First Week Of Postnatal Life Research Articles

Early and late postnatal lung distribution of collagen type VI in preterm and term infants

Collagen type VI (COL6) is an important component of the extracellular matrix (EM) and may have a major role in lung development and disease. Studies on COL6 expression during lung development are mainly based on animal models. The aim of the study was to define COL6 expression pattern in lung parenchyma in infants with different lung maturational stages.COL6 expression in 115 lung samples from deceased newborn infants (21–41 weeks’ gestational age; 0–228 days’ postnatal age) was studied by immunohistochemistry combined with digital image analysis.The distribution of COL6 expression was generally heterogeneous in the lung parenchyma of preterm and term infants. The size of the high-density and low-density areas appeared with logarithmic correlation and COL6 defined the basement membrane (BM) with a prominent expression around the air spaces in the canalicular stage during the first postnatal week. Infants at the alveolar stage showed linear correlation and a fine filamentous appearance during the first week of postnatal life, similarly to adults.COL6 is condensed to areas corresponding to the BM during the first postnatal week of the canalicular stage of lung development. After the first postnatal week COL6 expression changes to a microfibrillar appearance in the ECM, similar to the pattern that characterizes the later alveolar stage and adults. The localization of COL6 during the canalicular and saccular stages might have a higher impact on lung development than the amount of COL6.

Late maternal separation provides resilience to chronic variable stress-induced anxiety- and depressive-like behaviours in male but not female mice

Maternal separation can have long-lasting effects on an individual’s susceptibility to stress later in life. Maternal separation during the postnatal period is a commonly used paradigm in rodents to investigate the effects of early life stress on neurobehavioural changes and stress responsiveness. However, maternal separation during stress hyporesponsive and responsive periods of postnatal development may differ in its effects on stress resilience. Therefore, we hypothesised that late maternal separation (LMS) from postnatal day 10 to 21 in mice may have different effect on resilience than early maternal separation during the first week of postnatal life. Our results suggested that male LMS mice are more resilient to chronic variable stress (CVS)-induced anxiety and depressive-like behaviour as confirmed by the open field, light-dark field, elevated plus maze, sucrose preference and tail suspension tests. In contrast, female LMS mice were equally resilient as non-LMS female mice. We found increased expression of NPY, NPY1R, NPY2R, NPFFR1, and NPFFR2 in the hypothalamus of male LMS mice whereas the opposite effect was observed in the hippocampus. LMS in male and female mice did not affect circulating corticosterone levels in response to psychological or physiological stressors. Thus, LMS renders male mice resilient to CVS-induced neurobehavioural disorders in adulthood.

Dissecting signal transduction pathways that regulate cardiomyocyte proliferation

Abstract Funding Acknowledgements None. Introduction During cardiac development, the Notch, Hippo, and Wnt/β-catenin signalling pathways play a crucial role in the tuning of cardiomyocyte proliferation. The individual engagement of each of these pathways during the early postnatal life, however, is still unclear. Purpose We wanted to develop a method to visualize over time, both in vitro and in vivo, the topography of activation of the Notch, Wnt/β-catenin, and Hippo pathways and their crosstalk upon cardiomyocyte treatment with a series of pro-proliferative stimuli. Methods We obtained Adeno-Associated Virus (AAV) constructs expressing distinct fluorescent proteins (ECFP, GFP, mCherry, DsRed) under the control of promoters that are specifically activated downstream of the signalling cascades of interest (a synthetic promoter consisting of 12 CSL binding sites for Notch1, a synthetic promoter consisting of 8 TEAD binding sites for YAP, and a synthetic promoter containing 7 TCF/LEF1 binding sites for β-catenin). Results First, by high content microscopy we followed the time of the activation of the AAV vectors coding for fluorescent reporters, either alone or in combination. We observed that a crosstalk exists between Yap and Notch signalling in proliferating cardiomyocytes, as detected by the activation of their respective fluorescent reporters. We confirmed our data by gene expression analysis and co-immunoprecipitation using specific antibodies in fractionated cardiomyocyte extracts. Next, we observe that miR-1825, miR-199a-3p, and miR-590-3p – three pro-regenerative miRNAs in cardiomyocytes– specifically activate both Yap and Notch signalling. Finally we characterized the reporter systems in vivo, to dissect the intracellular signalling pathways that are active in the first week of postnatal life. Beta-catenin signalling was quite undetectable in any of the conditions tested. In contrast, both Notch and Yap showed significant activation, consistent with their role in regulating early postnatal cardiomyocyte proliferation. Conclusions The developed AAV-fluorescent reporters allow to efficiently and specifically visualize the pro-proliferative activation of Notch and Yap signalling both in vitro and in vivo. The results obtained are supportive of a crosstalk existing between Notch and Yap pathways in proliferating cardiomyocytes.

