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1.
J Nutr ; 150(5): 1144-1150, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32072161

RESUMO

BACKGROUND: There is evidence that microRNA (MIR) 122 is a biomarker for various liver diseases in adults and children. To date, MIR122 has not been explored in children with intestinal failure-associated liver disease (IFALD, or hyperbilirubinemia associated with prolonged parenteral nutrition). OBJECTIVES: This study's purpose was to investigate changes in plasma miR-122, correlate miR-122 with serum liver function tests and enzymes, and investigate changes in whole blood transcripts including miR-122 targets in a group of children with IFALD who received pure intravenous fish oil (FO) as a treatment for cholestasis. METHODS: This was a prospective, observational study that enrolled children with IFALD who received intravenous FO (1 g/kg/d) and whose cholestasis resolved with FO. Plasma miR-122 was measured using reverse transcription-quantitative real-time PCR, and whole blood miR-122 targets were quantified using RNA sequencing. RESULTS: Fourteen subjects with median age 6 mo (IQR: 3-65 mo) were enrolled. RNA sequence data were available for 4 subjects. When compared with the start of FO, median miR-122 concentrations at 6 mo of FO therapy decreased [1.0 (IQR: 1.0-1.0) compared with 0.04 (IQR: 0.01-0.6), P = 0.009]. At the start of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.038). At ∼3 mo of FO, miR-122 correlated with conjugated bilirubin (r = 0.56; P = 0.045). Reactive oxygen species, heme metabolism, coagulation, adipogenesis, IL-6-Janus kinase-signal transducer and activator of transcription (JAK-STAT) 3, IL-2-STAT5, transforming growth factor-ß, TNF-α, inflammatory response, mammalian target of rapamycin gene families (normalized enrichment scores < -1.4), and miR-122 target genes were significantly downregulated with FO. CONCLUSIONS: In this small cohort of young children with IFALD, miR-122 decreased with FO therapy and correlated with conjugated bilirubin. Key pathways involving oxidation, inflammation, cellular differentiation, and nutrient regulation were downregulated. Data from this study provide information about IFALD and FO. This trial was registered at www.clinicaltrials.gov as NCT00969332.

2.
J Neurosci Res ; 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31840315

RESUMO

To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10-19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), ß-III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl-2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro-survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3 months). Subanalysis by sex at E19 yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, female IUGR mice at E19 had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction-associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro-survival approach against nutritional adversity.

3.
J Magn Reson Imaging ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31680405

RESUMO

BACKGROUND: Noninvasive measurement of placental blood flow is the major technical challenge for predicting ischemic placenta (IPD). Pseudocontinuous arterial spin labeling (pCASL) MRI was recently shown to be promising, but the potential value in predicting the subsequence development of IPD is not known. PURPOSE: To derive global and regional placental blood flow parameters from longitudinal measurements of pCASL MRI and to assess the associations between perfusion-related parameters and IPD. STUDY TYPE: Prospective. POPULATION: Eighty-four women completed two pCASL MRI scans (first; 14-18 weeks and second; 19-24 weeks) from prospectively recruited 118 subjects. A total of 69 subjects were included for the analysis, of which 15 subjects developed IPD. FIELD STRENGTH/SEQUENCE: 3T/T2 -weighted half-Fourier single-shot turbo spin-echo (HASTE) and pCASL. ASSESSMENT: Four perfusion-related parameters in the placenta were derived: placenta volume, placental blood flow (PBF), high PBF (hPBF), and relative hPBF. The longitudinal changes of the parameters and their association with IPD were tested after being normalizing to the 16th and 20th weeks of gestation. STATISTICAL TESTS: Comparisons between two gestational ages within subjects were performed using the paired Wilcoxon tests, and comparisons between normal and IPD groups were performed using the unpaired Wilcoxon tests. RESULTS: The difference between the first and second MRI scans was statistically significant for volume (156.6 cm3 vs. 269.7 cm3 , P < 0.001) and PBF (104.9 ml/100g/min vs. 111.3 ml/100g/min, P = 0.02) for normal subjects, indicating an increase in pregnancy with advancing gestation. Of the parameters tested, the difference between the normal and IPD subjects was most pronounced in hPBF (278.1 ml/100g/min vs. 180.7 ml/100g/min, P < 0.001) and relative hPBF (259.1% vs. 183.2%, P < 0.001) at 16 weeks. DATA CONCLUSION: The high perfusion-related image parameters for IPD were significantly decreased from normal pregnancy at 14-18 weeks of gestation. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

