Search Results (1,315)

Hyaluronan (HA) is a ubiquitous extracellular matrix (ECM) component that is gaining significant attention for its diverse roles in cell signalling and disease. The biological functions of HA are dependent on its molecular weight (M_w): low M_w polysaccharide chains drive stimulatory processes such as inflammation and angiogenesis, whereas high M_w HA is stabilising and anti-inflammatory. Growing evidence indicates that HA is integral to brain function. The composition of HA in the brain is regulated by the balance of enzymatic synthesis and degradation, mediated by different isoforms of hyaluronan synthase (HAS) and hyaluronidase (HYAL) respectively. Fluctuating expression of the genes encoding the HAS and HYAL enzymes has been implicated in neuropathology and ageing, with some studies providing evidence towards epigenetic regulation of these genes. The regulatory environment of the brain confers a unique balance of enhanced protection alongside the requirement for maximum flexibility. This scoping review focuses on summarising current knowledge regarding epigenetic regulation of HAS and HYAL genes in neural contexts, as well as identifying gaps in knowledge against which future research can be directed. Understanding how these genes are regulated, particularly through epigenetic mechanisms, provides insight into how HA is regulated in the brain, facilitating understanding regarding its function in brain health and disease. Full article

Wilms tumor (WT), the most common kidney neoplasm in children, is closely associated with hereditary factors. This study included 134 WT patients (62 males, median age of 7 years, age at diagnosis of 24.9 months) with unilateral (n = 90, 67%) or bilateral WT (n = 44, 33%). Genetic testing was performed using targeted sequencing of 415 genes and multiplex ligation–dependent probe amplification (MLPA). Twenty-five mutations in eight genes were found in 17% (n = 23) of patients: WT1 (n = 10), TRIM28 (n = 4), REST (n = 3), CHEK2 (n = 3), BRCA2 (n = 2), NF1 (n = 1), RAD50 (n = 1), and CDC73 (n = 1). Large deletions of the 11p13 region were revealed in 6% (n = 5) of patients. The 11p15 locus methylation was studied in blood, tumor, and healthy kidney tissue of nine patients suspected of Beckwith–Wiedemann syndrome (BWS) using methylation-sensitive MLPA (MS–MLPA). BWS was diagnosed in 3% (n = 4) of cases (one patient had mosaic disease). Thus, genetic and epigenetic aberrations were identified in 32 WT patients (24%). These patients had a higher frequency of bilateral WT and a higher rate of abnormalities compared to patients without aberrations (56% vs. 25%, p = 0.002; and 86% vs. 25%, p < 0.0001, respectively). The detection of WT hereditary predisposing factors is crucial for treatment strategies and long-term patient surveillance. Full article

Autism spectrum disorder (ASD) has been associated with alterations in the gut microbiota and its metabolites, particularly short-chain fatty acids (SCFAs) and microbiota-derived tryptophan catabolites, which may influence neurodevelopment through immune and epigenetic mechanisms. We investigated whether stool SCFAs and tryptophan-pathway metabolites differ between children with ASD and typically developing controls, and whether these metabolites associate with ASD severity and systemic biochemical signatures. In this cross-sectional study, we analyzed stool samples from 229 children (160 with ASD, 69 controls) with complete SCFA and tryptophan-metabolite data, while urine metabolomics data were available for a subset and were used for exploratory stool–urine integration analyses. Children with ASD and controls were similar in age, but the ASD group had a higher proportion of males. Absolute concentrations of individual SCFAs, total SCFAs, and derived indices were broadly comparable between groups; nominal differences in propionate/acetate ratio and caproate did not remain significant after false discovery rate correction. Similarly, stool tryptophan-pathway metabolites reported as ng/a.u. based on the NanoDrop-derived proxy (tryptophan, kynurenine, indole-3-acetic, indole-3-lactic, indole-3-propionic, indole-3-aldehyde, N-acetyl-tryptophan, serotonin, melatonin, tryptamine) and functional ratios (kynurenine/tryptophan, indole-derived/tryptophan, serotonin/tryptophan) showed no robust ASD–control differences; N-acetyl-tryptophan was nominally higher in ASD but did not survive multiple-testing correction. In the ASD subgroup with available Childhood Autism Rating Scale (CARS) data (n = 34), SCFA and tryptophan indices showed only weak, non-significant correlations with global ASD severity. In contrast, correlation analyses revealed two coherent metabolic modules, i.e., an SCFA block with very strong internal correlations among individual SCFAs and total SCFAs and a tryptophan block with strong correlations between metabolites and their normalized ratios, while cross-module correlations were modest. These results indicate that stool SCFA and microbiota-derived tryptophan profiles do not robustly distinguish ASD from controls in this cohort, but they form stable metabolic modules compatible with microbiome–epigenome frameworks. Full article

