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Diafragma Pélvico/patología , Pronóstico , Curva ROC , Estudios RetrospectivosRESUMEN
Although endogenous digitalislike factor (EDLF) is associated with the development of various physical disorders, the role in preeclampsia remains unclear. This study investigated the effects of EDLF on vascular endothelial cell damage in patients with preeclampsia and the potential mechanisms. From July 2014 to July 2015, 120 singleton pregnancy cases underwent a prenatal examination, inpatient delivery and had normal blood pressure were included in the study, either as patients with severe preeclampsia or the control patients. Serum EDLF levels were compared in these two groups, and an in vitro hypoxic trophocyteinduced vascular endothelial cell damage model was established to explore the changes in hypoxic trophocyte EDLF level and the subsequent effects on human umbilical vein endothelial cells (HUVECs). Nuclear factorκB (NFκB) p65 gene expression was silenced in hypoxic trophocytes, and EDLF levels and HUVEC damage were subsequently assessed. Serum EDLF levels were significantly higher in the severe preeclampsia cases than in the controls at the same gestational week (P<0.001). EDLF levels in hypoxic trophocytes increased with the increasing coculture duration. Damage to the biofunctions of HUVECs cocultured with hypoxic trophocytes also increased with coculture duration. However, silencing of NFκB p65 in the hypoxic trophocytes reduced the EDLF levels. Annexin A2 was highly expressed in HUVECs, and no biofunctions were significantly damaged (P<0.05) compared with the group without receiving NFκB p65 silencing. Serum EDLF levels were significantly higher in patients with severe preeclampsia compared with the controls. The results of the current study indicate that NFκB p65 has a role in regulating EDLF production in hypoxic trophocytes.
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Preeclampsia/metabolismo , Anexina A2/metabolismo , Presión Sanguínea/fisiología , Cardenólidos/metabolismo , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Preeclampsia/patología , Embarazo , Saponinas/metabolismo , Factor de Transcripción ReIA/metabolismoRESUMEN
Although 5-fluorouracil (5-Fu) combination chemotherapy provides a satisfactory therapeutic response in patients with gestational trophoblastic neoplasms (GTNs), it has severe side effects. The current study analyzed the therapeutic effects and side effects of tegafur plus actinomycin D (Act-D) vs. 5-Fu plus Act-D for the treatment of GTNs based on controlled historical records. A total of 427 GTN cases that received tegafur and Act-D combination chemotherapy at the Second Xiangya Hospital of XiangYa Medical School between August 2003 and July 2013 were analyzed based on historical data. A total of 393 GTN cases that received 5-Fu plus Act-D between August 1993 and July 2003 at the same hospital were also analyzed, which constituted the control group. The therapeutic effects, toxicity and side effects after chemotherapy were compared between the groups. The overall response rate was 90.63% in the tegafur+Act-D group (tegafur group) and 92.37% in the 5-Fu+Act-D group (5-Fu group); these rates were not significantly different (P > 0.05). However, the incidence rates of myelosuppression (white blood cell decline), gastrointestinal reactions (nausea, vomiting, dental ulcer, and diarrhea), skin lesions and phlebitis were lower in the tegafur group than in the 5-Fu group (P < 0.05). The results of this study may provide useful data for the clinical application of tegafur in GTN treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dactinomicina/uso terapéutico , Fluorouracilo/química , Fluorouracilo/uso terapéutico , Enfermedad Trofoblástica Gestacional/tratamiento farmacológico , Tegafur/química , Adulto , Femenino , Humanos , EmbarazoRESUMEN
Corticotropin-releasing hormone (CRH) and connexin 43 (Cx43) play crucial roles in uterine contraction and the onset of labor. The aim of the present study was to investigate the regulatory effects of CRH on Cx43 expression in human myometrial smooth muscle cells (SMCs) and, potentially, its activation of the c-Fos/activator protein (AP)-1 signaling pathway. Human myometrial SMCs collected from nonpregnant women were treated with different concentrations of CRH. Transient transfection of AP-1 decoy oligodeoxynucleotide (ODN) was used to block AP-1 sites of Cx43. The transcriptional activity of AP-1 was detected by luciferase assay. Cx43 protein expression was visualized by immunofluorescence staining. mRNA and protein expression of c-Fos and Cx43 were demonstrated by real-time quantitative RT-PCR and Western blot, respectively. CRH facilitated Cx43 expression and enhanced AP-1 promoter activity in human uterine SMCs. After CRH treatment, Cx43 expression in the cytoplasm increased significantly. CRH significantly increased mRNA and protein expression of c-Fos and Cx43 in a dose-dependent manner (P < 0.01). A transient transfection of AP-1 decoy ODN did not affect CRH regulation of c-Fos (P > 0.05) but almost completely abolished CRH-induced enhancement of Cx43 expression (P < 0.01). In human primary myometrial SMCs, CRH enhances Cx43 mRNA and protein expression through upregulation of c-Fos expression. Blockade of AP-1 sites to the Cx43 promoter can neutralize the CRH-induced upregulation of Cx43.