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1.
Placenta ; 99: 45-49, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32755724

RESUMO

Vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and possible induction of pregnancy complications, including miscarriage, fetal malformations, fetal growth restriction and/or stillbirth, are serious concerns for pregnant individuals with COVID-19. According to clinical information, the incidence of vertical transmission of SARS-CoV-2 is limited to date. However, even if a neonate tests negative for SARS-CoV-2, frequent abnormal findings, including fetal and maternal vascular malperfusion, have been reported in cases of COVID-19-positive mothers. Primary receptor of SARS-CoV-2 is estimated as angiotensin-converting enzyme 2 (ACE2). It is highly expressed in maternal-fetal interface cells, such as syncytiotrophoblasts, cytotrophoblasts, endothelial cells, and the vascular smooth muscle cells of primary and secondary villi. However other route of transplacental infection cannot be ruled out. Pathological examinations have demonstrated that syncytiotrophoblasts are often infected with SARS-CoV-2, but fetuses are not always infected. These findings suggest the presence of a placental barrier, even if it is not completely effective. As the frequency and molecular mechanisms of intrauterine vertical transmission of SARS-CoV-2 have not been determined to date, intensive clinical examinations by repeated ultrasound and fetal heart rate monitoring are strongly recommended for pregnant women infected with COVID-19. In addition, careful investigation of placental samples after delivery by both morphological and molecular methods is also strongly recommended.


Assuntos
Betacoronavirus , Infecções por Coronavirus/transmissão , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Placenta , Pneumonia Viral/transmissão , Complicações Infecciosas na Gravidez/virologia , Antígenos Virais/análise , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Feminino , Doenças Fetais/epidemiologia , Doenças Fetais/virologia , Humanos , Recém-Nascido , Troca Materno-Fetal , Pandemias , Peptidil Dipeptidase A/análise , Placenta/irrigação sanguínea , Placenta/enzimologia , Placenta/virologia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Trofoblastos/virologia
2.
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
3.
Pregnancy Hypertens ; 20: 108-110, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32278308

RESUMO

Endothelin-converting enzyme-1(ECE-1) is a key regulatory enzyme in the processing of endothelin-1 (ET-1). We quantified and localized ECE-1 in normal and preeclamptic placentas. Normal (n=6) and preeclamptic (n=6) placentas were serially sectioned for immunofluorescence (IF). Cell type specific markers identified endothelial, trophoblast, macrophage, smooth muscle, and fibroblast cells. Quantitative analyses were performed by western blot and ELISA. IF identified ECE-1 expression within the stroma and villous space. Cellular localization of ECE-1 was limited to endothelial membranes. There was significantly less ECE-1 in preeclamptic placentas, suggesting ECE-1 is important for proper regulation of ET-1 within the placenta.


Assuntos
Enzimas Conversoras de Endotelina/análise , Placenta/enzimologia , Pré-Eclâmpsia/enzimologia , Adulto , Biomarcadores/análise , Estudos de Casos e Controles , Vilosidades Coriônicas/enzimologia , Regulação para Baixo , Células Endoteliais/enzimologia , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Gravidez , Células Estromais/enzimologia
4.
Int J Mol Sci ; 21(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012940

RESUMO

Maternal overweight in pregnancy alters the metabolic environment and generates chronic low-grade inflammation. This affects fetal development and programs the offspring's health for developing cardiovascular and metabolic disease later in life. MME (membrane-metalloendopeptidase, neprilysin) cleaves various peptides regulating vascular tone. Endothelial cells express membrane-bound and soluble MME. In adults, the metabolic environment of overweight and obesity upregulates endothelial and circulating MME. We here hypothesized that maternal overweight increases MME in the feto-placental endothelium. We used primary feto-placental endothelial cells (fpEC) isolated from placentas after normal vs. overweight pregnancies and determined MME mRNA, protein, and release. Additionally, soluble cord blood MME was analyzed. The effect of oxygen and tumor necrosis factor α (TNFα) on MME protein in fpEC was investigated in vitro. Maternal overweight reduced MME mRNA (-39.9%, p < 0.05), protein (-42.5%, p = 0.02), and MME release from fpEC (-64.7%, p = 0.02). Both cellular and released MME protein negatively correlated with maternal pre-pregnancy BMI. Similarly, cord blood MME was negatively associated with pre-pregnancy BMI (r = -0.42, p = 0.02). However, hypoxia and TNFα, potential negative regulators of MME expression, did not affect MME protein. Reduction of MME protein in fpEC and in cord blood may alter the balance of vasoactive peptides. Our study highlights the fetal susceptibility to maternal metabolism and inflammatory state.