Background: Gaucher disease (GD) arises from pathogenic variants in the GBA1 gene and is known for its wide range of clinical presentations—a variability that genotype alone cannot adequately account for. Objective: This study aimed to explore transcriptomic factors that might help explain why two genetically identical twins with type 1 GD developed noticeably different clinical outcomes. Methods: We isolated peripheral blood mononuclear cells from both twins and two age-matched controls, then differentiated them into macrophages in vitro before conducting RNA sequencing. Gene expression differences were analyzed using established bioinformatics pipelines, and a subset of genes were subsequently assessed by quantitative real-time PCR (qRT-PCR) to confirm the sequencing findings. Results: Both twins shared a GD-associated transcriptional signature broadly reflecting immune activation and lysosomal stress. Interestingly, the twin who experienced systemic complications had a relative enrichment of interferon-responsive transcripts, while the less severely affected twin showed more pronounced suppression of small nucleolar RNA clusters. That said, neither difference held up after correcting for multiple comparisons, so these patterns are best viewed as exploratory trends rather than definitive findings. The qRT-PCR results lend partial support to this picture: stress- and immune-related genes (DDIT4, RPH3A, SAMSN1) trended toward higher expression in patients versus controls, and interferon-stimulated genes (ISG15, RSAD2, IFI44L) were more elevated in M2 than in M1. Conclusions: Taken together, these findings suggest that factors beyond genetics—whether epigenetic, environmental, or otherwise—may play a meaningful role in shaping how GD manifests differently even between individuals with identical DNA. Although the data are preliminary, they point to transcriptomic profiling, paired with targeted validation, as a useful starting point for building hypotheses about why this disease looks so different from one patient to the next, even when the underlying mutation is the same. Full article

Leukocyte telomere length (LTL) is shortened in adults with type 1 diabetes (T1D), but less data is available concerning pediatric cases. Multiple factors affect LTL, namely genes, epigenetics, environmental factors, oxidation, and psychological stress. Children with T1D and their families experience chronic stress. This study aimed to investigate LTL in children with T1D (n = 35) aged 6–13 years old, in comparison to age-matched healthy counterparts (n = 35), and assess any correlation of LTL with perceived stress. Relative LTL (rLTL) was assessed through real-time qPCR. Morning serum cortisol, high-sensitivity C-Reactive Protein (hsCRP), and glycated hemoglobin (HbA1c) were measured. Children completed the validated questionnaires “Stress in Children” and “Pediatric Quality of Life”. Parents answered the “Perceived Stress Scale”. Children with T1D had a lower rLTL (p = 0.02) compared to age-matched healthy controls, higher hsCRP (p = 0.031), and a lower estimated quality of life (p = 0.01). RLTL was found to be lower in females with T1D (p < 0.001) and was positively related to the ‘gender–social support’ factor (p = 0.002) and diabetes duration (p = 0.045), adjusted for children’s age, parental age, and sociodemographic characteristics. These pilot findings indicate early emergence of shorter rLTL in T1D, pointing to a sexual dimorphism pattern. Insights into preventing LTL shortening in pediatric T1D can be gained from large-scale studies examining the impact of gender and social support. Full article