4.
J Nutr Biochem ; 73: 108220, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31630081

RESUMO

We examined the role of hepatocyte micro-RNA-122 and hypothalamic neuropeptides, in weanling (21d) female rats exposed to calorie restriction induced growth restriction either prenatally (IUGR), postnatally (PNGR) or both (IPGR) vs. ad lib fed controls (CON). IUGR were hyperinsulinemic, hyperleptinemic and dyslipidemic with high circulating miR-122. In contrast, PNGR and IPGR displayed insufficient glucose, insulin and leptin amidst high ketones with a dichotomy in circulating miR-122 of PNGR

5.
Nutr Res ; 69: 67-81, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31639589

RESUMO

Diet during pregnancy has long lasting consequences on the offspring, warranting a study on the impact of early exposure to a high fat diet on the adult offspring. We hypothesized that a prenatal n-6 enriched diet will have adverse metabolic outcomes on the adult offspring that may be reversed with a postnatal n-3 enriched diet. To test this hypothesis, we examined the adult offspring from three groups: (1) n-6 group: during gestation and lactation, dams consumed an n-6 polyunsaturated fatty acid enriched diet, (2) n-3 group: gestational n-6 diet was followed by an n-3 enriched diet during lactation, and (3) a control (CD) group that received standard diet throughout gestation and lactation. Offspring from all groups weaned to a control diet ad libitum. Beginning at postnatal day 2 (P < .03) and persisting at 360 days in males (P < .04), an increase in hypothalamic AgRP expression occurred in the n-6 and n-3 groups, with an increase in food intake (P = .01), and the n-3 group displaying lower body (P < .03) and brain (P < .05) weights. At 360 days, the n-6 and n-3 groups remained glucose tolerant and insulin sensitive, with increased phosphorylated-AMP-activated protein kinase (P < .05). n-6 group developed hepatic steatosis with reduced hepatic reflected as higher plasma microRNA-122 (P < .04) that targets pAMPK. We conclude that early life exposure to n-6 and n-3 led to hypothalamic AgRP-related higher food intake, with n-6 culminating in a fatty liver partially mitigated by postnatal n-3. While both diets preserved glucose tolerance and insulin sensitivity, postnatal n-3 displayed detrimental effects on the brain.

6.
Mol Genet Metab ; 127(2): 166-173, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31182397

RESUMO

OBJECTIVE: We examined Red Blood Cell (RBC) Glucose Transporter isoform 1 (GLUT1) and White Blood Cell (WBC) Glucose Transporter isoform 3 (GLUT3) protein concentrations to assess their potential as surrogate biomarkers for the presence of hypoxic-ischemic encephalopathy (HIE) and response to therapeutic hypothermia (TH), with respect to the neurodevelopmental prognosis. STUDY DESIGN: A prospective feasibility study of 10 infants with HIE and 8 age-matched control subjects was undertaken. Following parental consent, blood samples were obtained at baseline before institution of TH (<6 h of life), during TH, at rewarming and post-TH in the HIE group with a baseline sample from the control group. GLUT1 and GLUT3 were measured by Enzyme-linked immunosorbent assay (ELISA) with brain biomarkers, Neuron-Specific Enolase (NSE) and Glial Fibrillary Acidic Protein (GFAP). Novel "HIE-high risk" and "Neurological" scores were developed to help identify HIE and to assess severity and prognosis, respectively. RESULTS: RBC GLUT1 concentrations were increased at the baseline pre-TH time point in HIE versus control subjects (p = .006), normalizing after TH (p = .05). An association between GLUT1 and NSE concentrations (which was reflective of the HIE-high risk and the Neuro-scores) in controls and HIE pre-TH was seen (R2 = 0.36, p = .008), with GLUT1 demonstrating 90% sensitivity and 88% specificity for presence of HIE identified by Sarnat Staging. WBC GLUT3 concentrations were low and no different in HIE versus control, and GFAP concentrations trended higher during re-warming (p = .11) and post-TH (p = .16). We demonstrated a significant difference between HIE and controls for both the "HIE-high risk" and the "Neurological" Scores. The latter score revealing the severity of clinical neurological illness correlated with the corresponding RBC GLUT1 (R2 value = 0.39; p = .006). CONCLUSION: Circulating RBC GLUT1 concentrations with NSE demonstrate a significant potential in reflecting the severity of HIE pre-TH and gauging effectiveness of TH. In contrast, the low neonatal WBC GLUT3 concentrations make discerning differences between degrees of HIE as well as assessing effectiveness of TH difficult. The HIE-high risk and Neurological scores may extend the "Sarnat staging" towards assessing severity and neuro-developmental prognosis of HIE.

