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Chronic sleep disruption and shift work elevate the risk of neurodegeneration and Alzheimer's disease (AD). While disrupted sleep affects canonical AD biomarkers, its impact on other mechanisms, such as circulating microRNAs (miRNAs), remains less understood. Therefore, we here examined the effects of overnight wakefulness on plasma levels of several miRNAs implicated in neurodegeneration and AD, as well as in sleep and circadian regulation—namely miR‐127‐3p, miR‐132‐3p, and miR‐142‐3p. Following a baseline period in each highly controlled in‐lab session, in total 15 healthy normal‐weight young men underwent two conditions on separate occasions, in randomised order: a night of normal sleep, and a night of sustained wakefulness. After overnight wakefulness, morning plasma levels of miR‐127‐3p and miR‐142‐3p were significantly elevated compared with post‐sleep levels. These changes were not associated with the significant increase in self‐reported morning stress levels observed after wakefulness compared with sleep. This study is the first to demonstrate that a single night of wakefulness—mimicking overnight shift work—significantly elevates circulating levels of miR‐127‐3p and miR‐142‐3p in humans. These findings, though based on a limited sample size, suggest a potential molecular link between sleep loss and neurodegeneration, warranting further investigation. Trial Registration: Clinical Trial number: NCT01800253; www.clinicaltrials.gov

Background Circulating microRNAs have shown promise as non-invasive biomarkers and predictors of disease activity. Prior asthma studies using clinical, biochemical and genomic data have not shown excellent prediction of exacerbation. We hypothesized that a panel of circulating microRNAs in a pediatric asthma cohort combined with an exacerbation clinical score might predict exacerbation better than the latter alone. Methods Serum samples from 153 children at randomization in the Childhood Asthma Management Program were profiled for 754 microRNAs. Data dichotomized for asthma exacerbation one year after randomization to inhaled corticosteroid treatment were used for binary logistic regression with miRNA expressions and exacerbation clinical score. Results 12 of 125 well-detected circulating microRNAs had significant odd ratios for exacerbation with miR-206 being most significant. Each doubling of expression of the 12 microRNA corresponded to a 25–67% increase in exacerbation risk. Stepwise logistic regression yielded a 3-microRNA model (miR-146b, miR-206 and miR-720) that, combined with the exacerbation clinical score, had excellent predictive power with a 0.81 AUROC. These 3 microRNAs were involved in NF-kβ and GSK3/AKT pathways. Conclusions This combined circulating microRNA-clinical score model predicted exacerbation in asthmatic subjects on inhaled corticosteroids better than each constituent feature alone. Trial registration ClinicalTrials.gov Identifier: NCT00000575 .

Abstract Aims In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome [hemoglobin A1c (HbA1c) ≥ 8% for at least 6 months] within 4 years, which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating microRNA (miRNA) species associated with a decline in beta cell function. Methods Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. Results Using a backward selection approach, 4 baseline miRNA log2 fold-changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold-changes remained significant predictors of this C-peptide oDI decline ≥20% (P < .05). Increased levels of miRNA-155 [odds ratio (OR): 1.2, 95% confidence interval (CI): 1.1-1.4] and miRNA-130b (OR:1.3, 95% CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR: 0.6, 95% CI: .4-.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24 months (R = 0.22, P < .01 and R = 0.19, P < .01, respectively) and positively correlated with proinsulin at baseline, 24, and 60 months (R = 0.26, P < 0.01, R = 0.26, P < .01, R = 0.18, P < .01, respectively). Conclusion The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

Primary prevention of premature death is a public health concern worldwide. Circulating microRNAs (miRNAs) have been described as potential diagnostic biomarkers for diseases as cancer and cardiovascular disease (CVD). This case-cohort study aimed to investigate the potential relationship between circulating miRNAs and the risk of premature death. A total of 39,242 subjects provided baseline serum samples in 1988–1990. Of these, 345 subjects who died of intrinsic disease (< 65 years old) and for which measurable samples were available were included in this study. We randomly selected a sub-cohort of 879 subjects. Circulatring miR-21, miR-29a, and miR-126 were determined using qRT-PCR. Conditional logistic regression models were used to analyse the data with respect to stratified miRNA levels. Multivariable logistic regression revealed that subjects with high circulating miR-21 and miR-29a individual levels had a significantly higher risk of total death, cancer death, and CVD death than those with medium miR-21 and miR-29a individual levels. Conversely, subjects with low circulating miR-126 levels had a significantly higher risk of total death than those with medium levels. This suggests that circulating miRNAs are associated with the risk of premature death from cancer and CVD, identifying them as potential biomarkers for early detection of high-risk individuals.

