Search Results (1,096)

Cadmium (Cd) induces oxidative stress and disrupts nuclear organization and chromatin-associated metabolic processes in plant cells. Therefore, identifying natural, biodegradable, non-bioaccumulative compounds that enhance plant tolerance to heavy metals is crucial. We hypothesized that Cd exposure (175 µM CdCl₂, 24 h) activates mitogen-activated protein kinases (MAPKs), triggering defined epigenetic modifications that lead to transcriptional repression, and that thyme oil (TO; 0.03% (v/v), emulsified) mitigates these effects by stabilizing chromatin organization. We analyzed nuclear MAPK (p44/42) activation, global DNA methylation (5-methylcytosine; 5-mC), and selected histone modifications as key components of early stress signaling and epigenetic regulation. We found that Cd exposure doubled global 5-mC levels and caused pronounced alterations in histone marks, including decreases in H3K4Me2 (~34%), H3T45Ph (~48%), and H4K5Ac, accompanied by strong increases in H3K9Ac (~57%) and H3K56Ac (~148%). These changes were associated with chromatin condensation and reduced transcriptional activity. In contrast, co-treatment with TO maintained MAPK activity and epigenetic parameters close to control levels, preventing chromatin compaction and transcriptional repression. Together, these findings indicate that TO stabilizes the nuclear signaling–epigenetic interface under Cd stress and represents a promising bioprotective strategy. This work provides the first demonstration that TO modulates both MAPK activation and Cd-induced histone modifications in plants. Full article

Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID) arise from disruptions of molecular programmes that coordinate neurogenesis, synaptogenesis, and circuit maturation. While genomic studies have identified numerous susceptibility loci, genetic variation alone accounts for only part of disease heritability, underscoring the importance of post-transcriptional and epigenetic regulation. Among these regulatory layers, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNA-derived small RNAs (tsRNAs), have emerged as central modulators of neural differentiation, synaptic plasticity, and intercellular signalling. Recent multi-omics and single-cell studies reveal that ncRNAs fine-tune chromatin accessibility, transcriptional output, and translation through tightly integrated regulatory networks. miRNAs shape neurogenic transitions and circuit refinement; lncRNAs and circRNAs couple chromatin architecture to activity-dependent transcription; and tsRNAs and piRNAs extend this regulation by linking translational control to epigenetic memory and environmental responsiveness. Spatial transcriptomics further maps ncRNA expression to vulnerable neuronal and glial subtypes across cortical and subcortical regions. Clinically, circulating ncRNAs, especially those packaged in extracellular vesicles, exhibit stable, disease-associated signatures, supporting their potential as minimally invasive biomarkers for early diagnosis and patient stratification. Parallel advances in RNA interference, antisense oligonucleotides, CRISPR-based editing, and vesicle-mediated delivery highlight emerging therapeutic opportunities. These developments position ncRNAs as both mechanistic determinants and translational targets in NDDs, offering a unifying framework that links genome regulation, environmental cues, and neural plasticity, and paving the way for next-generation RNA-guided diagnostics and therapeutics. Full article

Diabetic retinopathy (DR), a leading cause of vision loss in diabetic patients, involves complex pathological mechanisms including neurodegeneration, microvascular damage, inflammation, and oxidative stress. Recent studies have identified ferroptosis—a ferrodependent cell death mechanism—as playing a pivotal role in DR development. Existing evidence indicates that oxidative stress and mitochondrial dysfunction induced by hyperglycemia may contribute to retinal damage through the ferroptosis pathway in DR. Ferroptosis inhibitors such as Ferostatin-1 have demonstrated protective effects against DR in animal models. The core mechanisms of ferroptosis involve iron homeostasis imbalance and lipid peroxidation, with key regulatory pathways including GPX4-dependent and non-dependent mechanisms (such as FSP1-CoQ10). Within the signaling network, Nrf2 inhibits ferroptosis, p53 promotes it, while Hippo/YAP functions are environment-dependent. Non-coding RNAs and epigenetic modifications (e.g., DNA methylation and histone modifications) also participate in regulation. In DR, iron overload, GPX4 dysfunction, and p53 upregulation collectively induce ferroptosis in various types of retinal cells, making these pathways potential therapeutic targets. This review not only elaborates the role of iron metabolism imbalance and ferroptosis pathway in the occurrence and development of DR but also summarizes the new therapeutic approaches of DR targeting ferroptosis pathway. Investigating the relationship between ferroptosis and DR not only helps unravel its core pathophysiological mechanisms but also provides theoretical foundations for developing novel therapeutic approaches. Full article

