Search Results (164)

Vitamin D signaling via the vitamin D receptor (VDR) regulates calcium–phosphate homeostasis and extensive gene programs controlling cell proliferation, differentiation, immune tone, and metabolism. However, systemic use of the natural agonist 1α,25-dihydroxyvitamin D₃ (calcitriol) for extraskeletal indications is limited by dose-limiting hypercalcemia. This review summarizes VDR biology and the structural basis of ligand action, emphasizing how ligand-induced repositioning of helix 12 and altered coregulator recruitment can be exploited to engineer selective VDR modulators. We highlight medicinal chemistry strategies spanning secosteroidal analogs with side-chain or ring modifications and emerging non-seco scaffolds and discuss clinically established agents (e.g., calcipotriol and paricalcitol) alongside experimental “super-agonists”, partial agonists, and antagonists designed to widen the therapeutic window. Finally, we discuss current evidence for VDR targeting across cancer, metabolic disease, fibrosis, and immune-inflammatory disorders, including mechanisms of resistance such as dysregulated vitamin D metabolism and epigenetic repression. Structural and epigenomic insights are positioning next-generation VDR ligands as tissue- and pathway-biased therapeutics that may enable safer, mechanism-guided translation beyond bone and mineral indications. Full article

Abiotic stresses such as drought, salinity, extreme temperatures, and heavy metal contamination severely limit global crop productivity and threaten food security. Plants have evolved epigenetic strategies, particularly DNA methylation, to perceive, adapt to, and memorize environmental challenges. This review systematically elucidates the dynamic regulatory mechanisms of DNA methylation—including establishment via RNA-directed DNA methylation (RdDM), maintenance by methyltransferases (MET1, CMT), and active removal by demethylases (ROS1)—in plant responses to diverse abiotic stresses. We highlight how stress-induced methylation reprogramming modulates gene expression, chromatin states, and physiological adaptations, contributing to both somatic and transgenerational stress memory. Furthermore, we discuss advanced detection technologies for profiling methylation patterns and evaluate their applications in epigenetic breeding, such as exploiting heritable epialleles, RdDM-based gene silencing, and methylation markers for heterosis prediction. Despite significant progress, translating epigenetic insights into predictable breeding tools remains challenging. Future efforts should focus on establishing causal links between methylation changes and stress phenotypes, improving epigenome editing precision, and integrating multi-omics approaches for the development of climate-resilient crops. This work provides a comprehensive epigenetic perspective for enhancing crop adaptability and sustainable agriculture. Full article

Background/Objectives Sports-related musculoskeletal injuries remain a major challenge in physically active populations, with substantial interindividual variability in susceptibility and recovery that cannot be fully explained by biomechanics or genetics alone. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, provide a dynamic interface through which mechanical loading, inflammation, and metabolic signals regulate gene expression during tissue adaptation and repair. This narrative review synthesizes current evidence on “epigenetically active” dietary supplements and their potential relevance to sports injuries, focusing on methyl donors, polyphenols, omega-3 fatty acids, vitamin D, and redox-active nutrients. Methods Targeted searches of PubMed, Scopus, and Web of Science (2000–2026) were performed using epigenetics-, injury-, exercise-, and supplementation-related terms, prioritizing mechanistic and translational evidence. Results Available data indicate that these compounds can influence molecular mechanisms implicated in musculoskeletal recovery. However, human evidence is largely derived from peripheral tissues and indirect molecular markers, with limited clear linkage to clinically significant injury outcomes such as injury incidence, severity, or return-to-play timelines. Accordingly, these nutrients are best viewed as modulators of recovery-related biology rather than as direct therapeutic agents. Conclusions This review highlights a notable translational gap between mechanistic plausibility and clinical evidence and discusses practical implications for sports nutrition from a personalized perspective. Future research priorities include tissue-relevant epigenetic assessments, integration of multi-omics approaches, and longitudinal trials incorporating injury endpoints. Nutritional epigenomics, therefore, represents a promising avenue to support musculoskeletal health while underscoring the need for rigorous clinical validation. Full article

