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Introduction: The COVID-19 pandemic has caused an unprecedented health threat globally, necessitating innovative and efficient diagnostic approaches for timely identification of infected individuals. Despite few emerging reports, the clinical utility of circulating microRNAs (miRNAs) in early and accurate diagnosis of COVID-19 is not well-evidenced. Hence, this meta-analysis aimed to explore the diagnostic potential of circulating miRNAs for COVID-19. The protocol for this study was officially recorded on PROSPERO under registration number CRD42023494959. Methods: Electronic databases including Embase, PubMed, Scopus, and other sources were exhaustively searched to recover studies published until 16th January, 2024. Pooled specificity, sensitivity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic ratio (DOR), positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were computed from the metadata using Stata 14.0 software. Risk of bias appraisal of included articles was carried out using Review Manager (Rev-Man) 5.3 package through the modified QUADAS-2 tool. Subgroup, heterogeneity, meta-regression and sensitivity analyses were undertaken. Publication bias and clinical applicability were also evaluated via Deeks' funnel plot and Fagan nomogram (scattergram), respectively. Result: A total of 43 studies from 13 eligible articles, involving 5175 participants (3281 COVID-19 patients and 1894 healthy controls), were analyzed. Our results depicted that miRNAs exhibit enhanced pooled specificity 0.91 (95% CI: 0.88–0.94), sensitivity 0.94 (95% CI: 0.91–0.96), DOR of 159 (95% CI: 87–288), and AUC values of 0.97 (95% CI: 0.95–0.98) with high pooled PPV 96% (95% CI: 94–97%) and NPV 88% (95% CI: 86–90%) values. Additionally, highest diagnostic capacity was observed in studies involving larger sample size (greater than 100) and those involving the African population, demonstrating consistent diagnostic effectiveness across various specimen types. Notably, a total of 12 distinct miRNAs were identified as suitable for both exclusion and confirmation of COVID-19 cases, denoting their potential clinical applicability. Conclusion: Our study depicted that miRNAs show significantly high diagnostic accuracy in differentiating COVID-19 patients from healthy counterparts, suggesting their possible use as viable biomarkers. Nonetheless, thorough and wide-ranging longitudinal researches are necessary to confirm the clinical applicability of miRNAs in diagnosing COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate among all major cancers due to a lack of symptoms in early stages, early detection tools, and optimal therapies for late-stage patients. Thus, effective and non-invasive diagnostic tests are greatly needed. Recently, circulating miRNAs have been reported to be altered in PDAC. They are promising biomarkers because of stability in the blood, ease of non-invasive detection, and convenient screening methods. This study aimed to use blood-based miRNA biomarkers and various analysis methods in the development of a machine-learning (ML) model for PDAC. Methods: Blood-based miRNAs associated with PDAC were collected from open sources. miRNA sequences, targeted genes, and involved pathways were used to construct a set of descriptors for an ML model. Results: Bioinformatics analysis revealed that most genes in pancreatic cancer and insulin signaling pathways were targeted by the PDAC-related miRNAs. The best-performing ML model with the Random Forest classifier was able to achieve an accuracy of 88.4%. Model evaluations of an independent PDAC-associated miRNAs test set had 100% accuracy while non-cancer miRNAs had 52.4% accuracy, indicating specificity to PDAC. Conclusions: Our results suggest an ML model developed using blood-based miRNA biomarkers’ target gene, pathway, and sequence features could be potentially implicated in PDAC diagnostics. [ABSTRACT FROM AUTHOR]

Circulating microRNAs (miRNAs) play a pivotal role in the occurrence and development of acute myocardial infarction (AMI), and precise detection of them holds significant clinical implications. The development of luminol-based luminophores in the field of electrochemiluminescence (ECL) for miRNA detection has been significant, while their effectiveness is hindered by the instability of co-reactant hydrogen peroxide (H2O2). In this work, an iron single-atom catalyst (Fe-PNC) was employed for catalyzing the luminol-O2 ECL system to achieve ultra-sensitive detection of myocardial miRNA. Target miRNA triggers a hybridization chain reaction (HCR), resulting in the generation of a DNA product featuring multiple sticky ends that facilitate the attachment of Fe-PNC probes to the electrode surface. The Fe-PNC catalyst exhibits high promise and efficiency for the oxygen reduction reaction (ORR) in electrochemical energy conversion systems. The resulting ECL biosensor allowed ultrasensitive detection of myocardial miRNA with a low detection limit of 0.42 fM and a wide linear range from 1 fM to 1.0 nM. Additionally, it demonstrates exceptional performance when evaluated using serum samples collected from patients with AMI. This work expands the application of single-atom catalysis in ECL sensing and introduces novel perspectives for utilizing ECL in disease diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Introduction The COVID-19 pandemic has caused an unprecedented health threat globally, necessitating innovative and efficient diagnostic approaches for timely identification of infected individuals. Despite few emerging reports, the clinical utility of circulating microRNAs (miRNAs) in early and accurate diagnosis of COVID-19 is not well-evidenced. Hence, this meta-analysis aimed to explore the diagnostic potential of circulating miRNAs for COVID-19. The protocol for this study was officially recorded on PROSPERO under registration number CRD42023494959. Methods Electronic databases including Embase, PubMed, Scopus, and other sources were exhaustively searched to recover studies published until 16th January, 2024. Pooled specificity, sensitivity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic ratio (DOR), positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were computed from the metadata using Stata 14.0 software. Risk of bias appraisal of included articles was carried out using Review Manager (Rev-Man) 5.3 package through the modified QUADAS-2 tool. Subgroup, heterogeneity, meta-regression and sensitivity analyses were undertaken. Publication bias and clinical applicability were also evaluated via Deeks’ funnel plot and Fagan nomogram (scattergram), respectively. Result A total of 43 studies from 13 eligible articles, involving 5175 participants (3281 COVID-19 patients and 1894 healthy controls), were analyzed. Our results depicted that miRNAs exhibit enhanced pooled specificity 0.91 (95% CI: 0.88–0.94), sensitivity 0.94 (95% CI: 0.91–0.96), DOR of 159 (95% CI: 87–288), and AUC values of 0.97 (95% CI: 0.95–0.98) with high pooled PPV 96% (95% CI: 94–97%) and NPV 88% (95% CI: 86–90%) values. Additionally, highest diagnostic capacity was observed in studies involving larger sample size (greater than 100) and those involving the African population, demonstrating consistent diagnostic effectiveness across various specimen types. Notably, a total of 12 distinct miRNAs were identified as suitable for both exclusion and confirmation of COVID-19 cases, denoting their potential clinical applicability. Conclusion Our study depicted that miRNAs show significantly high diagnostic accuracy in differentiating COVID-19 patients from healthy counterparts, suggesting their possible use as viable biomarkers. Nonetheless, thorough and wide-ranging longitudinal researches are necessary to confirm the clinical applicability of miRNAs in diagnosing COVID-19.

Abstract Background Human toxocariasis is a neglected parasitic disease characterised by the syndromes visceral, cerebral, and ocular larva migrans. This disease is caused by the migrating larvae of Toxocara roundworms from dogs and cats, affecting 1.4 billion people globally. Via extracellular vesicles (EVs), microRNAs have been demonstrated to play roles in host–parasite interactions and proposed as circulating biomarkers for the diagnosis and follow-up of parasitic diseases. Methods Small RNA-seq was conducted to identify miRNAs in the infective larvae of T. canis and plasma EV-containing preparations of infected BALB/c mice. Differential expression analysis and target prediction were performed to indicate miRNAs involved in host–parasite interactions and miRNAs associated with visceral and/or cerebral larva migrans in the infected mice. Quantitative real-time polymerase chain reaction (PCR) was used to amplify circulating miRNAs from the infected mice. Results This study reports host and parasite miRNAs in the plasma of BALB/c mice with visceral and cerebral larva migrans and demonstrates the alterations of these miRNAs during the migration of larvae from the livers through the lungs and to the brains of infected mice. After filtering unspecific changes in an irrelevant control, T. canis-derived miRNAs and T. canis infection-induced differential miRNAs are predicted to modulate genes consistently involved in mitogen-activated protein kinase (MAPK) signalling and pathways regulating axon guidance and pluripotency of stem in the infected mice with visceral and cerebral larva migrans. For these plasma circulating miRNAs predicted to be involved in host-parasite crosstalk, two murine miRNAs (miR-26b-5p and miR-122-5p) are experimentally verified to be responsive to larva migrans and represent circulating biomarker candidates for visceral and cerebral toxocariasis in BALB/c mice. Conclusions Our findings provide novel insights into the crosstalk of T. canis and the mammalian host via plasma circulating miRNAs, and prime agents and indicators for visceral and cerebral larva migrans. A deep understanding of these aspects will underpin the diagnosis and control of toxocariasis in humans and animals. Graphical Abstract

