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Background: Determining the role of epigenetics in systemic juvenile idiopathic arthritis (SJIA) provides an opportunity to explore previously unrecognized disease pathways and new therapeutic targets. Aim: We aimed to identify the clinical significance of microRNAs (miRNA-26a, miRNA-223) in SJIA. Materials and methods: This cross-sectional study was conducted on a group of children with SJIA attending to pediatric rheumatology clinic, at Mansoura University Children's Hospital (MUCH) from December 2021 to November 2022. Patient demographics, and clinical, and laboratory data were collected with the measurement of microRNAs by quantitative real-time PCR. The Mann–Whitney, Kruskal–Wallis, and Spearman correlation tests were used for variable comparison and correlations, besides the receiver operating characteristic (ROC) curve for microRNAs disease activity and treatment non-response discrimination. Results: Forty patients were included in the study. On comparison of miRNA-26a, and miRNA-223 levels to the clinical, assessment measures, and laboratory features, miRNA-26a was statistically higher in cases with systemic manifestations versus those without. Similarly, it was higher in children who did not fulfill the Wallace criteria for inactive disease and the American College of Rheumatology (ACR) 70 criteria for treatment response. Meanwhile, miRNA-223 was not statistically different between cases regarding the studied parameters. The best cut-off value for systemic juvenile arthritis disease activity score-10 (sJADAS-10) and the ability of miRNA-26a, and miRNA-223 to discriminate disease activity and treatment non-response were determined by the (ROC) curve. Conclusion: The significant association of miRNA-26a with SJIA features points out that this molecule may be preferentially assessed in SJIA disease activity and treatment non-response discrimination. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition of peripheral nerve because of chemotherapeutic agent exposure among cancer patients. Despite its relatively high prevalence, to date, there has been no specific or standardized diagnostic criteria for CIPN and establishing diagnosis can be burdensome with significant time and efforts. Therefore, there is a need for an accurate biomarker to aid in early and objective diagnosis of CIPN. Based on the relevant pathogenesis of CIPN, herein we discussed several potential biomarker candidates to be incorporated in the diagnosis of CIPN, ranging from bodily fluid-based biomarker such as neurotrophic factors and neurofilaments, genetic biomarker such as microRNAs, electrophysiologic biomarker such as quantitative sensory testing, and imaging biomarkers such as high-resolution ultrasound and magnetic resonance neurography. We also discussed the strengths and weaknesses of each biomarker type, and future directions to accelerate its translation into routine use in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Carotid endarterectomy (CEA) for the prevention of upcoming vascular and cerebral events is necessary in patients with high-grade stenosis (=70%). In the framework of the Italian National project Age.It, a pilot study was proposed aiming at the discovery of amolecular signature with predictive potential of carotid stenosis comparing 65+ asymptomatic and symptomatic inpatients. Methods: A total of 42 inpatients have been enrolled, including 26 men and 16 women, with a mean age of 74 ± 6 years. Sixteen symptomatic and 26 asymptomatic inpatients with =70% carotid stenosis underwent CEA, according to the recommendations of the European Society for Vascular Surgery and the Society for Vascular Surgeons. Plaque biopsies and peripheral blood samples from the same individuals were obtained. Hematobiochemical analyses were conducted on all inpatients, and plasma cytokines/molecules, such as microRNAs (miRs), IL-6, sIL-6Ralpha, sgp130, myostatin (GDF8), follistatin, activin