Search Results (4,711)

Female cancers such as breast and gynaecological cancers contribute to a significant global health burden and are a leading cause of fatality among women. With current treatment options often limited by resistance to cytotoxic drugs, side effects and lack of specificity to the cancer, there is a pressing need for alternative treatments. Recent research has highlighted the promising role of non-coding RNAs (ncRNA) in regulating these issues and providing more targeted approaches to suppressing key cancer pathways. This review explores the involvement of the various types of non-coding RNAs in regulating key oncogenic pathways, namely, the MAPK, PI3K/Akt/mTOR, Wnt/β-catenin and p53 pathways, in a range of female cancers such as breast, cervical, ovarian and endometrial cancers. Evidence from a multitude of studies suggests that non-coding RNAs function as double-edged swords, serving as both oncogenes and tumour suppressors, depending on their expression and cellular interactions. By mapping and investigating these regulatory interactions, this review demonstrates the complexity and dual functionality of ncRNAs in cancer. Understanding these complex mechanisms is essential for the development of new and effective ncRNA-based diagnostic methods and targeted therapies in female cancer treatment. Full article

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss among the elderly, and is influenced by a combination of genetic and environmental risk factors. While genetic associations in AMD are well-established, the molecular mechanisms underlying disease onset and progression remain poorly understood. A growing body of evidence suggests that epigenetic modifications may serve as a potential missing link regulating gene–environment interactions. This review incorporates recent findings on DNA methylation, including both hypermethylation and hypomethylation patterns affecting genes such as silent mating type information regulation 2 homolog 1 (SIRT1), glutathione S-transferase isoform (GSTM), and SKI proto-oncogene (SKI), which may influence key pathophysiological drivers of AMD. We also examine histone modification patterns, chromatin accessibility, the status of long non-coding RNAs (lncRNAs) in AMD pathogenesis and in regulating pathways pertinent to the pathophysiology of the disease. While the field of ocular epigenetics remains in its infancy, accumulating evidence to date points to a burgeoning role for epigenetic regulation in AMD, pre-clinical studies have yielded promising findings for the prospect of epigenetics as a future therapeutic avenue. Full article

Ferroptosis is a distinct form of regulated cell death driven by iron-dependent lipid peroxidation participating in various diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of cellular redox homeostasis and a key determinant of ferroptosis resistance. Nrf2 activates the expression of downstream antioxidant genes to protect cells from oxidative stress and ferroptosis. Consequently, precise regulation of Nrf2 expression is crucial. Recent studies have revealed that complex epigenetic mechanisms involving DNA methylation, histone modifications, and non-coding RNA networks regulate Nrf2 expression. DNA methylation usually suppresses while histone acetylation promotes Nrf2 expression. The influences of histone methylation on NFE2L2 are site- and methylation degree-dependent. m6A modification stabilizes NFE2L2 mRNA to promote Nrf2 expression and thereby inhibit ferroptosis. This article summarizes current understanding of the epigenetic mechanisms controlling Nrf2 expression and Nrf2-mediated ferroptosis pathways and their implications in disease models. The challenges associated with the epigenetic regulation of Nrf2 and future research directions are also discussed. A comprehensive understanding of this regulatory interplay could open new avenues for intervention in ferroptosis-related diseases by fine-tuning cellular redox balance through the epigenetic modulation of Nrf2. Full article

Background/Objectives: Non-coding microRNA-34a (miR-34a) regulates the expression of key factors involved in several cellular processes, such as differentiation, apoptosis, proliferation, cell cycle, and senescence. Deregulation of the expression of these factors is implicated in the onset and progression of several human diseases, including cancer, neurodegenerative disorders, and pathologies associated with viral infections and inflammation. Despite numerous studies, the molecular mechanisms regulated by miR-34a remain to be fully understood. The present study aimed to generate miR-34a knockout cell lines to identify novel genes potentially regulated by its expression. Methods: We employed the CRISPR-Cas9 gene editing system to knock out the hsa-miR-34a gene in HeLa and 293T cell lines, two widely used models for studying molecular and cellular mechanisms. We compared proliferation rates and gene expression profiles via RNA-seq and qPCR analyses between the wild-type and miR-34a KO cell lines. Results: Knockout of miR-34a resulted in a decreased proliferation rate in both cell lines. Noteworthy, the ablation of miR-34a resulted in increased expression of the long non-coding RNA MALAT1. Additionally, miR-34a-5p silencing in the A375 melanoma cell line led to MALAT1 overexpression. Conclusions: Our findings support the role of the miR-34a/MALAT1 axis in regulating proliferation processes. Full article