Breast-feeding as protective factor against bronchopulmonary dysplasia in preterm infants.

Breast-feeding is associated with fewer comorbidities in very-low-birth-weight (VLBW) preterm infants. Bronchopulmonary dysplasia (BPD) of VLBW infants is a multifactorial pathology in which nutritional aspects may be of special importance. The aim of this study is to determine, in a cohort of VLBW infants, whether breast milk nutrition is associated with a reduced prevalence and severity of BPD. A retrospective study was conducted to record the intake of mother's own milk (MOM), pasteurised donor human milk or preterm formula milk in the first 2 weeks of postnatal life of 566 VLBW newborns at our hospital during the period January 2008-December 2021. After applying the relevant exclusion criteria, data for 489 VLBW infants were analysed; 195 developed some degree of BPD. Moderate or severe BPD is associated with less weight gain. Moreover, the preferential ingestion of breast milk in the first and second postnatal weeks had effects associated with lower OR for BPD, which were statistically demonstrable for mild (OR 0·16; 95 % CI 0·03, 0·71) and severe (OR 0·08; 95 % CI 0·009, 0·91) BPD. Breast-feeding during the first weeks of postnatal life is associated with a reduced prevalence of BPD, which is frequently associated with less weight gain as a result of greater respiratory effort with greater energy expenditure.

Time-resolved transcriptomic profiling of the developing rabbit’s lungs: impact of premature birth and implications for modelling bronchopulmonary dysplasia

BackgroundPremature birth, perinatal inflammation, and life-saving therapies such as postnatal oxygen and mechanical ventilation are strongly associated with the development of bronchopulmonary dysplasia (BPD); these risk factors, alone or combined, cause lung inflammation and alter programmed molecular patterns of normal lung development. The current knowledge on the molecular regulation of lung development mainly derives from mechanistic studies conducted in newborn rodents exposed to postnatal hyperoxia, which have been proven useful but have some limitations.MethodsHere, we used the rabbit model of BPD as a cost-effective alternative model that mirrors human lung development and, in addition, enables investigating the impact of premature birth per se on the pathophysiology of BPD without further perinatal insults (e.g., hyperoxia, LPS-induced inflammation). First, we characterized the rabbit’s normal lung development along the distinct stages (i.e., pseudoglandular, canalicular, saccular, and alveolar phases) using histological, transcriptomic and proteomic analyses. Then, the impact of premature birth was investigated, comparing the sequential transcriptomic profiles of preterm rabbits obtained at different time intervals during their first week of postnatal life with those from age-matched term pups.ResultsHistological findings showed stage-specific morphological features of the developing rabbit’s lung and validated the selected time intervals for the transcriptomic profiling. Cell cycle and embryo development, oxidative phosphorylation, and WNT signaling, among others, showed high gene expression in the pseudoglandular phase. Autophagy, epithelial morphogenesis, response to transforming growth factor β, angiogenesis, epithelium/endothelial cells development, and epithelium/endothelial cells migration pathways appeared upregulated from the 28th day of gestation (early saccular phase), which represents the starting point of the premature rabbit model. Premature birth caused a significant dysregulation of the inflammatory response. TNF-responsive, NF-κB regulated genes were significantly upregulated at premature delivery and triggered downstream inflammatory pathways such as leukocyte activation and cytokine signaling, which persisted upregulated during the first week of life. Preterm birth also dysregulated relevant pathways for normal lung development, such as blood vessel morphogenesis and epithelial-mesenchymal transition.ConclusionThese findings establish the 28-day gestation premature rabbit as a suitable model for mechanistic and pharmacological studies in the context of BPD.

