Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.096
Filtrar
1.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806480

RESUMO

The pathogenesis of preeclampsia begins when a fertilized egg infiltrates the decidua, resulting in implantation failure (e.g., due to extravillous trophoblast infiltration disturbance and abnormal spiral artery remodeling). Thereafter, large amounts of serum factors (e.g., soluble fms-like tyrosine kinase 1 and soluble endoglin) are released into the blood from the hypoplastic placenta, and preeclampsia characterized by multiorgan disorder caused by vascular disorders develops. Successful implantation and placentation require immune tolerance to the fertilized egg as a semi-allograft and the stimulation of extravillous trophoblast infiltration. Recently, exosomes with diameters of 50-100 nm have been recognized to be involved in cell-cell communication. Exosomes affect cell functions in autocrine and paracrine manners via their encapsulating microRNA/DNA and membrane-bound proteins. The microRNA profiles of blood exosomes have been demonstrated to be useful for the evaluation of preeclampsia pathophysiology and prediction of the disease. In addition, exosomes derived from mesenchymal stem cells have been found to have cancer-suppressing effects. These exosomes may repair the pathophysiology of preeclampsia through the suppression of extravillous trophoblast apoptosis and promotion of these cells' invasive ability. Exosomes secreted by various cells have received much recent attention and may be involved in the maintenance of pregnancy and pathogenesis of preeclampsia.


Assuntos
Exossomos/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Animais , Comunicação Celular/fisiologia , Feminino , Humanos , MicroRNAs/metabolismo , Placenta/metabolismo , Placenta/patologia , Placentação/fisiologia , Gravidez , Trofoblastos/metabolismo , Trofoblastos/patologia
2.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809345

RESUMO

Physiological oxygen tension rises dramatically in the placenta between 8 and 14 weeks of gestation. Abnormalities in this period can lead to gestational diseases, whose underlying mechanisms remain unclear. We explored the changes at mRNA level by comparing the transcriptomes of human placentas at 8-10 gestational weeks and 12-14 gestational weeks. A total of 20 samples were collected and divided equally into four groups based on sex and age. Cytotrophoblasts were isolated and sequenced using RNAseq. Key genes were identified using two different methods: DESeq2 and weighted gene co-expression network analysis (WGCNA). We also constructed a local database of known targets of hypoxia-inducible factor (HIF) subunits, alpha and beta, to investigate expression patterns likely linked with changes in oxygen. Patterns of gene enrichment in and among the four groups were analyzed based on annotations of gene ontology (GO) and KEGG pathways. We characterized the similarities and differences between the enrichment patterns revealed by the two methods and the two conditions (age and sex), as well as those associated with HIF targets. Our results provide a broad perspective of the processes that are active in cytotrophoblasts during the rise in physiological oxygen, which should benefit efforts to discover possible drug-targeted genes or pathways in the human placenta.


Assuntos
Adaptação Fisiológica/genética , Pré-Eclâmpsia/genética , Primeiro Trimestre da Gravidez/genética , Transcriptoma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Hipóxia Celular/genética , Feminino , Humanos , Oxigênio/metabolismo , Placenta/metabolismo , Placenta/patologia , Placentação/genética , Pré-Eclâmpsia/patologia , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , RNA Mensageiro/genética , RNA-Seq
3.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673075

RESUMO

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE.


Assuntos
Retardo do Crescimento Fetal/sangue , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Placenta/metabolismo , Pré-Eclâmpsia/sangue , Feminino , Retardo do Crescimento Fetal/patologia , Humanos , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez
4.
Hum Genet ; 140(5): 827-848, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33433680

RESUMO

Two major obstetric diseases, preeclampsia (PE), a pregnancy-induced endothelial dysfunction leading to hypertension and proteinuria, and intra-uterine growth-restriction (IUGR), a failure of the fetus to acquire its normal growth, are generally triggered by placental dysfunction. Many studies have evaluated gene expression deregulations in these diseases, but none has tackled systematically the role of alternative splicing. In the present study, we show that alternative splicing is an essential feature of placental diseases, affecting 1060 and 1409 genes in PE vs controls and IUGR vs controls, respectively, many of those involved in placental function. While in IUGR placentas, alternative splicing affects genes specifically related to pregnancy, in preeclamptic placentas, it impacts a mix of genes related to pregnancy and brain diseases. Also, alternative splicing variations can be detected at the individual level as sharp splicing differences between different placentas. We correlate these variations with genetic variants to define splicing Quantitative Trait Loci (sQTL) in the subset of the 48 genes the most strongly alternatively spliced in placental diseases. We show that alternative splicing is at least partly piloted by genetic variants located either in cis (52 QTL identified) or in trans (52 QTL identified). In particular, we found four chromosomal regions that impact the splicing of genes in the placenta. The present work provides a new vision of placental gene expression regulation that warrants further studies.


