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1.
Adv Exp Med Biol ; 1237: 61-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31302870

RESUMO

Transamniotic stem cell therapy (TRASCET) is a novel prenatal therapeutic alternative for the treatment of congenital anomalies. It is based upon the principle of augmenting the pre-existing biological role of select populations of fetal stem cells for targeted therapeutic benefit. For example, amniotic fluid-derived mesenchymal stem cells (afMSCs) play an integral role in fetal tissue repair, validating the use of afMSCs in regenerative strategies. The simple intra-amniotic delivery of these cells in expanded numbers via TRASCET has been shown to promote the repair of and/or significantly ameliorate the effects associated with major congenital anomalies such as neural tube and abdominal wall defects. For example, TRASCET can induce partial or complete coverage of experimental spina bifida through the formation of a host-derived rudimentary neoskin, thus protecting the spinal cord from further damage secondary to amniotic fluid exposure. Furthermore, TRASCET can significantly reduce the bowel inflammation associated with gastroschisis, a common major abdominal wall defect. After intra-amniotic injection, donor stem cells home to the placenta and the fetal bone marrow in the spina bifida model, suggesting a role for hematogenous cell routing rather than direct defect seeding. Therefore, the expansion of TRASCET to congenital diseases without amniotic fluid exposure, such as congenital diaphragmatic hernia, as well as to maternal diseases, is currently under investigation in this emerging and evolving field of fetal stem cell therapy.


Assuntos
Âmnio/metabolismo , Doenças Fetais/metabolismo , Doenças Fetais/terapia , Transplante de Células-Tronco Mesenquimais , Líquido Amniótico/citologia , Feminino , Humanos , Células-Tronco Mesenquimais/citologia , Gravidez , Disrafismo Espinal/terapia
2.
Food Chem Toxicol ; 129: 312-327, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31063835

RESUMO

Among epigenetic mechanisms, DNA methylation has been widely studied with respect to many environmental factors. Smoking is a common factor which affects both global and gene-specific DNA methylation. It is supported that smoking directly affects DNA methylation, and these effects contribute to the development and progression of various diseases, such as cancer, lung and cardiovascular diseases and male infertility. In addition, prenatal smoking influences the normal development of the fetus via DNA methylation changes. The DNA methylation profile and its smoking-induced alterations helps to distinguish current from former smokers and non-smokers and can be used to predict the risk for the development of a disease. This review summarizes the DNA methylation changes induced by smoking, their correlation with smoking behavior and their association with various diseases and fetus development.


Assuntos
Metilação de DNA , Desenvolvimento Fetal , Doenças Fetais/metabolismo , Exposição Materna , Fumar/metabolismo , Feminino , Expressão Gênica , Humanos , Gravidez
3.
PLoS One ; 14(4): e0214951, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943260

RESUMO

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure.


Assuntos
Lesões Encefálicas , Doenças Fetais , Inflamação , Lipopolissacarídeos/toxicidade , Doenças Placentárias , Placenta , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Feminino , Doenças Fetais/induzido quimicamente , Doenças Fetais/metabolismo , Doenças Fetais/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Placenta/lesões , Placenta/metabolismo , Placenta/fisiologia , Doenças Placentárias/induzido quimicamente , Doenças Placentárias/metabolismo , Doenças Placentárias/patologia , Gravidez
4.
Am J Clin Nutr ; 109(3): 674-683, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30848279

RESUMO

BACKGROUND: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. OBJECTIVES: This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. METHODS: We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings). RESULTS: The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk. CONCLUSIONS: The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Doenças Fetais/enzimologia , Fígado/metabolismo , Defeitos do Tubo Neural/enzimologia , Vitamina B 12/metabolismo , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Estudos de Casos e Controles , Feminino , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Doenças Fetais/genética , Doenças Fetais/metabolismo , Ácido Fólico/análise , Ácido Fólico/metabolismo , Idade Gestacional , Humanos , Fígado/química , Fígado/embriologia , Fígado/enzimologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Gravidez , Vitamina B 12/análise
5.
Gen Physiol Biophys ; 38(1): 91-100, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30657461

