Search Results (8,892)

Milk-derived extracellular vesicles (EVs) transport microRNAs (miRNAs) that are unusually stable and have been proposed to survive digestion and modulate gene expression in the consumer, although their dietary bioavailability and physiological relevance remain debated. How the predicted regulatory potential of these miRNAs differs among the milks of different animals most relevant to human nutrition has not been systematically compared. Here, we performed an integrative in silico analysis of publicly available small-RNA sequencing data from 29 milk and milk-cell samples of human, cow, goat, and donkey origin. miRNAs were quantified against human (hsa) miRBase references—thereby restricting the analysis to evolutionarily conserved miRNAs with human orthologs—and their predicted effect on the human transcriptome was modeled by integrating predicted (mirDIP database) and experimentally supported (TarBase v9 database) miRNA–target interactions into a per-gene, per-species weighted targeting score. Because miRNAs act predominantly as repressors, this score is read as a prediction of which genes would be post-transcriptionally down-regulated in a recipient. miR-148a-3p dominated the exosomal spectrum of all four species (human, cow, goat, and donkey; ≈21.5% of pooled abundance), and the twenty most abundant miRNAs accounted for roughly three quarters of the signal. Of 4577 robustly targeted genes, a 1809-gene conserved “pan-milk” core showed the highest cross-species targeting and was enriched for transcriptional regulation, PI3K–Akt, MAPK, and TGF-β/SMAD signaling, autophagy and—strikingly—the components of the RNA-interference machinery itself. Species-restricted gene sets recapitulated biologically plausible programs, including a human-biased neuronal/axon-guidance and chromatin module, a donkey-biased transcriptional, epithelial, and immune (CD47) module, and a ruminant lipid/cholesterol and insulin–mTOR module. Across categories, we observed a reproducible confidence–exclusivity trade-off. We emphasize that these results are computational predictions that assume dietary miRNA uptake and do not constitute experimental validation. We provide the complete targetome as a hypothesis-generating resource to prioritize candidate genes, pathways, and milk types for future functional, nutritional, and epigenetic investigation. Across the 29 samples from the four species, miRNA composition segregated by species (silhouette width = 0.82, a cluster-separation measure ranging from −1 to 1, with values near 1 indicating well-separated groups) and the category structure exceeded a permutation null, indicating that the between-species signal is robust to differences in dataset origin and milk state. Full article

Cancer stem cells (CSCs) drive therapeutic resistance, metastasis, and tumor recurrence through reversible transitions among stem-like, differentiated, epithelial, and mesenchymal states, which are sustained by interconnected epigenetic mechanisms. To our knowledge, this is the first review to integrate curcumin-mediated regulation of DNA methylation, chromatin remodeling, and non-coding RNAs within a single CSC plasticity framework and to propose the concept of an “epigenetic collapse of CSC plasticity” as a mechanistic explanation for how curcumin may weaken stemness, state switching, and adaptive treatment resistance. Evidence was critically evaluated through structured searches of PubMed/MEDLINE, Scopus, Web of Science Core Collection, Google Scholar, and citation tracking, while direct curcumin–epigenetic evidence was distinguished from independent CSC evidence and inferential mechanistic links. Curcumin has been reported to modulate DNMT1 and locus-specific DNA methylation; regulate HDACs, p300/CBP, EZH2, H3K27me3, and BMI1; and alter selected microRNA, long non-coding RNA, and circular RNA pathways, with comparatively stronger evidence involving the miR-34 family, miR-200c, miR-21, H19, and circHN1. However, current evidence is constrained by the predominance of bulk cancer-cell models, heterogeneous formulations and exposure conditions, and the scarcity of epigenetic rescue experiments combined with rigorous functional CSC assays. By unifying previously fragmented epigenetic evidence, this review advances a new evidence-weighted model in which curcumin may suppress CSC persistence not through a single molecular target, but by destabilizing the multilayer epigenetic circuitry that enables plasticity. Curcumin should therefore be regarded as a context-dependent, multilayer epigenetic modulator rather than an established CSC-eradicating therapy, and its translational relevance requires validation in prospectively defined CSC models with pharmacologically justified delivery and exposure conditions. Full article