The nuclear kinases mitogen- and stress-activated kinase 1 and 2 (MSK1 and MSK2), through regulating transcriptional processes, are pivotal for various adaptive responses, including inflammation, learning and addiction. Transcriptional alterations in neurons and glia cells within the pain signal-processing (nociceptive) pathway, including the superficial spinal dorsal horn (SSDH), are critical for the development and persistence of inflammatory pain that results from tissue injuries and subsequent inflammatory reactions. While previous reports have indicated that MSK1 contributes to transcriptional changes in inflamed tissues, the impact of MSK1 on nociceptive processing in the SSDH are poorly understood at present. Here, we report MSK1 immunoreactivity (IR) in a group of excitatory and inhibitory neurons as well as in microglia and oligodendrocytes in the SSDH. Injecting Complete Freund’s Adjuvant into the mouse hind paw produced robust non-evoked pain-related behavior, which was significantly attenuated by global depletion of MSK1. In wild-type mice, the inflammatory pain was accompanied by transient MSK1-dependent phosphorylation of the MSK1 downstream effector histone 3 at serine 10 at one hour but not two days after the injection; still, the number of nuclei exhibiting activated MSK1 expression remained highly restricted even at 1 h post-injection. Our data indicate that MSK1 contributes to inflammatory pain via epigenetic and transcriptional alterations; however, once initiated, MSK1’s downstream effects do not require further drive from the persistent activity of the MSK1 signaling pathway in the SSDH. Full article

In animals and humans, nutrients influence signaling cascades, transcriptional programs, chromatin dynamics, and mitochondrial function, collectively shaping traits related to growth, immunity, reproduction, and stress resilience. This review synthesizes evidence supporting nutrient-mediated regulation of DNA methylation, histone modifications, non-coding RNAs, and mitochondrial biogenesis, and emphasizes their integration within metabolic and developmental pathways. Recent advances in epigenome-wide association studies (EWAS), single-cell multi-omics, and systems biology approaches have revealed how diet composition and timing can reprogram gene networks, sometimes across generations. Particular attention is given to central metabolic regulators (e.g., PPARs, mTOR) and to interactions among methyl donors, fatty acids, vitamins, and trace elements that maintain genomic stability and metabolic homeostasis. Nutrigenetic evidence further shows how genetic polymorphisms (SNPs) in loci such as IGF-1, MSTN, PPARs, and FASN alter nutrient responsiveness and influence traits like feed efficiency, body composition, and egg quality, information that can be exploited via marker-assisted or genomic selection. Mitochondrial DNA integrity and oxidative capacity are key determinants of feed conversion and energy efficiency, while dietary antioxidants and mitochondria-targeted nutrients help preserve bioenergetic function. The gut microbiome acts as a co-regulator of host gene expression through metabolite-mediated epigenetic effects, linking diet, microbial metabolites (e.g., SCFAs), and host genomic responses via the gut–liver axis. Emerging tools such as whole-genome and transcriptome sequencing, EWAS, integrated multi-omics, and CRISPR-based functional studies are transforming the field and enabling DNA-informed precision nutrition. Integrating genetic, epigenetic, and molecular data will enable genotype-specific feeding strategies, maternal and early-life programming, and predictive models that enhance productivity, health, and sustainability in poultry production. Translating these molecular insights into practice offers pathways to enhance animal welfare, reduce environmental impact, and shift nutrition from empirical feeding toward mechanistically informed precision approaches. Full article