Background: Human bloodstream microRNAs (miRNAs) have emerged as a promising predictive and diagnostic biomarker for a range of cancers, including breast cancer. Our objective was to look into new miRNA biomarkers for diagnosis in the serum of patients with breast cancer and track the expression levels at different stages using miRNA profiling. Methods: 53 breast cancer patients and 10 healthy controls had blood samples tested for three miRNAs. miRNAs were extracted from blood and evaluated using real-time quantitative polymerase chain reaction. After extracting genomic DNA, miRNA primer-produced PCR products were sequenced to discover point mutations that may contribute to the illness. Results: After examining miR195, miR200b, and miR331, breast cancer patients had a significantly lower miR195 level than healthy persons. In addition, miR200b expression levels were significantly lower in breast cancer patients than in healthy individuals. In advanced stages, miR331 expression was substantially higher than in healthy people. Conclusion: The findings of our study demonstrated a significant association between the expression of miRNAs and the prognosis of breast cancer. Additional research is necessary to study better the correlation between these circulating miRNAs and the stages of breast cancer. [ABSTRACT FROM AUTHOR]

Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 mg) induced shortterm (,24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 mg), induced persistent mechanical allodynia for .2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator. [ABSTRACT FROM AUTHOR]

Summary: Adipose tissue is the first and primary target organ of obesity and the main source of circulating miRNAs in patients with obesity. This systematic review aimed to analyze and summarize the generation and mechanisms of adipose‐derived miRNAs and their role as early predictors of various obesity‐related complications. Literature searches in the PubMed and Web of Science databases using terms related to miRNAs, obesity, and adipose tissue. Pre‐miRNAs from the Human MicroRNA Disease Database, known to regulate obesity‐related metabolic disorders, were combined for intersection processing. Validated miRNA targets were sorted through literature review, and enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes via the KOBAS online tool, disease analysis, and miRNA transcription factor prediction using the TransmiR v. 2.0 database were also performed. Thirty miRNAs were identified using both obesity and adipose secretion as criteria. Seventy‐nine functionally validated targets associated with 30 comorbidities of these miRNAs were identified, implicating pathways such as autophagy, p53 pathways, and inflammation. The miRNA precursors were analyzed to predict their transcription factors and explore their biosynthesis mechanisms. Our findings offer potential insights into the epigenetic changes related to adipose‐driven obesity‐related comorbidities. [ABSTRACT FROM AUTHOR]

Background: Human toxocariasis is a neglected parasitic disease characterised by the syndromes visceral, cerebral, and ocular larva migrans. This disease is caused by the migrating larvae of Toxocara roundworms from dogs and cats, affecting 1.4 billion people globally. Via extracellular vesicles (EVs), microRNAs have been demonstrated to play roles in host–parasite interactions and proposed as circulating biomarkers for the diagnosis and follow-up of parasitic diseases. Methods: Small RNA-seq was conducted to identify miRNAs in the infective larvae of T. canis and plasma EV-containing preparations of infected BALB/c mice. Differential expression analysis and target prediction were performed to indicate miRNAs involved in host–parasite interactions and miRNAs associated with visceral and/or cerebral larva migrans in the infected mice. Quantitative real-time polymerase chain reaction (PCR) was used to amplify circulating miRNAs from the infected mice. Results: This study reports host and parasite miRNAs in the plasma of BALB/c mice with visceral and cerebral larva migrans and demonstrates the alterations of these miRNAs during the migration of larvae from the livers through the lungs and to the brains of infected mice. After filtering unspecific changes in an irrelevant control, T. canis-derived miRNAs and T. canis infection-induced differential miRNAs are predicted to modulate genes consistently involved in mitogen-activated protein kinase (MAPK) signalling and pathways regulating axon guidance and pluripotency of stem in the infected mice with visceral and cerebral larva migrans. For these plasma circulating miRNAs predicted to be involved in host-parasite crosstalk, two murine miRNAs (miR-26b-5p and miR-122-5p) are experimentally verified to be responsive to larva migrans and represent circulating biomarker candidates for visceral and cerebral toxocariasis in BALB/c mice. Conclusions: Our findings provide novel insights into the crosstalk of T. canis and the mammalian host via plasma circulating miRNAs, and prime agents and indicators for visceral and cerebral larva migrans. A deep understanding of these aspects will underpin the diagnosis and control of toxocariasis in humans and animals. [ABSTRACT FROM AUTHOR]

Background: There are currently no laboratory tests that can accurately predict the likelihood of developing acute graft‐versus‐host disease (aGVHD), a patient's response to treatment, or their survival chance. This research aimed to establish circulating miRNAs as diagnostic, prognostic, or predictive biomarkers of aGVHD. Methods: In a prospective cohort, we studied the incidence of cutaneous aGVHD in AML patients undergoing allo‐HSCT at Shariati Hospital in Tehran, Iran during 2020–2023. Patients with cutaneous aGVHD were labeled as the case group, while patients without cutaneous aGVHD were selected as the control group. Accordingly, the expression levels of six significant miRNAs (miR‐638, miR‐6511b‐5p, miR‐3613‐5p, miR‐455‐3p, miR‐5787, miR‐548a‐3p) were evaluated by quantitative reverse transcription–polymerase chain reaction (RTqPCR) in three different time‐points: before transplantation, on day 14 and day 21 after transplantation. Results: The levels of plasma miR‐455‐3p, miR‐5787, miR‐638, and miR‐3613‐5p were significantly downregulated, while miR‐548a‐3p, and miR‐6511b‐5p were significantly upregulated in individuals with cutaneous aGVHD in comparison to patients without GVHD. Additionally, the possibility for great diagnostic accuracy for cutaneous aGVHD was revealed by ROC curve analysis of differentially expressed miRNAs (DEMs). Conclusion: The study findings encourage us to hypothesize that the aforementioned miRNAs may contribute to the predominance of aGVHD, particularly low‐grade cutaneous aGVHD. [ABSTRACT FROM AUTHOR]

Abstract Background Cervical cancer is a prevalent malignancy of the female reproductive system. Cervical intraepithelial neoplasia (CIN) is a precursor lesion for CC. Various studies have examined circulating microRNAs (miRNAs) as potential early diagnostic markers for CC and CIN. However, the findings have been inconclusive. Therefore, it is necessary to evaluate the diagnostic accuracy and identify potential sources of variability among these studies. Methods: The PubMed, Cochrane Library, Embase, and Web of Science databases were searched to identify relevant literature. Then, Stata 14.0 was utilized to calculate summary estimates for diagnostic parameters, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic (ROC). To scrutinize the heterogeneity, the Cochran-Q test and I2 statistic were utilized. As significant heterogeneity was observed, the random effects model was chosen. To explore potential sources of the heterogeneity, subgroup and regression analyses were conducted. Results: We analysed 12 articles reporting on 24 studies involving 1817 patients and 1731 healthy controls. The pooled sensitivity was 0.77 (95% CI 0.73–0.81), the specificity was 0.81 (95% CI 0.73–0.86), the PLR was 3.99 (95% CI 2.81–5.65), the NLR was 0.28 (95% CI 0.23–0.35), the DOR was 14.18 (95% CI 8.47–23.73), and the area under the curve (AUC) was 0.85 (95% CI 0.81–0.87). Subgroup analysis revealed that multiple miRNAs can improve diagnostic performance; the pooled sensitivity of multiple miRNAs was 0.78 (95% CI 0.68–0.86), the specificity was 0.85 (95% CI 0.78–0.90), and the AUC was 0.89 (95% CI 0.86–0.91). Conclusion: This study suggested that circulating microRNAs may be biomarkers for early CC diagnosis.