Assuntos
Processamento Alternativo/genética , Retardo do Crescimento Fetal/genética , Placenta/patologia , Pré-Eclâmpsia/genética , Feminino , Retardo do Crescimento Fetal/patologia , Humanos , Pré-Eclâmpsia/patologia , Gravidez , Complicações na Gravidez/genética , Locos de Características Quantitativas/genética
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429954

RESUMO

Previous studies have described increased circulating cell-free DNA (cfDNA) in hypertensive disorders of pregnancy (HDP). Here, we aimed first to confirm this information using a simple, but sensible fluorescent assay, and second to investigate whether total cfDNA is associated with circulating factors known to be linked to the pathophysiology of HDP as well as with poor maternal-fetal outcomes. We studied 98 women with healthy pregnancies (HP), 88 with gestational hypertension (GH), and 91 with preeclampsia (PE). Total DNA was extracted from plasma using the QIAamp DNA blood mini kit and quantified using Quant-iT™ PicoGreen® dsDNA fluorescent detection kit. We found higher total cfDNA levels in GH and PE (197.0 and 174.2 ng/mL, respectively) than in HP (140.5 ng/mL; both p < 0.0001). Interestingly, total cfDNA levels were elevated in both male and female-bearing pregnancies diagnosed with either HDP, and in more severe versus less severe HDP cases, as classified according to responsiveness to antihypertensive therapy. In addition, total cfDNA was independently associated with HDP, and a cutoff concentration of 160 ng/mL provided appropriate sensitivity and specificity values for diagnosing GH and PE compared to HP (70-85%, both p < 0.0001). Moreover, high total cfDNA was associated with adverse clinical outcomes (high blood pressure, low platelet count, preterm delivery, fetal growth restriction) and high prohypertensive factors (sFLT-1, sEndoglin, MMP-2). These findings represent a step towards to the establishment of cfDNA as a diagnostic tool and the need to understand its role in HDP.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA/sangue , Hipertensão Induzida pela Gravidez/sangue , Hipertensão/sangue , Adulto , Endoglina/sangue , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/patologia , Humanos , Hipertensão/patologia , Hipertensão Induzida pela Gravidez/patologia , Metaloproteinase 2 da Matriz/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/patologia , Gravidez , Primeiro Trimestre da Gravidez/sangue , Nascimento Prematuro/sangue , Nascimento Prematuro/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
6.
Biochim Biophys Acta Mol Basis Dis ; 1867(1): 165993, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33096224

RESUMO

Late-onset preeclampsia (LOPE) associates with reduced umbilical vein reactivity and endothelial nitric oxide synthase (eNOS) activity but increased human cationic amino acid (hCAT-1)-mediated L-arginine transport involving A2A adenosine receptor in the fetoplacental unit. This study addresses the A2B adenosine receptor (A2BAR)-mediated response to insulin in the fetoplacental vasculature from LOPE. Umbilical veins and HUVECs were obtained from women with normal (n = 37) or LOPE (n = 35) pregnancies. Umbilical vein rings reactivity to insulin was assayed in the absence or presence of adenosine and MRS-1754 (A2BAR antagonist) in a wire myograph. HUVECs were exposed to insulin, MRS-1754, BAY60-6583 (A2BAR agonist), NECA (general adenosine receptors agonist) or NG-nitro-L-arginine methyl ester (NOS inhibitor). A2BAR, hCAT-1, total and phosphorylated eNOS, Akt and p44/42mapk protein abundance were determined by Western blotting. Insulin receptors A (IR-A) and B (IR-B), eNOS and hCAT-1 mRNA were determined by qPCR. Firefly/Renilla luciferase assay was used to determine -1606 bp SLC7A1 (hCAT-1) promoter activity. L-Citrulline content was measured by HPLC, L-[3H]citrulline formation from L-[3H]arginine by the Citrulline assay, and intracellular cGMP by radioimmunoassay. LOPE-reduced dilation of vein rings to insulin was restored by MRS-1754. HUVECs from LOPE showed higher A2BAR, hCAT-1, and IR-A expression, Akt and p44/42mapk activation, and lower NOS activity. MRS-1754 reversed the LOPE effect on A2BAR, hCAT-1, Akt, and eNOS inhibitory phosphorylation. Insulin reversed the LOPE effect on A2BAR, IR-A and eNOS, but increased hCAT-1-mediated transport. Thus, LOPE alters endothelial function, causing an imbalance in the L-arginine/NO signalling pathway to reduce the umbilical vein dilation to insulin requiring A2BAR activation in HUVECs.