RESUMO

Pregnant Wistar rats were exposed to ethanol under chronic conditions using the gavage method to assess the complement activation and effects of oxidative stress on fetus lymphoid organs and liver. The effects were monitored on both the 10th (G10) and the 30th (G30) day of the offspring of alcoholic mother rats. Maternal ethanol caused a significant decrease in the glutathione level, whereas malondialdehyde and carbonyl levels increased in the liver and lymphoid tissues. Na+,K+-ATPase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase activities in these organs also decreased. Furthermore, complement C3 and C5 activities of G10 and G30 groups were significantly higher compared with those of the control group. In conclusion, the results demonstrated that alcohol was capable of triggering damage to the membranes of the liver and lymphoid tissues of G10 and G30 groups, and C3 and C5 contributed to the development of alcohol-induced fetal tissue injury.


Assuntos
Animais Recém-Nascidos/imunologia , Animais Recém-Nascidos/metabolismo , Ativação do Complemento/efeitos dos fármacos , Etanol/farmacologia , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/metabolismo , Mães , Estresse Oxidativo , Animais , Antioxidantes , Etanol/efeitos adversos , Feminino , Doenças Fetais/induzido quimicamente , Doenças Fetais/imunologia , Doenças Fetais/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Tecido Linfoide/imunologia , Gravidez , Ratos , Ratos Wistar
6.
Medicine (Baltimore) ; 98(1): e13947, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30608428

RESUMO

BACKGROUND: Spinal anesthesia is the standard technique for elective cesarean section, but the incidence of maternal hypotension in this setting is reportedly about 80%, without any prophylactic management. Vasopressors are the most reliable method for counteracting the hypotension induced by spinal anesthesia. However, studies investigating the effects of vasopressors have yielded inconsistent and debatable results. Therefore, we plan to conduct a systematic review and network meta-analysis to identify the most effective vasopressor to prevent maternal hypotension, and to decrease fetal acidosis in women undergoing spinal anesthesia for elective cesarean section. METHODS: A systematic and comprehensive search to detect all the randomized controlled studies on vasopressors for the management of maternal hypotension during cesarean section under spinal anesthesia will be performed using information in the databases, MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar, beginning from their inception to October 2018. We will conduct a network meta-analysis to combine the direct and indirect comparisons of the vasopressors. We will use the surface under the cumulative ranking curve (SUCRA) values and rankograms to present the hierarchy of vasopressors. A comparison-adjusted funnel plot will be used to assess the presence of small-study effects. The quality of the studies included will be assessed using the risk of bias tool. All statistical analyses will be performed using Stata SE version 15.0. ETHICS AND DISSEMINATION: This systematic review and meta-analysis will be published in a peer-reviewed journal. Ethical approval and informed consent are not required, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care. TRIAL REGISTRATION NUMBER: The protocol for this review has been registered in the PROSPERO network (registration number: CRD42018111852).


Assuntos
Raquianestesia/efeitos adversos , Cesárea/efeitos adversos , Hipotensão/tratamento farmacológico , Vasoconstritores/uso terapêutico , Acidose/prevenção & controle , Feminino , Doenças Fetais/tratamento farmacológico , Doenças Fetais/metabolismo , Humanos , Hipotensão/induzido quimicamente , Metanálise em Rede , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Vasoconstritores/administração & dosagem
7.
J Perinat Med ; 47(2): 222-240, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30231013

RESUMO

Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.