A, CXCL9, FGF21, and fibronectin, were measured using the ELISA standard technique. MiR profiles were obtained in the discovery phase including four symptomatic and four asymptomatic inpatients (both plasma and plaque samples), testing 734 miRs. MiRs emerging from the profiling comparison were validated through RT-qPCR analysis in the total cohort. Results and conclusion: The two groups of inpatients differ in the expression levels of blood c-miRs-126-5p and -1271-5p (but not in their plaques), which are more expressed in symptomatic subjects. Three cytokines were significant between the two groups: IL-6, GDF8, and CXCL9. Using receiver operating characteristic (ROC) analysis with a machine learning-based approach, the most significant blood molecular signature encompasses albumin, C-reactive protein (CRP), the percentage of monocytes, and CXCL9, allowing for the distinction of the two groups (AUC = 0.83, 95% c.i. [0.85, 0.81], p = 0.0028). The potential of the molecular signature will be tested in a second cohort of monitored patients, allowing the application of a predictive model and the final evaluation of cost/benefit for an assessable screening test. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is a leading cause of death among gynaecological malignancies. The haemostatic system, which controls blood flow and prevents clotting disorders, paradoxically drives OC progression while increasing the risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) have emerged as crucial in understanding VTE pathogenesis. Exploring the connection between cancer and thrombosis through these RNAs could lead to novel biomarkers of cancer-associated thrombosis (CAT) and OC, as well as potential therapeutic targets for tumour management. Thus, this study examined the impact of eight plasma miRNAs targeting the tissue factor (TF) coagulation pathway—miR-18a-5p, -19a-3p, -20a-5p, -23a-3p, -27a-3p, -103a-3p, -126-5p and -616-3p—in 55 OC patients. Briefly, VTE occurrence post-OC diagnosis was linked to shorter disease progression time (log-rank test, p = 0.024) and poorer overall survival (OS) (log-rank test, p < 0.001). High pre-chemotherapy levels of miR-20a-5p (targeting coagulation factor 3 (F3) and tissue factor pathway inhibitor 2 (TFPI2)) and miR-616-3p (targeting TFPI2) predicted VTE after OC diagnosis (χ2, p < 0.05). Regarding patients' prognosis regardless of VTE, miR-20a-5p independently predicted OC progression (adjusted hazard ratio (aHR) = 6.13, p = 0.005), while miR-616-3p significantly impacted patients' survival (aHR = 3.72, p = 0.020). Further investigation is warranted for their translation into clinical practice. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes mellitus (GDM) poses significant health risks for both mothers and children, contributing to long-term complications such as type 2 diabetes and cardiovascular disease. This study explores the potential of microRNAs (miRNAs) as biomarkers for GDM by analyzing peripheral blood samples from GDM patients. Method: Ten samples, including peripheral blood from 5 GDM patients and 5 controls, were collected to perform the RNA sequencing analysis. Differentially expressed miRNAs were further validated by quantitative real-time polymerase chain reaction. Results: A total of 2287 miRNAs were identified, 229 of which showed differential expression. Validation by qRT-PCR confirmed significant up-regulation of miR-5193, miR-5003-3p, miR-3127-5p, novel-miR-96, miR-6734-5p, and miR-122-5p, while miR-10395-3p was down-regulated. Bioinformatics analyses revealed the involvement of these miRNAs in pathways associated with herpes simplex virus 1 infection. Conclusion: This study provides insights into the differential expression of miRNAs in GDM patients and their potential roles in disease pathogenesis. It suggests that the differentially expressed miRNAs could serve as potential biomarkers for GDM, shedding light on the complex molecular mechanisms involved. [ABSTRACT FROM AUTHOR]

Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post‐transcriptional level, are differentially regulated in the circulatory system of young, middle‐aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50–80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT ‐ common vs. GT ‐ longevity) and validated the findings through RT‐qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF‐β, FoxO, AMPK, Pi3K‐Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity. [ABSTRACT FROM AUTHOR]

Radiotherapy is a key treatment option for a wide variety of human tumors, employed either alone or alongside with other therapeutic interventions. Radiotherapy uses high-energy particles to destroy tumor cells, blocking their ability to divide and proliferate. The effectiveness of radiotherapy is due to genetic and epigenetic factors that determine how tumor cells respond to ionizing radiation. These factors contribute to the establishment of resistance to radiotherapy, which increases the risk of poor clinical prognosis of patients. Although the mechanisms by which tumor cells induce radioresistance are unclear, evidence points out several contributing factors including the overexpression of DNA repair systems, increased levels of reactive oxygen species, alterations in the tumor microenvironment, and enrichment of cancer stem cell populations. In this context, dysregulation of microRNAs or miRNAs, critical regulators of gene expression, may influence how tumors respond to radiation. There is increasing evidence that miRNAs may act as sensitizers or enhancers of radioresistance, regulating key processes such as the DNA damage response and the cell death signaling pathway. Furthermore, expression and activity of miRNAs have shown informative value in overcoming radiotherapy and long-term radiotoxicity, revealing their potential as biomarkers. In this review, we will discuss the molecular mechanisms associated with the response to radiotherapy and highlight the central role of miRNAs in regulating the molecular mechanisms responsible for cellular radioresistance. We will also review radio-miRs, radiotherapy-related miRNAs, either as sensitizers or enhancers of radioresistance that hold promise as biomarkers or pharmacological targets to sensitize radioresistant cells. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is associated with a high fatality rate and a heavy global health care burden. Glucagon-like peptide-1 (GLP-1) exerts positive cardiovascular effects, although the molecular mechanisms are unclear. Therefore, this study aimed to verify whether the cardioprotective effects of GLP-1 are mediated through the regulation of micro-RNA (miRNA) expression. Follow-up assessments were conducted for 116 patients with type 2 diabetes mellitus (T2DM) alone (controls) and 123 patients with both T2DM and CAD. After matching, each group comprised 63 patients, and age, body mass index, and serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides (TG), and hemoglobin A1C (HbA1c) were compared. Subsequently, the expression profiles of four circulating miRNAs (miR-203a-3p, miR-429, miR-205-5p, and miR-203b-5p) were assessed via quantitative reverse transcription real-time polymerase chain reaction in the 63 patients with diabetes and CAD between 6 months (baseline) and 12 months after the initiation of GLP-1 receptor (GLP-1R) therapy. As expected, the metabolic factors were significantly improved after 6 months of treatment with GLP-1R compared with pre-treatment values, and the expression levels of two of the miRNAs (miR-203a-3p and miR-429) decreased from baseline levels in those with diabetes and CAD. The results suggest that the cardiovascular benefits induced by GLP-1R are mediated via suppressed expression of two miRNAs: miR-203a-3p and miR-429. [ABSTRACT FROM AUTHOR]

The expression of inflamma-miRs and human leukocyte antigen (HLA) haplotypes could indicate mild cognitive impairment (MCI) and Alzheimer's disease (AD). We used international databases to conduct a systematic review of studies on HLA variants and a meta-analysis of research on microRNAs (miRNAs). We aimed to analyze the discriminative value of HLA variants and miRNAs in MCI, AD and controls to evaluate the protective or causative effect of HLA in cognitive decline, establish the role of miRNAs as biomarkers for the early detection of AD, and find a possible link between miRNAs and HLA. Statistical analysis was conducted using Comprehensive Meta-analysis software, version 2.2.050 (Biostat Inc., Englewood, NJ, USA). The effect sizes were estimated by the logarithm base 2 of the fold change. The systematic review revealed that some HLA variants, such as HLA-B*4402, HLA-A*33:01, HLA-A*33:01, HLA-DPB1, HLA-DR15, HLA-DQB1*03:03, HLA-DQB1*06:01, HLA-DQB1*03:01, SNPs on HLA-DRB1/DQB1, and HLA-DQA1, predisposed to cognitive decline before the occurrence of AD, while HLA-A1*01, HLA-DRB1∗13:02, HLA-DRB1*04:04, and HLA-DRB1*04:01 demonstrated a protective role. The meta-analysis identified let-7 and miR-15/16 as biomarkers for the early detection of AD. The association between these two miRNA families and the HLA variants that predispose to AD could be used for the early screening and prevention of MCI. [ABSTRACT FROM AUTHOR]

