Search Results (251)

Pediatric asthma is a multifactorial and heterogeneous disease determined by the dynamic interplay of genetic susceptibility, environmental exposures, and immune dysregulation. Recent advances have highlighted the pivotal role of epigenetic mechanisms, in particular, DNA methylation, histone modifications, and non-coding RNAs, in the regulation of inflammatory pathways contributing to asthma phenotypes and endotypes. This review examines the role of respiratory viruses such as respiratory syncytial virus (RSV), rhinovirus (RV), and other bacterial and fungal infections that are mediators of infection-induced epithelial inflammation that drive epithelial homeostatic imbalance and induce persistent epigenetic alterations. These alterations lead to immune dysregulation, remodeling of the airways, and resistance to corticosteroids. A focused analysis of T2-high and T2-low asthma endotypes highlights unique epigenetic landscapes directing cytokines and cellular recruitment and thereby supports phenotype-specific aspects of disease pathogenesis. Additionally, this review also considers the role of miRNAs in the control of post-transcriptional networks that are pivotal in asthma exacerbation and the severity of the disease. We discuss novel and emerging epigenetic therapies, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, miRNA-based treatments, and immunomodulatory probiotics, that are in preclinical or early clinical development and may support precision medicine in asthma. Collectively, the current findings highlight the translational relevance of including pathogen-related biomarkers and epigenomic data for stratifying pediatric asthma patients and for the personalization of therapeutic regimens. Epigenetic dysregulation has emerged as a novel and potentially transformative approach for mitigating chronic inflammation and long-term morbidity in children with asthma. Full article

Cancer remains a major cause of mortality worldwide, driven by complex molecular mechanisms that promote metastasis and resistance to therapy. Receptor for hyaluronan-mediated motility (RHAMM) has emerged as a multifunctional regulator in cancer, contributing to cell motility, invasion, proliferation, and fibrosis. In addition to being regulated by non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, RHAMM serves as a promising therapeutic target. Recent developments in RHAMM-targeted strategies include function-blocking peptides (e.g., NPI-110, NPI-106, and P15-1), hyaluronan (HA) oligomers, and anti-RHAMM antibodies, all shown to modulate tumor stroma and suppress tumor invasiveness. Importantly, RHAMM-targeted peptide vaccines, such as the RHAMM-R3 epitope, have demonstrated immunogenicity and anti-leukemia efficacy in both pre-clinical and early clinical studies, suggesting their potential to elicit specific CD8⁺ T-cell responses and enhance graft-versus-leukemia effects. This review summarizes the intricate roles of RHAMM in cancer progression, its modulation by ncRNAs, and the translational promise of novel RHAMM-targeting approaches, providing insights into future directions for precision cancer therapy. Full article

Resistance exercise can enhance or preserve muscle mass and/or strength. Modifying factors are secreted following resistance exercise. Biomarkers like cytokines and extracellular vesicles, especially small extracellular vesicles, are released into the circulation and play an important role in cell-to-cell and inter-tissue communications. There is increasing evidence that physical activity itself promotes the release of extracellular vesicles into the bloodstream, suggesting the importance of vesicles in mediating systemic adaptations following exercise. Extracellular vesicles contain proteins, nucleic acids like miRNAs, and other molecules targeting different cell types and tissues of distant organs. Therefore, extracellular vesicles and encapsulated miRNAs are fine tuners of protein synthesis and are important in the adaptation after resistance training. However, there is a lack of strong data supporting the precise mechanisms of these processes. In this literature review, we collected publications related to miRNA and extracellular vesicle profile changes induced by resistance exercise. To the best of our knowledge, the changes in human extracellular vesicle and microRNA profiles following resistance exercise have not been reviewed yet. We aimed to assess the shortcomings and difficulties characterizing this research area, to summarize the existing results to date, and to propose possible solutions that could help standardize the implementation of future investigations. Full article

