Explore the vast range of titles available.

The differential diagnosis of erosive osteoarthritis of the hand (EHOA) and psoriatic arthritis (PsA) is challenging, especially considering the absence of specific diagnostic biomarkers. The aim of the present study was to evaluate whether a pattern of microRNAs (miRNAs) (miR-21, miR-140, miR-146a, miR-155, miR-181a, miR-223), pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, IL-17a, IL-23a, and tumor necrosis factor (TNF)-α], and adipokines (adiponectin, chemerin, leptin, resistin, and visfatin) could help to differentiate EHOA from PsA. Fifty patients with EHOA, fifty patients with PsA, and fifty healthy subjects (HS) were studied. The gene expression of miRNAs and cytokines were evaluated by real-time PCR from peripheral blood mononuclear cells and serum levels of cytokines and adipokines were quantified by ELISA in PsA and EHOA patients and HS. Gene expression showed the significant up-regulation of the analyzed miRNAs in EHOA and PsA patients as compared to HS and higher miR-155 in EHOA vs. PsA patients. The expression levels of IL-1β and IL-6 did not show any significant differences between EHOA and PsA, while IL-17a and IL-23a were significantly up-regulated in PsA compared to EHOA. Circulating TNF-α levels were higher in EHOA compared to PsA, while PsA patients exhibited significantly elevated levels of IL-23a. The combination of miR-155 with C-reactive protein enhanced the ability to differentiate EHOA from PsA, further supporting the potential of miR-155 as a diagnostic biomarker.

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1 . TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population. Self-renewal of cancer stem cells can contribute to glioma progression. Here, the authors show that Notch1 activation in glioma stem cells induces expression of the lncRNA TUG1 , which promotes self-renewal through the repression of differentiation genes, and that targeting TUG1 represses glioma growth in vivo .

Background Type 2 diabetes (T2D) is associated with coronary microvascular dysfunction, which is thought to contribute to compromised diastolic function, ultimately culminating in heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms remain incompletely understood, and no early diagnostics are available. We sought to gain insight into biomarkers and potential mechanisms of microvascular dysfunction in obese mouse ( db/db ) and lean rat (Goto-Kakizaki) pre-clinical models of T2D-associated diastolic dysfunction. Methods The microRNA (miRNA) content of circulating extracellular vesicles (EVs) was assessed in T2D models to identify biomarkers of coronary microvascular dysfunction/rarefaction. The potential source of circulating EV-encapsulated miRNAs was determined, and the mechanisms of induction and the function of candidate miRNAs were assessed in endothelial cells (ECs). Results We found an increase in miR-30d-5p and miR-30e-5p in circulating EVs that coincided with indices of coronary microvascular EC dysfunction (i.e., markers of oxidative stress, DNA damage/senescence) and rarefaction, and preceded echocardiographic evidence of diastolic dysfunction. These miRNAs may serve as biomarkers of coronary microvascular dysfunction as they are upregulated in ECs of the left ventricle of the heart, but not other organs, in db/db mice. Furthermore, the miR-30 family is secreted in EVs from senescent ECs in culture, and ECs with senescent-like characteristics are present in the db/db heart. Assessment of miR-30 target pathways revealed a network of genes involved in fatty acid biosynthesis and metabolism. Over-expression of miR-30e in cultured ECs increased fatty acid β-oxidation and the production of reactive oxygen species and lipid peroxidation, while inhibiting the miR-30 family decreased fatty acid β-oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to down-regulate the expression of eNOS, a key regulator of microvascular and cardiomyocyte function. Finally, knock-down of the miR-30 family in db/db mice decreased markers of oxidative stress and DNA damage/senescence in the microvascular endothelium. Conclusions MiR-30d/e represent early biomarkers and potential therapeutic targets that are indicative of the development of diastolic dysfunction and may reflect altered EC fatty acid metabolism and microvascular dysfunction in the diabetic heart.