Functional state of the kidneys in the neonatal period in children with very low and extremely low body weight

BACKGROUND. Preterm birth is still associated with an increased risk of neonatal morbidity and mortality in the early neonatal period. There is strong evidence demonstrating an association between a decrease in the number of nephrons in preterm infants and an increase in blood pressure, the risk of developing chronic kidney disease, which undoubtedly negatively affects the quality of life. THE AIM: to assess the functional state of the kidneys in children with very low (VLBW) and extremely low body weight (ELBW) in the first 8 weeks of postnatal life. PATIENTS AND METHODS. The study involved 134 newborns less than 37 weeks of gestation, who were divided into three groups depending on birth weight. The levels of protein and fluid intake, serum creatinine concentration, GFR according to Schwartz were taken into account as evaluation parameters. The Python programming language, t-tests, ShapiroWilk and d'Agostino tests were used as statistical methods. A threshold level of 0.05 was chosen to interpret the value of p tests for normality testing. RESULTS. There were no differences in the amount of protein received by preterm infants in the study groups both in the first week and subsequent 2–8 weeks of life. The average level of incoming fluid in the first week of postnatal life increased from 1 to 7 days in all study groups. There was a trend towards a more significant decrease in serum creatinine in children born with a larger birth weight. Analyzing the level of glomerular filtration rate in the studied groups, there is a clear picture of a progressive increase in the rate with age. CONCLUSION. The values of diuresis, creatinine level and GFR in premature babies with birth weight less than 1500 grams in the first 2 months of life have been established, which can be used in practice for comparison in the study of various pathologies.

Fetal echocardiography and early neonatal balloon valvuloplasty improved overall survival in prenatally detected aortic stenosis over 25 years of tertiary center experience.

This article aimed to present the factors determining survival and prognosis in fetuses and newborns with critical prenatal aortic stenosis (AS) and to present 26 years of tertiary center experience. Study included 87 fetuses with critical AS requiring surgical intervention during neonatal period. All results were expressed as means ± SD, in numbers and percentages. The statistically significant results were those with p < 0.05. An increase in the number of cases of AS was observed in our center along with a decrease in gestational age of our patients during the first echocardiographic exam. The survival rate of newborns was considerably higher when born in due time (p < 0.05) with body weight > 2500 g (p < 0.05). Balloon valvuloplasty performed in the first days after birth occurred to be an optimal solution in these cases. Fetal echocardiography and special perinatal care with transplacental maternal pharmacotherapy in selected cases and an early neonatal aortic balloon valvuloplasty have shown improvement in survival rate. The most dangerous for the newborn with AS was the first week of postnatal life. It is vital to refer the fetuses with AS to the reference centers which offer the possibility of invasive cardiac intervention on the first day after birth, and it might be an optimal solution.

Formation of N-acyl-phosphatidylethanolamines by cytosolic phospholipase A2ε in an ex vivo murine model of brain ischemia

N-Acyl-phosphatidylethanolamines (NAPEs), a minor class of membrane glycerophospholipids, accumulate along with their bioactive metabolites, N-acylethanolamines (NAEs) during ischemia. NAPEs can be formed through N-acylation of phosphatidylethanolamine by cytosolic phospholipase A2ε (cPLA2ε, also known as PLA2G4E) or members of the phospholipase A and acyltransferase (PLAAT) family. However, the enzyme responsible for the NAPE production in brain ischemia has not yet been clarified. Here, we investigated a possible role of cPLA2ε using cPLA2ε-deficient (Pla2g4e−/−) mice. As analyzed with brain homogenates of wild-type mice, the age dependency of Ca2+-dependent NAPE-forming activity showed a bell-shape pattern being the highest at the first week of postnatal life, and the activity was completely abolished in Pla2g4e−/− mice. However, liquid chromatography-tandem mass spectrometry revealed that the NAPE levels of normal brain were similar between wild-type and Pla2g4e−/− mice. In contrast, post-mortal accumulations of NAPEs and most species of NAEs were only observed in decapitated brains of wild-type mice. These results suggested that cPLA2ε is responsible for Ca2+-dependent formation of NAPEs in the brain as well as the accumulation of NAPEs and NAEs during ischemia, while other enzyme(s) appeared to be involved in the maintenance of basal NAPE levels.