Background/Objectives: Male infertility is a major health concern with a complex etiopathology, yet a substantial proportion of cases remain idiopathic. Mitochondrial dysfunction and non-coding RNA (ncRNA) deregulation have both been implicated in impaired spermatogenesis, but their interplay remains poorly understood. This study aimed to identify infertility-specific variants in ncRNAs that affect mitochondrial dynamics and homeostasis and to explore their roles. Methods: Whole-genome sequencing (WGS) was performed on genomic DNA samples from teratozoospermic, asthenozoospermic, oligozoospermic, and normozoospermic men. Variants uniquely present in infertile individuals and mapped to ncRNAs that affect mitochondrial dynamics were selected and prioritized using bioinformatics tools. An independent transcriptomic validation was conducted using RNA-sequencing data from testicular biopsies of men with non-obstructive azoospermia (NOA) to determine whether the ncRNAs harboring WGS-derived variants were transcriptionally altered. Results: We identified several infertility-specific variants located in lncRNAs known to interact with mitochondrial regulators, including GAS5, HOTAIR, PVT1, MEG3, and CDKN2B-AS1. Transcriptomic analysis confirmed significant deregulation of these lncRNAs in azoospermic testicular samples. Bioinformatic analysis also implicated the disruption of lncRNA–miRNA–mitochondria networks, potentially contributing to mitochondrial membrane potential loss, elevated reactive oxygen species (ROS) production, impaired mitophagy, and germ cell apoptosis. Conclusions: Our integrative genomic and transcriptomic analysis highlights lncRNA–mitochondrial gene interactions as a novel regulatory layer in male infertility, while the identified lncRNAs hold promise as biomarkers and therapeutic targets. However, future functional studies are warranted to elucidate their mechanistic roles and potential for clinical translation in reproductive medicine. Full article

Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving tumor progression, therapy resistance, and clinical outcomes. This review aims to explore the interplay between metabolic and epigenetic mechanisms in medulloblastoma, with a focus on their functional roles and therapeutic implications. Methods: A comprehensive literature review was conducted using PubMed and relevant databases, focusing on recent studies examining metabolic pathways and epigenetic regulation in medulloblastoma subtypes. Particular attention was given to experimental findings from in vitro and in vivo models, as well as emerging preclinical therapeutic strategies targeting these pathways. Results: Medulloblastoma exhibits metabolic adaptations such as increased glycolysis, lipid biosynthesis, and altered amino acid metabolism. These changes support rapid cell proliferation and interact with the tumor microenvironment. Concurrently, epigenetic mechanisms—including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation—contribute to tumor aggressiveness and treatment resistance. Notably, metabolic intermediates often serve as cofactors for epigenetic enzymes, creating feedback loops that reinforce oncogenic states. Preclinical studies suggest that targeting metabolic vulnerabilities or epigenetic regulators—and particularly their combination—can suppress tumor growth and overcome resistance mechanisms. Conclusions: The metabolic–epigenetic crosstalk in medulloblastoma represents a promising area for therapeutic innovation. Understanding subtype-specific dependencies and integrating biomarkers for patient stratification could facilitate the development of precision medicine approaches that improve outcomes and reduce long-term treatment-related toxicity in pediatric patients. Full article