An important role of neuroinflammation in the pathogenesis of Parkinson’s disease (PD) has been proposed. Since some microRNAs (miRNAs), and miR-155 in particular, are involved in neuroinflammatory processes, a previous study reported an association between one of the most common single nucleotide variants (SNVs), rs767649, in the MIR155 gene, and risk for PD. The aim of the current study was to replicate this finding in a larger Spanish population case–control series. We analyzed genotype and allele frequencies of the MIR155 rs767649 SNV in a Spanish Caucasian cohort consisting of 459 PD patients and 460 age- and sex-matched healthy controls, using a TaqMan allelic discrimination assay specifically designed for rs767649. The genotype frequencies of the MIR155 rs767649, under codominant, dominant, recessive, and overdominant inheritance models, as well as allelic frequencies, showed no significant differences between PD patients and healthy controls. Likewise, the age at PD onset did not differ among the three MIR-155 rs767649 genotypes. These data did not identify a statistically significant association between MIR155 rs767649 variants and PD risk. However, the low frequency of the variant allele resulted in limited statistical power, and modest genetic effects cannot be excluded. Full article

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8⁺ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8⁺ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8⁺ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8⁺ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8⁺ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8⁺ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8⁺ T cells. Conversely, activated CD8⁺ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8⁺ T cell-derived vesicles. Full article

Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA–mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions. Full article

MicroRNAs (miRNAs) have been proposed as promising biomarkers for periodontal disease because of their role in regulating inflammation and tissue remodeling. This study evaluated the salivary expressions of miR-34a, miR-155, and miR-146a and their relationships with periodontal disease and its clinical severity. Saliva samples were collected from 35 patients with periodontal disease and 35 healthy controls, and miRNA expression was quantified by quantitative real-time PCR (qRT-PCR). Fold-change values were log2-transformed, and analyses included differential expression (Mann–Whitney U with Benjamini–Hochberg correction), Spearman correlation with clinical attachment loss (CAL), logistic regression/ROC modeling with internal cross-validation, and an exploratory differential co-expression analysis. None of the three miRNAs was significantly differentially expressed between groups (all FDR-adjusted p > 0.40; the result was unchanged after adjustment for age), and none correlated with CAL after accounting for the healthy-versus-diseased separation. miR-34a showed poor stand-alone diagnostic performance (AUC = 0.58; five-fold cross-validation 0.56). Patients were significantly older than controls (41.1 vs. 37.1 years; p < 0.001), and age was the strongest single discriminator (AUC = 0.82), indicating that age acts as an important confounder. In an exploratory analysis, the positive co-expression observed among the three miRNAs in healthy controls was attenuated in disease (e.g., miR-155/miR-146a Spearman rho = 0.68 vs. 0.27; permutation p approximately 0.06). These findings indicate that salivary miR-34a, miR-155 and miR-146a abundance do not discriminate periodontitis in this cohort, but underline age as a critical confounder and suggest that altered miRNA co-expression, rather than differential abundance, may warrant further investigation in larger, age-matched studies. In addition, miR-34a and miR-146a showed reduced expression dispersion in disease; because the reduced dispersion and the reduced co-expression cannot be fully separated in a sample of this size, these network-level observations are regarded as jointly hypothesis-generating. Full article

Hepatocellular carcinoma (HCC) lacks effective early diagnostic markers and is heavily driven by angiogenesis and hypoxia. Emerging evidence indicates that metabolic enzymes and noncoding RNAs coordinate these processes. Here, we reveal that phosphoserine phosphatase (PSPH), a serine biosynthesis enzyme, is significantly upregulated in HCC, correlating with angiogenic markers and poor prognosis. Clinical data and functional assays demonstrated that miR-101-3p directly targets the PSPH 3′ UTR to suppress its expression, while lncRNA GSEC acts as a competing endogenous RNA to sponge miR-101-3p. In vitro, GSEC knockdown or miR-101-3p overexpression decreased PSPH and HIF1α levels, strongly inhibiting HCC angiogenesis, migration, invasion, and proliferation. Crucially, these anti-tumor effects were reversed by restoring PSPH. In vivo, modulating the GSEC/PSPH axis significantly altered xenograft tumor growth and vascularization. Conclusively, the GSEC/miR-101-3p/PSPH regulatory axis drives HIF1α-dependent angiogenesis and HCC progression, highlighting PSPH as a promising diagnostic biomarker and therapeutic target. Full article

