Search Results (4,514)

There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma and whether these vesicles can be selectively targeted using a glycan-binding affinity resin. Large (100–500 nm) and small (40–200 nm) EVs were isolated from post-acute COVID-19 plasma and analyzed by nanoparticle flow cytometry to assess surface glycosylation. Small EV capture assays were performed using Galanthus nivalis agglutinin (GNA) affinity resin. Plasma miRNA profiles before and after GNA treatment were evaluated using NanoString nCounter analysis, and potential downstream pathway effects were computationally inferred using validated miRNA–mRNA interactions and PROGENy. Mannose-positive large EVs were significantly increased in Long COVID compared to recovered controls (p < 0.05). GNA-mediated small EV capture correlated with mannose-positive EV abundance (r = 0.341, p < 0.05), and seven miRNAs were significantly reduced following treatment. Computational pathway analysis suggested modulation of key signaling pathways, including JAK-STAT, Estrogen, VEGF, and PI3K. These findings suggest a glycan-associated EV signature in Long COVID and support further investigation of lectin-based capture as a potential strategy to target vesicle-associated molecular cargo. Full article

Background: Minimally invasive surgery (MIS) for hallux valgus (HAV) correction may benefit from using the medial eminence to enhance lateral capital fragment translation. This study investigates whether osteotomy placement through the medial eminence correlates with improved HAV and forefoot width (FW) correction. A retrospective analysis of 20 patients who underwent MIS bunion correction was performed. Pre- and postoperative radiographs were reviewed to assess hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle (DMAA), sesamoid position, osteotomy location, osteotomy angle, capital fragment shift, and forefoot width. Pearson correlation and multivariable linear regression were used to identify associations. Chart review was performed at the one-year mark for complications (recurrence, infection, non-union, hardware failure). Significant correlations were found between DMAA and HVA (r = 0.883, p < 0.001), DMAA and IMA (r = 0.573, p = 0.008), and HVA and capital fragment shift (r = 0.541, p = 0.014). Osteotomy location and angle were not significantly associated with correction. Multivariable analysis showed DMAA was independently associated with HVA correction (β = 0.679, p < 0.001), and both capital fragment shift and metatarsal head angulation were associated with FW narrowing. Additionally, no patients in this cohort experienced complications. Use of the medial eminence in MIS osteotomy was not associated with improved HAV or FW correction. Angular deformity parameters and lateral fragment shift were more predictive of radiographic outcomes. Full article

Cervical cancer is a malignant disease that affects women worldwide and is associated with both high incidence and a high mortality rate. miR-34 is a direct transcriptional-target of p53 and is downregulated in several types of cancers. 1,4-Naphthoquinones (NQs) have anticancer properties and have been used to modulate miR-34 expression. We tested (3-chloro-NQ-2-yl)-alanine (ANQCl), -methionine (MNQCl), -glycine (GNQCl), -phenylalanine (FNQCl), -asparagine (NNQCl), and (1,4-napthoquinon-2-yl)-asparagine (NNQ) in immortal and tumorigenic cells, both HPV-positive and -negative, simulating precancerous and cancerous status to observe the response of the p53-miR-34 system, migration and invasion. A dose–response was achieved to determine the IC50 of the compounds in SiHa, CaLo, C33-A and HaCaT cells. HaCaT cell migration inhibition was more potent than in SiHa, CaLo, and C33-A cells, while invasion hindrance was more evident in the tumorigenic SiHa, CaLo and C33-A. NNQCl, GNQCl, ANQCl and FNQCl compounds induced p53 overexpression in SiHa and CaLo cells. Compound ANQCl in SiHa and FNQCl in CaLo induced miR-34a overexpression, probably via p53. Migration and invasion of most compounds decreased independently of p53-miR-34. NQ-amino acids exert effect on cell proliferation, migration and invasion in cervical cancer cells, suggesting their potential use in the field of cancer treatment. Full article

