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AIM: To evaluate the relationship between long-term antenatal magnesium sulfate (MgSO4 ) administration and neonatal bone mineralization. METHODS: Infants born at 28-33 weeks of gestation (n = 163) were divided into three groups: long-term Mg administration group (infants received antenatal MgSO4 for ≥40 days), short-term Mg administration group (infants received antenatal MgSO4 for <40 days), and non-Mg group. Serum calcium, phosphorus, Mg, and alkaline phosphatase were measured weekly up to 1 month of age, and the bone speed of sound (SOS) values were measured using quantitative ultrasound (QUS) at 1 week and 1 month after birth. RESULTS: In the long-term Mg administration group, the serum calcium values were significantly lower, and the serum phosphorus, Mg, and alkaline phosphatase values were significantly higher than those in the non-Mg group at birth. Although these biochemical differences disappeared around the age of 2 weeks, the SOS values of the long-term Mg administration group were significantly lower than those of the non-Mg group both at 1 week and 1 month after birth (p = 0.02 and <0.001, respectively). When less than 10th percentile of SOS values at 1 month after birth in the non-Mg group was defined as poor bone mineralization, the cut-off value for the duration of antenatal MgSO4 administration was 67 days. CONCLUSIONS: Long-term antenatal MgSO4 administration affects bone mineralization during the early neonatal period, but the clinically acceptable duration of the administration based on its effects of bone mineralization assessed with QUS might be longer than a few weeks.
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Recien Nacido Prematuro , Sulfato de Magnesio , Lactante , Recién Nacido , Femenino , Embarazo , Humanos , Sulfato de Magnesio/farmacología , Calcificación Fisiológica , Fosfatasa Alcalina , Calcio , FósforoRESUMEN
Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival. Cells exhibit three main mechanisms against the accumulation of aggregates: protein refolding by upregulation of chaperones, reduction of protein overload by translational inhibition, and protein degradation by the ubiquitin-proteasome and autophagy-lysosome systems. Deletion of autophagy-related genes reportedly contributes to intracellular protein aggregation in vivo. Some proteins recognized in aggregates in preeclamptic placentas include those involved in neurodegenerative diseases. As aggregates are derived both intracellularly and extracellularly, special endocytosis for extracellular aggregates also employs the autophagy machinery. In this review, we discuss how the deficiency of aggrephagy and/or macroautophagy leads to poor placentation, resulting in preeclampsia or fetal growth restriction.
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Macroautofagia , Placenta/fisiopatología , Preeclampsia/fisiopatología , Animales , Femenino , Humanos , Lisosomas/metabolismo , Placenta/metabolismo , Preeclampsia/etiología , Preeclampsia/metabolismo , Embarazo , Agregación Patológica de ProteínasRESUMEN
Hypertensive disorders of pregnancy, including preeclampsia, directly affect maternal and perinatal morbidity and mortality. As the pathophysiology of preeclampsia is multi-factorial and has been studied using different approaches, we have demonstrated that impaired autophagy is an intertwined risk factor for preeclampsia. This concept has been verified in both in vitro and in vivo experiments. Autophagy is primarily involved in maintaining cellular homeostasis, and in immune regulation, longevity, cytokines secretion and a variety of other biological functions. Here, we review the role of autophagy in normal embryogenesis and placentation. Once placental autophagy is impaired by metabolic stress such as hypoxia, endoplasmic reticulum stress or starvation, placental development could be disrupted, resulting in functional maladaptations at the maternal-fetal interface. These malfunctions may result in fetal growth restriction or preeclampsia.
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Placental homeostasis is directly linked to fetal well-being and normal fetal growth. Placentas are sensitive to various environmental stressors, including hypoxia, endoplasmic reticulum stress, and oxidative stress. Once placental homeostasis is disrupted, the placenta may rebel against the mother and fetus. Autophagy is an evolutionally conservative mechanism for the maintenance of cellular and organic homeostasis. Evidence suggests that autophagy plays a crucial role throughout pregnancy, including fertilization, placentation, and delivery in human and mouse models. This study reviews the available literature discussing the role of autophagy in preeclampsia.