Background: Cervical cancer is a prevalent malignancy of the female reproductive system. Cervical intraepithelial neoplasia (CIN) is a precursor lesion for CC. Various studies have examined circulating microRNAs (miRNAs) as potential early diagnostic markers for CC and CIN. However, the findings have been inconclusive. Therefore, it is necessary to evaluate the diagnostic accuracy and identify potential sources of variability among these studies. Methods: The PubMed, Cochrane Library, Embase, and Web of Science databases were searched to identify relevant literature. Then, Stata 14.0 was utilized to calculate summary estimates for diagnostic parameters, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic (ROC). To scrutinize the heterogeneity, the Cochran-Q test and I2 statistic were utilized. As significant heterogeneity was observed, the random effects model was chosen. To explore potential sources of the heterogeneity, subgroup and regression analyses were conducted. Results: We analysed 12 articles reporting on 24 studies involving 1817 patients and 1731 healthy controls. The pooled sensitivity was 0.77 (95% CI 0.73–0.81), the specificity was 0.81 (95% CI 0.73–0.86), the PLR was 3.99 (95% CI 2.81–5.65), the NLR was 0.28 (95% CI 0.23–0.35), the DOR was 14.18 (95% CI 8.47–23.73), and the area under the curve (AUC) was 0.85 (95% CI 0.81–0.87). Subgroup analysis revealed that multiple miRNAs can improve diagnostic performance; the pooled sensitivity of multiple miRNAs was 0.78 (95% CI 0.68–0.86), the specificity was 0.85 (95% CI 0.78–0.90), and the AUC was 0.89 (95% CI 0.86–0.91). Conclusion: This study suggested that circulating microRNAs may be biomarkers for early CC diagnosis. [ABSTRACT FROM AUTHOR]

In searching for new biomarkers, high throughput technique has been widely used by researchers, including for gene expression study. However, the reliability and accuracy of results from high throughput study critically depends on appropriate data management, including normalization methods. Data driven normalization has been introduced as a normalization method for high throughput gene expression study. Thus, this study was conducted to evaluate the performance of various data driven and reference genes normalization methods using a high throughput circulating microRNA expression dataset. A quantification cycle (Cq) dataset generated from a high throughput circulating microRNA study was used to test the normalization methods using HTqPCR package in R software. The normalized Cq generated from different methods were compared descriptively using box plot analysis and coefficient of variance. The box plot analysis showed that quantile normalization produced more homogenous Cq distribution, lesser outliers and reduced coefficient of variance as compared to other normalization methods in screening and validation phases. The overview on quantile normalized Cq showed consistency in its level of expression before and after 2-Cq calculation indicating the reliability of quantile normalized Cq. Quantile normalization is suggested to be used in high throughput miRNA expression study due to its performance in homogenizing the data, reduce outliers and coefficient of variance. [ABSTRACT FROM AUTHOR]

The potential of liquid biopsy for the prognosis and diagnosis of diseases is unquestionable. Within the evolving landscape of disease diagnostics and personalized medicine, circulating microRNAs (c-miRNAs) stand out among the biomarkers found in blood circulation and other biological fluids due to their stability, specificity, and non-invasive detection in biofluids. However, the complexity of human diseases and the limitations inherent in single-marker diagnostics highlight the need for a more integrative approach. It has been recently suggested that a multi-analyte approach offers advantages over the single-analyte approach in the prognosis and diagnosis of diseases. In this review, we explore the potential of combining three well-studied classes of biomarkers found in blood circulation and other biofluids—miRNAs, DNAs, and proteins—to enhance the accuracy and efficacy of disease detection and monitoring. Initially, we provide an overview of each biomarker class and discuss their main advantages and disadvantages highlighting the superiority of c-miRNAs over the other classes of biomarkers. Additionally, we discuss the challenges and future directions in integrating these biomarkers into clinical practice, emphasizing the need for standardized protocols and further validation studies. This integrated approach has the potential to revolutionize precision medicine by offering insights into disease mechanisms, facilitating early detection, and guiding personalized therapeutic strategies. The collaborative power of c-miRNAs with other biomarkers represents a promising frontier in the comprehensive understanding and management of complex diseases. Nevertheless, several challenges must be addressed before this approach can be translated into clinical practice. [ABSTRACT FROM AUTHOR]

Background and Objectives: MicroRNAs are short noncoding RNAs that play an essential role in controlling gene expression at the posttranscriptional level. They can serve as biomarkers in the management of obesity. Circulating miRNAs levels change with exercise, impacting various physiological and biological systems, including structural and functional changes. Aim: The purpose of this study is to evaluate the levels of miRNAs 423-5p and 128-1 in young adolescents with obesity before and after an aerobic exercise programme. We also analyse the relationship between those microRNAs and obesity-related parameters in response to aerobic exercise training. Materials and Methods: A total of 64 adolescent individuals (32 individuals with obesity and 32 healthy individuals) were enrolled in the study to participate in a 6-month aerobic exercise programme. Anthropometric measurements, biochemical parameters and blood samples were collected from all the participants prior to exercise training and after the 6-month programme. Gene expression analysis of the study participants was performed using quantitative real-time PCR. Results: Expression levels of circulating microRNAs 423-5p (p < 0.01) and 128-1 (p < 0.01) differed significantly before and after exercise in the study population. Circulating miRNA 423-5p increased and correlated significantly with BMI while circulating miRNA 128-1 decreased and also significantly correlated with BMI after the 6-month aerobic exercise programme. Logistic regression analysis shows that the elevation in miRNAs expression levels has a strong significant association with the increased levels of the cytokines IL-6 and TNF-α (p < 0.05). Conclusions: Obesity leads to alterations in the expressions of miRNA 423-5p and miRNA 128-1. The significant changes observed after an aerobic exercise programme demonstrate the potential of these miRNAs as diagnostic and prognostic biomarkers for obesity. [ABSTRACT FROM AUTHOR]

Context: The severity of visceral adipose tissue (VAT) inflammation in individuals with obesity is thought to signify obesity subphenotype(s) associated with higher cardiometabolic risk. Yet, this tissue is not accessible for direct sampling in the nonsurgical patient. Objective: We hypothesized that circulating miRNAs (circ-miRs) could serve as biomarkers to distinguish human obesity subgroups with high or low extent of VAT inflammation. Methods: Discovery and validation cohorts of patients living with obesity undergoing bariatric surgery (n = 35 and 51, respectively) were included. VAT inflammation was classified into low/high based on an expression score derived from the messenger RNA levels of TNFA, IL6, and CCL2 (determined by reverse transcription polymerase chain reaction). Differentially expressed circ-miRs were identified, and their discriminative power to detect low/high VAT inflammation was assessed by receiver operating characteristic–area under the curve (ROCAUC) analysis. Results: Fifty three out of 263 circ-miRs (20%) were associated with high-VAT inflammation according to Mann-Whitney analysis in the discovery cohort. Of those, 12 (12/53 = 23%) were differentially expressed according to Deseq2, and 6 significantly discriminated between high- and low-VAT inflammation with ROC-AUC greater than 0.8. Of the resulting 5 circ-miRs that were differentially abundant in all 3 statistical approaches, 3 were unaffected by hemolysis and validated in an independent cohort. Circ-miRs 181b-5p, 1306-3p, and 3138 combined with homeostatic model assessment of insulin resistance (HOMA-IR) exhibited ROC-AUC of 0.951 (95% CI, 0.865-1) and 0.808 (95% CI, 0.654-0.963) in the discovery and validation cohorts, respectively, providing strong discriminative power between participants with low- vs high-VAT inflammation. Predicted target genes of these miRNAs are enriched in pathways of insulin and inflammatory signaling, circadian entrainment, and cellular senescence. Conclusion: Circ-miRs that identify patients with low- vs high-VAT inflammation constitute a putative tool to improve personalized care of patients with obesity. [ABSTRACT FROM AUTHOR]

Abstract Non-traumatic intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke, most often occurring between the ages of 45 and 60. Hypertension is most often the cause of ICH. Less often, atherosclerosis, blood diseases, inflammatory changes in cerebral vessels, intoxication, vitamin deficiencies, and other reasons cause hemorrhages. Cerebral hemorrhage can occur by diapedesis or as a result of a ruptured vessel. This very dangerous disease is difficult to treat, requires surgery and can lead to disability or death. MicroRNAs (miRNAs) are a class of non-coding RNAs (about 18-22 nucleotides) that are involved in a variety of biological processes including cell differentiation, proliferation, apoptosis, etc., through gene repression. A growing number of studies have demonstrated miRNAs deregulation in various cardiovascular diseases, including ICH. In addition, given that computed tomography (CT) and/or magnetic resonance imaging (MRI) are either not available or do not show clear signs of possible vessel rupture, accurate and reliable analysis of circulating miRNAs in biological fluids can help in early diagnosis for prevention of ICH and prognosis patient outcome after hemorrhage. In this review, we highlight the up-to-date findings on the deregulated miRNAs in ICH, and the potential use of miRNAs in clinical settings, such as therapeutic targets and non-invasive diagnostic/prognostic biomarker tools.