Assuntos
Regulação para Baixo , Células Endoteliais/enzimologia , Sangue Fetal/enzimologia , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Neprilisina/biossíntese , Obesidade Materna/enzimologia , Placenta/enzimologia , Adulto , Linhagem Celular , Células Endoteliais/patologia , Feminino , Humanos , Obesidade Materna/patologia , Placenta/patologia , Gravidez
5.
BMC Res Notes ; 12(1): 785, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783915

RESUMO

OBJECTIVE: NRK is a unique X chromosome-linked protein kinase expressed predominantly in placenta. The gene knockout causes placental overgrowth and delayed labor of Nrk-null fetuses from dams in mouse. To clarify unknown mechanisms behind the Nrk-null phenotypes, protein expression profiles were analyzed in the Nrk-null placenta using a high-performance two-dimensional electrophoresis methodology. RESULTS: Among around 1800 spots detected, we characterized a dozen protein spots whose expression levels were significantly altered in the Nrk-null placenta compared to wild-type. Analyzing these data sets is expected to reflect the difference physiologically in the presence or absence of NRK, facilitating the development of therapeutic strategies.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Placenta/enzimologia , Placenta/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteômica , Animais , Eletroforese em Gel Bidimensional , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Gravidez , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo
6.
Int J Mol Sci ; 20(24)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847104

RESUMO

Aldehyde dehydrogenase 3B2 (ALDH3B2) gene contains a premature termination codon, which can be skipped or suppressed resulting in full-length protein expression. Alternatively, the longest putative open reading frame starting with the second in-frame start codon would encode short isoform. No unequivocal evidence of ALDH3B2 expression in healthy human tissues is available. The aim of this study was to confirm its expression in human placenta characterized by the highest ALDH3B2 mRNA abundance. ALDH3B2 DNA and mRNA were sequenced. The expression was investigated using western blot. The identity of the protein was confirmed using mass spectrometry (MS). The predicted tertiary and quaternary structures, subcellular localization, and phosphorylation sites were assessed using bioinformatic analyses. All DNA and mRNA isolates contained the premature stop codon. In western blot analyses, bands corresponding to the mass of full-length protein were detected. MS analysis led to the identification of two unique peptides, one of which is encoded by the nucleotide sequence located upstream the second start codon. Bioinformatic analyses suggest cytoplasmic localization and several phosphorylation sites. Despite premature stop codon in DNA and mRNA sequences, full-length ALDH3B2 was found. It can be formed as a result of premature stop codon readthrough, complex phenomenon enabling stop codon circumvention.


Assuntos
Aldeído Oxirredutases , Códon sem Sentido , Regulação Enzimológica da Expressão Gênica , Placenta/enzimologia , Proteínas da Gravidez , Biossíntese de Proteínas , Aldeído Oxirredutases/biossíntese , Aldeído Oxirredutases/genética , Códon sem Sentido/genética , Códon sem Sentido/metabolismo , Feminino , Humanos , Espectrometria de Massas , Gravidez , Proteínas da Gravidez/biossíntese , Proteínas da Gravidez/genética
7.
Biochem J ; 476(21): 3313-3331, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31652308