PD-L1, a key inhibitory immune receptor, has crucial functions in cancer immune evasion, but whether PD-L1 promotes the malignant properties of cervical cancer (CC) cells and the mechanism by which PD-L1 is regulated in CC remains unclear. We report that PD-L1 is overexpressed in CC, and shRNA-mediated PD-L1 depletion suppresses the proliferation, invasion, and tumorigenesis of CC cells. Loss of miR-140/142/340/383 contributes to PD-L1 upregulation. miR-18a enhances PD-L1 levels by targeting PTEN , WNK2 (ERK1/2 pathway inhibitor), and SOX6 (Wnt/β-catenin pathway inhibitor and p53 pathway activator) to activate the PI3K/AKT, MEK/ERK, and Wnt/β-catenin pathways and inhibit the p53 pathway, and miR-18a also directly suppresses the expression of the tumor suppressors BTG3 and RBSP3 (CTDSPL). miR-18a overexpression in CC cells is triggered by OCT4 overexpression. Our data implicate PD-L1 as a novel oncoprotein and indicate that miR-140/142/340/383 and miR-18a are key upstream regulators of PD-L1 and potential targets for CC treatment.

Genomic studies have yielded important insights into the pathogenesis of obesity. Circulating microRNAs (miRNAs) are valuable biomarkers of systemic diseases and potential therapeutic targets. We sought to define the circulating pattern of miRNAs in obesity and examine changes after weight loss. We assessed the genomewide circulating miRNA profile cross-sectionally in 32 men and after surgery-induced weight loss in 6 morbidly obese patients. The most relevant miRNAs were cross-sectionally validated in 80 men and longitudinally in 22 patients (after surgery-induced weight loss). We evaluated the effects of diet-induced weight loss in 9 obese patients. Thirty-six circulating miRNAs were associated with anthropometric variables in the initial sample. In the validation study, morbidly obese patients showed a marked increase of miR-140-5p, miR-142-3p (both P < 0.0001), and miR-222 (P = 0.0002) and decreased levels of miR-532-5p, miR-125b, miR-130b, miR-221, miR-15a, miR-423-5p, and miR-520c-3p (P < 0.0001 for all). Interestingly, in silico targets leukemia inhibitory factor receptor (LIFR) and transforming growth factor receptor (TGFR) of miR-140-5p, miR-142-3p, miR-15a, and miR-520c-3p circulated in association with their corresponding miRNAs. Moreover, a discriminant function of 3 miRNAs (miR-15a, miR-520c-3p, and miR-423-5p) was specific for morbid obesity, with an accuracy of 93.5%. Surgery-induced (but not diet-induced) weight loss led to a marked decrease of miR-140-5p, miR-122, miR-193a-5p, and miR-16-1 and upregulation of miR-221 and miR-199a-3p (P < 0.0001 for all). Circulating miRNAs are deregulated in severe obesity. Weight loss-induced changes in this profile and the study of in silico targets support this observation and suggest a potential mechanistic relevance.