Abstract Aims Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking cardiovascular therapy and clinical outcome has been the dream of scientists for decades. Concepts involving embryonic pathways to regenerate adult failing hearts became popular in the early millennium. Since then, abundant data on stem cell research have been published, never reaching widespread application in heart failure therapy. Another conceptual access, using mechanotransduction in cardiac veins to limit myocardial decay, is pressure‐controlled intermittent coronary sinus occlusion (PICSO). Recently, we reported acute molecular signs and signals of PICSO activating regulatory miRNA and inducing cell proliferation mimicking cardiac development in adult failing hearts. According to a previously formulated hypothesis, ‘embryonic recall’, this study aimed to define molecular signals involved in endogenous heart repair during PICSO and study their relation to patient survival. Methods and results We previously reported a study on the acute molecular effects of PICSO in an observational non‐randomized study. Eight out of the thirty‐two patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) were treated with PICSO. Survival was monitored over 10 years, and coronary sinus blood samples were collected during intervention before and after 20 min and tested for miRNA signalling and proliferation when co‐cultured with cardiomyocytes. A numerically lower death rate post‐CRT and PICSO as compared with control CRT only, and a non‐significant reduction in all‐cause mortality risk of 42% was observed (37.5% vs. 54.0%, relative risk = 0.58, 95% confidence interval: 0.17–2.05; P = 0.402). Four miRNAs involved in cell cycle, proliferation, morphogenesis, embryonic development, and apoptosis significantly increased concomitantly in survivors and PICSO compared with a decrease in non‐survivors (hsa‐miR Let7b, P

Objective: Melanoma is the most aggressive and deadly form of skin cancer, especially at later stages. There is currently no excellent diagnostic test established for the diagnosis of melanoma; however, circulating microRNAs (miRNAs) have shown some promise. We seek to conduct a systematic review and meta-analysis to establish the clinical utility of circulating miRNAs in diagnosing melanoma. Methods: PubMed, Wiley, and Web of Science were searched for studies that determined miRNA sensitivity and specificity in patients with melanoma. The included studies were assessed in Stata, and the sensitivity, specificity, summary receiver operating characteristic (SROC), positive likelihood ratio, negative likelihood ratio, and the area under the SROC curve (AUC) were calculated. Results: 9 studies with 898 melanoma patients were included in the meta-analysis. The circulating miRNAs showed high diagnostic accuracy with a sensitivity of 0.89 (p < 0.001), specificity of 0.85 (p < 0.001), diagnostic odds ratio of 45, and an area under the curve of 0.93. Conclusion: Circulating miRNAs have shown a high diagnostic power in detecting melanoma. [ABSTRACT FROM AUTHOR]

Non-traumatic intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke, most often occurring between the ages of 45 and 60. Hypertension is most often the cause of ICH. Less often, atherosclerosis, blood diseases, inflammatory changes in cerebral vessels, intoxication, vitamin deficiencies, and other reasons cause hemorrhages. Cerebral hemorrhage can occur by diapedesis or as a result of a ruptured vessel. This very dangerous disease is difficult to treat, requires surgery and can lead to disability or death. MicroRNAs (miRNAs) are a class of non-coding RNAs (about 18-22 nucleotides) that are involved in a variety of biological processes including cell differentiation, proliferation, apoptosis, etc., through gene repression. A growing number of studies have demonstrated miRNAs deregulation in various cardiovascular diseases, including ICH. In addition, given that computed tomography (CT) and/or magnetic resonance imaging (MRI) are either not available or do not show clear signs of possible vessel rupture, accurate and reliable analysis of circulating miRNAs in biological fluids can help in early diagnosis for prevention of ICH and prognosis patient outcome after hemorrhage. In this review, we highlight the up-to-date findings on the deregulated miRNAs in ICH, and the potential use of miRNAs in clinical settings, such as therapeutic targets and non-invasive diagnostic/prognostic biomarker tools. [ABSTRACT FROM AUTHOR]

Malnutrition is prevalent in patients with chronic kidney disease (CKD), especially those on hemodialysis. Recently, our group described that a new oral nutritional supplement (ONS), specifically designed for malnourished (or at risk) hemodialysis patients with a "similar to the Mediterranean diet" pattern, improved caloric-protein intake, nutritional status and biomarkers of inflammation and oxidation. Our aim in this study was to evaluate whether the new ONS, associated with probiotics or not, may produce changes in miRNA's expression and its target genes in malnourished hemodialysis patients, compared to individualized diet recommendations. We performed a randomized, multicenter, parallel-group trial in malnourished hemodialysis patients with three groups (1: control (C) individualized diet (n = 11); 2: oral nutritional supplement (ONS) + placebo (ONS-PL) (n = 10); and 3: ONS + probiotics (ONS-PR) (n = 10)); the trial was open regarding the intake of ONS or individualized diet recommendations but double-blinded for the intake of probiotics. MiRNAs and gene expression levels were analyzed by RT-qPCR at baseline and after 3 and 6 months. We observed that the expression of miR-29a and miR-29b increased significantly in patients with ONS-PR at 3 months in comparison with baseline, stabilizing at the sixth month. Moreover, we observed differences between studied groups, where miR-29b expression levels were elevated in patients receiving ONS-PR compared to the control group in the third month. Regarding the gene expression levels, we observed a decrease in the ONS-PR group compared to the control group in the third month for RUNX2 and TNFα. TGFB1 expression was decreased in the ONS-PR group compared to baseline in the third month. PTEN gene expression was significantly elevated in the ONS-PR group at 3 months in comparison with baseline. LEPTIN expression was significantly increased in the ONS-PL group at the 3-month intervention compared to baseline. The new oral nutritional supplement associated with probiotics increases the expression levels of miR-29a and miR-29b after 3 months of intervention, modifying the expression of target genes with anti-inflammatory and anti-fibrotic actions. This study highlights the potential benefit of this oral nutritional supplement, especially associated with probiotics, in malnourished patients with chronic renal disease on hemodialysis. [ABSTRACT FROM AUTHOR]

White matter lesions (WML) emerge as a consequence of vascular injuries in the brain. While they are commonly observed in aging, associations have been established with neurodegenerative and neurological disorders such as dementia or stroke. Despite substantial research efforts, biological mechanisms are incomplete and biomarkers indicating WMLs are lacking. Utilizing data from the population-based Study of Health in Pomerania (SHIP), our objective was to identify plasma-circulating micro-RNAs (miRNAs) associated with WMLs, thus providing a foundation for a comprehensive biological model and further research. In linear regression models, direct association and moderating factors were analyzed. In 648 individuals, we identified hsa-miR-425-5p as directly associated with WMLs. In subsequent analyses, hsa-miR-425-5p was found to regulate various genes associated with WMLs with particular emphasis on the SH3PXD2A gene. Furthermore, miR-425-5p was found to be involved in immunological processes. In addition, noteworthy miRNAs associated with WMLs were identified, primarily moderated by the factors of sex or smoking status. All identified miRNAs exhibited a strong over-representation in neurodegenerative and neurological diseases. We introduced hsa-miR-425-5p as a promising candidate in WML research probably involved in immunological processes. Mir-425-5p holds the potential as a biomarker of WMLs, shedding light on potential mechanisms and pathways in vascular dementia. [ABSTRACT FROM AUTHOR]