Exogenous RNA application, also known as spray-induced gene silencing (SIGS), is a new approach in plant biotechnology that utilizes RNA interference (RNAi) to modify plant traits. This technique involves applying RNA solutions of double-stranded RNA (dsRNA), hairpin RNA (hpRNA), small interfering RNA (siRNA), or microRNA (miRNA) directly onto plant surfaces. This triggers RNAi-mediated silencing of specific genes within the plant or invading pathogens. While extensively studied for enhancing resistance to pathogens, the application of exogenous RNA to regulate plant endogenous genes remains less explored, creating a rich area for further research. This review summarizes and analyzes the studies reporting on the exogenously induced silencing of plant endogenes and transgenes using various RNA types. We also discuss the RNA production and delivery approaches, analyze the uptake and transport of exogenous RNAs, and the mechanism of action. The analysis revealed that SIGS/exoRNAi affects the expression of plant genes, which may contribute to crop improvement and plant gene functional studies. Full article

Small-for-gestational-age (SGA) infants who experience a marked postnatal catch-up, mainly in weight, are at risk for developing metabolic disorders; however, the underlying mechanisms are imprecise. Exosomes and their cargo (including miRNAs) mediate intercellular communication and may contribute to altered crosstalk among tissues. We assessed the miRNA profile in cord blood-derived exosomes from 10 appropriate-for-gestational-age (AGA) and 10 SGA infants by small RNA sequencing; differentially expressed miRNAs with a fold change ≥2.4 were validated by RT-qPCR in 40 AGA and 35 SGA infants and correlated with anthropometric, body composition (DXA) and endocrine–metabolic parameters at 4 and 12 mo. miR-1-3p, miR-133a-3p and miR-206 were down-regulated, whereas miR-372-3p, miR-519d-3p and miR-1299 were up-regulated in SGA infants. The target genes of these miRNAs related to insulin, RAP1, TGF beta and neurotrophin signaling. Receiver operating characteristic analysis disclosed that these miRNAs predicted with accuracy the 0–12 mo changes in body mass index and in total and abdominal fat and lean mass. In conclusion, the exosomal miRNA profile at birth differs between AGA and SGA infants and associates with measures of catch-up growth, insulin resistance and body composition through late infancy. Further follow-up of this population will disclose whether these associations persist into childhood, puberty and adolescence. Full article

Ferroptosis is a type of cell death executed by phospholipid peroxidation in an iron-dependent manner. Ferroptosis plays a central role in inhibiting tumor growth, enhancing the immune response, and is now considered a strategy to combat resistance to anticancer therapies. The oncosuppressor p53 is one of the major regulators of ferroptosis and can either promote or inhibit ferroptosis, depending on the context and/or extent of the damage. p53 governs the transcription of many genes that modulate cell susceptibility to ferroptosis, using this manner of death to fulfill its role as tumor suppressor. The diverse functions of p53 are related to non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), since they can either regulate p53 or be regulated by p53. Therefore, an intricate metabolic network between ncRNAs and p53 ensures the correct response. In this review, we will discuss recent studies on the molecular interplay between p53-mediated ferroptosis and ncRNAs and how this contributes directly or indirectly to the outcome of ferroptosis. Full article

Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified miR-185 as a predictive biomarker where reduced expression in CD34⁺ treatment-naïve CML cells was associated with TKI resistance. We have also identified PAK6 as a target gene of miR-185 that was upregulated in CD34⁺ TKI-nonresponder cells. However, its role in regulating TKI resistance remains largely unknown. In this study, we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34⁺ stem/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy. Interestingly, the genetic and pharmacological suppression of PAK6 significantly reduced proliferation and increased apoptosis in TKI-resistant cells. Cell survivability was further diminished when IM was combined with PAK6 knockdown. Importantly, PAK6 inhibition in TKI-resistant cells induced cell cycle arrest in the G2-M phase and cellular senescence, accompanied by increased levels of DNA damage-associated senescence markers. Mechanically, we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus, PAK6 plays a critical role in determining alternative cell fates in leukemic cells, and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells. Full article