Assuntos
Eritropoetina/análise , Morte Fetal/etiologia , Doenças Fetais , Hipóxia Fetal , Proteína Glial Fibrilar Ácida/análise , Cardiopatias , Natimorto , Troponina I/análise , Adulto , Amniocentese/métodos , Líquido Amniótico/metabolismo , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico , Causas de Morte , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/metabolismo , Hipóxia Fetal/complicações , Hipóxia Fetal/diagnóstico , Cardiopatias/complicações , Cardiopatias/diagnóstico , Humanos , Imuno-Histoquímica , Placenta/patologia , Placenta/fisiopatologia , Gravidez , Distribuição Aleatória , Estudos Retrospectivos , Estados Unidos
8.
Semin Pediatr Neurol ; 28: 17-28, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30522724

RESUMO

The human cerebral vasculature originates in the fourth week of gestation and continues to expand and diversify well into the first few years of postnatal life. A key feature of this growth is smooth muscle differentiation, whereby smooth muscle cells within cerebral arteries transform from migratory to proliferative to synthetic and finally to contractile phenotypes. These phenotypic transformations can be reversed by pathophysiological perturbations such as hypoxia, which causes loss of contractile capacity in immature cerebral arteries. In turn, loss of contractility affects all whole-brain cerebrovascular responses, including those involved in flow-metabolism coupling, vasodilatory responses to acute hypoxia and hypercapnia, cerebral autoregulation, and reactivity to activation of perivascular nerves. Future strategies to minimize cerebral injury following hypoxia-ischemic insults in the immature brain might benefit by targeting treatments to preserve and promote contractile differentiation in the fetal cerebrovasculature. This could potentially be achieved through inhibition of receptor tyrosine kinase-mediated growth factors, such as vascular endothelial growth factor and platelet-derived growth factor, which are mobilized by hypoxic and ischemic injury and which facilitate contractile dedifferentiation. Interruption of the effects of other vascular mitogens, such as endothelin and angiotensin-II, and even some miRNA species, also could be beneficial. Future experimental work that addresses these possibilities offers promise to improve current clinical management of neonates who have suffered and survived hypoxic, ischemic, asphyxic, or inflammatory cerebrovascular insults.


Assuntos
Artérias Cerebrais , Transtornos Cerebrovasculares , Doenças Fetais , Hipóxia Encefálica , Artérias Cerebrais/embriologia , Artérias Cerebrais/crescimento & desenvolvimento , Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/fisiopatologia , Doenças Fetais/metabolismo , Doenças Fetais/fisiopatologia , Humanos , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/fisiopatologia
9.
Semin Pediatr Neurol ; 28: 29-37, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30522725

RESUMO

The objective of this article is to understand the complex role of the central autonomic nervous system in normal and complicated fetal-neonatal transition and how autonomic nervous system dysfunction can lead to brain injury. The central autonomic nervous system supports coordinated fetal transitional cardiovascular, respiratory, and endocrine responses to provide safe transition of the fetus at delivery. Fetal and maternal medical and environmental exposures can disrupt normal maturation of the autonomic nervous system in utero, cause dysfunction, and complicate fetal-neonatal transition. Brain injury may both be caused by autonomic nervous system failure and contribute directly to autonomic nervous system dysfunction in the fetus and newborn. The central autonomic nervous system has multiple roles in supporting transition of the fetus. Future studies should aim to improve real-time monitoring of fetal autonomic nervous system function and in supporting typical autonomic nervous system development even under complicated conditions.


Assuntos
Doenças do Sistema Nervoso Autônomo , Sistema Nervoso Autônomo , Sistema Nervoso Central , Doenças Fetais , Doenças do Recém-Nascido , Sistema Nervoso Autônomo/crescimento & desenvolvimento , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/metabolismo , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Doenças Fetais/diagnóstico , Doenças Fetais/metabolismo , Doenças Fetais/fisiopatologia , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/metabolismo , Doenças do Recém-Nascido/fisiopatologia
10.
Pathol Res Pract ; 214(12): 1940-1951, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30377024