Purpose: Common variable immunodeficiency (CVID) is a primary antibody deficiency that commonly manifests as recurrent infections. Many CVID patients also suffer from immune dysregulation, an inflammatory condition characterized by polyclonal lymphocytic tissue infiltration and associated with increased morbidity and mortality. The genetic cause is unknown in most CVID patients and epigenetic alterations may contribute to the broad range of clinical manifestations. MicroRNAs are small non-coding RNAs that are involved in epigenetic modulation and may contribute to the clinical phenotype in CVID. Methods: Here, we determined the circulating microRNAome and plasma inflammatory proteins of a cohort of CVID patients with various levels of immune dysregulation and compared them to healthy controls. A set of deregulated microRNAs was validated by qPCR and correlated to inflammatory proteins and clinical findings. Results: Levels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID. Conclusion: Collectively, our data show that microRNAs correlate with the inflammatory response in CVID. Further investigations are needed to elucidate the role of miRNAs in the development of CVID-related immune dysregulation. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy (CH) is an adaptational enlargement of the myocardium, in exposure to altered stress conditions or in case of injury which can lead to heart failure and death. MicroRNAs (miRNAs) are non-coding RNAs that play a significant role in modulating gene expression. Here, we aimed to identify new miRNAs effective in an experimental CH model and to find an epigenetic biomarker that could demonstrate therapeutic targets responsible for the pathology of heart tissue and serum. In this study, Sprague–Dawley male rats were divided into the training group (TG, n=9) and the control group (CG, n=6). Systolic and diastolic dimensions of the left ventricle and myocardial wall thickness were measured by echocardiography to assess CH. After the exercise program of the rats, miRNA expression measurements and histological analyses were performed. The 25,000 genes in the rat genome were searched using microarray analysis. A total of 128 miRNAs were selected according to the fold change rates, and nine miRNAs were validated for expression analysis. The terminal deoxynucleotidyl transferase dUTP nick (TUNEL) method was used to detect apoptotic cells. Cell proliferation was evaluated by the proliferative cell nuclear antigen (PCNA) method. Necrosis, bleeding, and intercellular edema were detected in TG. The mean histopathological score was higher in TG (p=0.03). There were rarely positive cells for apoptosis of both groups in cardiomyocytes. In the receiver characteristic curve analysis (ROC), the heart tissue rno-miR-290 had an area under the curve (AUC) of 0.920 with 100% sensitivity and 89.90% specificity (p=0.045), rno-miR-194-5p had AUC of 0.940 with 83.33% sensitivity and 100% specificity (p=0.003), and the serum rno-miR-132-3p AUC was 0.880 with 66.67% sensitivity and 100% specificity (p=0.004) in TG. miR-194-5p was used as a therapeutic target for remodeling the cardiac process. While miR-290 contributes to CH as a negative regulator, miR-132 in serum is effective in the pathological and physiological cardiac remodeling process and is a candidate biomarker. [ABSTRACT FROM AUTHOR]

Aims: Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking cardiovascular therapy and clinical outcome has been the dream of scientists for decades. Concepts involving embryonic pathways to regenerate adult failing hearts became popular in the early millennium. Since then, abundant data on stem cell research have been published, never reaching widespread application in heart failure therapy. Another conceptual access, using mechanotransduction in cardiac veins to limit myocardial decay, is pressure‐controlled intermittent coronary sinus occlusion (PICSO). Recently, we reported acute molecular signs and signals of PICSO activating regulatory miRNA and inducing cell proliferation mimicking cardiac development in adult failing hearts. According to a previously formulated hypothesis, 'embryonic recall', this study aimed to define molecular signals involved in endogenous heart repair during PICSO and study their relation to patient survival. Methods and results: We previously reported a study on the acute molecular effects of PICSO in an observational non‐randomized study. Eight out of the thirty‐two patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) were treated with PICSO. Survival was monitored over 10 years, and coronary sinus blood samples were collected during intervention before and after 20 min and tested for miRNA signalling and proliferation when co‐cultured with cardiomyocytes. A numerically lower death rate post‐CRT and PICSO as compared with control CRT only, and a non‐significant reduction in all‐cause mortality risk of 42% was observed (37.5% vs. 54.0%, relative risk = 0.58, 95% confidence interval: 0.17–2.05; P = 0.402). Four miRNAs involved in cell cycle, proliferation, morphogenesis, embryonic development, and apoptosis significantly increased concomitantly in survivors and PICSO compared with a decrease in non‐survivors (hsa‐miR Let7b, P < 0.01; hsa‐miR‐ 421, P < 0.006; hsa‐miR 363‐3p, P < 0.03 and hsa‐miR 19b‐3p P < 0.01). In contrast, three miRNAs involved in proliferation and survival, determining cell fate, and recycling endosomes decreased in survivors and PICSO (hsa miR 101‐3p, P < 0.03; hsa‐miR 25‐3p, P < 002; hsa‐miR 30d‐5p P < 0.04). In vitro cellular proliferation increased in survivors and lowered in non‐survivors showing a pattern distinction, discriminating longevity according to up to 10‐year survival in heart failure patients. Conclusions: This study proposes that generating regenerative signals observed during PICSO intervention relate to patient outcomes. Morphogenetic pathways induced by periods of flow reversal in cardiac veins in a domino‐like pattern transform embryonic into regenerative signals. Studies supporting the conversion of mechanochemical signals into regenerative molecules during PICSO are warranted to substantiate predictive power on patient longevity, opening new therapeutic avenues in otherwise untreatable heart failure. [ABSTRACT FROM AUTHOR]

Abstract Presbyacusis, sudden sensorineural hearing loss (SNHL), noise‐induced hearing loss, and drug‐induced deafness are the most common types of acquired SNHL. At present, the diagnosis of these hearing disorders is mainly based on the medical history and audiological examination. Due to the lack of diagnostic biomarkers, diagnosis of acquired sensorineural hearing loss is difficult. Previous studies have suggested that microRNAs (miRNAs) serve essential roles in pathophysiological processes, and they are stable, tissue enriched, and could be determined in a quantitative manner. Therefore, they could be potential noninvasive biomarkers for acquired SNHL. This review provided a comprehensive overview of the similarities and differences in altered circulating miRNAs (cimiRNAs) (plasma, serum, whole blood, and perilymph) in various disorders, and highlighted the regulatory functions of cimiRNAs on the development, monitoring and prognosis of the four most common types of acquired SNHL.

Abstract Background and aim Certain serum levels of microRNAs (miRNAs) throughout the body can be helpful for cancer diagnosis and prognosis. The miRNAs can be secreted from the papillary thyroid cancer (PTC) into the circulatory system. Accordingly, this study aimed to measure the serum levels of miR-146b, miR-155 and miR-375 to evaluate their diagnostic potentials in distinguish of benign from malignant lesions. Materials and methods The serum levels of miRNAs were measured by real-time quantitative RT-PCR among100 patients with benign thyroid nodules and 30 patients with PTC. Results The mean miR-375 and miR-155 expression levels in the PTC group were greater when compared with the benign group. The area under the ROC curve (AUC) was estimated at 0.81 for the miR-375 with 0.76% sensitivity and 0.80% specificity to distinguish between benign and PTC lesions. The AUC was calculated to be 0.75 for the miR-155 with 0.69% sensitivity and 0.90% specificity. Conclusion According to the results of this study, the serum levels of miR-155 and miR-375 were increased in the patients with PTC, which may be useful as alternative seromarkers for the PTC.

Abstract Background MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Differential miRNA expression, which is widely shown to be associated with the pathogenesis of various diseases, can be influenced by lifestyle factors, including smoking. This study aimed to investigate the plasma miRNA signature of smoking habits, the potential effect of smoking cessation on miRNA levels, and relate the findings with lung cancer incidence. Results A targeted RNA-sequencing approach measured plasma miRNA levels in 2686 participants from the population-based Rotterdam study cohort. The association between cigarette smoking (current versus never) and 591 well-expressed miRNAs was assessed via adjusted linear regression models, identifying 41 smoking-associated miRNAs that passed the Bonferroni-corrected threshold (P

Objective: Melanoma is the most aggressive and deadly form of skin cancer, especially at later stages. There is currently no excellent diagnostic test established for the diagnosis of melanoma; however, circulating microRNAs (miRNAs) have shown some promise. We seek to conduct a systematic review and meta-analysis to establish the clinical utility of circulating miRNAs in diagnosing melanoma.Methods: PubMed, Wiley, and Web of Science were searched for studies that determined miRNA sensitivity and specificity in patients with melanoma. The included studies were assessed in Stata, and the sensitivity, specificity, summary receiver operating characteristic (SROC), positive likelihood ratio, negative likelihood ratio, and the area under the SROC curve (AUC) were calculated.Results: 9 studies with 898 melanoma patients were included in the meta-analysis. The circulating miRNAs showed high diagnostic accuracy with a sensitivity of 0.89 (p < 0.001), specificity of 0.85 (p < 0.001), diagnostic odds ratio of 45, and an area under the curve of 0.93.Conclusion: Circulating miRNAs have shown a high diagnostic power in detecting melanoma.

