Search Results (335)

Background: Mini-puberty is a transient but critical postnatal activation of the hypothalamic–pituitary–gonadal axis, essential for male gonadal maturation, penile and testicular growth, and future reproductive potential: this physiological hormonal surge is absent or blunted in congenital hypogonadotropic hypogonadism (CHH), often manifesting as micropenis, cryptorchidism, and impaired Sertoli cell proliferation. Objective: The aim of this review is to summarize current evidence on the impact of early gonadotropin therapy in male infants with CHH. Methods: We conducted a comprehensive literature review using PubMed, including studies reporting on male infants with confirmed or suspected CHH receiving gonadotropin therapy. Keywords included “mini-puberty and hypogonadism”, “gonadotropins and infancy,” and “gonadotropin therapy in CHH.” Eligible studies reported biochemical outcomes (luteinizing hormone, follicle-stimulating hormone, testosterone, inhibin B, anti-Müllerian hormone) and clinical measures (penile length, testicular volume, testicular descent). Data extraction focused on endocrine responses, genital growth, and safety. Results: Twelve studies including 95 infants were analyzed. Early gonadotropin therapy effectively restored postnatal hormonal levels, with consistent increases in testosterone, inhibin B, and anti-Müllerian hormone. Clinically, treatment induced significant penile growth, increased testicular volume and partial or complete testicular descent in the majority of cases. Both continuous infusion and intermittent injection regimens were effective, though hormone kinetics and growth responses varied. No serious adverse events were reported, and therapy was generally well tolerated. Conclusions: Early gonadotropin therapy during mini-puberty represents a safe and effective intervention to replicate the physiological postnatal hormonal surge in male infants with CHH. Prospective longitudinal studies are warranted to evaluate sustained effects on puberty, fertility, and adult reproductive function. Full article

Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T < 10.4 nmol/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 ± 0.38 ng/mL vs. 1.83 ± 0.37 ng/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone. Full article

Sodium (Na) is essential not only for maintaining extracellular fluid homeostasis as the dominant extracellular cation, but also for supporting the rapid tissue growth characteristic of the neonatal period. Despite its importance, the precise sodium requirements of preterm infants remain insufficiently defined. The immature renal tubules of preterm neonates lead to significant renal sodium losses, making negative sodium balance a common feature in this population. This issue has become increasingly relevant as survival rates improve among extremely preterm infants, while most available data are derived from studies involving more mature preterm or even full-term neonates. Fractional excretion of sodium (FENa) shows a clear inverse correlation with both gestational age and postnatal age, highlighting the developmental limitations in sodium retention among the youngest and most vulnerable infants. Current guidelines on sodium supplementation aim to promote optimal growth and neurodevelopment but vary across organizations. For instance, the most recent ESPGHAN recommendations suggest higher sodium intakes, in the range of 3–8 mEq/kg/day, whereas the American Academy of Pediatrics (AAP) provides more conservative guidance. These discrepancies underscore ongoing uncertainty in determining optimal sodium provision. This narrative review examines both classic and contemporary data on sodium needs in preterm neonates, with the goal of clarifying existing evidence and offering practical insights for clinical care. It also emphasizes unresolved questions and the need for well-designed studies that address the unique physiology of extremely preterm infants. A deeper understanding of sodium metabolism in this population is crucial for improving outcomes and guiding evidence-based supplementation strategies. Full article

The cardiac extracellular matrix (ECM) is a dynamic, tissue-specific scaffold essential for cardiovascular development, homeostasis, and disease. Once considered a passive structural framework, the ECM is now recognized as an active regulator of mechanical, electrical, and biochemical signaling in the heart. Its composition evolves from embryogenesis through adulthood, coordinating cardiomyocyte maturation, chamber formation, and postnatal remodeling. In pathological states, diverse stimuli—including ischemia, pressure or volume overload, metabolic dysfunction, and aging—disrupt ECM homeostasis, triggering fibroblast activation, myofibroblast transformation, and maladaptive collagen deposition. These processes underpin myocardial fibrosis, a key driver of impaired contractility, diastolic dysfunction, arrhythmogenesis, and heart failure across ischemic and non-ischemic cardiac diseases. ECM alterations also exhibit age- and sex-specific patterns that influence susceptibility to cardiovascular pathology. Advances in imaging and circulating biomarkers have improved fibrosis assessment, though limitations persist. Therapeutic strategies targeting ECM remodeling, including modulation of profibrotic signaling pathways, non-coding RNAs, cellular therapies, and nano-delivery systems, show promise but remain largely experimental. Collectively, expanding knowledge of ECM biology highlights its central role in cardiovascular physiology and pathology and underscores the need for targeted diagnostic and therapeutic innovations. Full article