Assuntos
Arginina/metabolismo , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Insulina/metabolismo , Óxido Nítrico/metabolismo , Pré-Eclâmpsia/metabolismo , Receptor A2B de Adenosina/metabolismo , Transdução de Sinais , Adulto , Endotélio Vascular/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Pré-Eclâmpsia/patologia , Gravidez
7.
Cell Prolif ; 54(2): e12968, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33332660

RESUMO

OBJECTIVES: Pre-eclampsia is a leading cause of morbidity and mortality during pregnancy. Although the two forms of this disorder, early- (EOPE) and late-onset of pre-eclampsia (LOPE) are different, the underlying pathology remains elusive. We aim to unravel the difference and to identify novel biomarkers for EOPE and LOPE. MATERIALS AND METHODS: A complete comparison of both placental and peripheral blood transcriptomes was performed to investigate the pathology of pre-eclampsia. Single-cell transcriptomics of the maternal-fetal interface were integrated to identify novel biomarkers for EOPE and LOPE which were further verified at protein or mRNA level in patients. RESULTS: We found that the transcriptomes of placentae from EOPE, but not LOPE, were significantly different from their respective controls. Conversely, the transcriptomes of peripheral blood from LOPE were more different from their controls than EOPE. Importantly, we identified that several classical biomarkers of pre-eclampsia were expressed specifically in extravillous trophoblast and syncytiotrophoblast and only upregulated in EOPE, suggesting they should not be applied to all pre-eclampsia patients in general. We further identified novel biomarkers for EOPE and LOPE from differentially expressed genes (DEGs) of placental and peripheral blood, respectively. The new biomarkers EBI3, IGF2, ORMDL3, GATA2 and KIR2DL4 were experimentally verified with patient blood samples. CONCLUSION: Our data demonstrate distinct pathology of EOPE and LOPE, and uncover new biomarkers that can be applied in diagnosis for pre-eclampsia.


Assuntos
Biomarcadores/metabolismo , Pré-Eclâmpsia/patologia , Transcriptoma , Biomarcadores/sangue , Estudos de Casos e Controles , Biologia Computacional , Feminino , Fator de Transcrição GATA2/sangue , Fator de Transcrição GATA2/metabolismo , Humanos , Interleucinas/sangue , Interleucinas/metabolismo , Transtornos de Início Tardio , Proteínas de Membrana/sangue , Proteínas de Membrana/metabolismo , Antígenos de Histocompatibilidade Menor/sangue , Antígenos de Histocompatibilidade Menor/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Mapas de Interação de Proteínas , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Análise de Célula Única
8.
PLoS One ; 15(12): e0243455, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382728