Background Micro-RNAs (miRNAs) have been reported to play an important role during orthodontic tooth movement (OTM) through the regulation of periodontal soft and hard tissue homeostasis and functions. The aim of the present study was to assess the effects of miRNAs on OTM and to evaluate possible predictors that influenced the overall OTM amount at a 3-month follow-up. Methods Through a split-mouth design, 21 healthy patients (mean age 13.2 ± 1.8 years) were enrolled in the present study. Clinical parameters and gingival crevicular fluid (GCF) sampling were performed on both compression and tension sides of a random canine to be distalized (test groups) at baseline and at 1 h, 1 day, 1 month and at 3-month after OTM, while the contralateral canine served as a control group. miRNAs − 7a-3p, -7a-2-3p, -7a-5p, -21-3p, -21-5p, -100-3p, -100-5p, -125b-2-3p, -125b-5p, -200b-3p, and − 200b-5p expression was analyzed using a real-time quantitative polymerase chain reaction (RT-PCR). Data were analyzed to assess miRNAs change following OTM. Spearman test, two-way ANOVA and a multivariate regression model were established to evaluate the correlation among miRNAs and clinical parameters and to explore possible predictors of OTM amount at 3-month follow-up. Results At 3-month follow-up, there was an increase of miRNA-7a-2-3p, -21-5p, -100-5p, a decrease of miRNA-125b-5p, 200b-3p and − 200b-5p in the compression side and an increase of miRNA-7a-3p, 100-5p in the tension side ( p  < 0.05). The two-way ANOVA revealed that OTM determined, on the compression side, a significant upregulation on miRNA-7a-3p ( p  = 0.017), -7a-2-3p ( p  = 0.023), -21-5p ( p  = 0.007), -100-5p ( p  = 0.025) and a significant downregulation of miRNA-125b-2-3p ( p  = 0.019) and − 200b-5p ( p  = 0.017). The multivariate model highlighted that high baseline miRNA-7a2-3p ( p  = 0.025), -21-5p ( p  = 0.014), -200b-3p ( p  = 0.041), young age ( p  = 0.042), lower bleeding on probing (BOP) ( p  = 0.021) and miRNA-125b-2-3p ( p  = 0.021) levels were significant predictors of OTM at 3-month follow-up. Conclusions In the present study, OTM significantly impacted the expression of the miRNAs analyzed, in both the tension and compression side of traction tooth at 3-month follow-up. High baseline miRNA-7a2-3p, -21-5p, -200b-3p, and lower miRNA-125b-2-3p, together with younger age and lower BOP, were significant predictors of OTM amount at 3-month follow-up. Trial registration ClinicalTrials.gov NCT06023433 (retrospectively registered).

MicroRNAs (miRNAs) are a key factor in epigenetic regulation of gene expression, but miRNA responses to fine particulate matter (PM ) air pollution and their potential contribution to cardiovascular effects of PM are unknown. We explored the potential influence of PM on the expression of selected cytokines relevant to systemic inflammation, coagulation, and vasoconstriction, and on miRNAs that may regulate their expression. We designed a double-blind, randomized crossover study in which true and sham air purifiers were used to expose 55 healthy young adult students in Shanghai, China, to reduced or ambient levels of indoor PM during two-week periods, and we measured the expression (mRNA and protein) of 10 serum cytokines, and miRNAs that target them, after each intervention period. We used linear mixed-effect models to estimate associations of the intervention, and time-weighted personal PM exposures, with the cytokines, mRNA, and miRNAs; we also explored potential mediation by miRNAs. The findings were generally consistent for associations with the intervention and for associations with an interquartile range increase in time-weighted PM . Specifically, higher PM exposure was positively associated with the expression (mRNA, protein, or both) of interleukin-1 (encoded by ), IL6, tumor necrosis factor (encoded by ), toll-like receptor 2 (encoded by ), coagulation factor 3 (encoded by ), and endothelin 1 (encoded by ), and was negatively associated with miRNAs (miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and miR-199a-5p) predicted to target mRNAs of , , , and . Our findings require confirmation but suggest that effects of PM on cardiovascular diseases may be related to acute effects on cytokine expression, which may be partly mediated through effects of PM on miRNAs that regulate cytokine expression. https://doi.org/10.1289/EHP1447.

