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1.
PLoS One ; 15(6): e0234145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497126

RESUMO

Oxidative stress and inflammation determine retinal ganglion cell degeneration, leading to retinal impairment and vision loss. Müller glial cells regulate retinal repair under injury, through gliosis. Meanwhile, reactive gliosis can turn in pathological effects, contributing to neurodegeneration. In the present study, we tested whether Cord Blood Serum (CBS), rich of growth factors, might improve the viability of Müller cells under in vitro damage. BDNF, NGF, TGF-α, GDNF and EGF levels were measured in CBS samples by Human Magnetic Luminex Assay. CBS effects were evaluated on rat (rMC-1) and human (MIO-M1) Müller cells, under H2O2 and IL-1ß damage. Cells grown with FBS or CBS both at 5% were exposed to stress and analyzed in terms of cell viability, GFAP, IL-6 and TNF-α expression. CBS was also administrated after treatment with K252a, inhibitor of the neurotrophin receptor Trk. Cell viability of rMC-1 and MIO-M1 resulted significantly improved when pretreated with CBS and exposed to H2O2 and IL-1ß, in comparison to the standard culture with FBS. Accordingly, the gliosis marker GFAP resulted down-regulated following CBS priming. In parallel, we observed a lower expression of the inflammatory mediators in rMC-1 (TNF-α) and MIO-M1 (IL-6, TNF- α), especially in presence of inflammatory damage. Trk inhibition through K252a administration impaired the effects of CBS under stress conditions on MIO-M1 and rMC-1 viability, not significantly different from FBS condition. CBS is enriched with neurotrophins and its administration to rMC-1 and MIO-M1 attenuates the cytotoxic effects of H2O2 and IL-1ß. Moreover, the decrease of the main markers of gliosis and inflammation suggests a promising use of CBS for neuroprotection aims. This study is a preliminary basis that prompts future investigations to deeply explore and confirm the CBS potential.


Assuntos
Células Ependimogliais/citologia , Células Ependimogliais/efeitos dos fármacos , Sangue Fetal/metabolismo , Soro/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Ependimogliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Humanos , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
2.
PLoS One ; 15(5): e0232002, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379777

RESUMO

BACKGROUND: In pregnant women with gestational diabetes, glyburide can be an alternative to insulin despite concerns about its transplacental transfer. However, transplacental transfer of glyburide is poorly quantified and the relationship between cord blood glyburide concentration and hypoglycemia has not been studied. Our objective was to quantify the transplacental transfer of glyburide at delivery and to study the association between the cord blood glyburide concentration and the risk of neonatal hypoglycemia in patients with gestational diabetes treated with glyburide. METHODS AND FINDINGS: INDAO was a multicenter, noninferiority, randomized trial conducted between May 2012 and November 2016 in 914 women with singleton pregnancies and gestational diabetes. An ancillary study was conducted in the 87 patients of the Bicêtre University Hospital Center. The sample consisted of 46 patients with utilizable assays at delivery. The relationships between glyburide concentration and the time since the last intake of glyburide and between fetal glyburide concentration and neonatal hypoglycemia were modeled with linear or logistic regressions using fractional polynomials. There was placental transfer of glyburide at a fetal to maternal ratio of 62% (95% CI [50; 74]). Umbilical cord blood glyburide concentration decreased steeply after the last maternal glyburide intake. After 24 hours, the mean umbilical cord blood concentration was less than 5 ng/mL. Neonatal hypoglycemia risk was increased with an odds ratio of hypoglycemia equal to 3.70 [1.40-9.77] for each 10 ng/mL increase in the cord blood glyburide concentration. However, no newborns were admitted to the NICU because of clinical signs of hypoglycemia or for treatment of hypoglycemia. CONCLUSION: Considering that neonatal glyburide exposure may be limited by stopping treatment a sufficient time before labor, there may still be a place for glyburide in the management of gestational diabetes.


Assuntos
Diabetes Gestacional/tratamento farmacológico , Glibureto/efeitos adversos , Hipoglicemia/etiologia , Hipoglicemiantes/uso terapêutico , Doenças do Recém-Nascido/etiologia , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Feminino , Sangue Fetal/química , Sangue Fetal/metabolismo , Glibureto/análise , Glibureto/uso terapêutico , Humanos , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/análise , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Modelos Lineares , Modelos Logísticos , Troca Materno-Fetal , Razão de Chances , Gravidez
3.
PLoS One ; 15(4): e0231239, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294121