7.
Pediatr Clin North Am ; 66(2): 403-423, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30819345

RESUMO

Intrauterine growth restriction (IUGR) is an important cause of fetal, perinatal and neonatal morbidity and mortality. IUGR occurs because of multiple reasons. Neonates with IUGR experience acute problems in the perinatal and early neonatal period that can be life-threatening. The unfavorable uterine environment causing growth restriction results in programming that predisposes IUGR infants to long-term health issues such as poor physical growth, metabolic syndrome, cardiovascular disease, neurodevelopmental impairment and endocrine abnormalities, warranting careful monitoring. It is imperative to strike the balance between achieving optimal catch-up to promote normal development, while preventing the onset of cardiovascular and metabolic disorders in the long-term.


Assuntos
Desenvolvimento Infantil , Retardo do Crescimento Fetal/diagnóstico , Doenças do Recém-Nascido/etiologia , Monitorização Fisiológica/métodos , Feminino , Retardo do Crescimento Fetal/terapia , Humanos , Lactente , Recém-Nascido , Gravidez
8.
Sci Rep ; 9(1): 1243, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718791

RESUMO

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease.

9.
J Magn Reson Imaging ; 49(1): 291-303, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30142239

RESUMO

BACKGROUND: Multiecho gradient-echo Cartesian MRI characterizes placental oxygenation by quantifying R 2 * . Previous research was performed at 1.5T using breath-held 2D imaging during later gestational age (GA). PURPOSE: To evaluate the accuracy and repeatability of a free-breathing (FB) 3D multiecho gradient-echo stack-of-radial technique (radial) for placental R 2 * mapping at 3T and report placental R 2 * during early GA. STUDY TYPE: Prospective. POPULATION: Thirty subjects with normal pregnancies and three subjects with ischemic placental disease (IPD) were scanned twice: between 14-18 and 19-23 weeks GA. FIELD STRENGTH: 3T. SEQUENCE: FB radial. ASSESSMENT: Linear correlation (concordance coefficient, ρc ) and Bland-Altman analyses (mean difference, MD) were performed to evaluate radial R 2 * mapping accuracy compared to Cartesian in a phantom. Radial R 2 * mapping repeatability was characterized using the coefficient of repeatability (CR) between back-to-back scans. The mean and spatial coefficient of variation (CV) of R 2 * was determined for all subjects, and separately for anterior and posterior placentas, at each GA range. STATISTICAL TESTS: ρc was tested for significance. Differences in mean R 2 * and CV were tested using Wilcoxon Signed-Rank and Rank-Sum tests. P < 0.05 was considered significant. Z-scores for the IPD subjects were determined. RESULTS: FB radial demonstrated accurate (ρc ≥0.996; P < 0.001; |MD|<0.2s-1 ) and repeatable (CR<4s-1 ) R 2 * mapping in a phantom, and repeatable (CR≤4.6s-1 ) R 2 * mapping in normal subjects. At 3T, placental R 2 * mean ± standard deviation was 12.9s-1 ± 2.7s-1 for 14-18 and 13.2s-1 ± 1.9s-1 for 19-23 weeks GA. The CV was significantly greater (P = 0.043) at 14-18 (0.63 ± 0.12) than 19-23 (0.58 ± 0.13) weeks GA. At 19-23 weeks, the CV was significantly lower (P < 0.001) for anterior (0.49 ± 0.08) than posterior (0.67 ± 0.11) placentas. One IPD subject had a lower mean R 2 * than normal subjects at both GA ranges (Z<-2). DATA CONCLUSION: FB radial provides accurate and repeatable 3D R 2 * mapping for the entire placenta at 3T during early GA. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:291-303.