Neonatal hyperoxia induces oxidative and inflammatory stress that disrupts cardiac maturation and contributes to long-term cardiovascular morbidity in individuals born preterm. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with antioxidant and anti-inflammatory properties, has demonstrated protective effects in neonatal hyperoxic injury in other organs; however, its impact on the developing heart remains unclear. This study investigated whether CBD mitigates hyperoxia-induced cardiac injury in a neonatal mouse model. Newborn mice were exposed to 80% O₂ for 48 h from postnatal day (P)5 to P7 and received vehicle, 10 mg/kg CBD, or 30 mg/kg CBD intraperitoneally, while controls remained in room air. Hearts were collected at P7 or after recovery until P14. Hyperoxia triggered oxidative stress (Nrf2), inflammation (IL1β, TNFα, IL6, CXCL1; p < 0.05), and dysregulated apoptosis/autophagy, leading to reduced cardiomyocyte proliferation (Ki67⁺ −50% at P14; p < 0.01) and adverse remodeling (hypertrophy, fibrosis; p < 0.01). CBD attenuated these responses and normalized autophagy (Atg5, Atg12; p < 0.05). Notably, 10 mg/kg CBD, but not 30 mg/kg, preserved proliferative capacity and reduced wall thickness, suggesting a narrow therapeutic window, while both doses limited collagen deposition and apoptosis (Casp3, AIF; p < 0.05). Several effects were sex-dependent, with males exhibiting more pronounced long-term structural and proliferative impairments and greater responsiveness to low-dose CBD. These findings identify CBD as a potential cardioprotective modulator of neonatal hyperoxia-induced injury and highlight the importance of dose- and sex-specific mechanisms in early cardiac maturation. Full article

Postnatal muscle development involves complex transcriptional regulation that remains poorly characterized in goats. This study employed RNA-Seq to profile the Longissimus dorsitranscriptome of Leizhou Black goats across three developmental stages: birth, six months, and two years. We identified dynamic gene expression patterns, widespread alternative splicing events, and stage-specific co-expression networks that collectively orchestrate muscle maturation. A significant transcriptional shift occurred between six months and two years, marked by the downregulation of proliferation-related genes (e.g., RRM2, TOP2A) and the activation of pathways governing muscle contraction and energy metabolism. Functional enrichment analyses highlighted the importance of PI3K-Akt, PPAR, and calcium signaling pathways throughout development. Additionally, 905 novel transcripts were discovered, many enriched in mitochondrial functions, indicating incompleteness in the current goat genome annotation. Weighted gene co-expression network analysis revealed modules correlated with developmental stages, and protein–protein interaction analysis identified hub genes regulating cell cycle progression and muscle function. Key results were validated via qRT-PCR, confirming the temporal expression patterns of genes such as CYP4B1, HACD1, and ACTC1. These findings provide mechanistic insights into the transcriptional reprogramming driving postnatal muscle development and offer valuable genetic resources for improving meat production in goats through molecular breeding. Full article

