Search Results (1,664)

Background: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The AR gene, located on chromosome Xq11–12, is accompanied by several X-linked genes that modulate AR expression and function, including FLNA, UXT, and members of the melanoma antigen gene (MAGE) family (MAGEA1, MAGEA11, MAGEC1, MAGEC2). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. Methods: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2–4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. Results: AR nuclear positivity correlated significantly with male sex (p = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (p = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (p = 0.02). AR expression was associated with unmethylated MGMT promoter status (p = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal–Wallis p < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. Conclusions: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted. Full article

Polyamines are polycationic compounds present in all living cells that exert functions at different levels in the metabolism. They bind to DNA and RNA and modulate DNA replication and gene expression. Some of these regulatory effects are exerted by promoting condensation of nucleosomes, a mechanism closely connected with epigenetic modification by histone methylation and acetylation. The polyamines 1,3-diaminopropane and spermidine induce expression of the global regulator LaeA and increase by several folds the formation of the α-NAC transcriptional co-activator, a subunit of the nascent polypeptide-associated complex. The global regulator LaeA controls the switch from primary growth to secondary metabolite production and differentiation when an essential nutrient in the growth medium becomes limiting. α-NAC exerts significant control over the biosynthesis of secondary metabolites and fungal pathogenicity on plants. When purified α-NAC protein is added to a tomato host plant, it induces plant resistance to fungal infections and triggers the development of system-acquired resistance in other plants. Spermidine extends the life of yeast cells and prolongs the half-life of penicillin gene transcripts in Penicillium chrysogenum. This article discusses advances in the basis of understanding the mechanism of plant–fungi interaction and the effect of small fungal metabolites and epigenetic modifiers in this interaction. Full article

Neuronutrition to improve brain resilience to stress and human health has received considerable attention. The use of specific nutrients is effective in preventing and slowing neurodegenerative and neuropsychiatric disorders. Selective neuronutrients, including polyphenols, short-chain fatty acids (SCFAs), tryptophan, tyrosine, and sulfur metabolites, can modulate the dysregulated nuclear factor erythroid 2 (Nrf2) pathway through neuroepigenetic modifications and altered levels of neurotransmitters such as serotonin, melatonin, and dopamine. In particular, abnormal epigenetic alterations in the promoter function of the NFE2L2/Nrf2 gene may contribute to the onset and progression of various diseases by disrupting cellular homeostasis. Recent evidence has documented that polyphenols are capable of modulating Nrf2 signaling; to do this, they must reverse hypermethylation in the CpG islands of the NFE2L2 gene. This process is achieved by modifying the activity of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Furthermore, a diverse group of polyphenolic metabolites can be identified and quantified using innovative mass spectrometry platforms in both in vitro models and human urine samples to investigate redox metabolic homeostasis under physiological and pathophysiological conditions. This review aims to deepen the current understanding of the role of nutrient-derived secondary metabolites. It highlights innovative strategies to effectively prevent, slow, or potentially reverse neuroinflammation and oxidative stress, key drivers of neuronal damage. The targeted application of these metabolites can be considered a novel, personalized neuronutritional approach to promote brain health and neuronal adaptation. Full article

BECLIN-1 is a multidomain protein that, through dynamic interaction with a variety of partners, controls autophagy and apoptosis, two processes dysregulated in cancer cells, thus playing a crucial role in cell fate. Although mutations in the BECN1 gene are rare in cancer, its frequent monoallelic deletion contributes to spontaneous cancer initiation by impairing autophagy, establishing it as a haploinsufficient tumor suppressor gene. The expression and activity of BECLIN-1 are further modulated by epigenetic mechanisms, alternative splicing, post-translational modifications, and alternative partner interactions. These layers of regulation critically affect the autophagy response, with an impact on cell proliferation, motility, and resistance to multiple stress stimuli. In this review article we outline the structural and functional properties of BECLIN-1 and discuss how its altered expression and protein–protein interactions can be harnessed for diagnostic and therapeutic purposes in cancer. Full article

