Search Results (10,179)

Background and aims: The senescent phenotype transition of vascular smooth muscle cells (VSMCs) is a crucial risk factor for the occurrence and development of vascular diseases. Intermedin (IMD) has various protective effects on cardiovascular diseases. In this study, we aimed to explore the role and the related mechanism of IMD in the senescent phenotype transition of VSMCs of aorta in mice. Methods: The senescent phenotype transition of VSMCs was induced by angiotensin II (Ang II) administered by mini-osmotic pumps in Adm2^fl/fl and Adm2^fl/flTagCre mice. Mouse VSMCs from aorta were used in in vitro experiments. Results: The aortic mRNA level of IMD, namely Adm2, was significantly decreased in Ang II-treated mice. Senescence-associated β-galactosidase activity and protein expressions of p16 and p21 were increased in the aortas of Adm2^fl/flTagCre mice, which were further elevated in Ang II-treated Adm2^fl/flTagCre mice. In addition, Adm2 deficiency in VSMCs further increased the protein expressions of DNA damage markers including 53BP1 and γH2AX in aortas of Adm2^fl/flTagCre mice, and Ang II treatment increased their levels in aortas of Adm2^fl/flTagCre mice or in VSMCs. However, Ang II-induced increases in senescence-associated proteins and DNA damage markers could be mitigated by the administration of IMD in vitro. Mechanistically, IMD increased intracellular NAD⁺ by activating nicotinamide phosphoribosyl transferase (NAMPT), followed by enhancing poly (ADP-ribose) polymerase-1 (PARP1) activity. Inhibitors of PARP1 or NAMPT effectively blocked the beneficial role of IMD in the DNA damage of VSMCs. Conclusions: IMD alleviates DNA damage partially by activating NAMPT/PARP1, thereby inhibiting the senescent phenotype transition of VSMCs of aorta, which might shed new light on the prevention of vascular aging. Full article

Introduction: Fusobacterium nucleatum, a common oral microbe associated with periodontal disease, has emerged as a significant prognostic indicator in colorectal cancer (CRC). This organism is notably enriched in CRC tissues and is associated with reduced survival times and relapse. Fusobacterium is implicated in encouraging the development of chemoresistance through diverse tumor-promoting pathways that are increasingly being elucidated across molecular domains. Methods: This work uses a combined analysis of public data examining the role of F. nucleatum in CRC by investigating multiple transcriptomic datasets derived from co-culture infections in vitro. Results: In tandem with previously identified mechanisms known to be influenced by F. nucleatum, this analysis revealed that the bacterium activates multiple chemoresistance-associated pathways, including those driving inflammation, immune evasion, DNA damage, and metastasis. Notably, this study uncovered a novel induction of type I and type II interferon signaling, suggesting activation of a pseudo-antiviral state. Furthermore, pathway analysis (IPA) predicted altered regulation of several therapeutic agents, suggesting that F. nucleatum may compromise drug efficacy through transcriptional reprogramming. Conclusions: These findings reinforce the role of F. nucleatum in modulating host cellular pathways and support the hypothesis that bacterial association potentiates chemoresistance. Full article

Background/Objectives: Gestational weight gain (GWG) is a crucial factor influencing mother and fetal health, as high GWG is associated with adverse pregnancy outcomes and an increased long-term risk of obesity and metabolic issues in the children. In addition to controlling weight, maternal physical activity (PA) during pregnancy may influence fetal development through potential epigenetic mechanisms, including histone modifications, DNA methylation, and the production of non-coding RNA. Methods: This narrative review synthesizes evidence from randomized controlled trials (RCTs; n = 11, 3654 participants) investigating the impact of aerobic PA on GWG, while also highlighting emerging, primarily indirect findings on maternal–fetal epigenetic programming. Results: The majority of RCTs found that supervised PA interventions, especially when paired with nutritional counseling, decreased both the incidence of excessive GWG and total GWG. Enhancements in lipid metabolism, adipokine profiles, and maternal insulin sensitivity point to likely biochemical mechanisms that connect PA to epigenetic modification of fetal metabolic genes (e.g., IGF2, PGC-1α, LEP). Animal and observational studies suggest that maternal activity may influence offspring epigenetic pathways related to obesity and cardiometabolic conditions, although direct human evidence is limited. Conclusions: In addition to potentially changing gene–environment interactions throughout generations, prenatal PA is a low-cost, safe method of improving maternal and newborn health. Future RCTs ought to incorporate molecular endpoints to elucidate the epigenetic processes by which maternal exercise may provide long-term health benefits. Full article