Uterine Fibroids (UFs) are the most common benign tumors in women of reproductive age, affecting ~77% of women overall and are clinically manifest in ~25% by age 50. Bromodomain and extra-terminal domain (BET) proteins play key roles in epigenetic transcriptional regulation, influencing many biological processes, such as proliferation, differentiation, and DNA damage response. Although BET dysregulation contributes to various diseases, their specific role in the pathogenesis of UFs remains largely unexplored. The present study aimed to determine the expression pattern of BET proteins in UFs and matched myometrium and further assess the impact of BET inhibitors on UF phenotype and epigenetic changes. Our studies demonstrated that the levels of Bromodomain-containing protein (BRD)2 and detection rate of BRD4 were significantly altered in UFs compared to matched myometrium, suggesting that aberrant BET protein expression may contribute to the pathogenesis of UFs. To investigate the biological effects of BET proteins, two small-molecule inhibitors, JQ1 and I-BET762, were used to assess their impact on UF cell behavior and transcriptomic profiles. Targeted inhibition of BET proteins markedly reduced UF cell viability compared with myometrial cells and induced cell cycle arrest. Unbiased transcriptomic profiling coupled with bioinformatic analysis revealed that BET inhibition altered multiple biological pathways, including G2M checkpoint, E2F targets, mitotic spindle, mTORC1 signaling, TNF-α signaling via NF-κB, and inflammatory response, as well as reprogrammed the UF cell epigenome. Notably, BET inhibition decreased the expression of several genes encoding extracellular matrix (ECM) proteins, a hallmark of UFs. Collectively, these results support that BET proteins play a pivotal role in regulating key signaling pathways and cellular processes in UFs. Targeting BET proteins may therefore represent a promising non-hormonal therapeutic strategy for UF treatment. Full article

The chromatin remodelling proteins DAXX and ATRX are key regulators of genome stability and epigenetic processes. Alterations in their expression have been associated with tumour stage and prognostic outcomes in various human cancer types, whereas their role in veterinary oncology has received little investigation to date. We analysed canine prostate and urinary bladder samples, including 18 prostate carcinomas (12 adenocarcinomas and 6 prostatic urothelial carcinomas), 10 non-malignant prostate tissues, 22 urinary bladder carcinomas, and 6 non-malignant bladder tissues. Nuclear expression of DAXX and ATRX was assessed using fully quantitative digital immunohistochemistry. Overall, DAXX exhibited consistently higher expression than ATRX across benign and malignant samples from the prostate and bladder. DAXX and ATRX expression demonstrated a positive correlation across all samples (ρ = 0.553, p < 0.05), suggesting coordinated regulation. They displayed organ-specific expression patterns: prostate carcinomas showed increased expression of DAXX compared with non-malignant prostate tissues (p < 0.05). In contrast, in the bladder, expression of DAXX and ATRX declined with increasing tumour grade (p < 0.05). Our findings provide new insights into the potential of DAXX and ATRX as biomarkers, offering new insights into their clinical relevance in dogs. Full article

Physical exercise is a potent non-pharmacological strategy for the prevention and management of chronic non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular diseases, obesity, and certain cancers. Growing evidence demonstrates that the benefits of exercise extend beyond its physiological effects and are largely mediated by coordinated molecular and cellular adaptations. This review synthesizes current knowledge on the key mechanisms through which exercise modulates metabolic health, emphasizing intracellular signaling pathways, epigenetic regulation, and myokine-driven inter-organ communication. Exercise induces acute and chronic activation of pathways such as AMPK, PGC-1α, mTOR, MAPKs, and NF-κB, leading to enhanced mitochondrial biogenesis, improved oxidative capacity, refined energy sensing, and reduced inflammation. Additionally, repeated muscle contraction stimulates the release of myokines—including IL-6, irisin, BDNF, FGF21, apelin, and others—that act through endocrine and paracrine routes to regulate glucose and lipid metabolism, insulin secretion, adipose tissue remodeling, neuroplasticity, and systemic inflammatory tone. Epigenetic modifications and exercise-responsive microRNAs further contribute to long-term metabolic reprogramming. Collectively, these molecular adaptations establish exercise as a systemic biological stimulus capable of restoring metabolic homeostasis and counteracting the pathophysiological processes underlying NCDs. Understanding these mechanisms provides a foundation for developing targeted, personalized exercise-based interventions in preventive and therapeutic medicine. 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

