Search Results (5,139)

IBD pathogenesis is underpinned by an imbalance between excess inflammation caused by effector T-cells and inadequate suppression by regulatory T-cells (Tregs). Interleukin-37 (IL-37) is a potent, anti-inflammatory cytokine that signals via its receptors IL-1R5 and IL-1R8. Hence, augmenting anti-inflammatory mechanisms that drive IL-37 expression is a strategy to control IBD-associated inflammation. However, the role of IL-37 and its receptors in T-cells remains incompletely understood. Here, we investigated T-cell expression profiles of IL-37 and its receptors to understand the drivers of dysregulated T-cell responses in IBD and develop novel, more effective therapies. T-cell subsets from healthy control (HC), Crohn’s disease (CD) and ulcerative colitis (UC) peripheral blood mononuclear cells (PBMC) and lamina propria mononuclear cells (LPMC) were assessed for expression of IL-37 and its receptors by flow cytometry. CD3+IL-1R8+ T-cell transcriptomes underwent RNA sequencing. The phenotype and suppressive capacity of Tregs supplemented with IL-37 was assessed in vitro. Our results indicate that IL-37 and its receptors were differentially expressed among PBMC and LPMC T-cell subsets in IBD patients compared to HC. Transcription signatures unique to IBD were revealed, particularly histone and mitochondrial pathways. Remarkably, culturing Tregs with IL-37 preserved FOXP3 expression and suppressiveness at a level comparable to treatment with the well-established Treg stabilizing agent rapamycin. Altogether, our study identified differences in T-cells expressing IL-37 and its receptors that are indicative of T-cell dysfunction in IBD. These findings highlight a novel and promising avenue for restoring immune homeostasis in IBD by targeting and boosting the IL-37 signalling pathway. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental competence contribute to infertility. The disease is driven by a multifactorial interplay of somatic mutations, epigenetic remodeling, immune dysregulation, and aberrant steroid signaling, which together create a pro-inflammatory, oxidative, and fibrotic microenvironment. Elevated cytokines, reactive oxygen species, and disrupted granulosa-cell function within the follicular niche impair meiotic progression, cytoplasmic maturation, and mitochondrial integrity, potentially accelerating oocyte aging and diminishing reproductive longevity. Epigenetic and post-transcriptional disturbances—including altered DNA methylation, histone modifications, and RNA-splicing defects—further reinforce estrogen dominance, progesterone resistance, and impaired decidualization, with downstream consequences for ovarian–endometrial communication. Although morphological abnormalities have been documented in oocytes from women with endometriosis, clinical outcomes remain heterogeneous, highlighting the need for integrative models that connect molecular alterations to functional reproductive endpoints. A deeper understanding of these mechanisms is essential for identifying biomarkers of oocyte competence and modifiable strategies—ranging from nutritional optimization to reduction of environmental risk factors—in clinical care to safeguard the reproductive potential of women with endometriosis. Full article

MicroRNA (miRNA) is a type of small non-coding RNA that influences various biological processes by targeting gene expression. However, the roles of microRNA in mediating ruminant mammary cell proliferation and survival remain poorly understood. This study aimed to elucidate how miR-215-5p regulates cell cycle and apoptosis-related genes in goat mammary epithelial cells (GMECs). The effects of miR-215-5p on cell cycle and apoptosis were assessed by flow cytometry. A combination of bioinformatics analysis was conducted to predict the target genes of miR-215-5p; this was followed by experimental validation using techniques such as luciferase reporter assays. The effects of CTCF, the targeting gene of miR-215-5p, on cell cycle and apoptosis were examined by qRT-PCR, Western blot and flow cytometry in GMECs. The study demonstrated that miR-215-5p induced cell-cycle arrest at the G0/G1 phase and promoted apoptosis in GMECs. Mechanistically, miR-215-5p downregulated CTCF expression by directly targeting its 3′-untranslated region (3′UTR). This miR-215-5p-mediated depletion of CTCF inhibits CDK2 and CDK6 activity, consequently downregulating genes involved in cell-cycle progression. Furthermore, the miR-215-5p/CTCF axis was found to promote apoptosis by downregulating the protein expression of Bcl-xL and upregulating the gene expression of Bax. In summary, miR-215-5p suppresses GMEC proliferation and survival through CTCF-dependent histone modifications. Full article