Background: Human breast milk (HBM), as the initial food for humans, is quite essential for infant development and also for health throughout the lifespan. Exosomes are bioactive components in HBM, yet their nutritional role remains poorly recognized. Objectives: This study investigates how HBM exosomes change with lactation and their potential role in infant growth and development. Methods: HBM samples were obtained at 2 and 6 months postpartum from a well-established birth cohort. Purified exosomes were detected using transcriptomic, lipidomic, and proteomic approaches. Then, multi-omics data were analyzed to compare differentially expressed miRNAs, lipids, and proteins along with different lactation periods and their association with the infant growth process. Results: Compared with the 2-month postpartum group, the expression levels of miR-214-3p, miR-199a-5p, miR-126-3p, miR-127-5p, miR-144-3p, and miR-4787-5p were down-regulated in the 6-month postpartum group. In addition, 190 lipids and 269 proteins were up-regulated in the 6-month postpartum group, whereas 15 lipids and 244 proteins were down-regulated. Enrichment analysis revealed that the predicted target genes of differentially expressed miRNAs were primarily involved in cell communication and axon guidance. In parallel, the differentially expressed proteins were enriched in biosynthesis of unsaturated fatty acids and fatty acid metabolism pathway, implying a potential role in adipogenesis and neurodevelopment. Conclusions: This study reveals that the cargo contents of HBM exosomes change with the lactation period and may adapt to the needs of infant growth and development, particularly adipogenesis and neurodevelopment. HBM exosomes may play an important role in transferring genetic information from mothers to infants and be related to infants’ development. The underlying mechanisms warrant further investigation and validation. Full article

The multifaceted oncogenic role of teratocarcinoma-derived growth factor 1 (TDGF1) in colon cancer remains incompletely understood. Through integrative bioinformatic and functional analyses, we identified a novel competing endogenous RNA (ceRNA) axis wherein the long non-coding RNA OLMALINC directly sponges hsa-miR-3614-5p, leading to the derepression of TDGF1. This OLMALINC/miR-3614-5p/TDGF1 axis promoted colon cancer cell proliferation, migration, invasion, and anti-apoptosis in vitro, whereas TDGF1 knockdown significantly suppressed tumor growth in vivo. Mechanistically, TDGF1 co-activated oncogenic signaling via the Thr88-dependent Nodal/Smad2 cascade and the Glypican-1-mediated MAPK/AKT pathway. Beyond cell-autonomous effects, transcriptomic and single-cell analyses revealed that elevated TDGF1 correlates with an immunosuppressive microenvironment, characterized by reduced immune infiltration and altered LGALS9-CD44 malignant-T cell communication. Clinically, high TDGF1 expression in a tissue microarray cohort was significantly associated with advanced T stage, reduced expression of specific mismatch repair proteins (MLH1/PMS2), and poor overall survival. Collectively, this study delineates the OLMALINC/miR-3614-5p/TDGF1 regulatory circuit and establishes TDGF1 as a multifaceted driver of tumor progression, highlighting its potential as a prognostic biomarker and therapeutic target in colon cancer. Full article

People living with HIV (PLWHIV) have an increased risk of developing metabolic disorders, including type 2 diabetes (T2D), partly driven by chronic low-grade inflammation and immune dysregulation. This study evaluated the potential role of circulating miR-23a-3p as a possible early biomarker of prediabetes (preT2D) in PLWHIV. In this cross-sectional study, 80 adults were divided into five groups (n = 16 each): normoglycemic PLWHIV, PLWHIV with preT2D, PLWHIV with T2D, HIV-negative individuals with T2D, and controls. Clinical, anthropometric, biochemical, inflammatory, and insulin resistance (IR) markers were assessed, while plasma miR-23a-3p was quantified by digital PCR (dPCR). Bioinformatic network analysis was performed to identify potential molecular targets. PLWHIV with T2D showed the most unfavorable metabolic and inflammatory profile, including higher HbA1c, triglycerides, IL-6, TNF-α, hs-CRP, and GDF-15. In contrast, PLWHIV with preT2D exhibited significant overexpression of miR-23a-3p, whereas lower levels were observed in normoglycemic PLWHIV. miR-23a-3p correlated positively with IL-6 and GDF-15. ROC analyses showed good discriminative performance of miR-23a-3p for preT2D in PLWHIV (AUC = 0.80), and logistic regression confirmed its association with preT2D. In silico network analysis suggested potential inflammatory and metabolic targets of miR-23a-3p; however, these findings require experimental validation. These findings suggest that miR-23a-3p may represent a potential early biomarker of preT2D and immunometabolic dysfunction in PLWHIV. Full article