Intrauterine inflammation exacerbates maladaptive remodeling of the immature myocardium after preterm birth in lambs

BackgroundAntenatal conditions that are linked with preterm birth, such as intrauterine inflammation, can influence fetal cardiac development thereby rendering the heart more vulnerable to the effects of prematurity. We aimed to investigate the effect of intrauterine inflammation, consequent to lipopolysaccharide exposure, on postnatal cardiac growth and maturation in preterm lambs.MethodsPreterm lambs (~129 days gestational age) exposed antenatally to lipopolysaccharide or saline were managed according to contemporary neonatal care and studied at postnatal day 7. Age-matched fetal controls were studied at ~136 days gestational age. Cardiac tissue was sampled for molecular analyses and assessment of cardiac structure and cardiomyocyte maturation.ResultsLambs delivered preterm showed distinct ventricular differences in cardiomyocyte growth and maturation trajectories as well as remodeling of the left ventricular myocardium compared to fetal controls. Antenatal exposure to lipopolysaccharide resulted in further collagen deposition in the left ventricle and a greater presence of immune cells in the preterm heart.ConclusionsAdverse impacts of preterm birth on cardiac structure and cardiomyocyte growth kinetics within the first week of postnatal life are exacerbated by intrauterine inflammation. The maladaptive remodeling of the cardiac structure and perturbed cardiomyocyte growth likely contribute to the increased vulnerability to cardiac dysfunction following preterm birth.ImpactPreterm birth induces maladaptive cardiac remodeling and adversely impacts cardiomyocyte growth kinetics within the first week of life in sheep.These effects of prematurity on the heart are exacerbated when preterm birth is preceded by exposure to intrauterine inflammation, a common antecedent of preterm birth.Inflammatory injury to the fetal heart coupled with preterm birth consequently alters neonatal cardiac growth and maturation and thus, may potentially influence long-term cardiac function and health.

PECULIARITIES OF ELECTRON MICROSCOPIC HIPPOCAMPAL FORMATION DEVELOPMENT CHARACTERISTICS IN POSTERITY OF RATS AFTER PGE2 INJECTION FOR LABOR INDUCTION

The aim: To determine the peculiarities of electron microscopic hippocampal formation development characteristics in postetry of rats during two first weeks of postnatal life after intravaginal injection of prostaglandin E2 for labor induction. Materials and methods: The ultrastructural changes of hippocampal formation in posterity of white syngenic rats at the 1st, 7th and 14th days of postnatal life were examined. In this study we used electron-microscopic method. Brain tissue from experimental animals underwent standart stages necessary for electron microscopy and poured into pure Epon. Epon polymerization was carried out in two stages at 36 ° C (12 h) and 56 ° C (24 h). Ultrathin (50-60 nm) sections were obtained on a PowerTome RMC Boeckeler ultratome and then contrasted according to the E. Reynolds method. Ultrathin sections were studied in a PEM-100 electron microscope with an accelerating voltage 60 kV. Results: Based on the obtained data in the study of the hippocampal formation in postery of rats after induction of labor, analysis of the literature devoted to the electron microscopic study of the brain after ischemic injuries, it can be concluded that on the background of stimulation of labor by PgE2, changes corresponding to ischemic damage take place in the rat brain. Conclusions: In posterity of rats after receiving PgE2 for labour induction it was revealed microcirculatory changes; edema of the presynaptic endings, synaptic vesicles aggregation in the center of the presynaptic processes, swelling and destruction of mitochondria; oligodendroglia changes; ultrastructural changes in neurons like edema and vacuolization of mitochondria.

