Search Results (4,153)

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

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransferase deficiency with two clinical variants (fish-eye Disease and the p.Leu364Pro mutation), lead to NS through mechanisms involving podocyte and lipid metabolism dysfunction. Congenital disorders of glycosylation and Nail–Patella Syndrome emphasize the role of deranged protein processing and transcriptional regulation in glomerular injury. The link of NS with type 1 diabetes, though rare, suggests an etiology on the basis of common HLA loci and immune dysregulation. Histopathological analysis, particularly electron microscopy, shows mainly podocyte damage, mesangial sclerosis, and alteration of the basement membrane, which aids in differentiating rare forms. Prompt recognition of these novel etiologies by genetic analysis, renal biopsy, and an interdisciplinary panel is essential to avoid delays in diagnosis and tailored treatment. Full article

Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus. This review synthesizes the current evidence on glial cell aging across the CNS, emphasizing how cerebellar circuits follow distinct trajectories in terms of cellular remodeling, transcriptional reprogramming, and structural vulnerability. Recent findings highlight that cerebellar astrocytes and microglia exhibit specific signatures related to aging compared to their cortical counterpart, including moderate reactivity, selective immune response, and spatial reorganization. Cerebellar white matter (WM) undergoes structural alteration, suggesting that oligodendroglial cells may undergo region-specific alterations, particularly within WM tracts, although these aspects remain underexplored. Despite the presence of glial remodeling, the CBL maintains a notable degree of structural and functional integrity during aging. This resilience may be the result of the CBL’s ability to maintain synaptic adaptability and homeostatic balance, supported by its highly organized and compartmentalized architecture. A better understanding of the dynamics of cerebellar glial cells in aging may provide new insight into the mechanisms of brain maintenance and identify potential biomarkers for healthy brain aging. Full article

Background: Congenital diarrhea is persistent diarrhea that manifests during the neonatal period. Mutations in DGAT1, which is crucial for triglyceride synthesis and lipid absorption in the small intestine, are causal factors for congenital diarrhea. In this study, we aimed to determine the value of tissue RNA sequencing (RNA-seq) for assisting with the clinical diagnosis of some genetic variants of uncertain significance. Methods: We clinically evaluated a patient with watery diarrhea, vomiting, severe malnutrition, and total parenteral nutrition dependence. Possible pathogenic variants were detected using whole-exome sequencing (WES). RNA-seq was utilized to explore the transcriptional alterations in DGAT1 variants identified by WES with unknown clinical significance, according to the American College of Medical Genetics guidelines. Systemic examinations, including endoscopic and histopathological examinations of the intestinal mucosa, were conducted to rule out other potential diagnoses. Results: We successfully diagnosed a patient with congenital diarrhea and protein-losing enteropathy caused by a DGAT1 mutation and reviewed the literature of 19 cases of children with DGAT defects. The missense mutation c.620A>G, p.Lys207Arg located in exon 15, and the intronic mutation c.1249-6T>G in DGAT1 were identified by WES. RNA-seq revealed two aberrant splicing events in the DGAT1 gene of the patient’s small intestinal tissue. Both variants lead to loss-of-function consequences and are classified as pathogenic variants of congenital diarrhea. Conclusions: Rare DGAT1 variants were identified as pathogenic evidence of congenital diarrhea, and the detection of tissue-specific mRNA splicing and transcriptional effects can provide auxiliary evidence. Full article

Bladder cancer pathogenesis is closely linked to epigenetic alterations, particularly DNA methylation and demethylation processes. Environmental carcinogens and persistent inflammatory stimuli—such as recurrent urinary tract infections—can induce aberrant DNA methylation, altering gene expression profiles and contributing to malignant transformation. This review synthesizes current evidence on the role of DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and the hypermethylation of key tumour suppressor genes, including A2BP1, NPTX2, SOX11, PENK, NKX6-2, DBC1, MYO3A, and CA10, in bladder cancer. It also evaluates the therapeutic application of DNA-demethylating agents such as 5-azacytidine and highlights the impact of chronic inflammation on epigenetic regulation. Promoter hypermethylation of tumour suppressor genes leads to transcriptional silencing and unchecked cell proliferation. Urine-based DNA methylation assays provide a sensitive and specific method for non-invasive early detection, with single-target approaches offering high diagnostic precision. Animal models are increasingly employed to validate these findings, allowing the study of methylation dynamics and gene–environment interactions in vivo. DNA methylation represents a key epigenetic mechanism in bladder cancer, with significant diagnostic, prognostic, and therapeutic implications. Integration of human and experimental data supports the use of methylation-based biomarkers for early detection and targeted treatment, paving the way for personalized approaches in bladder cancer management. Full article

