Search Results (365)

Serotonin is a critical morphogen in early development, yet the mechanisms regulating its homeostasis in the preimplantation embryo remain unclear, particularly under conditions of maternal antidepressant exposure. Here, we investigated embryonic serotonergic autonomy using mouse models of pharmacological transport blockade (maternal fluoxetine treatment) and in vitro treatment with the monoamine oxidase inhibitor pargyline. We employed immunofluorescence, RT-qPCR, and live-cell imaging to assess metabolic flux, gene expression, and physiological health. We demonstrate that monoamine oxidase functions as a metabolic firewall, progressively maturing from zygote to blastocyst to degrade excess amines. Paradoxically, maternal serotonin transporter blockade triggered significant intracellular serotonin hyper-accumulation in blastocysts, associated with a trend toward a compensatory upregulation of the biosynthetic gene Ddc. While this serotonin overload did not compromise morphology, mitochondrial function, or pluripotency marker expression, it induced a robust epigenetic response. Excess serotonin promoted elevated H3Q5ser immunoreactivity in both nuclear and cytoplasmic compartments via a transglutaminase-dependent mechanism. These findings reveal that the preimplantation embryo possesses a resilient, autonomous serotonergic system capable of compensatory synthesis. However, environmental fluctuations are chemically recorded via transglutaminase-mediated serotonylation, representing an epigenetic mark that warrants further long-term study within the Developmental Origins of Health and Disease (DOHaD) framework. Full article

Reproductive dysfunction in captive-bred males of the flatfish Solea senegalensis remains a major bottleneck for its aquaculture. To clarify the molecular basis underlying these impairments, we performed an integrated analysis of transcriptomes, proteomes and methylomes from gonads of wild-type individuals and first-generation (F1) captive fish of both sexes. Nineteen RNA-seq libraries and eighteen LC–MS/MS proteomes were generated, allowing the quantification of more than 32,000 genes and 2221 proteins. Differential expression and principal component analyses revealed that sex was the primary driver of molecular variation, whereas origin (F1 vs. wild-type) had a more moderate effect. Multi-omics integration showed a partial and comparison-dependent correspondence between RNA and protein levels, with a marked RNA–protein decoupling in F1 males. Despite this limited concordance, functional enrichment analyses identified consistent regulation of key biological processes, including translation, energy metabolism, and reproductive pathways such as gametogenesis, fertilization, and early embryonic development. Within this regulatory framework, previously characterized DNA methylation landscapes in gonadal tissue suggest an additional epigenetic layer modulating the transcriptional potential of reproductive genes, particularly in captive-bred males. F1 males exhibited coordinated down-regulation of reproductive functions across omic layers, consistent with altered post-transcriptional and post-translational regulation. Overall, this study provides the first comprehensive multi-omics framework integrating transcriptomic, proteomic, and epigenetic information in S. senegalensis gonads, offering mechanistic insights into the molecular basis of reproductive dysfunction in F1 broodstock and supporting future strategies to improve reproductive performance in aquaculture. Full article

Congenital thoracoabdominal wall defects in dogs are uncommon and challenging to classify due to their overlapping anatomical and developmental features. This study analyzes three original canine cases alongside 17 published cases to clarify the relationships among Cantrell syndrome (CS), amniotic band syndrome (ABS), and body stalk anomaly (BSA). All of the original cases exhibited thoracoabdominal involvement with variations in umbilical cord morphology and associated anomalies. A comparative analysis revealed that these conditions form a syndromic continuum rather than distinct entities, influenced by the timing and mechanism of embryonic disruption. Early developmental insults were associated with multisystem malformations resembling CS or BSA, whereas later vascular disruptions produced more localized defects, such as gastroschisis. Umbilical cord morphology emerged as a key diagnostic discriminator across cases. Based on these findings, we developed an anatomically driven diagnostic decision tree to support clinical evaluation when information is incomplete. This study emphasizes the importance of integrating embryologic context with anatomical assessment and identifies significant gaps in molecular and genetic data. A developmental continuum model offers a more flexible, clinically meaningful framework for diagnosing congenital body wall defects in dogs. Full article