The mammalian immune system, including key components such as toll-like receptors (TLRs), lymphocytes, and cytokines, plays a vital role in defending against diseases. In dogs, genetic polymorphisms and epigenetic regulation of immune-related genes contribute to breed-specific differences in susceptibility or resistance to infectious, autoimmune, and inflammatory diseases. Cytokines, essential for immune cell differentiation and activation, exhibit variable expression among breeds due to genetic factors like single-nucleotide polymorphisms (SNPs) and miRNA regulation. This variability influences immune responses not only to infections but also to chronic inflammatory conditions and cancer, providing insights for improved diagnosis, treatment, and breeding. Selective breeding has further shaped diverse immune phenotypes across breeds, especially through genetic variations in the major histocompatibility complex (MHC) region, which affect vulnerability to immune-mediated and immunodeficiency disorders. Recent studies emphasize the role of specific miRNAs in modulating immune responses during parasitic and viral infections, opening new avenues for precision veterinary medicine and immunotherapy. This review highlights the genetic and epigenetic regulation of immune genes in dogs and explores their potential applications in advancing veterinary diagnostics, therapeutics, and breeding strategies to enhance canine health. Full article

The R2R3-MYB transcription factor GAMYB plays crucial roles in plant growth and development, but the biological functions of SlGAMYB1 in tomato remain poorly understood. Here, we investigated the roles of SlGAMYB1 by overexpressing a miR159-resistant version (35S:SlGAMYB1^m) in tomato. Transgenic plants exhibited a dwarf phenotype with reduced internode elongation, which was associated with decreased bioactive gibberellin (GA) levels due to transcriptional repression of SlGA3ox1 and activation of SlGA2ox1/2/4/5. Additionally, 35S:SlGAMYB1^m altered leaf morphology by inhibiting cell proliferation through downregulation of cell cycle genes, resulting in larger but fewer epidermal cells. Intriguingly, 35S:SlGAMYB1^m plants displayed increased floral organ number, a process likely mediated by the upregulation of SlWUS rather than GA signaling. These findings demonstrate that SlGAMYB1 regulates diverse aspects of tomato development through both GA-dependent and independent pathways, providing new insights into the functional diversification of GAMYB genes and potential strategies for genetic improvement of tomato architecture and yield. Full article

Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs, are pivotal regulators of gene expression and contributors to disease pathogenesis. This study elucidated the biogenesis, functional significance, and regulatory network of circRNA_4083, a novel exon-derived circRNA originating from exons 22 and 23 of the MSH3 gene in chicken. Through comprehensive molecular characterization—including Sanger sequencing, RNase R digestion assays, and subcellular localization—we confirmed the robust stability and predominant cytoplasmic localization of circRNA_4083 across diverse chicken tissues. Mechanistic investigations revealed that reverse complementary sequences within flanking intronic regions are indispensable for its circularization, as demonstrated by overexpression plasmids (#1–#4) in DF-1 cells. Functional analyses demonstrated that circRNA_4083 significantly inhibited cell apoptosis and increased cellular viability. Integrative bioinformatics approaches predicted a competing endogenous RNA (ceRNA) network comprising 12 miRNAs and 2132 target genes (FDR < 0.05), with significant enrichment in pathways critical to genomic stability, including non-homologous end joining (NHEJ) and ubiquitin-mediated proteolysis. These findings position circRNA_4083 as a key modulator of cellular viability and genomic integrity, with potential implications for avian leukosis virus-J (ALV-J) pathogenesis and resistance breeding strategies. This work advances our understanding of circRNA-driven regulatory mechanisms in avian species and underscores their relevance in poultry health. Full article