RESUMO

OBJECTIVE: To determine the placental pathologies and maternal factors associated with stillbirth at Kilimanjaro Christian Medical Centre, a tertiary referral hospital in Northern Tanzania. METHODS: A 1:2 unmatched case-control study was carried out among deliveries over an 8-month period. Stillbirths were a case group and live births were the control group. Respective placentas of the newborns from both groups were histopathologically analyzed. Maternal information was collected via chart review. Mean and standard deviation were used to summarize the numerical variables while frequency and percentage were used to summarize categorical variables. Crude and adjusted logistic regressions were done to test the association between each variable and the risk of stillbirth. RESULTS: A total of 2305 women delivered during the study period. Their mean age was 30 ± 5.9 years. Of all deliveries, 2207 (95.8%) were live births while 98 (4.2%) were stillbirths. Of these, 96 stillbirths (cases) and 192 live births (controls) were enrolled. The average gestational age for the enrolled cases was 33.8 ±3.2 weeks while that of the controls was 36.3±3.6 weeks, (p-value 0.244). Of all stillbirths, nearly two thirds 61(63.5%) were males while the females were 35(36.5%). Of the stillbirth, 41were fresh stillbirths while 55 were macerated. The risk of stillbirth was significantly associated with lower maternal education [aOR (95% CI): 5.22(2.01-13.58)], history of stillbirth [aOR (95%CI): 3.17(1.20-8.36)], lower number of antenatal visits [aOR (95%CI): 6.68(2.71-16.48), pre/eclampsia [aOR (95%CI): 4.06(2.03-8.13)], and ante partum haemorrhage [OR (95%CI): 2.39(1.04-5.53)]. Placental pathology associated with stillbirth included utero-placental vascular pathology and acute chorioamnionitis. CONCLUSIONS: Educating the mothers on the importance of regular antenatal clinic attendance, monitoring and managing maternal conditions during antenatal periods should be emphasized. Placentas from stillbirths should be histo-pathologically evaluated to better understand the possible aetiology of stillbirths.


Assuntos
Placenta/patologia , Natimorto , Adolescente , Adulto , Estudos de Casos e Controles , Corioamnionite/diagnóstico , Corioamnionite/patologia , Escolaridade , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Pré-Eclâmpsia/patologia , Gravidez , Complicações na Gravidez , Cuidado Pré-Natal/estatística & dados numéricos , Fatores de Risco , Tanzânia , Adulto Jovem
9.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321877

RESUMO

Adipocytokines are hormonally active molecules that are believed to play a key role in the regulation of crucial biological processes in the human body. Numerous experimental studies established significant alterations in the adipokine secretion patterns throughout pregnancy. The exact etiology of various gestational complications, such as gestational diabetes, preeclampsia, and fetal growth abnormalities, needs to be fully elucidated. The discovery of adipokines raised questions about their potential contribution to the molecular pathophysiology of those diseases. Multiple studies analyzed their local mRNA expression and circulating protein levels. However, most studies report conflicting results. Several adipokines such as leptin, resistin, irisin, apelin, chemerin, and omentin were proposed as potential novel early markers of heterogeneous gestational complications. The inclusion of the adipokines in the standard predictive multifactorial models could improve their prognostic values. Nonetheless, their independent diagnostic value is mostly insufficient to be implemented into standard clinical practice. Routine assessments of adipokine levels during pregnancy are not recommended in the management of both normal and complicated pregnancies. Based on the animal models (e.g., apelin and its receptors in the rodent preeclampsia models), future implementation of adipokines and their receptors as new therapeutic targets appears promising but requires further validation in humans.


Assuntos
Adipocinas/metabolismo , Diabetes Gestacional/metabolismo , Pré-Eclâmpsia/metabolismo , Animais , Biomarcadores/metabolismo , Diabetes Gestacional/patologia , Feminino , Humanos , Pré-Eclâmpsia/patologia , Gravidez
10.
Life Sci ; 261: 118314, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835699

RESUMO

AIMS: Placental tissues from patients with preeclampsia (PE) and in the lipopolysaccharide (LPS)-induced PE-like model were used to investigate the implication of placental inflammation and apoptosis in PE. Whether the beneficial effects of nicotine are related to inhibition of placental inflammation and apoptosis in the PE-like model were investigated. MAIN METHODS: Placental apoptosis was detected in PE patients and the PE-like rat model by TUNEL staining. Changes in the number of CD68+ macrophages in placental tissues from PE patients were detected by immunofluorescent staining. The mRNA expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL-1ß), MCP-1, and proteins involved in extrinsic or intrinsic apoptosis signaling in the PE-like model was determined by qRT-PCR; immunofluorescent staining was used to detect the expression of TNF-α receptor (TNFR1), MCP-1 and apoptosis-related proteins. KEY FINDINGS: Placental apoptosis was increased in both PE patients and the PE-like model, more macrophages infiltrated into placenta in PE patients. A significant upregulation in mRNA expression of TNF-α, IL-1ß, MCP-1, and caspase 3, caspase 8, caspase 9 was found in the PE-like rats compared to the control animals, the immunoreactivity of placental MCP-1, TNFR1, and apoptosis-related proteins (caspase 3, caspase 8, caspase 9, Bax) was also enhanced; nicotine treatment significantly reversed those changes. SIGNIFICANCE: Our data suggests that the protective effects of nicotine are associated with inhibiting placenta inflammation and apoptosis, and nicotine might be a potentially therapeutic candidate for preventing preeclampsia.