ABSTRACT Background MicroRNAs (miRNAs) are small noncoding RNAs involved in posttranscriptional regulation. miRNAs can be secreted and found in many body fluids, and although they are particularly abundant in breastmilk, their functions remain elusive. Human milk (HM) miRNAs start to raise considerable interest, but a comprehensive understanding of the repertoire and expression profiles along lactation has not been well characterized. Objectives This study aimed to characterize the longitudinal profile of HM miRNA between the second week and third month postpartum. Methods We used a new sensitive technology to measure HM miRNAs in a cohort of 44 French mothers [mean ± SD age: 31 ± 3.5; BMI (in kg/m2) 21.8 ± 2.3] who delivered at term and provided HM samples at 3 time points (17 ± 3 d, 60 ± 3 d, and 90 ± 3 d) during follow-up visits. Results We detected 685 miRNAs, of which 35 showed a high and stable expression along the lactation period analyzed. We also described for the first time a set of 11 miRNAs with a dynamic expression profile. To gain insight into the potential functional relevance of this set of miRNAs, we selected miR-3126 and miR-3184 to treat undifferentiated Caco-2 human intestinal cells and then assessed differentially expressed genes and modulation of related biological pathways. Conclusions Overall, our study provides new insights into HM miRNA composition and, to our knowledge, the first description of its longitudinal dynamics in mothers who delivered at term. Our in vitro results obtained in undifferentiated Caco-2 human intestinal cells transfected with HM miRNAs also provide further support to the hypothesized mother-to-neonate signaling role of HM miRNAs. This trial was registered at clinicaltrials.gov as NCT01894893.

Background The growth and development of skeletal muscle are regulated by protein-coding genes and non-coding RNA. Circular RNA (circRNA) is a type of non-coding RNA involved in a variety of biological processes, especially in post-transcriptional regulation. To better understand the regulatory mechanism of circRNAs during the development of muscle in chicken, we performed RNA-seq with linear RNA depletion for chicken breast muscle in 12 (E 12) and17 (E 17) day embryos, and 1 (D 1), 14 (D 14), 56 (D 56), and 98 (D 98) days post-hatch. Results We identified 5755 differentially expressed (DE)-circRNAs during muscle development. We profiled the expression of DE-circRNAs and mRNAs (identified in our previous study) at up to six time points during chicken muscle development and uncovered a significant profile (profile 16) for circRNA upregulation during aging in muscle tissues. To investigate competing endogenous RNA (ceRNA) regulation in muscle and identify muscle-related circRNAs, we constructed a circRNA-miRNA-mRNA regulatory network using the circRNAs and mRNAs from profile 16 and miRNAs identified in our previous study, which included 361 miRNAs, 68 circRNAs, 599 mRNAs, and 31,063 interacting pairs. Functional annotation showed that upregulated circRNAs might contribute to glycolysis/gluconeogenesis, biosynthesis of amino acids, pyruvate metabolism, carbon metabolism, glycogen and sucrose metabolism through the ceRNA network, and thus affected postnatal muscle development by regulating muscle protein deposition. Of them, circRNA225 and circRNA226 from the same host gene might be key circRNAs that could regulate muscle development by interacting with seven common miRNAs and 207 mRNAs. Our experiments also demonstrated that there were interactions among circRNA225, gga-miR-1306-5p, and heat shock protein alpha 8 (HSPA8). Conclusions Our results suggest that adequate supply of nutrients such as energy and protein after hatching may be a key factor in ensuring chicken yield, and provide several candidate circRNAs for future studies concerning ceRNA regulation during chicken muscle development.

The transcription factor gene MYB was identified recently as an oncogene that is rearranged/duplicated in some human leukemias. Here we describe a new mechanism of activation of MYB in human cancer involving gene fusion. We show that the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB. The minimal common part of MYB deleted as the result of fusion was exon 15 including the 3'-UTR, which contains several highly conserved target sites for miR-15a/16 and miR-150 microRNAs. These microRNAs recently were shown to regulate MYB expression negatively. We suggest that deletion of these target sites may disrupt repression of MYB leading to overexpression of MYB-NFIB transcripts and protein and to activation of critical MYB targets, including genes associated with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion. Forced overexpression of miR-15a/16 and miR-150 in primary fusion-positive ACC cells did not significantly alter the expression of MYB as compared with leukemic cells with MYB activation/duplication. Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC. Our findings also suggest that the gain-of-function activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.