Background/Objectives: Gastroschisis is a congenital abdominal wall defect characterized by herniation of bowel loops without a covering membrane and typically located to the right of the umbilical cord. Although contemporary management is well established, its historical study development has not been comprehensively synthesized. This review examines the chronological evolution of focus of interest in gastroschisis and highlights how research priorities shifted across eras, shaping current anatomical understanding, diagnostic strategies, and surgical management. Methods: A structured literature search was performed in PubMed, Web of Science, and Scopus. Studies in English, Spanish, Turkish, and Arabic were included. Titles, abstracts, and full texts were screened independently. Eligible publications addressed historical descriptions, differentiation from omphalocele, advancements in imaging, surgical techniques, or experimental modeling. Results: Sixty-eight studies met the inclusion criteria. Early reports from the sixteenth to eighteenth centuries provided descriptive accounts without distinguishing gastroschisis from omphalocele. The nineteenth century introduced the term “gastroschisis,” and definitive clinical differentiation was achieved in the mid twentieth century. Surgical innovation progressed from primary closure in the 1940s to the development of preformed and spring-loaded silos, which improved physiologic tolerance and survival. Animal models clarified mechanisms of bowel injury, including the effects of amniotic exposure and delayed maturation of interstitial cells of Cajal. Advances in ultrasound and magnetic resonance imaging facilitated prenatal risk stratification and shifted research attention toward predicting complex gastroschisis and optimizing perinatal planning. Conclusions: The historical trajectory of studies about gastroschisis demonstrates a coherent pattern in which developments in anatomical definition, surgical innovation, and mechanistic research sequentially enabled modern prenatal diagnostic and prognostic strategies. Recognizing these temporal shifts provides important context for current practice and highlights opportunities to improve prenatal markers of bowel compromise and refine individualized postnatal care. Full article

Postnatal testicular maturation in domestic cats remains poorly quantified despite its relevance for reproductive biology, veterinary practice, and the management of threatened felid species. This study aimed to characterize age-related changes in testicular structure from six to thirty-six months of age. Testes were collected from clinically healthy cats undergoing routine orchiectomy, and design-based stereology was used to estimate the volumes and densities of the main testicular components, including the seminiferous epithelium, interstitial tissue, Sertoli cells, and Leydig cells. Immunohistochemical detection of Desert Hedgehog, a developmental signaling molecule, was performed to assess interstitial maturation. Testicular volume and the absolute volumes of the seminiferous epithelium, Sertoli cells, and Leydig cells increased significantly with age, while the numerical density of Leydig cells remained stable, indicating hypertrophy rather than proliferation. Desert Hedgehog immunoreactivity declined progressively across age groups, consistent with the transition from immature to mature interstitial cells. Principal component analysis revealed a clear separation between immature and mature testes based on volumetric and density variables. These results demonstrate that feline testicular maturation follows a coordinated pattern of tubular and interstitial growth and provide quantitative reference values useful for reproductive assessment, comparative studies, and conservation programs in domestic and wild felids. Full article

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and vascular maturation. In a postnatal high-oxygen-induced rat model of BPD-associated lung injury, three or five days of exposure to 80% oxygen was found to disrupt developmental signaling pathways, downregulating genes essential for alveolarization and angiogenesis while inducing profibrotic mediators and collagen expression (Sirius Red staining). These changes resulted in simplified alveolar architecture, as quantified by toluidine blue staining and mean linear intercept analysis of normalized volumes of parenchyma, non-parenchyma, airspaces, septa, and edema. Acting as a multifunctional antioxidant with antifibrotic activity, caffeine mitigated structural lung damage and normalized the transcription of angiogenic and fibrotic genes. It counteracted TGF-β/CTGF-driven fibrogenic signaling and promoted recovery of normal lung morphology following hyperoxic injury. Under normoxic conditions, however, caffeine transiently upregulated profibrotic mediators. Overall, caffeine mitigates hyperoxia-induced lung injury and may actively promote physiological lung maturation, warranting future studies to define optimal dosing windows, clarify context-dependent fibrotic signaling, and translate gene-level effects into long-term clinical outcomes. Full article

The regenerative potential of the mammalian retina is limited, yet identifying signaling pathways that influence progenitor cell behavior remains an important step toward understanding the mechanisms of retinal development and plasticity. Epidermal Growth Factor Receptor (EGFR) signaling has been implicated in regulating proliferation and differentiation in the central nervous system, but its role in the postnatal retina is less defined. In this study, we employed an ex vivo explant model of the postnatal mouse retina to investigate the effects of sustained Epidermal Growth Factor (EGF) stimulation. Our results demonstrate that EGF extends the proliferative activity of progenitors that are normally quiescent after birth. However, the sustained EGFR activation (10 ng/mL, for 7 days) in the postnatal retina not only promotes EGFR+ progenitor proliferation but also maintains co-expression of Otx2 and Chx10, revealing a distinct progenitor population, suggesting that extended EGF signaling influences lineage allocation. These findings indicate that EGFR activation can modulate both the maintenance and differentiation potential of retinal progenitors in a context-dependent manner. While additional studies are needed to determine whether these progenitors develop into mature, functional neurons, our work provides a framework for future investigations into signaling pathways that may be leveraged to influence retinal development and plasticity. Full article