Exercise plays a crucial role in promoting overall health by activating molecular pathways that contribute to the prevention and management of chronic diseases, slowing epigenetic aging, improving body composition, and reducing the risk of obesity. In skeletal muscle, these benefits are largely mediated by exercise-induced transcriptional and epigenetic responses. Recent advances in epigenetics have intensified interest in understanding how physical activity influences long-term health and body composition at the molecular level. Epigenetic modifications, which regulate gene expression without altering the DNA sequence, are key mechanisms in this process. Emerging research has provided deeper insights into the processes such as DNA methylation, histone modification, and non-coding RNAs, and their connection to exercise. While numerous studies have demonstrated the influence of exercise on the epigenome, fewer have directly examined how these molecular changes relate to alterations in fat mass, lean body mass, and other components of body composition. This comprehensive review synthesizes the current evidence on the interplay between exercise, epigenetic regulation, and body composition, with a focus on adolescents and adults. We highlight key genes involved in metabolism, fat storage, muscle development, and epigenetic aging, and explore how their regulation may contribute to individual variability in exercise response. Understanding these molecular pathways may provide valuable insights for optimizing exercise interventions aimed at improving health outcomes across the lifespan. Full article

Background: Posttraumatic growth (PTG) refers to positive psychological change following trauma. While its psychological aspects are well-documented, the biological mechanisms remain unclear. Epigenetic changes, such as DNA methylation (DNAm), may offer insight into PTG’s neurobiological basis. Aims: This study aimed to identify epigenetic markers associated with PTG using an epigenome-wide association study (EWAS), the first of its kind in a trauma-exposed population. Methods: A longitudinal EWAS design was used to assess DNAm before and after trauma exposure in first-year paramedicine students (n = 39). Genome-wide methylation data were analyzed for associations with PTG, applying epigenome-wide and gene-wise statistical thresholds. Pathway enrichment analysis was also conducted. Results: The study identified two CpGs (cg09559117 and cg05351447) within the PCDHA1/PCDHA2 and PDZD genes significantly associated with PTG at the epigenome-wide threshold (p < 9.42 × 10^–8); these were replicated in an independent sample. DNAm in 5 CpGs across known PTSD candidate genes ANK3, DICER1, SKA2, IL12B and TPH1 were significantly associated with PTG after gene-wise Bonferroni correction. Pathway analysis revealed that PTG-associated genes were overrepresented in the Adenosine triphosphate Binding Cassette (ABC) transporters pathway (p = 2.72 × 10⁻⁴). Conclusions: These results identify genes for PTG, improving our understanding of the neurobiological underpinnings of PTG. Full article

The genetic material in living systems is mainly stored in DNA molecules, which in turn play a dominant biological role in relation to the coding and transfer of genetic information, the biosynthesis of proteins and RNA and the packaging and regulation of DNA expression and accessibility. These features, strictly dictated by the three-dimensional structure of DNA, are governed by non-covalent chemical interactions that drive the folding process of these biological macromolecules. The Main Mechanical Forces (MMFs) approach is a recently formulated calculation method, based on the accurate prediction of structural features of biomolecules through an in-depth assessment of the interplay between specific non-covalent chemical interactions and related mechanical forces developed during the folding process. By adopting the MMFs method in the context of nucleic acids, we report here the results obtained in terms of predicting three-dimensional DNA oligomer tertiary structures. To this end, we have developed tailored nucleic acid-specific equations, enabling to predict the torsion angles (with a relevant level of agreement with experimental values) of the phosphate-sugar backbone of the three model molecules A-, B- and Z- DNA used in this study. To increase the validity of this methodology, we have conducted RMSD measurements, indicating that there is a weak but rather acceptable match between the calculated vs. predicted A-DNA structure, whereas the prediction of the BII-DNA and Z-DNA tertiary structures was fully correct. Full article

Aging of the central nervous system (CNS) involves widespread transcriptional and structural remodeling, prominently marked by synaptic loss, impaired neurogenesis, and glial dysfunction. While age-related gene expression changes have been documented for decades, recent genome-wide next-generation sequencing studies emphasize the importance of epigenetic mechanisms—such as DNA methylation and histone modification—in shaping these profiles. Notably, these modifications are potentially reversible, making them promising targets for therapeutic intervention. However, the mechanisms by which age-associated factors, such as inflammation and oxidative stress, orchestrate these epigenetic alterations across distinct CNS cell types remain poorly understood. In this review, we propose a framework for understanding how aging and neuroinflammation are regulated by epigenetic mechanisms, contributing to brain dysfunction and disease vulnerability. Full article

