Search Results (4,451)

Prenatal exposure to ionizing radiation is a known risk factor for neurodevelopmental deficits; however, the molecular mechanisms linking chronic embryonic insult to abnormal brain development remain poorly understood. This study investigated the long-term consequences of chronic prenatal gamma irradiation throughout gestation in C57BL/6 mice. Behavioural analysis of adult offspring revealed a specific increase in depression-like behaviours, with no significant alterations in anxiety or general exploratory activity. Immunohistochemical assessment demonstrated a significant reduction in adult hippocampal neurogenesis, marked by decreased doublecortin (DCX)-positive newborn neurons in the subgranular zone and fewer NeuN-positive mature neurons in the dentate gyrus hilus. Integrated RNA-seq, qPCR, and Western blot analyses implicated the upregulation of the Mef2c/Egr1 signalling pathway in this neurogenic deficit. Furthermore, miRNA sequencing identified a pronounced decrease in miR-1843a-3p, which was subsequently validated to directly target Mef2c. Collectively, these findings suggest that prenatal gamma irradiation disrupts neurogenic processes and adult brain function, leading to specific behavioral abnormalities. This long-term impairment is associated with, and may be at least partially mediated by, dysregulation of the miR-1843a-3p/Mef2c/Egr1 pathway. Full article

Background: Postmenopausal osteoporosis is associated with cellular senescence and the accumulation of the senescence-associated secretory phenotype (SASP). While mesenchymal stem cell (MSC)-derived exosomes show tissue repair potential, the efficacy and mechanisms of MSC-derived apoptotic vesicles (apoVs) remain unclear. This study compared MSC-apoVs and exosomes in postmenopausal osteoporosis and investigated the underlying epigenetic mechanisms. Methods: Therapeutic efficacy was evaluated in an ovariectomized (OVX) mouse model and senescent human bone marrow mesenchymal stem cells (hBMMSCs). Small RNA sequencing identified differential microRNA (miRNA) cargos between vesicle types. SASP-related cytokine expression (IL-6, TNF-α, MCP-1) and pathway activation were assessed by RT-qPCR, ELISA, and Western blot. Results: MSC-apoV treatment attenuated bone loss in OVX mice and reduced SASP expression in senescent hBMMSCs to a greater extent than exosomes. Small RNA sequencing revealed that apoVs were enriched with a specific miRNA cluster, including hsa-let-7b-5p, hsa-miR-92a-3p, and hsa-miR-98-5p. Bioinformatic analyses identified BRAF and CRKL as downstream targets of this miRNA cluster, supported by reduced protein levels after apoV treatment. Subsequent molecular assays showed that apoV treatment inhibited the phosphorylation of both the MAPK (p38 and JNK) and NF-κB (p65) signaling pathways, which correlated with reduced local inflammation in the bone marrow microenvironment and preserved osteogenic differentiation capacity. Conclusions: MSC-apoVs attenuate postmenopausal osteoporosis more effectively than exosomes. This enhanced efficacy is associated with the delivery of an enriched miRNA cluster that inhibits MAPK and NF-κB signaling, together with suppression of BRAF and CRKL protein expression. ApoVs may represent a cell-free therapeutic strategy for age-related bone loss. Full article

Meningiomas are the most common intracranial tumors. DNA methylation analysis in benign and aggressive meningiomas showed decreased MIR21 methylation and overexpression of hsa-miR-21-5p in atypical and anaplastic tumors. Transcriptomic analysis of distinct WHO grade meningiomas showed multiple predicted hsa-miR-21-5p target genes as differentially expressed. They were mainly related to processes of intercellular and intracellular signaling. Intercellular communication in meningioma was investigated using the deposited scRNA-seq dataset and deconvolution of our RNA-seq data. We found WHO grade-related differences in the microenvironment including inverse correlation between the count of border-associated macrophages (BAM) and the level of hsa-miR-21-5p. Single-cell transcriptomics suggests the role of interleukin 6 in direct communication between tumor cells and BAMs. IL6R and IL6ST are predicted targets of hsa-miR-21-5p downregulated in atypical/anaplastic meningiomas. IL6R downregulation was also confirmed by immunohistochemistry. Hsa-miR-21-5p enhanced proliferation and viability of KT21-MG1 meningioma cells and showed a regulatory effect on IL6R, IL6ST and other predicted target genes TIMP3, PIK3R, RHOB, and SASH1 by interacting with 3′UTRs. DNA hypomethylation-related overexpression of hsa-miR-21-5p contributes to aggressive meningioma growth by interaction with multiple target genes, and probably affects microenvironment communication between meningioma cells and BAMs by lowering the IL6R level in tumor tissue. Full article