Herein, we report the mechanochemical synthesis of a novel hybrid molecule, N-(4-methoxyphenethyl)-2-propylpentanamide. This solvent-minimized synthesis aligns with the principles of Green Chemistry and exemplifies the emerging paradigm of medicinal mechanochemistry, offering an efficient, sustainable route to pharmaceutically relevant amides. The newly synthesized compound was fully characterized by melting point determination, ¹H and ¹³C NMR spectroscopy, infrared (IR) spectroscopy, and mass spectrometry. Full article

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005–May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21^CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1–dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers. Full article

Resistance to 5-fluorouracil (5-FU), a cornerstone chemotherapy for gastric cancer (GC), is a major clinical obstacle, often driven by the upregulation of its target enzyme, thymidylate synthase (TS). In this study, we investigated the potential of the pan-histone deacetylase inhibitor (HDACi) panobinostat to synergize with 5-FU. In GC cell lines, panobinostat treatment alone suppressed cell viability, clonogenicity, and migration, and this was associated with the induction of G1-phase cell cycle arrest and mitochondria-mediated apoptosis. Crucially, Panobinostat acted synergistically with 5-FU, leading to enhanced cytotoxicity. Mechanistically, 5-FU treatment alone induced a compensatory upregulation of TS protein, a known resistance mechanism. Panobinostat not only suppressed basal TS expression but, more importantly, abrogated this 5-FU-induced upregulation. Furthermore, panobinostat downregulated a network of oncogenes and cell cycle regulators, including c-Myc and key cyclins. These findings indicate that panobinostat can enhance 5-FU cytotoxicity by targeting TS expression and reprogramming oncogenic transcriptional networks, supporting its potential as a complementary strategy for overcoming fluoropyrimidine resistance in GC therapy. Full article

Sex steroid hormones play a pivotal role in maintaining systemic homeostasis throughout life. Their age-related decline is closely associated with the onset of frailty, including sarcopenia and dementia. Here, this article provides a narrative review of the existing literature about the multifaceted roles of sex steroid hormones, particularly estrogens and androgens, in aging and age-related diseases. Sex steroid action is mediated by nuclear receptors such as estrogen receptor alpha (ERα) and androgen receptor (AR). Transcriptional activation through these receptors is orchestrated by epigenetic mechanisms, including histone modifications and chromatin remodeling. Beyond their reproductive functions, sex hormones also influence systemic physiology, metabolism, immune responses, and neuroplasticity. Clinical studies on hormone-deprivation therapies for prostate and breast cancers, as well as animal models, have revealed the key contributions of AR and ER activity to muscle integrity, bone density, and cognitive function. The sexual dimorphism in cognitive decline, especially in postmenopausal women, suggests the therapeutic potential of hormone supplementation and receptor-targeted strategies. Thus, AR- and ER-associated genes are considered promising targets for preventing frailty, sarcopenia, osteoporosis, and dementia. This review summarizes the current knowledge on sex hormone signaling in aging, with an emphasis on translational implications and future research directions. Full article

Triplexes (TRX) are a class of flipons that can form due to the interaction of RNA with B-DNA. While many proteins have been proposed to bind triplexes, structural models of these interactions do not exist. Here, I present AlphaFold V3 (AF3) models that reveal interactions between the high-mobility group protein B1 (HMGB1), HNRNPU (SAF-A), TP53, ARGONAUTE (AGO), and REL domain proteins. The TRXs result from the sequence-specific docking of RNAs to DNA via Hoogsteen base pairing. The RNA and DNA strands in apolar TRX are oriented in the opposite 5′ to 3′ direction, while copolar TRX have RNA and DNA strands pointing in the same 5′ to 3′ direction. TRXs can incorporate different RNA classes, including long noncoding RNAs (lncRNAs), short RNAs, such as miRNAs, piRNAs, and tRNAs, nascent RNA fragments, and non-canonical base triplets. Many pathways regulated by TRX formation have evolved to constrain retroelements (EREs), which are both an existential threat to the host and a source of genotypic variation. TRXs help set the boundaries of active chromatin, repressing the expression of most EREs, while depending on other flipons to modulate cellular programs. The TRXs help nucleate folding of intrinsically disordered proteins. Full article