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) is a rare, neurodegenerative movement disorder. Together with multiple system atrophy (MSA), Dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD), PSP forms a group of atypical parkinsonisms. The latest diagnostic criteria, published in 2017 by the Movement Disorders Society, classify PSP diagnosis into defined, probable, and possible categories based on clinical examination. However, no single test is specific and sensitive for this disease. Microribonucleic acids (miRNAs) are promising molecules, particularly in the case of diseases that lack appropriate diagnostic and treatment tools, which supports exploring their role in PSP. We aimed to systematically review the current knowledge about the role of miRNAs in PSP. This study was registered in the Open Science Framework Registry, and the protocol is available online. Primary original studies, both clinical and preclinical, written in English and assessing miRNAs in PSP were included. Systematic reviews, meta-analyses, reviews, case reports, letters to editors, commentaries, conference abstracts, guidelines/statements, expert opinions, preprints, and book chapters were excluded. The following five databases were searched: Embase, Medline Ultimate, PubMed, Scopus, and Web of Science. Each database was last searched on 18 June 2024. Eventually, nine original studies relevant to the discussed area were included. The risk of bias was not assessed. The selected research suggests that miRNAs may be considered promising biomarkers in PSP. However, the exact involvement of miRNAs in the pathogenesis of PSP is still to be determined. Several microRNAs were found to be dysregulated in patients with PSP. This applies to both brain tissue and fluids like cerebrospinal fluid CSF or blood. Several miRNAs were found that could potentially be helpful in differentiating among PSP patients, PD patients, and healthy individuals. Although some correlations and alterations have already been found, this field requires much more research. MicroRNAs are exciting and promising small molecules, and their investigation into many diseases, including PSP, may lead to significant discoveries. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Although the incidence is decreasing in developed countries, the treatment results are still unsatisfactory. The standard treatment for locally advanced gastric cancer (LAGC) is gastrectomy with perioperative chemotherapy. The association of selected microRNAs (miRNAs) with chemoresistance was assessed using archival material of patients with LAGC. Histological material was obtained from each patient via a biopsy performed during gastroscopy and then after surgery, which was preceded by four cycles of neoadjuvant chemotherapy (NAC) according to the FLOT or FLO regimen. The expression of selected miRNAs in the tissue material was assessed, including miRNA-21-3p, miRNA-21-5p, miRNA-106a-5p, miRNA-122-3p, miRNA-122-5p, miRNA-143-3p, miRNA-143-5p, miRNA-203a-3p, miRNA-203-5p, miRNA-551b-3p, miRNA-551b-5p, and miRNA-574-3p. miRNA expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The response to NAC was assessed using computed tomography of the abdomen and chest and histopathology after gastrectomy. The statistical analyses were performed using GraphPad Prism 9. The significance limit was set at p < 0.05. We showed that the expression of miR-143-3p, miR-143-5p, and miR-574-3p before surgery, and miR-143-5p and miR-574-3p after surgery, decreased in patients with GC. The expression of miR-143-3p, miR-143-5p, miR-203a-3p, and miR-551b-5p decreased in several patients who responded to NAC. The miRNA most commonly expressed in these cases was miRNA-551b-5p. Moreover, it showed expression in a patient whose response to chemotherapy was inconsistent between the histopathological results and computed tomography. The expression of miR-143-3p, miR-143-5p, miR-203a-3p, and miR-551b-5p in formalin-fixed paraffin-embedded tissue (FFPET) samples can help differentiate between the responders and non-responders to NAC in LAGC. miR-143-3p, miR-143-5p, and miR-574-3p expression may be used as a potential diagnostic tool in GC patients. The presence of miR-551b-5p may support the correct assessment of a response to NAC in GC via CT. [ABSTRACT FROM AUTHOR]

MicroRNAs could be promising biomarkers for various diseases, and small RNA drugs have already been FDA approved for clinical use. This area of research is rapidly expanding and has significant potential for the future. Fennel (Anethum foeniculum) is a highly esteemed spice plant with economic and medicinal benefits, making it an invaluable asset in the pharmaceutical industry. To characterize the fennel miRNAs and their Arabidopsis thaliana and Homo sapience targets with functional enrichment analysis and human disease association. A homology-based computational approach characterized the MiRnome of the Anethum foeniculum genome and assessed its impact on Arabidopsis thaliana and Homo sapience transcriptomes. In addition, functional enrichment analysis was evaluated for both species' targets. Moreover, PPI network analysis, hub gene identification, and MD simulation analysis of the top hub node with fennel miRNA were incorporated. We have identified 100 miRNAs of fennel and their target genes, which include 2536 genes in Homo sapiens and 1314 genes in Arabidopsis thaliana. Functional enrichment analysis reveals 56 Arabidopsis thaliana targets of fennel miRNAs showed involvement in metabolic pathways. Highly enriched human KEGG pathways were associated with several diseases, especially cancer. The protein–protein interaction network of human targets determined the top ten nodes; from them, seven hub nodes, namely MAPK1, PIK3R1, STAT3, EGFR, KRAS, CDC42, and SMAD4, have shown their involvement in the pancreatic cancer pathway. Based on the Blast algorithm, 21 fennel miRNAs are homologs to 16 human miRNAs were predicted; from them, the CSPP1 target was a common target for afo-miR11117a-3p and has-miR-6880-5p homologs miRNAs. Our results are the first to report the 100 fennel miRNAs, and predictions for their endogenous and human target genes provide a basis for further understanding of Anethum foeniculum miRNAs and the biological processes and diseases with which they are associated. [ABSTRACT FROM AUTHOR]