Background: Hippocampal neurogenesis in the dentate gyrus persists into adulthood and plays a crucial role in learning and memory. Early-life exposure to low-dose propofol has been reported to enhance neural development in rodent models, but detailed mechanisms remain unclear. To address this gap, we aimed to investigate how low-dose propofol alters neurogenic lineage differentiation, transcriptional programs, and underlying molecular mechanisms within the early postnatal hippocampal neurogenic niche. Results: We conducted an in-depth re-analysis of a published single-nucleus RNA-sequencing (snRNA-seq) dataset from hippocampal tissue of postnatal day 10 (PND10) mice, collected 3 days after low-dose propofol treatment. Uniform Manifold Approximation and Projection (UMAP)-based clustering revealed twelve major cell types, including a population of Ntng1⁺Fxyd7⁺Pcp1⁺ immature pyramidal neurons (imPYR), lacking the mature markers Meis2 and Spock1. Trajectory analysis revealed two neurogenic lineages (granule and pyramidal) and indicated that propofol biases progenitor fate commitment towards the granule lineage. CellChat analysis demonstrated that propofol enhances Neurexin (Nrxn) signaling to neural progenitor cells, suggesting increased synaptic adhesion and maturation. Differential expression analysis (|log₂FC| ≥ 0.26, adjusted p < 0.01) followed by pathway enrichment revealed that propofol upregulates neurogenic maturation pathways—including synaptogenesis, synaptic transmission, dendritic morphogenesis, and memory-related processes—specifically within neural intermediate progenitor cells (nIPC). Conclusions: Together, these findings delineate a coordinated transcriptional and intercellular mechanism by which low-dose propofol reprograms hippocampal neurogenesis during early postnatal development, highlighting progenitor-specific and synapse-oriented processes that may underlie its cognitive-enhancing effects. Full article

Intramuscular fat (IMF) refers to the adipose tissue located between muscle fibers and is a major determinant of meat quality in cattle. The cellular origin of bovine intramuscular adipocytes remains unclear. Therefore, the objective of this study was to investigate this origin. We derived single-preadipocyte clones from IMF and subcutaneous fat (SF) of cattle through single-cell cloning and subsequent validation of their potential to differentiate into adipocytes. Transcriptomic analysis of selected single-preadipocyte clones revealed that although both IMF- and SF-derived preadipocyte clones expressed classical preadipocyte markers such as PDGFRA, DLK1, and ZNF423, they differed significantly in global gene expression profile. Notably, many muscle-specific genes (e.g., MYOG, MB, and MYH3) were expressed at high levels in IMF-derived preadipocyte clones while not expressed in SF-derived clones. Functional enrichment analysis of differentially expressed genes between IMF- and SF-derived preadipocyte clones indicated that many muscle-related functions were enriched in the former. Furthermore, high-level expression of muscle-specific genes persisted in mature adipocytes differentiated from IMF-derived preadipocyte clones. We also found that bovine satellite cells, the widely considered progenitor cells of myocytes in postnatal animals, had the ability to form both myocytes and adipocytes under respective differentiation conditions. Based on these findings, we conclude that in cattle, at least some intramuscular adipocytes are derived from satellite cells. Full article

