Search Results (1,292)

Background/Objectives Studies in rodents indicate that disruptions in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways are involved in the development of hyperactive behavior. We examined whether vinpocetine, a phosphodiesterase type 1 inhibitor that enhances brain cAMP and cGMP levels, could mitigate locomotor hyperactivity in mice exposed to lead during early development. Methods Swiss mice were exposed to 90 ppm of lead in their drinking water throughout gestation and the first ten postnatal days. At postnatal day 10 (PN10), blood lead levels (BLLs) were about 30 µg/dL. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or a vehicle 4 h before the evaluation of locomotor activity in the open field. Results Lead-exposed males did not display differences in locomotor activity compared to controls, while lead-exposed females showed a significant increase in locomotion. Vinpocetine treatment significantly reversed the lead-induced hyperactivity in females. Conclusions These findings suggest that the cAMP and cGMP signaling pathways play a role in the hyperactivity induced by lead exposure. Full article

The developmental origins of adult disease theory support the concept that undernourished fetuses are at risk of developing metabolic syndrome due to the energy-saving ‘Thrifty Phenotype’. This metabolic plasticity represents an evolutionary adaptation that allows individuals to resist the intense pressure caused by cyclically recurring periods of nutritional deprivation. A comprehensive review was conducted following an extensive literature search in the PubMed/Medline and EMBASE databases concerning reports on fetal/intrauterine growth restriction and its metabolic-related long-term outcomes. We only included articles written in English that were published before July 1, 2024. There are several underlying mechanisms and metabolic and endocrine adjustments shaped by the perinatal environment, and they all contribute to progression towards adult disease. From in utero malnutrition or other insults during the fetal period to fetal programing and postnatal catch-up growth, it is difficult to identify the exact moment when this adaptative phenomenon meant to assure fetal survival and to set children on their own physiological growth curves lose its beneficial effect, establishing the trajectory to obesity, insulin resistance, and other hallmarks of metabolic syndrome. With clinical correspondence to an altered body mass, composition, and eating behaviors, it is evident that the metabolic complications linked to FGR are intricate and arise from disturbances in several pathways and organs, but the underlying processes responsible for the long-term consequences are just starting to be understood. The lack of continuity in perinatal-to-pediatric FGR research sets the challenge of exploring new directions in future scientific opportunities. These will hopefully represent a cornerstone in the management of FGR-related metabolic disorders in children, preventing these disorders from evolving into adult disease. Full article

Photoreceptor/retinal degeneration is the major cause of blindness. Induced and inherited mouse models of retinal degeneration are valuable tools for investigating disease mechanisms and developing therapeutic interventions. This study investigated the potential of the antioxidant resveratrol to relieve photoreceptor degeneration using mouse models. Clinical studies have shown a potential association between thyroid hormone (TH) signaling and age-related retinal degeneration. Excessive TH signaling induces oxidative stress/damage and photoreceptor death in mice. C57BL/6 (rod-dominant) and Nrl⁻/⁻ (cone-dominant) mice at postnatal day 30 (P30) received triiodothyronine (T3) via drinking water (20 µg/mL) with or without concomitant treatment with resveratrol via drinking water (120 µg/mL) for 30 days, followed by evaluation of photoreceptor degeneration, oxidative damage, and retinal stress responses. In experiments using Leber congenital amaurosis model mice, mother Rpe65^−/− and Rpe65^−/−/Nrl^−/− mice received resveratrol via drinking water (120 µg/mL) for 20 days and 10–13 days, respectively, beginning on the day when the pups were at P5, and pups were then evaluated for cone degeneration. Treatment with resveratrol significantly diminished the photoreceptor degeneration induced by T3 and preserved photoreceptors in Rpe65-deficient mice, manifested as preserved retinal morphology/outer nuclear layer thickness, increased cone density, reduced photoreceptor oxidative stress/damage and apoptosis, reduced upregulation of genes involved in cell death/inflammatory responses, and reduced macroglial cell activation. These findings demonstrate the role of oxidative stress in photoreceptor degeneration, associated with TH signaling and Rpe65 deficiency, and support the therapeutic potential of resveratrol/antioxidants in the management of retinal degeneration. Full article