Background: Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA‐mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes. Methods: Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real‐time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool. Results: Alterations were found in circulating miRNAs in CP patients compared to healthy controls. Further studies were conducted on 12 circulating miRNAs enriched in the pancreas, other tissues and other diseases including cancer and fibrosis. Approximately 2888 mRNAs in the pancreas were their targets, demonstrating interactions with 76 small molecules. Three miRNAs exhibited interactions with morphine and five exhibited interactions with glucose. The miRNA panel targeted 22 genes associated with pancreatitis. The islet‐specific, acinar cell‐specific and liver‐specific miRNAs were elevated at 6 h after islet infusion and returned to baseline levels 3 months after TPIAT. Circulating levels of miRNAs returned to pre‐transplant levels 1‐year post‐transplant. Circulating miRNAs measured before and 6 h after islet infusion were directly or inversely associated with metabolic outcomes at 3 and 6 months post‐transplant. Conclusions: miRNAs may contribute to CP pathogenesis, and elevated circulating levels may be specific to pancreatic inflammation and fibrosis, warranting further investigation. [ABSTRACT FROM AUTHOR]

The three most common genitourinary malignancies (prostate/kidney/bladder cancers) constitute a substantial proportion of all cancer cases, mainly in the elderly population. Early detection is key to maximizing the patients' survival, but the lack of highly accurate biomarkers that might be used through non-/minimally invasive methods has impaired progress in this domain. Herein, we sought to develop a minimally invasive test to detect and discriminate among those urological cancers based on miRNAs assessment through ddPCR. Plasma samples from 268 patients with renal cell (RCC; n = 119), bladder (BlCa; n = 73), and prostate (PCa; n = 76) carcinomas (UroCancer group), and 74 healthy donors were selected. Hsa-miR-126-3p, hsa-miR-141-3p, hsa-miR-153-5p, hsa-miR-155-5p, hsa-miR-182-5p, hsa-miR-205-5p, and hsa-miR-375-3p levels were assessed. UroCancer cases displayed significantly different circulating hsa-miR-182-5p/hsa-miR-375-3p levels compared to healthy donors. Importantly, the hsa-miR-155-5p/hsa-miR-375-3p panel detected RCC with a high specificity (80.54%) and accuracy (66.04%). Furthermore, the hsa-miR-126-3p/hsa-miR-375-3p panel identified BlCa with a 94.87% specificity and 76.45% NPV whereas higher hsa-miR-126-3p levels were found in PCa patients. We concluded that plasma-derived miRNAs can identify and discriminate among the main genitourinary cancers, with high analytical performance. Although validation in a larger cohort is mandatory, these findings demonstrate that circulating miRNA assessment by ddPCR might provide a new approach for early detection and risk stratification of the most common urological cancers. [ABSTRACT FROM AUTHOR]

There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage degradation and joint inflammation. As the most common aging-related joint disease, OA is marked by inadequate extracellular matrix synthesis and the breakdown of articular cartilage. However, traditional diagnostic methods for OA, relying on clinical assessments and radiographic imaging, often need to catch up in detecting early-stage disease or i accurately predicting its progression. Consequently, there is a growing interest in identifying reliable biomarkers that can facilitate early diagnosis and prognosis of OA. MicroRNAs (miRNAs) have emerged as potential candidates due to their involvement in various cellular processes, including cartilage homeostasis and inflammation. This review explores the feasibility of circulating miRNAs as diagnostic and prognostic biomarkers in OA, focusing on knee OA while shedding light on the challenges and opportunities associated with their implementation in clinical practice. [ABSTRACT FROM AUTHOR]

Background and Objectives: MicroRNAs are short noncoding RNAs that play an essential role in controlling gene expression at the posttranscriptional level. They can serve as biomarkers in the management of obesity. Circulating miRNAs levels change with exercise, impacting various physiological and biological systems, including structural and functional changes. Aim: The purpose of this study is to evaluate the levels of miRNAs 423-5p and 128-1 in young adolescents with obesity before and after an aerobic exercise programme. We also analyse the relationship between those microRNAs and obesity-related parameters in response to aerobic exercise training. Materials and Methods: A total of 64 adolescent individuals (32 individuals with obesity and 32 healthy individuals) were enrolled in the study to participate in a 6-month aerobic exercise programme. Anthropometric measurements, biochemical parameters and blood samples were collected from all the participants prior to exercise training and after the 6-month programme. Gene expression analysis of the study participants was performed using quantitative real-time PCR. Results: Expression levels of circulating microRNAs 423-5p (p < 0.01) and 128-1 (p < 0.01) differed significantly before and after exercise in the study population. Circulating miRNA 423-5p increased and correlated significantly with BMI while circulating miRNA 128-1 decreased and also significantly correlated with BMI after the 6-month aerobic exercise programme. Logistic regression analysis shows that the elevation in miRNAs expression levels has a strong significant association with the increased levels of the cytokines IL-6 and TNF-α (p < 0.05). Conclusions: Obesity leads to alterations in the expressions of miRNA 423-5p and miRNA 128-1. The significant changes observed after an aerobic exercise programme demonstrate the potential of these miRNAs as diagnostic and prognostic biomarkers for obesity.

Background: Circulating miRNAs have been implicated in various aspects of diabetic wound healing, including inflammation, angiogenesis, and extracellular matrix remodeling. Thus, in alternative herbal medicine strategies, miRNAs will be potential therapeutic molecular targets in nonhealing wounds. These could be valuable elements for understanding the molecular basis of diabetic wound healing and could be used as good elements in bioinformatics. Objectives: To elucidate the molecular mechanisms of microRNAs in association with apoptosis-inducing genes in controlling skin wound healing in diabetic wounds treated with green tea polyphenols (GTPs). Methods: Green tea hydro extract (GTE) at doses of100–200 mg/ml was topically applied to the skin tissues of rats with T1DM induced by a single dose of streptozotocin (STZ; 100 mg/kg, in 0.01 M sodium citrate, pH 4.3–4.5) injected intraperitoneally for seven consecutive days to induce T1DM. The rats were treated with green tea for three weeks. A sterile surgical blade was used to inflict a circular wound approximately 2 cm in diameter on the anterior-dorsal side of previously anesthetized rats by a combination of ketamine hydrochloride (50 mg/kg, i.e., body weight) and xylazine hydrochloride. Afterward, the molecular roles of the circulating miRNAs miR-21, miR-23a, miR-146a, and miR-29b and apoptotic genes were determined by quantitative real-time PCR to evaluate Bax, Caspase-3, and Bcl-2 in wound healing. In addition, HPLC analysis was also performed to estimate the active polyphenols (GTPs) present in the hydro extract of green tea leaves. Results: Wound healing was improved in diabetic skin wounds following treatment with GTE at doses of 100–200 mg/dl for three weeks. The wound parameters contraction, epithelialization, and scar formation significantly improved in a short time (14 days) compared to the longer periods identified in diabetic non-treated rats (20 days) and the standard control (15.5 days). Molecular analyses reported a significant increase in the levels of miR-21, miR-23a, and miR-146a and a decrease in the levels of miR-29b in green tea-treated diabetic rats compared to those in the standard control and STZ-diabetic non-treated rats. In addition, the molecular apoptotic genes Bax and caspase-3 significantly increased, and the BcL-2 gene significantly decreased following treatment with green tea polyphenols. Conclusions: The data showed that active green tea polyphenols (GTPs) present in GTE significantly improved diabetic wound healing by controlling apoptotic genes and the circulating microRNAs miR-21, miR-23a, miR-146a, and miR-29b, which might be involved in cellular apoptosis and angiogenesis processes. Thus, to establish a future model for the treatment of diabetic wounds, further studies are needed to understand the potential association of these biological parameters with the wound-healing process in diabetic wounds.