Background and Objectives: Treatment-resistant depression (TRD) is a major clinical challenge in the management of major depressive disorder (MDD). While pharmacogenetics has been suggested to be clinically useful in guiding antidepressant treatment, few studies have explored if and how pharmacogenes can be involved in TRD pathophysiology and its clinical outcomes. Material amd Methods: We explored the role of differences in metabolizer phenotypes, gene expression levels, and microRNAs of three key pharmacogenes (CYP2D6, CYP2C19, CYP2B6) in TRD pathophysiology and antidepressant response in a cohort of 300 patients with MDD from the PROMPT consortium. Results: CYP2D6 phenotype distribution did not differ significantly between TRD and non-TRD groups, but mRNA expression was significantly upregulated in TRD. Hsa-miR-26b-5p, a microRNA predicted to regulate CYP2D6, was significantly downregulated in TRD. For CYP2C19, intermediate metabolizers (IMs) were underrepresented in TRD versus non-TRD (IMs vs. normal metabolizers (NMs): χ² = 6.07, p = 0.019). microRNA hsa-let-7d-5p and hsa-miR-27a-3p, predicted to regulate CYP2C19, were significantly downregulated in TRD. No significant differences were found for CYP2B6. Conclusions: This study contributes valuable insights to the PROMPT project on how pharmacokinetic gene variants and their expression and regulatory mechanisms may influence antidepressant response and resistance in MDD. Full article

Background/Objectives: Neuroblastoma is the most frequent solid tumor outside the brain in children and is associated with unfavorable outcomes in high-risk patients. Tannic acid, a naturally occurring polyphenolic compound, has been reported to exhibit anticancer activity; however, its molecular effects in neuroblastoma remain incompletely characterized. The present study aimed to evaluate the antiproliferative effects of tannic acid in SH-SY5Y neuroblastoma cells and to explore its potential associations with Toll-like receptor (TLR) signaling and selected microRNAs in an exploratory and correlative manner. Methods: Cell viability was assessed using the CCK-8 assay, which showed that tannic acid was associated with reduced cell proliferation in a dose- and time-dependent manner. Changes in the expression of TLR-related genes and selected microRNAs were analyzed by real-time PCR. TLR-4, NF-κB, and Caspase-3 protein concentrations were determined using ELISA assays. Results: Tannic acid treatment was associated with decreased expression of several TLR genes, with statistically significant reductions observed in TLR2, TLR4, and TLR7. Consistently, protein analyses indicated reduced NF-κB levels. MicroRNA analysis revealed a tendency toward increased expression of hsa-miR-146a-5p, whereas no significant changes were detected in other examined microRNAs. Conclusions: Overall, these findings suggest that tannic acid exhibits antiproliferative activity in SH-SY5Y cells and is associated with alterations in TLR-related gene expression and microRNA profiles. However, these observations are descriptive and correlative in nature and do not establish direct mechanistic relationships. Further in vivo and functional studies are required to validate these findings and to clarify their potential biological and therapeutic relevance. Full article

High-altitude hypoxic adaptation in mammals involves complex molecular mechanisms, with non-coding RNAs (ncRNAs) increasingly reported to participate in hypoxia-related regulation. However, the contribution of circRNAs in cardiac adaptation to chronic hypoxia remains largely unexplored. This study performed an integrative competitive endogenous RNA (ceRNA) analysis to investigate circRNA-mediated regulatory networks in the hearts of Tibetan pigs and Yorkshire pigs maintained under high- and low-altitude conditions, using four comparison groups (TH, TL, YH, and YL). Using Ribo-Zero RNA sequencing, we identified 961 circRNAs in heart tissues, with 358 differentially expressed circRNAs (DE-circRNAs) detected across the four groups. Functional enrichment analysis revealed that their host genes were associated with hypoxia-related pathways, including HIF-1, VEGF, AMPK, and autophagy, critical for energy metabolism and mitochondrial function. A HIF-1-specific ceRNA network was constructed, identifying key axes including circDUSP16–ssc-miR-671-5p–CAMK2A, circTLK1–ssc-miR-331-3p–SERPINE1, and circTLK1–novel-miR-624–ENO1. JASPAR analysis predicted potential HIF-1α binding sites in the promoters of ENO1, SERPINE1, and CAMK2A, supporting their regulatory roles. These findings provide a transcriptomic overview of circRNA expression patterns in pig heart tissues under different altitude conditions and prioritize candidate ceRNA relationships for further functional investigation. Full article

