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Background: In neonatal intensive care units across the world, premature neonates are exposed to a very stressful environment with high levels of noise, bright lights, pain, infections, invasive procedures, and a lack of maternal contact. Stress is manifested by increased cortisol levels and clinical signs of stress. Objective: To assess the impact of Vimala massage on (1) salivary cortisol levels (primary outcome) and (2) clinical signs of stress (secondary outcomes) in premature neonates. Methods: Neonates (28-36 weeks gestational age) admitted to a nursery unit were randomized one-to-one to receive 15-20 min of Vimala massage administered by their parents twice daily and usual care, or to usual care alone. Salivary cortisol levels were measured by enzyme-linked immunosorbent assay (ELISA) on days 1 and 5. Heart rate, respiratory rate, caloric intake, weight gain, and growth were recorded daily. Groups were compared with t tests, U-tests, and repeated measures analysis of variance. Results: Seventy neonates, 35 in each group, were included. Groups were comparable at baseline. The median decrease in salivary cortisol levels was 0.12 µg/dL in the massage group and 0.07 µg/dL in the control group (p = 0.22). Over 5 days, the massage group had significant decreases in resting heart rate (p = 0.003) and respiratory rate (p = 0.028), and greater weight gains (p = 0.0002), relative to controls. Conclusions: In this randomized trial, adding Vimala massage to usual nursery care was not associated with a significant decrease in salivary cortisol levels in premature neonates, when compared with usual nursery care alone. There were improvements in clinical signs of stress.

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BACKGROUND: and purpose: Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHS-R1). Ghrelin, and GHS-R1, may have a role in placental growth and function, and its unacylated form desacylghrelin (DAG) could be involved in fetal growth. Nevertheless, the effects of DAG on placental function, and the receptor involved in its actions, remain to be determined. We aimed to investigate the effect of DAG in placental BeWo cells viability, proliferation, differentiation, and GSH-R1 expression. METHODS: BeWo cells, a human trophoblast cell line, was cultured with 3 nM DAG during 12, 24, 48, and 72 h. Cell viability, proliferation, differentiation (assessed by human Chorionic Gonadotropin quantification), and GSH-R1 expression were analyzed. To evaluate the mechanism of DAG effect on GSH-R1, 30 nM receptor antagonist ([D-Lys3]-GHRP-6) was added alone or in combination with 3 nM DAG during 12 h and 24 h. RESULTS: DAG has no effect on cell proliferation or viability, but it has an inhibitory effect on cell differentiation. DAG had a stimulatory effect on GSH-R1 expression at 12 and 24 h (p = 0.029 and p = 0.025, respectively). On the contrary, culture with 48 h DAG inhibits GSH-R1 expression compared to the control (p = 0.005), while GSH-R1 antagonist inhibited the effect of DAG on GSH-R1 expression. DAG also reduces intracellular (p = 0.020) and secreted (p = 0.011) hCG concentration in BeWo cells. CONCLUSION: DAG increases GHS-R1 expression, potentially mediated through GHS-R1 itself. DAG may also inhibit placental BeWo cell differentiation, suggesting a possible role of DAG in placental and fetal physiology.

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Nonalcoholic fatty liver disease (NAFLD) is the main liver disease worldwide, and its prevalence in children and adolescents has been increasing in the past years. It has been demonstrated that parental exposure to different conditions, both preconceptionally and during pregnancy, can lead to fetal programming of several metabolic diseases, including NAFLD. In this article, we review some of the maternal and paternal conditions that may be involved in early-life programing of adult NAFLD. First, we describe the maternal nutritional factors that have been suggested to increase the risk of NAFLD in the offspring, such as an obesogenic diet, overweight/obesity, and altered lipogenesis. Second, we review the association of certain vitamin supplementation and the use of some drugs during pregnancy, for instance, glucocorticoids, with a higher risk of NAFLD. Furthermore, we discuss the evidence showing that maternal-fetal pathologies, including gestational diabetes mellitus (GDM), insulin resistance (IR), and intrauterine growth restriction (IUGR), as well as the exposure to environmental contaminants, and the impact of microbiome changes, are important factors in early-life programming of NAFLD. Finally, we review how paternal preconceptional conditions, such as exercise and diet (particularly obesogenic diets), may impact fetal growth and liver function. Altogether, the presented evidence supports the hypothesis that both in utero exposure and parental conditions may influence fetal outcomes, including the development of NAFLD in early life and adulthood. The study of these conditions is crucial to better understand the diverse mechanisms involved in NAFLD, as well as for defining new preventive strategies for this disease.