Abstract Context Obesity is a global epidemic and an independent risk factor for several diseases. miRNAs are gaining interest as early molecular regulators of various pathological processes. Objective To examine the miRNA signatures in women who are obese and determine the response of miRNAs to acute weight loss. Methods Plasma samples were collected from women who are obese (n = 80) before and after acute weight loss (mean, 7.2%). Plasma samples from age-matched lean volunteers (n = 80) were used as controls. Total RNA was extracted from the plasma samples and subjected to NanoString analysis of 822 miRNAs. The expression level of candidate miRNAs was validated in all participants using quantitative real-time PCR analysis. Results NanoString analysis identified substantial dysregulation of 21 miRNAs in women who are obese that were associated with impaired glucose tolerance, senescence, cardiac hypertrophy, angiogenesis, inflammation, and cell death. Acute weight loss reversed the expression pattern of 18 of these miRNAs toward those seen in the lean control group. Furthermore, real-time PCR validation of all the samples for 13 miRNAs with at least twofold upregulation or downregulation confirmed substantial dysregulation of all the chosen miRNAs in women who are obese at baseline. After acute weight loss, the levels of seven miRNAs in women who are obese and who are lean were comparable, with no statistically significant evidence for differences between the two groups. Conclusions Our study has provided evidence that the circulating miRNAs associated with various disorders are dysregulated in women who are obese. We also found that seven of these miRNAs showed levels comparable to those in lean controls after acute weight loss in women who are obese. Acute weight loss normalized dysregulated circulating microRNAs in women who are obese, providing evidence for microRNAs as potential biomarkers to determine the beneficial effects of weight loss.

BackgroundmiRNAs play a crucial role in the anti-inflammatory effects of inhaled corticosteroids (ICS) in asthma. Vitamin D can modulate the expression of several miRNAs and reduces asthma exacerbations, but its molecular interaction with ICS remains unclear.ObjectiveWe hypothesised that vitamin D influences long-term ICS response through miRNA regulation.MethodsBaseline serum miRNAs were sequenced from 462 subjects in the Childhood Asthma Management Program (CAMP), with 187 randomised to ICS treatment included in this study. Linear regression assessed associations between miRNA expression and prebronchodilator forced expiratory volume in 1 s per cent predicted (FEV1%) change over 4 years, stratified by baseline vitamin D levels and tested in interaction models. Microarray analysis of lymphoblastoid B cells (lymphoblastoid cell lines (LCLs)) from 22 CAMP subjects treated with dexamethasone (DEX), vitamin D or sham identified differentially expressed genes (DEGs). An miRNA target gene network was constructed, clustered and annotated by enrichment analysis. Top miRNAs were evaluated for ICS response prediction.Results12 miRNAs were significantly associated with ICS-mediated FEV1% change in vitamin D insufficient subjects, and 11 miRNAs showed significant interaction with vitamin D (p≤0.05). Three miRNAs were approximately replicated in the Genetics of Asthma in Costa Rica Study. Microarray analysis identified 220 and 240 DEGs in DEX and vitamin D-treated LCLs, respectively. miRNAs hsa-miR-125a-5p, hsa-miR-181a-5p, hsa-miR-101-3p and hsa-miR-107 were enriched in haemopoiesis and leucocyte differentiation pathways (p≤0.05). Two miRNAs, hsa-miR-125a-5p and hsa-miR-181a-5p, predicted ICS response with an area under the receiver operating characteristic curve of 0.86 in the vitamin D insufficient group.ConclusionsVitamin D may modulate ICS response through miRNAs involved in immune cell differentiation, which could serve as biomarkers for ICS response, particularly in vitamin D insufficient individuals.

AimsRemote ischemic conditioning (RIC) alleviates ischemia–reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection.Methods and resultsWe block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0–T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 μm, p = 0.03 and PWV:0.4 ± 0.21 vs −1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC.ConclusionRIC evokes “vascular conditioning” likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling.Clinical Trial Registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT03984123.