RESUMO

BACKGROUND: Chorioamnionitis has been linked to spontaneous preterm labor and complications such as neonatal sepsis. We hypothesized that microbial cell-free (cf) DNA would be detectable in maternal plasma in patients with chorioamnionitis and could be the basis for a non-invasive method to detect fetal exposure to microorganisms. OBJECTIVE: The purpose of this study was to determine whether next generation sequencing could detect microbial cfDNA in maternal plasma in patients with chorioamnionitis. STUDY DESIGN: Maternal plasma (n = 94) and umbilical cord plasma (n = 120) were collected during delivery at gestational age 28-41 weeks. cfDNA was extracted and sequenced. Umbilical cord plasma samples with evidence of contamination were excluded. The prevalence of microorganisms previously implicated in choriomanionitis, neonatal sepsis and intra-amniotic infections, as described in the literature, were examined to determine if there was enrichment of these microorganisms in this cohort. Specific microbial cfDNA associated with chorioamnionitis was first detected in umbilical cord plasma and confirmed in the matched maternal plasma samples (n = 77 matched pairs) among 14 cases of histologically confirmed chorioamnionitis and one case of clinical chorioamnionitis; 63 paired samples were used as controls. A correlation of rank of a given microorganism across maternal plasma and matched umbilical cord plasma was used to assess whether signals found in umbilical cord plasma were also present in maternal plasma. RESULTS: Microbial DNA sequences associated with clinical and/or histological chorioamnionitis were enriched in maternal plasma in cases with suspected chorioamnionitis when compared to controls (12/14 microorganisms, p = 0.02). Analysis of the microbial cfDNA in umbilical cord plasma among the 1,251 microorganisms detectable with this assay identified Streptococcus mitis, Ureaplasma spp., and Mycoplasma spp. in cases of suspected chorioamnionitis. This assay also detected cfDNA from Lactobacillus spp. in controls. Comparison between maternal plasma and umbilical cord plasma confirmed these signatures were also present in maternal plasma. Unbiased analysis of microorganisms with significantly correlated signal between matched maternal plasma and umbilical cord plasma identified the above listed 3 microorganisms, all of which have previously been implicated in patients with chorioamnionitis (Mycoplasma hominis p = 0.0001; Ureaplasma parvum p = 0.002; Streptococcus mitis p = 0.007). These data show that the pathogen signal relevant for chorioamnionitis can be identified in both maternal and umbilical cord plasma. CONCLUSION: This is the first report showing the detection of relevant microbial cell-free cfDNA in maternal plasma and umbilical cord plasma in patients with clinical and/or histological chorioamnionitis. These results may lead to the development of a specific assay to detect perinatal infections for targeted therapy to reduce early neonatal sepsis complications.


Assuntos
Ácidos Nucleicos Livres/sangue , Corioamnionite/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Cordão Umbilical/microbiologia , Adulto , Corioamnionite/microbiologia , Estudos de Coortes , Feminino , Sangue Fetal/química , Sangue Fetal/metabolismo , Sangue Fetal/microbiologia , Idade Gestacional , Humanos , Recém-Nascido , Mycoplasma/genética , Mycoplasma/patogenicidade , Sepse Neonatal/sangue , Sepse Neonatal/diagnóstico , Sepse Neonatal/microbiologia , Gravidez , Streptococcus mitis/genética , Streptococcus mitis/patogenicidade , Cordão Umbilical/patologia , Ureaplasma/genética , Ureaplasma/patogenicidade , Adulto Jovem
4.
Zhonghua Yu Fang Yi Xue Za Zhi ; 54(3): 289-293, 2020 Mar 06.
Artigo em Chinês | MEDLINE | ID: mdl-32187934

RESUMO

Objective: To understand the levels of Pb, Cd, As, Hg, Mn, and Se in maternal and umbilical cord blood, and to explore the transplacental transfer efficiency (TTE). Methods: From September 2010 to December 2013, a total of 773 pregnant women and their newborns (Laizhou Bay Birth Cohort) were recruited from a second grade hospital in the south bank of Laizhou Bay, Bohai, Shandong Province. According to different detection methods, the six measured elements are classified into three groups including the Hg measurement group (595 mother-newborn pairs), the Pb measurement group (534 mother-newborn pairs), and the Cd, As, Mn and Se measurement group (244 mother-newborn pairs). The demographic characteristics of pregnant women and their newborns were obtained by the questionnaire. The concentrations of elements in maternal and umbilical cord blood were detected and the TTE of each element (elemental concentration in cord blood/elemental concentration in maternal blood) was calculated. The correlation of elements between maternal and cord blood was analyzed using Spearman's rank correlation coefficient. Results: The mean±SD of maternal age, gestational week and newborn birth weight of 773 mother-infant pairs were (28.34±4.50) years, (39.47±1.39) weeks and (3 419.47±497.39) g respectively. The median concentrations of Pb, Cd, As, Hg, Mn and As in maternal and cord blood were 31.12 and 30.02, 1.19 and 0.47, 8.05 and 6.03, 0.69 and 1.26, 100.70 and 105.55, 127.25 and 115.00 µg/L, respectively. The TTE of Pb, Cd, As, Hg, Mn, and Se was 0.98, 0.41, 0.73, 1.73, 0.96 and 0.91, respectively. Pb, Cd, Hg, Mn, and Se showed a significant positive correlation between maternal blood and cord blood, with Spearman correlation coefficients of 0.397, 0.298, 0.698, 0.555, and 0.285 (all P values<0.001). Conclusion: Each element was commonly detected in maternal blood and cord blood. The TTE of Hg was the highest.


Assuntos
Cádmio/sangue , Sangue Fetal/química , Sangue Fetal/metabolismo , Chumbo/sangue , Manganês/sangue , Troca Materno-Fetal , Mercúrio/sangue , Selênio/sangue , Cordão Umbilical/química , Biomarcadores/análise , Biomarcadores/sangue , Feminino , Humanos , Recém-Nascido , Gravidez , Oligoelementos/análise , Oligoelementos/sangue , Cordão Umbilical/irrigação sanguínea
5.
PLoS One ; 15(3): e0230682, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210456