microRNAs are candidate diagnostic biomarkers for Alzheimer's disease. This study aimed to compare Silymarin with Rosuvastatin and placebo on total-Tau protein level and expression levels of microRNAs and TGF-β and COX-2 in Alzheimer's patients with secondary dyslipidemia. 36 mild AD patients with dyslipidemia were divided into three groups of 12. The first group received silymarin (140mg), the second group received placebo (140mg), and the third group recieved Rosuvastatin (10mg). Tablets were administered three times a day for Six months. The blood samples of the patients were collected before and after the intervention and the serum was separated. Using the RT-qPCR method, the expression levels of miR-124-3p and miR-125b-5p were assessed, and the serum levels of total-Tau, TGF-β, and COX-2 enzyme were measured using the ELISA method. Data were analyzed with SPSS software. In this study, the level of Δtotal-Tau was significantly lower in the Rosuvastatin group compared to the placebo (P = 0.038). Also, a significant reduction in the level of ΔTGF-β was observed in the Silymarin to Rosuvastatin group (p = 0.046) and ΔmiR-124-3p was significantly increased in the Rosuvastatin compared to the placebo group (p = 0.044). Rosuvastatin outperformed silymarin in decreasing Δtotal-Tau serum levels and enhancing expression of ΔmiR-124-3p, attributed to Rosuvastatin's capacity to lower cholesterol levels and inflammation concurrently. Conversely, silymarin was more effective than Rosuvastatin in reducing levels of ΔTGF-β. Serum miR-124-3p could serve as a promising diagnostic biomarker and a new therapeutic focus in AD. [ABSTRACT FROM AUTHOR]

We developed a technology for detecting and quantifying trace nucleic acids using a bracketing protocol designed to yield a copy number with approximately ± 20% accuracy across all concentrations. The microRNAs (miRNAs) let-7b, miR-15b, miR-21, miR-375 and miR-141 were measured in serum and urine samples from healthy subjects and patients with breast, prostate or pancreatic cancer. Detection and quantification were amplification-free and enabled using osmium-tagged probes and MinION, a nanopore array detection device. Combined serum from healthy men (Sigma-Aldrich, St. Louis, MO, USA #H6914) was used as a reference. Total RNA isolated from biospecimens using commercial kits was used as the miRNA source. The unprecedented ± 20% accuracy led to the conclusion that miRNA copy numbers must be normalized to the same RNA content, which in turn illustrates (i) independence from age, sex and ethnicity, as well as (ii) equivalence between serum and urine. miR-21, miR-375 and miR-141 copies in cancers were 1.8-fold overexpressed, exhibited zero overlap with healthy samples and had a p-value of 1.6 × 10−22, tentatively validating each miRNA as a multi-cancer biomarker. miR-15b was confirmed to be cancer-independent, whereas let-7b appeared to be a cancer biomarker for prostate and breast cancer, but not for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Spodoptera frugiperda poses a severe threat to crops, causing substantial economic losses. The increased use of chemical pesticides has led to resistance in S. frugiperda populations. Micro ribonucleic acids (MicroRNAs or miRNAs) are pivotal in insect growth and development. This study aims to identify miRNAs across different developmental stages of S. frugiperda to explore differential expression and predict target gene functions. High-throughput sequencing of miRNAs was conducted on eggs, 3rd instar larvae, pupae, and adults. Bioinformatics analyses identified differentially expressed miRNAs specifically in larvae, with candidate miRNAs screened to predict target genes, particularly those involved in detoxification pathways. A total of 184 known miRNAs and 209 novel miRNAs were identified across stages. Comparative analysis revealed 54, 15, and 18 miRNAs differentially expressed in larvae, compared to egg, pupa, and adult stages, respectively. Eight miRNAs showed significant differential expression across stages, validated by quantitative reverse transcription PCR (qRT-PCR). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses predicted target genes' functions, identifying eight differentially expressed miRNAs targeting 10 gene families associated with detoxification metabolism, including P450s, glutathione S-transferase (GSTs), ATP-binding cassette (ABC) transporters, and sodium channels. These findings elucidate the species-specific miRNA profiles and regulatory mechanisms of detoxification-related genes in S. frugiperda larvae, offering insights and strategies for effectively managing this pest. [ABSTRACT FROM AUTHOR]