Background/Objective: Exertional rhabdomyolysis (ER) is primarily driven by mechanical stress on muscles during strenuous or unaccustomed exercise, often exacerbated by environmental factors like heat and dehydration. While the general cellular pathway involving energy depletion and calcium overload is understood in horse ER models, the underlying mechanisms specific to the ER are not universally known within humans. This study aimed to evaluate whether patients with ER exhibited transcriptional signatures that were significantly different from those of healthy individuals. Methods: This study utilized RNA sequencing on skeletal muscle samples from 19 human patients with ER history, collected at a minimum of six months after the most recent ER event, and eight healthy controls to investigate the transcriptomic landscape of ER. To identify any alterations in biological processes between the case and control groups, functional pathway analyses were conducted. Results: Functional pathway enrichment analyses of differentially expressed genes revealed strong suppression of mitochondrial function. This suppression included the “aerobic electron transport chain” and “oxidative phosphorylation” pathways, indicating impaired energy production. Conversely, there was an upregulation of genes associated with adhesion and extracellular matrix-related pathways, indicating active restoration of muscle function in ER cases. Conclusions: The study demonstrated that muscle tissue exhibited signs of suppressed mitochondrial function and increased extracellular matrix development. Both of these facilitate muscle recovery within several months after an ER episode. Full article

Root-knot nematode (Meloidogyne incognita) is a globally destructive plant-parasitic nematode that severely impedes the sustainable production of horticultural crops. Metabolic reprogramming in plant roots represents the host response to M. incognita infection that can also be exploited by the nematode to facilitate its parasitism. In this study, untargeted metabolomics was employed to analyze metabolic changes in cucumber roots following nematode inoculation, with the goal of identifying differentially accumulated metabolites that may influence M. incognita behavior. Metabolomic analysis revealed that M. incognita significantly altered the cucumber root metabolome, triggering an accumulation of lipids and organic acids and enriching biotic stress-related pathways such as alkaloid biosynthesis and linoleic acid metabolism. Among differentially accumulated metabolites, myristic acid and hexadecanal were selected for further study due to their potential roles in nematode inhibition. In vitro assays demonstrated that both metabolites suppressed egg hatching and reduced infectivity of M. incognita, while pot experiments indicated a correlation between their application and reduced root gall formation. Chemotaxis assays further revealed that both metabolites exerted repellent effects on the chemotactic migration of M. incognita J2 and suppressed the transcriptional expression of two motility-and feeding-related neuropeptides, Mi-flp-1 and Mi-flp-18. In conclusion, this study demonstrates the significant potential of differentially accumulated metabolites induced by M. incognita infection for nematode disease control, achieved by interfering with nematode chemotaxis and subsequent infection. This work also provides deeper insights into the metabolomic mechanisms underlying the cucumber-M. incognita interaction. Full article

MicroRNA-211 (miR-211) is a versatile regulatory molecule that plays critical roles in cellular homeostasis and disease progression through the post-transcriptional regulation of gene expression. This review comprehensively examines miR-211’s multifaceted functions across various biological systems, highlighting its context-dependent activity as both a tumor suppressor and oncogene. In physiological contexts, miR-211 regulates cell cycle progression, metabolism, and differentiation through the modulation of key signaling pathways, including TGF-β/SMAD and PI3K/AKT. miR-211 participates in retinal development, bone physiology, and protection against renal ischemia–reperfusion injury. In pathological conditions, miR-211 expression is altered in various diseases, particularly cancer, where it may be a useful diagnostic and prognostic biomarker. Its stability in serum and differential expression in various cancer types make it a promising candidate for non-invasive diagnostics. The review also explores miR-211’s therapeutic potential, discussing both challenges and opportunities in developing miRNA-based treatments. Understanding miR-211’s complex regulatory interactions and context-dependent functions is crucial for advancing its clinical applications for diagnosis, prognosis, and targeted therapy in multiple diseases. Full article