RESUMO

Atherosclerosis is a chronic inflammatory disease and major cause of mortality worldwide. One of the crucial steps for atherosclerotic plaque development is oxidation of low-density lipoprotein (LDL). Through the oxidation, highly immunogenic epitopes are created and the immune system is activated. Association between atherosclerosis and periodontal diseases is well documented, and one of the main oral pathogens common in periodontitis is Aggregatibacter actinomycetemcomitans (Aa). Heat shock protein 60 (HSP60) is an important virulence factor for Aa bacteria and a strong activator of the immune system. Cross-reactivity of HSP60 and oxidized LDL (OxLDL) antibodies could be a potential mechanism in the progression of atherosclerosis and one possible link between atherosclerosis and periodontitis. Human plasma samples from neonates and mothers were analyzed to determine if antibody titer to Aa-HSP60 protein is already present in newborns. Further objectives were to characterize antibody response in Aa-HSP60 immunized mice and to determine possible antibody cross-reaction with oxidized LDL. We demonstrated that newborns already have IgM antibody levels to Aa-HSP60. We also showed that in mice, Aa-HSP60 immunization provoked IgG and IgM antibody response not only to Aa-HSP60 but also to malondialdehyde acetaldehyde-modified LDL (MAA-LDL). Competition assay revealed that the antibodies were specific to Aa-HSP60 and cross-reacted with MAA-LDL. Our results suggest a possibility of molecular mimicry between Aa-HSP60 and MAA-LDL, making it intriguing to speculate on the role of HSP60 protein in atherosclerosis that manifests at young age.


Assuntos
Aggregatibacter actinomycetemcomitans/metabolismo , Chaperonina 60/imunologia , Imunidade Humoral , Lipoproteínas LDL/imunologia , Aggregatibacter actinomycetemcomitans/imunologia , Animais , Reações Antígeno-Anticorpo , Chaperonina 60/genética , Chaperonina 60/metabolismo , Reações Cruzadas , Feminino , Sangue Fetal/metabolismo , Humanos , Imunoensaio , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
6.
Environ Res ; 183: 109134, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32018205

RESUMO

BACKGROUND: Fetal epigenetic programming plays a critical role in development. DNA methyltransferase 3 alpha (DNMT3A), which is involved in de novo DNA methylation (DNAm), is a prime candidate gene as a mediator between prenatal exposures and birth outcomes. We evaluated the relationships between in utero arsenic (As) exposure, birth outcomes, and DNMT3A DNAm. METHODS: In a prospective Bangladeshi birth cohort, cord blood DNAm of three DNMT3A CpGs was measured using bisulfite pyrosequencing. Maternal toenail As concentrations at birth were measured to estimate in utero exposure. Among vaginal births (N = 413), structural equation models (SEMs) were used to evaluate relationships between DNMT3A methylation, log2 (toenail As), birth weight, and gestational age. RESULTS: In an adjusted SEM including birth weight and gestational age, maternal toenail As levels were associated with DNMT3A DNAm (B = 0.40; 95% CI: 0.15, 0.66) and gestational age (B = -0.19 weeks; 95% CI: 0.36, -0.03). DNMT3A DNAm was associated with gestational age (B = -0.10 weeks; 95% CI: 0.16, -0.04) and birth weight (B = -11.0 g; 95% CI: 21.5, 0.4). There was an indirect effect of As on gestational age mediated through DNMT3A DNAm (B = -0.04; 95% CI: 0.08, -0.01), and there were indirect effects of maternal toenail As levels on birth weight through pathways including gestational age (B = -14.4 g; 95% CI: 29.2, -1.9), DNMT3A DNAm and gestational age (B = -3.1 g; 95% CI: 6.6, -0.8), and maternal weight gain and gestational age (B = -5.1 g; 95% CI: 9.6, -1.5). The total effect of a doubling in maternal toenail As concentration is a decrease in gestational age of 2.1 days (95% CI: 0.9, 3.3) and a decrease in birth weight of 29 g (95% CI: 14, 46). CONCLUSIONS: DNMT3A plays a critical role in fetal epigenetic programming. In utero arsenic exposure was associated with greater methylation of CpGs in DNMT3A which partially mediated associations between prenatal As exposure and birth outcomes. Additional studies are needed to verify this finding.


Assuntos
Arsênico , DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Exposição Materna , Arsênico/toxicidade , Bangladesh , Peso ao Nascer , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos
7.
Ecotoxicol Environ Saf ; 191: 110235, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31986458

RESUMO

Six parabens and their four metabolites were measured in paired maternal serum (MS) and cord serum (CS) samples collected from 95 pregnant women to elucidate placental transfer of this class of compounds. Matched maternal urine (MU) and amniotic fluid (AF) collected from 13 of 95 pregnant women were also analyzed to examine partition of these chemicals between maternal and fetal tissues. The placental transfer rates (PTRs; concentration ratio of parabens between CS and MS) of methyl- (MeP), ethyl- (EtP), propyl-parabens (PrP) were 0.81, 0.63, and 0.60, respectively. Furthermore, the PTRs of OH-MeP (0.93) and OH-EtP (1.8) were higher than those of their corresponding parent parabens, which suggested that hydroxylation increased placental transfer rates of parabens. Structure-dependent placental transfer mechanisms were observed. A significant negative correlation between molecular weights (or log Kow) of MeP, EtP, PrP, and p-hydroxy benzoic acid (4-HB) and PTRs suggested passive diffusion as a mechanism of placental transfer of these chemicals. Nevertheless, other hydroxylated metabolites (OH-EtP, OH-MeP, and 3,4-dihydroxy benzoic acid (3,4-DHB)) showed a positive correlation between molecular weight (or log Kow) and PTRs, which suggested that the placental transfer is mediated by protein binding of these metabolites. The MU to MS concentration ratios of MeP (MU/MSMeP) and PrP (MU/MSPrP) were 71 and 81, respectively, and MU/MSMeP was two orders of magnitude higher than that found for the metabolite (MU/MSOH-MeP: 0.35), suggesting that hydroxylation metabolite reduced urinary elimination of parabens. To our knowledge, this is the first time to report the occurrence and distribution of parabens and their metabolites in paired maternal-fetal serum, urine, and AF samples in China. Our results provide novel information on placental transfer of parabens and their metabolites.