Background: Long INterspersed Element-1 (LINE-1) retrotransposons comprise 17–20% of the human genome. These retroelements are normally silenced early in embryonic development through epigenetic mechanisms and reawakened during oncogenesis, leading to transcriptional dysregulation, genomic instability, and immune evasion. Methods: In the present study, we categorized LINE-1 transcripts across 121 non-small cell lung cancer (NSCLC) cell lines from the Cancer Cell Line Encyclopedia (CCLE) by subfamily, length, orientation, chromosomal origin, and distribution. In addition, high-prevalence insertions were mapped to nearby genes to assess potential functional interactions. Results: LINE-1 transcript abundance and length in NSCLC were dominated by evolutionarily young subfamilies, particularly L1HS and L1PA2 through L1PA5. Chromosomal patterns were conserved across NSCLC subtypes, with modest enrichment of L1HS activity on Chromosome 4 and the X Chromosome. The lung squamous cell carcinoma (LSQCC) subtype exhibited the highest total levels of L1HS expression relative to other NSCLC subtypes. Race modestly influenced LINE-1 transcript abundance, with cell lines derived from self-identified African American individuals showing elevated overall LINE-1 and L1HS expression. Age showed a weak positive correlation with total LINE-1 abundance. Integrative analysis revealed recurrent hotspots at 22q12.1 and 20p11.21 that were transcriptionally active across subtypes and coincided with previously reported intact LINE-1 elements active in epithelial cancers. Recurrent insertions were located near cancer-associated genes, including RB1, NEDD4, FTO, LAMA2, NOD1, and KCNB2, implicating LINE-1 activity in cis-regulatory remodeling of oncogenic pathways. Conclusions: Together, these findings indicate that LINE-1 transcript heterogeneity in NSCLC is shaped by host genomic architecture and conserved functional hotspots, providing new insights into the mechanisms of genetic and epigenetic dysregulation associated with LINE-1 retroelements. Full article

As the brain’s resident macrophages, microglia on the one side are increasingly recognized as essential players in discrete developmental stages, where immune, metabolic, and activity-derived signals are coordinately integrated to guide brain development. On the other side, the precise temporal and molecular coordination of microglial maturation is imperative for the structural and functional integrity of the developing central nervous system (CNS). In this review, we synthesize recent data that reposition microglia from a uniform population of immune sentinels to temporally programmed and regionally specialized regulators of circuit maturation. This involves dissecting the embryonic origins and migratory pathways of microglial progenitors in mouse and human systems and illustrating how gradual transcriptional and morphological maturation aligns the biology of microglia with progressive phases of neurogenesis, synaptic fine-tuning, myelination, and vascular stabilization. In addition, we discuss how individual gene mutations, inflammatory insults during perinatal life, and environmental disturbances intersect with these temporal programs to alter microglial phenotypes and compromise circuit formation. With a special emphasis on epilepsy and autism spectrum disorder, often sharing the common etiology, we illustrate how early malfunction of microglia may drive neural network dysfunction. Full article

Infectious Bronchitis Virus is one of several major viral infections in poultry, affecting the respiratory, reproductive, and renal systems and causing significant economic losses worldwide. Current vaccines, including the H120 strain, provide limited cross-protection against emerging variants, underscoring the need for improved vaccine strategies. In this study, the complete genome of IBV H120 was divided into 12 fragments, synthesized, and assembled using the Golden Gate Assembly (GGA) method. The recombinant virus (rH120) was successfully rescued in chicken fibroblast cells and propagated in embryonated specific-pathogen-free (SPF) chicken eggs. Growth kinetics in embryonated SPF chicken eggs revealed similar replication patterns between rH120 and the original H120 strain. In broiler chickens, rH120 replicated efficiently, as confirmed by viral RNA detection in throat and cloacal swabs, and induced a stronger antibody response by 14 days post-infection. The rH120 virus proved to be genetically stable, infectious, and immunogenic, indicating that GGA-based reverse genetics is an effective system for IBV vaccine development. Full article