The rabies virus (RABV) phosphoprotein (P protein) has multiple functions, including acting as the essential non-catalytic cofactor of the viral polymerase (L protein) for genome replication and transcription; the principal viral antagonist of the interferon (IFN)-mediated innate immune response; and the chaperone for the viral nucleoprotein (N protein). Although P protein is known to undergo phosphorylation by cellular kinases, the location and functions of the phosphorylation sites remains poorly defined. Here, we report the identification by mass-spectrometry (MS) of residues of P protein that are modified by phosphorylation in mammalian cells, including several novel sites. Analysis of P protein with phospho-mimetic and phospho-inhibitory mutations of three novel residues/clusters that were commonly identified by MS (Ser48, Ser183/187, Ser217/219/220) indicate that phosphorylation at each of these sites does not have a major influence on nuclear trafficking or antagonistic functions toward IFN signalling pathways. However, phosphorylation of Ser48 in the N-terminus of P protein impaired function in transcription/replication and in the formation of replication structures that contain complexes of P and N proteins, suggestive of altered interactions of these proteins. The crystal structure of P protein containing the S48E phospho-mimetic mutation indicates that Ser48 phosphorylation facilitates the binding of residues 41–52 of P protein into the RNA-binding groove of non-RNA-bound N protein (N⁰), primarily through the formation of a salt bridge with Arg434 of N protein. These data indicate that Ser48 modification regulates the cycling of P-N⁰ chaperone complexes that deliver N protein to RNA to enable transcription/replication, such that enhanced interaction due to S48E phospho-mimetic mutation reduces N protein delivery to the RNA, inhibiting subsequent transcription/replication processes. These data are, to our knowledge, the first to implicate phosphorylation of RABV P protein in conserved replication functions of the P gene. Full article

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

Radish (Raphanus sativus), a commonly grown root vegetable prized for its nutrition and culinary use, is particularly vulnerable to lead (Pb) stress, which mainly results in Pb accumulation in the roots. However, the molecular mechanisms underlying Pb accumulation in radish remain largely unknown. In this study, we investigated the role of BASIC PENTACYSTEINE (BPC) genes in radish’s response to Pb stress. Phylogenetic analysis revealed that radish contains 10 BPC genes, which are distinctly clustered in Cluster III. Expression analysis revealed that, except for RsBPC2, RsBPC4, and RsBPC7, the expression of most RsBPC genes was significantly altered under Pb stress. Notably, the expression of RsBPC5 gradually decreased with prolonged Pb exposure. Subcellular localization analysis confirmed that RsBPC5 is localized in the nucleus and acts as a transcriptional repressor. Functional assays demonstrated that transient overexpression of RsBPC5 enhanced the tolerance of radish plants to Pb stress via reducing Pb accumulation and activating the antioxidant defense system. Collectively, our findings suggest that RsBPC5 plays a key role in radish’s response to Pb stress, potentially improving Pb tolerance by modulating Pb uptake and strengthening antioxidant defense mechanisms. Full article

Zearalenone (ZEN), a mycotoxin commonly found in cereal crops and foods, induces testicular damage and disrupts gut microbial composition. Curcumin (CUR), a bioactive compound derived from turmeric, is known to enhance intestinal microbial balance and exhibit anti-inflammatory properties. This study aimed to investigate the mechanism by which CUR alleviates ZEN-induced reductions in sperm quality through the modulation of the gut microbiota–testis axis. Forty-eight 6-week-old Balb/c male mice were randomly assigned to four treatment groups: control (CON), CUR (200 mg/kg body weight CUR), ZEN (40 mg/kg body weight ZEN), and ZEN + CUR (200 mg/kg CUR + 40 mg/kg ZEN). The degree of sperm damage was quantified by assessing both the survival rate and the morphological integrity of the spermatozoa. CUR was found to mitigate ZEN-induced reductions in the testosterone levels, testicular structural damage, and disrupted spermatogenesis. Exposure to ZEN markedly perturbed the gut microbiota, characterized by increased relative abundances of Prevotella and Bacteroides and a concomitant reduction in Lactobacillus. These alterations were accompanied by pronounced activation of the IL-17A–TNF-α signaling axis, as demonstrated by elevated transcriptional and translational expression of pathway-associated genes and proteins. Co-administration of CUR effectively reinstated microbial homeostasis and mitigated ZEN-induced IL-17A pathway activation. In conclusion, ZEN induces testicular inflammation and reduced sperm quality by lowering testosterone levels and disrupting gut microbial balance, which drives the testicular IL-17A signaling pathway. CUR alleviates ZEN-induced testicular inflammation and sperm quality reduction by restoring beneficial gut microbes and testosterone levels. Full article