The red seaweed Jania rubens (J. rubens) is prevalent along the Lebanese coast and has drawn attention for its notable antineoplastic properties. Our previous data showed that its dichloromethane–methanol (DM) extract possesses antioxidant, cytotoxic, and anti-migratory effects on colon cancer cells. In the present study, a GC-MS analysis of DM extract identified a diverse profile of bioactive compounds, including flavonoids and pyrazole derivatives with antioxidant and anticancer activities. In vitro assays demonstrated that the DM extract exerts significant cytotoxic activity against various cancer cell lines, including colon, breast, and cervical types. Further investigation into the underlying molecular mechanisms revealed that the extract induces G2/M cell cycle arrest and reduces the expression of EMT (epithelial–mesenchymal transition) markers, N-cadherin and Twist. In addition, the extract showed anti-metastatic properties through its ability to decrease MMP-2 and MMP-9 activity. Mechanistically, DM caused a substantial reduction in Ten-Eleven Translocation (TET) enzymes TET-1, TET-2, and TET-3, which are essential DNA demethylation regulators, thus decreasing their enzymatic product 5-hydroxymethylcytosine (5-hmC). Interestingly, despite a significant increase in intracellular ROS (reactive oxygen species), suggesting a contribution to cytotoxicity, no substantial change in the biogenesis of promyelocytic leukemia nuclear bodies (PML-NBs) was detected. These findings demonstrate that J. rubens DM extract contains bioactive compounds with multiple anticancer effects, thus making it a promising candidate for developing new therapeutic agents. Full article

N⁶-methyladenosine (m⁶A), the most abundant internal modification in eukaryotic mRNA, regulates gene expression by modulating mRNA metabolism. Demethylases (“erasers”) specifically remove these m⁶A marks. In mammals, FTO and ALKBH5 (ALKBH family members) are key erasers regulating metabolism, reproduction, and development. Notably, heterologous expression of human FTO in rice and potato significantly increase yield. In contrast, research on plant m⁶A demethylases is still in its infancy, though several ALKBH family members have been identified. These enzymes play crucial roles in regulating plant growth and development, as well as in mediating stress responses, highlighting their considerable potential in enhancing crop yield and improving agronomic traits. This review summarizes current knowledge on identified m⁶A demethylases, conducts a phylogenetic analysis of the ALKBH family across representative plant species, and elaborates on the roles of these enzymes in key biological processes such as flowering time regulation, fruit ripening, male fertility, and responses to both biotic and abiotic stresses. Further research on plant RNA m⁶A demethylases will deepen our understanding of RNA epigenetic regulatory mechanisms, uncover valuable genetic resources, and ultimately facilitate the breeding of high-yielding, high-quality crop varieties. Full article

Background/Objectives: Epigenetics refers to heritable modifications in gene expression that do not involve changes to the DNA sequence. Among these, DNA methylation, histone modifications, and non-coding RNAs play a key role in regulating gene activity and are influenced by environmental factors, including exposure to psychoactive substances. In recent years, it has been hypothesized that such alterations may serve as molecular markers with forensic relevance. This systematic review aims to evaluate whether current evidence supports the use of drug-induced epigenetic changes as potential toxicological fingerprints in human subjects. Methods: A systematic literature search was conducted following PRISMA guidelines, including articles published on PubMed between 1 January, 2010, and 31 December, 2025. Only studies conducted on human samples and published in English were considered; animal studies and articles lacking epigenetic data were excluded. Results: Forty-two studies met the inclusion criteria. The most commonly investigated substances (alcohol, cocaine, methamphetamine, cannabis, and opioids) were found to induce specific and, in some cases, persistent epigenetic changes. These include alterations in CpG methylation in promoter regions, variations in miRNA expression, and modulation of epigenetic enzymes. Such changes were observed in brain tissue, blood cells, and semen, with evidence of persistence even after drug cessation. Conclusions: Current evidence confirms that psychoactive substance use is associated with specific epigenetic modifications. However, forensic application remains limited due to confounding factors such as age, co-exposures, and post-mortem interval. Further standardized research is necessary to validate their use as forensic biomarkers. Full article

Exosomes are lipid bilayer vesicles approximately 30–150 nm in diameter that serve as key mediators of intercellular communication. By transporting diverse bioactive molecules, including proteins and nucleic acids, they play a crucial role in tumor initiation and progression. Among their functional cargo, exosomal microRNAs (miRNAs) are central to epigenetic regulation and intercellular signaling, significantly influencing tumor biology. This review provides a comprehensive overview of the multifaceted roles of exosomal miRNAs in remodeling the tumor microenvironment (TME) and regulating cancer stem cells (CSCs). Specifically, exosomal miRNAs modulate various immune cells (such as macrophages, T cells, and NK cells) as well as cancer-associated fibroblasts (CAFs), thereby promoting immune evasion, angiogenesis, epithelial–mesenchymal transition (EMT), and metastatic progression. At the same time, they enhance CSC stemness, self-renewal, and therapeutic resistance, ultimately driving tumor recurrence and dissemination. Furthermore, exosome-mediated miRNA signaling acts as a critical force in malignant progression. Finally, we discuss the clinical potential of exosomal miRNAs as diagnostic and prognostic biomarkers, therapeutic targets, and vehicles for targeted drug delivery, highlighting their translational value and future directions in cancer research. Full article