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Adverse environmental factors in early life result in fetal metabolic programming and increased risk of adult diseases. Birth weight is an indirect marker of the intrauterine environment, modulated by nutrient availability and placental transport capacity. However, studies of placental transporters in idiopathic birth weight alterations and in maternal obesity in relation to neonatal metabolic outcomes are scarce. We aimed to analyze the placental nutrient transporter protein expression in small (SGA, n = 14), adequate (AGA, n = 18), and large (LGA n = 10) gestational age term for newborns from healthy or obese mothers (LGA-OB, n = 9) and their association with maternal fatty acids, metabolic status, placental triglycerides, and neonatal outcomes. The transporter expression was determined by Western blot. The fatty acid profile was evaluated by gas chromatography, and placental triglycerides were quantified by an enzymatic colorimetric method. GLUT1 was higher in LGA and lower in SGA and positively correlated with maternal HbA1c and placental weight (PW). SNAT2 was lower in SGA, while SNAT4 was lower in LGA-OB. FATP1 was lower in SGA and higher in LGA. SNAT4 correlated negatively and FATP1 correlated positively with the PW and birth anthropometry (BA). Placental triglycerides were higher in LGA and LGA-OB and correlated with pregestational BMI, maternal insulin, and BA. Maternal docosahexaenoic acid (DHA) was higher in SGA, specifically in male placentas, correlating negatively with maternal triglycerides, PW, cord glucose, and abdominal perimeter. Palmitic acid (PA) correlated positively with FATP4 and cord insulin, linoleic acid correlated negatively with PA and maternal cholesterol, and arachidonic acid correlated inversely with maternal TG and directly with FATP4. Our study highlights the importance of placental programming in birth weight both in healthy and obese pregnancies.

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BACKGROUND AND PURPOSE: Neonates at the highest and lowest percentiles of birth weight present an increased risk of developing metabolic diseases in adult life. While environmental events in utero may play an important role in this association, some genetic variants are associated both with birth weight and type 2 diabetes mellitus (T2DM), suggesting a genetic link between intrauterine growth and metabolism in adult life. Variants rs11708067 in ADCY5 and rs7754840 in CDKAL1 are associated with low birth weight, risk of T2DM, and lower insulin secretion in adults. We aimed to investigate whether, besides birth weight, these polymorphisms were related to insulin secretion at birth. METHODS: A cohort of 218 healthy term newborns from uncomplicated pregnancies were evaluated for anthropometric and biochemical variables. Cord blood insulin and C-peptide were analyzed by ELISA. Genotyping of rs11708067 in ADCY5 and rs7754840 in CDKAL1 was performed. RESULTS: Newborns carrying the A allele of ADCY5 rs11708067 had lower cord blood insulin and C-peptide, even after adjusting by maternal glycemia, HbA1c, and pregestational BMI. Lower birth weight was found for AA-AG genotypes compared to GG, but no differences were seen in adjusted birth weight or z-score. Variant rs7754840 in CDKAL1 was not associated with birth weight, neonatal insulin, or C-peptide for any genotype or genetic model. CONCLUSIONS: The variant rs11708067 in ADCY5 is associated with lower neonatal insulin and C-peptide concentrations. Our results suggest that the genetic influence on insulin secretion may be evident from birth, even in healthy newborns, independently of maternal glycemia and BMI.

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Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.

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BACKGROUND: According to the literature, probiotics are an attractive alternative to prevent necrotizing enterocolitis (NEC). However, due to differences in probiotic composition, randomized controlled trials are necessary to compare different probiotic mixtures. The objective of this study was to compare single strain (Lactobacillus acidophilus boucardii) versus multispecies probiotics on NEC incidence and faecal secretory Immunoglobulin A (sIgA) levels in very low preterm newborns. METHODS: We performed a double-blind randomized trial in 90 newborns. L. acidophilus boucardii strain or multispecies probiotics were randomly assigned to preterm newborns. As the primary outcome, we evaluated NEC incidence on the total length of neonatal intensive care unit (NICU) stay. As the secondary outcome, we measured the change in faecal sIgA levels from baseline to 3 weeks following the use of probiotics. RESULTS: NEC incidence was similar between groups (0% vs. 2.2% for the single strain and multispecies probiotic, respectively). Faecal sIgA levels increased significantly (p < 0.001) within groups (31% for single strain and 47% for multispecies probiotic), but this increase was not different between groups. Neonates with a faecal sIgA level increment >0.45 mg/dl showed higher gestational age, birth weight, and weight at the second and third weeks of follow up than neonates with a faecal sIgA level increment ≤0.45 mg/dl. No adverse effects were found after probiotics use. CONCLUSIONS: No difference between strains of probiotics used was found on NEC incidence or in the increase of faecal sIgA levels. Faecal sIgA levels were positively related to gestational age and body weight in very low preterm infants. ClinicalTrials.gov/NCT02245815.