The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal cancer (CC) remain unclear. In this study, we show that CBX genes are significantly dysregulated in CC tissues and cell models compared to normal colorectal tissue. Among them, CBX4 and CBX8 emerged as the most upregulated isoforms in tumors. Functional analyses revealed that CBX4 overexpression enhances CC cell proliferation, while its silencing reduces tumor growth. Similarly, pharmacological inhibition of CBX4 in patient-derived tumor organoids led to decreased proliferation, supporting its pro-tumorigenic role. Immunofluorescence analysis further revealed alterations in NF-κB signaling upon CBX4 inhibition, along with reduced mRNA levels of pathway components including NF-κB, TNF, IL-1, and c-Myc. These findings point to a potential interplay between CBX4 and inflammation-related pathways in CC. Overall, our study highlights the oncogenic role of CBX4 in colorectal cancer and supports its potential as a novel therapeutic target and early biomarker for disease progression. Full article

Grapholita molesta is a globally significant fruit pest. Females achieve maximal reproductive output through efficient sperm utilization following a single copulation. Post-mating maturation of eupyrene sperm is a critical step in reproductive success. Here, we report that a male accessory gland-derived serine protease (named GmAGSP1) is essential for this process. GmAGSP1 was only distantly related to other identified sperm-activating SPs, and its transcript was highly expressed in the AG at 48 h after emergence. RNAi-mediated knockdown of GmAGSP1 in males did not affect courtship rate, copulation duration, or mating frequency, whereas male fertility decreased significantly. Mating with GmAGSP1-knockdown males markedly impaired eupyrene sperm maturation in the spermatophores, with phenotypes including failure of eupyrene sperm bundles to dissociate normally and marked reduction in viability of the dissociated eupyrene sperm. Finally, untargeted metabolomic analysis preliminarily demonstrated marked alterations in multiple metabolic pathways within the spermatophore following mating with GmAGSP1-knockdown males. This study advances our understanding of the regulatory mechanism of “sperm activation in the spermatophore’s metabolic microenvironment mediated by male AG-derived SP” while providing critical insights for the development of novel genetic control strategies targeting G. molesta. Full article

Background/Objectives: Chronic inflammation and Western-style diets elevate colorectal cancer (CRC) risk, particularly in individuals with colitis, a feature of inflammatory bowel disease (IBD). Diets rich in polyphenol-containing functional foods, such as cocoa, may reduce gut inflammation and modulate the gut microbiome. This study investigated the impact of cocoa polyphenol (CP) supplementation on inflammation and microbiome composition in mice with colitis, fed either a healthy or Western diet, before, during, and after the onset of disease. We hypothesized that CPs would attenuate inflammation and promote distinct shifts in the microbiome, especially in the context of a Western diet. Methods: A 2 × 2 factorial design tested the effects of the basal diet (AIN93G vs. total Western diet [TWD]) and CP supplementation (2.6% w/w CocoaVia™ Cardio Health Powder). Inflammation was induced using the AOM/DSS model of colitis. Results: CP supplementation did not reduce the severity of colitis, as measured by disease activity index or histopathology. CPs did not alter gene expression in healthy tissue or suppress the colitis-associated pro-inflammatory transcriptional profile in either of the two diet groups. However, fecal microbiome composition shifted significantly with CPs before colitis induction, with persistent effects on several rare taxa during colitis and recovery. Conclusions: CP supplementation did not mitigate inflammation or mucosal injury at the tissue level, nor did it affect the expression of immune-related genes. While CPs altered microbiome composition, most notably in healthy mice before colitis, these shifts did not correspond to changes in inflammatory signaling. Basal diet remained the primary determinant of inflammation, mucosal damage, and colitis severity in this model. Full article