Cryptorchidism, characterized by undescended testes, is associated with infertility and increased cancer risk through complex, multifactorial pathophysiological mechanisms involving interconnected alterations in testicular microenvironment, including but not limited to elevated temperature, hormonal dysregulation, altered vascular perfusion, and immune responses. These factors interact synergistically to drive testicular pathology. Using a surgically induced bilateral cryptorchid mouse model established at postnatal day 21 (PND21), we investigated phase-specific pathological mechanisms through analyses at prepubertal (PND35) and sexually mature (PND70) phases. Our transcriptome analysis revealed distinct molecular signatures at different developmental phases, with prepubertal cryptorchid testes showing 2570 differentially expressed genes predominantly enriched in immunoproteasome components and inflammatory pathways, while sexually mature testes exhibited 883 differentially expressed genes primarily related to extracellular matrix (ECM) remodeling and oncogenic pathways. Prepubertal molecular changes indicated immunoproteasome activation and inflammatory responses, whereas mature-phase alterations were characterized by ECM reorganization and fibrotic remodeling. Functional analysis demonstrated prepubertal enrichment in spermatogenesis regulation and interferon responses, while mature-phase signatures were associated with apoptosis, epithelial–mesenchymal transition, and inflammatory signaling cascades. Phase-specific oncogenic pathway correlations revealed distinct mechanisms: metabolic reprogramming and epigenetic regulation in prepubertal testes versus structural remodeling and invasion-related pathways in mature testes. Molecular validation confirmed elevated PI3K-Akt and NF-κB signaling at both developmental phases, identifying these as potential therapeutic targets. This first phase-resolved characterization of cryptorchidism pathology provides insights into developmental phase-specific mechanisms and suggests timing-dependent therapeutic strategies. Although differing from human congenital cryptorchidism in developmental timing and etiology, our surgically induced model recapitulates anatomical testicular malposition with multiple inseparable pathophysiological alterations, and the identified molecular signatures reflect integrated responses to the complex cryptorchid microenvironment. Full article

Background/Objectives: The guinea pig is a unique experimental model because of the evolutionary loss of the GULO gene, which encodes an enzyme involved in vitamin C synthesis. Since vitamin C plays an essential role in collagen biochemistry, numerous studies have investigated the effects of pre- and postnatal vitamin C deficiency. However, only a few studies, including ours, have indicated a possible link between vitamin C deprivation and potential weakening of the basement membrane, which may lead to significant alterations in brain structure. Methods: The experiment included guinea pig foetuses completely deprived from the 10th (E2 group) and the 20th (E1 group) to the 50th day of intrauterine life. Tissue samples from the cerebrum and cerebellum were taken for biochemical, molecular, and immunohistochemical analyses. Results: In the E2 group alone, we found marked gross changes: cerebral bleeding, porencephaly, and a lissencephalic cerebellar surface. Microscopic examination revealed diffuse bleeding in the cerebrum along with a loss of neurons in the area of the defect, specifically in the E2 group. The complete maturation of ectopic neurons characterised dysplastic changes in the cerebellum. Hydroxyproline analysis of both the cerebrum and cerebellum showed no significant differences among the E1, E2, and control groups. However, decreased expression of COL1, COL4A1, and SLC23A1 was observed solely in the cerebellar tissue of the E1 group. Conclusions: The morphological, biochemical, and molecular results represent preliminary associations with vitamin C deficiency, but require further validation. Full article

Glucocorticoids are essential for fetal organ maturation and form the basis of antenatal corticosteroid therapy that has significantly reduced preterm-related morbidity such as respiratory distress syndrome (RDS). However, neonatal morbidity remains a clinical challenge regardless of antenatal corticosteroid therapy. Currently, it is thought that adverse intrauterine environments dysregulate glucocorticoid receptor (GR) homeostasis, yet the biological mechanisms remain poorly understood. Therefore, we aimed to study ex vivo glucocorticoid sensitivity in cord blood immune cells from two independent preterm cohorts to identify associations with neonatal morbidity and uncover potential mechanisms of dysregulated glucocorticoid homeostasis. In the first cohort, thawed cord blood mononuclear cells were exposed to betamethasone in the presence of lipopolysaccharides (LPS) for 4 h. In the second cohort, freshly isolated white blood cells were treated with dexamethasone under unstimulated and LPS-stimulated conditions for 48 h. GR isoform expression and regulation of transactivated and transrepressed genes were assessed via qPCR, immunoblotting, flow cytometry, and ELISA. In both cohorts, reduced GR expression, particularly of the GRα isoform, was observed in neonates with morbidity, but only with culture time and not in freshly isolated cells. Ex vivo impaired glucocorticoid-mediated transrepression of proinflammatory genes IL6 and TNF was also observed in the morbidity groups. In contrast, all samples were comparable in basal immune cell distributions and transactivation of glucocorticoid response element (GRE)-dependent genes GILZ and FKBP5, irrespective of neonatal morbidity. These findings suggest that neonates that develop morbidities experience an early postnatal GR dysfunction that is potentially programmed in utero. Moreover, under conditions of decreased GR abundance, classical transactivation functions appear to be preserved at the expense of more complex regulatory mechanisms such as transrepression. Full article