Background/Objectives: The oral–gut–lung axis represents a dynamic system where exosomes carrying mRNAs and non-coding RNAs might help to regulate microbiota and human cell crosstalk to establish transcriptional regulatory networks controlling cellular biological processes and signaling pathways. Methods: We conducted a comprehensive transcriptomic analysis to characterize the molecular cargo of extracellular exosomes in the context of gut and lung cancer. Results: By analyzing gut and lung exosomes cargo with our previous transcriptomic studies from tumoral and inflammatory tissues, we found that exosomes can transport key RNAs that codify specific receptors that facilitate pathogenic interaction with microorganisms and RNAs that are part of interacting gene and transcriptional regulatory networks that control the function of differentially expresses genes, all involved in biological processes like cell cycle, plasticity and growth regulation, invasion, metastasis, microenvironmental remodeling, epigenetic, and microbial and immunological modulation, during the unlocking of phenotypic plasticity for the acquisition of the hallmarks of cancer in the oral–gut–lung axis. Conclusions: Exosomal RNA regulation of transcriptional networks represents a pivotal axis in the interplay between inflammation and cancer, offering opportunities for innovative diagnostic and therapeutic approaches. Full article

Histone deacetylases (HDACs) are pivotal epigenetic regulators that control gene expression, cell proliferation, and differentiation, and their dysregulation is closely associated with the onset and progression of multiple cancers. The therapeutic importance of these enzymes is reflected by FDA approval of HDAC inhibitors for oncology indications. Despite this clinical success, most FDA-approved agents employ conventional zinc-binding groups (ZBGs) such as hydroxamic acid and 2-aminoanilide, which are frequently linked to metabolic instability, genotoxicity, and poor pharmacokinetic behavior. These limitations have spurred the development of structurally diverse and safer HDAC inhibitors incorporating alternative ZBGs. This review provides a comprehensive analysis of recently developed HDAC inhibitors reported in the last few years, emphasizing their structure–activity relationships (SARs), chemical scaffolds, and binding features—including cap, linker, and ZBG motifs. Both hydroxamate-based and non-hydroxamate inhibitors, such as benzamides, hydrazides, and thiol-containing analogs, are critically evaluated. Moreover, the potency and selectivity profiles of these inhibitors are summarized across different cancer and normal cell lines, as well as specific HDAC isoforms, providing a clearer understanding of their therapeutic potential. Emerging dual-target HDAC inhibitors, such as HDAC–tubulin, HDAC–PI3K and HDAC–CDK hybrids, are also discussed for their synergistic anticancer effects. Full article

Hepatitis C virus (HCV) infection remains a major global health challenge and often progresses to chronic liver disease and hepatocellular carcinoma (HCC). Growing evidence indicates that epigenetic regulation mediated by non-coding RNAs plays a critical role in viral pathogenesis and tumor development. This review provides an integrated overview of the functions of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in HCV-induced liver injury. We highlight the dual roles of these molecules, demonstrating how some ncRNAs promote viral replication, whereas others act as tumor suppressors that become dysregulated during infection. Particular emphasis is placed on interaction networks in which lncRNAs and circRNAs function as molecular sponges for miRNAs, thereby modulating signaling pathways essential for hepatic homeostasis. Disruption of these networks contributes to a pro-inflammatory and pro-tumorigenic microenvironment. Finally, we discuss the potential of these transcripts as diagnostic biomarkers and as emerging therapeutic targets in HCV-associated HCC. Full article