RESUMO

Aromatase CYP19A1 catalyzes the synthesis of estrogens in endocrine, reproductive and central nervous systems. Higher levels of 17ß-estradiol (E2) are associated with malignancies and diseases of the breast, ovary and endometrium, while low E2 levels increase the risk for osteoporosis, cardiovascular diseases and cognitive disorders. E2, the transcriptional activator of the estrogen receptors, is also known to be involved in non-genomic signaling as a neurotransmitter/neuromodulator, with recent evidence for rapid estrogen synthesis (RES) within the synaptic terminal. Although regulation of brain aromatase activity by phosphorylation/dephosphorylation has been suggested, it remains obscure in the endocrine and reproductive systems. RES and overabundance of estrogens could stimulate the genomic and non-genomic signaling pathways, and genotoxic effects of estrogen metabolites. Here, by utilizing biochemical, cellular, mass spectrometric, and structural data we unequivocally demonstrate phosphorylation of human placental aromatase and regulation of its activity. We report that human aromatase has multiple phosphorylation sites, some of which are consistently detectable. Phosphorylation of the residue Y361 at the reductase-coupling interface significantly elevates aromatase activity. Other sites include the active site residue S478 and several at the membrane interface. We present the evidence that two histidine residues are phosphorylated. Furthermore, oxidation of two proline residues near the active site may have implications in regulation. Taken together, the results demonstrate that aromatase activity is regulated by phosphorylation and possibly other post-translational modifications. Protein level regulation of aromatase activity not only represents a paradigm shift in estrogen-mediated biology, it could also explain unresolved clinical questions such as aromatase inhibitor resistance.


Assuntos
Aromatase/metabolismo , Placenta/enzimologia , Motivos de Aminoácidos , Aromatase/química , Aromatase/genética , Estrogênios/metabolismo , Feminino , Humanos , Fosforilação , Placenta/metabolismo , Gravidez
8.
Oxid Med Cell Longev ; 2019: 2481592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662816

RESUMO

Maternal obesity is associated with placental oxidative stress. However, the mechanism underlying this association remains poorly understood. In the present study, a gilt obesity model was developed by exposure to different energy diets and used to investigate the role of NADPH oxidase 2 (Nox2) in the placenta. Specifically, 99 gilts (Guangdong Small-ear Spotted pig) at day 60 of gestation were randomly assigned to one of the following three treatments: low-energy group (L, DE = 11.50 MJ/kg), medium-energy group (M, DE = 12.41 MJ/kg), and high-energy group (H, DE = 13.42 MJ/kg), with 11 replicate pens per treatment and 3 gilts per pen. At the start of the study, maternal body weight and backfat thickness were not significantly different in the three treatments. After the study, data indicated that the H group had higher body weight and backfat thickness gain for gilts during gestation and lower piglet birth weight compared with the other two groups. Additionally, the H group showed glucolipid metabolic disorders and increased triglyceride and nonesterified fatty acid contents in the placenta of gilts. Compared with the L group, the H group exhibited lower mitochondrial biogenesis and increased oxidative damage in the placenta. Importantly, increased mRNA expression and protein abundance of Nox2 were observed for the first time in H group placentae. Furthermore, compared with the L group, the H group showed a decrease in the density of placental vessels and the protein levels of vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor A (VEGF-A), and phosphorylation of vascular endothelial growth factor receptor 2 (p-VEGFR2) as well as the immunostaining intensity of platelet endothelial cell adhesion molecule-1 (CD31). Our findings suggest that maternal high-energy diet-induced obesity increases placental oxidative stress and decreases placental angiogenesis possibly through the upregulation of Nox2.


Assuntos
Dieta , NADPH Oxidase 2/metabolismo , Neovascularização Fisiológica , Obesidade/patologia , Estresse Oxidativo , Placenta/irrigação sanguínea , Placenta/patologia , Regulação para Cima , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Alimentar , Feminino , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Neovascularização Fisiológica/genética , Obesidade/enzimologia , Biogênese de Organelas , Placenta/enzimologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos , Fator de von Willebrand/metabolismo
9.
Eur Rev Med Pharmacol Sci ; 23(15): 6404-6410, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378878

RESUMO

OBJECTIVE: The aim of this study was to investigate the expression of cyclooxygenase-2 (COX-2) in eclampsia patients, and to explore the correlation between COX-2 polymorphism and incidence of eclampsia. PATIENTS AND METHODS: From January 2016 to January 2018, a total of 280 pregnant women diagnosed in the Obstetrics and Gynecology Department of our hospital were selected for this study. All patients were divided into two groups, including normal pregnancy control group (n=120) and eclampsia group (n=160). The expression of COX-2 in placenta and umbilical cord tissues of eclampsia group and normal group was detected via Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blotting and immunohistochemical staining. The single-nucleotide polymorphisms (rs1526172, rs1245231 and rs2198532) in the promoter region of the COX-2 gene were typed via conformation difference gel electrophoresis. Whether the distribution frequency of COX-2 genotypes met Hardy-Weinberg equilibrium law was detected via the Chi-square test. Meanwhile, the correlation between COX-2 alleles and gene polymorphisms and the incidence of eclampsia was analyzed. RESULTS: The messenger ribonucleic acid (mRNA) and protein expression levels of COX-2 in the eclampsia group were significantly higher than those of the normal group (p<0.05). According to the analysis, three polymorphisms of COX-2 gene were all in line with Hardy-Weinberg equilibrium distribution (p>0.05). Gene association analysis revealed that only polymorphisms (rs1526172 and rs1245231) and alleles were correlated with the incidence of eclampsia (p<0.05). However, polymorphism rs2198532 and alleles were not correlated with the incidence of eclampsia (p>0.05). CONCLUSIONS: Rs1526172 and rs1245231 in the promoter region of COX-2 are correlated with the incidence of eclampsia, while rs2198532 has no correlation with eclampsia.