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, classically characterized by right ventricular outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Recent advances in molecular and genomic research indicate that TOF is part of a phenotypic continuum encompassing Trilogy, Tetralogy, and Pentalogy of Fallot, in which the variability of anatomical presentation reflects shared genetic and epigenetic mechanisms with highly variable penetrance and expressivity. Variants in NOTCH1, FLT4, KDR, GATA6, and TBX1 highlight key pathways in conotruncal development and endothelial–mesenchymal transition, yet these well-known genes explain only a fraction of the genetic landscape. Emerging studies have identified additional candidate genes and networks involved in cardiac morphogenesis, including transcriptional regulators, signaling mediators, chromatin-remodeling factors, and splicing-associated genes such as PUF60 and DVL3. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, further modulate phenotypic expressivity and contribute to variability along the Trilogy–Tetralogy–Pentalogy spectrum. This review integrates current genomic and clinical evidence to provide a comprehensive overview of the molecular architecture of Fallot-type conotruncal malformations, emphasizing the interplay between genetic and epigenetic mechanisms, genotype–phenotype correlations, and implications for diagnosis, risk stratification, counseling, and personalized management in the era of precision cardiology. Full article

Immune checkpoint proteins including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT regulate T-cell functions, which are essential for anti-tumor immunity. Over-expression of these immune checkpoint proteins leads to T-cell exhaustion and a significant impairment of anti-tumor immunity. Rejuvenation of effector T-cell function with immune checkpoint inhibitors (ICI) restores anti-tumor immunity, which translates into clinical efficacy in the frontline and salvage treatment of various hematological malignancies. Efficacy of ICIs is highest in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and NK/T-cell lymphomas, and modest in immune-privileged-site lymphomas and cutaneous T-cell lymphoma. However, in myeloid malignancies and multiple myeloma, the efficacy of ICIs remains doubtful. In addition to being used as single agents, ICIs have also been combined with other ICIs; as well as chemotherapy, antibody drug conjugates, and epigenetic agents (histone deacetylase inhibitors and hypomethylating agents). More innovative strategies include the use of ICIs in the context of allogeneic haematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. This review synthesizes current evidence for the use of ICI in different haematological malignancies, and highlights future directions toward biomarker-driven, rationally designed therapeutic combinations. Full article

Higher-order chromatin structures (HOCS) are fundamental to genome organization, gene regulation, and cellular homeostasis. This review examines the epigenetic mechanisms shaping HOCS, including DNA methylation, histone modifications, chromatin remodeling, and RNA-based regulatory processes. We also discuss the role of architectural proteins in maintaining chromatin topology while allowing dynamic changes to chromatin structure, thereby influencing gene expression. Growing evidence indicates that disruptions in HOCS contribute to a diverse array of human diseases, including cancer, aging-related disorders, and congenital abnormalities, primarily through aberrant gene regulation. We further discuss the concept of distinct genomic areas, in which specific chromatin regions orchestrate three-dimensional (3D) genome dynamics, positioning them as potential biomarkers and therapeutic targets. By emphasizing chromatin architecture on a global scale rather than at the level of individual genes, this review underscores its emerging relevance to precision medicine. Finally, we synthesize current technical advances, outline future directions for leveraging chromatin topology in disease diagnosis and treatment, and highlight key biological insights to reshape our understanding of genome function. Full article

Cancer is one of the leading causes of mortality worldwide, with breast and colon cancers being among the most common neoplasms in men and women, respectively. Despite significant advancements in treatment, there is a pressing need to enhance specificity and reduce systemic side effects. Importantly, a distinctive feature of cancer cells is their acidic extracellular environment, which profoundly influences cancer progression. In this study, we evaluated the anticancer activity of a pH-sensitive nanocomposite based on silver nanoparticles and pegylated carboxymethyl chitosan (AgNPs-CMC-PEG) in breast cancer (MCF-7) and colon cancer (HCT 116) cell lines. To achieve this, we synthesized and characterized the nanocomposite using UV-Vis spectroscopy, Dynamic Light Scattering (DLS), Fourier-Transform Infrared Spectroscopy (FT-IR), and Scanning Electron Microscopy (STEM-in-SEM). Furthermore, we assessed cytotoxic effects, apoptosis, and reactive oxygen species (ROS) generation using MTT, DAPI, and H2DCFDA assays. Additionally, we analyzed the expression of DNA methyltransferases (DNMT3a) and histone acetyltransferases (MYST4, GCN5) at the mRNA level using RT-qPCR, along with the acetylation and methylation of H3K9ac and H3K9me2 through Western blot analysis. The synthesized nanocomposite demonstrated an average hydrodynamic diameter of approximately 175.4 nm. In contrast, STEM-in-SEM analyses revealed well-dispersed nanoparticles with an average core size of about 14 nm. Additionally, Fourier-transform infrared (FTIR) spectroscopy verified the successful surface functionalization of the nanocomposite with polyethylene glycol (PEG), indicating effective conjugation and structural stability. The nanocomposite exhibited a pH and concentration dependent cytotoxic effect, with enhanced activity observed at an acidic pH 6.5 and at concentrations of 150 µg/ml, 75 µg/ml, and 37.5 µg/ml for both cell lines. Notably, the nanocomposite preferentially induced apoptosis accompanied by ROS generation. Moreover, expression analysis revealed a decrease in H3K9me2 and H3K9ac in both cell lines, with a more pronounced effect in MCF-7 at an acidic pH. Furthermore, the expression of DNMT3a at the mRNA level significantly decreased, particularly at acidic pH. Regarding histone acetyltransferases, GCN5 expression decreased in the HCT 116 line, while MYST4 expression increased in the MCF-7 line. These findings demonstrate that the AgNPs-CMC-PEG nanocomposite has therapeutic potential as a pH-responsive nanocomposite, capable of inducing significant cytotoxic effects and altering epigenetic markers, particularly under the acidic conditions of the tumor microenvironment. Overall, this study highlights the advantages of utilizing pH-sensitive materials in cancer therapy, paving the way for more effective and targeted treatment strategies. Full article