Periodontal disease is a chronic inflammatory condition that destroys tooth-supporting tissues, particularly the alveolar bone and the periodontal ligament, and effective regenerative therapies remain limited. While the role of metabolic–epigenomic crosstalk in determining cell fate is well established, the specific mechanism by which a tricarboxylic acid (TCA) cycle metabolite can modulate chromatin regulation to promote periodontal regeneration remains to be elucidated. The impact of one TCA cycle metabolite, alpha-ketoglutarate (α-KG), was examined in human periodontal ligament fibroblasts cultured under osteogenic induction and profiled by ALP assays, RT-qPCR, analyses of multiple histone modifications, ATAC-seq, and RNA-seq. α-KG increased ALP activity and upregulated genes associated with osteogenesis and the extracellular matrix (ECM). ATAC-seq revealed minimal genome-wide accessibility changes, whereas histone analyses showed reduced H3K27me3, consistent with an epigenetic mechanism that does not require extensive chromatin opening. The RNA-seq identified 14 upregulated α-KG-induced genes, including multiple components of the OGN-OMD-PLAP1/ASPN-ECM2 loci, supporting an osteogenic/ECM transcriptional program. In a mouse periodontal regeneration model, oral administration of α-KG enhanced alveolar bone regeneration and reduced H3K27me3 signals and collagen-rich tissue organization within the periodontal ligament space. These findings identify α-KG as a metabolite-driven epigenetic modulator that alleviates H3K27me3-mediated repression and supports periodontal regeneration. Full article

Adolescence represents a critical window of metabolic plasticity, during which profound hormonal, neurobiological, and physiological remodelling increases susceptibility to nutritional exposures. In parallel with the rising prevalence of obesity, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease among young people, there is growing interest in the potential for functional food components to modulate epigenetic pathways that govern metabolic programming. This narrative review synthesises current evidence (2015–2025) from PubMed, Scopus, Web of Science, and Embase to elucidate how diet-derived bioactive compounds influence epigenetic regulation relevant to adipogenesis, appetite control, insulin signalling, and lipid homeostasis during adolescence. Particular emphasis is placed on molecular mechanisms, including DNA methylation changes in genes regulating adipocyte differentiation, hypothalamic neuropeptide expression, and pancreatic β-cell function; histone modifications, such as acetylation and methylation events that remodel chromatin accessibility in metabolic tissues; and modulation of microRNA networks implicated in lipid metabolism, inflammatory signalling, and insulin secretion. Furthermore, the review examines the interplay between diet, the gut microbiota, and the epigenome, highlighting the role of microbially derived short-chain fatty acids (SCFAs) as endogenous histone deacetylase inhibitors and mediators of epigenetic remodelling in adipose tissue. By linking these mechanisms to specific functional food components, including polyphenols, long-chain omega-3 fatty acids, fermentable dietary fibre, and other bioactive molecules, we demonstrate how nutritional signals can counteract maladaptive metabolic trajectories and potentially reduce the intergenerational transmission of metabolic risk. A deeper understanding of these epigenetic effects provides the foundation for developing personalised nutrition strategies aimed at preventing metabolic disorders from emerging during adolescence and beyond. Full article

Chromatin dynamics are usually modulated by histone epigenetic post-translational modifications, which rapidly and reversibly govern accessibility and transcriptional responsiveness. During microbial infection, this regulatory layer becomes a highly contested interface where host defense mechanisms and pathogen-driven subversion strategies converge and compete. Many infectious agents exploit chromatin to reprogram gene expression, creating cellular environments that are conducive to infection, proliferation, and persistence. Diverse strategies have been described for viruses, bacteria, fungi, protozoa and nematodes, including the direct secretion of acetyltransferases and methyltransferases, interference with host chromatin-binding proteins, subcellular localization of transcriptional factors or epigenetic regulators, and metabolic availability manipulation. Concurrently, host cells activate immune and stress-response genes to mount rapid, adaptable antimicrobial responses. Recent advances in genome-wide, single-cell, and spatial omics profiling have begun to reveal the temporal and cell-type-specific dynamics of the host genome at the core of infection. This review synthesizes current insights into how chromatin is rewired by the major categories of pathogens during infection, highlighting representative case studies across infective agents and the functional consequences for immunity and cell fate. In addition, we discuss emerging techniques for epigenomic and transcriptomic data collection, and the potential of targeted host-directed therapeutic strategies. Chromatin regulation is thus a promising field of study and a possible target for next-generation interventions. Full article