Recent studies support that hematopoietic stem cell (HSC)-derived myeloid dendritic cells, monocytes/macrophages (Mo/Mϕ), and osteoclast precursors (OCps) share common progenitor(s) during development. This occurs mainly through receptor activator of NF-κB ligand (RANKL) signaling via its cytoplasmic adaptor protein complex (TRAF6) to subsequent osteoclastogenesis for bone loss and/or remodeling. Presently, mounting new evidence suggests that erythro-myeloid progenitor (EMP)-derived macrophages (Mϕ) and HSC-derived monocytes (Mo) produce embryonic, fetal, and postnatal OCp pools (i.e., primitive OCp), pinpointing a complex network of multiple OCp developmental origins. However, their ontogenic developments, lineage interactions, and contributions to the alternative osteoclastogenesis—in contrast to overall bone remodeling or loss—remain elusive. Interestingly, studies have also elucidated the contributions of immature CD11c⁺ myeloid DC-like OCps to osteoclastogenesis, with or without the classical so-called Mo/Mϕ-derived OCp subsets, and described that CD11c⁺ myeloid DCs (mDCs) develop into functionally active OCs; meanwhile, the cytokine TGF-β mediates a stepwise regulation of de novo immature mDCs/OCps through distinct crosstalk(s) with IL-17, an unrecognized interaction featuring TRAF6^(−/−)CD11c⁺ mDDOCps that coexist and proficiently colocalize in the local environment to drive a bona fide route for alternative osteoclastogenesis in vivo. Collectively, new findings—critically hinged on progenitor osteoclastogenic pathways (primitive OCps, mDCs/OCps, osteomorphs, etc.) and involving classical and/or alternative routes to inflammation-induced bone loss—are discussed via the illustrated schemes. This review highlights plausible ontogenic vs. principal or alternative developmental paths and their consequential downstream effects. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a devastating complication arising primarily after invasive dentoalveolar procedures in patients treated with antiresorptive, antiangiogenic, or targeted therapies. Although recognized risk factors are established, the distinctive vulnerability of jawbones compared to long bones is not fully understood. This review comprehensively synthesizes recent advances regarding the embryological, anatomical, and physiological disparities that contribute to region-specific susceptibility to MRONJ. Recent evidence suggests that jawbones diverge significantly from long bones in embryonic origin, ossification pathways, vascular architecture, innervation patterns, and regenerative capacities. These differences affect bone metabolism, healing dynamics, response to pharmacologic agents, and local cellular activities, such as enhanced bisphosphonate uptake and specialized microcirculation. Experimental and clinical evidence reveals that mandibular periosteal cells exhibit superior osteogenic and angiogenic potentials, and the jaws respond differently to metabolic challenges, trauma, and medication-induced insults. Furthermore, site-specific pharmacologic and inflammatory interactions, including altered periosteal microcirculation and leukocyte–endothelial interactions, may explain the development of MRONJ, although rare cases of medication-related osteonecrosis have also been reported in long bones. Emerging research demonstrates that immune dysregulation, particularly M1 macrophage polarization with overexpression of matrix metalloproteinase-13 (MMP-13), plays a crucial role in early MRONJ development. Understanding these mechanisms highlights the critical need for region-specific preventive measures and therapeutic strategies targeting the unique biology of jawbones. This comparative perspective offers new translational insights for designing targeted interventions, developing tissue engineering solutions, and improving patient outcomes. Future research should focus on gene expression profiling and cellular responses across skeletal regions to further delineate MRONJ pathogenesis and advance personalized therapies for affected patients. Full article

Cellular memory, or epigenetic memory, represents the capacity for cells to retain information beyond the underlying DNA sequence. This heritable characteristic is primarily governed by epigenetic mechanisms which enable cells to maintain specialized characteristics across divisions. This persistent cellular state is essential for fundamental biological processes, such as maintaining tissue identity and facilitating cell differentiation, especially embryonic cells. Early-stage perturbations such as assisted reproductive technologies (ART) and nutritional stress links embryonic exposures to adult health and disease within the Developmental Origins of Health and Disease (DOHaD) framework. Crucially, memory established during early embryogenesis links these epigenetic modifications to adult long-term phenotypes related to metabolic disorders. These modifications—including DNA methylation, histone modifications, and non-coding RNAs—support cellular memory transmission across cell divisions, and in certain organisms, can be transmitted across generations without alterations to the DNA sequence. This review synthesizes recent advances in epigenetic pathways that mediate cellular memory, highlights critical preimplantation windows of vulnerability and outlines gaps necessary for mammalian developing interventions that safeguard future generations. Full article