10.
J Nutr Biochem ; 62: 192-201, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30308381

RESUMO

We examined the effect of a high-fat diet (HFD) vs. control diet (CD) upon pregestational and gestational wild-type (wt) and glucose transporter (glut)3 heterozygous (glut3+/-) female mice and observed an increase in pregestational body weights, white adiposity (wt > glut3+/-), circulating cholesterol, and high-density lipoproteins, with glucose intolerance in both genotypes. The HFD-exposed offspring displayed reduced birth weight with catch up to CD-fed in wt vs. an increased birth weight persisting as such at weaning by day 21 in glut3+/- mice. To decipher the mechanism behind this genotype-specific difference in the HFD offspring's phenotype, we first examined placental macronutrient transporters and noted HFD-induced increase in CD36 in wt with no change in other FATPs, sodium-coupled neutral amino acid transporters and system L amino acid transporter in both genotypes. In contrast, while placental Glut1 increased in both the genotypes, only Glut3 increased in the glut3+/- genotype in response to HFD. Hence, we next assessed glut3+/- embryonic (ES) cells under differing stressors of low glucose, hypoxia and inhibition of oxidative phosphorylation. Reduced Glut3-mediated glucose uptake in glut3+/- vs. wt ES cells culminated in deficient growth. We conclude that maternal HFD affects the in utero growth potential of the offspring by altering placental CD36 and Glut1 concentrations. In contrast, a differential effect on placental Glut3 concentrations between glut3+/- and wt genotypes is evident, with an increase occurring in the glut3+/- genotype alone. Deficient Glut3 in ES cells interferes with glucose uptake, cell survival and growth being further exaggerated with low glucose, hypoxia and inhibition of oxidative phosphorylation.


Assuntos
Adiposidade/fisiologia , Dieta Hiperlipídica/efeitos adversos , Transportador de Glucose Tipo 3/genética , Obesidade/etiologia , Placenta/metabolismo , Animais , Animais Recém-Nascidos , Blastocisto/metabolismo , Peso Corporal , Antígenos CD36/metabolismo , Feminino , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Heterozigoto , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Nutrientes/metabolismo , Tamanho do Órgão , Fosforilação Oxidativa , Gravidez
11.
J Neurosci ; 38(44): 9579-9599, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30232223

RESUMO

We created a neural-specific conditional murine glut3 (Slc2A3) deletion (glut3 flox/flox/nestin-Cre+) to examine the effect of a lack of Glut3 on neurodevelopment. Compared with age-matched glut3 flox/flox = WT and heterozygotes (glut3 flox/+/nestin-Cre+), we found that a >90% reduction in male and female brain Glut3 occurred by postnatal day 15 (PN15) in glut3 flox/flox/nestin-Cre+ This genetic manipulation caused a diminution in brain weight and cortical thickness at PN15, a reduced number of dendritic spines, and fewer ultrasonic vocalizations. Patch-clamp recordings of cortical pyramidal neurons revealed increased frequency of bicuculline-induced paroxysmal discharges as well as reduced latency, attesting to a functional synaptic and cortical hyperexcitability. Concomitant stunting with lower glucose concentrations despite increased milk intake shortened the lifespan, failing rescue by a ketogenic diet. This led to creating glut3 flox/flox/CaMK2α-Cre+ mice lacking Glut3 in the adult male limbic system. These mice had normal lifespan, displayed reduced IPSCs in cortical pyramidal neurons, less anxiety/fear, and lowered spatial memory and motor abilities but heightened exploratory and social responses. These distinct postnatal and adult phenotypes, based upon whether glut3 gene is globally or restrictively absent, have implications for humans who carry copy number variations and present with neurodevelopmental disorders.SIGNIFICANCE STATEMENT Lack of the key brain-specific glucose transporter 3 gene found in neurons during early postnatal life results in significant stunting, a reduction in dendritic spines found on neuronal processes and brain size, heightened neuronal excitability, along with a shortened lifespan. When occurring in the adult and limited to the limbic system alone, lack of this gene in neurons reduces the fear of spatial exploration and socialization but does not affect the lifespan. These features are distinct heralding differences between postnatal and adult phenotypes based upon whether the same gene is globally or restrictively lacking. These findings have implications for humans who carry copy number variations pertinent to this gene and have been described to present with neurodevelopmental disorders.