Background/Objectives: The numerical risk of bronchopulmonary dysplasia (BPD) and/or death could be estimated using the National Institute of Child Health and Human Development (NICHD) BPD outcome estimator 2022 in extremely low gestational age (ELGA) infants during the first 4 weeks of life to facilitate prognostication, and center-specific targeted improvement interventions. However, the 2022 NICHD BPD outcome estimator’s performance in the Canadian setting has not been validated. Our objective is to validate the NICHD BPD outcome estimator 2022 in predicting death and or moderate to severe BPD at 36 weeks in infants less than 29 weeks admitted to NICU. Methods: A retrospective observational study (March 2022–August 2023) was conducted on both inborn and outborn preterm infants excluding neonates with major congenital anomalies. Infants were classified into six groups based on the predicted risk of death or Grade 2 or 3 BPD (<10%, 10–20%, 20–30%, 30–40%, 50–59%, ≥60%) followed by noting observed outcomes from the unit’s database. A receiver operating characteristics (ROC) curve was used to assess the accuracy of the NICHD BPD outcome estimator 2022, with an area under curve (AUC) > 0.7 defined a priori as an acceptable predictive accuracy for local use. Results: Among 99 infants included, 13 (13.1%) died, and 40 (40.4%) developed BPD. Median gestational age was 26 weeks, and median birth weight was 914 g. Twenty-three infants (23.2%) received postnatal steroids. The AUC values for death or moderate to severe BPD on days 1, 3, 7, 14, and 28 were 0.803, 0.806, 0.837, 0.832, and 0.843, respectively. The AUC values for moderate to severe BPD alone on those days were 0.766, 0.746, 0.785, 0.807, and 0.818 respectively. Conclusions: The 2022 BPD estimator adequately predicted the death and/or moderate to severe BPD on days 1, 3, 7, 14, and 28 of life. This tool could serve as a valid adjunct to facilitate discussion between clinicians and families on initiating time-sensitive targeted interventions to prevent or alter the course of BPD. Full article

Understanding hormonal and molecular changes during the transition from preterm to near-term gestation is essential for investigating how pregnancy complications impact fetal heart development and contribute to long-term cardiovascular risks for offspring. This study examines these cardiac changes in fetal sheep, focusing on the changes between 116 days (preterm) and 140 days (near term) of gestation (dG, term = 150) using Western blotting, LC-MS/MS, and histological techniques. We observed a strong correlation between cortisol and T₃ (Triiodothyronine) in heart tissue in near-term fetuses, highlighting the role of glucocorticoid signalling in fetal heart maturation. Protein expression patterns in the heart revealed a decrease in multiple glucocorticoid receptor isoforms (GRα-A, GR-P, GR-A, GRα-D2, and GRα-D3), alongside a decrease in IGF-1R (a marker of cardiac proliferative capacity) and p-FOXO1(Thr24) but an increase in PCNA (a marker of DNA replication), indicating a shift towards cardiomyocyte maturation from preterm to near term. The increased expression of proteins regulating mitochondrial biogenesis and OXPHOS complex 4 reflects the known transition from glycolysis to oxidative phosphorylation, essential for meeting the energy demands of the postnatal heart. We also found altered glucose transporter expression, with increased pIRS-1(ser789) and GLUT-4 but decreased GLUT-1 expression, suggesting improved insulin responsiveness as the heart approaches term. Notably, the reduced protein abundance of SIRT-1 and SERCA2, along with increased phosphorylation of cardiac Troponin I(Ser23/24), indicates adaptations for more energy-efficient contraction in the near-term heart. In conclusion, these findings show the complex interplay of hormonal, metabolic, and growth changes that regulate fetal heart development, providing new insights into heart development that are crucial for understanding pathological conditions at birth and throughout life. Full article

Human genome studies have suggested that strawberry notch homologue 1 (SBNO1) is crucial for normal brain development, with mutations potentially contributing to neurodevelopmental disorders. In a previous study, we observed significant developmental abnormalities in the neocortex of Sbno1 as early as one week after birth. In the present study, we conducted an extensive analysis of Sbno1 postnatal expression in the brain of C57BL/6 mice using a newly developed in-house polyclonal antibody against Sbno1. We found that Sbno1 is expressed in all neurons, with certain neuronal populations exhibiting distinct dynamic changes (both temporal and spatial) in expression level. These findings suggest that the neuronal expression of Sbno1 is developmentally regulated after birth. They also indicate that while Sbno1 may play a general role across all neurons, it may also serve more specialized functions in certain neuronal types and/or for certain cellular activities related to particular neuronal pathways. Full article