There is considerable interest in the connection between alcohol-induced oxidative stress, DNA methylation, antioxidants, and accelerated aging across diverse populations. Nevertheless, self-reported alcohol consumption is prone to bias, and objective biomarkers of alcohol intake are needed. Our aims were to investigate the performance of an epigenomic biomarker of alcohol consumption in a Mediterranean population using self-reported data and the biomarker gamma-glutamyl transferase (GGT); to examine the effects of alcohol (self-reported and biomarker-assessed) on epigenome-wide methylation; to analyze the association between alcohol (self-reported and biomarker-assessed) and telomere length and other aging biomarkers; and to explore the modulating effect of the Mediterranean diet (MedDiet). We performed blood epigenome-wide methylation studies (EWAS) in a Mediterranean cohort (aged 55–75 years). Self-reported alcohol consumption and MedDiet were assessed by questionnaires. A replication cohort (cohort 2) from the same area was also analyzed. For both cohorts, the DNA methylation-based biomarker (450-CpGs) was computed alongside epigenetic clocks for the following biological age acceleration metrics: DNAm telomere length, GrimAgeAcceleration, PhenoAgeAcceleration, and CausalityAgeYing (cohort 1). The association between the epigenomic biomarker and self-reported alcohol consumption was significant (p < 0.001) in both cohorts, but modest. However, the association was stronger when predicting high alcohol intake (AUC: 0.76; 95%CI: 0.65–0.86; p < 0.0001). In the EWAS, the hit (cg06690548-SLC7A11, in a cystine transporter that enhances glutathione production for antioxidant defense) was shared among the self-reported alcohol consumption, GGT, and the epigenomic biomarker, with alcohol linked to hypomethylation. We detected differential methylation in pre-selected oxidative stress-related genes. Enrichment analysis revealed “Rap1 signaling pathway” as the hit (p < 0.00001). High self-reported alcohol consumption and the epigenomic biomarker were associated with shorter telomere length (p < 0.05) in cohort 1. Additionally, a modulation by Mediterranean diet adherence was hypothesized. No significant associations were found between self-reported alcohol intake and the other aging biomarkers; however, the epigenomic score was directly associated with GrimAge, PhenoAge and CausAgeYing biomarkers in cohort 1 (p < 0.001), and two were replicated in cohort 2. In conclusion, alcohol intake has an impact on DNA methylation at the epigenome-wide level in this Mediterranean population, replicating the main hits from other populations and validating the epigenomic biomarker for intake, although improvement is needed. Moreover, several associations with aging biomarkers were observed. Full article

Over the past two decades, advances in the understanding of epigenetic mechanisms—driven by the rapid expansion of omics technologies—have catalyzed a major paradigm shift in biology: from the genetic determinism and linear causality of the Central Dogma toward the dynamic, networked complexity of systems biology and multilevel regulation. This reconceptualization extends to inheritance itself, highlighting the crucial role of the epigenome as a molecular interface between the genome and the exposome—the cumulative set of internal and external environmental influences experienced across the lifespan. Within this evolving framework, neurodevelopmental disorders exemplify the deep entanglement between genetic predisposition, environmental exposure, and epigenetic modulation. Their increasing global prevalence and frequent comorbidities underscore the need for an integrated etiological understanding that transcends reductionist models. This review tries to synthesize current evidence on the shared molecular and systemic mechanisms underlying neurodevelopmental spectrum disorders and examines how environmental and epigenetic factors jointly shape neurodevelopmental trajectories across generations. Finally, it discusses the broader implications of this paradigm shift for early diagnosis, prevention, and public health policies aimed at fostering healthy brain development in future generations. Full article

Purpose: The reversible deviant in epigenomic modulations is the highlight of developing new anti-cancer drugs, necessitating the use of fisetin as an epigenetic modifier in the study. Methods: In silico and molecular studies were performed to analyze the modulatory effect of fisetin on various writers and erasers. Further, whole genome DNA methylation sequencing and expression studies were performed. Global DNA methylation-LINE 1 kit was used to check global DNA methylation. Additionally, the effect of fisetin on migration was evaluated by colony, scratch, and invasion assays and qPCR and protein expression studies of migration-related genes were carried out on HeLa cells. Results: In silico studies have supported that fisetin interacts with writers and erasers in their catalytic site and the simulation studies showed minimum fluctuations in energy and temperature over a 10 ns timescale indicating that these complexes are likely to remain stable. Fisetin (20–50 µM) dose-dependently inhibited DNA methyltransferases (DNMT), histone deacetyl transferases (HDAC), histone acetyl transferases (HAT), and histone methyltransferases (HMT) activities at 48 h, with inhibition ranging from 24 to 72% compared to the control. The expression and enzymatic activity of these proteins, along with various H4 and H3 modification marks, were observed to be altered following fisetin treatment at 48 h. Fisetin treatment reduced promoter methylation in various tumor suppressor genes ranging from 15.29% to 76.23% and leading to the corresponding reactivation of important tumor suppressor genes; however, it did not lead to any alteration in the global DNA methylation compared to untreated controls linked with the anti-migratory properties of fisetin as the percentage of migrated cells dropped from ~40% to ~8%. Conclusions: This study gives a mechanistic insight of fisetin as a potential epigenetic modifier in HeLa cells. Full article