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Cancer-associated fibroblasts (CAFs) are a key constituent of the tumor microenvironment. CAFs may affect the development of tumor cells. The critical role of CAFs in the tumor microenvironment is linked to their epigenetic modifications, as a stable yet reversible regulation of cellular phenotypes. Current evidence indicates that their formation and function are closely linked to epigenetic mechanisms. Existing research indicates that the epigenetic alteration abnormalities are triggered by metabolic cues and stabilize the acquired phenotype of CAFs. This process is associated with transcriptional changes and patient outcomes in various tumors, providing a biological rationale and translational potential for reprogramming CAFs. Understanding of epigenetic modifications in CAFs remain insufficient, while DNA methylation in CAFs can alter CAF states through multiple pathways and thereby influence tumor progression. It is necessary to investigate the unique, identifiable epigenetic signatures of CAF. As an epigenetic reader couple histone acetylation to high-output oncogenic transcription; meanwhile, noncoding RNAs modulate CAF formation and therapeutic responses via bidirectional crosstalk between tumor cells and stroma. The interactions between different epigenetic modifications and their underlying regulatory logic may play a crucial role in developing new therapeutic strategies. This review focuses on the roles of DNA methylation, histone acetylation, and enhancer reprogramming in CAFs. Full article

Extracellular vesicles (EVs) secreted by glioblastoma multiforme and other types of cancer cells are key factors contributing to the aggressiveness of the disease and its resistance to therapy. Chloroquine (CHQ), a lysosomal inhibitor, has shown potential as an enhancer of temozolomide (TMZ) cytotoxicity against glioblastoma cells. Since both CHQ and TMZ are known to modulate EV secretion, we sought to investigate their potential interplay in this process. Simultaneous treatment of TMZ-sensitive (U87-MG) and TMZ-resistant (U138-MG) glioblastoma cells with TMZ and CHQ led to a synergistic upregulation of EV secretion. Although CHQ did not enhance the TMZ cytotoxicity in U87-MG cells, it synergized with the latter to upregulate the release of extracellular nucleic acids implicating activation of unconventional secretory pathways. Synergistic upregulation of the autophagy markers LC3B-II and p62 by CHQ and TMZ in both cells and EVs indicates that secretory autophagy is likely involved in the observed unconventional secretion. Moreover, a significant enrichment of caveolin-1 in small EVs highlights their potential role in modulating tumor aggressiveness. The synergy in EV upregulation was not confined to the specific biological activity of TMZ and CHQ; similar effects were observed upon co-treatments with CHQ and etoposide (a topoisomerase inhibitor) and TMZ and Bafilomycin A1 (another lysosomal inhibitor). Heightened EV release was also observed in THP-1 monocytes and macrophages treated with Bafilomycin and TMZ, highlighting a broader, cell-type-independent mechanism. These findings indicate that combined DNA damage and lysosomal inhibition synergistically stimulate secretory autophagy and EV release, potentially impacting the tumor microenvironment and driving disease progression. Full article

The Mongolian wild ass (Equus hemionus hemionus) is a flagship species of the desert-steppe ecosystem in Asia, and understanding its strategies for coping with cold environments is vital for both revealing its survival mechanisms and informing conservation efforts. In this study, we employed metagenomic sequencing to characterize the composition and functional potential of the gut microbiota, and applied DNA metabarcoding of the chloroplast trnL (UAA) g–h fragment to analyze dietary composition, aiming to reveal seasonal variations and the interplay between dietary plant composition and gut microbial communities. In the cold season, Bacteroidota and Euryarchaeota were significantly enriched, suggesting enhanced fiber degradation and energy extraction from low-quality forage. Moreover, genera such as Bacteroides and Alistipes were also significantly enriched and associated with short-chain fatty acid (SCFA) metabolism, bile acid tolerance, and immune modulation. In the cold season, higher Simpson index values and tighter principal coordinates analysis (PCoA) clustering indicated a more diverse and stable microbiota under harsh environmental conditions, which may represent an important microecological strategy for the host to cope with extreme environments. Functional predictions based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) further indicated upregulation of metabolic and signaling pathways, including ABC transporters, two-component systems, and quorum sensing, suggesting multi-level microbial responses to low temperatures and nutritional stress. trnL-based plant composition analysis indicated seasonal shifts, with Tamaricaceae detected more in the warm season and Poaceae, Chenopodiaceae, and Amaryllidaceae detected more in the cold season. Correlation analyses revealed that dominant microbial phyla were associated with the degradation of fiber, polysaccharides, and plant secondary metabolites, which may help maintain host energy and metabolic homeostasis. Despite the limited sample size and cross-sectional design, our findings highlight that gut microbial composition and structure may be important for host adaptation to cold environments and may also serve as a useful reference for future studies on the adaptive mechanisms and conservation strategies of endangered herbivores, including the Mongolian wild ass. Full article

Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16^INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions. Full article

Bacillus subtilis DinG/XPD-like paralogues, DinG and YpvA, have been implicated in overcoming replication stress. DinG possesses a DEDD exonuclease and DNA helicase domains, whereas YpvA lacks the DEDD exonuclease domain. We report that DinG·Mg²⁺ (hereafter referred to as DinG) degrades linear single-stranded (lss) DNA with 3′→5′ polarity and binds lssDNA with higher affinity than its exonuclease-deficient mutant DinG D10A E12A. DinG’s ssDNA-dependent ATPase activity neither stimulates nor inhibits DNA degradation. When bound to the 3′-end of forked DNA, DinG destabilises and degrades the substrate; however, in the presence of ATP, DinG dissociates before reaching the duplex junction. DinG degrades the RNA strand within RNA–DNA hybrids but does not cleave lssRNA unless complexed with Mn²⁺. DinG removes genomic R-loops, as RnhC and PcrA do. DinG physically interacts with RecA and PolA and functions in the same pathway as translesion synthesis (TLS) DNA polymerases (DNAPs) to respond to both spontaneous and methyl methanesulphonate (MMS)-induced mutagenesis. DinG-mGold forms spontaneous foci at or near replication forks, which become enriched following MMS or rifampicin treatment. We propose that DinG contributes to mitigating replication stress by degrading R-loop barriers and facilitating TLS, potentially via RecA-linked mechanisms. Full article

The present study aimed to identify genes encoding enzymes involved in the biotransformation of monoterpenoid (–)-isopulegol by Rhodococcus rhodochrous IEGM 1362. This strain is able to transform (–)-isopulegol with formation of two novel metabolites with promising antitumor and analeptic activities. Cell fractions of rhodococci and specific inhibitor of cytochrome P450-dependent oxygenase activity were used to establish the localization and type of biotransformation enzymes. The expression of nine CYP450 genes selected by bioinformatics analysis was analyzed by quantitative real-time PCR (qRT-PCR). Selection of optimal reference genes for normalization of qRT-PCR results was performed using BestKeeper, Normfinder, geNorm, Delta CT, and RefFinder algorithms. As a result of these studies, the role of CYP450 enzyme complexes in the biotransformation of (–)-isopulegol was confirmed, and their cytoplasmic localization was established. The genes encoding DNA gyrase subunit B (gyrB) and protein translocase subunit A (secA) were selected as the most stable reference genes. The induced expression of the gene encoding CYP450 hydroxylase in the presence of (–)-isopulegol was determined. The obtained data allow us to identify the specific CYP450 enzyme involved in (–)-isopulegol biotransformation by R. rhodochrous IEGM 1362 and lay the foundation for further studies of molecular and genetic mechanisms of monoterpenoid biotransformation. Full article

Pediatric tumors such as neuroblastoma are characterized by a genome-wide ‘transcriptional burden’, surmising the involvement of multiple alterations of gene expression. Search for master regulators of transcription whose inactivation is lethal for tumor cells identified the non-POU domain-containing octamer-binding protein (NONO), a member of the Drosophila Behavior/Human Splicing family known for the ability to form complexes with macromolecules. NONO emerges as an essential mechanism in normal neurogenesis as well as in tumor biology. In particular, NONO interactions with RNAs, largely with long non-coding MYCN transcripts, have been attributed to the aggressiveness of neuroblastoma. Broadening its significance beyond MYCN regulation, NONO guards a subset of transcription factors that comprise a core regulatory circuit, a self-sustained loop that maintains transcription. As a component of protein–protein complexes, NONO has been implicated in the control of cell cycle progression, double-strand DNA repair, and, generally, in cell survival. Altogether, the pro-oncogenic roles of NONO justify the need for its inactivation as a therapeutic strategy. However, considering NONO as a therapeutic target, its druggability is a challenge. Recent advances in the inactivation of NONO and downstream signaling with small molecular weight compounds make promising the development of pharmacological antagonists of NONO pathway(s) for neuroblastoma treatment. Full article