MicroRNAs play crucial roles in plant growth, development, and disease resistance. Transcriptome screening previously identified three late blight-responsive miRNAs (sly-miR172a, sly-miR156e, and sly-miR395a) in tomato whose biological functions remain uncharacterized. Here, CRISPR/Cas9 editing vectors targeting each miRNA were transformed into the tomato cultivar ‘Micro-Tom’. sly-miR395a showed the highest T0 editing efficiency (77.78%), followed by sly-miR172a (48.00%) and sly-miR156e (40.74%). T1 segregation ratios were approximately 1:12.3, 1:1.83, and 1:13 for the three targets. Stable T2 homozygous lines were obtained, and qRT-PCR confirmed average mature miRNA inhibition rates of 78.00%, 79.50%, and 87.50%. To assess editing specificity, genome-wide off-target prediction and Sanger sequencing of top high-risk loci were performed; no unintended indels were detected, confirming sgRNA specificity. Agronomic phenotyping revealed divergent developmental phenotypes: sly-miR172a knockout caused dwarfism, leaf senescence and reduced flower number; sly-miR156e mutants exhibited taller plants and increased floral production; sly-miR395a mutants had normal vegetative growth but fewer flowers. Resistance assays demonstrated distinct responses to Phytophthora infestans. Loss of sly-miR172a increased pathogen biomass by 1.6–2.3-fold and aggravated susceptibility, likely by de-repressing AP2/TOE to disrupt oxidative homeostasis. In contrast, both sly-miR156e and sly-miR395a negatively regulate late blight resistance. This could be because sly-miR156e knockout relieved the repression of SPL transcription factors, significantly restricting pathogen proliferation and lesion formation, and notably broke the canonical plant growth–defense trade-off to achieve simultaneous improvement of agronomic traits and disease resistance. sly-miR395a knockout enhanced tomato immunity potentially by activating sulfur metabolism-related pathways to accumulate defensive metabolites, with negligible adverse effects on vegetative growth. Nevertheless, this study has several limitations: the proposed regulatory cascades, including miRNA–AP2, miRNA–SPL, and miRNA–sulfur metabolism modules remain hypothetical without direct molecular validation of target interactions. Collectively, this study genetically validates that sly-miR172a, sly-miR156e, and sly-miR395a exert divergent functions in regulating tomato growth and immunity against late blight, providing valuable germplasm and gene resources for tomato disease-resistance breeding. Full article

Long non-coding RNAs (lncRNAs) participate in insect immune regulation, but their relationship with antioxidant responses during fungal infection remains unclear. Here, we examined a candidate regulatory relationship among lncRNA1386.1, novel-miR0032-5p, and the catalase gene (CAT) in Apis cerana worker larvae infected with Ascosphaera apis. Dual-luciferase reporter assays showed that M-miR0032-5p reduced the activity of reporters containing the predicted miRNA response element within lncRNA1386.1 or CAT, whereas mutation of these sequences weakened or abolished the response. In infected larvae, lncRNA1386.1 silencing and novel-miR0032-5p overexpression reduced CAT transcript abundance and CAT protein concentration, and increased dihydroethidium (DHE) fluorescence intensity. These treatments were also accompanied by alterations in the transcript abundance of the host genes Dorsal1 and Relish and the fungal genes Chit3 and STE11-like. Novel-miR0032-5p inhibition generally produced opposite changes in CAT-related measurements, DHE fluorescence intensity, and the selected host and fungal transcripts. lncRNA1386.1 silencing was associated with increased larval survival, whereas novel-miR0032-5p inhibition was associated with a higher hazard of first visible external mycelial growth without significantly affecting survival. These findings support a negative regulatory role of novel-miR0032-5p in CAT expression and indicate that lncRNA1386.1 participates in a candidate shared miRNA-responsive regulatory relationship. This candidate regulatory relationship was associated with CAT-related antioxidant regulation, superoxide-associated DHE fluorescence, immune-related transcription, selected fungal transcriptional responses, and visible external mycelial growth during A. apis infection. Full article