We analyzed the transcriptome data of wildtype and estrogen receptor β knockout (Erβ^KO) rat ovaries during the early postnatal period and detected remarkable changes in epigenetic regulators and transcription factors. Compared with postnatal day (PD) 4.5 ovaries, PD 6.5 wildtype ovaries possessed 581 differentially expressed downstream transcripts (DEDTs), including 17 differentially expressed epigenetic regulators (DEERs) and 23 differentially expressed transcription factors (DETFs). Subsequently, compared with PD 6.5 ovaries, PD 8.5 wildtype ovaries showed 920 DEDTs, including 24 DEERs and 68 DETFs. The DEDTs, DEERs, and DETFs in wildtype ovaries represented the gene expression during primordial follicle activation and the gradual development of primary follicles of first-wave origin because the second-wave follicles remained dormant during this developmental period. When we compared the transcriptome data of age-matched Erβ^KO ovaries, we observed that PD 6.5 Erβ^KO ovaries had 744 DEDTs compared with PD 4.5 ovaries, including 46 DEERs and 55 DETFs. The loss of ERβ rapidly activated the primordial follicles of both first- and second-wave origin on PD 6.5 and showed a remarkable increase in DEDTs (744 vs. 581). However, compared with PD 6.5 ovaries, PD 8.5 Erβ^KO ovaries showed only 191 DEDTs, including 8 DEERs and 10 DETFs. This finding suggests that the PD 8.5 Erβ^KO ovaries did not undergo remarkable ovarian follicle activation greater than that had already occurred in PD 6.5 Erβ^KO ovaries. The results also showed that the numbers of DEERs and DETFs were associated with increased changes in DEDTs; the greater the number of DEERs or DETFs, the larger the number of DEDTs. In addition to the quantitative differences in DEERs and DETFs between the wildtype and Erβ^KO ovaries, the differentially expressed regulators showed distinct patterns. We identified that 17 transcripts were tied to follicle assembly, 6 to follicle activation, and 12 to steroidogenesis. Our observations indicate that a loss of ERβ dysregulates the epigenetic regulators and transcription factors in Erβ^KO ovaries, which disrupts the downstream genes in ovarian follicles and increases follicle activation. Further studies are required to clarify if ERβ directly or indirectly regulates DEDTs, including DEERs and DETFs, during the neonatal development of rat ovarian follicles. Full article

The ability to reproduce depends on metabolic status. In rodents, the ventral premammillary nucleus (PMv) integrates metabolic and reproductive signals. While leptin (adiposity-related) signaling in the PMv is critical for female fertility, male reproductive functions are strongly influenced by glucose homeostasis. The anorexigenic peptide nesfatin-1 is a leptin-independent central regulator of blood glucose. Therefore, its integrative role in male rats can be assumed. To investigate this, we mapped the distribution of nesfatin-1 mRNA- and protein-producing cells in the PMv during postnatal development via in situ hybridization and immunohistochemistry, respectively. Fos-nesfatin-1, double immunostaining was used to determine the combined effect of heterosexual pheromone challenge and insulin-induced hypoglycemia on neuronal activation in adults. We found that ~75% of the pheromone-activated neurons were nesfatin-1 cells. Hypoglycemia reduced pheromone-induced cell activation, particularly in nesfatin-1 neurons. Immuno-electron microscopy revealed innervation of PMv nesfatin-1 neurons by urocortin3-immunoreactive terminals, reportedly originating from the medial amygdala. Nesfatin-1 immunopositive neurons expressed GPR10 mRNA, a receptor associated with metabolic signaling, but did not respond with accumulation of phosphorylated STAT3 immunopositivity, a marker of leptin receptor signaling, in response to intracerebroventricular leptin treatment. Our results suggest that PMv nesfatin-1 neurons are primarily responsible for integrating reproductive and metabolic signaling in male rats. Full article