Gestational diabetes mellitus (GDM) exposes the fetus to chronic hyperglycemia, promoting early cardiac remodeling and increasing the risk of diabetic cardiomyopathy later in life. Epigenetic regulators such as p53 tumor suppressor gene (p53), microRNA-34a (miR-34a), and the sirtuins 1 and 7 (SIRT1/SIRT7) may contribute to this programming process; however, their temporal dynamics during postnatal cardiac development remain unclear. This study aimed to characterize structural and molecular alterations in the hearts of offspring exposed to GDM and to determine the involvement of the p53–miR-34a–SIRT1/SIRT7 axis in early cardiac remodeling. Cardiac morphometry was assessed at birth (newborn [NB]) and at 8, 15, 25, and 35 days. Left ventricles were examined through hematoxylin/eosin staining. SIRT1, SIRT7, Bcl-2, and Bax were evaluated by immunofluorescence, while p53 and miR-34a were evaluated by RT-PCR. Molecular interactions were integrated using IPA software, version 159584291. Offspring exposed to GDM exhibited a reduced cardiac area and ventricular lumen, along with increased left ventricular wall thickness and fibrosis during early postnatal stages. The cardiomyocyte area was elevated at all ages. The level of miR-34a increased early, preceding p53 upregulation. SIRT1 presences decreased from NB to 35 days, whereas SIRT7 expression remained consistently elevated. These findings suggest that GDM induces early and sustained cardiac remodeling associated with dysregulation of the p53–miR-34a–SIRT1/SIRT7 axis, a pattern that could increase susceptibility to diabetic cardiomyopathy. Full article

Root knot nematodes (RKNs) induce galls, containing multinucleated giant cells (GCs) to nourish them. The differentiation of precursor cells to galls/GCs involves extensive cellular reprogramming with multiple layers of regulation. Epigenetic regulation during the early stages of infection indicates that RNA-directed DNA methylation (RdDM) and microRNA-dependent gene silencing contribute to transcriptional and post-transcriptional reprogramming during gall organogenesis. Although later stages of galls/GC development are crucial for nematode life-cycle maintenance, epigenetic reprogramming events remain largely unexplored. An integrative analysis of sRNAs, DNA methylation, and transcriptomic dynamics in galls induced by Meloidogyne javanica revealed that enrichment of 24 nt sRNAs represents a gall hallmark across early and late developmental stages. Fewer gall-distinctive sRNAs were detected at mid-to-late stages than at early stages, alongside a pronounced spatial reorganization of rasiRNA accumulation. At early stages, gall-distinctive rasiRNAs preferentially accumulated in pericentromeric retrotransposon-rich regions, whereas, at mid-to-late stages, they predominantly localized to chromosome arms, matching DNA transposons, promoters, and gene bodies. A decline in the regulatory influence of miRNAs was observed as infection progressed, possibly reflecting a transition toward specialized regulatory states associated with gall maintenance. Moreover, three regulatory modules, miR2111-5p/HOLT, miR172/AP2, and miR156/SPL10, were tightly but oppositely regulated at 3 and 14 days post-infection. Furthermore, miR156/SPL10 showed crucial functions during gall formation and/or maintenance, possibly influenced by hormonal cues involving ARF8 among other ARFs. Our results highlight stage-specific patterns involving sRNA dynamics, DNA methylation, and transcriptomic changes underlying nematode feeding site development and maintenance. Full article

Background: Brugada Syndrome (BrS) is a cardiac arrhythmia associated with an increased risk of ventricular arrhythmias and sudden cardiac arrest. Although the arrhythmic substrate is traditionally localized to the ventricles, atrial fibrillation (AF) is frequently observed, suggesting a shared molecular substrate between atrial and ventricular arrhythmias. C-type natriuretic peptide (CNP) and related microRNAs (miRNAs) modulate atrial and ventricular physiology, but their roles in exosomes in BrS have not been investigated. Objectives: To investigate alterations in CNP mRNA expression and changes in the expression of selected CNP-associated miRNAs implicated in AF, both analyzed in exosomes isolated from individuals with BrS and from healthy controls. Methods: Exosomes were isolated from the plasma of BrS patients without a history of overt AF and from healthy controls. In silico analyses identified CNP-targeting miRNAs implicated in AF. Exosomal CNP and CNP-related miRNAs were analyzed using Droplet Digital PCR. Results: BrS patients exhibited a significant increase in exosomal CNP mRNA expression levels compared with controls. MiR-138-5p was selectively downregulated, whereas other AF-related CNP-targeting miRNAs (miR-4443, miR-206, miR-142-5p, miR-223-5p) showed comparable levels between groups. A positive correlation between exosomal CNP and miR-223-5p and miR-4443 suggests shared regulatory pathways. Conclusions: these findings indicate that exosomal profiling may provide a more sensitive approach than conventional circulating measurements to detect molecular remodeling in BrS. The observed alterations highlight a potential shared molecular substrate between atrial and ventricular arrhythmias and may inform future studies aimed at refining diagnostics and developing targeted therapeutic strategies. Full article