Background: Obesity and its complications have increased in both adults and children, with pediatric populations developing metabolic disorders at earlier ages. Long non-coding RNAs, particularly MEG3, are involved in obesity through regulation of lipogenic genes including ATF4, FTO, SREBP1, FASN, and ACACA. However, data on MEG3 expression in pediatric obesity are limited. This study evaluated MEG3, FTO, and ATF4 expression in PBMCs from children with obesity and their associations with added sugar intake and lipid metabolism genes. Methods: In this cross-sectional study 71 children within the age range of 6 to 12 years were included (28 normal weight and 43 with obesity). Anthropometrical and clinical parameters and dietary added sugar consumption were analyzed. Real-time PCR was performed to assess MEG3, FTO, ATF4, SREBP1, FASN, and ACACA gene expression in peripheral blood mononuclear cells. Results: The expression of MEG3, ATF4, FTO, SREBP1, FASN, and ACACA was decreased in children with obesity. MEG3 and FTO showed sex-dependent expression in children without obesity, while additional sex-related differences were observed for SREBP1, FASN, ACACA, FTO, and MEG3 in children with obesity. MEG3 was associated with the expression of SREBP1, FASN, ACACA, FTO, and ATF4. In insulin-resistant (IR) children, MEG3, ATF4, FTO, ACACA, and SREBP1 were reduced, while FASN was increased. Added sugar intake negatively correlated with FTO, SREBP1, and ACACA. Conclusions: The MEG3, FTO, and ATF4 expression was altered in children with obesity, showing sex- and IR-related differences. Added sugar intake correlated negatively with lipogenic gene expression. Full article

Long non-coding RNAs (lncRNAs) interact with a variety of biomolecules, including DNA, mRNAs, microRNA, and proteins, to regulate various cellular processes. Recently, their interactions with lipids have gained increasing attention as an emerging research area. Both lipids and lncRNAs play central roles in cellular regulation, and growing evidence reveals a complex interplay between these molecules. These interactions contribute to key biological functions, such as cancer progression, lipid droplet transport, autophagy, liquid−liquid phase separation, and the formation of organelles without membranes. Understanding the lipid−lncRNA interface opens new avenues for unraveling cellular regulation and disease mechanisms, holding great potential not only for elucidating the fundamental aspects of cellular biology but also for identifying innovative therapeutic targets for metabolic disorders and cancer. This review highlights the biological relevance of lipid–lncRNA interactions by exploring their roles in cellular organization, regulation, and diseases, including metabolic and cancer-related disorders. Full article

Stress granule formation is a type of liquid–liquid phase separation in the cytoplasm, leading to RNA–protein condensates that are associated with various cellular stress responses and implicated in numerous pathologies, including cancer, neurodegeneration, inflammation, and cellular senescence. One of the key components of mammalian stress granules is the DEAD-box RNA helicase DDX3, which unwinds RNA in an ATP-dependent manner. DDX3 is involved in multiple steps of RNA metabolism, facilitating gene transcription, splicing, and nuclear export and regulating cytoplasmic translation. In this study, we investigate the role of the RNA helicase DDX3’s enzymatic activity in shaping the RNA content of ribonucleoprotein (RNP) condensates formed during arsenite-induced stress by inhibiting DDX3 activity with RK-33, a small molecule previously shown to be effective in cancer clinical studies. Using the human osteosarcoma U2OS cell line, we purified the RNP granule fraction and performed RNA sequencing to assess changes in the RNA pool. Our results reveal that RK-33 treatment alters the composition of non-coding RNAs within the RNP granule fraction. We observed a DDX3-dependent increase in circular RNA (circRNA) content and alterations in the granule-associated intronic RNAs, suggesting a novel role for DDX3 in regulating the cytoplasmic redistribution of non-coding RNAs. Full article

Disparities in the functional classification of secretory genes among aphid taxa may be attributed to variations in coding sequences and gene expression profiles. However, the driving factors that regulate sequence evolution remain unclear. This study aimed to investigate the differences in coding sequences and expression patterns of secretory genes between the rose grain aphid (Metopolophium dirhodum) and the pea aphid (Acrythosiphon pisum), with a particular focus on their roles in evolutionary adaptations and functional diversity. The study involved the rearing of aphids, RNA extraction, de novo transcriptome assembly, functional annotation, secretory protein prediction, and comparative analysis of coding sequences and expression patterns across various functional categories using bioinformatics tools. The results revealed that metabolic genes exhibited greater coding sequence divergence, indicating the influence of positive selection. Moreover, significant expression divergence was noted among functional categories, particularly in metabolic and genetic information processing genes, which exhibited higher variability. This study enhances our understanding of the molecular mechanisms that contribute to phenotypic and genetic diversity among aphid species. This study elucidates the relationship between variations in coding sequences and differences in gene expression among functional categories, thereby establishing a foundation for future studies on gene evolution in response to environmental pressures. Full article