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

Agricultural systems face mounting pressures from climate change, as rising temperatures, elevated CO₂, and shifting precipitation patterns intensify plant disease outbreaks worldwide. Conventional strategies, such as breeding for resistance, pesticides, and even transgenic approaches, are proving too slow or unsustainable to meet these challenges. Synthetic biology offers a transformative paradigm for reprogramming plant immunity through genetic circuits, RNA-based defences, epigenome engineering, engineered microbiomes, and artificial intelligence (AI). We introduce the concept of synthetic immunity, a unifying framework that extends natural defence layers, PAMP-triggered immunity (PTI), and effector-triggered immunity (ETI). While pests and pathogens continue to undermine global crop productivity, synthetic immunity strategies such as CRISPR-based transcriptional activation, synthetic receptors, and RNA circuit-driven defences offer promising new avenues for enhancing plant resilience. We formalize synthetic immunity as an emerging, integrative concept that unites molecular engineering, regulatory rewiring, epigenetic programming, and microbiome modulation, with AI and computational modelling accelerating their design and climate-smart deployment. This review maps the landscape of synthetic immunity, highlights technological synergies, and outlines a translational roadmap from laboratory design to field application. Responsibly advanced, synthetic immunity represents not only a scientific frontier but also a sustainable foundation for climate-resilient agriculture. Full article

Melanin pigments are ubiquitous biopolymers across diverse life forms and play multifaceted roles in cellular defense and environmental adaptation. The specialized neuromelanin in human brains accumulates mainly within catecholaminergic neurons of the substantia nigra and locus coeruleus, serving as a crucial modulator of brain homeostasis, metal detoxification, and oxidative stress responses. The intricate processes of human melanogenesis, encompassing both cutaneous and neuronal forms, are governed by complex genetic networks. Concurrently, melanin in fungi (synthesized through distinct genetic pathways) confers remarkable resistance to environmental stressors, including ionizing radiation. Recent advancements in omics technologies—including transcriptomics, proteomics, metabolomics, and epigenomics—have profoundly enhanced our understanding of neuromelanin’s molecular environment in health, aging, and neurodegenerative conditions such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological disorders. This article reviews the genetic underpinnings of human melanogenesis and fungal melanogenesis, explores the convergent and divergent evolutionary pressures driving their functions, and synthesizes the rapidly accumulating omics data to elucidate neuromelanin’s critical, and often dual, role in human brain pathology. Moreover, we discuss the intriguing parallels between neuromelanin and fungal melanin, highlighting radioprotection and its potential implications for neuroprotection and astrobiology, with a special emphasis on the need to investigate neuromelanin’s potential for radioprotection in light of fungal melanin’s remarkable protective properties. Full article

Background/Objectives: Endocrine autoimmune diseases, including autoimmune thyroid, pituitary, parathyroid, adrenal, and gonadal diseases, result from complex interactions between genetic susceptibility and environmental triggers. Advances in genomics and epigenomics have provided novel insights into the molecular pathways leading to immune dysregulation and endocrine tissue destruction. This review summarizes recent progress in understanding the genetic and epigenetic bases, emphasizing shared and disease-specific mechanisms that contribute to autoimmunity and endocrine dysfunction. Methods: A comprehensive literature search was performed in PubMed, Scopus, and Web of Science up to August 2025, focusing on genome-wide association studies (GWAS), next-generation sequencing, and epigenetic profiling (DNA methylation, histone modification, and non-coding RNA regulation). Results: More than 60 susceptibility loci have been identified across endocrine autoimmune diseases (EADs), including key genes in immune tolerance (HLA, CTLA4, PTPN22) and endocrine-specific pathways. Epigenetic studies reveal that altered DNA methylation and histone acetylation patterns in immune and endocrine cells modulate gene expression without changing the DNA sequence, linking environmental exposures to disease onset. Dysregulated microRNAs further influence immune signaling and cytokine networks. Conclusions: Genetic and epigenetic discoveries highlight the multifactorial nature of EADs and reveal potential biomarkers for early detection and targets for precision immunotherapy. Future research integrating multi-omics and longitudinal analyses will be crucial to unravel causal mechanisms and develop personalized preventive strategies. Full article