Assuntos
Encéfalo/metabolismo , Comportamento Exploratório/fisiologia , Deleção de Genes , Transportador de Glucose Tipo 3/deficiência , Transportador de Glucose Tipo 3/genética , Fenótipo , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Espinhas Dendríticas/genética , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética
12.
Nutr Res ; 54: 93-104, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29685622

RESUMO

Intrauterine growth restriction is linked to decreased lean body mass and insulin resistance. The mammalian target of rapamycin (mTOR) regulates muscle mass and glucose metabolism; however, little is known about maternal dietary restriction and skeletal muscle mTOR in offspring. We hypothesized that early dietary restriction would decrease skeletal muscle mass and mTOR in the suckling rat. To test this hypothesis, ab libitum access to food or dietary restriction during gestation followed by postnatal cross-fostering to a dietary-restricted or ad libitum-fed rat dam during lactation generated 4 groups: control (CON), intrauterine dietary restricted (IUDR), postnatal dietary restricted (PNDR), and IUDR+PNDR (IPDR). At day 21, when compared to CON, the IUDR group demonstrated "catchup" growth, but no changes were observed in the mTOR pathway. Despite having less muscle mass than CON and IUDR (P < .001), in IPDR and PNDR rats mTOR remained unchanged. IPDR and PNDR (p)-tuberous sclerosis complex 2 was less than the IUDR group (P < .05). Downstream, IPDR's and PNDR's phosphorylated (p)-ribosomal s6 (rs6)/rs6 was less than that of CON (P < .05). However, male IPDR's and PNDR's p-mitogen activated protein kinase MAPK/MAPK was greater than CON (P < .05) without a change in p90 ribosomal s6 kinase (p90RSK). In contrast, in females, MAPK was unchanged, but IPDR p-p90RSK/p90RSK was less than CON (P = .01). In conclusion, IPDR and PNDR reduced skeletal muscle mass but did not decrease mTOR. In IPDR and PNDR, a reduction in tuberous sclerosis complex 2 may explain why mTOR was unchanged, whereas, in males, an increase in MAPK with a decrease in rs6 may suggest a block in MAPK signaling.


Assuntos
Restrição Calórica , Ingestão de Energia , Fenômenos Fisiológicos da Nutrição Materna , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Esclerose Tuberosa/metabolismo , Animais , Composição Corporal , Feminino , Retardo do Crescimento Fetal , Resistência à Insulina , Lactação , Masculino , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
13.
PLoS One ; 13(3): e0193583, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29590129

RESUMO

BACKGROUND: Intrauterine growth restriction (IUGR) results from a lack of nutrients transferred to the developing fetus, particularly oxygen and glucose. Increased expression of the cytoprotective mitochondrial peptide, humanin (HN), and the glucose transporter 8, GLUT8, has been reported under conditions of hypoxic stress. However, the presence and cellular localization of HN and GLUT8 in IUGR-related placental pathology remain unexplored. Thus, we undertook this study to investigate placental expression of HN and GLUT8 in IUGR-affected versus normal pregnancies. RESULTS: We found 1) increased HN expression in human IUGR-affected pregnancies on the maternal aspect of the placenta (extravillous trophoblastic (EVT) cytoplasm) compared to control (i.e. appropriate for gestational age) pregnancies, and a concomitant increase in GLUT8 expression in the same compartment, 2) HN and GLUT8 showed a protein-protein interaction by co-immunoprecipitation, 3) elevated HN and GLUT8 levels in vitro under simulated hypoxia in human EVT cells, HTR8/SVneo, and 4) increased HN expression but attenuated GLUT8 expression in vitro under serum deprivation in HTR8/SVneo cells. CONCLUSIONS: There was elevated HN expression with cytoplasmic localization to EVTs on the maternal aspect of the human placenta affected by IUGR, also associated with increased GLUT8 expression. We found that while hypoxia increased both HN and GLUT8, serum deprivation increased HN expression alone. Also, a protein-protein interaction between HN and GLUT8 suggests that their interaction may fulfill a biologic role that requires interdependency. Future investigations delineating molecular interactions between these proteins are required to fully uncover their role in IUGR-affected pregnancies.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Placenta/metabolismo , Adulto , Citoplasma/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Placenta/patologia , Gravidez , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Trofoblastos/patologia , Regulação para Cima
14.
Front Genet ; 9: 642, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619467