Canine osteosarcoma (OSA) is a highly aggressive primary bone tumor and a valuable model in comparative oncology. Nevertheless, commonly used canine in vitro models remain incompletely and inconsistently characterized, while exhibiting substantial biological heterogeneity affecting experimental outcomes. This study aimed to comparatively characterize three canine osteosarcoma cell lines (OSCA8, OSCA29, and D17) in reference to canine hTERT fibroblasts, and with a focus on functional properties and selected molecular features, namely including miR-27b-3p and IGF2BP3 expression. The cytophysiological profile of the cells was evaluated in relation proliferation and migratory capacity. In turn, gene expression was determined with RT-qPCR, and proteins detected with Western blotting. The D17 cell line showed the highest metabolic activity and the largest fraction of S-phase cells, whereas OSCA8 cells demonstrated the greatest clonogenic potential and the highest migratory activity in the wound healing assay. OSCA29 cells displayed an intermediate functional profile, while all OSA cell lines exhibited comparable migratory capacity in transwell assay. At the molecular level, miR-27b-3p expression was significantly higher in OSCA8 and D17 cells than in OSCA29 cells. In turn, IGF2BP3 transcript levels were lower in OSCA29 cells, whereas protein analysis revealed distinct immunoreactive forms. Together, these findings highlight the functional heterogeneity of commonly used canine osteosarcoma cell lines and broaden their current characterization. Full article

Heart failure (HF) is one of the largest contributors to disease burden and healthcare expenditure worldwide. Countless studies have shown that microRNAs (miRNAs) are pivotal regulators of heart homeostasis and promising biomarkers for the diagnosis and management of HF. Among the reported miRNAs, miR-106b-5p and miR-185-5p have been implicated in various cardiovascular diseases through involvement in cardiac injury, fibrosis, and cell survival pathways. Although cellular functions of miR-106b-5p and miR-185-5p have been investigated intensively, their circulating levels remain largely elusive in patients with HF. This study examined expression levels of plasma miR-106b-5p and miR-185-5p by quantitative reverse transcription PCR (RT-qPCR) in a study cohort comprising 41 chronic HF patients and 41 matched, non-HF subjects. Bioinformatic analysis was conducted for miR-106b-5p and miR-185-5p to discover their potential target genes, biological functions, and association with cardiovascular-related clinical phenotypes. Chronic HF patients presented a significant increase in plasma miR-106b-5p and miR-185-5p levels. Diverse expressive patterns of miR-106b-5p and miR-185-5p were observed in different types and functional classes of HF. A positive correlation between plasma miR-106b-5p and miR-185-5p was also identified. In silico analysis suggested that many genes related to cell proliferation and metabolic pathways were shared targets of miR-106b-5p and miR-185-5p. Our study reveals dysregulation of plasma miR-106b-5p and miR-185-5p in patients with chronic HF that may contribute to the pathological course of this disease. Full article