RESUMO

This literature review aims to address the main scientific findings on oxidative stress activity in different gestational disorders, as well as the function and application of melatonin in the treatment of fetal and neonatal changes. Oxidative stress has been associated with the etiopathogenesis of recurrent miscarriages, preeclampsia, intrauterine growth restriction, and stillbirth. Both, the exacerbated consumption of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and the increased synthesis of reactive oxygen species, such as superoxide, peroxynitrite, and hydrogen peroxide, induce phospholipid peroxidation and endothelial dysfunction, impaired invasion and death of trophoblast cells, impaired decidualization, and remodeling of maternal spiral arteries. It has been postulated that melatonin induces specific biochemical responses that regulate cell proliferation in fetuses, and that its antioxidant action promotes bioavailability of nitric oxide and, thus, placental perfusion and also fetal nutrition and oxygenation. Therefore, the therapeutic action of melatonin has been the subject of major studies that aim to minimize or prevent different injuries affecting this pediatric age group, such as intrauterine growth restriction, encephalopathy, chronic lung diseases, retinopathy of prematurity Conclusion: the results antioxidant and indicate that melatonin is an important therapy for the clinical treatment of these diseases.


Assuntos
Antioxidantes/uso terapêutico , Doenças Fetais/tratamento farmacológico , Melatonina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Feminino , Doenças Fetais/metabolismo , Humanos , Melatonina/farmacologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Espécies Reativas de Oxigênio/metabolismo
11.
Prenat Diagn ; 38(11): 876-882, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30094843

RESUMO

OBJECTIVE: The objective of the study was to perform maternal plasma metabolic fingerprinting to evaluate differences in plasma metabolites between healthy and Down syndrome (DS) pregnancies and to indicate novel non-invasive markers for DS prenatal diagnostics. METHODS: This was a case-control study of pregnancies between 15th and 18th gestational week. LC-MS-based metabolic fingerprinting of plasma samples was performed. RESULTS: Levels of five metabolites were significantly lower in the plasma of DS pregnancies. The majority of the statistically significant metabolites may be connected with fetal brain and central nervous system development (eg, fatty acid amides). According to the receiver operating characteristic (ROC), the combination of linoleamide and piperine has the highest diagnostic potential: area under the curve (AUC) = 0.878, sensitivity of 100%, and specificity of 73.3%. CONCLUSIONS: The study indicates disturbances in maternal metabolic pathways evoked by fetal DS. Novel potential maternal plasma metabolomic markers for non-invasive prenatal diagnostics of fetal DS are proposed.


Assuntos
Síndrome de Down , Doenças Fetais/metabolismo , Metaboloma , Plasma/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez
12.
Pediatr Res ; 84(6): 807-812, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895839

RESUMO

Fetal erythropoietin (EPO), in addition to regulating erythropoiesis, has also tissue-protective properties based on its anti-inflammatory, anti-apoptotic, antioxidant, and neurotrophic effects. Notably, EPO concentrations needed for tissue protection are 100-1000 times higher than concentrations needed for regulating erythropoiesis. This dual effect of EPO is based on EPO-receptor (EPO-R) isoforms, which differ structurally and functionally. We hypothesize in this Integrated Mechanism Review that during severe fetal hypoxia the observed, but poorly understood, marked increases of fetal plasma EPO concentrations occur to protect the brain, heart, and other vital fetal organs. We further hypothesize that the concurrent marked increases of EPO in the amniotic fluid during fetal hypoxia, occur to protect newborn infants from necrotizing enterocolitis. This review presents experimental and clinical evidence in support of these hypotheses and points out unknown or poorly understood functions of EPO in the fetus. If these novel hypotheses are correct, the importance of fetal EPO as an antenatal hypoxia biomarker will become apparent. It will also likely point the way to important diagnostic and therapeutic fetal and neonatal interventions.