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Placenta/fisiopatología , Preeclampsia/fisiopatología , Autofagia , Estrés del Retículo Endoplásmico , Femenino , Homeostasis , Humanos , Estrés Oxidativo , Placenta/metabolismo , Preeclampsia/metabolismo , Embarazo , Transducción de SeñalRESUMEN
Hypertensive disorder of pregnancy (HDP) is a serious pregnancy complication that is life threatening to both the mother and fetus. Understanding HDP pathophysiology is important for developing medical treatments. This study demonstrates the involvement of autophagy deficiency in adverse maternal and fetal outcomes using trophoblast-specific autophagy related (Atg)7, an autophagy-related protein, knockout mice. Atg7 conditional knockout (cKO) placentas were significantly smaller than controls in the spongiotrophoblast layer but not the labyrinth layer, which significantly elevated blood pressure in dams. A marker of autophagy deficiency, sequestosome 1/p62, was accumulated in giant trophoblast cells and in the spongiotrophoblast layer, accompanying increased apoptosis. However, neither proteinuria in dams nor fetal growth restriction was observed. Regarding trophoblast function, the number of trophoblasts migrating into the maternal decidua was significantly reduced, and the wall/lumen ratio of the spiral arteries was significantly increased in cKO placentas, suggesting shallow trophoblast invasion and inadequate vascular remodeling. The relative expression of placental growth factor mRNA was significantly decreased in cKO placentas compared with the control, likely causing poor placentation; however, other factors were unchanged in cKO placentas. This is the first report of autophagy deficiency leading to impaired placentation complicated by maternal HDP attributable to trophoblast dysfunction, and it suggests that placental autophagy is required for normal placentation.
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Proteína 7 Relacionada con la Autofagia/fisiología , Autofagia , Retardo del Crecimiento Fetal/etiología , Hipertensión Inducida en el Embarazo/etiología , Placenta/fisiopatología , Preeclampsia/fisiopatología , Trofoblastos/patología , Animales , Femenino , Retardo del Crecimiento Fetal/patología , Hipertensión Inducida en el Embarazo/patología , Ratones , Ratones Noqueados , Embarazo , Proteinuria , Trofoblastos/metabolismoRESUMEN
Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy. This role includes supporting extravillous trophoblasts (EVTs) that invade the decidua (endometrium) until the first third of uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions in early pregnancy. In addition, autophagy inhibition has been linked to poor placentation-a feature of preeclamptic placentas-in a placenta-specific autophagy knockout mouse model. Studies of autophagy in human placentas have revealed controversial results, especially with regard to preeclampsia and gestational diabetes mellitus (GDM). Without precise estimation of autophagy flux, wrong interpretation would lead to fixed tissues. This paper presents a review of the role of autophagy in pregnancy and elaborates on the interpretation of autophagy in human placental tissues.
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Autofagia , Animales , Autofagia/genética , Femenino , Humanos , Modelos Biológicos , Placentación , Embarazo , Complicaciones del Embarazo/patología , ReproducciónRESUMEN
Autophagy is a well-conserved mechanism in cells from yeast to mammals, and autophagy maintains homeostasis against stress. The role of autophagy was originally shown to be a mechanism of energy production under starvation. In fact, multiple lines of evidence reveal that autophagy has numerous functions, such as protection from stress, energy regulation, immune regulation, differentiation, proliferation, and cell death. In the field of reproduction, the role of autophagy in implantation, embryogenesis, placentation, and delivery has become clearer. In addition, recent study has elucidated that the placenta has the ability to protect extraplacental cells from virus infection by activating autophagy. During resent research into autophagy, several issues have occurred in the interpretation of the autophagy status. In this review, we discuss the relation between autophagy and reproductive events, and show the importance of autophagy for placentation and pre-eclampsia.
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Autofagia/fisiología , Implantación del Embrión/fisiología , Desarrollo Embrionario/fisiología , Oogénesis/fisiología , Placentación/fisiología , Preeclampsia/fisiopatología , Animales , Femenino , Humanos , EmbarazoRESUMEN
Gain of methylation (GOM) at the H19-differentially methylated region (H19-DMR) is one of several causative alterations in Beckwith-Wiedemann syndrome (BWS), an imprinting-related disorder. In most patients with epigenetic changes at H19-DMR, the timing of and mechanism mediating GOM is unknown. To clarify this, we analyzed methylation at the imprinting control regions of somatic tissues and the placenta from two unrelated, naturally conceived patients with sporadic BWS. Maternal H19-DMR was abnormally and variably hypermethylated in both patients, indicating epigenetic mosaicism. Aberrant methylation levels were consistently lower in placenta than in blood and skin. Mosaic and discordant methylation strongly suggested that aberrant hypermethylation occurred after implantation, when genome-wide de novo methylation normally occurs. We expect aberrant de novo hypermethylation of H19-DMR happens to a greater extent in embryos than in placentas, as this is normally the case for de novo methylation. In addition, of 16 primary imprinted DMRs analyzed, only H19-DMR was aberrantly methylated, except for NNAT DMR in the placental chorangioma of Patient 2. To our knowledge, these are the first data suggesting when GOM of H19-DMR occurs.