The cannabinoid receptor type 2 (CB₂) is increasingly recognized as a crucial regulator of neuroimmune balance in the brain. In addition to its well-established role in immunity, the CB₂ receptor has been identified in specific populations of neurons and glial cells throughout various brain regions, and its expression is dynamically increased during inflammatory and neuropathological conditions, positioning it as a potential non-psychoactive target for modifying neurological diseases. The expression of the CB₂ gene (CNR2) is finely tuned by epigenetic processes, including promoter CpG methylation, histone modifications, and non-coding RNAs, which regulate receptor availability and signaling preferences in response to stress, inflammation, and environmental factors. CB₂ signaling interacts with TRP channels (such as TRPV1), nuclear receptors (PPARγ), and orphan G Protein-Coupled Receptors (GPCRs, including GPR55 and GPR18) within the endocannabinoidome (eCBome), influencing microglial characteristics, cytokine production, and synaptic activity. We review how these interconnected mechanisms affect neurodegenerative and neuropsychiatric disorders, underscore the species- and cell-type-specificities that pose challenges for translation, and explore emerging strategies, including selective agonists, positive allosteric modulators, and biased ligands, that leverage the signaling adaptability of the CB₂ receptor while reducing central effects mediated by the CB₁ receptor. This focus on the neuro-centric perspective repositions the CB₂ receptor as an epigenetically informed, context-dependent hub within the eCBome, making it a promising candidate for precision therapies in conditions featuring neuroinflammation. Full article

Antibiotic resistance (AR) has long been interpreted through the lens of genetic mutations and horizontal gene transfer. Yet, mounting evidence suggests that epigenetic regulation, including DNA and RNA methylation, histone-like proteins, and small non-coding RNAs, plays a similarly critical role in bacterial adaptability. These reversible modifications reshape gene expression without altering the DNA sequence, enabling transient resistance, phenotypic heterogeneity, and biofilm persistence under antimicrobial stress. Advances in single-molecule sequencing and methylome mapping have uncovered diverse DNA methyltransferase systems that coordinate virulence, efflux, and stress responses. Such epigenetic circuits allow pathogens to survive antibiotic exposure, then revert to susceptibility once pressure subsides, complicating clinical treatment. Parallel advances in CRISPR-based technologies now enable direct manipulation of these regulatory layers. CRISPR interference (CRISPRi) and catalytically inactive dCas9-fused methyltransferases can silence or reactivate genes in a programmable, non-mutational manner, offering a new route to reverse resistance or sensitize pathogens. Integrating methylomic data with transcriptomic and proteomic profiles further reveals how epigenetic plasticity sustains antimicrobial tolerance across environments. This review traces the continuum from natural bacterial methylomes to engineered CRISPR-mediated epigenetic editing, outlining how this emerging interface could redefine antibiotic stewardship. Understanding and targeting these reversible, heritable mechanisms opens the door to precision antimicrobial strategies that restore the effectiveness of existing drugs while curbing the evolution of resistance. Full article

Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide, and resistance to therapy continues to pose a major clinical challenge. Increasing evidence highlights the relevance of the gut–lung axis in immune response modulation, tumor progression, and treatment outcomes. Within this inter-organ network, bacterial extracellular vesicles (bEVs), nanosized particles containing proteins, nucleic acids, and metabolites, serve as important mediators of host–microbiota communication, influencing immune regulation, metabolic pathways, and tumor biology. This review explores EV-mediated mechanisms involved in LC pathogenesis, including immune modulation, epigenetic regulation, and microbial metabolite signaling. The mechanistic influence of environmental and dietary factors on bEV composition and function is further explored, and emerging translational applications, ranging from diagnostic biomarker development to drug delivery strategies and modulation of immunotherapy responses, are discussed. Moreover, ongoing clinical trials testing microbiota-based strategies in non-small cell lung cancer (NSCLC) are summarized, offering potential new perspectives for personalized cancer management. Full article