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BACKGROUND: The signals that determine atherosclerosis-specific DNA methylation profiles are only partially known. We previously identified a 29-bp DNA motif (differential methylation motif [DMM]) proximal to CpG islands (CGIs) that undergo demethylation in advanced human atheromas. Those data hinted that the DMM docks modifiers of DNA methylation and transcription. METHODS AND RESULTS: We sought to functionally characterize the DMM. We showed that the DMM overlaps with the RNA polymerase III-binding B box of Alu short interspersed nuclear elements and contains a DR2 nuclear receptor response element. Pointing to a possible functional role for an Alu DMM, CGIs proximal (<100 bp) to near-intact DMM-harboring Alu are significantly less methylated relative to CGIs proximal to degenerate DMM-harboring Alu or to DMM-devoid mammalian-wide interspersed repeat short interspersed nuclear elements in human arteries. As for DMM-binding factors, LXRB (liver X receptor ß) binds the DMM in a DR2-dependent fashion, and LXR (liver X receptor) agonists induce significant hypermethylation of the bulk of Alu in THP-1 cells. Furthermore, we describe 3 intergenic long noncoding RNAs that harbor a DMM, are under transcriptional control by LXR agonists, and are differentially expressed between normal and atherosclerotic human aortas. Notably, CGIs adjacent to those long noncoding RNAs tend to be hypomethylated in symptomatic relative to stable human atheromas. CONCLUSIONS: Collectively, the data suggest that a DMM is associated with 2 distinct methylation states: relatively low methylation of in cis CGIs and Alu element hypermethylation. Based on the known atheroprotective role of LXRs, we propose that LXR agonist-induced Alu hypermethylation, a landmark of atherosclerosis, is a compensatory rather than proatherogenic response.

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Alterations in birth weight impact postnatal outcome and adult metabolic health. Therefore, fetal growth regulation is crucial for preventing chronic metabolic diseases. Leptin has been suggested to play an important role in placental and fetal growth, albeit its specific mechanisms of action have not been elucidated. The aim of this study was to analyze leptin concentrations in placenta, cord blood, and maternal blood of SGA, AGA, and LGA (small, adequate and large for gestational age, respectively) newborns, as well as placental leptin receptor (LEPRa and LEPRb) protein expression. We performed a cross-sectional comparative study in 3 groups of healthy mothers and their term newborns at delivery (SGA, AGA, and LGA, n=20 per group). Placental, maternal blood, and cord blood leptin content were measured by ELISA. Placental LEPRa and LEPRb protein expression were determined by Western Blot. Maternal leptin concentrations correlated positively with maternal weight before and at the end of gestation, without differences between groups. Cord leptin is higher in LGA and lower in SGA, whereas placental leptin is higher in SGA. Placental leptin was inversely correlated with placental weight, independently from maternal weight and gestational age. Both LEPRa and LEPRb expression are lower in SGA, while LEPRa positively correlated with placental weight and birthweight. The current findings indicate that placental leptin and its receptors are differentially expressed in SGA, AGA, and LGA newborns. We suggest that placental leptin and LEPR protein expression may influence placental growth and thus, birth weight.

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Abnormal fatty acid metabolism and availability are landmarks of metabolic diseases, which in turn are associated with aberrant DNA methylation profiles. To understand the role of fatty acids in disease epigenetics, we sought DNA methylation profiles specifically induced by arachidonic (AA) or oleic acid (OA) in cultured cells and compared those with published profiles of normal and diseased tissues. THP-1 monocytes were stimulated with AA or OA and analyzed using Infinium HumanMethylation450 BeadChip (Illumina) and Human Exon 1.0 ST array (Affymetrix). Data were corroborated in mouse embryonic fibroblasts. Comparisons with publicly available data were conducted by standard bioinformatics. AA and OA elicited a complex response marked by a general DNA hypermethylation and hypomethylation in the 1-200 µM range, respectively, with a maximal differential response at the 100 µM dose. The divergent response to AA and OA was prominent within the gene body of target genes, where it correlated positively with transcription. AA-induced DNA methylation profiles were similar to the corresponding profiles described for palmitic acid, atherosclerosis, diabetes, obesity, and autism, but relatively dissimilar from OA-induced profiles. Furthermore, human atherosclerosis grade-associated DNA methylation profiles were significantly enriched in AA-induced profiles. Biochemical evidence pointed to ß-oxidation, PPAR-α, and sirtuin 1 as important mediators of AA-induced DNA methylation changes. In conclusion, AA and OA exert distinct effects on the DNA methylome. The observation that AA may contribute to shape the epigenome of important metabolic diseases, supports and expands current diet-based therapeutic and preventive efforts.

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