Assuntos
Inflamação/tratamento farmacológico , Nicotina/farmacologia , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/prevenção & controle , Adulto , Animais , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Adulto Jovem
11.
Zhonghua Fu Chan Ke Za Zhi ; 55(8): 535-543, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32854478

RESUMO

Objective: To observe the changes of the expression level of long non-coding RNA (lncRNA) KCNQ1OT1 and microRNA (miR)-146a-3p in placenta tissues of preeclampsia (PE) patients, as well as their effect and mechanism on the biological functions of trophoblast cells. Methods: A total of 45 cases of hospitalized PE patients in Hainan General Hospital from July 2017 to July 2018 were selected as the PE group, 55 normal pregnant women during the same period were chosed as the control group. The expression level of KCNQ1OT1 mRNA and miR-146a-3p in the placenta tissues between two groups were detected by using quantitative real time (qRT)-PCR. Pearson's test was furtherly analyzed the correlation between them. Human trophoblast cell line (HTR8/SVneo) were randomly divided into control and lipopolysaccharide (LPS) groups, and then LPS group were divide into four sub-groups,included LPS group, short hairpin RNA (sh)-KCNQ1OT1 (after silencing the expression of KCNQ1OT1), miR-146a-3p inhibitor and sh-KCNQ1OT1+miR-146a-3p inhibitor. The targeting relationship between KCNQ1OT1 and miR-146a-3p were predicted by bioinformatics software and confirmed by luciferase assay. The cell proliferation and invasion capacities were respectively detected by cell counting kit-8 (CCK-8) and transwell assay. The expression level of KCNQ1OT1 mRNA and miR-146a-3p were detected by qRT-PCR and the protein expression level of CXC chemokine ligand 12 (CXCL12) and CXC chemokine receptor type 4 (CXCR4) were tested by western blot. Results: (1) The mRNA expression level of KCNQ1OT1 in the placenta of PE group was lower than that of control group (0.23±0.03 vs 0.51±0.04, P<0.05), and the miR-146a-3p expression level was higher than that of the control group (0.49±0.03 vs 0.31±0.03, P<0.05), there were statistical significant differences between the two groups. (2) Luciferase assay showed that there was a targeting relationship between KCNQ1OT1 and mir-146a-3p. Compared with the control group, the mRNA expression level of KCNQ1OT1 in the LPS group were significantly decreased (0.91±0.03 vs 0.35±0.03, P<0.05), and the expression level of miR-146a-3p were significantly increased (0.22±0.03 vs 0.63±0.04, P<0.05). The cell proliferation, invasion and migration capacities and the protein expression of CXCL12 and CXCR4 significantly reduced in the LPS group compared with control group (all P<0.05). The mRNA expression level of KCNQ1OT1 (0.23±0.03) in the sh-KCNQ1OT1 group were further decreased, the expression of miR-146a-3p (0.85±0.03) were further increased, and the cell proliferation, invasion and migration capacities and the protein expression of CXCL12 and CXCR4 were all further reduced compared with control group,there were significant difference between two groups (all P<0.05). Comparing the miR-146a-3p inhibitor group, and sh-KCNQ1OT1+miR-146a-3p inhibitor group with the sh-KCNQ1OT1 group, respectively, the expression level of KCNQ1OT1 mRNA (0.78±0.04 vs 0.50±0.03) increased, and the expression level of miR-146a-3p (0.42±0.03 vs 0.46±0.03) decreased, the cell proliferation, invasion and migration capacities and the protein expression of CXCL12 and CXCR4 were all increased ,there were statistically significant differences (all P<0.05). Conclusion: KCNQ1OT1 could target the regulation of miR-146a-3p through CXCL12/CXCR4 pathway in the proliferation, invasion an migration of HTR8/SVneo cells, which may be involved in the pathogenesis of PE.