Assuntos
Encéfalo/embriologia , Eritropoetina/biossíntese , Hipóxia , Líquido Amniótico/metabolismo , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Enterocolite Necrosante/metabolismo , Feminino , Sangue Fetal , Doenças Fetais/metabolismo , Hematopoese , Humanos , Recém-Nascido , Inflamação , Intestinos/patologia , Neuroproteção , Gravidez , Isoformas de Proteínas , Espécies Reativas de Oxigênio/metabolismo
13.
Cell Host Microbe ; 23(5): 672-685.e6, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29746837

RESUMO

Progress toward understanding Zika virus (ZIKV) pathogenesis is hindered by lack of immunocompetent small animal models, in part because ZIKV fails to effectively antagonize Stat2-dependent interferon (IFN) responses in mice. To address this limitation, we first passaged an African ZIKV strain (ZIKV-Dak-41525) through Rag1-/- mice to obtain a mouse-adapted virus (ZIKV-Dak-MA) that was more virulent than ZIKV-Dak-41525 in mice treated with an anti-Ifnar1 antibody. A G18R substitution in NS4B was the genetic basis for the increased replication, and resulted in decreased IFN-ß production, diminished IFN-stimulated gene expression, and the greater brain infection observed with ZIKV-Dak-MA. To generate a fully immunocompetent mouse model of ZIKV infection, human STAT2 was introduced into the mouse Stat2 locus (hSTAT2 KI). Subcutaneous inoculation of pregnant hSTAT2 KI mice with ZIKV-Dak-MA resulted in spread to the placenta and fetal brain. An immunocompetent mouse model of ZIKV infection may prove valuable for evaluating countermeasures to limit disease.


Assuntos
Camundongos/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Zika virus/patogenicidade , Animais , Encéfalo , Sobrevivência Celular , Modelos Animais de Doenças , Feminino , Doenças Fetais/metabolismo , Doenças Fetais/virologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imunidade , Transmissão Vertical de Doença Infecciosa , Interferon beta/metabolismo , Interferons/metabolismo , Camundongos/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Placenta/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/virologia , RNA Helicases/genética , Receptor de Interferon alfa e beta , Fator de Transcrição STAT2/metabolismo , Serina Endopeptidases/genética , Proteínas não Estruturais Virais/genética , Zika virus/genética , Infecção por Zika virus/virologia
14.
Am J Physiol Regul Integr Comp Physiol ; 315(3): R500-R508, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29791204

RESUMO

Fetal anemia causes rapid and profound changes in cardiac structure and function, stimulating proliferation of the cardiac myocytes, expansion of the coronary vascular tree, and impairing early contraction and relaxation. Although hypoxia-inducible factor-1α is sure to play a role, adenosine, a metabolic byproduct that increases coronary flow and growth, is implicated as a major stimulus for these adaptations. We hypothesized that genes involved in myocardial adenosine signaling would be upregulated in chronically anemic fetuses and that calcium-handling genes would be downregulated. After sterile surgical instrumentation under anesthesia, gestationally timed fetal sheep were made anemic by isovolumetric hemorrhage for 1 wk (16% vs. 35% hematocrit). At 87% of gestation, necropsy was performed to collect heart tissue for PCR and immunohistochemical analysis. Anemia increased mRNA expression levels of adenosine receptors ADORA 1, ADORA2A, and ADORA2B in the left and right ventricles (adenosine receptor ADORA3 was unchanged). In both ventricles, anemia also increased expression of ectonucleoside triphosphate diphosphohydrolase 1 and ecto-5'-nucleotidase. The genes for both equilibrative nucleoside transporters 1 and 2 were expressed more abundantly in the anemic right ventricle but were not different in the left ventricle. Neither adenosine deaminase nor adenosine kinase cardiac levels were significantly changed by chronic fetal anemia. Chronic fetal anemia did not significantly change cardiac mRNA expression levels of the voltage-dependent L-type calcium channel, ryanodine receptor 1, sodium-calcium exchanger, sarcoplasmic/endoplasmic reticulum calcium transporting ATPase 2, phospholamban, or cardiac calsequestrin. These data support local metabolic integration of vascular and myocyte function through adenosine signaling in the anemic fetal heart.