Background and Objective: Reliable medical research depends on data integrity, yet clinical datasets often contain real and systematically missing values. This study aimed to develop a robust, clinically realistic imputation framework for a raw Multiple Sclerosis (MS) dataset affected by real-world missingness. Methods: We propose an innovative data-driven approach called the Sequential Multiple Imputation Bootstrapping (SMIB) model, which orders imputation based on feature correlation and incorporates bootstrapping to enhance stability and generalizability. Relevant features were identified using RF importance and Mutual Information scores and imputed using a hybrid machine learning framework that combines Random Forest (RF), Multilayer Perceptron (MLP), k-Nearest Neighbors (kNN), and a multiple imputation (MI) algorithm. The proposed method was evaluated using 15-fold cross-validation and a masking-based evaluation strategy. Model performance was assessed using accuracy, precision, recall, specificity, F1 score, Mean Squared Error (MSE), Mean Absolute Error (MAE), and R². Results: RF-based SMIB achieved superior performance, with final imputation accuracy reaching up to 97% for categorical outcomes and strong numerical performance (R² up to 0.999; MSE as low as 2.48 × 10⁻⁵). Sequential ordering and weighted bootstrapping improved stability in imbalanced clinical data under real-world missingness. Compared with the widely adopted Multiple Imputation by Chained Equations (MICE) approach, the proposed SMIB framework consistently demonstrated superior predictive performance across all evaluated categorical and numerical outcomes. Conclusions: The SMIB framework provides a robust and clinically aligned strategy for handling real-world missing values in MS datasets, improving imputation accuracy while preserving feature dependencies and feature relationships. The method supports reliable predictive analytics in healthcare contexts. Full article

We explored the potential functions of differentially expressed miRNAs, mRNAs, lncRNAs, and circRNAs identified in the ovaries of gilts with normal estrus (NE) and follicular cyst-associated anestrus (AE), as well as their putative competing endogenous RNA (ceRNA) regulatory networks. Ovarian morphology was assessed via ultrasonography, and serum concentrations of Follicle-stimulating hormone (FSH), (Estradiol) E2, and Progesterone(P4) were measured. Ovarian tissues were harvested after slaughter for whole-transcriptome sequencing. Bioinformatic tools were used to screen differentially expressed RNAs(DERNAs) between NE and AE gilts. We further predicted target interactions among these transcripts, conducted functional enrichment analysis on target genes, and constructed candidate ceRNA regulatory networks potentially associated with gilt estrus. Phenotypic verification confirmed that ovarian ultrasonographic characteristics, histological morphology, and serum reproductive hormone levels were consistent with the physiological status of NE and AE gilts. Under the screening thresholds of p < 0.05 and |log₂FC| ≥ 1, we identified 22 lncRNAs that may interact with 21 mRNAs via 50 miRNAs, alongside 39 circRNAs predicted to regulate 26 mRNAs through 72 miRNAs. Functional enrichment analysis indicated that target genes of these differentially expressed transcripts were predominantly enriched in the lysosome pathway, PPAR signaling pathway, chemokine signaling pathway, cholesterol metabolism and NOD-like receptor signaling pathway. Hub molecules including FGF1, GHR, TLR2, ssc-miR-370, and miR-21-5p were shared in lncRNA/circRNA-miRNA-mRNA regulatory networks; these molecules have been reported to participate in progesterone synthesis, estrus modulation, and endocrine homeostasis. Of particular interest, two non-coding RNAs, MSTRG.1285.1 and novel_circ_056113, were predicted to act as candidate ceRNAs that may sponge ssc-miR-370 and miR-21-5p, which could in turn modulate the expression of estrus-associated mRNAs including FGF1, GHR, and TLR2. The expression trends of MSTRG.1285.1, novel_circ_056113, miR-370, miR-21-5p, GHR, TLR2, and FGF1 were validated by qRT-PCR, and the quantification results agreed with transcriptome sequencing data. Collectively, this study constructed a predicted ceRNA regulatory network of ovarian transcripts comparing NE and AE gilts and uncovered multiple RNA molecules potentially involved in estrus regulation. These findings offer preliminary theoretical clues for exploring the onset of puberty in gilts. Full article

In this comparative study of 12 pigs (six Songlei black [SL] and six Duroc × Landrace × Yorkshire [DLY]), small RNA sequencing was performed on longissimus dorsi muscle samples to identify miRNAs associated with meat quality traits. A total of 343 known and 191 novel miRNAs were identified, including 21 differentially expressed miRNAs (DE-miRNAs) between breeds. Enrichment analysis showed that their target genes were enriched in the PI3K-Akt, MAPK, and calcium signaling pathways. Integration of miRNA and transcriptome datasets identified a regulatory network comprising five key miRNAs (ssc-miR-10383, ssc-miR-127, ssc-miR-370, ssc-miR-874, and a novel miRNA, novel_494) and 32 target genes annotated to autophagy, AMPK, mTOR, and FoxO signaling pathways. All five miRNAs were negatively correlated with IMF content (r = −0.77 to −0.95) and positively correlated with shear force (r = 0.62 to 0.76). This study provides the first miRNA expression profile of the longissimus dorsi muscle in SL and DLY pigs. These findings suggest that coordinated miRNA regulation may contribute to breed-specific differences in fat deposition and meat tenderness, providing candidate biomarkers for improving pork quality. Full article