Assuntos
Líquido Amniótico/química , Sangue Fetal/química , Exposição Materna , Troca Materno-Fetal , Parabenos/análise , Placenta/química , Líquido Amniótico/metabolismo , China , Cosméticos , Feminino , Sangue Fetal/metabolismo , Humanos , Parabenos/metabolismo , Placenta/metabolismo , Gravidez
8.
Toxicol Lett ; 322: 32-38, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31923464

RESUMO

Neonicotinoids (NNs), a widely used class of systemic pesticides, are regarded as exhibiting selective toxicity in insects. However, NNs are suspected of exerting adverse effects on mammals as well, including humans. To date, only adult male animal models have been subjected to general toxicity studies of NNs; fetuses have yet to be considered in this context. Here, we focused on the NN clothianidin (CLO) for the first quantitative LC-MS/MS analysis of maternal-to-fetal transfer and residual property of once-daily (single or multiple days), orally administered CLO and its metabolites in mice. The results revealed the presence of CLO and its five metabolites at approximately the same respective blood levels in both dams and fetuses. In the dams, CLO showed a peak value 1 h after administration, after which levels rapidly decreased at 3 and 6 h. In the fetuses of each group, levels of CLO were almost the same as those observed in the corresponding dams. The present results clearly demonstrated rapid passage of CLO through the placental barrier. However, metabolite-dependent differences observed in blood pharmacokinetics and residual levels. This is the first quantitative demonstration of the presence of CLO and its metabolites in fetal mouse blood.


Assuntos
Sangue Fetal/metabolismo , Guanidinas/sangue , Inseticidas/sangue , Troca Materno-Fetal , Neonicotinoides/sangue , Tiazóis/sangue , Animais , Biotransformação , Feminino , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Guanidinas/toxicidade , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Inseticidas/toxicidade , Exposição Materna , Camundongos Endogâmicos ICR , Neonicotinoides/administração & dosagem , Neonicotinoides/farmacocinética , Neonicotinoides/toxicidade , Gravidez , Medição de Risco , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Tiazóis/toxicidade , Toxicocinética
9.
J Phys Act Health ; 17(2): 236-241, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945742

RESUMO

BACKGROUND: Physical activity performed while pregnant is beneficially associated with maternal cardiovascular health. It is unknown if benefits extend to neonatal cardiovascular health. This study investigated associations of maternal physical activity with neonatal cord blood lipid and lipoprotein concentrations. METHODS: Cord blood lipids were measured at birth in a pseudorandomly selected subgroup of Born in Bradford birth cohort participants (N = 1634). Pregnant women were grouped into 4 activity categories (inactive/somewhat active/moderately active/active) based on their self-reported physical activity at 26- to 28-weeks gestation. Regression was used to calculate adjusted mean differences in neonatal cord blood lipid concentrations among the 4 groups of physical activity. RESULTS: Maternal physical activity was associated with higher neonatal cord blood high-density lipoprotein cholesterol. Cord blood high-density lipoprotein cholesterol was higher in neonates of women who were somewhat and moderately active compared with neonates of women who were inactive. There were no associations of pregnancy physical activity with triglycerides, low-density lipoprotein, very low-density lipoprotein cholesterol, or adiponectin levels. CONCLUSIONS: Maternal physical activity is favorably associated with neonatal cord blood high-density lipoprotein cholesterol levels. This novel beneficial finding highlights the potential for physical activity in pregnancy to aid the early prevention of cardiovascular disease.


Assuntos
Exercício Físico/fisiologia , Sangue Fetal/metabolismo , Lipídeos/sangue , Saúde Materna/normas , Adulto , Estudos de Coortes , Feminino , Humanos , Gravidez , Estudos Prospectivos
10.
J Steroid Biochem Mol Biol ; 199: 105591, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31954177

RESUMO

Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analysed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p < 0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75~-0.41 cm, p = 2.45×10-11). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68~39.88 cm, p = 4.62×10-4) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring's development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.


Assuntos
Encéfalo/metabolismo , Sangue Fetal/metabolismo , Cabeça/anatomia & histologia , Fumar/efeitos adversos , Adulto , Antropometria , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Mães , Fosfatidilcolinas/sangue , Gravidez
11.
Artigo em Inglês | MEDLINE | ID: mdl-31954174

RESUMO

Perinatal and long-term offspring morbidities are strongly dependent on the preservation of placental vascular homeostasis during pregnancy. In adults, the HDL-apoM-S1P complex protects the endothelium and maintains vascular integrity. However, the metabolism and biology of cord blood-derived HDLs (referred to as neonatal HDL, nHDL) strikingly differ from those in adults. Here, we investigate the role of neonatal HDLs in the regulation of placental vascular function. We show that nHDL is a major carrier of sphingosine-1-phosphate (S1P), which is anchored to the particle through apoM (rs = 0.90, p < 0.0001) in the fetal circulation. Furthermore, this complex interacts with S1P receptors on the feto-placental endothelium and activates specifically extracellular signal-regulated protein kinases 1 and 2 (ERK) and phospholipase C (PLC) downstream signaling, promotes endothelial cell proliferation and calcium flux. Notably, the nHDL-S1P complex triggers actin filaments reorganization, leading to an enhancement of placental endothelial barrier function. Additionally, nHDL induces vasorelaxation of isolated placental chorionic arteries. Taken together, these results suggest that circulating nHDL exerts vasoprotective effects on the feto-placental endothelial barrier mainly via S1P signaling.