Lung cancer is one of the deadliest forms of cancer. Its prognosis becomes even worse when it co-occurs with other diseases, such as chronic obstructive pulmonary disease (COPD). Both illnesses have numerous shared risk factors, including the use of tobacco smoke, and have similar underlying mechanisms like long-term inflammation. There are some other less studied but equally important molecules, like small extracellular vesicles (sEVs), that have been shown to mediate effective communication at the cellular level and may affect the progression of a disease or cause resistance to therapies. In sEVs from lung cancer tumors, there are onco-proteins (e.g., tumor initiator EGFR mutations, onco-miR, miR-21), while in sEVs from patients with COPD, there are pro-inflammatory cytokines like IL-6 and TNF-α that enhance airway inflammation. These potential biomarkers of sEVs from chronic lung disease have great value in defense against emerging health problems; however, limitations in sample extraction and analysis are obstacles that hinder clinical enhanced applicability. This review focuses on sEV-derived biomarkers in lung cancer and COPD for diagnostic, prognostic, and therapeutic monitoring purposes. To make these molecules more useful in real-life therapy and determine their signature’s role, further investigation with a high-scale study is necessary. Full article

Background/Objectives: Natural killer (NK) cells play a crucial role in immune surveillance against melanoma, yet they frequently exhibit dysfunction in the tumor microenvironment. This study aims to establish an NK cell activation-related prognostic signature and identify potential druggable targets to overcome NK cell dysfunction. Methods: A prognostic signature was developed using the TCGA-SKCM cohort and validated across independent datasets. NK cell activation and cytotoxicity were evaluated in melanoma-NK-92MI co-culture systems via flow cytometry. Mechanistic studies employed Western blotting, co-immunoprecipitation, ELISA, and qRT-PCR. Single-cell RNA-seq data were used to analyze cell–cell communication. Results: A four-gene NK cell activation signature was identified and validated for prognostic significance across five independent melanoma datasets. Among the identified genes, cyclin B1 (CCNB1) emerged as a novel therapeutic target for overcoming NK cell resistance. In vivo, pharmacological inhibition of the CCNB1/Cyclin-dependent kinase 1 (CDK1) complex with RO-3306 significantly suppressed melanoma growth by enhancing NK cell infiltration and IFN-γ production. In vitro, CCNB1 knockdown in melanoma cells augmented NK-92MI activation, as evidenced by increased expression of CD69, CD107a, IFN-γ, and NKG2D, thereby improving NK cell-mediated cytotoxicity. Mechanistically, in melanoma cells, the CCNB1/CDK1 complex phosphorylates STAT3, activating the IL-6/STAT3 positive feedback loop, which upregulates PD-L1 and enables resistance to NK cell-mediated cytotoxicity. Beyond its role in immune evasion, CCNB1 also promoted melanoma invasiveness by inducing epithelial–mesenchymal transition (EMT) through the TGF-β-SMAD2/3 signaling. Conclusions: This study establishes CCNB1/CDK1 as a novel immunotherapeutic target and uncovers a new role for CDK1 inhibitors in enhancing NK cell function and suppressing melanoma progression. Full article