Assuntos
Ciclo-Oxigenase 2/genética , Eclampsia/diagnóstico , Eclampsia/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto , Ciclo-Oxigenase 2/metabolismo , Eclampsia/metabolismo , Feminino , Humanos , Placenta/enzimologia , Gravidez , Cordão Umbilical/enzimologia
10.
Metabolism ; 100: 153959, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31401027

RESUMO

BACKGROUND: A newborn's birth weight for gestational age provides important insights into his or her fetal growth and well-being. While the underlying mechanisms regulating fetal growth remain to be fully elucidated, the IGF axis plays an important role. Some components of this axis have been well-characterized in umbilical cord blood, but others have not yet been studied. We measured the proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and the established molecules IGF-I and -II in umbilical cord blood to better characterize the IGF axis in relation to birth weight and length. METHODS: We performed a case-control study of 180 neonates born at a tertiary teaching hospital in Boston. To maximize power, infants were recruited in a 1:3:1 ratio with 37 SGA, 111 AGA, and 37 LGA infants matched by gestational age, sex, and delivery mode. IGF-I, IGF-II, IGFBP-4, IGFBP-5, PAPP-A, and PAPP-A2 were measured in umbilical cord blood by ELISA. Associations between birth weight and birth length Z-scores and the Z-scores of the above molecules were analyzed using linear regression models and analysis of covariance. RESULTS: Birth weight and length Z-scores were positively associated with Z-scores of IGF-I, IGF-II, total IGFBP-4, and IGFBP-5, with IGF-I having the strongest association. Birth weight and length Z-scores were negatively associated with Z-scores of intact IGFBP-4, PAPP-A, and PAPP-A2 levels. CONCLUSIONS: We confirm previous findings of significant associations between the IGFs in cord blood and newborn size and for the first time show positive associations between cord blood total IGFBP-4 and -5 and birth weight and a negative association between intact IGFBP-4 and birth weight. We also show for the first time a reciprocal relationship between cord blood levels of PAPP-A and PAPP-A2 and newborn size. The implications of these findings need to be further examined in large longitudinal studies and likely have diagnostic and therapeutic potential.


Assuntos
Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Isoenzimas/metabolismo , Placenta/enzimologia , Proteína Plasmática A Associada à Gravidez/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Isoenzimas/química , Gravidez , Proteína Plasmática A Associada à Gravidez/química , Ligação Proteica , Proteólise
11.
Anal Bioanal Chem ; 411(26): 7005-7013, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440781

RESUMO

Estrogens are key factors in the development of the estrogen receptor-positive (ER+) breast cancer. Estrogens, estrone (E1), and estradiol (E2) production is achieved by aromatase, a cytochrome P450 enzyme that has androgens, androstenedione (AD), and testosterone (T) as substrates. Nowadays, third-generation aromatase inhibitors (AIs) are considered the gold-standard treatment for ER+ breast cancer in postmenopausal women as well as in premenopausal women with ovary ablation. Aromatase activity assessment still relies on radiometric assays that are expensive, hazardous, and non-environmentally friendly. Thus, in order to overcome these disadvantages, a new methodology was developed to evaluate aromatase activity, based on dispersive liquid-liquid microextraction (DLLME) followed by gas chromatography-mass spectrometry (GC-MS). The enzymatic reaction was carried out in human placental microsomes, using AD as substrate, and the anti-aromatase activity was measured by determining the conversion percentage of AD into E1 (ratio E1/AD) using isotopic analogues as internal standards. The method showed good linearity (r2 = 0.9908 for AD and 0.9944 for E1), high accuracy (more than 74% for AD and more than 66% for E1), high extraction efficiency, and good intra-day and inter-day precision (below 14%, 4 levels). In this work, the IC50 values of the third-generation AIs, anastrozole, letrozole, and exemestane, obtained from the radiometric assay are also compared, and similar IC50 values are described. This method is a good alternative to the current radiometric assay, being fast and sensitive with a good extraction efficiency, accuracy, and recovery. In addition, it may be applied for the evaluation of the anti-aromatase activity of new potential AIs. Graphical abstract.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Microssomos/enzimologia , Aromatase/análise , Ensaios Enzimáticos/métodos , Feminino , Humanos , Microextração em Fase Líquida/métodos , Placenta/enzimologia , Gravidez
12.
Adv Exp Med Biol ; 1155: 775-785, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468447