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Síndrome de Beckwith-Wiedemann/genética , Metilación de ADN , Placenta/metabolismo , ARN no Traducido/genética , Alelos , Femenino , Impresión Genómica , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Embarazo , ARN Largo no CodificanteRESUMEN
A pregnant woman was diagnosed with acute promyelocytic leukemia at 38 weeks of gestation. Induction of labor was successful, and the patient delivered a healthy male baby. Soon after delivery, she was treated with chemotherapy using all-trans-retinoic acid (ATRA). The number of white blood cells was increased on the fifth postpartum day and retinoic acid syndrome (RAS) was considered a concern. On the sixth postpartum day, remission induction chemotherapy with idarubicin and cytosine arabinoside was started. On the seventh postpartum day, massive uterine bleeding of more than 1300 mL suddenly occurred. As administration of cytotoxic agents may induce disseminated intravascular coagulation, we should take care to avoid uterine bleeding after chemotherapy in acute promyelocytic leukemia cases treated soon after delivery.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/complicaciones , Hemorragia Posparto/etiología , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Adulto , Citarabina/uso terapéutico , Femenino , Humanos , Idarrubicina/uso terapéutico , Quimioterapia de Inducción , Leucemia Promielocítica Aguda/tratamiento farmacológico , Embarazo , Tretinoina/uso terapéuticoRESUMEN
Beckwith-Wiedemann syndrome (BWS) is a common overgrowth syndrome that involves abdominal wall defects, macroglossia, and gigantism. It is sometimes complicated by placental tumor and polyhydramnios. We report a case of BWS, prenatally diagnosed with ultrasonography. A large and well-circumscribed tumor also existed on the fetal surface of the placenta, which was histologically diagnosed as chorangioma after delivery. Polyhydramnios was obvious and the fetal heart enlarged progressively during pregnancy. Because the biophysical profiling score dropped to 4 points at 33 weeks of gestation, we carried out cesarean section. By epigenetic analysis, H19-differentially methylated region hypermethylation was observed in the placental tumor, normal placental tissue, and cord blood mononuclear cells. This is the first report of BWS with placental tumor due to H19-differentially methylated region hypermethylation.
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Síndrome de Beckwith-Wiedemann/genética , Metilación de ADN , Hemangioma/genética , Placenta/diagnóstico por imagen , Síndrome de Beckwith-Wiedemann/diagnóstico por imagen , Síndrome de Beckwith-Wiedemann/patología , Femenino , Hemangioma/diagnóstico por imagen , Hemangioma/patología , Humanos , Placenta/patología , Embarazo , UltrasonografíaRESUMEN
Cytotrophoblasts differentiate in two directions during early placentation: syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). STBs face maternal immune cells in placentas, and EVTs, which invade the decidua and uterine myometrium, face the cells in the uterus. This situation, in which trophoblasts come into contact with maternal immune cells, is known as the maternal-fetal interface. Despite fetuses and fetus-derived trophoblast cells being of the semi-allogeneic conceptus, fetuses and placentas are not rejected by the maternal immune system because of maternal-fetal tolerance. The acquired tolerance develops during normal placentation, resulting in normal fetal development in humans. In this review, we introduce placental development from the viewpoint of molecular biology. In addition, we discuss how the disruption of placental development could lead to complications in pregnancy, such as hypertensive disorder of pregnancy, fetal growth restriction, or miscarriage.
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Decidua/inmunología , Células Gigantes/inmunología , Placenta/inmunología , Embarazo/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autofagia , Femenino , Histocompatibilidad Materno-Fetal , Humanos , Tolerancia InmunológicaRESUMEN
Nanoparticles are widely used in commodities, and pregnant women are inevitably exposed to these particles. The placenta protects the growing fetus from foreign or toxic materials, and provides energy and oxygen. Here we report that autophagy, a cellular mechanism to maintain homeostasis, engulfs platinum nanoparticles (nPt) to reduce their cytotoxicity in trophoblasts. Autophagy was activated by nPt in extravillous trophoblast (EVT) cell lines, and EVT functions, such as invasion and vascular remodeling, and proliferation were inhibited by nPt. These inhibitory effects by nPt were augmented in autophagy-deficient cells. Regarding the dynamic state of nPt, analysis using ICP-MS demonstrated a higher accumulation of nPt in the autophagosome-rich than the cytoplasmic fraction in autophagy-normal cells. Meanwhile, there were more nPt in the nuclei of autophagy-deficient cells, resulting in greater DNA damage at a lower concentration of nPt. Thus, we found a new protective mechanism against the cytotoxicity of nPt in human trophoblasts.