The Xenopus oocyte has long served as a versatile and powerful model for dissecting the molecular underpinnings of reproductive and developmental processes. Its large size, manipulability, and well-characterized cell cycle states have enabled generations of researchers to illuminate key aspects of oocyte maturation, fertilization, and early embryogenesis. This review provides an integrated overview of the cellular and molecular events that define the Xenopus oocyte’s transition from meiotic arrest to embryonic activation—or alternatively, to programmed demise if fertilization fails. We begin by exploring the architectural and biochemical landscape of the oocyte, including polarity, cytoskeletal organization, and nuclear dynamics. The regulatory networks governing meiotic resumption are then examined, with a focus on MPF (Cdk1/Cyclin B), MAPK cascades, and translational control via CPEB-mediated cytoplasmic polyadenylation. Fertilization is highlighted as a calcium-dependent trigger for oocyte activation. During fertilization in vertebrates, sperm-delivered phospholipase C zeta (PLCζ) is a key activator of Ca²⁺ signaling in mammals. In contrast, amphibian species such as Xenopus lack a PLCZ1 ortholog and instead appear to rely on alternative protease-mediated signaling mechanisms, including the uroplakin III–Src tyrosine kinase pathway and matrix metalloproteinase (MMP)-2 activity, to achieve egg activation. The review also addresses the molecular fate of unfertilized eggs, comparing apoptotic and necrotic mechanisms and their relevance to reproductive health. Finally, we discuss recent innovations in Xenopus-based technologies such as mRNA microinjection, genome editing, and in vitro ovulation systems, which are opening new avenues in developmental biology and translational medicine. By integrating classic findings with emerging frontiers, this review underscores the continued value of the Xenopus model in elucidating the fundamental processes of life’s origin. We conclude with perspectives on unresolved questions and future directions in oocyte and early embryonic research. Full article

Neuroblastoma is an embryonal tumour that arises from the malignant transformation of neural crest cells and remains one of the deadliest malignancies in children under five. Neural crest development is regulated by dynamic switches in transcriptional programmes, guided by a variety of growth factors. Due to its developmental origin, neuroblastoma is unique in that these tumours often retain overactivation of growth factor signalling, which can be targeted by receptor tyrosine kinase (RTK) inhibitors. However, mutations in kinases, except for ALK, are extremely rare in neuroblastoma. Furthermore, the high degree of intratumoural heterogeneity often renders RTK inhibition ineffective as a monotherapy. For high-risk tumours, which lack effective treatment options, there remains an unmet need for targeted therapies. This review summarises the roles of growth factor receptors in neural crest and neuroblastoma development in light of recent single-cell studies. We provide a systematic overview of RTK inhibitors that can target growth factor signalling in neuroblastoma and detail their current status in clinical development. We also explore the role of intratumoural heterogeneity in resistance to RTK inhibitors, focusing on the adrenergic-to-mesenchymal transition, which drives a switch in growth factor receptor expression. Finally, we discuss strategies to overcome RTK inhibitor resistance by targeting neuroblastoma cell plasticity, disrupting downstream signalling pathways, or inhibiting escape mechanisms from cell death. This review provides a theoretical basis for developing novel combination therapies incorporating RTK inhibitors. Full article

Mucosal melanoma (MM) is a rare, aggressive cancer whose incidence has increased continuously over the years. This subtype of melanoma arises from melanocytes on hairless surfaces, typically in the respiratory tract, gastrointestinal (GI) tract, and urogenital tract. The most common sites of occurrence include the head and neck, the anorectal region, and the vulvovaginal region, while the rare sites of MM are the urinary tract and the upper and lower GI tract, including the esophagus, duodenum and the gallbladder. MM arises in melanocytes of the ectodermal mucosa that originate from neural crest cells and migrate through embryonic mesenchyme to their destination. Although melanocytes are located mainly in the epidermis and dermis, their presence in various extracutaneous sites, such as the eyes, mucosal tissue, and leptomeninges, is known. Although both cutaneous melanoma (CM) and MM differ in their epidemiology, genetic profile, and clinical presentation, their treatment options are similar. In contrast to the higher treatment response of CM, MM is characterized by a lower response rate to available treatment options, resulting in a poorer survival rate. In this review, we provide an overview of the biology of MM and the mechanisms regulating its development, progression and treatment resistance. Full article