RESUMO

Thyroid hormones are key hormones involved in growth and development. Changes in their levels can cause embryonic brain developmental damage in the first trimester. Studies have shown that polybrominated diphenyl ethers (PBDEs) have developmental neurotoxicity as environmental pollutants, and exposure during pregnancy can cause irreversible brain damage in offspring, similar to the interference effects of thyroid hormones, but its mechanism has not yet been understood. Since the physiological environment for placental cells is highly hypoxic, in the current study, the human placenta-derived JEG cells were cultured at 1% oxygen, 4% carbon dioxide and 94% nitrogen, to reflect in vivo scenario, and the possible protection of taurine on BDE 209-mediated toxicity in JEG cells was studied. Our data showed that different concentrations of BDE 209 can have profound effects on cell viability and placental deiodinase 3 expression under hypoxic culture condition. Taurine was found to improve BDE 209-induced reductions in cell viability and altered gene and protein expressions of placental deiodinases. The results provide a reference for the establishment of early biomarkers and effective preventive measures.


Assuntos
Éteres Difenil Halogenados/efeitos adversos , Iodeto Peroxidase/metabolismo , Placenta/enzimologia , Taurina/farmacologia , Hipóxia Celular , Linhagem Celular , Feminino , Humanos , Placenta/citologia , Gravidez
13.
Toxicology ; 425: 152253, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31351905

RESUMO

Human placental 3ß-hydroxysteroid dehydrogenase/steroid Δ5, 4-isomerase 1 (HSD3B1), a high-affinity type I enzyme, uses pregnenolone to make progesterone, which is critical for maintenance of pregnancy. HSD3B1 is located in the mitochondrion and the smooth endoplasmic reticulum of placental cells and is encoded by HSD3B1 gene. HSD3B1 contains GATA and TEF-5 regulatory elements. Many endocrine disruptors, including phthalates, methoxychlor and its metabolite, organotins, and gossypol directly inhibit placental HSD3B1 thus blocking progesterone production. In this review, we discuss the placental HSD3B1, its gene regulation, biochemistry, subcellular location, and inhibitors from the environment.


Assuntos
Complexos Multienzimáticos/metabolismo , Placenta/enzimologia , Progesterona Redutase/metabolismo , Esteroide Isomerases/metabolismo , Poluentes Ambientais/efeitos adversos , Feminino , Regulação da Expressão Gênica , Humanos , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/química , Complexos Multienzimáticos/genética , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Progesterona Redutase/antagonistas & inibidores , Progesterona Redutase/química , Progesterona Redutase/genética , Esteroide Isomerases/antagonistas & inibidores , Esteroide Isomerases/química , Esteroide Isomerases/genética
14.
J Immunol ; 203(5): 1198-1207, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31315888