In 1961, Los Angeles experienced the disastrous Bel Air fire, which swept through an affluent neighborhood situated in a hilly, WUI (wildland–urban interface) location. In January 2025, the city was devastated again by a nearly-simultaneous series of wildfires, the most severe of which took place close to the 1961 fire location. Disastrous WUI fires are, unfortunately, an anticipatable occurrence in many U.S. cities. A number of issues identified earlier remained the same. Some were largely solved, while other new ones have emerged. The paper examines the Palisades Fire of January, 2025 in this context. In the intervening decades, the population of the city grew substantially. But firefighting resources did not keep pace. Very likely, the single-most-important factor in causing the 2025 disasters is that the Los Angeles Fire Department operational vehicle count shrank to 1/5 of what it was in 1961 (per capita). This is likely why critical delays were experienced in the initial attack on the Palisades Fire, leading to a runaway conflagration. Two other crucial issues were the management of vegetation and the adequacy of water supplies. On both these issues, the Palisades Fire revealed serious problems. A problem which arose after 1961 involves the unintended consequences of environmental legislation. Communities will continue to be devastated by wildfires unless adequate vegetation management is accomplished. Yet, environmental regulations are focused on maintaining the status quo, often making vegetation management difficult or ineffective. House survival during a wildfire is strongly affected by whether good vegetation management practices and good building practices (“ignition-resistant” construction features) have been implemented. The latter have not been mandatory for housing built prior to 2008, and the vast majority of houses in the area predated such building code requirements. California has also suffered from a highly counterproductive stance on insurance regulation. This has resulted in some residents not having property insurance, due to the inhospitable operating conditions for insurance firms in the state. Because of the historical precedent, the details in this paper focus on the Palisades Fire; however, many of the lessons learned apply to managing fires in all WUI areas. Policy recommendations are offered, which could help to reduce the potential for future conflagrations. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression and are involved in diverse physiological and pathological processes, including carcinogenesis. In bladder cancer (BCa), dysregulation of NR signaling pathways has been linked to tumor initiation, progression, therapy resistance, and immune evasion. Recent evidence highlights the intricate crosstalk between NRs and microRNAs (miRNAs), which are small non-coding RNAs that posttranscriptionally modulate gene expression. This review provides an integrated overview of the molecular interactions between key NRs and miRNAs in BCa. We investigated how miRNAs regulate NR expression and function and, conversely, how NRs influence miRNA biogenesis, thereby forming regulatory feedback loops that shape tumor behavior. Specific miRNA–NR interactions affecting epithelial-to-mesenchymal transition, metabolic reprogramming, angiogenesis, and chemoresistance are discussed in detail. Additionally, we highlight therapeutic strategies targeting NR–miRNA networks, including selective NR modulators, miRNA mimics and inhibitors, as well as RNA-based combinatorial approaches focusing on their utility as diagnostic biomarkers and personalized treatment targets. Understanding the molecular complexity of NR–miRNA regulation in BCa may open new avenues for improving therapeutic outcomes and advancing precision oncology in urological cancers. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article

There has been a widely held view for some time that school teachers and principals need to possess a level of knowledge and understanding of the legal regulation of schools and that of their workers. This study explores the level of understanding of legal matters pertaining to the school environment that independent school teachers hold in Queensland. This level of ‘legal literacy’ is investigated in a qualitative research study that explains the various areas of education law that are known and those that are less understood by such educators. Data was analysed using content analysis methodology, using a coding scale that was created specifically for the purposes of coding the participants’ scenario responses. Overall, it was discovered that the level of legal literacy held by Queensland independent school teachers was alarmingly low. This varied across the myriad topics, but essentially, the educators surveyed did not demonstrate an adequate legal understanding to successfully complete their roles. More education in this area should be made available for educators to better equip them with such an understanding to ensure they know when and how to more capably protect themselves and the children entrusted to their care. Full article