RESUMO

Early life nutritional imbalances are risk factors for metabolic dysfunctions in adulthood, but the long term effects of perinatal exposure to high versus low protein diets are not completely understood. We exposed C57BL/6J offspring to a high protein/low carbohydrate (HP/LC) or low protein/high carbohydrate (LP/HC) diet during gestation and lactation, and measured metabolic phenotypes between birth and 10 months of age in male offspring. Perinatal HP/LC and LP/HC exposures resulted in a decreased ability to clear glucose in the offspring, with reduced baseline insulin and glucose concentrations in the LP/HC group and a reduced insulin response post-glucose challenge in the HP/LC group. The LP/HC diet group also showed reduced birth and weanling weights, whereas the HP/LC offspring displayed increased weanling weight with increased adiposity beyond 5 months of age. Gene expression profiling of hypothalamus and liver revealed alterations in diverse molecular pathways by both diets. Specifically, hypothalamic transcriptome and pathway analyses demonstrated perturbations of MAPK and hedgehog signaling, processes associated with neural restructuring and transmission, and phosphate metabolism by perinatal protein imbalances. Liver transcriptomics revealed changes in purine and phosphate metabolism, hedgehog signaling, and circadian rhythm pathways. Our results indicate maternal protein imbalances perturbing molecular pathways in central and peripheral metabolic tissues, thereby predisposing the male offspring to metabolic dysfunctions.

15.
J Magn Reson Imaging ; 47(6): 1667-1676, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29135072

RESUMO

BACKGROUND: Placenta influences the health of both a woman and her fetus during pregnancy. Maternal blood supply to placenta can be measured noninvasively using arterial spin labeling (ASL). PURPOSE: To present a multidelay pseudocontinuous arterial spin labeling (pCASL) combined with a fast 3D inner-volume gradient- and spin-echo (GRASE) imaging technique to simultaneously measure placental blood flow (PBF) and arterial transit time (ATT), and to study PBF and ATT evolution with gestational age during the second trimester. The PBF values were compared with uterine arterial Doppler ultrasound to assess its potential clinical utility. STUDY TYPE: This was a prospective study. SUBJECTS: Thirty-four pregnant women. FIELD STRENGTH/SEQUENCE: Multidelay 3D inner-volume GRASE pCASL sequence on 3T MR scanners. ASSESSMENT: Subjects underwent two longitudinal MRI scans within the second trimester, conducted between 14-16 and 19-22 weeks of gestational age, respectively. Placental perfusion was measured using the free-breathing pCASL sequence at three postlabeling delays (PLDs), followed by offline motion correction and model fitting for estimation of PBF and ATT. STATISTICAL TESTS: A paired t-test was conducted to evaluate the significance of PBF/ATT variations with placental development. A two-sample t-test was conducted to evaluate the significance of PBF difference in subjects with and without early diastolic notch. RESULTS: The mean PBF and ATT for the second trimester were 111.4 ± 26.7 ml/100g/min and 1387.5 ± 88.0 msec, respectively. The average PBF increased by 10.4% (P < 0.05), while no significant change in ATT (P = 0.72) was found along gestational ages during the second trimester. PBF decreased 20.3% (P < 0.01) in subjects with early diastolic notches in ultrasound flow waveform patterns. DATA CONCLUSION: Multidelay pCASL with inner-volume 3D GRASE is promising for noninvasive assessment of PBF during pregnancy. Its clinical use for the detection of aberrations in placental function and prediction of fetal developmental disorders awaits evaluation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1667-1676.


Assuntos
Artérias/diagnóstico por imagem , Imageamento Tridimensional/métodos , Angiografia por Ressonância Magnética/métodos , Imagem por Ressonância Magnética , Placenta/irrigação sanguínea , Placenta/diagnóstico por imagem , Marcadores de Spin , Ultrassonografia Doppler , Adulto , Algoritmos , Circulação Cerebrovascular/fisiologia , Diástole , Feminino , Idade Gestacional , Humanos , Aumento da Imagem/métodos , Movimento (Física) , Perfusão , Gravidez , Segundo Trimestre da Gravidez , Estudos Prospectivos
16.
Reprod Sci ; 25(4): 523-539, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28693373