Sex-specific effects of neonatal progestin receptor antagonism on juvenile social play behavior in rats

Developing mammals are exposed to progesterone through several sources; however, the role of progesterone in early development is not well understood. Males express more progestin receptors (PRs) than females within several brain regions during early postnatal life, suggesting that PRs may be important for the organization of the sex differences in the brain and behavior. Indeed, previous studies showed cognitive impairments in male rats treated neonatally with a PR antagonist. In the present study, we examined the role of PRs in organizing juvenile behaviors. Social play behavior and social discrimination were examined in juvenile male and female rats that had been treated with CDB, a PR antagonist, during the first week of postnatal life. Interestingly, neonatal PR antagonism altered different juvenile behaviors in males and females. A transient disruption in PR signaling during development had no effect on social discrimination but increased play initiation and pins in females. These data suggest that PRs play an important role in the organization of sex differences in some social behaviors.

Whole Ovary Immunofluorescence, Clearing, and Multiphoton Microscopy for Quantitative 3D Analysis of the Developing Ovarian Reserve in Mouse.

Female fertility and reproductive lifespan depend on the quality and quantity of the ovarian oocyte reserve. An estimated 80% of female germ cells entering meiotic prophase I are eliminated during Fetal Oocyte Attrition (FOA) and the first week of postnatal life. Three major mechanisms regulate the number of oocytes that survive during development and establish the ovarian reserve in females entering puberty. In the first wave of oocyte loss, 30-50% of the oocytes are eliminated during early FOA, a phenomenon that is attributed to high Long interspersed nuclear element-1 (LINE-1) expression. The second wave of oocyte loss is the elimination of oocytes with meiotic defects by a meiotic quality checkpoint. The third wave of oocyte loss occurs perinatally during primordial follicle formation when some oocytes fail to form follicles. It remains unclear what regulates each of these three waves of oocyte loss and how they shape the ovarian reserve in either mice or humans. Immunofluorescence and 3D visualization have opened a new avenue to image and analyze oocyte development in the context of the whole ovary rather than in less informative 2D sections. This article provides a comprehensive protocol for whole ovary immunostaining and optical clearing, yielding preparations for imaging using multiphoton microscopy and 3D modeling using commercially available software. It shows how this method can be used to show the dynamics of oocyte attrition during ovarian development in C57BL/6J mice and quantify oocyte loss during the three waves of oocyte elimination. This protocol can be applied to prenatal and early postnatal ovaries for oocyte visualization and quantification, as well as other quantitative approaches. Importantly, the protocol was strategically developed to accommodate high-throughput, reliable, and repeatable processing that can meet the needs in toxicology, clinical diagnostics, and genomic assays of ovarian function.

Weight gain in the first week of life and its association with morbidity and mortality in extremely low birthweight (ELBW) infants

BackgroundWeight gain in the first week of life is indicative of fluid excess in preterm neonates. AimsTo determine if morbidity and/or mortality of extremely low birthweight (ELBW) infants was lower in those who did not have excess weight gain in the first week of life, compared with those who did. Study designRetrospective cohort study. SubjectsELBW infants born from 1st May 2014 – 31st May 2019. Exclusions: major congenital abnormalities (including hydrops), died within the first 7 days, no recorded weight on day 6, 7 or 8. Outcome measuresWe compared infants whose weight was greater than birthweight by day 7 and infants whose weight remained at, or below, birthweight by day 7. ResultsThere were 312 ELBW infants in the study population: 15 (5%) died before discharge from hospital. Holding birthweight and gestational age (GA) constant, the odds of death in neonates with day 7 weight >birthweight was about 3 times the odds of death in neonates with day 7 weight ≤birthweight (adjusted odds ratio 3.18, 95% confidence interval 0.66–15.26, p = 0.15). Neonates with day 7 weight >birthweight were more likely to have had a PDA that required treatment than those with day 7 weight ≤birthweight (65% versus 43% respectively; p <0.001). ConclusionsELBW infants who gain weight in the first week of postnatal life, have a greater risk of PDA requiring treatment and may have a higher risk of mortality than infants who lose weight in the first week of life.