This discovery study investigated in healthy subjects whether a short‐term cold exposure may alter circulating microRNAs and metabolic parameters and if co‐expression networks between these factors could be identified. This open randomized crossover (cold vs no cold exposure) study with blind end‐ point evaluation was conducted at 1 center with 10 healthy adult male volunteers. Wearing a cooling vest perfused at 14°C for 2 h reduced the local skin temperature without triggering shivering, increased norepinephrine and blood pressure while decreasing copeptin, C‐peptide and heart rate. Circulating microRNAs measured before and after wearing the cooling vest twice (4 time points) identified 196 mature microRNAs with excellent reproducibility over 72 h. Significant correlations of microRNA expression with copeptin, norepinephrine and C‐peptide were found. A co‐expression‐based microRNA‐microRNA network, as well as microRNA pairs displaying differential correlation as a function of temperature were also detected. This study demonstrates that circulating miRNAs are differentially expressed and coregulated upon cold exposure in humans, supporting their use as predictive and dynamic biomarkers of cardio‐metabolic disorders.

Background Circulating miRNAs (c-miR) have been shown to be potential biomarkers in sarcopenia, but the miRNAs response to aerobic exercise in older people remains inconclusive. We sought to examine the exercise benefits on physical fitness and miRNAs, and to explore the mediating effect of miRNAs on training-induced fitness changes. Methods This controlled trial recruited 58 community-dwelling older adults and randomized them into exercise group (EX) and control group (CON). EX received 8-week supervised moderate intensity cycling training 3x/week. C-miR expression (c-miR-21, c-miR-126, c-miR-146a, c-miR-222), physical fitness (body composition, cardiorespiratory fitness, muscular fitness) and physical activity level (PAL, measured as in daily step counts) were evaluated at baseline, post-training, and post-16-week follow-up. The mediating effect of miRNA expression onto exercise-induced physical fitness change was determined by causal mediation analysis (CMA). Results Exercise significantly improved body fat and cardiorespiratory fitness in older people while maintaining muscle mass and strength, and augmented expression of c-miR-126, c-miR-146a, and c-miR-222 for up to 16 weeks post-training. Notably, older people in EX had substantially higher daily step counts than CON throughout the study even after the active training period. However, CMA revealed no significant indirect effect but a potential mediating effect of c-miR-21, but not the rest, onto the body composition, cardiorespiratory fitness, and lower limb strength. Conclusion An eight-week supervised MICT program promoted a higher level of physical activity up to 16 weeks post-training, which induces better cardiorespiratory fitness and resists decline in muscular measures. C-miRNA, especially c-miR-21, potentially mediates the training effect upon fitness.

MicroRNAs (miRNAs) are a class of small regulatory RNAs around 21-25 nucleotides in length which govern many aspects of immunity including the host innate and adaptive responses to infection. RT-qPCR studies of select microRNAs show that vaccination alters the expression circulating microRNAs but the effect of vaccination on the global microRNA population (i.e. micronome) has never been studied. To describe vaccine associated changes in the expression of microRNAs 21 days after vaccination in children receiving a pandemic influenza (H1N1) vaccination. Serum samples were obtained from children aged 6 months to 12 years enrolled in an open label randomised control trial of two pandemic influenza (H1N1) vaccines, in which participants received either ASO3B adjuvanted split virion or a whole virion non-adjuvanted vaccine. MicroRNA expression was profiled in a discovery cohort of participants prior to, and 21 days after vaccination using an Agilent microarray platform. Findings were followed up by RT-qPCR in the original discovery cohort and then in a validation cohort of participants taken from the same study. 44 samples from 22 children were assayed in a discovery cohort. The microarray results revealed 19 microRNAs were differentially expressed after vaccination after adjustment for multiple testing. The microarray detected ubiquitous expression of several microRNAs which could not be validated by RT-qPCR, many of which have little evidence of existence in publicly available RNA sequencing data. Real time PCR (RT-qPCR) confirmed downregulation of miR-142-3p in the discovery cohort. These findings were not replicated in the subsequent validation cohort (n = 22). This study is the first study to profile microRNA expression after vaccination. An important feature of this study is many of the differentially expressed microRNAs could not be detected and validated by RT-qPCR. This study highlights the care that should be taken when interpreting omics biomarker discovery, highlighting the need for supplementary methods to validate microRNA microarray findings, and emphasises the importance of validation cohorts. Data from similar studies which do not meet these requirements should be interpreted with caution.