RESUMO

Inherent genetic programming and environmental factors affect fetal growth in utero. Epidemiologic data in growth-altered fetuses, either intrauterine growth restricted (IUGR) or large for gestational age (LGA), demonstrate that these newborns are at increased risk of cardiometabolic disease in adulthood. There is growing evidence that the in utero environment leads to epigenetic modification, contributing to eventual risk of developing heart disease or diabetes. In this study, we used reduced representation bisulfite sequencing to examine genome-wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA) and to identify differential methylation of genes important for conferring risk of cardiometabolic disease. We found that there were distinct methylation signatures for IUGR, LGA, and AGA groups and identified over 500 differentially methylated genes (DMGs) among these group comparisons. Functional and gene network analyses revealed expected relationships of DMGs to placental physiology and transport, but also identified novel pathways with biologic plausibility and potential clinical importance to cardiometabolic disease. Specific loci for DMGs of interest had methylation patterns that were strongly associated with anthropometric presentations. We further validated altered gene expression of these specific DMGs contributing to vascular and metabolic diseases (SLC36A1, PTPRN2, CASZ1, IL10), thereby establishing transcriptional effects toward assigning functional significance. Our results suggest that the gene expression and methylation state of the human placenta are related and sensitive to the intrauterine environment, as it affects fetal growth patterns. We speculate that these observed changes may affect risk for offspring in developing adult cardiometabolic disease.


Assuntos
Peso ao Nascer/genética , Metilação de DNA , Desenvolvimento Fetal/genética , Placenta/metabolismo , Epigênese Genética , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Gravidez
17.
PLoS One ; 12(5): e0176493, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28463968

RESUMO

Placental insufficiency leading to intrauterine growth restriction (IUGR) demonstrates perturbed gene expression affecting placental angiogenesis and nutrient transfer from mother to fetus. To understand the post-transcriptional mechanisms underlying such placental gene expression changes, our objective was to identify key non-coding microRNAs that express biological function. To this end, we initially undertook microarrays targeting microRNAs in a small sub-set of placentas of appropriate (AGA) versus small for gestational age (SGA) weight infants, and observed up-regulation of 97 miRs and down-regulation of 44 miRs in SGA versus AGA. In a larger cohort of samples (AGA, n = 21; SGA, n = 11; IUGR subset, n = 5), we validated by qRT-PCR differential expression of three specific microRNAs (miR-10b, -363 and -149) that target genes mediating angiogenesis and nutrient transfer. Validation yielded an increase in miR-10b and -363 expression of ~2.5-fold (p<0.02 each) in SGA versus AGA, and of ~3-fold (p<0.005) in IUGR versus AGA, with no significant change despite a trending increase in miR-149. To further establish a cause-and-effect paradigm, employing human HTR8 trophoblast cells, we assessed the effect of nutrient deprivation on miR expression and inhibition of endogenous miRs on target gene expression. In-vitro nutrient deprivation (~50%) increased the expression of miR-10b and miR-149 by 1.5-fold (p<0.02) while decreasing miR-363 (p<0.0001). Inhibition of endogenous miRs employing antisense sequences against miR-10b, -363 and -149 revealed an increase respectively in the expression of the target genes KLF-4 (transcription factor which regulates angiogenesis), SNAT1 and 2 (sodium coupled neutral amino acid transporters) and LAT2 (leucine amino acid transporter), which translated into a similar change in the corresponding proteins. Finally to establish functional significance we performed dual-luciferase reporter assays with 3'-insertion of miR-10b alone and observed a ~10% reduction in the 5'-luciferase activity versus the control. Lastly, we further validated by microarray and employing MirWalk software that the pathways and target genes identified by differentially expressed miRs in SGA/IUGR compared to AGA are consistent in a larger cohort. We have established the biological significance of various miRs that target common transcripts mediating pathways of importance, which are perturbed in the human IUGR placenta.


Assuntos
Aminoácidos/metabolismo , Retardo do Crescimento Fetal/metabolismo , MicroRNAs/metabolismo , Neovascularização Fisiológica/fisiologia , Placenta/metabolismo , Western Blotting , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Masculino , MicroRNAs/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Placenta/fisiologia , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Trofoblastos/metabolismo , Trofoblastos/fisiologia
18.
Endocrinology ; 158(4): 936-949, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28324109

RESUMO

We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (ß-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid ß1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Dieta Cetogênica , Transportador de Glucose Tipo 3/metabolismo , Convulsões/dietoterapia , Comportamento Social , Animais , Encéfalo/fisiopatologia , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Eletroencefalografia , Feminino , Glucose/metabolismo , Transportador de Glucose Tipo 3/genética , Masculino , Memória/fisiologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Fatores Sexuais , Aprendizagem Espacial/fisiologia , Vocalização Animal/fisiologia
19.
Nutr Res ; 36(10): 1055-1067, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27865347