Haemoglobin Levels in Early Life among Infants with and without Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder attributed to an ischaemic stimulus in preterm infants. Haemoglobin, the main component for oxygen transportation, may be implicated in ROP development. This retrospective study compared the mean weekly haemoglobin levels between infants with and without ROP over the first six weeks of life. Premature infants of less than 32 weeks gestational age and less than 1.5 kg birth weight were grouped into age and birth weight-matched ROP cases and controls. Weekly mean haemoglobin levels were documented. An independent t-test was used to analyze the difference in mean haemoglobin levels between infants with ROP and infants without ROP. Adjustment for confounders was performed using one-way analysis of covariance. There was a statistically significant difference in adjusted mean haemoglobin levels between the ROP and non-ROP group during the first week of life (p = 0.038). No significant intergroup differences were observed at the other weeks. Haemoglobin monitoring during the first week of postnatal life may be useful to guide ROP screening in premature infants.

The biology of bilirubin production: overview of detection and inhibition

: Newborn jaundice is a benign condition commonly seen in the first postnatal week of life (or the transitional period). It is primarily due to an imbalance between the rate of production of the yellow-orange pigment bilirubin and its elimination by the liver. Infants with high bilirubin production rates (such as those who are undergoing hemolysis) or with insufficient hepatic bilirubin conjugating ability [such as those with uridine 5'-diphosho-glucuronosyltransferase (UGT1A1) deficiencies] can subsequently develop excessive circulating total serum/plasma bilirubin (TB) levels or hyperbilirubinemia. Bilirubin is formed during the degradation of heme, derived from the turnover of red blood cells (RBCs). In this reaction, which is catalyzed by the rate-limiting enzyme heme oxygenase (HO), carbon monoxide (CO), iron (Fe2+), and bilirubin are produced in equimolar quantities. As a result, measurements of total body CO production rates can be used as indices of bilirubin production. Standard treatment strategies for hyperbilirubinemia involves the use of phototherapy (specifically narrow-band blue wavelength light) and/or exchange transfusion. However, if infants with excessive hyperbilirubinemia are not identified or treated in a timely manner, they are at risk for developing bilirubin neurotoxicity, which can manifest as bilirubin-induced neurologic dysfunction (BIND) and result in neurologic sequelae (such as acute or chronic bilirubin encephalopathy. Here, we review the biology of bilirubin production and current technologies and approaches to identify and treat these high-risk infants.

The Consequences of Prior Initiation of Breast Feeding on Blood Glucose Levels in Neonates Born In a Tertiary Care Hospital

Background: Hypoglycemia is the most common event of failure of metabolic adjustments in the newborn. Changes in maternal and fetal monitoring techniques, administration of glucose-containing solutions during labor, delivery and early feeding in neonates significantly alter blood glucose concentrations during the first week of postnatal life. Subjects and Methods: A total of 90 healthy (60 born by FTND, 30 born by LSCS) term, AGA infants were longitudinally evaluated at birth, at one hour after feeds (post feed), and after 6 hours of life. Plasma glucose was estimated from Heel Prick capillary samples by glucometer method. The influence of mode of delivery, the interval between feeds, sex, birth weight, on blood glucose was analyzed. Results: The way of delivery did not affect the plasma glucose concentration in neonates. There was a substantial increase in blood glucose concentration after the first feed irrespective of their birth weight. It was found that female babies had a higher blood glucose concentration than male babies during our study period. All babies maintained normal blood glucose with the continuation of breastfeeding. Conclusion: Plasma glucose levels are satisfactorily maintained in healthy term infants without resort to pre-lacteal feeds and mode of delivery did not influence plasma glucose. There is no need to check blood glucose levels routinely in an asymptomatic, healthy, term, breastfed infants.

Mature and immature platelets during the first week after birth and incidence of patent ductus arteriosus.