Background: Miscarriage is defined as the spontaneous loss of a pregnancy before fetal viability and includes all pregnancy losses occurring from conception until 24 weeks of gestation. Recurrent pregnancy loss (RPL) is traditionally defined as three or more consecutive miscarriages. Emerging evidence suggests that both miR-99a and miR-143 may serve as promising biomarkers for recurrent pregnancy loss. Methods: A total of 42 women of reproductive age (18–45 years) were enrolled in this study. The control group consisted of 13 women with no history of recurrent miscarriage, whereas the study group included 29 women diagnosed with spontaneous miscarriages/recurrent implantation failure. Results: Both miR-99a and miR-143 showed significantly lower relative expression in women with recurrent miscarriage/recurrent implantation failure compared with the control group. Conclusions: Despite the relatively small sample size, statistically significant differences in the expression of miR-99a and miR-143 were observed between the case and control groups, with lower relative expression of both miRNAs in the case group. These findings suggest that both microRNAs may be associated with molecular pathways involved in reproductive failure. Furthermore, investigating the expression patterns of miR-99a and miR-143 may contribute to a better understanding of the molecular mechanisms underlying recurrent miscarriage/recurrent implantation failure. Such insights may facilitate the development of genetic risk profiles for women with unexplained pregnancy loss and implantation failure, as well as support the identification of potential therapeutic targets. Further studies are required to determine their potential value as molecular markers and to clarify their functional relevance in reproductive failure. Full article

Purpose of Review: Obesity is a growing global health challenge, with severe obesity projected to affect up to 25% of individuals with obesity by 2030. Bariatric surgery remains the most effective treatment, yet the molecular mechanisms underlying its metabolic benefits are not fully understood. This review summarizes current evidence on the role of microRNAs in bariatric/metabolic surgery and evaluates their potential as biomarkers and therapeutic targets. Recent Findings: Bariatric surgery induces significant alterations in circulating and tissue-specific miRNA profiles, particularly those involved in glucose metabolism, inflammation, and adipose tissue remodeling. Among the most frequently reported candidates, miR-122, miR-221, miR-27a, miR-126, miR-144, miR-222, miR-223, miR-375, miR-92a, and miR-155 have been associated with weight loss, improved insulin sensitivity, and diabetes remission. Emerging data suggest that these miRNAs may act not only as biomarkers of metabolic recovery but also as regulators of insulin signaling, inflammatory pathways, and adipocyte function. Summary: Current evidence supports a role for miRNAs in the metabolic adaptations observed after bariatric surgery. Although further validation is required, miRNAs show promise as minimally invasive biomarkers for predicting and monitoring treatment response and may provide insight into the molecular mechanisms underlying obesity remission and improvement of obesity-related comorbidities. Full article

Adipose tissue development significantly influences meat quality and economic traits in beef cattle. In this study, we identified a novel circular RNA derived from two exons (exons 3 and exons 9) of the NID2 gene, designated as circNID2, which exhibits high structural stability and marked upregulation during bovine adipocyte differentiation. Functional assays demonstrated that circNID2 suppresses the proliferation and apoptosis of bovine preadipocytes while robustly promoting adipogenic differentiation and lipid accumulation. Although containing several putative open reading frames, circNID2 lacks protein-coding potential. Mechanistically, circNID2 functions as a competing endogenous RNA by sponging miR-339a, thereby relieving the post-transcriptional repression of its downstream target, Neuronatin (NNAT). Functional rescue experiments further validated that circNID2 partially neutralizes the regulatory effects of miR-339a on preadipocyte proliferation, apoptosis, and differentiation. Collectively, these findings demonstrate that circNID2 regulates bovine preadipocyte function through the newly established circNID2/miR-339a/NNAT axis. This study provides novel insights into the post-transcriptional mechanisms governing mammalian adipogenesis and highlights circNID2 as a potential molecular target for improving fat deposition traits in cattle. Full article