Assuntos
Adenosina/metabolismo , Anemia/metabolismo , Sinalização do Cálcio , Vasos Coronários/metabolismo , Doenças Fetais/metabolismo , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Anemia/sangue , Anemia/embriologia , Anemia/genética , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apirase/genética , Apirase/metabolismo , Sinalização do Cálcio/genética , Doença Crônica , Vasos Coronários/embriologia , Modelos Animais de Doenças , Proteínas de Transporte de Nucleosídeo Equilibrativas/genética , Proteínas de Transporte de Nucleosídeo Equilibrativas/metabolismo , Feminino , Doenças Fetais/sangue , Doenças Fetais/genética , Regulação da Expressão Gênica no Desenvolvimento , Neovascularização Fisiológica/genética , Gravidez , Receptores Purinérgicos P1/genética , Receptores Purinérgicos P1/metabolismo , Carneiro Doméstico
15.
Food Funct ; 9(5): 2634-2643, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29561026

RESUMO

Sodium valproate (VPA) is an anti-epileptic drug, but has a strong embryotoxicity due to its induced disturbance of folate-homocysteine (Hcy) metabolism and fatty acid metabolism. The aim of the present study was to investigate whether polyunsaturated fatty acid (PUFA) intake during pregnancy can relieve the embryotoxicity of VPA. VPA (dose: 500 mg kg-1, concentration: 38.5 mg ml-1) was intraperitoneally injected into pregnant mice on day 8.5 of gestation (E8.5d). PUFA intake significantly decreased fetal mortality and NTD incidence induced by VPA: n-3 long chain PUFAs (n-3 LCPUFAs) in fish oil had the best decreasing effect, followed by C18:3n-3 in flaxseed oil and then C18:2n-6 in corn oil. VPA administration inhibited the mRNA and protein expressions of a series of enzymes involved in folate-Hcy metabolism in the liver of pregnant mice; however, it led to the mRNA and protein overexpression of these enzymes in embryos. An elevated Hcy level in embryos was observed 6 h after VPA injection. n-3 PUFA intake effectively relieved this disturbance of folate-Hcy metabolism in pregnant mice and embryos, and this relieving effect of n-3 LCPUFAs and C18:3n-3 is better than that of C18:2n-6. In addition, n-3 PUFA intake also relieved the growth retardation induced by VPA. In conclusion, PUFA intake during pregnancy can effectively decrease embryotoxicity of VPA by relieving VPA-induced disturbance of folate-Hcy metabolism in pregnant mice and embryos, and n-3 LCPUFA in fish oil had the optimal protection effect.


Assuntos
Anticonvulsivantes/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Ácidos Graxos Ômega-3/administração & dosagem , Doenças Fetais/prevenção & controle , Ácido Valproico/toxicidade , Animais , Anticonvulsivantes/uso terapêutico , Feminino , Doenças Fetais/metabolismo , Ácido Fólico/metabolismo , Homocisteína/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Ácido Valproico/uso terapêutico
16.
Braz J Med Biol Res ; 51(5): e7132, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29561958

RESUMO

Gastroschisis (GS) is an abdominal wall defect that results in histological and morphological changes leading to intestinal motility perturbation and impaired absorption of nutrients. Due to its anti-inflammatory, antioxidant, and neuroprotective effects, cannabidiol (CBD) has been used as a therapeutic agent in many diseases. Our aim was to test the effect of maternal CBD in the intestine of an experimental model of GS. Pregnant rats were treated over 3 days with CBD (30 mg/kg) after the surgical induction of GS (day 18.5 of gestation) and compared to controls. Fetuses were divided into 4 groups: 1) control (C); 2) C+CBD (CCBD); 3) gastroschisis (G), and 4) G+CBD (GCBD). On day 21.5 of gestation, the fetuses were harvested and evaluated for: a) body weight (BW), intestinal weight (IW), and IW/BW ratio; b) histometric analysis of the intestinal wall; c) immunohistochemically analysis of inflammation (iNOS) and nitrite/nitrate level. BW: GCBD was lower than CCBD (P<0.005), IW and IW/BW ratio: GCBD was smaller than G (P<0.005), GCBD presented lower thickness in all parameters compared to G (P<0.005), iNOS and nitrite/nitrate were lower concentration in GCBD than to G (P<0.005). Maternal use of CBD had a beneficial effect on the intestinal loops of GS with decreased nitrite/nitrate and iNOS expression.