Assuntos
Sangue Fetal/metabolismo , Lipoproteínas HDL/metabolismo , Lisofosfolipídeos/metabolismo , Placenta/irrigação sanguínea , Esfingosina/análogos & derivados , Apolipoproteínas M/sangue , Apolipoproteínas M/metabolismo , Células Cultivadas , Endotélio Vascular/metabolismo , Feminino , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/sangue , Sistema de Sinalização das MAP Quinases , Gravidez , Esfingosina/sangue , Esfingosina/metabolismo , Fosfolipases Tipo C/metabolismo
12.
Eur J Cell Biol ; 99(2-3): 151069, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31982141

RESUMO

Adipose-tissue derived stromal cells (ASCs) are currently considered as a full value alternative source of bone marrow MSCs for prevention of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation due to their immunosuppressive potential. Besides, ASCs are known to support ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). Ex vivo expansion enables to amplify significantly the number of HSPCs of different commitment. Mononuclear cells (MNCs) from cord blood (cb) contain HSPCs and are easily assessed. The rarity of those HSPCs is a serious limitation of its application in cell therapy. Here we expanded cbMNCs in stroma-dependent setting to generate heterocellular associates consisting of ASCs and undifferentiated and low committed hematopoietic cbHSPCs. A part of cbHSPCs in associates demonstrated a primitive phenotype confirmed by formation of "cobblestone areas". ASCs associated with cbHSPCs demonstrated up-regulation of immunosuppressive indoleamine 2,3-dioxygenase (IDO), leukemia inhibitory factor (LIF), cyclooxygenase-2 (PTGS2) genes. ASC-cbHSPCs as well as ASCs provoked the suppression of HLA-DR activation and apoptosis of mitogen-stimulated T cells. VEGF transcription and secretion were elevated providing stimulation of blood vessel formation in ovo. Thus, ASCs retain immunosuppressive and proangiogenic capacities evidencing "third party" potential along with the effective support of ex vivo expansion of cbHSPCs. Above functions expand the relevance of ASCs for needs of regenerative medicine.


Assuntos
Tecido Adiposo/metabolismo , Técnicas de Cocultura/métodos , Sangue Fetal/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células Estromais/metabolismo , Células Cultivadas , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/citologia , Humanos , Células Estromais/citologia
13.
Int J Mol Sci ; 21(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947745

RESUMO

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5'-C-phosphate-G-3' (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother-child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (ß = -2.69, p = 0.05) and fat distribution (ß = -0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (ß = -0.01, p = 0.04) and neonatal leptinemia (ß = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.


Assuntos
Metilação de DNA , Diabetes Gestacional/genética , Hiperglicemia/genética , Leptina/genética , Obesidade/etiologia , Adiposidade , Adulto , Pré-Escolar , Diabetes Gestacional/metabolismo , Epigênese Genética , Feminino , Sangue Fetal/metabolismo , Loci Gênicos , Humanos , Hiperglicemia/metabolismo , Recém-Nascido , Leptina/metabolismo , Masculino , Obesidade/genética , Obesidade/metabolismo , Placenta/metabolismo , Gravidez , Adulto Jovem
14.
Am J Obstet Gynecol ; 222(6): 610.e1-610.e13, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31954155

RESUMO

BACKGROUND: Zika virus infection during pregnancy can cause serious birth defects, which include brain and eye abnormalities. The clinical importance of detection of Zika virus RNA in amniotic fluid is unknown. OBJECTIVE: The purpose of this study was to describe patterns of Zika virus RNA testing of amniotic fluid relative to other clinical specimens and to examine the association between Zika virus detection in amniotic fluid and Zika-associated birth defects. Our null hypothesis was that Zika virus detection in amniotic fluid was not associated with Zika-associated birth defects. STUDY DESIGN: We conducted a retrospective cohort analysis of women with amniotic fluid specimens submitted to Colombia's National Institute of Health as part of national Zika virus surveillance from January 2016 to January 2017. Specimens (maternal serum, amniotic fluid, cord blood, umbilical cord tissue, and placental tissue) were tested for the presence of Zika virus RNA with the use of a singleplex or multiplex real-time reverse transcriptase-polymerase chain reaction assay. Birth defect information was abstracted from maternal prenatal and infant birth records and reviewed by expert clinicians. Chi-square and Fisher's exact tests were used to compare the frequency of Zika-associated birth defects (defined as brain abnormalities [with or without microcephaly, but excluding neural tube defects and their associated findings] or eye abnormalities) by frequency of detection of Zika virus RNA in amniotic fluid. RESULTS: Our analysis included 128 women with amniotic fluid specimens. Seventy-five women (58%) had prenatally collected amniotic fluid; 42 women (33%) had amniotic fluid collected at delivery, and 11 women (9%) had missing collection dates. Ninety-one women had both amniotic fluid and other clinical specimens submitted for testing, which allowed for comparison across specimen types. Of those 91 women, 68 had evidence of Zika virus infection based on detection of Zika virus RNA in ≥1 specimen. Testing of amniotic fluid that was collected prenatally or at delivery identified 39 of these Zika virus infections (57%; 15 [22%] infections were identified only in amniotic fluid), and 29 infections (43%) were identified in other specimen types and not amniotic fluid. Among women who were included in the analysis, 89 had pregnancy outcome information available, which allowed for the assessment of the presence of Zika-associated birth defects. Zika-associated birth defects were significantly (P<.05) more common among pregnancies with Zika virus RNA detected in amniotic fluid specimens collected prenatally (19/32 specimens; 59%) than for those with no laboratory evidence of Zika virus infection in any specimen (6/23 specimens; 26%), but the proportion was similar in pregnancies with only Zika virus RNA detected in specimens other than amniotic fluid (10/23 specimens; 43%). Although Zika-associated birth defects were more common among women with any Zika virus RNA detected in amniotic fluid specimens (ie, collected prenatally or at delivery; 21/43 specimens; 49%) than those with no laboratory evidence of Zika virus infection (6/23 specimens; 26%), this comparison did not reach statistical significance (P=.07). CONCLUSION: Testing of amniotic fluid provided additional evidence for maternal diagnosis of Zika virus infection. Zika-associated birth defects were more common among women with Zika virus RNA that was detected in prenatal amniotic fluid specimens than women with no laboratory evidence of Zika virus infection, but similar to women with Zika virus RNA detected in other, nonamniotic fluid specimen types.


