Search Results (3,018)

Genitourinary (GU) cancers, including prostate, bladder, and renal cancers, represent a significant burden on global health. Conventional treatments, while effective in certain contexts, face limitations due to tumor heterogeneity, therapeutic resistance, and relapse. Recent advances in cancer immunotherapy, particularly in the development of personalized mRNA and DNA-based vaccines, have opened new avenues for precise and durable antitumor responses. These vaccines are being developed to leverage neoantigen identification and next-generation sequencing technologies, with the goal of tailoring immunotherapeutic interventions to individual tumor profiles. mRNA vaccines offer rapid, non-integrative, and scalable, with encouraging results reported in infectious diseases and early-phase cancer trials. DNA vaccines, known for their stability and ease of modification, show promise in generating robust cytotoxic T-cell responses. This review discusses the current landscape, preclinical findings, and ongoing clinical trials of mRNA and DNA-based vaccines in GU cancers, highlighting delivery technologies, combination strategies with immune checkpoint inhibitors, and future challenges, including tumor immune evasion and regulatory hurdles. Integrating immunogenomics and artificial intelligence into vaccine design is poised to further enhance precision in cancer vaccine development. As GU malignancies remain a leading cause of cancer-related morbidity and mortality, mRNA and DNA vaccine strategies represent a promising and rapidly evolving area of investigation in oncology. Full article

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. Full article

Numerous infants have been conceived by in vitro fertilization (IVF) and other assisted reproductive technologies (ART). Increasing evidence indicates that these approaches induce minor alterations in molecules during the initial phases of embryogenesis. This narrative review examines the molecular pathophysiology of embryonic cardiogenesis in the context of assisted reproductive technology, emphasizing transcriptional and epigenetic regulation. Essential transcription factors for cardiac development, including NKX2-5, GATA4, TBX5, ISL1, MEF2C, and HAND1/2, play a crucial role in mesodermal specification, heart tube formation, and chamber morphogenesis. Animal models and human preimplantation embryos have demonstrated that ART-related procedures, including gamete micromanipulation, supraphysiological hormone exposure, and extended in vitro culture, can alter the expression or epigenetic programming of these genes. Subsequent to ART, researchers have identified anomalous patterns of DNA methylation, alterations in histones, and modifications in chromatin accessibility in cardiogenic loci. These alterations indicate that errors occurred during the initial reprogramming process, potentially resulting in structural congenital heart abnormalities (CHDs) or modifications in cardiac function later in life. Analysis of the placental epigenome in babies conceived using assisted reproductive technology reveals that imprinted and developmental genes critical for cardiac development remain dysfunctional. This review proposes a mechanistic theory about the potential subtle alterations in the cardiogenic gene network induced by ART, synthesizing findings from molecular embryology, transcriptomics, and epigenomics. Understanding these molecular issues is crucial not only for enhancing ART protocols but also for evaluating the cardiovascular risk of children conceived by ART postnatally and for early intervention. Full article