Background/Objective: Colon cancer, the third most diagnosed cancer worldwide, is anatomically classified into right- and left-sided colon cancers based on embryonic origin and vascular supply. The aim of this study was to investigate molecular differences between patients with right- and left-sided colon cancer. Methods: In this pilot study, Blood samples from right-sided (n = 6) and left-sided (n = 6) colon cancer patients, as well as healthy controls (n = 6), were analyzed for 92 cancer-related genes via RT-qPCR. KEGG pathway analysis was performed with ShinyGO 0.82, and gene–metabolite interactions were assessed using EnrichR and MetaboAnalyst 6.0. Additionally, patients’ sociodemographic and clinical data were analyzed. Results: KEGG analysis revealed that p53, HIF-1, TNF, PI3K/Akt, MAPK, and Rap1 signaling pathways were enriched in right-sided colon cancer, whereas VEGF, HIF-1, MAPK, PI3K/Akt, Rap1, and Ras signaling pathways were implicated in left-sided colon cancer. In the gene–metabolite analysis, key metabolites identified in right-sided colon cancer included palmitic acid, adenosine triphosphate (ATP), glycerol, and adenosine diphosphate (ADP), associated with genes such as ACSL4, TP53, MAPK14, FLT1, AURKA, KDR, ERCC3, and PFKL. For left-sided colon cancer, glucose-6-phosphate (G6P), ATP, ADP, glycerol, and palmitoyl-CoA were key metabolites forming the basis of the gene–metabolite network, along with genes including G6PD, PFKL, MAPK14, FLT1, CDK4, AURKA, MAP2K1, ERCC3, TP53, WEE1, and GPD2. Conclusions: These findings highlight distinct molecular profiles between right- and left-sided colon cancers, particularly in pathways related to angiogenesis, apoptosis, ferroptosis, and fatty acid metabolism, which may inform therapeutic strategies. Full article

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants recognized for their toxicological significance. Increasing evidence suggests that chronic exposure to low-molecular-weight PAHs (LMW-PAHs) contributes to heightened disease vulnerability and immune dysregulation, particularly among rural female populations. Recent studies have further linked a significant association between PAH exposure and gut microbiome (GM) modifications. Considering the common embryonic origin of the intestinal and respiratory systems, cross-organ communication under conditions of PAH exposure warrants deeper exploration. Although current gut–lung axis research largely emphasizes microbial metabolites such as short-chain fatty acids and bile acids, the contribution of arachidonic acid (AA) metabolites in LMW-PAH-induced pulmonary inflammation via this axis remains poorly defined. To address this knowledge gap, we developed an animal model employing integrated 16S rRNA sequencing and metabolomics approaches to systematically examine phenanthrene (Phe) and fluorene (Flu) induced GM compositional shifts and associated metabolic reprogramming. Through comprehensive profiling, we identified candidate microorganisms and metabolites potentially involved in dysbiosis-mediated pulmonary inflammation, thereby elucidating the mechanistic basis of Phe and Flu-associated health risks. Full article

Background/Objectives: Approximately 50% of infertility cases are attributable to male factors; yet conventional semen examination can not identify the molecular abnormalities that hinder sperm functionality. Extracellular vesicles (EVs) derived from sperm, such as testicular EVs, prostasomes, and epididymosomes, have become important modulators of oocyte activation, sperm maturation, capacitation, acrosome stability, motility, and early embryonic development. This study aimed to evaluate the potential diagnostic and translational uses of sperm-associated extracellular vesicles (EVs) in male infertility and assisted reproduction, while also consolidating recent insights on their origins, composition, and functional significance. Methods: A focused narrative search of PubMed (2000–2025) was conducted using backward and forward citation tracking. Studies that qualified included human clinical cohorts, functional sperm extracellular vesicle tests, and omics analyses using MISEV-aligned extracellular vesicle isolation and characterisation methodologies. When human mechanistic understanding was constrained, knowledge from animal research was selectively integrated. Results: The cargo signatures specific to the source identified in sperm-derived and seminal EVs encompass proteins, small RNAs, lipids, and enzymatic modules that govern sperm maturation, capacitation, acrosome reaction, redox balance, calcium signalling, zona binding, and DNA integrity. Density-resolved seminal extracellular vesicle subfractions (EV-H/EV-M/EV-L) have unique functional and proteomic characteristics linked to progesterone-induced hyperactivation, oxidative stress, and motility. Asthenozoospermia and oligoasthenoteratozoospermia are associated with changes in extracellular vesicle composition, reduced embryonic developmental potential, compromised oocyte activation (related to PLCζ), and increased sperm DNA fragmentation. Numerous EV-related miRNA and protein signatures may predict TESE results, identify functional sperm anomalies not recognised by conventional semen analysis, and differentiate between obstructive and non-obstructive azoospermia. Conclusions: The available findings indicate that sperm-derived extracellular vesicles are significant functional regulators of sperm physiology and may serve as valuable non-invasive indicators for male infertility. The standardisation of EV isolation, characterisation, and clinical validation is essential prior to widespread use; nonetheless, their integration into liquid biopsy methods and assisted reproductive technology processes represents a significant improvement. Full article