Assuntos
MicroRNAs/genética , Pré-Eclâmpsia/genética , RNA Longo não Codificante/genética , Trofoblastos/patologia , Feminino , Humanos , Placenta/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Pré-Eclâmpsia/patologia , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Trofoblastos/metabolismo
12.
Life Sci ; 261: 118351, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32858039

RESUMO

AIMS: Numerous studies suggest that excessive maternal inflammation and defective extravillous trophoblast (EVT) invasion could contribute to the development of preeclampsia (PE), but the underlying mechanism remains unclear. Some evidence suggests that CyPA is elevated in PE. This research aims to investigate the effect of recombinant human CyPA on trophoblast migration and invasion both in vitro and in vivo. MATERIALS AND METHODS: We detected the expression and localization of CyPA in human placenta and explored the effects of CyPA on cell migration and invasion on HTR8/SVneo cell. Additionally, the expression levels of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway were detected. We established a mouse model by injecting pregnant mice with recombinant human CyPA and measured blood pressure, albumin/creatinine ratio, fetal and placenta weight of mice. Moreover, we examined the placental histology and MMP-2/9 and p38/ERK/JNK expression. KEY FINDINGS: Our results showed that CyPA inhibited the migration and invasion of HTR8/SVneo cells in a dose-dependent manner, decreasing the expression of matrix metalloproteinase (MMP)-2/9 and molecules in the p38/ERK/JNK signaling pathway. Silencing CyPA could reverse the above effects. Moreover, CyPA could induce PE-like features in pregnant mice and disrupt the structure of the mouse placenta by reducing the junctional zone area. CyPA attenuated the trophoblast invasiveness in mice placenta by downregulating MMP-2/9 expression and p38/ERK/JNK pathway activity. SIGNIFICANCE: We proposed that CyPA could inhibit trophoblast migration and invasion both in vitro and in vivo, which was involved in PE development.


Assuntos
Movimento Celular , Ciclofilina A/metabolismo , Sistema de Sinalização das MAP Quinases , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/patologia , Trofoblastos/enzimologia , Trofoblastos/patologia , Adulto , Animais , Regulação para Baixo/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Rim/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Placenta/enzimologia , Placenta/patologia , Gravidez , Resultado da Gravidez
13.
Am J Pathol ; 190(10): 2111-2122, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32679230

RESUMO

After a child is born, the examination of the placenta by a pathologist for abnormalities, such as infection or maternal vascular malperfusion, can provide important information about the immediate and long-term health of the infant. Detection of the pathologic placental blood vessel lesion decidual vasculopathy (DV) has been shown to predict adverse pregnancy outcomes, such as preeclampsia, which can lead to mother and neonatal morbidity in subsequent pregnancies. However, because of the high volume of deliveries at large hospitals and limited resources, currently a large proportion of delivered placentas are discarded without inspection. Furthermore, the correct diagnosis of DV often requires the expertise of an experienced perinatal pathologist. We introduce a hierarchical machine learning approach for the automated detection and classification of DV lesions in digitized placenta slides, along with a method of coupling learned image features with patient metadata to predict the presence of DV. Ultimately, the approach will allow many more placentas to be screened in a more standardized manner, providing feedback about which cases would benefit most from more in-depth pathologic inspection. Such computer-assisted examination of human placentas will enable real-time adjustment to infant and maternal care and possible chemoprevention (eg, aspirin therapy) to prevent preeclampsia, a disease that affects 2% to 8% of pregnancies worldwide, in women identified to be at risk with future pregnancies.


Assuntos
Decídua/patologia , Placenta/patologia , Pré-Eclâmpsia/patologia , Doenças Vasculares/patologia , Adulto , Feminino , Humanos , Recém-Nascido , Redes Neurais de Computação , Gravidez , Resultado da Gravidez
14.
Proc Natl Acad Sci U S A ; 117(27): 15772-15777, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581122

RESUMO

During pregnancy, invading HLA-G+ extravillous trophoblasts (EVT) play a key role in placental development, uterine spiral artery remodeling, and prevention of detrimental maternal immune responses to placental and fetal antigens. Failures of these processes are suggested to play a role in the development of pregnancy complications, but very little is known about the underlying mechanisms. Here we present validated methods to purify and culture primary HLA-G+ EVT from the placental disk and chorionic membrane from healthy term pregnancy. Characterization of HLA-G+ EVT from term pregnancy compared to first trimester revealed their unique phenotypes, gene expression profiles, and differing capacities to increase regulatory T cells (Treg) during coculture assays, features that cannot be captured by using surrogate cell lines or animal models. Furthermore, clinical variables including gestational age and fetal sex significantly influenced EVT biology and function. These methods and approaches form a solid basis for further investigation of the role of HLA-G+ EVT in the development of detrimental placental inflammatory responses associated with pregnancy complications, including spontaneous preterm delivery and preeclampsia.