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Proteínas Relacionadas con la Autofagia/metabolismo , Platino (Metal)/toxicidad , Trofoblastos/citología , Remodelación Vascular/efectos de los fármacos , Autofagia , Proteínas Relacionadas con la Autofagia/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Citoplasma/genética , Citoplasma/metabolismo , Femenino , Humanos , Nanopartículas del Metal/toxicidad , Tamaño de la Partícula , Embarazo , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismoRESUMEN
Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.
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Autofagia , Estrés del Retículo Endoplásmico , Lisosomas/patología , Preeclampsia/patología , Trofoblastos/patología , Adulto , Biomarcadores/sangre , Biomarcadores/metabolismo , Línea Celular , Medios de Cultivo/metabolismo , Exocitosis , Femenino , Humanos , Proteínas de Membrana de los Lisosomas/sangre , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/metabolismo , Placentación , Preeclampsia/sangre , Preeclampsia/diagnóstico , Embarazo , Cultivo Primario de Células , Trofoblastos/citología , beta-Galactosidasa/sangre , beta-Galactosidasa/metabolismoRESUMEN
Recent advances in nanotechnology have led to the development of nanoparticles with innovative functions in various fields. However, the biological effects of nanoparticles-particularly those on the fetus-need to be investigated in detail, because several previous studies have shown that various nanoparticles induce pregnancy complications in mice. In this regard, our previous findings in mice suggested that the increase in peripheral neutrophil count induced by treatment with silica nanoparticles with a diameter of 70 nm (nSP70) may play a role in the associated pregnancy complications. Therefore, here, we sought to define the role of neutrophils in nSP70-induced pregnancy complications. The peripheral neutrophil count in pregnant BALB/c mice at 24 h after treatment with nSP70 was significantly higher than in saline-treated mice. In addition, maternal body weight, uterine weight, and the number of fetuses in nSP70-treated mice pretreated with anti-antibodies, which deplete neutrophils, were significantly lower than those in nSP70-treated mice pretreated with phosphate-buffered saline or isotype-matched control antibodies. Histology revealed that neutrophil depletion increased nSP70-induced placental damage from the decidua through the spongiotrophoblast layer and narrowed spiral arteries in the placentae. In addition, depletion of neutrophils augmented nSP70-induced cytotoxicity to fetal vessels, which were covered with endothelium. The rate of apoptotic cell death was significantly higher in the placentae of anti-nSP70-treated mice than in those from mice pretreated with isotype-matched control antibodies. Therefore, impairment of placental vessels and apoptotic cell death due to nSP70 exposure is exacerbated in the placentae of nSP70-treated mice pretreated with anti-antibodies. Depletion of neutrophils worsens nSP70-induced pregnancy complications in mice; this exacerbation was due to enhanced impairment of placental vessels and increased apoptotic cell death in maternal placentae. Our results provide basic information regarding the mechanism underlying silica-nanoparticle-induced pregnancy complications.
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Nanopartículas del Metal/efectos adversos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Placenta/metabolismo , Placenta/patología , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/metabolismo , Dióxido de Silicio/efectos adversos , Animales , Apoptosis , Biomarcadores , Modelos Animales de Enfermedad , Femenino , Ratones , Placenta/irrigación sanguínea , Embarazo , Complicaciones del Embarazo/patologíaRESUMEN
Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis against stress. This process has two main functions: producing energy and quality control of intracellular proteins. During early pregnancy, extravillous trophoblasts (EVTs) invade the uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions. Autophagy activation is observed in EVTs under these conditions, suggesting that EVTs use autophagy for adjusting to such harsh conditions. On the other hand, soluble endoglin, which is increased in sera in preeclamptic cases, inhibits autophagy in vitro, resulting in suppression of EVT functions, invasion and vascular remodeling. In addition, p62/SQSTM1, a substrate degraded by autophagy, accumulates in EVTs in preeclamptic placental biopsy samples, exhibiting impaired autophagy in vivo. There are, however, some opposing reports in which autophagy activation, an increase of autophagy vacuoles or LC3 dots, was more frequently observed in preeclamptic or FGR placentas than in normal pregnancy. Thus, changes in autophagy status are seen in preeclamptic placentas, but the mechanism by which autophagy modulates biological changes in the placentas is still unknown. Recently, there is increasing evidence that autophagy is involved in maintaining pregnancy. This review introduces the role of autophagy for maintaining pregnancy and its correlation with preeclampsia.