Severe traumatic brain injury (TBI) is a leading cause of mortality and long-term disability in polytrauma (PT) patients, and its clinical outcome remains difficult to predict due to clinical heterogeneity and secondary injury mechanisms. Current diagnostic and prognostic approaches based on clinical assessment and imaging are limited, particularly in PT where neurological evaluation is often impaired. This study aimed to compare plasma- and extracellular vesicle (EV)-associated microRNA (miRNA) signatures in patients with severe TBI and healthy controls to identify their potential as minimally invasive biomarkers and to improve understanding of molecular responses. For profiling circulating miRNAs, blood samples were collected at ≤3 h and at 48 h after admission. In the screening phase, plasma samples of n = 15 patients with severe isolated TBI (Abbreviated Injury Scale [AIS]Head ≥ 4, all other AIS ≤ 1) and n = 15 age- and sex-matched healthy controls were pooled (n = 5/pool) and subjected to next-generation sequencing (NGS). In the following validation phase, n = 25 severely injured trauma patients (Injury Severity Score [ISS] ≥ 16) were enrolled and stratified into PT without TBI (PT; AISHead = 0; n = 13) and isolated TBI (n = 12). Differentially expressed candidate miRNAs identified in the screening phase were validated in individual plasma and EV samples using reverse transcription droplet digital polymerase chain reaction (RT-ddPCR). Functional enrichment and pathway analyses were performed using miRNet. NGS identified more differentially expressed miRNAs in plasma (ER: 103; 48 h: 65) than in EVs (Emergency Room [ER]: 14; 48 h: 32). Functional enrichment analysis indicated associations with pathways related to cellular stress, senescence, growth factor signaling, transcriptional regulation, and apoptosis. In validation, 12 of 16 plasma and 10 of 15 EV-miRNAs were confirmed as differentially expressed in TBI patients; among these, three plasma and four EV miRNAs differed between TBI and PT. After adjustment, most plasma miRNAs were associated with injury severity rather than group status. EV miRNA profiles showed heterogeneous patterns, with miR-1469 associated with TBI group status in adjusted analysis, while miR-1237-5p was linked to injury severity and other EV miRNAs showed no consistent group-specific effects. Plasma miRNAs mainly correlated with systemic injury markers, whereas EV miR-1469 showed a moderate association with the Glasgow Coma Scale (GCS). Overall, circulating miRNA profiles after injury appear to be predominantly influenced by systemic trauma severity rather than TBI-specific effects. Plasma miRNAs mainly reflected general injury burden, whereas EV-associated miRNAs showed more heterogeneous patterns, with miR-1469 emerging as a candidate associated with TBI after adjustment for clinical covariates. These findings suggest that EV-derived miRNAs, particularly miR-1469, may provide more targeted signals related to brain injury and warrant further investigation. Full article

Chromium (Cr) is one of the most toxic heavy metals in the environment. The tolerance to metal stress involves sophisticated regulation of gene expression networks, which involve microRNAs (miRNAs). However, the role of miRNAs in Cr stress response in Avicennia marina has not been resolved, and was addressed here. The analysis of response characteristics revealed that morpho-physiological traits such as root length, Cr accumulation level and antioxidant enzyme activity all exhibit significant changes under Cr stress. Via sRNA sequencing, a total of 27 known and 149 novel miRNAs were identified, 63 of which showed differential expression after Cr stress (q-value < 0.001). Further, 571 miRNA-target interaction pairs were identified for differentially expressed miRNAs, corresponding to 355 target genes. GO and KEGG analyses indicated that these target genes could participate in stress-related biological processes such as signal transduction, transcription regulation, protein synthesis and the MAPK signaling pathway. 54 miRNA target genes, corresponding to 37 miRNAs such as Ama-miR160, Ama-nmiR25-5p and Ama-nmiR118-5p, were enriched for “plant signal hormone transduction” (ko04075), “phenylpropanoid biosynthesis” (ko00940) and “MAPK signaling pathway” (ko04016), which indicated an important role of these miRNAs in regulating Cr stress response in A. marina. Based on the findings, a Cr stress-responsive regulatory model was developed, offering new insights into the molecular regulatory mechanisms of Cr response. In conclusion, this study shows the identity and potential role of miRNAs in the heavy metal stress response of A. marina, and provides the foundation for future research. Full article

Objective: This study aimed to systematically compare the short-term outcomes of minimally invasive pancreatic enucleation (MI-pEn), including laparoscopic and robotic-assisted approaches, and open pancreatic enucleation (O-pEn). Methods: A systematic search of PubMed, MEDLINE, Embase, and Web of Science was conducted for studies published between January 1990 and December 2025 that compared various types of pancreatic enucleation. The literature screening, data extraction, and quality assessment followed the PRISMA guidelines. The meta-analysis was performed using RevMan 5.4.1 and R 4.3.0. Results: Fifteen studies were included, with thirteen comparative studies (463 MI-pEn, 547 O-pEn) incorporated into the meta-analysis. Two studies comparing laparoscopic and robot-assisted enucleation were also included. No significant difference in clinically relevant postoperative pancreatic fistula (CR-POPF) was detected between MI-pEn and O-pEn (OR = 0.78; 95% CI: 0.56–1.07; p = 0.12). However, MI-pEn was associated with significantly reduced operation time (MD = −21.24; p = 0.01), blood loss (MD = −75.88; p < 0.00001), hospital stay (MD = −2.07; p = 0.001), and wound infection (OR = 0.3; p = 0.03). Direct comparisons between robotic and laparoscopic enucleation revealed no significant differences in any outcomes. Conclusions: MI-pEn is safe and feasible and offers advantages in terms of operative time, blood loss, and recovery without increasing complications. Robotic and laparoscopic approaches yield comparable short-term outcomes in pancreatic enucleation, although the potential advantage of robotic surgery in reducing pancreatic fistula risk warrants further validation. Full article