Prenatal hypoxia (PH) is a key factor in the development of long-term cardiovascular disorders, which are caused by various mechanisms of endothelial dysfunction (ED), including those associated with NO deficiency. This emphasizes the potential of therapeutic agents with NO modulator properties, such as Thiotriazoline, Angiolin, Mildronate, and L-arginine, in the treatment of PH. Methods: Pregnant female rats were given a daily intraperitoneal dose of 50 mg/kg of sodium nitrite starting on the 16th day of pregnancy. A control group of pregnant rats received saline instead. The resulting offspring were divided into the following groups: Group 1—intact rats; Group 2—rat pups subjected to prenatal hypoxia (PH) and treated daily with physiological saline; and Groups 3 to 6—rat pups exposed to prenatal hypoxia and treated daily from the 1st to the 30th day after birth. Levels of sEPCR, Tie2 tyrosine kinase, VEGF-B, SOD1/Cu-Zn SOD, GPX4, and GPX1 in the heart’s cytosolic homogenate were assessed using ELISA. The expression of VEGF and VEGF-B mRNA was analyzed via real-time polymerase chain reaction, and the nuclear area of myocardial microvessel endothelial cells was evaluated morphometrically. Results: We have shown that only two representatives of this group—Angiolin and Thiotriazoline—are able to exert full effect on the indices of endothelial dysfunction after PH to decrease sEPCR, increase Tie-2, VEGF-B and VEGF-B mRNA, Cu/ZnSOD, and GPX in myocardial cytosol, and increase the area of endotheliocyte nuclei in 1- and 2-month-old rats in comparison with the control. Conclusions: Our results experimentally substantiate the necessity of early postnatal cardio- and endothelioprotection using NO modulators, taking into account the role of NO-dependent mechanisms in the pathogenesis of cardiovascular system disorders in neonates after PH. Full article

Macrophages play important roles in metabolic dysfunction-associated steatohepatitis (MASH), an advanced and inflammatory stage of metabolic dysfunction-associated steatotic liver disease (MASLD). In humans and mice, the cellular heterogeneity and diverse function of hepatic macrophages in MASH have been investigated by single cell RNA sequencing (scRNA-seq). However, little is known about their roles in rats. Here, we collected liver tissues at the postnatal week 16, when our previously characterized Lep^{∆I14/∆I14} rats developed MASH phenotypes. By scRNA-seq, we found an increase in the number of macrophages and endothelial cells and a decrease in that of NK and B cells. Hepatic macrophages in rats underwent a unique M1 to M2 transition without expression of the classical markers such as Arg1 and Nos2, except for Cd163. Lipid-associated macrophages (LAMs) were increased, which could be detected by the antibody against Cd63. In the microenvironment, macrophages had an increased number of interactions with hepatocytes, myofibroblasts, T cells, neutrophils, and dendritic cells, while their interaction strengths remained unchanged. Finally, the macrophage migration inhibitory factor (MIF) pathway was identified as the top upregulated cell-communication pathway in MASH. In conclusion, we dissected hepatic macrophage dynamics during MASH at single cell resolution and provided fundamental tools for the investigation of MASH in rat models. Full article

Background: We sought to develop a structural equation model (SEM) identifying physical and clinical risk factors associated with treatment for retinopathy of prematurity (ROP). Methods: This retrospective, observational, case–control study included 314 infants screened for ROP between April 2004 and July 2024. A bivariate binary logistic regression model, decision tree, and structural equation model (SEM) were employed to develop a more general model for ROP requiring treatment. Results: In the SEM, the factors significantly associated with ROP treatment included the retinal avascular area according to disk diameter (DD) (p < 0.001), weekly vascularisation rate (DD/w) (p < 0.001), and duration of intubation (days) (p < 0.001). In addition, the following significant associations were identified in both the bivariate analysis and the SEM: lower gestational age (p < 0.001) and birth weight (p <0.001) were associated with greater retinal avascular area; low postnatal weight gain (p < 0.027) was associated with a slow rate of retinal vascularisation; sepsis (p < 0.001), ductus arteriosus (p < 0.001), and the need for transfusion (p < 0.001) were associated with longer intubation mechanical ventilation (IMV). Conclusions: Lower gestational age, lower birth weight, sepsis, ductus arteriosus, transfusion, and lower weight gain increase the risk of requiring ROP treatment. In the SEM, this association is represented through three intermediate physical endogenous variables, namely, the greater temporal avascular area of the retina, the lower postnatal vascularisation rate, and the greater duration of IMV. Full article

Intrauterine growth restriction (IUGR) is a risk factor for postnatal cardiovascular, metabolic, and psychiatric disorders. In most IUGR models, placental dysfunction that causes reduced 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) activity, which degrades glucocorticoids (GCs) in the placenta, resulting in fetal GC overexposure. This overexposure to GCs continues to affect not only intrauterine fetal development itself, but also the metabolic status and neural activity in adulthood through epigenetic changes such as microRNA change, histone modification, and DNA methylation. We have shown that the IUGR model induced DNA hypomethylation in the paraventricular nucleus (PVN) in the brain, which in turn activates sympathetic activities, the renin–angiotensin system (RAS), contributing to the development of salt-sensitive hypertension. Even in adulthood, strong stress and/or exogenous steroids have been shown to induce epigenetic changes in the brain. Furthermore, DNA hypomethylation in the PVN is also observed in other hypertensive rat models, which suggests that it contributes significantly to the origins of elevated blood pressure. These findings suggest that if we can alter epigenetic changes in the brain, we can treat or prevent hypertension. Full article