A CHA-based fluorescent DNA tetrahedral probe (FDTp) has been designed to detect the microRNAs miR-21 and miR-155 sensitively and specifically in living cells. The design consisted of functional elements (H1, H2, and Protector) connected to a DNA tetrahedron modified with two pairs of fluorophores and quenching groups. In the presence of miR-21, the chain displacement effect was triggered and Cy3 fluorescence was emitted. In the presence of miR-155, the signal of the catalytic hairpin assembly (CHA) between H1 and H2 on FDTp was amplified, making the fluorescence of FAM sensitive to miR-155. Using this method, the detection limit for miR-155 was 5 pM. The FDTp successfully imaged miR-21 and miR-155 in living cells and distinguished a variety of cell lines based on their expression levels of miR-21 and miR-155. The detection and imaging of dual targets in this design ensured the accuracy of tumor diagnosis and provided a new method for early tumor diagnosis. [ABSTRACT FROM AUTHOR]

Since the first description of adenomyosis more than 150 years ago, multiple hypotheses have attempted to explain its pathogenesis. Indeed, research over recent years has greatly enhanced our knowledge of the underlying causes. This has opened up avenues for the development of strategies for both disease prevention and treatment of its main symptoms, such as pelvic pain, heavy menstrual bleeding, and infertility. However, the current means are still largely ineffective, so it is vital that we shed light on the pathways involved. Dysregulated mechanisms and aberrant protein expression have been identified as contributing factors in interactions between endometrial epithelial and stromal cells, ultimately leading to the growth of adenomyotic lesions. These include collective cell migration, epithelial-to-mesenchymal transition, hormonal influence, and signaling from non-coding RNAs and extracellular vesicles. We provide a concise summary of the latest insights into the crosstalk between glands and stroma in ectopic adenomyotic lesion formation. While there is an abundance of literature on similarities between adenomyosis and deep endometriosis, there are insufficient data on the cytochemical, molecular, and pathogenetic mechanisms of these two disorders. However, various shared features, including alterations of cell adhesion molecules, abnormal hormone regulation, and the presence of cancer-driving mutations and epigenetic modifications, have been identified. Nevertheless, the pathogenic mechanisms that contribute to the cause and development of these enigmatic diseases have not been fully elucidated yet. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD), has emerged as the leading cause of liver failure and related death. Currently, no medication is specifically approved to treat NAFLD or NASH. Here we report that oral administration of honey vesicle-like nanoparticles (H-VLNs) to naturally aged mice protects the liver from NASH development. H-VLNs are dominantly taken up by Kupffer cells in the liver and suppress hepatic chronic inflammation and further development of fibrosis and nodule formation in aged mice. Besides their reported anti-inflammasome function, H-VLNs are found to inhibit the transcriptional activities of C-JUN and nuclear factor-kappa B (NF- κ B). MicroRNAs miR5119 and miR5108 and phenolic compound luteolin in H-VLNs are identified in suppressing both the C-JUN and NF- κ B pathways. Collectively, oral intake of H-VLNs represents a promising new user-friendly modality to prevent the development of NASH. Oral administered H-VLNs alleviated inflammation, fibrosis development, and nodule formation in naturally aged liver. Their bioactive cargos inhibited the activities of the NLRP3 inflammasome, NF- κ B, and c-Jun in Kupffer cells/macrophages. [Display omitted] [ABSTRACT FROM AUTHOR]