DNA methylation holds promise for the early detection of tissue damage, making it crucial for identifying polycyclic aromatic hydrocarbon (PAH)-associated epigenetic biomarkers in childhood asthma. Sulforaphane (SFN), as a potential epigenetic modulator, can alleviate the adverse effects of environmental pollutants. This study quantified serum PAHs in 370 children via gas chromatography–mass spectrometry, assessed the methylation of target genes using bisulfite sequencing PCR (BSP), and performed mediation analysis to estimate the mediating effects of methylation levels between PAHs and childhood asthma. Murine models exposed to PAHs prenatally or postnatally, with offspring challenged with ovalbumin (OVA), were analyzed for lung DNA methylation. In vitro, HBE cells and HBSMCs treated with benzo(a)pyrene (BaP) and/or SFN were tested for inflammatory cytokines, methylation-related enzymes, and matrix metallopeptidase 9 (MMP9) modifications. The results showed total PAHs were associated with childhood asthma, with mediating effects of long interspersed nuclear element-1 (LINE-1) methylation. Prenatal PAH exposure enriched differentially methylated genes in the extracellular matrix (ECM)-receptor interaction pathway, while postnatal exposure enriched those in purine metabolism, and postnatal exposure also elevated Mmp9 expression via hypomethylation. BaP increased the expression of interferon gamma (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A), transforming growth factor beta 1 (TGF-β), and ten-eleven translocation methylcytosine dioxygenases (TETs), and it upregulated MMP9 via enhancer hypomethylation and H3K27ac enrichment, while SFN reversed these effects by downregulating histone methyltransferase (HMT), leading to reduced H3K4me1 and subsequent H3K27ac depletion, thus suppressing MMP9 transcription. This study demonstrates that DNA methylation mediates PAH–childhood asthma associations, with distinct patterns in different exposure windows; MMP9 could serve as a crucial target for epigenetic modification during lung inflammation induced by PAH exposure, and SFN reverses PAH-induced epigenetic changes, aiding prevention strategies. Full article

JmjC domain proteins play crucial roles in plant growth and development, regulation of epigenetic processes, flowering control, and stress defence. However, these proteins have not been systematically identified or characterised in tomato. Here, we performed a genome-wide identification of JmjC domain-containing genes (JMJ family) in tomato and identified 23 SlJMJ genes within the tomato genome. Expression analysis indicated that SlJMJ15 was responsive to drought stress, prompting us to investigate its functional role in tomato plants. We found that SlJMJ15-RNAi lines displayed a severe dwarf phenotype, whereas SlJMJ15-overexpression lines exhibited increased drought sensitivity compared to wild-type plants, indicating that SlJMJ15 negatively regulates drought tolerance in tomatoes. Further investigation suggests that SlJMJ15 may reduce drought tolerance in tomatoes by modulating the expression of key genes involved in abscisic acid signalling pathways through its demethylation activity. This study deepens our understanding of the roles of SlJMJ family genes in tomato growth and abiotic stress responses, laying the foundation for developing strategies to improve drought stress tolerance in tomatoes. Full article

Over the last decade, immunotherapy has revolutionized lung cancer treatments, particularly in non-small cell lung cancer, where immune checkpoint inhibitors have achieved significant clinical success. However, high percentages of patients do not respond initially or eventually develop a resistance to these therapies. This review explores the evolution and challenges of immunotherapy in lung cancer, highlighting its clinical milestones and intrinsic and extrinsic resistance mechanisms. We investigate tumor-intrinsic resistance factors, including alterations in antigen presentation, the loss of Beta-2 microglobulin function, impaired interferon signaling, immune editing, epigenetic modifications, and tumor-extrinsic resistance, such as an immunosuppressive lung tumor microenvironment, dysregulated cytokine profiles, and the upregulation of immune checkpoints. Then, we focus on the emerging role of resistance biomarkers and the development of personalized treatment strategies to overcome these challenges. The complex interplay between tumor biology and immune modulation in lung cancer paves the way for novel approaches for improving the effectiveness of immunotherapeutic treatments. Full article