From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca²⁺ transfers. In addition, from around the eighth week of gestation, increasing amounts of calcium must be routed directly from maternal blood to the foetus for bone mineralisation through a flow-through system, which does not impact the intracellular Ca²⁺ concentration. These different processes are mediated by numerous membrane-sited Ca²⁺ channels, transporters, and exchangers. Understanding the mechanisms is essential to direct interventions to optimise foetal development and postnatal bone health and to protect the mother and foetus from pre-eclampsia. Ethical issues limit the availability of human foetal tissue for study. Our insight into the processes of placental Ca²⁺ handling is advancing rapidly, enabled by developing genetic, analytical, and computer technology. Because of their diverse sources, the reports of new findings are scattered. This review aims to pull the data together and to highlight areas of uncertainty. Areas needing clarification include trafficking, membrane expression, and recycling of channels and transporters in the placental microvilli; placental metabolism of vitamin D in gestational diabetes and pre-eclampsia; and the vascular effects of increased endothelial Orai expression by pregnancy-specific beta-1-glycoproteins PSG1 and PSG9. Full article

Background: Respiratory syncytial virus (RSV) infections usually cause mild, cold-like symptoms in most people, but are a leading infectious disease causing infant death and hospitalization and can result in increased morbidity and mortality in older adults and at-risk individuals. Pfizer has developed Abrysvo^®, an unadjuvanted bivalent recombinant protein subunit vaccine containing prefusion-stabilized fusion (F) proteins representing RSV A and RSV B subgroups (RSVpreF). It is the only RSV vaccine approved for both maternal immunization to protect infants and active immunization of older adults (≥60 years) and 18–59-year-old individuals with high-risk conditions for prevention of RSV disease. Methods: Nonclinical safety studies, including a repeat-dose toxicity (RDT) study in rats and a combined developmental and reproductive toxicity (DART) study in rabbits, were conducted to support early clinical development. Study designs and parameters evaluated in these studies were consistent with principles and practices as outlined in relevant regulatory guidelines. RSVpreF bivalent vaccine, with or without Al(OH)₃, was administered intramuscularly (IM) at 2× the human dose to animals in both studies. Results: Locally tolerated, reversible, inflammatory responses at the injection sites and the draining lymph nodes were observed as typical findings following vaccination. No effect of RSVpreF, with or without Al(OH)₃, was observed on female fertility or on embryo–fetal or postnatal survival, growth, or development in the DART study. In both studies, robust immune responses to both RSV A and B antigens were observed, especially with the Al(OH)₃ formulation. Conclusions: RSVpreF was well-tolerated both locally and systemically without any adverse effects on reproductive and developmental endpoints. Full article

Amniotic band syndrome is a constrictive phenomenon in fetal development that can provoke limb autoamputation, malformation, trunk division, and umbilical cord strangulation. The latter two complications will ultimately lead to fetal demise if left untreated. If detected early enough, select cases may benefit from prenatal resection of the amniotic bands, thus preventing amputation and fetal death. Yet, especially in the presence of complete chorioamniotic separation, these procedures are rare, technically difficult, and not without significant risk. Objectives: The purpose of this report is to present the surgical technique and outcome of a challenging percutaneous fetoscopic intervention in a human fetus with amniotic band constrictions of a fetal thigh, retroplacental hematoma, partial placental abruption, subtotal chorioamniotic separation, and multiple amniotic bands encircling the umbilical cord. Methods: Minimally invasive, fetoscopic surgery to salvage the fetal life and lower leg was performed at 22 + 2 weeks of gestation under general maternofetal anesthesia. Results: Total resection of all amniotic bands was achieved, notwithstanding the aforementioned challenges. No surgical complications were observed. Despite preterm delivery at 25 + 4 weeks of gestation, the postnatal experience for the infant was favorable and uncomplicated as it furthermore benefitted from neonatal intensive care. At almost three years of age, the child remains healthy and demonstrates normal function of the formerly constricted leg. Conclusions: Our case shows that the combination of tested percutaneous fetoscopic techniques, high-risk obstetrics, and modern neonatology can overcome multiple obstacles in order to save a fetal patient stuck in a near-hopeless situation. Full article