RESUMO

It is increasingly recognized that excessive glucocorticoids induce fetal intrauterine growth restriction (IUGR). Placental 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2), a glucocorticoid-catalyzing enzyme, prevents active glucocorticoids from maternal circulation into the fetus, thus protecting against IUGR. Previous studies demonstrated gestational LPS exposure caused fetal IUGR. The aim of the current study was to investigate the effects of LPS on 11ß-HSD2 in mice placentas and human placental trophoblasts. Pregnant ICR(CD-1) mice were i.p. injected with LPS (200 µg/kg) on gestational day 16. As expected, gestational LPS exposure downregulated 11ß-HSD2 in mice placentas. In vitro, LPS downregulated 11ß-HSD2 in human placental trophoblasts. Additional experiment showed that LPS, which activated NF-κB, suppressed rosiglitazone-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) in mice placentas and human placental trophoblasts. Moreover, NF-κB p65 knockdown and specific NF-κB inhibitor attenuated LPS-induced suppression of PPARγ nuclear translocation in human placental trophoblasts. In addition, NF-κB p65 knockdown attenuated LPS-induced downregulation of 11ß-HSD2 in human placental trophoblasts. Mechanically, LPS promoted physical interaction between NF-κB p65 and PPARγ in the cytoplasm and nucleus of placental trophoblasts. Finally, pretreatment with rosiglitazone, a PPARγ agonist, partially alleviated LPS-induced reduction of fetal weight and crown-rump length. Taken together, these results suggest that LPS downregulates 11ß-HSD2 through suppressing PPARγ in placental trophoblasts. Placental 11ß-HSD2 downregulation may contribute partially to LPS-induced fetal IUGR.


Assuntos
11-beta-Hidroxiesteroide Desidrogenases/genética , Lipopolissacarídeos/toxicidade , PPAR gama/antagonistas & inibidores , Placenta/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Animais , Células Cultivadas , Regulação para Baixo , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , PPAR gama/fisiologia , Placenta/enzimologia , Gravidez , Rosiglitazona/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/fisiologia , Trofoblastos/enzimologia
15.
Klin Lab Diagn ; 64(5): 260-264, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31185147

RESUMO

The activity of amino acid metabolism enzymes and the content of free amino acids in the placenta during physiological pregnancy and placental insufficiency (PI) were studied using spectrophotometric methods and ion-exchange chromatography. It was found that in PI placental activity of the studied enzymes: alanine-, cysteine-e, tyrosine-, glutamino- transferase, glutathione synthetase, glutamate dehydrogenase decreases at different periods of gestation. The opposite variations occur for aspartataminotranferase and glutaminase. Similar changes are detected for amino acids synthesized or used in the course of appropriate reactions: aspartic acid, glutamic acid, glutamine, alanine, cysteine, tyrosine, arginine. The correlation between enzyme activity and amino acid content was revealed. Different periods of pregnancy are characterized by varying degrees of change, especially expressed in the second trimester, characterized by the most intense growth and development of the fetus, and its increased needs for trophic material. The revealed changes obviously play a pathogenetic role in the formation and further development of PI.


Assuntos
Aminoácidos/metabolismo , Placenta/enzimologia , Complicações na Gravidez/enzimologia , Aspartato Aminotransferases/metabolismo , Feminino , Glutaminase/metabolismo , Humanos , Oxirredutases/metabolismo , Insuficiência Placentária/enzimologia , Gravidez
16.
Eur J Obstet Gynecol Reprod Biol ; 238: 78-85, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31121342

RESUMO

OBJECTIVE: Gestational diabetes mellitus is associated with increased oxidative stress. Oxidative stress may contribute to the risk for pregnancy pathologies associated with gestational diabetes mellitus. In this study we investigated the expression of placental nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant enzymes of gestational diabetes mellitus and healthy pregnant women and correlated them with the maternal and cord plasma as well as placental tissue oxidative stress parameters. STUDY DESIGN: A cross sectional study was carried out in a South Indian Tamil population. Forty healthy pregnant women and forty gestational diabetes mellitus patients in the gestational age of 32 ± 4weeks were recruited. Maternal plasma, cord plasma and placental oxidative stress parameters were measured. Placental expression of Nrf2, phospho Nrf2, catalase and superoxide dismutase 1(SOD1) were analyzed by western blotting and immunohistochemistry. RESULTS: Placental expression of Nrf2, catalase and SOD1 were found to be significantly higher in gestational diabetes mellitus. The maternal plasma, cord plasma and placental tissue oxidative stress parameters, total antioxidant status (TAS) levels were significantly lower; whereas MDA (malondialdehyde) and MDA/TAS levels were significantly higher in gestational diabetes mellitus. Placental Nrf2 expression correlated positively with the placental catalase expression and negatively with placental TAS levels in both groups. CONCLUSION: Maternal, fetal and placental oxidative stress was observed in gestational diabetes mellitus. The gestational diabetic placenta had an increased Nrf2 protein expression. The activated placental Nrf2/ antioxidant response element (ARE) pathway might have led to an increased expression of antioxidant enzymes SOD1 and catalase. This may be viewed as a protective mechanism in placenta from the further onslaught of oxidative stress.