Magnesium (Mg) alloys, particularly Mg AZ31, have emerged as promising biomaterials for orthopedic applications due to their biodegradability and favorable mechanical characteristics. Among these, the Mg AZ31+SPF alloy, subjected to hydrothermal (HT) treatment, has demonstrated enhanced bioactivity. Our previous research established that this surface modification supports the osteogenic differentiation of human mesenchymal stem cells (hMSCs) by modulating both canonical and non-canonical signaling pathways, including those implicated in osteogenesis, hypoxic response, exosome biogenesis, and lipid metabolism. In the present study, we extended our investigation to assess the effects of Mg AZ31+SPF+HT and Mg AZ31+SPF extracts on murine pre-osteoclasts (RAW 264.7 cells) over 3- and 6-day treatment periods. The primary objectives were to evaluate biocompatibility and to investigate potential impacts on osteoclastogenesis induction and miRNA expression profiles. Methods: To assess cytocompatibility, metabolic activity, DNA integrity, and morphological alterations in RAW 264.7 cells were evaluated. Osteoclast differentiation was quantified using TRAP staining, alongside the assessment of osteoclastogenic marker expression by qRT-PCR and ELISA. The immunomodulatory properties of the extracts were examined using multiplex BioPlex assays to quantify soluble factors involved in bone healing. Additionally, global miRNA expression profiling was performed using a specialized panel targeting 82 microRNAs implicated in bone remodeling and inflammatory signaling. Results: Mg AZ31+SPF+HT extract exhibited high biocompatibility, with no observable adverse effects on cell viability. Notably, a significant reduction in the number of TRAP-positive and multinucleated cells was observed relative to the Mg AZ31+SPF group. This effect was corroborated by the downregulation of osteoclast-specific gene expression and decreased MMP9 protein levels. Cytokine profiling indicated that Mg AZ31+SPF+HT extract promoted an earlier release of key cytokines involved in maintaining the balance between bone formation and resorption, suggesting a beneficial role in bone healing. Furthermore, miRNA profiling revealed a distinct regulatory signature in Mg AZ31+SPF+HT-treated cells, with differentially expressed miRNAs associated with inflammation, osteoclast differentiation, apoptosis, bone resorption, hypoxic response, and metabolic processes compared to Mg AZ31+SPF-treated cells. Conclusions: Collectively, these findings indicate that hydrothermal treatment of Mg AZ31+SPF (resulting in Mg AZ31+SPF+HT) attenuates pre-osteoclast activation by influencing cellular morphology, gene and protein expression, as well as post-transcriptional regulation via modulation of miRNAs. The preliminary identification of miRNAs and the activation of their regulatory networks in pre-osteoclasts exposed to hydrothermally treated Mg alloy are described herein. In the context of orthopedic surgery—where balanced bone remodeling is imperative—our results emphasize the dual significance of promoting bone formation while modulating bone resorption to achieve optimal implant integration and ensure long-term bone health. Full article

Obesity represents a global medical and social challenge characterized by pathological accumulation of adipose tissue as a result of complex interactions among genetic, environmental, and epigenetic factors. Recent studies have highlighted the pivotal role of epigenetic mechanisms in the pathogenesis of this condition, including abnormal DNA methylation of metabolic genes, dysregulation of microRNAs, and chromatin remodeling. These modifications are reversible and can be modulated by dietary, behavioral, and pharmacological interventions. This review provides a comprehensive analysis of tissue-specific epigenetic alterations identified not only in adipocytes and hepatocytes but also in peripheral blood cells, offering promising opportunities for the development of novel diagnostic biomarkers and targeted epigenetic therapeutic strategies. Full article

Guanine-rich nucleic acid sequences can adopt G-quadruplex (G4) structures, which pose barriers to DNA replication and repair. The FANCJ helicase contributes to genome stability by resolving these structures, a function linked to its G4-binding site that features an AKKQ amino acid motif. This site is thought to recognize oxidatively damaged G4, specifically those containing 8-oxoguanine (8oxoG) modifications. We hypothesize that FANCJ AKKQ recognition of 8oxoG-modified G4s (8oxoG4s) depends on the sequence context, the position of the lesion within the G4, and overall structural stability. Using fluorescence spectroscopy, we measured the binding affinities of a FANCJ AKKQ peptide for G4s formed by (GGGT)₄, (GGGTT)₄, and (TTAGGG)₄ sequences. G4 conformation and thermal stability were assessed by circular dichroism spectroscopy. Each sequence was modified to include a single 8oxoG at the first (8oxo1), third (8oxo3), or fifth (8oxo5) guanine position. In potassium chloride (KCl), the most destabilized structures were (GGGT)₄ 8oxo1, (GGGTT)₄ 8oxo1, and (TTAGGG)₄ 8oxo5. In sodium chloride (NaCl), the most destabilized were (GGGT)₄ 8oxo1, (GGGTT)₄ 8oxo5, and (TTAGGG)₄ 8oxo5. FANCJ AKKQ binding affinities varied according to damage position and sequence context, with notable differences for (GGGT)₄ in KCl and (TTAGGG)₄ in NaCl. These findings support a model in which FANCJ binding to G4 and 8oxoG4 structures is modulated by both the oxidative damage position and the G4 local sequence environment. Full article