Assuntos
Anti-Inflamatórios/uso terapêutico , Canabidiol/uso terapêutico , Enterite/prevenção & controle , Doenças Fetais/metabolismo , Gastrosquise/metabolismo , Intestinos/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Doenças Fetais/patologia , Gastrosquise/patologia , Imuno-Histoquímica , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II/análise , Nitritos/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
17.
Am J Reprod Immunol ; 79(5): e12829, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29484761

RESUMO

PROBLEM: Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring. METHOD OF STUDY: Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry. RESULTS: CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI. CONCLUSION: Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Heme Oxigenase-1/deficiência , Doenças do Recém-Nascido/imunologia , Inflamação/imunologia , Complicações na Gravidez/imunologia , Baço/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Feminino , Doenças Fetais/imunologia , Doenças Fetais/metabolismo , Humanos , Recém-Nascido , Doenças do Recém-Nascido/metabolismo , Inflamação/metabolismo , Relações Mãe-Filho , Gravidez , Complicações na Gravidez/metabolismo , Baço/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
18.
Am J Obstet Gynecol ; 218(4): 438.e1-438.e16, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29475580

RESUMO

BACKGROUND: Most early preterm births are associated with intraamniotic infection and inflammation, which can lead to systemic inflammation in the fetus. The fetal inflammatory response syndrome describes elevations in the fetal interleukin-6 level, which is a marker for inflammation and fetal organ injury. An understanding of the effects of inflammation on fetal cardiac development may lead to insight into the fetal origins of adult cardiovascular disease. OBJECTIVE: The purpose of this study was to determine whether the fetal inflammatory response syndrome is associated with disruptions in gene networks that program fetal cardiac development. STUDY DESIGN: We obtained fetal cardiac tissue after necropsy from a well-described pregnant nonhuman primate model (pigtail macaque, Macaca nemestrina) of intrauterine infection (n=5) and controls (n=5). Cases with the fetal inflammatory response syndrome (fetal plasma interleukin-6 >11 pg/mL) were induced by either choriodecidual inoculation of a hypervirulent group B streptococcus strain (n=4) or intraamniotic inoculation of Escherichia coli (n=1). RNA and protein were extracted from fetal hearts and profiled by microarray and Luminex (Millipore, Billerica, MA) for cytokine analysis, respectively. Results were validated by quantitative reverse transcriptase polymerase chain reaction. Statistical and bioinformatics analyses included single gene analysis, gene set analysis, Ingenuity Pathway Analysis (Qiagen, Valencia, CA), and Wilcoxon rank sum. RESULTS: Severe fetal inflammation developed in the context of intraamniotic infection and a disseminated bacterial infection in the fetus. Interleukin-6 and -8 in fetal cardiac tissues were elevated significantly in fetal inflammatory response syndrome cases vs controls (P<.05). A total of 609 probe sets were expressed differentially (>1.5-fold change, P<.05) in the fetal heart (analysis of variance). Altered expression of select genes was validated by quantitative reverse transcriptase polymerase chain reaction that included several with known functions in cardiac injury, morphogenesis, angiogenesis, and tissue remodeling (eg, angiotensin I converting enzyme 2, STEAP family member 4, natriuretic peptide A, and secreted frizzled-related protein 4; all P<.05). Multiple gene sets and pathways that are involved in cardiac morphogenesis and vasculogenesis were downregulated significantly by gene set and Ingenuity Pathway Analysis (hallmark transforming growth factor beta signaling, cellular morphogenesis during differentiation, morphology of cardiovascular system; all P<.05). CONCLUSION: Disruption of gene networks for cardiac morphogenesis and vasculogenesis occurred in the preterm fetal heart of nonhuman primates with preterm labor, intraamniotic infection, and severe fetal inflammation. Inflammatory injury to the fetal heart in utero may contribute to the development of heart disease later in life. Development of preterm labor therapeutics must also target fetal inflammation to lessen organ injury and potential long-term effects on cardiac function.