Plants have several mechanisms to adapt or acclimate to environmental stress. Morphological, physiological, or genetic changes are examples of complex plant responses. In recent years, our understanding of the role of epigenetic regulation, which encompasses changes that do not alter the DNA sequence, as an adaptive mechanism in response to stressful conditions has advanced significantly. Some studies elucidated and synthesized epigenetic mechanisms and their relationships with environmental change, while others explored the interplay between epigenetic modifications and environmental shifts, aiming to deepen our understanding of these complex processes. In this study, we performed a systematic review of the literature to analyze the progression of epigenetics studies on plant species' responses to abiotic factors. We also aimed to identify the most studied species, the type of abiotic factor studied, and the epigenetic technique most used in the scientific literature. For this, a search for articles in databases was carried out, and after analyzing them using pre-established inclusion criteria, a total of 401 studies were found. The most studied species were Arabidopsis thaliana and Oryza sativa, highlighting the gap in studies of non-economic and tropical plant species. Methylome DNA sequencing is the main technique used for the detection of epigenetic interactions in published studies. Furthermore, most studies sought to understand the plant responses to abiotic changes in temperature, water, and salinity. It is worth emphasizing further research is necessary to establish a correlation between epigenetic responses and abiotic factors, such as extreme temperatures and light, associated with climate change. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) affects 10–15% of hospitalised patients and arises after severe infections, major surgeries, or exposure to nephrotoxic drugs. AKI diagnosis based on creatinine level changes lacks specificity and may be delayed. MicroRNAs are short non-coding RNA secreted by all cells. This review of studies measuring miRNAs in AKI aimed to verify miRNAs as diagnostic markers. The study included data from patients diagnosed with AKI due to sepsis, ischaemia, nephrotoxins, radiocontrast, shock, trauma, and cardiopulmonary bypass. Out of 71 studies, the majority focused on AKI in sepsis patients, followed by cardiac surgery patients, ICU patients, and individuals receiving nephrotoxic agents or experiencing ischaemia. Studies that used untargeted assays found 856 differentially regulated miRNAs, although none of these were confirmed by more than one study. Moreover, 68 studies measured miRNAs by qRT-PCR, and 2 studies reported downregulation of miR-495-3p and miR-370-3p in AKI patients with sepsis after the AKI diagnosis. In three studies, upregulation of miR-21 was reported at the time of the AKI diagnosis with a significant pooled effect of 0.56. MiR-21 was also measured 19–24 h after cardiac surgery in three studies. However, the pooled effect was not significant. Despite the considerable research into miRNA in AKI, there is a knowledge gap in their applicability as diagnostic markers of AKI in humans. [ABSTRACT FROM AUTHOR]

Exposure to blue light can lead to retinal degeneration, causing adverse effects on eye health. Although the loss of retinal cells due to blue light exposure has been observed, the precise molecular mechanisms underlying this process remain poorly understood. In this study, we investigate the role of alpha-crystallin A (CRYAA) in neuro-retinal degeneration and their regulation by blue light. We observed significant apoptotic cell death in both the retina of rats and the cultured neuroretinal cells. The expressions of Cryaa mRNA and protein were significantly downregulated in the retina exposed to blue light. We identified that miR-325-3p reduces Cryaa mRNA and protein by binding to its 3′-untranslated region. Upregulation of miR-325-3p destabilized Cryaa mRNA and suppresses CRYAA, whereas downregulation of miR-325-3p increased both expressions. Blue light-induced neuro-retinal cell death was alleviated by CRYAA overexpression. These results highlight the critical role of Cryaa mRNA and miR-325-3p molecular axis in blue light-induced retinal degeneration. Consequently, targeting CRYAA and miR-325-3p presents a potential strategy for protecting against blue light-induced retinal degeneration. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry (VM) alludes to the ability of cancer cells to organize on three-dimensional channel-like structures to obtain nutrients and oxygen. This mechanism confers an aggressive phenotype, metastatic potential, and resistance to chemotherapy resulting in a poor prognosis. Recent studies have been focused on the identification of microRNAs (miRNAs) that regulate the VM representing potential therapeutic targets in cancer. An overview of the roles of miRNAs on VM development and their functional relationships with tumor microenvironment. The functions of cancer stem-like cells in VM, and resistance to therapy are also discussed. Moreover, the modulation of VM by natural compounds is explored. The clinical significance of deregulated miRNAs as potential therapeutic targets in tumors showing VM is further highlighted. The miRNAs are regulators of protein-encoding genes involved in VM; however, their specific expression signatures with clinical value in large cohorts of patients have not been established yet. We considered that genomic profiling of miRNAs could be useful to define some hallmarks of tumors such as stemness, drug resistance, and VM in cancer patients. However, additional studies are needed to establish the relevant role of miRNAs as effective therapeutic targets in tumors that have developed VM. [ABSTRACT FROM AUTHOR]