Abstract Background Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA‐mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes. Methods Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real‐time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool. Results Alterations were found in circulating miRNAs in CP patients compared to healthy controls. Further studies were conducted on 12 circulating miRNAs enriched in the pancreas, other tissues and other diseases including cancer and fibrosis. Approximately 2888 mRNAs in the pancreas were their targets, demonstrating interactions with 76 small molecules. Three miRNAs exhibited interactions with morphine and five exhibited interactions with glucose. The miRNA panel targeted 22 genes associated with pancreatitis. The islet‐specific, acinar cell‐specific and liver‐specific miRNAs were elevated at 6 h after islet infusion and returned to baseline levels 3 months after TPIAT. Circulating levels of miRNAs returned to pre‐transplant levels 1‐year post‐transplant. Circulating miRNAs measured before and 6 h after islet infusion were directly or inversely associated with metabolic outcomes at 3 and 6 months post‐transplant. Conclusions miRNAs may contribute to CP pathogenesis, and elevated circulating levels may be specific to pancreatic inflammation and fibrosis, warranting further investigation.

Modern dietary habits are linked to high exposure to Advanced Glycation End products (AGEs) mainly due to the dramatic increase in the consumption of highly processed foods in recent years. Body levels of these compounds vary with food intake and are almost interconnected with age and health status, formally embodying indicators of oxidative stress and inflammation in adults. However, the relationship between AGEs and health issues has not been definitively understood in children, and several pediatric investigations have produced conflicting evidence. Besides, despite extensive research, there are no universally accepted analytical techniques for measuring AGE levels in the human body, with several approaches available, each with its advantages and disadvantages. This pilot study aimed to investigate the association between urinary AGEs, measured using spectrofluorimetry-based assays, and circulating microRNAs (c-miRNAs) in a subsample (n = 22) of Italian children participating in the I.Family Study. Anthropometric measurements, biochemical markers, and miRNA profiles were assessed. The first indication of a relationship between urinary AGEs and c-miRNAs in the context of obesity was found. Specifically, four miRNAs, hsa-miR-10b-5p, hsa-miR-501-5p, hsa-miR-874-3p, and hsa-miR-2355-5p were significantly associated with levels of urinary AGEs. The association between AGEs, obesity, inflammation markers, and specific miRNAs highlights the complex interplay between these factors and their potential impact on cellular and tissue homeostasis. The discovery of altered c-miRNAs profiling has the potential to offer innovative methods for assessing early changes in the body's AGE pool and allow recognition of an increased risk of disease susceptibility, routinely undetected until metabolic complications are identified. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is the most common cause of cancer death, with 75% of cases being diagnosed in late stages. This study aimed to determine potential miRNAs as biomarkers for the early detection of LC in chronic obstructive pulmonary disease (COPD) cases. Ninety-nine patients were included, with registered clinical and lung function parameters followed for 6 years. miRNAs were determined in 16 serum samples from COPD patients (four with LC and four controls) by next generation sequencing (NGS) at LC diagnosis and 3 years before. The validation by qPCR was performed in 33 COPD-LC patients and 66 controls at the two time points. Over 170 miRNAs (≥10 TPM) were identified; among these, miR-224-5p, miR-206, miR-194-5p, and miR-1246 were significantly dysregulated (p < 0.001) in COPD-LC 3 years before LC diagnosis when compared to the controls. The validation showed that miR-1246 and miR-206 were differentially expressed in COPD patients who developed LC three years before (p = 0.035 and p = 0.028, respectively). The in silico enrichment analysis showed miR-1246 and miR-206 to be linked to gene mediators in various signaling pathways related to cancer. Our study demonstrated that miR-1246 and miR-206 have potential value as non-invasive biomarkers of early LC detection in COPD patients who could benefit from screening programs. [ABSTRACT FROM AUTHOR]

Background and aim: Certain serum levels of microRNAs (miRNAs) throughout the body can be helpful for cancer diagnosis and prognosis. The miRNAs can be secreted from the papillary thyroid cancer (PTC) into the circulatory system. Accordingly, this study aimed to measure the serum levels of miR-146b, miR-155 and miR-375 to evaluate their diagnostic potentials in distinguish of benign from malignant lesions. Materials and methods: The serum levels of miRNAs were measured by real-time quantitative RT-PCR among100 patients with benign thyroid nodules and 30 patients with PTC. Results: The mean miR-375 and miR-155 expression levels in the PTC group were greater when compared with the benign group. The area under the ROC curve (AUC) was estimated at 0.81 for the miR-375 with 0.76% sensitivity and 0.80% specificity to distinguish between benign and PTC lesions. The AUC was calculated to be 0.75 for the miR-155 with 0.69% sensitivity and 0.90% specificity. Conclusion: According to the results of this study, the serum levels of miR-155 and miR-375 were increased in the patients with PTC, which may be useful as alternative seromarkers for the PTC. [ABSTRACT FROM AUTHOR]

Background and aim—Alterations in circulating microRNA (miRNA) expression patterns are thought to be involved in the early stages of prediabetes, as well as in the progression to overt type 2 diabetes mellitus (T2D) and its vascular complications. However, most research findings are conflicting, in part due to differences in miRNA extraction and normalization methods, and in part due to differences in the study populations and their selection. This cross-sectional study seeks to find new potentially useful biomarkers to predict and/or diagnose T2D by investigating the differential expression patterns of circulating miRNAs in the serum of patients with impaired fasting glucose (IFG) and new-onset T2D, with respect to euglycemic controls, using a high-throughput 384-well array and real-time PCR. Methods—Thirty subjects, aged 45–65 years, classified into three matched groups (of 10 participants each) according to their glycometabolic status, namely (1) healthy euglycemic controls, (2) patients with IFG and (3) patients with new-onset, uncomplicated T2D (<2 years since diagnosis) were enrolled. Circulating miRNAs were extracted from blood serum and profiled through real-time PCR on a commercial 384 well-array, containing spotted forward primers for 372 miRNAs. Data analysis was performed by using the online data analysis software GeneGlobe and normalized by the global Ct mean method. Results—Of the 372 analyzed miRNAs, 33 showed a considerably different expression in IFG and new-onset T2D compared to healthy euglycemic controls, with 2 of them down-regulated and 31 up-regulated. Stringent analysis conditions, using a differential fold regulation threshold ≥ 10, revealed that nine miRNAs (hsa-miR-3610, hsa-miR-3200-5p, hsa-miR-4651, hsa-miR-3135b, hsa-miR-1281, hsa-miR-4301, hsa-miR-195-5p, hsa-miR-523-5p and hsa-let-7a-5p) showed a specific increase in new-onset T2D patients compared to IFG patients, suggesting their possible role as early biomarkers of progression from prediabetes to T2D. Moreover, by conventional fold regulation thresholds of ±2, hsa-miR-146a-5p was down-regulated and miR-1225-3p up-regulated in new-onset T2D patients only. Whereas hsa-miR-146a-5p has a well-known role in glucose metabolism, insulin resistance and T2D complications, no association between hsa-miR-1225-3p and T2D has been previously reported. Bioinformatic and computational analysis predict a role of hsa-miR-1225-3p in the pathogenesis of T2D through the interaction with MAP3K1 and HMGA1. Conclusions—The outcomes of this study could aid in the identification and characterization of circulating miRNAs as potential novel biomarkers for the early diagnosis of T2D and may serve as a proof-of-concept for future mechanistic investigations. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Differential miRNA expression, which is widely shown to be associated with the pathogenesis of various diseases, can be influenced by lifestyle factors, including smoking. This study aimed to investigate the plasma miRNA signature of smoking habits, the potential effect of smoking cessation on miRNA levels, and relate the findings with lung cancer incidence. Results: A targeted RNA-sequencing approach measured plasma miRNA levels in 2686 participants from the population-based Rotterdam study cohort. The association between cigarette smoking (current versus never) and 591 well-expressed miRNAs was assessed via adjusted linear regression models, identifying 41 smoking-associated miRNAs that passed the Bonferroni-corrected threshold (P < 0.05/591 = 8.46 × 10–5). Moreover, we found 42 miRNAs with a significant association (P < 8.46 × 10–5) between current (reference group) and former smokers. Then, we used adjusted linear regression models to explore the effect of smoking cessation time on miRNA expression levels. The expression levels of two miRNAs were significantly different within 5 years of cessation (P < 0.05/41 = 1.22 × 10–3) from current smokers, while for cessation time between 5 and 15 years we found 19 miRNAs to be significantly different from current smokers, and finally, 38 miRNAs were significantly different after more than 15 years of cessation time (P < 1.22 × 10–3). These results imply the reversibility of the smoking effect on plasma levels of at least 38 out of the 41 smoking-miRNAs following smoking cessation. Next, we found 8 out of the 41 smoking-related miRNAs to be nominally associated (P < 0.05) with the incidence of lung cancer. Conclusions: This study demonstrates smoking-related dysregulation of plasma miRNAs, which might have a potential for reversibility when comparing different smoking cessation groups. The identified miRNAs are involved in several cancer-related pathways and include 8 miRNAs associated with lung cancer incidence. Our results may lay the groundwork for further investigation of miRNAs as potential mechanism linking smoking, gene expression and cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent decades, neoadjuvant chemotherapy has proven to be a viable therapeutic option, particularly in cases of high-risk early or locally advanced breast cancer, for reducing tumor size, improving surgical outcomes, and evaluating full histological responses. Thus, individualizing post-neoadjuvant therapy has the potential to enhance prognosis. However, individual responses to therapy and long-term prognosis remain highly unpredictable. The current scenario requires the identification of biomarkers that accurately forecast responses to neoadjuvant therapy and identify patients who will not benefit from standard regimens. Circulating microRNAs have emerged as potential non-invasive biomarkers for breast cancer management. However, discrepancies between different studies currently hamper the implementation of circulating microRNAs, as a significant biomarker, in clinical practice. The potential role of circulating microRNAs (miRNAs) as biomarkers in breast cancer (BC) management has been widely reported. However, the numerous discrepancies between studies in this regard hinders the implementation of circulating miRNAs in routine clinical practice. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of predicting NAC response may lead to prognostic improvements by individualizing post-neoadjuvant therapy. In this context, the present meta-analysis aims to clarify circulating miRNAs' predictive role with respect to NAC response among BC patients. We conducted a comprehensive literature search on five medical databases until 16 February 2023. We pooled the effect sizes of each study by applying a random-effects model. Cochran's Q test (p-level of significance set at 0.05) scores and I2 values were assessed to determine between-study heterogeneity. The PROBAST (Prediction Model Risk of Bias Assessment Tool) tool was used to evaluate the selected studies' risk of bias. Overall, our findings support the hypothesis that circulating miRNAs, specifically miR-21-5p and miR-155-5p, may act as predictive biomarkers in the neoadjuvant setting among BC patients. However, due to the limited number of studies included in this meta-analysis and the high degrees of clinical and statistical heterogeneity, further research is required to confirm the predictive power of circulating miR-21-5p and miR-155-5p. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a leading cause of cancer-related deaths among women worldwide. Neoadjuvant therapy (NAT) is increasingly being used to reduce tumor burden prior to surgical resection. However, current techniques for assessing tumor response have significant limitations. Additionally, drug resistance is commonly observed, raising a need to identify biomarkers that can predict treatment sensitivity and survival outcomes. Circulating microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have been shown to play a significant role in cancer progression as tumor inducers or suppressors. The expression of circulating miRNAs has been found to be significantly altered in breast cancer patients. Moreover, recent studies have suggested that circulating miRNAs can serve as non-invasive biomarkers for predicting response to NAT. Therefore, this review provides a brief overview of recent studies that have demonstrated the potential of circulating miRNAs as biomarkers for predicting the clinical response to NAT in BC patients. The findings of this review will strengthen future research on developing miRNA-based biomarkers and their translation into medical practice, which could significantly improve the clinical management of BC patients undergoing NAT. [ABSTRACT FROM AUTHOR]