Background/Objectives: The prevalence of allergic diseases has markedly increased in developed countries, with environmental and dietary factors considered important contributors. Folic acid is an essential micronutrient involved in one-carbon metabolism and DNA methylation, playing a key role in epigenetic regulation of immune function. Both high and low folate exposure have been associated with allergic outcomes, but the data on postnatal folate status in paediatric populations remain limited. This study aimed at assessing serum folate status in children with atopic diseases compared with children without chronic allergic disease in Croatia. Methods: This cross-sectional study included 292 paediatric patients from the University Hospital in Split and a paediatric primary care practice between January 2024 and January 2025. Serum folic acid concentrations were measured using electrochemiluminescence immunoassay. Additional laboratory parameters included vitamin B12, total IgE levels, and eosinophil counts. Demographic and clinical data were obtained from medical records. Statistical analyses included Chi-square tests, Mann–Whitney U tests, linear regression modelling, and analysis of covariance with statistical significance set at p < 0.05. Results: Folic acid deficiency was present in 66.4% of all participants. Children with atopic diseases were significantly more likely to have folate deficiency and had lower mean serum folate concentrations compared to children without allergic disease. There were no significant differences in folate levels between children with and without asthma. Lower folate levels were associated with higher IgE levels, higher eosinophil counts, and older age. When controlling for the effects of age on folic acid levels, the differences between participants with and without atopic diseases remained significant. Conclusions: Folic acid deficiency is highly prevalent among children in the Mediterranean region of Croatia and is significantly associated with atopic diseases and markers of allergic inflammation. These findings highlight a potential role of folate status in paediatric allergic disease and support the need for longitudinal studies to clarify causality and potential clinical implications. Full article

The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH and MAGL), has been increasingly implicated in the pathophysiology of neuropsychiatric disorders, including mood, anxiety, psychotic, stress-related, and eating disorders. Altered endocannabinoid signaling contributes to maladaptive stress responses, emotional dysregulation, and impaired synaptic plasticity, highlighting the role of the ECS as a core integrative mechanism. Therapeutic strategies targeting ECS, particularly through FAAH inhibition and the use of plant-derived cannabinoids, such as cannabidiol (CBD), show promise in restoring endogenous homeostasis while minimizing the adverse cognitive and affective effects associated with direct CB1 activation. ECS function and treatment response are further influenced by genetic polymorphisms in CNR1, CNR2, FAAH, and MGLL, as well as epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. Despite these advances, clinical translation remains limited by interindividual variability, the complexity of ECS interactions, and the relatively small size of existing clinical studies. Future research integrating longitudinal clinical trials with multi-omics approaches is essential to support the development of evidence-based, personalized interventions. Overall, understanding ECS mechanisms and dysregulation provides a valuable framework for the development of targeted therapies in neuropsychiatric disorders. Full article

Human endogenous retroviruses (HERVs) represent 8% of our genome. They are remnants of ancient infections of germinal cells. HERVs are no longer infectious, but their enhanced expression is implicated in several diseases, including neuropsychiatric disorders. Their transcription is regulated by TRIM28 and SETDB1, which are involved in the regulation of epigenetic processes, in neural cell differentiation, and brain inflammation. We explored the expressions of HERVs and TRIM28/SETDB1 in adolescents affected by anorexia nervosa (AN). Through real-time PCR, we assessed the transcription levels of pol genes of HERV-H, -K, and -W, of env genes of Syncytin 1 (SYN1), Syncytin 2 (SYN2), and of HERV-W, and of TRIM28 and SETDB1 in whole blood of 37 adolescents with AN and in healthy controls (HCs) of comparable age. HERV-H-pol, HERV-K-pol and SETDB1 transcriptional levels were significantly higher in adolescents with AN as compared with HCs, while HERV-W-pol and -env were downregulated in the former. No differences were observed for SYN1, SYN2, and TRIM28 between the two groups. The observed expression pattern of HERVs is specific for AN as compared to other neuropsychiatric disorders. These aberrant expressions suggest a potential role of retroviral elements in the pathophysiology of AN, opening the way for innovative diagnostic and therapeutic strategies. Full article

Colorectal cancer (CRC) shows consistent sex-related differences in incidence, anatomic distribution, molecular subtype, immune context, and clinical outcome. However, these differences are often discussed through broad parallel themes such as hormones, genetics, or the microbiome, rather than through the biological settings in which sex meaningfully modifies tumor behavior. This review argues that sex is most informative in CRC when treated as a contextual modifier whose relevance emerges only after integrating tumor sidedness, mismatch repair status, oncogenic background, immune ecology, and age at onset. The clearest signals arise from interaction-based contexts, particularly when sex is interpreted together with tumor sidedness and dMMR/MSI-H or BRAF-linked disease states. Current evidence indicates that women are enriched for proximal or right-sided, microsatellite instability-high, mismatch repair-deficient, CpG island methylator phenotype-high, and BRAF-associated CRC, whereas men more often present with distal disease and a higher overall burden. Mechanistic studies further show that sex-related differences extend beyond hormone exposure to include KRAS–STAT4–KDM5D signaling, site-specific immune-checkpoint programs, metabolic phenotypes, epigenetic biomarker variation, and microbiota–hormone crosstalk. These effects are most evident in defined clinical niches, particularly right-sided CRC, mismatch repair-deficient disease, BRAF-mutated metastatic CRC, and early-onset CRC. A sex-aware, subtype-aware, and location-aware framework therefore offers a more clinically useful interpretation of CRC heterogeneity than descriptive male-versus-female comparisons alone. Full article