Assuntos
Antioxidantes/metabolismo , Diabetes Gestacional/enzimologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Placenta/enzimologia , Adulto , Estudos de Casos e Controles , Catalase/metabolismo , Estudos Transversais , Diabetes Gestacional/sangue , Feminino , Sangue Fetal/metabolismo , Humanos , Gravidez , Superóxido Dismutase-1/metabolismo , Adulto Jovem
17.
Placenta ; 81: 9-17, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31138432

RESUMO

OBJECTIVE: Intrauterine growth restriction (IUGR) is a complication of pregnancy that has both short- and long-term sequelae for affected mothers and offspring. The pathophysiology of disease stems from poor nutrient and oxygen provision to the fetus, resulting in increased oxidative stress within the placenta. As the milieu within the local microenvironment alters macrophage differentiation, we hypothesized that macrophage plasticity may be altered in placentas associated with IUGR, and that macrophages would show hallmarks of lipid peroxidation including altered aldehyde metabolism. METHODS: In human placentas taken from normal pregnancies resulting in appropriate-for-gestational-age (AGA) newborns and placentas associated with IUGR, placental macrophages were evaluated by immunohistochemistry and shown in IUGR to resemble pro-inflammatory activated M1-type macrophages. To link oxidative stress to macrophages, the expression of aldehyde dehydrogenase (ALDHs) isozymes ALDH1, ALDH2, and ALDH3 was assessed. RESULTS: All three isozymes displayed preferential staining for distinct cellular populations within the term human placenta. ALDH1 and ALDH2 were strongly expressed in placental Hofbauer and decidual stromal cells. ALDH3, in contrast, was present in extravillous trophoblasts. Comparing AGA and IUGR-associated placentas, ALDH1 and ALDH2 trended to have greater expression in macrophage populations but lower expression in decidual cell populations in IUGR-associated placentas. ALDH3 had higher expression in IUGR-associated placentas but localized specifically to extravillous trophoblast populations. CONCLUSION: Therefore, we speculate that specific ALDH isozymes have cell-specific functions related to differentiation, inflammation, or oxidative stress responses that are altered in IUGR-associated term human placentas. This family of isozymes may be a novel method to identify human placentas affected by placental insufficiency/IUGR.


Assuntos
Aldeído Desidrogenase/metabolismo , Retardo do Crescimento Fetal/enzimologia , Macrófagos/metabolismo , Placenta/enzimologia , Adulto , Feminino , Retardo do Crescimento Fetal/imunologia , Humanos , Gravidez , Isoformas de Proteínas/metabolismo
18.
Reprod Domest Anim ; 54(7): 1010-1017, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066470

RESUMO

The objectives of this study were to determine the effects of acupuncture in dairy cows (Bos taurus) on caruncular matrix metalloproteinase type-2 (MMP2) at 0, 2 and 4 hr after calving. Acupuncture (n = 6) was applied at 0 and 2 hr after calving to 6 points that relax the cervix and stimulate uterine contractions. Controls (n = 9) were kept in a stanchion for 15 min without acupuncture. All of the cows in the study delivered their placenta in <4 hr. Formalin-fixed caruncles were paraffin-embedded and subjected to routine immunohistochemistry to determine MMP2 expression, which was scored by a single observer. Flash frozen caruncles were homogenized, and protein concentration was determined. MMP2 concentrations were calculated using commercial bovine ELISAs. MMP2 enzyme activity was determined using zymography. The mean value for each time point for each cow was used to calculate the mean ± SEM for each treatment group. MMP2 was predominantly localized to the epithelial and subepithelial stromal cells of the caruncles in both treatment groups. MMP2 immunoexpression was lower 4 hr after calving in the control cows (p = 0.012) but not in the acupuncture treated cows indicating that acupuncture treatment maintained MMP expression. MMP2 tissue concentration was lower 2 hr after calving in the control cows (p = 0.048) but not in the acupuncture treated cows. MMP2 enzyme activity decreased from 0 to 2 hr after calving in control cows (p = 0.046) but not in acupuncture treated cows. This study provides physiologic evidence for the effects of acupuncture on the bovine reproductive tract and substantiates the use of this treatment in cases of placental retention.