Background: Robust evidence supports the role of tetrahydrobiopterin (BH4) metabolism in sustaining inflammation; however, the mechanisms underlying the persistent upregulation of the BH4 pathway remain incompletely understood. This study investigated the epigenetic regulation of BH4 metabolism following a single injection of lipopolysaccharide (LPS) in the mouse hippocampus. Methods: Male C57BL/6J mice received either saline or LPS (0.33 mg/kg, i.p.) and were sacrificed at 4 h or 24 h post injection. Behavioral assessments and analyses of hippocampal neurotransmitter metabolism, DNA methylation profile, oxidative stress, and inflammasome activation were performed. Neopterin levels, a marker of immune system activation, were measured in both the plasma and hippocampus. Results: LPS-treated mice exhibited sickness behavior, including reduced locomotor and exploratory activity at both 4 and 24 h. While exploratory behavior showed partial recovery by 24 h, locomotor activity remained impaired. Neopterin levels increased in both the plasma and hippocampus following LPS administration but returned to baseline in the hippocampus by 24 h. Despite the normalization of neopterin, a persistent pro-inflammatory state in the hippocampus was evident at 24 h, as shown by increased expression of Ikbkb and components of the NLRP3 inflammasome, along with elevated oxidative stress markers. Upregulation of Nrf-2 and Hmox1 suggested activation of a protective antioxidant response. Dopaminergic metabolism was disrupted, indicating impaired BH4-dependent dopamine turnover. Epigenetic analysis revealed increased expression of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) and Tet2, along with reduced expression of Tet1 and Tet3. Promoter hypomethylation of Gch1 and Ptps was observed, correlating with increased hippocampal expression and potentially elevated BH4 levels. Conclusions: Together, these findings show that a single LPS challenge was sufficient to induce the activation of the BH4 synthesis pathway during the late acute inflammatory phase, both systemically and in the hippocampus, potentially driven by epigenetic modifications such as promoter hypomethylation. This may contribute to the perpetuation of neuroinflammation. Full article

Objectives: Obesity has become a major health issue, with multifactorial etiologies involving lifestyle, genetic, and neuroendocrine mechanisms. Despite public health campaigns and lifestyle interventions, long-term weight loss is often difficult to achieve or sustain. This literature review aims to summarize current knowledge on the main molecular mechanisms that hinder weight loss and to summarize the newest therapeutic strategies targeting obesity. Methods: The literature review was conducted using PubMed, Scopus, and Web of Science databases, with a preference for peer-reviewed original articles, systematic reviews, and meta-analyses. Eligible studies were required to be published in the English language and within the last ten years (2015–2025), with the exception of historically significant publications. A total of 112 articles were included in our review. Results: Obesity is a complex, chronic, recurrent metabolic condition that requires personalized, multidisciplinary treatment approaches. In this review, we summarize the major molecular mechanisms underlying weight gain and weight maintenance in obesity. In this literature review, we address the metabolic memory and epigenetics that act through DNA and histone modifications and micro interfering RNAs, resulting in an energy imbalance that can be passed on to further generations. The dysfunction of adipose tissue contributes to chronic low-grade inflammation and insulin resistance, leading to more severe obesity. The ratio of white, beige, and brown adipocytes also plays an important role in regulating energy balance. Novel medical interventions offer promising results in attenuating these mechanisms against successful weight loss. Conclusions: Current interventions, including calorie restriction, physical activity, and pharmacological treatment together, may show great promise in combating obesity, but long-term efficacy and safety remain to be established. Full article

Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1 presents with café-au-lait macules; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal abnormalities; learning disabilities; and optic pathway gliomas, while NF2 is characterised by bilateral vestibular schwannomas, multiple meningiomas, ependymomas, and peripheral nerve schwannomas. Although germline mutations in the NF1 and NF2 tumour suppressor genes are well established, they do not fully explain the broad clinical variability observed, even among individuals carrying identical mutations. As increasingly recognised in other genetic diseases, epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA (ncRNA) regulation, play a critical role in modulating gene expression and influencing disease severity. Despite important findings, the research remains fragmented, and a unified model is lacking. This review organises the current knowledge, emphasising how epigenetic alterations impact disease behaviour and outlining their potential as prognostic biomarkers and therapeutic targets. A deeper understanding of these mechanisms could lead to improved personalised management and the development of targeted epigenetic therapies for individuals with NF1 and NF2. Full article

Colchicine is commonly prescribed for inflammation and gout, but its nephrotoxicity and underlying mechanisms remain incompletely understood. The objective of this research was to clarify the association between m6A methylation modifications and nephrotoxicity caused by colchicine. A significant decrease in HK2 cell viability was observed following colchicine treatment, and mRNA sequencing (mRNA-seq) revealed the differential expression of genes associated with DNA damage and autophagy. Further methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed an association between N6-methyladenosine (m6A) modifications and the expression of genes involved in DNA damage and autophagy after colchicine exposure. Molecular docking and a molecular dynamics (MD) analysis identified ZC3H13 as a potential regulator of colchicine-induced cytotoxicity in HK2. Experimental validation confirmed that colchicine induces DNA damage and autophagy in HK2 cells, with ZC3H13 playing a significant role in these processes. In conclusion, the findings suggested that colchicine-induced damage in HK2 cells is associated with changes in m6A methylation levels in target genes and the altered expression of m6A regulator. Full article

The hydrocoral Millepora complanata (fire coral) plays a critical role in reef structure and relies on a symbiotic relationship with Symbiodiniaceae algae. Environmental stressors derived from climate change, such as UV radiation and elevated temperatures, disrupt this symbiosis, leading to bleaching and threatening reef survival. To gain insight into the thermal stress response of this reef-building hydrocoral, this study investigates the proteomic response of M. complanata to bleaching during the 2015–2016 El Niño event. Fragments from non-bleached and bleached colonies of the hydrocoral M. complanata were collected from a coral reef in the Mexican Caribbean, and proteomic extracts were analyzed using nano-liquid chromatography–tandem mass spectrometry (nano-LC-MS/MS). Uni- and multivariate analyses were applied to identify significant differences in protein abundance. A total of 52 proteins showed differential abundance, including 24 that showed increased expression and 28 whose expression decreased in bleached fragments. Differentially abundant proteins were associated with amino acid biosynthesis, carbohydrate metabolism, cytoskeleton organization, DNA repair, extracellular matrix composition, redox homeostasis, and protein modification. These molecular alterations reflect critical physiological adaptations that may influence stress sensitivity or tolerance in hydrocorals. The findings indicate that heat stress induces molecular responses involving protein refolding, enhanced vesicular transport, cytoskeletal reorganization, and modulation of redox activity. This contributes to a deeper understanding of the molecular mechanisms underlying bleaching in reef-building hydrozoans and broadens current knowledge beyond the more extensively studied anthozoan corals. Full article

The term chromosomal imprinting was introduced to denote the parent-of-origin-dependent behavior of chromosomes in the fungus gnat originally named Sciara coprophila (current taxonomic name is Bradysia coprophila). Such behavior is observed in Sciara coprophila embryos, where paternal X chromosomes (X_p) are specifically eliminated during the 7th–8th cleavage divisions. Elimination is regulated by a controlling element (CE) that has been mapped to heterochromomere II (H2) within the sub-telomeric short arm of polytene X chromosomes. Here, using a combination of a new Sciara genome assembly, along with ChIP-Seq and MeDIP analyses, we show that a 1.2 Mb region within the CE locus has a repressive epigenetic signature that is characterised by enrichments of H3K9me3, H4K20me3 and 5′-methyl cytosine (5meC). These data provide evidence for a model where the H3K9me3/HP1/H4K20me3 pathway operates to assemble a heterochromatin-like complex at the CE that renders it silent on X_p chromosomes that are not eliminated. In this regard, our findings support the idea that the H3K9me3/HP1/H4K20me3 pathway represents the most evolutionarily conserved mechanism linked to chromosomal imprinting in animals. Full article