Resistance to tyrosine kinase inhibitors (TKIs, e.g., sorafenib and lenvatinib) presents a significant hurdle for hepatocellular carcinoma (HCC) treatment, underscoring the need to decipher the underlying mechanisms for improved therapeutic strategies. MicroRNAs (miRNAs) have emerged as critical modulators in HCC progression and TKI resistance. In this study, we report a positive correlation between the expression levels of a tumor suppressor miRNA, miR-142-3p, and increased sensitivity to sorafenib and lenvatinib, supported by clinical data from the BIOSTORM HCC cohort. Overexpression of miR-142-3p in TKI-resistant HCC cells significantly inhibited proliferation and colony formation, induced apoptosis, increased cell cycle arrest at the G2 phase, and reduced migration and invasion by reversing epithelial–mesenchymal transition. Notably, combining miR-142-3p with lenvatinib synergistically inhibited growth in both inherent and acquired TKI-resistant HCC cells by modulating critical signaling pathways, including STAT3, PI3K/AKT, MAPK, YAP1, and by impeding autophagic influx. RNA-sequencing of a TKI-resistant HCC cell line ± miR-142-3p overexpression identified YES1 and TWF1 as direct downstream target genes of miR-142-3p, both of which are key genes associated with drug resistance in HCC. Small interfering RNA (siRNA)-mediated knockdown of these genes mirrored the antitumor effects of miR-142-3p and enhanced TKI sensitivity, with YES1 knockdown decreasing YAP1 phosphorylation, and TWF1 knockdown inhibiting autophagy. Collectively, these findings indicate that restoring miR-142-3p expression or targeting its downstream effectors YES1 and TWF1 offers a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. Full article

Understanding the resistance mechanisms of plants against pests contributes to the sustainable deployment of plant resistance in Integrated Pest Management (IPM) programmes. The Mi-1 gene in tomato is the only one described with the capacity to provide resistance to different types of harmful organisms such as plant parasitic nematodes and pest insects, including the whitefly Bemisia tabaci MED (Mediterranean species). In this work, gene expression in the interaction of B. tabaci with susceptible tomato plants lacking the Mi-1 gene (cv. Moneymaker, compatible interaction), and with resistant plants carrying the Mi-1 gene (cv. Motelle, incompatible interaction) was studied using the oligonucleotide microarray technique. Both interactions were studied 2 and 12 days post infestation (dpi) of plants with adult insects. At 2 dpi, 159 overexpressed and 189 repressed transcripts were detected in the incompatible interaction, while these figures were 32 and 47 in the compatible one. Transcriptional reprogramming was more intense at 12 dpi but, as at 2 dpi, the number of transcripts overexpressed and repressed was higher in the incompatible (595 and 437, respectively) than in the compatible (71 and 52, respectively) interaction. According to the Mapman classification, these transcripts corresponded mainly to genes in the protein and RNA categories, some of which are involved in the defence response (signalling, respiratory burst, regulation of transcription, PRs, HSPs, cell wall or hormone signalling). These results provide a wealth of information about possible genes related to the resistance provided by the Mi-1 gene to B. tabaci, and whose role deserves further investigation. Full article

Background: The EGF domain-specific O-GlcNAc transferase (EOGT), a migrasome marker, plays emerging roles in cancer biology through O-GlcNAcylation modifications, yet its pan-cancer functions and therapeutic implications remain underexplored. This study aimed to systematically characterize EOGT’s oncogenic mechanisms across malignancies, with particular focus on hepatocellular carcinoma (HCC) progression and sorafenib resistance. Methods: Multi-omics analysis integrated TCGA/GTEx data from 33 cancer types with spatial/single-cell transcriptomics and 10 HCC cohorts. Functional validation employed Huh7 cell models with EOGT modulation, RNA sequencing, and ceRNA network construction. Drug sensitivity analysis leveraged GDSC/CTRP/PRISM databases, while immune microenvironment assessment utilized ESTIMATE/TIMER algorithms. Results: EOGT showed cancer-specific dysregulation, marked by significant upregulation in HCC correlating with advanced stages and poor survival. Pan-cancer analysis revealed EOGT’s association with genomic instability, tumor stemness, and angiogenesis. Experimental validation demonstrated EOGT’s promotion of HCC proliferation and migration. A novel exosomal circ_0058189/miR-130a-3p/EOGT axis was identified, showing that circ_0058189 was upregulated in HCC tissues, plasma samples and exosomes of sorafenib-resistant cells. Conclusion: This study establishes EOGT as a pan-cancer angiogenesis biomarker, while elucidating its role in therapeutic resistance via exosomal circRNA-mediated regulation, providing mechanistic insights for targeted intervention strategies. Full article