p53, miR-34a, and SIRT-1 are involved in cellular stress responses, senescence, and inflammation—processes central to the pathophysiology of atrial fibrillation (AF). In this study, circulating TP53 and SIRT-1 serum miR-34a expression were determined in patients with and without AF, in order to assess their associations with AF. We also checked their potential diagnostic utility as systemic biomarkers associated with AF. The study included 189 adults, 94 AF+, 95 AF−. Clinical, anthropometric, and biochemical data were collected. Whole-blood TP53 and SIRT-1 mRNA expression and serum miR-34a expression were quantified by RT-qPCR. ROC analysis and Youden-derived odds ratios assessed exploratory diagnostic performance. AF patients had significantly higher expression of TP53 (0.0352 vs. 0.0253; p < 0.001) and miR-34a (0.0215 vs. 0.0099; p < 0.001), but significantly lower expression of SIRT-1 (0.0079 vs. 0.0145; p < 0.001). The level of SIRT-1 expression showed the highest discriminatory performance (exploratory AUC = 0.6987; p < 0.0001). TP53 expression levels exceeding 0.0295 were associated with nearly threefold higher odds of AF (OR = 2.92, 95% CI: 1.61–5.28, p = 0.0006), whereas the expression levels of SIRT-1 and miR-34a were not significantly associated with AF in cut-off analysis. In the AF group, a positive correlation was found between the expression of TP53 and SIRT-1 (Rho = 0.3609, p < 0.001); however, it was not consistent with a canonical model of miR-34a-mediated SIRT-1 suppression. In turn, the expression of miR-34a correlated positively with age and C-reactive protein level and negatively with estimated glomerular filtration rate (eGFR). The obtained results suggest that AF is associated with altered expression of circulating TP53, SIRT-1, and miR-34a. However, due to the fact that the expression levels were measured in peripheral compartments, and not in atrial tissue, the obtained results should not be interpreted as direct evidence of AF-related atrial remodeling. For these reasons, further investigations involving simultaneous measurements of the TP53/miR-34a/SIRT-1 regulatory axis, both in the circulating compartment and atrial tissue, should be performed. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is strongly associated with atrial structural remodeling driven by activated cardiac fibroblasts. Autophagy has been implicated in AF-related atrial remodeling; however, the non-coding RNA mechanisms that govern autophagic activation in atrial fibroblasts under rapid electrical stress remain poorly understood. Methods: Human cardiac fibroblasts from adult atria (HCF-aa) were subjected to rapid electrical stimulation (RES) at 0.5 V/cm and 10 Hz. Expression levels of exosomal metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), cytoplasmic miR-204-5p, and microtubule-associated protein light chain 3B (LC3B) were measured using quantitative real-time PCR and Western blot analyses. Luciferase reporter assays were performed to confirm direct molecular interactions. The functional roles of MALAT1 siRNA, miR-204-5p mimics/antagomirs, rapamycin, and 3-methyladenine (3-MA) on LC3B expression and autophagic activation were assessed by Western blot and immunofluorescence confocal microscopy for LC3B puncta formation. Results: RES significantly induced exosomal MALAT1 expression in a voltage- and time-dependent manner, peaking at 2 h post-stimulation, while cytoplasmic MALAT1 levels remained unchanged. Cytoplasmic miR-204-5p exhibited an initial transient rise followed by a significant decline at 2 h, inversely correlating with peak MALAT1 levels. LC3B mRNA and protein expression subsequently increased, peaking at 6 and 16 h, respectively. Luciferase reporter assays confirmed that miR-204-5p directly binds both the MALAT1 transcript and the 3′-UTR of LC3B mRNA. MALAT1 knockdown augmented miR-204-5p levels and suppressed LC3B expression, while miR-204-5p overexpression attenuated RES-induced LC3B upregulation and LC3B puncta accumulation. Conversely, miR-204-5p inhibition further enhanced autophagic activation, as evidenced by increased LC3B puncta density. Conclusions: In HCF-aa subjected to RES, MALAT1 functions intracellularly as a competing endogenous RNA to putatively sequester miR-204-5p, thereby de-repressing LC3B expression and promoting autophagic activation. Concurrent exosomal secretion of MALAT1 may additionally serve as a paracrine signal to neighboring cells, though this requires future conditioned-media transfer experiments to confirm. Full article