Assuntos
Líquido Amniótico/virologia , Encéfalo/anormalidades , Anormalidades do Olho/epidemiologia , Microcefalia/epidemiologia , Complicações Infecciosas na Gravidez/metabolismo , RNA Viral/metabolismo , Infecção por Zika virus/metabolismo , Zika virus/genética , Adulto , Líquido Amniótico/metabolismo , Estudos de Coortes , Colômbia/epidemiologia , Feminino , Sangue Fetal/metabolismo , Sangue Fetal/virologia , Humanos , Recém-Nascido , Malformações do Sistema Nervoso/epidemiologia , Placenta/metabolismo , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cordão Umbilical/metabolismo , Cordão Umbilical/virologia , Adulto Jovem , Infecção por Zika virus/epidemiologia
15.
Am J Obstet Gynecol ; 222(1): 81.e1-81.e13, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306649

RESUMO

BACKGROUND: Doppler ultrasound measurements of the peak systolic velocity of the middle cerebral artery can be used to noninvasively diagnose fetal anemia but are less precise following fetal blood transfusion and in late gestation. We have previously demonstrated the feasibility of estimating fetal hematocrit in vitro using magnetic resonance imaging relaxation times. Here we report the use of magnetic resonance imaging as a noninvasive tool to accurately detect fetal anemia in vivo. OBJECTIVES: This study has 2 objectives: (1) to determine the feasibility and accuracy of magnetic resonance imaging in estimating hematocrit in anemic fetuses and (2) to compare magnetic resonance imaging and middle cerebral artery Doppler in detecting moderate to severe fetal anemia. STUDY DESIGN: Fetuses undergoing fetal blood sampling or transfusion underwent magnetic resonance imaging examinations prior to and following their procedures at 1.5 Tesla (Siemens Avanto). A modified Look-Locker inversion pulse sequence and T2 preparation sequence were applied for T1 and T2 mapping of the intrahepatic umbilical vein. Estimated fetal hematocrit was calculated using a combination of T1 and T2 values and compared with conventional hematocrit obtained from fetal blood samples and middle cerebral artery Doppler measurements. RESULTS: Twenty-three fetuses were assessed during 33 magnetic resonance imaging scans. The mean absolute difference between the laboratory and magnetic resonance imaging-estimated hematocrit was 0.06 ± 0.05 with a correlation of 0.77 (P < .001) determined by a multilevel, mixed-effects model adjusting for the repeated measurements from the same participants, multiple gestation pregnancies, and the scan type (ie, before or after transfusion scan). Bland-Altman analysis revealed a systematic bias of -0.03 between the magnetic resonance imaging and fetal blood sampling measurements. Magnetic resonance imaging and middle cerebral artery Doppler had similar sensitivities of approximately 90% to detect moderate to severe anemia. However, magnetic resonance imaging had a higher specificity (93% [13/14], 95% confidence interval, 66-100%) than Doppler (71% [10/14], 95% confidence interval, 42-92%). CONCLUSION: Moderate to severe fetal anemia can be detected noninvasively by magnetic resonance imaging with high sensitivity and specificity. Our results suggest an adjunct role for magnetic resonance imaging in fetuses with suspected anemia, particularly following previous transfusion and in late gestation.


Assuntos
Anemia/diagnóstico por imagem , Doenças Fetais/diagnóstico por imagem , Hematócrito , Artéria Cerebral Média/diagnóstico por imagem , Anemia/diagnóstico , Anemia/terapia , Velocidade do Fluxo Sanguíneo , Incompatibilidade de Grupos Sanguíneos/complicações , Transfusão de Sangue Intrauterina , Estudos Transversais , Feminino , Sangue Fetal/metabolismo , Doenças Fetais/diagnóstico , Doenças Fetais/terapia , Transfusão Feto-Fetal/complicações , Transfusão Feto-Fetal/terapia , Humanos , Imagem por Ressonância Magnética , Gravidez , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Ultrassonografia Doppler
16.
BJOG ; 127(3): 405-413, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31762140