Assuntos
Doenças Fetais/metabolismo , Miocárdio/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Animais , Fator Natriurético Atrial/genética , Biomarcadores/metabolismo , Corioamnionite/metabolismo , Regulação para Baixo , Feminino , Coração/microbiologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Macaca nemestrina , Proteínas de Membrana/genética , Análise em Microsséries , Modelos Animais , Trabalho de Parto Prematuro , Oxirredutases/genética , Peptidil Dipeptidase A/genética , Gravidez , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
19.
Clin Perinatol ; 45(1): 31-40, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29406005

RESUMO

Neonatal thyrotoxicosis (hyperthyroidism) is less prevalent than congenital hypothyroidism; however, it can lead to significant morbidity and mortality if not promptly recognized and adequately treated. Most cases are transient, secondary to maternal autoimmune hyperthyroidism (Graves disease [GD]). This article summarizes recommendations for screening and management of hyperthyroidism in both the fetal and neonatal periods, with a focus on neonatal thyrotoxicosis secondary to maternal GD. Early monitoring and treatment are crucial for optimizing short-term and long-term patient outcomes.


Assuntos
Doenças Fetais/metabolismo , Doença de Graves/metabolismo , Hipertireoidismo/metabolismo , Doenças do Recém-Nascido/metabolismo , Complicações na Gravidez/metabolismo , Tireotoxicose/metabolismo , Antagonistas Adrenérgicos beta/uso terapêutico , Antitireóideos/uso terapêutico , Feminino , Doenças Fetais/etiologia , Doença de Graves/complicações , Doença de Graves/tratamento farmacológico , Humanos , Hipertireoidismo/tratamento farmacológico , Imunoglobulinas Glândula Tireoide-Estimulantes/metabolismo , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/etiologia , Troca Materno-Fetal , Metimazol/uso terapêutico , Gravidez , Propranolol/uso terapêutico , Tireoidite Autoimune/complicações , Tireotoxicose/tratamento farmacológico , Tireotoxicose/etiologia
20.
Prenat Diagn ; 38(3): 190-195, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29327361

RESUMO

OBJECTIVE: Fetal aortic stenosis (AS) imposes pressure load on the developing left ventricle (LV) and leads to derangements in myocardial structure and function via mechanisms that are not well characterized. METHODS: We compared amniotic fluid NT-BNP and troponin levels in fetuses with AS prior to fetal valvuloplasty and controls. We estimated correlations between NT-BNP and fetal echo parameters and identify NT-BNP cutoff associated with biventricular outcome RESULTS: Median NT-BNP level was higher in fetal AS than controls (3858 vs 1737 pg/mL, P < 0.012). By contrast, troponin levels were lower in fetal AS, with troponin > detectable in 0/25 (0%) AS cases compared with 22/85 (26%) controls (P = 0.03). Of 25 fetal AS cases, 12 (48%) had biventricular outcome. Fetuses with NT-BNP < 910 pg/mL were more likely to have biventricular (OR =10) compared with those ≥910 pg/mL (P = 0.045). Higher NT-BNP correlated with earlier gestational age and measures of larger left heart size. CONCLUSION: NT-BNP is elevated in fetal AS, suggesting that LV pressure load and increased wall stress lead to maladaptive stretch-related myocardial remodeling. Troponin is normal in mid-gestation fetal AS, suggesting that ischemia is not the primary factor in fetal response to LV pressure load.


Assuntos
Estenose da Valva Aórtica/metabolismo , Doenças Fetais/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Troponina/metabolismo , Remodelação Ventricular , Líquido Amniótico/metabolismo , Estenose da Valva Aórtica/complicações , Feminino , Humanos , Gravidez , Estudos Retrospectivos
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