Type 2 diabetes mellitus (T2DM) is a major driver of chronic kidney disease and cardiovascular morbidity worldwide. Extracellular vesicles (EVs), particularly exosomes, carry microRNAs (miRNAs) that reflect the pathophysiological state of their parent cells and represent promising non-invasive biomarkers. This review comprehensively examines the diagnostic and mechanistic roles of EV-derived miRNAs in diabetic nephropathy (DN) and cardiovascular diseases (CVDs) associated with T2DM. A PRISMA-guided literature search of PubMed, Scopus, Web of Science, and Embase identified 847 articles published between January 2020 and June 2026, of which 156 studies met the inclusion criteria. Several urinary exosomal miRNAs demonstrated significant diagnostic performance for DN, including miR-4534 (AUC = 0.786), miR-136-5p (sensitivity 72.2%, specificity 78.4%), and miR-142-3p. A meta-analysis of circulating miRNAs in diabetic kidney disease reported a pooled AUC of 0.79. In the cardiovascular setting, exosomal miR-155-5p (AUC = 0.901), miR-15a-3p (AUC = 0.874), and a four-miRNA panel (miR-433-3p/let-7b/miR-30-5p/miR-122-5p; AUC = 0.833) demonstrated strong diagnostic performance for ischemic heart disease and carotid atherosclerosis in T2DM. Mechanistically, key EV-associated miRNAs, including miR-21, miR-192, and the anti-fibrotic miR-29 family, participate in fibrosis, inflammation, oxidative stress, endothelial dysfunction, and cardiac remodeling pathways. EV-derived miRNAs therefore represent highly promising non-invasive biomarkers for the early diagnosis and monitoring of diabetic renal and cardiovascular complications. However, clinical translation requires standardized EV isolation and miRNA detection protocols, together with validation in large multicenter prospective cohorts. This review highlights the considerable diagnostic and translational potential of EV-derived miRNAs for precision medicine and liquid biopsy applications in T2DM complications. Full article

Objective: To evaluate the efficacy of NADPH oxidase 4 and miR-146a-5p in current treatment planning for ascending aortic aneurysms, independent of aortic diameter, and to develop protocols that will ensure the treatment of ascending aortic aneurysms, which pose a risk for aortic dissection, without complications. Methods: Patients who met the inclusion criteria and underwent surgery at Dr. Siyami Ersek Chest, Heart, and Vascular Surgery Training and Research Hospital for ascending aortic aneurysms and coronary artery disease between 2023 and 2024 were included in the study. This study was designed as a prospective study. Demographic, biochemical, radiological, and echocardiographic data were collected, and NOX4 mRNA and miR-146a-5p expressions were examined and compared in tissue samples. Results: The study was conducted on a total of 50 patients, with 25 patients in the aneurysm group and 25 patients in the control group. miR-146a-5p expression levels were found to be significantly decreased in the patient group compared to the control group (p = 0.001). When NOX4 mRNA expression levels were examined, no significant difference was found between the control and aneurysm groups. No correlation was found between NOX4 mRNA and miR-146a-5p levels (p = 0.764). When the relationship between ascending aorta diameter and both NOX4 mRNA and miR-146a-5p was examined, it was found that miR-146a-5p expression was negatively correlated with ascending aorta diameter (p = 0.036) and did not show a significant correlation with NOX4 mRNA levels (p = 0.318). A similar correlation was also found with ascending aorta length. The correlation of NOX4 mRNA and miR-146a-5p expression levels with age, gender, and ejection fraction was investigated separately. No significant correlation was found for all three variables. The optimum cut-off value to be used to separate the patient group from the control group using miR-146a-5p expression levels, as well as the sensitivity and specificity of miR-146a-5p expression levels when this cut-off value was used, was calculated using an ROC curve. Specificity for miR-146a-5p expression was found to be 88%, and sensitivity was found to be 66%. Conclusions: The study found promising results indicating that NOX4, shown to be a determinant of vascular oxidative stress, is not involved in the development of ascending aortic aneurysms; however, miR-146a-5p, which functions in the regulation of many inflammatory responses, including the regulation of NOX4 expression, may help prevent the development of ascending aortic aneurysms. Further studies aimed at elucidating the genetic and biochemical processes involved in aneurysm development suggest that miR-146a-5p could be a therapeutic target for preventing aneurysms. Full article

The continuous expression of HPV oncogenes E6 and E7 contributes to the maintenance of the cervical cancer (CC) phenotype by altering gene expression programs involved in tumor progression and aggressiveness. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression in CC, including miR-218-5p, which has been described as a tumor suppressor. In this study, we investigated the impact of HPV-16 oncoproteins E6 and E7 on the regulation of miR-218-5p expression and its target gene PIK3C2A, as well as their functional and clinical relevance in CC. We found that miR-218-5p expression is significantly reduced in HPV-16-positive CC cell lines, while PIK3C2A expression is increased. Silencing the expression of the E6/E7 oncogenes in Ca Ski cells restored miR-218-5p levels and reduced PIK3C2A expression. Conversely, overexpression of the E6 and E7 oncogenes in C-33 A cells significantly decreased miR-218-5p expression and increased PIK3C2A expression. Functional assays performed on C-33 A cells expressing E6 and E7 revealed that ectopic expression of miR-218-5p suppresses cell proliferation and migration, effects that are partially mediated by PIK3C2A. Bioinformatics analysis showed that low miR-218-5p expression and high PIK3C2A expression are associated with reduced overall survival in patients with cervical cancer. Our findings identify the miR-218-5p/PIK3C2A axis as a novel regulatory pathway modulated by HPV-16 oncoproteins E6 and E7 that contributes to CC cell proliferation and migration. Furthermore, miR-218-5p and PIK3C2A emerge as potential prognostic biomarkers in CC. Full article