RESUMO

OBJECTIVE: To determine variations in cord blood gas (CBG) parameters after 3-minute delayed cord clamping (DCC) in vaginal deliveries (VDs) and caesarean deliveries (CDs) at term without fetal distress. DESIGN: Prospective observational study. SETTING: University hospital. SAMPLE: CBG from 97 VDs and 124 CDs without fetal distress. METHODS: Comparison of paired arterial-venous CBG parameters drawn at birth from the unclamped cord and after 3-minutes DCC for VDs and CDs. MAIN OUTCOME MEASURES: Base excess, bicarbonate, haematocrit and haemoglobin from both arterial and venous cord blood, lactate, neonatal outcomes, partial pressure of oxygen (pO2 ), partial pressure of carbon dioxide (pCO2 ), pH, and postpartum haemorrhage. RESULTS: Arterial cord blood pH, bicarbonate ( HCO 3 - , mmol/l), and base excess (BE, mmol/l) decreased significantly after 3-minute DCC both in VDs (pH = 7.23 versus 7.27; P < 0.001; HCO 3 -  = 23.3 versus 24.3; P = 0.004; BE = -5.1 versus -2.9; P < 0.001) and CDs (pH = 7.28 versus 7.34; P < 0.001; HCO 3 -  = 26.2 versus 27.2; P < 0.001; BE = -1.5 versus 0.7; P < 0.001). After 3-minute DCC, pCO2 increased in CDs only (57 versus 51; P < 0.001), whereas lactate increased more in CDs compared with VDs (lactate, +1.1 [0.9, 1.45] versus +0.5 [-0.65, 2.35]; P = 0.01). Postpartum maternal haemorrhage, neonatal maximum bilirubin concentration, and need for phototherapy were similar between the two groups. Newborns born by CD more frequently required postnatal clinical monitoring or admission to a neonatal intensive care unit. CONCLUSIONS: After 3-minute DCC, the acid-base status shifted towards mixed acidosis in CDs and prevalent metabolic acidosis in VDs. CDs were associated with a more pronounced increase in arterial lactate, compared with VDs. TWEETABLE ABSTRACT: By 3-minute DCC, acid-base status shifts towards mixed and metabolic acidosis in caesarean and vaginal delivery, respectively.


Assuntos
Acidose , Cesárea , Parto Obstétrico , Sangue Fetal/metabolismo , Complicações do Trabalho de Parto , Cordão Umbilical/cirurgia , Acidose/sangue , Acidose/diagnóstico , Acidose/etiologia , Gasometria/métodos , Cesárea/efeitos adversos , Cesárea/métodos , Cesárea/estatística & dados numéricos , Constrição , Parto Obstétrico/efeitos adversos , Parto Obstétrico/métodos , Parto Obstétrico/estatística & dados numéricos , Feminino , Humanos , Recém-Nascido , Itália/epidemiologia , Masculino , Complicações do Trabalho de Parto/diagnóstico , Complicações do Trabalho de Parto/epidemiologia , Complicações do Trabalho de Parto/etiologia , Gravidez , Resultado da Gravidez/epidemiologia , Tempo para o Tratamento
17.
Biomed Pharmacother ; 121: 109310, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710895

RESUMO

Currently, there is no effective method to prevent renal interstitial fibrosis after acute kidney injury (AKI). In this study, we established and screened a new renal interstitial fibrosis rat model after cisplatin-induced AKI. Our results indicated that rats injected with 4 mg/kg cisplatin once a week for two weeks after firstly administrated with 6.5 mg/kg loading dose of cisplatin could set up a more accurate model reflecting AKI progression to renal interstitial fibrosis. Then, we investigated the effects and possible mechanisms of human umbilical cord blood mononuclear cells (hUCBMNCs) on renal tubular interstitial fibrosis after cisplatin-induced AKI. In rats injected with hUCBMNCs for four times, level of matrix metalloproteinase 7(MMP-7)in serum and urine, urinary albumin/creatinine ratio, tubular pathological scores, the relative collagen area of the tubulointerstitial region, endoplasmic reticulum dilation and the mitochondrial ultrastructural damage were significantly improved. The level of reactive oxygen species, α-smooth muscle actin (α-SMA), [NOD]-like pyrin domain containing protein 3 and cleaved-Caspase 3 in renal tissue decreased significantly. However, in rats injected with hUCBMNCs for two times, no significant difference was discovered in MMP-7 levels and urinary albumin/creatinine ratio. Although expression of α-SMA and the percentage areas of collagen staining in tubulointerstitial tissues were ameliorated in rats injected with hUCBMNCs for two times, the effects were significantly weaker than those in rats injected with hUCBMNCs for four times. Taken together, our study constructed a highly efficient, duplicable novel rat model of renal fibrosis after cisplatin-induced AKI. Multiple injections of hUCBMNCs may prevent renal interstitial fibrosis after cisplatin-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Cisplatino/farmacologia , Sangue Fetal/metabolismo , Fibrose/tratamento farmacológico , Túbulos Renais/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Cordão Umbilical/metabolismo , Animais , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
18.
Artigo em Inglês | MEDLINE | ID: mdl-31843384

RESUMO

BACKGROUND: To our knowledge, we lack a complete understanding of the lipidomes alterations caused by maternal supraphysiological hypercholesterolemia (MSPH) at the third trimester. OBJECTIVES: The aim of this study was to investigate lipidomes alterations in maternal and umbilical venous (UV) serum and explore the association between these alterations and MSPH. METHODS: We conducted a nest case-control study between maternal physiological hypercholesterolemia (MPH) and MSPH subjects during pregnancy. Lipidomic profiling of maternal serum at the first trimester of gestation and UV serum was performed by ultra-high-performance liquid chromatography system connected to a quadrupole time-of-light/mass spectrometer. RESULTS: Several glycerophospholipids and sphingolipids (C18 sphingoid base) species were distinctly altered in maternal serum and/or UV serum with MSPH versus MPH. Glycerophospholipid metabolism, sphingolipid metabolism and propanoate metabolism were the main pathways that involved the most of discriminate metabolites. Higher HDL-c and phosphatidylcholine (16:0/0:0) (PC (16:0/0:0)) during pregnancy, higher PC (16:0/0:0) and lower cholesterol ester 20:4(8Z,11Z,14Z,17Z) (CE (20:4(8Z,11Z,14Z,17Z))) in the UV serum may be the risk factors for the increased placental circulation resistance. The total cholesterol levels of maternal serum both at the first trimester and at the third trimester were significantly correlated with some lipid species of UV serum. CONCLUSION: This study clarifies the differential lipid profiles to distinguish MSPH from MPH and the pathway which is influenced under the condition of MSPH. Also, it provides a resource to look for potential therapeutic targets for MSPH.