The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment. Full article

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality. A central driver in its pathogenesis is alveolar epithelial cell (AEC) dysfunction, which leads to disruption of the epithelial barrier, impaired fluid clearance, and dysregulated inflammatory responses. This review summarizes the key mechanisms underlying AEC injury, including programmed cell death (apoptosis, pyroptosis, necroptosis, ferroptosis), oxidative stress, mitochondrial dysfunction, epigenetic reprogramming (DNA methylation, histone modifications), metabolic rewiring (succinate accumulation), and spatiotemporal heterogeneity revealed by single-cell sequencing and spatial transcriptomics. Multicellular crosstalk involving epithelial–immune–endothelial networks and the gut-lung axis further shapes disease progression. Building on these mechanistic foundations, we evaluate emerging AEC-targeted interventions such as pharmacologic agents (antioxidants, anti-inflammatories), biologics (mesenchymal stem cells and engineered exosomes), and gene-based approaches (adeno-associated virus and CRISPR-Cas9 systems delivered via smart nanocarriers). Complementary strategies include microbiome modulation through probiotics, short-chain fatty acids, or fecal microbiota transplantation, and biomarker-guided precision medicine (e.g., sRAGE, exosomal miRNAs) to enable promise individualized regimens. We also discuss translational hurdles, including nanotoxicity, mesenchymal stem cell (MSC) heterogeneity, and gene-editing safety, and highlight future opportunities involving AI-driven multi-omics, lung-on-chip platforms, and epithelium-centered regenerative therapies. By integrating mechanistic insights with innovative therapeutic strategies, this review aims to outline a roadmap toward epithelium-targeted, precision-guided therapies for ARDS. Full article

Carcinogenesis is a complex process characterized by the uncontrolled proliferation of abnormal cells, influenced by environmental, genetic, and epigenetic factors. Chronic inflammation is undoubtedly one of the key contributors to carcinogenesis. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC) due to persistent inflammation resulting from continuous immune system activation and excessive immune cell recruitment. IBD is also linked to certain nutritional deficiencies, primarily due to dietary modifications necessitated by the disease’s pathophysiology. Consequently, individualized nutritional supplementation appears to be a rational approach to addressing these deficiencies. The use of functional foods, including anti-inflammatory nutraceuticals, in individuals with IBD may play a crucial role in modulating cellular pathways that inhibit the release of inflammatory mediators. Thus, the regulation of the aryl hydrocarbon receptor (AhR) and G protein-coupled receptor 35 (GPR35) through dietary ligands appears to be of significant importance not only in the treatment of IBD and maintenance of remission but also in the prevention of tumorigenic transformation, particularly in genetically predisposed individuals. This narrative review was conducted using PubMed, Scopus, and Web of Science databases. The search covered literature published between January 2000 and June 2024. Keywords included ‘inflammatory bowel disease’, ‘colorectal cancer’, ‘AhR’, ‘aryl hydrocarbon receptor’, ‘GPR35’, ‘cytochrome P450’, ‘nutraceuticals’, ‘probiotics’, and ‘superfoods’. Only English-language articles were included. The selection focused on studies investigating mechanistic pathways and the role of dietary ligands in AhR and GPR35 activation in IBD and CRC. The SANRA guidelines for narrative reviews were followed to ensure transparency and minimize bias. Full article

Organophosphorus flame retardants (OPFRs) are emerging alternatives to halogenated compounds, yet their environmental toxicity remains underexplored. This study evaluated the developmental toxicity of two aryl-OPFRs, triphenyl phosphate (TPP) and tricresyl phosphate (TCP), in zebrafish (Danio rerio) from 2 h to 5 days post fertilization (hpf–dpf). Survival, hatching rate, and malformations were assessed across concentrations of 250–1000 µg/L, alongside with gene expression analysis at 5 dpf (250 and 500 µg/L) targeting detoxification (ces2), immune responses (il1β, casp9), and epigenetic markers (dnmt1, dnmt3). In vitro enzymatic assays evaluated interactions of both aryl-OPFRs with carboxylesterase (CE) and acetylcholinesterase (AChE) enzymes. While no significant morphological effects were observed, TPP showed higher toxicity than TCP. Notably, TCP (500 µg/L) downregulated genes linked to metabolism and immunity. CE activity and ces2 modulation may suggest CE as a potential biomarker for aryl-OPFR exposure. These findings, although at concentrations above the environmental ones, may be valuable for mechanistic purposes and underscore the need for further investigation in developmental toxicity given their lipophilic nature and distinct molecular responses. Full article