Assuntos
Terapia por Acupuntura/veterinária , Metaloproteinase 2 da Matriz/metabolismo , Período Pós-Parto/fisiologia , Animais , Bovinos , Feminino , Metaloproteinase 2 da Matriz/genética , Placenta/enzimologia , Gravidez , Distribuição Tecidual
19.
Diabetes Care ; 42(5): 964-971, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30833369

RESUMO

OBJECTIVE: Fetal excessive exposure to glucocorticoids may program cardiometabolic risk. Placental 11 ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) serves as a barrier to prevent fetal overexposure to maternal glucocorticoids. It has not been explored whether placental 11ß-HSD2 levels are associated with cardiometabolic health in postnatal life. RESEARCH DESIGN AND METHODS: In a prospective birth cohort study of 246 mother-infant pairs, we measured placental 11ß-HSD2 expression and maternal (32-35 weeks of gestation) and cord plasma cortisol concentrations. The primary outcomes were HOMA of insulin resistance (IR) and blood pressure (BP) in infants at age 1 year. Other outcomes included fasting insulin, HOMA ß-cell function, carotid intima-media thickness, weight z score, and skinfold thickness (triceps and subscapular) at age 1 year. RESULTS: Placental 11ß-HSD2 expression was negatively correlated with HOMA-IR (r = -0.17, P = 0.021) and fasting insulin (r = -0.18, P = 0.017) and marginally negatively correlated with systolic BP (r = -0.16, P = 0.057) but was not correlated with HOMA of ß-cell function, diastolic BP, carotid intima-media thickness, and skinfold thickness (all P > 0.1) in infants at age 1 year. Cord plasma cortisol was negatively correlated to skinfold thickness (r = -0.20, P = 0007) but was not correlated with other outcomes at age 1 year. Maternal plasma cortisol was positively correlated with maximal carotid intima-media thickness (r = 0.20, P = 0.03) but was not correlated with other outcomes. Adjusting for maternal and infant characteristics, the associations were similar. CONCLUSIONS: The study is the first to show that higher placental 11ß-HSD2 expression is associated with lower IR in infancy. Independent cohort studies are required to confirm this novel finding.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Biomarcadores/metabolismo , Doenças Cardiovasculares/diagnóstico , Saúde do Lactente , Doenças Metabólicas/diagnóstico , Placenta/metabolismo , Adulto , Biomarcadores/análise , Doenças Cardiovasculares/metabolismo , Espessura Intima-Media Carotídea , Desenvolvimento Infantil/fisiologia , Estudos de Coortes , Feminino , Indicadores Básicos de Saúde , Humanos , Hidrocortisona/sangue , Lactente , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/metabolismo , Resistência à Insulina/fisiologia , Masculino , Doenças Metabólicas/metabolismo , Placenta/enzimologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/metabolismo , Estudos Prospectivos
20.
Food Chem Toxicol ; 128: 46-53, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30922969

RESUMO

Human placental CYP19A1 catalyzes the estrogen synthesis from androgens. The enzyme is encoded by CYP19A1 gene located in chromosome 15q21. This enzyme is a monooxygenase in the smooth endoplasmic reticulum. The various promoters of the CYP19A1 gene determine its expression in different tissues and the distal promoter I.1 controls its expression in the placenta and retinoids can regulate the expression. Many food components and environmental chemicals inhibit CYP19A1 activity via different modes of action. These chemicals include gossypol, flavones, flavanones, chalconoids, resveratrol, and tobacco alkaloids derived from foods as well as phthalates, insecticides, fungicides, and biocides in the contaminated foods. The inhibition of placental CYP19A1 could impair pregnancy.


Assuntos
Inibidores da Aromatase/toxicidade , Aromatase/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Moduladores de Receptor Estrogênico/toxicidade , Análise de Alimentos , Placenta/efeitos dos fármacos , Aromatase/química , Aromatase/genética , Moduladores de Receptor Estrogênico/química , Feminino , Humanos , Placenta/enzimologia , Gravidez , Regiões Promotoras Genéticas/efeitos dos fármacos
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