Assuntos
Hipercolesterolemia/sangue , Fosfatidilcolinas/sangue , Complicações na Gravidez/sangue , Esfingolipídeos/sangue , Adulto , Biomarcadores/sangue , Colesterol/sangue , Feminino , Sangue Fetal/metabolismo , Humanos , Hipercolesterolemia/prevenção & controle , Lipidômica , Espectrometria de Massas , Gravidez , Primeiro Trimestre da Gravidez/sangue
19.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536623

RESUMO

INTRODUCTION: Perfluoroalkyl substances (PFAS) were among various persistent organic pollutants suspected to have been released during the collapse of the World Trade Center (WTC) on 9/11/2001. Evidence suggests that PFAS may have cardiometabolic effects, including alterations in lipid profiles. This study evaluated the association between cord blood PFAS and lipids in a population prenatally exposed to the WTC disaster. STUDY POPULATION: 222 pregnant women in the Columbia University WTC birth cohort enrolled between December 13, 2001 and June 26, 2002 at hospitals located near the WTC site: Beth Israel, St. Vincent's, and New York University Downtown. METHODS: We evaluated the association between 5 cord blood PFAS-perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecane sulfonate (PFDS)-and cord blood lipids (total lipids, total cholesterol, triglycerides). RESULTS: Median (interquartile range [IQR]) concentrations of PFAS were 6.32 (4.58-8.57), 2.46 (1.77-3.24), 0.38 (0.25-0.74), 0.66 (0.48-0.95) and 0.11 (0.09-0.16) ng/mL for PFOS, PFOA, PFNA, PFHxS, and PFDS, respectively. Median (IQR) for lipids were 59.0 (51.5-68.5) mg/dL for total cholesterol, 196.5 (170.5-221.2) mg/dL for total lipids and 33.1 (24.2-43.9) mg/dL for triglycerides. In fully adjusted models, several PFAS were associated with higher lipid levels, including evidence of a strong linear trend between triglycerides and both PFOA and PFHxS. CONCLUSIONS: Findings support previous evidence of an association between PFAS exposure and altered lipid profiles and add novel information on this relationship in cord blood, as well as for an understudied PFAS, PFDS (J Clin Endocrinol Metab XX: 0-0, 2019).


Assuntos
Ácidos Alcanossulfônicos/sangue , Biomarcadores/sangue , Caprilatos/sangue , Poluentes Ambientais/sangue , Sangue Fetal/metabolismo , Fluorcarbonetos/sangue , Lipídeos/sangue , Ácidos Sulfônicos/sangue , Adolescente , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Gravidez , Prognóstico , Adulto Jovem
20.
Oxid Med Cell Longev ; 2019: 1509798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871538

RESUMO

An understanding of the basic pathophysiological mechanisms of neonatal diseases necessitates detailed knowledge about the wide range of complications in the circulating fetal RBCs. Recent publications on adult red blood cells (RBCs) provide evidence that RBCs carry an active nitric oxide synthase (NOS3) enzyme and contribute to vascular functioning and integrity via their active nitric oxide synthesis. The aim of this study was to determine the effect of maternal smoking on the phenotypical appearance and functionality of fetal RBCs, based on morphological and molecular studies. We looked for possible links between vascular dysfunction and NOS3 expression and activation and its regulation by arginase (ARG1). Significant morphological and functional differences were found between fetal RBCs isolated from the arterial cord blood of neonates born to nonsmoking (RBC-NS, n = 62) and heavy-smoking (RBC-S, n = 51) mothers. Morphological variations were quantified by Advanced Cell Classifier, microscopy-based intelligent analysis software. To investigate the relevance of the newly suggested "erythrocrine" function in fetal RBCs, we measured the levels of NOS3 and its phosphorylation in parallel with the level of ARG1, as one of the major influencers of NOS3 dimerization, by fluorescence-activated cell sorting. Fetal RBCs, even the "healthy-looking" biconcave-shaped type, exhibited impaired NOS3 activation in the RBC-S population, which was paralleled with elevated ARG1 level, thus suggesting an increased redox burden. Our molecular data indicate that maternal smoking can exert marked effects on the circulating fetal RBCs, which could have a consequence on the outcome of in utero development. We hypothesize that any endothelial dysfunction altering NO production/bioavailability can be sensed by circulating fetal RBCs. Hence, we are putting forward the idea that neonatal RBC could serve as a real-time sensor for not only monitoring RBC-linked anomalies but also predicting the overall status of the vascular microenvironment.


Assuntos
Acetatos/toxicidade , Cádmio/toxicidade , Eritrócitos/metabolismo , Exposição Materna/efeitos adversos , Fumar/efeitos adversos , Arginase/metabolismo , Candida/patogenicidade , Células Cultivadas , Eritrócitos/efeitos dos fármacos , Feminino , Sangue Fetal/metabolismo , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Ácido Peroxinitroso/metabolismo , Fosforilação , Gravidez
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