Assuntos
Antígenos HLA-G/imunologia , Imunidade Inata/genética , Placentação/imunologia , Pré-Eclâmpsia/imunologia , Linhagem Celular , Movimento Celular/imunologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Humanos , Relações Materno-Fetais , Placenta/imunologia , Placenta/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Primeiro Trimestre da Gravidez , Trofoblastos/imunologia
15.
J Clin Invest ; 130(9): 4947-4953, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32573498

RESUMO

BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Placenta/patologia , Placenta/virologia , Pneumonia Viral/complicações , Complicações Infecciosas na Gravidez/etiologia , Complicações Infecciosas na Gravidez/virologia , Aborto Terapêutico , Descolamento Prematuro da Placenta/etiologia , Descolamento Prematuro da Placenta/patologia , Descolamento Prematuro da Placenta/virologia , Adulto , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Betacoronavirus/patogenicidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Microscopia Eletrônica de Transmissão , Pandemias , Filogenia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/virologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Segundo Trimestre da Gravidez , RNA Viral/genética , RNA Viral/isolamento & purificação , Carga Viral
16.
Arch Gynecol Obstet ; 302(2): 293-303, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32556514

RESUMO

Autophagy exists widely in eukaryotic cells and is regulated by a variety of molecular mechanisms. Its physiological functions include providing energy, maintaining cell homeostasis, and promoting apoptosis of abnormal cells. At present, the regulation of autophagy in tumor, degenerative disease, and cardiovascular disease has attracted much attention. Gradually, the role of autophagy in pregnancy tends to be valued. The previous literature has shown that autophagy can influence the occurrence and maintenance of pregnancy from three aspects: embryo (affecting the process of fertilization and embryonic development and the function of trophoblast cells), maternal (decidualization), and maternal-to-fetal immune crosstalk. Undoubtedly, abnormalities in autophagy levels are associated with a variety of pregnancy complications, such as preeclampsia, fetal growth restriction, and preterm delivery which have been proven by human, animal, and in vitro experiments. The regulation of autophagy is expected to be a target for the treatment of these pregnancy complications. This article reviews the research on autophagy, especially about its physiological and pathological regulation during pregnancy.


Assuntos
Autofagia/fisiologia , Pré-Eclâmpsia/patologia , Trofoblastos/fisiologia , Animais , Desenvolvimento Embrionário , Feminino , Retardo do Crescimento Fetal/patologia , Humanos , Gravidez , Nascimento Prematuro
18.
PLoS One ; 15(4): e0230638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271787

RESUMO

BACKGROUND: Preeclampsia refers to the new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman. Pregnant women with preeclampsia are at an increased risk of adverse maternal, fetal and neonatal complications. The objective of the study is, therefore, to determine the maternal and perinatal outcome of preeclampsia without severity feature among women managed at a tertiary referral hospital in urban Ethiopia. METHODS: A hospital-based prospective observational study was conducted to evaluate the maternal and perinatal outcome of pregnant women who were on expectant management with the diagnosis of preeclampsia without severe feature at a referral hospital in urban Ethiopia from August 2018 to January 2019. RESULTS: There were a total of 5400 deliveries during the study period, among which 164 (3%) women were diagnosed with preeclampsia without severe features. Fifty-one (31.1%) patients with preeclampsia without severe features presented at a gestational age between 28 to 33 weeks plus six days, while 113 (68.9%) presented at a gestational age between 34 weeks to 36 weeks. Fifty-two (31.7%) women had maternal complication of which, 32 (19.5%) progressed to preeclampsia with severe feature Those patients with early onset of preeclampsia without severe feature were 5.22 and 25.9 times more likely to develop maternal and perinatal complication respectively compared to late-onset after 34 weeks with P-value of <0.0001, (95% CI 2.01-13.6) and <0.0001(95% CI 5.75-115.6) respectively. CONCLUSION: In a setting where home-based self-care is poor expectant outpatient management of preeclampsia without severe features with a once per week visit is not adequate. It's associated with an increased risk of maternal and perinatal morbidity and mortality. Our findings call for special consideration and close surveillance of those women with early-onset diseases.