The Mediterranean Diet (MD) is recognized for promoting longevity and reducing the risk of chronic disease, yet the mechanisms underlying these benefits remain uncharacterized. This review highlights the diverse nutritional and phytoactive constituents of the MD and research exploring its complex network of polyphenols. It discusses data evaluating MD-derived constituents formulated into a dietary supplement capsule developed using a systems and network biology framework. Component selection was based on their actions on enzyme systems involved in senescence-related pathways and health preservation. This review highlights how MD components synergistically modulate pathways central to antioxidant activity, cognitive health, and aging. Liquid chromatography–mass spectrometry identified phytochemically diverse constituents in capsules (supplied by DailyColors™, Warwickshire, UK and Sebastopol, CA, USA) derived from primary color groups in sixteen Mediterranean plants. These constituents were mapped to bioactive networks targeting enzymes linked to inflammation, metabolic regulation, and cellular senescence. Preclinical studies demonstrated the modulation of mitochondrial and metabolic health markers, with complementary effects on cytokine inhibition and glucose sensitivity. Two clinical studies confirmed broad proteomic and epigenetic effects on pathways governing immunity, skeletal muscle, cognition, and inflammation. Therefore, this review advances a novel perspective that MD polyphenols act through synergistic, multi-pathway interactions that link dietary patterns to coordinated regulation of longevity and healthy aging. Full article

With global life expectancy steadily rising, promoting healthy aging is becoming a critical objective of public health. Physical function tends to decline gradually, often beginning in midlife, when subtle changes start to occur and accumulate undetected until later years. This study examines the feasibility of using DNA methylation-based epigenetic clocks as biomarkers for cumulative physical performance in 24 community-dwelling adults aged 39 years and older. Our findings reveal that several epigenetic age estimators, particularly DNAmAgeHannum, are significantly associated with a novel composite score criterion derived from standardized motor function assessments (DNAmAge: ρ = −0.48, p < 0.026; DNAmPhenoAge: ρ = −0.48, p < 0.026) with DNAmAgeHannum (ρ = −0.59, p < 0.005). These findings support the potential of using epigenetic aging markers to detect early physiological decline, even in relatively healthy, midlife populations, offering a promising tool for the early identification of age-related functional deterioration. Full article

Male reproductive aging is increasingly recognized as a systemic process in which inflammaging drives progressive dysfunction of urogenital tissues. Key mechanisms include immune–metabolic alterations, activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, as well as epigenetic remodeling. Evidence from experimental and clinical studies suggests that these processes are often investigated independently, and integrative models in humans remain limited. Here, we propose a conceptual framework linking the prostate, testis, and skeletal muscle, in which oxidative stress may act as a mediator amplifying systemic dysregulation at different levels during the aging process. Lifestyle and metabolic interventions, including caloric restriction, resistance exercise, and selected nutraceuticals, may act as key modulators of inflammaging pathways, thus highlighting new potential targets for precision medicine approaches. Full article