Abstract Background Early diagnosis of medically intractable epilepsy is challenging in clinical work. P-glycoprotein (P-gp) is one of the most important multidrug efflux transporters, which has been demonstrated to contribute to the drug resistance of intractable epilepsy. The present study was aimed to explore the diagnostic value of microRNAs (miRNAs) targeting P-gp for medically intractable epilepsy. Methods Thirty-six patients with intractable epilepsy and 36 epilepsy patients responsive to anti-epilepsy drugs, who visited Jinshan Hospital of Fudan University from September 2014 to September 2016, were enrolled in this study. Clinical information of the patients was obtained by retrospectively reviewing medical records. MiRNAs with differential serum expression between the two groups of patients were detected by microarray assay. Meanwhile, miRNAs that were confirmed to regulate P-gp in vitro by western blot were selected for further validation. In the validation phase, reverse transcription quantitative PCR (RT-qPCR) was conducted to confirm the differential expression of the candidate miRNAs in the epilepsy cohorts. Receiver operating characteristic (ROC) curve analysis was carried out to evaluate the diagnostic value of the miRNAs for intractable epilepsy. Results Three miRNAs including miR-6514-3p, miR-6076-5p, and miR-6855-3p were identified to be candidate miRNAs by microarray assay. The results of western blotting validated that miR-146a-5p and miR-138-5p could regulate P-gp expression in vitro, so they were included in the candidate miRNAs for further validation. In the validation phase, the results of RT-qPCR indicated that compared with drug-responsive patients, the patients with intractable epilepsy showed decreased level of miR-138-5p and increased level of miR-146a-5p. The results of ROC curve analysis indicated that miR-138-5p (AUC = 0.877) and miR-146a-5p (AUC = 0.866) had high diagnostic value for intractable epilepsy. In addition, the miR-panel composed of miR-138-5p and miR-146a-5p showed higher diagnostic value (AUC = 0.926) than the miRNAs selected by microarray assay. Conclusions Our results indicated that the dysregulated miR-138-5p and miR-146a-5p which target P-gp expression have high potential as peripheral biomarkers for medically intractable epilepsy.

Insulin resistance (IR) is type 2 diabetes’ hallmark. MiRNAs regulate many target genes that makes them attractive candidates for regulating insulin production, secretion and action. Therefore, we anticipate a change in the circulatory profile of miRNAs in IR subjects compared to normal glucose tolerance subjects. In the present study, we sought to identify the circulating miRNAs associated with IR as biomarkers in Qatari population. The circulating miRNA profile was assessed in a pilot study of healthy volunteers (n = 22) whose insulin sensitivity was quantitated by euglycemic hyperinsulemic clamp. Moreover, in the validation phase (n = 40) subjects were added including lean and obese T2D. MiR-186 showed a consistent significant increase in insulin resistance subjects compared to NGT in the discovery and validation phase analysis. In addition, intergroup comparison of circulating miRNA pinpointed 2 miRNAs: MiR-122 increased substantially in obese T2D subjects, with diagnostic value to predict obesity in T2D subjects, and let-7b increased significantly in lean T2D subjects. Our results suggest that circulating miRNAs serve as biomarkers for IR, T2D and obesity in Qatari population. Further functional studies are warranted to better identify the targets of these miRNAs and understand the underlying molecular and cellular mechanisms.

Neurologically deceased organ donors (NDDs) generally display an immune response involving an intense production of pro-inflammatory cytokines referred to as the cytokine storm. The sudden surge of inflammatory mediators in circulation promotes tissue and organ damages and ultimately leads to poor transplant outcome. As microRNAs (miRNAs) are frequently proposed as key regulators of inflammation and are relatively stable in circulation, changes in their profiles could play a role in the onset of the cytokine storm in NDDs. In this proof-of-concept study, we sought to investigate differentially abundant circulating miRNAs in a temporal manner between neurological death and organ recovery and to assess the association between specific miRNAs and levels of inflammatory cytokines in blood. Plasma samples from five NDDs were obtained at multiple time points between organ donation consent and organ recovery. Using a time-course analysis and miRNA sequencing, we identified 32 plasma miRNAs fluctuating between consent and organ recovery (false discovery rate; q-value < 0.1). Eleven miRNAs relatively abundant (>100 reads) and detected in all samples were selected for further biological pathway analysis (miR-486-3p, miR-103a-3p, miR-106b-3p, miR-182-5p, miR-101-3p, miR-10a-5p, miR-125a-5p, miR-146b-5p, miR-26a-5p, miR-423-5p, miR-92b-3p). These miRNAs targeted genes such as c-JUN (TNF signalling pathway) and eEF2 (AMPK pathway), suggesting a potential role in regulation of inflammation. Our results contribute to a better understanding of the miRNAs dynamic after neurological death in organ donors and could potentially be used to predict the related early cytokine storm.Trial registration: ClinicalTrials.gov ID NCT03786991. Registered December 2018