The study of Palaearctic enchytraeid taxonomic richness revealed the limitations of applying morphological identification methods to certain species of the genus Cognettia. The use of molecular approaches enabled the identification of individuals belonging to C. chlorophila among immature and fragmented enchytraeids that had initially been identified morphologically as C. sphagnetorum s.l. These findings substantially extend the known distribution range of C. chlorophila eastward. Reliable distribution data for C. chlorophila and C. sphagnetorum s.s., obtained through genetic analysis, complement existing evidence of their coexistence in shared habitats and highlight questions concerning their biotopic preferences. It is hypothesized that the relatively low level of genetic diversity in these species is associated with potential postglacial dispersal routes of C. sphagnetorum s.l. from Scandinavian refugia and with species-specific biological characteristics. Full article

Background: Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes due to its rapid growth, poor prognosis, and low response to chemotherapies owing to a lack of therapeutic targets and drug resistance. Histone deacetylases (HDACs) induce stromal changes that increase extracellular matrix density through the activity of cancer-associated fibroblasts (CAFs). HDACs are overexpressed in TNBC and have been linked to the activation and sustained activity of CAFs. Additionally, HDAC inhibitors decrease the fibroblastic activity. Objectives: We aimed to analyze the antifibrotic effect of the N-(2′-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), an inhibitor of the HDAC1, 6, and 8 (iHDAC) on TNBC. Methods: The TNBC (4T1) cell line was inoculated under the dorsal skin in mice to develop a TNBC tumor. CAF’s activation was determined by measuring collagen-1 and alpha-smooth muscle actin (α-SMA), as well as their association with the G-protein-coupled estrogenic receptor (GPER1) and HDAC1 expression. Results: Dose of 20 mg/kg of HO-AAVPA decreased tumor fibrosis by inducing decreased collagen-1 and alpha-smooth muscle actin (α-SMA) levels and increased GPER1 expression. Moreover, HO-AAVPA reduced the activation and activity of CAFs. Conclusion: Our results support the notion that HDAC1 inhibition may be a novel approach to sensitizing resistant tumor cells to chemotherapy and radiotherapy by increasing GPER1 expression, and thus the use of antiproliferative GPER1 agonists/antagonists, at least in the early stages, without causing significant changes in liver function or morphological alterations. Full article

Lactylation serves as a vital link between cellular metabolism and epigenetic regulation and plays a pivotal role in muscle biology. Muscle tissue is the primary site of lactate production; its unique metabolic environment confers dynamism, specificity and functional diversity for lactylation. Under physiological conditions, lactylation regulates myocyte energy metabolism, proliferation, differentiation, and exercise adaptation through a dynamic “writer–eraser–reader” mechanism. In pathological states, lactate imbalance directly contributes to the progression of various muscular disorders. For instance, diminished histone lactylation during muscle aging suppresses the expression of genes critical for DNA repair and protein homeostasis. Aberrant lactylation is involved in the development of insulin resistance and diabetic cardiomyopathy. Furthermore, lactylation exerts dual effects in cardiovascular diseases; it provides protection by enhancing the transcription of repair genes and simultaneously aggravates injury by promoting processes such as fibrosis and ferroptosis. Collectively, these findings underscore the importance of lactylation in muscular pathologies and provide a theoretical foundation for the development of therapies that target this modification process. As the regulatory mechanisms of lactylation have become clearer, precise interventions targeting specific modification sites are expected to open new therapeutic avenues for muscular diseases. Full article