The ketogenic diet (KD) is a metabolic intervention characterized by high fat and very low carbohydrate intake, showing significant metabolic, neuroprotective, and therapeutic effects. However, its efficacy varies widely due to individual genetic and epigenetic factors. This review synthesizes current knowledge of genes most strongly associated with KD response, including polymorphisms in FTO, APOA2, PPAR, SCN1A, KCNQ2, STXBP1, CDKL5, the MODY gene group, and SLC2A1, which shape outcomes across lipid metabolism, energy expenditure, inflammation, and neurotransmission. Epigenomic modifications induced by a KD, such as changes in DNA methylation and histone acetylation involving BDNF, SLC12A5, KLF14, and others, modulate functional metabolic and neurological effects. Sex and age further modulate KD effects through distinct patterns of gene activation and hormonal interactions. These variables together impact metabolic and neurological outcomes and are critical for developing personalized nutrition and disease management strategies. Based on the reviewed evidence, genetic and epigenetic profiling can help identify patients who are likely to benefit from a KD (e.g., GLUT1DS, PDH deficiency) and those in whom a KD may be ineffective or harmful (e.g., SCOT or SLC2A1-independent defects). The review concludes that genetic and epigenetic profiling is recommended for personalized dietary interventions. Full article

This article aims to point out new perspectives opened by genomics and epigenomics in skin rejuvenation strategies which target the main hallmarks of the ageing. In this respect, this article presents a concise overview on: the clinical relevance of the most important clocks and biomarkers used in skin anti-ageing strategy evaluation, the fundamentals, the main illustrating examples preclinically and clinically tested, the critical insights on knowledge gaps and future research perspectives concerning the most relevant skin anti-ageing and rejuvenation strategies based on novel epigenomic and genomic acquisitions. Thus the review dedicates distinct sections to: senolytics and senomorphics targeting senescent skin cells and their senescent-associated phenotype; strategies targeting genomic instability and telomere attrition by stimulation of the deoxyribonucleic acid (DNA) repair enzymes and proteins essential for telomeres’ recovery and stability; regenerative medicine based on mesenchymal stem cells or cell-free products in order to restore skin-resided stem cells; genetically and chemically induced skin epigenetic partial reprogramming by using transcription factors or epigenetic small molecule agents, respectively; small molecule modulators of DNA methylases, histone deacetylases, telomerases, DNA repair enzymes or of sirtuins; modulators of micro ribonucleic acid (miRNA) and long-non-coding ribonucleic acid (HOTAIR’s modulators) assisted or not by CRISPR-gene editing technology (CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats); modulators of the most relevant altered nutrient-sensing pathways in skin ageing; as well as antioxidants and nanozymes to address mitochondrial dysfunctions and oxidative stress. In addition, some approaches targeting skin inflammageing, altered skin proteostasis, (macro)autophagy and intercellular connections, or skin microbiome, are very briefly discussed. The review also offers a comparative analysis among the newer genomic/epigenomic-based skin anti-ageing strategies vs. classical skin rejuvenation treatments from various perspectives: efficacy, safety, mechanism of action, evidence level in preclinical and clinical data and regulatory status, price range, current limitations. In these regards, a concise overview on senolytic/senomorphic agents, topical nutrigenomic pathways’ modulators and DNA repair enzymes, epigenetic small molecules agents, microRNAs and HOTAIRS’s modulators, is illustrated in comparison to classical approaches such as tretinoin and peptide-based cosmeceuticals, topical serum with growth factors, intense pulsed light, laser and microneedling combinations, chemical peels, botulinum toxin injections, dermal fillers. Finally, the review emphasizes the future research directions in order to accelerate the clinical translation of the (epi)genomic-advanced knowledge towards personalization of the skin anti-ageing strategies by integration of individual genomic and epigenomic profiles to customize/tailor skin rejuvenation therapies. Full article