Dental caries is now recognised as a multifactorial disease shaped by complex interactions among genetic, epigenetic, microbiological, environmental, and social factors. This narrative review synthesises recent findings on the influence of genetic and epigenetic factors on caries susceptibility, exploring implications for personalised prevention strategies, including novel vaccine approaches. Numerous gene polymorphisms in pathways related to enamel formation, saliva composition, immune response, and taste perception have been linked to increased caries risk, with some effects modulated by sex and tooth-specific factors. Early-life environmental exposures (diet, tobacco, and antibiotic use) have been demonstrated to further alter risk through epigenetic modifications such as DNA methylation, microRNA regulation, and histone changes. The recognition of this landscape of inherited and acquired vulnerabilities has given rise to interest in innovative preventive measures. In particular, anti-caries vaccines targeting Streptococcus mutans are being developed using protein subunits, DNA constructs, and even plant-based antigen production. Notwithstanding the challenges that still need to be overcome—chiefly the achievement of robust mucosal immunity, the assurance of safety, and the enhancement of production—these vaccines are proving to be a promising addition to traditional oral hygiene and fluoride measures. The integration of genetic and epigenetic insights with immunological advances has the potential to facilitate the development of more effective, personalised interventions to prevent dental caries. Full article

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of addressing these challenges by enhancing intracellular drug accumulation, enabling targeted delivery and facilitating stimuli-responsive and controlled release. This review provides a comprehensive overview of the molecular and cellular mechanisms underlying MDR and critically examines recent advances in nanoparticle strategies developed to overcome it. Various nanoparticle designs are analysed in terms of their structural and functional features, including surface modifications, active targeting ligands and responsiveness to tumour-specific cues. Particular emphasis is placed on the co-delivery of chemotherapeutic agents with gene regulators, such as siRNA, and the use of nanoparticles to deliver CRISPR/Cas9 gene editing tools as a means of re-sensitising resistant cancer cells. While significant progress has been made in preclinical settings, challenges such as tumour heterogeneity, limited clinical translation and immune clearance remain. Future directions include the integration of precision nanomedicine, scalable manufacturing and non-viral genome editing platforms. Collectively, nanoparticle-based drug delivery systems offer a multifaceted approach to combat MDR and hold great promise for improving therapeutic outcomes in resistant cancers. Full article

Uterine leiomyomas (ULM) and uterine leiomyosarcomas (ULMS) represent smooth muscle tumors with similar initial presentations but drastically different outcomes. This literature review analyzes the similarities and differences in their epigenetic profiles to identify diagnostic biomarkers and potential therapeutic targets that could improve clinical management. Both tumor types exhibit mostly distinct epigenetic signatures while sharing key pathway dysregulations. ULMS demonstrates global DNA hypomethylation, increased histone acetyltransferase activity, elevated Histone Deacetylase (HDAC) class I expression, and characteristic microRNA profiles. ULM displays focal methylation patterns and specific microRNA alterations that promote extracellular matrix accumulation. Despite these differences in epigenetic mechanisms, both tumors converge on dysregulation of signaling pathways including PI3K/AKT/mTOR, Wnt/β-catenin, and Transforming Growth Factor beta (TGF-β) signaling, suggesting common downstream effects from distinct epigenetic origins. Understanding the shared and distinct epigenetic landscape between ULM and ULMS will enhance our insights into tumor pathogenesis and may offer promising biomarkers and therapeutic targets. Full article