Assuntos
Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/terapia , Resultado da Gravidez/epidemiologia , Adulto , Parto Obstétrico/efeitos adversos , Parto Obstétrico/métodos , Parto Obstétrico/mortalidade , Parto Obstétrico/estatística & dados numéricos , Etiópia/epidemiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Assistência Perinatal/organização & administração , Assistência Perinatal/normas , Pré-Eclâmpsia/patologia , Gravidez , Índice de Gravidade de Doença , Centros de Atenção Terciária , Resultado do Tratamento , População Urbana/estatística & dados numéricos , Adulto Jovem
19.
Sci Rep ; 10(1): 3956, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127613

RESUMO

Women with preeclampsia (PE) form a vulnerable group for vitamin D3 deficiency. Reabsorption of vitamin D3 occurs in the proximal tubule after being endocytosed in combination with DBP (vitamin D binding protein) by the megalin/cubilin receptor. Because proteinuria promotes tubule injury and dysfunction, we hypothesized that the proteinuria present in PE could promote the loss of these components into the urine. Twenty preeclamptic patients and ten normal pregnant women with a gestational age greater than 20 weeks composed three groups: NC, normotensive control pregnant patients; PE, non-proteinuric preeclamptic patients; and PPE, preeclamptic patients with proteinuria. When proteinuria was absent, preeclampsia was diagnosed accordingly to the American College of Obstetricians and Gynecologists' (ACOG) guideline. The presence of 24-hour proteinuria equal to or greater than 300 mg was considered to form the PPE group. Urinary cubilin, megalin, and DBP were measured by ELISA and normalized by urinary creatinine. Regarding gestational age, there was no difference between the groups. NC group had arterial pressure within normal values, whereas PE and PPE groups had a significant increase (p < 0.01). As expected, PPE group presented elevated ACR (p < 0.05), accompanied by large amounts of cubilin and DBP in the urine (p < 0.05 vs. NC and PE). No difference was found in urinary megalin. PPE patients showed more chance of shedding cubilin into the urine compared to non-proteinuric patients (odds ratio 12.7 (1.2-136.3). In conclusion, this study further tightens the relationship between PE and vitamin D3 deficiency, since proteinuria present in PE induces the loss of molecules responsible for renal tubular vitamin D3 reabsorption for subsequent activation. Combined with other factors, the proteinuria may intensify vitamin D3 deficiency in PE.


Assuntos
Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/urina , Receptores de Superfície Celular/metabolismo , Proteína de Ligação a Vitamina D/urina , Adolescente , Adulto , Feminino , Idade Gestacional , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Razão de Chances , Gravidez , Adulto Jovem
20.
Hum Cell ; 33(3): 512-520, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32130677

RESUMO

Pre-eclampsia (PE) is a disorder of pregnancy characterized by proteinuria and high blood pressure, affecting 2-8% of pregnancies worldwide. Previous studies have shown that PE is closely associated with trophoblast cell dysfunction. Here, we investigated the role of tissue factor pathway inhibitor-2 (TFPI-2) in regulating the biological processes of trophoblast cells. The TFPI-2 levels in plasma samples and placental tissues were tested by ELISA, immunohistochemistry, qRT-PCR, and western blot. HTR8/Svneo cell line was used to simulate the primary trophoblast cells and H/R culture was applied to mimic the oxidative stress state of PE. MTT assay, Annexin V/propidium iodide (PI) apoptosis assay, and transwell assay were used to determine the cell proliferation, apoptosis, and invasion. The expression levels of matrix metalloproteinases (MMPs) were evaluated by western blot. The expression of TFPI-2 was remarkably up-regulated in both the serum and placenta of PE patients. Hypoxia/reoxygenation increased the expression of TFPI-2 in HTR-8/SVneo cell line. TFPI-2 promoted that cell proliferation and inhibited the cell apoptosis of HTR8/SVneo cells in H/R condition. In addition, downregulation of TFPI-2 increased the cell invasion and the expression of MMP2 and MMP9. This study reveals that TFPI-2 plays a crucial role in monitoring the biological function of trophoblast cells, which might provide theoretical basis and therapeutic targets for the treatment of PE.


Assuntos
Proliferação de Células/genética , Glicoproteínas/fisiologia , Pré-Eclâmpsia/patologia , Trofoblastos/patologia , Células Cultivadas , Feminino , Expressão Gênica/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Terapia de Alvo Molecular , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/terapia , Gravidez , Regulação para Cima/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...