Thrombocytopenia is a risk factor for patent ductus arteriosus. Immature and mature platelets exhibit distinct haemostatic properties; however, whether platelet maturity plays a role in postnatal, ductus arteriosus closure is unknown. In this observational study, counts of immature and mature platelets (=total platelet count - immature platelet count) were assessed on days 1, 3, and 7 of life in very low birth weight infants (<1500 g birth weight). We performed echocardiographic screening for haemodynamically significant patent ductus arteriosus on day 7. Counts of mature platelets did not differ on day 1 in infants with (n = 24) and without (n = 45) haemodynamically significant patent ductus arteriosus, while infants with significant patent ductus arteriosus exhibited lower counts of mature platelet on postnatal days 3 and 7. Relative counts of immature platelets (fraction, in %) were higher in infants with patent ductus arteriosus on day 7 but not on days 1 and 3. Receiver operating characteristic curve analysis unraveled associations between both lower mature platelet counts and higher immature platelet fraction (percentage) values on days 3 and 7, with haemodynamically significant ductus arteriosus. Logistic regression analysis revealed that mature platelet counts, but not immature platelet fraction values, were independent predictors of haemodynamically significant patent ductus arteriosus. During the first week of postnatal life, lower counts of mature platelets and higher immature platelet fraction values are associated with haemodynamically significant patent ductus arteriosus. Lower counts of mature platelet were found to be independent predictors of haemodynamically significant patent ductus arteriosus.

LPA3-mediated lysophosphatidic acid signaling promotes postnatal heart regeneration in mice.

Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA1 and LPA3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA1 and LPA3 in the heart is unknown.Methods and Results: By using LPA3 and LPA1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA1/LPA3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA3 knockout mice and the Ki16425-treated rats but not in the LPA1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA3 KO mice and increased in the AAV9-mediated cardiac-specific LPA3 overexpression mice. By using lineage tracing and AAV9-LPA3, we further found that LPA3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA3 signaling in vivo.Conclusion: Our study reports that LPA3-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.

Influence of obestatin on the histological development of the small intestine in piglets during the first week of postnatal life

Obestatin is a gastrointestinal peptide having wide-ranging effects on cell proliferation; however, its mechanism of action remains poorly understood. Thus, the aim of the study was to elucidate the effect of exogenous obestatin on the postnatal structural development of the small intestine. Seven-day-old piglets with an average BW of 1.56 ± 0.23 kg were divided into four groups (n = 10) that received intragastrically obestatin (2, 10 or 15 μg/kg BW) or vehicle. After a 6-day experimental period, morphological analysis of gastrointestinal tract and small intestine wall (mitosis and apoptosis indexes, histomorphometry of mucosa and muscularis layers) was performed. The study revealed a seemingly incoherent pattern of the histological structure of the small intestine among the experimental groups, suggesting that the effect of obestatin is both intestinal segment specific and dose dependent. Histomorphometric analysis of the small intestine showed that higher doses of obestatin seem to promote the structural development of the duodenum while simultaneously hindering the maturation of more distal parts of the intestine. Intragastric administration of obestatin increased the crypt mitotic index in all segments of the small intestine with the strongest pro-mitotic activity following the administration of obestatin at a dose of 10 and 15 μg/kg BW. The significant differences in the number of apoptotic cells in the intestinal villi among the groups were observed only in proximal jejunum and ileum. In conclusion, it seems that obestatin shows a broad-spectrum of activity in the gastrointestinal tract of newborn piglets, being able to accelerate its structural development. However, the varied effect depending on the intestinal segment or the concentration of exogenous obestatin causes that further research is needed to clarify the exact mechanism of this phenomenon.

Postnatal genistein administration selectively abolishes sexual dimorphism in specific hypothalamic dopaminergic system in mice

As demonstrated in previous studies, early postnatal genistein (GEN) administration to mice pups of both sexes, at doses similar to that of infant soy-based formulas, may affect the development of some steroid-sensitive neuronal circuits (i.e. nitrergic and vasopressinergic systems), causing irreversible alterations in adults. Here, we investigated the hypothalamic and mesencephalic dopaminergic system (identified with tyrosine hydroxylase immunohistochemistry). GEN administration (50 mg/kg) to mice of both sexes during the first week of postnatal life specifically affected tyrosine hydroxylase immunohistochemistry in the hypothalamic subpopulation of neurons, abolishing their sexual dimorphism. On the contrary, we did not observe any effects in the mesencephalic groups. Due to the large involvement of dopamine in circuits controlling rodent sexual behavior and food intake, these results clearly indicate that the early postnatal administration of GEN may irreversibly alter the control of reproduction, of energetic metabolism, and other behaviors. These results suggest the need for a careful evaluation of the use of soy products in both human and animal newborns.