Background: Etiologies of neural tube defects (NTDs) are multifactorial. Genetic, epigenetic and environmental factors may contribute to their reported variation in prevalence across the globe. Ethiopia has among the highest reported NTD prevalence globally, making investigation of genetic determinants in this high-risk population particularly important for advancing the understanding of NTD etiology. Genes involved in folate metabolism, such as the reduced folate carrier 1 (RFC1), have been investigated for the potential associations with NTDs, but findings throughout the literature remain inconsistent and inconclusive. Objective: The aim of this study was to determine an association of RFC-1 polymorphism at rs1131596 and rs1051266 loci (functional variants previously implicated in folate transport efficiency and NTD susceptibility) among mothers with the occurrence of NTDs in their offspring in Ethiopia. Methods: A case–control study involving 250 mothers (187 controls and 63 cases) of children with or without NTDs was conducted in Addis Ababa, Ethiopia from April 2022, to September 2024. A total of 250 maternal whole blood samples were systematically collected and subjected to genetic analysis at loci rs1131596 and rs1051266 by polymerase chain reaction (PCR) and Sanger sequencing. Results: Detection of heterozygous (TC) and homozygous (CC) genotypes for SNP rs1131596 (−43T>C) in the RFC1 gene was 27.2%, with heterozygous (TC) comprising 10.4% and homozygous (CC) 16.8%. In contrast, for the rs1051266 (80A>G), the prevalence of the AG polymorphism was 28% while the GG polymorphism was 16.4%, resulting in a cumulative prevalence of 44.4%. The presence of maternal RFC-1 polymorphism at these two locations were not associated with significantly (p = 0.601 & p = 0.225 respectively) higher odds for NTD births. Conclusions: This study did not reveal significant association between maternal RFC1 gene polymorphisms and NTD-affected births. Comprehensive whole-genome sequencing of affected off-spring is essential to identify specific mutations or polymorphisms that may individually or collaboratively affect the risk of NTDs in the Ethiopian context. Full article

Background/Objectives: Physical activity is one of the most powerful lifestyle factors influencing brain health, with growing evidence supporting its role in promoting neuroplasticity, cognitive function, and resilience to age-related neurological decline. Recent studies indicate that these effects are mediated by coordinated molecular responses involving epigenetics, activity-dependent gene expression, metabolic adaptation, and inter-organ communication pathways. This narrative review synthesizes current knowledge from experimental and clinical studies on the neurogenomic and epigenetic mechanisms underlying exercise-induced brain plasticity. Methods: Literature searches were conducted in PubMed, Scopus, Web of Science, and Google Scholar to identify studies examining neurogenomic and epigenetic mechanisms underlying neuroplasticity and cognitive adaptations in response to exercise, with an emphasis on mechanistic and translational evidence. Results: Available evidence, derived predominantly from animal studies and supported by more limited, often indirect human data, indicates that physical activity induces epigenetic modifications, including changes in DNA methylation, histone modifications, and microRNA expression, which contribute to lasting changes in exercise-responsive genes involved in brain plasticity. These adaptations include the upregulation of key neuroplasticity-related mediators that support neurogenesis, synaptic plasticity, angiogenesis, and metabolic adaptation, alongside the downregulation of pathways linked to neuroinflammation, oxidative stress, and apoptotic signalling. Conclusions: Integrating neurogenomics with systems biology approaches offers promising opportunities to better understand how physical activity influences brain plasticity throughout life. These insights may support the development of personalized exercise medicine to improve cognitive health and reduce the risk of neurodegenerative disorders. Full article

Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease characterized by marked clinical heterogeneity. While the genetic architecture underlying disease susceptibility is well established, the role of genetic factors in shaping disease prognosis remains clearly defined. In this structured narrative review, we examine available evidence on genetic contribution to key MS prognostic domains. This includes clinical outcomes, such as age at onset, relapse rate, disability progression, neurological sequelae, and cognitive impairment. We also consider radiological measures like brain and spinal cord lesion burden, gadolinium-enhancing lesions, and atrophy, as well as laboratory biomarkers, such as oligoclonal bands and Immunoglobulin G (IgG) index. Overall, current evidence suggests that genetic influences on prognosis are modest and highly heterogeneous. Only a limited number of associations—primarily from genome-wide association studies (GWAS)—have shown consistent replication, whereas many reported findings come from small candidate-gene studies and remain unconfirmed. Among these, the largest GWAS on age-related Multiple Sclerosis Severity Score (MSSS) identified a locus in the DYSF–ZNF638 region reaching genome-wide significance. The strongest evidence from GWAS relates to relapse rate, magnetic resonance imaging (MRI) measures (e.g., thalamic atrophy) and intrathecal IgG synthesis, the latter also reaching genome-wide significance. Interpretation of genotype–phenotype associations is further limited by small sample sizes, limited replication, heterogeneity in study design with the predominance of candidate-gene approaches, variability in outcome definitions, treatment exposure, and population ancestry. These limitations currently preclude the routine use of genetic markers for prognostic stratification in clinical practice. Larger studies and collaborative genetic consortia efforts are needed to improve statistical power and reproducibility. Additionally, emerging epigenetic studies may provide valuable insights into prognosis and disease management. Understanding which genetic factors can predict diverse MS courses could enhance patient management and enable personalized treatment approaches. Full article