Background: Acquired tolerance to temozolomide (TMZ) remains one of the main obstacles to enduring therapeutic success in glioblastoma (GBM). While tumor-derived extracellular vesicles are known to orchestrate therapy evasion by horizontally transferring molecules across the tumor microenvironment, the precise regulatory roles of specific exosomal circular RNAs (circRNAs) in establishing this refractory state require further elucidation. Methods: The expression of circ_0050688 in TMZ-resistant GBM clinical tissues and cell lines was evaluated. Exosomes derived from resistant cells were isolated and confirmed via transmission electron microscopy (TEM) and marker analysis. PKH67 fluorescent tracking was utilized to visually demonstrate exosome internalization by sensitive recipient cells. Biological functions, including the expression of the multidrug resistance protein P-glycoprotein (P-gp) and the proliferation marker Ki-67, were evaluated. The competing endogenous RNA mechanism was validated using RNA FISH, dual-luciferase reporters, and functional rescue experiments. In vivo efficacy was determined using subcutaneous xenograft mouse models. Results: Clinical and in vitro analyses revealed that circ_0050688 is upregulated in TMZ-refractory GBM, predicting adverse patient survival. Through PKH67-based tracing, we confirmed that resistant cells actively secrete circ_0050688-enriched exosomes, which are subsequently engulfed by drug-sensitive bystander cells. This vesicular transfer directly instigates a chemoresistant and highly proliferative phenotype, marked by elevated P-gp and Ki-67 levels. At the molecular level, circ_0050688 operates as a molecular decoy for miR-508-5p, thereby preventing the suppression of its downstream target, MDM2. Functionally, circ_0050688 depletion eradicated these aggressive traits and restored TMZ vulnerability across both cellular and murine xenograft models. Furthermore, rescue assays confirmed that this circ_0050688-driven chemoresistance is fundamentally dependent on the miR-508-5p/MDM2 signaling axis. Conclusions: Current data uncover an intercellular signaling network driven by vesicular circ_0050688, which functions as a mobile oncogene to reshape the TMZ-refractory microenvironment. Targeting this exosomal circ_0050688/miR-508-5p/MDM2 network to suppress P-gp and Ki-67 expression represents a highly promising therapeutic strategy for refractory GBM. Full article

Background/Objectives: Sarcopenic obesity (SO) represents a severe clinical phenotype characterized by the coexistence of reduced skeletal muscle mass and excess adiposity, and is associated with insulin resistance, dyslipidemia, and systemic inflammation. However, easily accessible biomarkers that capture early molecular changes underlying SO are lacking. The aim of this pilot study was to compare circulating microRNA (miRNA) profiles in patients with severe obesity and a sarcopenic obesity phenotype with those of healthy controls and to identify candidate miRNAs suitable for further validation. To the best of our knowledge, this represents one of the first broad screening studies of circulating miRNAs specifically conducted in patients with severe obesity and DXA-confirmed sarcopenic obesity. Methods: In this single-center pilot study conducted in the Czech Republic, fasting plasma samples from 12 adult participants (6 with severe obesity and sarcopenic obesity phenotype, body mass index > 45 kg/m²; 6 healthy controls; age 18–65 years) were analyzed using an RT-qPCR panel comprising 384 assays, including technical controls and 352 target circulating miRNAs. Following predefined quality control and filtering criteria, 224 miRNAs were retained for the final statistical analysis. Six patients with severe obesity were classified according to the ESPEN/EASO 2022 consensus criteria for sarcopenic obesity, while EWGSOP2-based assessment was used for functional evaluation of sarcopenia. Differential expression was evaluated using fold change and exploratory statistical testing. Results: We identified a set of miRNAs with significantly altered expression in SO, including increased muscle-enriched miR-486-5p and hepatocyte-enriched miR-122-5p, and decreased vascular miR-145-5p, as well as several additional miRNAs related to myogenesis, lipid metabolism and inflammatory signaling. miR-451a, a recognized marker of hemolysis, was also increased but was interpreted with caution. Conclusions: Despite the limited sample size, the results of this study suggest that specific circulating miRNAs may reflect key pathophysiological pathways in SO and could serve as promising biomarkers to support risk stratification and monitoring in larger, hypothesis-driven studies. Full article