RESUMO

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long-term sequelae for offspring. The mechanisms underlying IUGR are poorly understood, but it is known that healthy placentation is essential for nutrient provision to fuel fetal growth, and is regulated by immunologic inputs. We hypothesized that in pregnancy, maternal food restriction (FR) resulting in IUGR would decrease the overall immunotolerant milieu in the placenta, leading to increased cellular stress and death. Our specific objectives were to evaluate (1) key cytokines (eg, IL-10) that regulate maternal-fetal tolerance, (2) cellular processes (autophagy and endoplasmic reticulum [ER] stress) that are immunologically mediated and important for cellular survival and functioning, and (3) the resulting IUGR phenotype and placental histopathology in this animal model. After subjecting pregnant mice to mild and moderate FR from gestational day 10 to 19, we collected placentas and embryos at gestational day 19. We examined RNA sequencing data to identify immunologic pathways affected in IUGR-associated placentas and validated messenger RNA expression changes of genes important in cellular integrity. We also evaluated histopathologic changes in vascular and trophoblastic structures as well as protein expression changes in autophagy, ER stress, and apoptosis in the mouse placentas. Several differentially expressed genes were identified in FR compared with control mice, including a considerable subset that regulates immune tolerance, inflammation, and cellular integrity. In summary, maternal FR decreases the anti-inflammatory effect of IL-10 and suppresses placental autophagic and ER stress responses, despite evidence of dysregulated vascular and trophoblast structures leading to IUGR.


Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Retardo do Crescimento Fetal/etiologia , Transtornos da Nutrição Fetal/etiologia , Interleucina-10/metabolismo , Placenta , Fenômenos Fisiológicos da Nutrição Pré-Natal , Animais , Apoptose , Vasos Sanguíneos , Ingestão de Alimentos , Ingestão de Energia , Feminino , Retardo do Crescimento Fetal/metabolismo , Transtornos da Nutrição Fetal/metabolismo , Tolerância Imunológica , Inflamação/etiologia , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Mães , Placenta/imunologia , Placenta/metabolismo , Placenta/patologia , Gravidez , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Trofoblastos
20.
Endocrinology ; 157(10): 4041-4054, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27494059

RESUMO

We examined the effect of mild (Mi; ∼25%) and moderate (Mo; ∼50%) maternal calorie restriction (MCR) vs ad libitum-fed controls on placental glucose and leucine transport impacting fetal growth potential. We observed in MiMCR a compensatory increase in transplacental (TP) glucose transport due to increased placental glucose transporter isoform (GLUT)-3 but no change in GLUT1 protein concentrations. This change was paralleled by increased glut3 mRNA and 5-hydroxymethylated cytosines with enhanced recruitment of histone 3 lysine demethylase to the glut3 gene locus. To assess the biologic relevance of placental GLUT1, we also examined glut1 heterozygous null vs wild-type mice and observed no difference in placental GLUT3 and TP or intraplacental glucose and leucine transport. Both MCR states led to a graded decrease in TP and intraplacental leucine transport, with a decline in placental L amino acid transporter isoform 2 (LAT2) concentrations and increased microRNA-149 (targets LAT2) and microRNA-122 (targets GLUT3) expression in MoMCR alone. These changes were accompanied by a step-wise reduction in uterine and umbilical artery Doppler blood flow with decreased fetal left ventricular ejection fraction and fractional shortening. We conclude that MiMCR transactivates placental GLUT3 toward preserving TP glucose transport in the face of reduced leucine transport. This contrasts MoMCR in which a reduction in placental GLUT3 mediated glucose transport with a reciprocal increase in miR-122 expression was encountered. A posttranscriptional reduction in LAT2-mediated leucine transport also occurred with enhanced miR-149 expression. Both MCR states, although not affecting placental GLUT1, resulted in uteroplacental insufficiency and fetal growth restriction with compromised cardiovascular health.


Assuntos
Restrição Calórica/efeitos adversos , Placenta/metabolismo , Insuficiência Placentária/etiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Desenvolvimento Embrionário , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Leucina/metabolismo , Camundongos Endogâmicos C57BL , Placenta/patologia , Circulação Placentária , Insuficiência Placentária/metabolismo , Gravidez
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