Cancer patients, prone to severe COVID-19, face immune challenges due to their disease and treatments. Identifying biomarkers, particularly extracellular vesicle (EV)-derived microRNAs (miRNAs), is vital for comprehending their response to COVID-19 vaccination. Therefore, this study aimed to investigate specific EV-miRNAs in the plasma of cancer patients under active treatment who received the COVID-19 booster vaccine. The selected miRNAs (EV-hsa-miR-7-5p, EV-hsa-miR-15b-5p, EV-hsa-miR-24-3p, EV-hsa-miR-145- 5p, and EV-hsa-miR-223-3p) are involved in regulating SARS-CoV-2 spike protein and cytokine release, making them potential biomarkers for vaccination response. The study involved 54 cancer patients. Plasma and serum samples were collected at pre-boost vaccination, and at 3 and 6 months post-boost vaccination. Anti-spike antibody levels were measured. Additionally, RNA was extracted from EVs isolated from plasma and the expression levels of miRNAs were assessed. The results showed a significantly positive antibody response after COVID-19 boost vaccination. The expression levels of EV-hsa-miR-7-5p, EV-hsa-miR-15b-5p, EV-hsa-miR-24-3p, and EV-hsa-miR-223-3p increased significantly after 6 months of COVID-19 booster vaccination. Interestingly, an increased expression of certain EV-hsa-miRNAs was positively correlated. Bioinformatic analysis revealed that these correlated miRNAs play a critical role in regulating the targets present in antiviral responses and cytokine production. These findings suggest that EV-hsa-miR-15b-5p, EV-hsa-miR-24-3p, and EV-hsa-miR-223-3p may be crucial in immune response induced by mRNA vaccines. [ABSTRACT FROM AUTHOR]

Plants evolved, over millions of years, complex defense systems against pathogens. Once infected, the interaction between pathogen effector molecules and host receptors triggers plant immune responses, which include apoptosis, systemic immune response, among others. An important protein family responsible for pathogen effector recognition is the nucleotide binding site-leucine repeat rich (NBS-LRR) proteins. The NBS-LRR gene family is the largest disease resistance gene class in plants. These proteins are widely distributed in vascular plants and have a complex multigenic cluster distribution in plant genomes. To counteract the genetic load of such a large gene family on fitness cost, plants evolved a mechanism using post transcriptional gene silencing induced by small RNAs, particularly microRNAs. For the NBS-LRR gene family, the small RNAs involved in this silencing mechanism are mainly the microRNA482/2118 superfamily. This suppression mechanism is relieved upon pathogen infection, thus allowing increased NBS-LRR expression and triggering plant immunity. In this review, we will discuss the biogenesis of microRNAs and secondary RNAs involved in this silencing mechanism, biochemical and structural features of NBS-LRR proteins in response to pathogen effectors and the evolution of microRNA-based silencing mechanism with a focus on the miR482/2118 family. Furthermore, the biotechnological manipulation of microRNA expression, using both transgenic or genome editing approaches to improve cultivated plants will be discussed, with a focus on the miR482/2118 family in soybean. [ABSTRACT FROM AUTHOR]

Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

We report on the identification of extracellular miRNA (ex-miRNA) biomarkers for early diagnosis and prognosis of preeclampsia (PE). Small RNA sequencing of maternal serum prospectively collected from participants undergoing evaluation for suspected PE revealed distinct patterns of ex-miRNA expression among different categories of hypertensive disorders in pregnancy. Applying an iterative machine learning method identified three bivariate miRNA biomarkers (miR-522-3p/miR-4732-5p, miR-516a-5p/miR-144-3p, and miR-27b-3p/let-7b-5p) that, when applied serially, distinguished between PE cases of different severity and differentiated cases from controls with a sensitivity of 93%, specificity of 79%, positive predictive value (PPV) of 55%, and negative predictive value (NPV) of 89%. In a small independent validation cohort, these ex-miRNA biomarkers had a sensitivity of 91% and specificity of 57%. Combining these ex-miRNA biomarkers with the established sFlt1:PlGF protein biomarker ratio performed better than either set of biomarkers alone (sensitivity of 89.4%, specificity of 91.3%, PPV of 95.5%, and NPV of 80.8%).

Microglia and macrophages are pivotal to the brains innate immune response and have garnered considerable attention in the context of glioblastoma (GBM) and Alzheimers disease (AD) research. This review delineates the complex roles of these cells within the neuropathological landscape, focusing on a range of signaling pathways-namely, NF-κB, microRNAs (miRNAs), and TREM2-that regulate the behavior of tumor-associated macrophages (TAMs) in GBM and disease-associated microglia (DAMs) in AD. These pathways are critical to the processes of neuroinflammation, angiogenesis, and apoptosis, which are hallmarks of GBM and AD. We concentrate on the multifaceted regulation of TAMs by NF-κB signaling in GBM, the influence of TREM2 on DAMs responses to amyloid-beta deposition, and the modulation of both TAMs and DAMs by GBM- and AD-related miRNAs. Incorporating recent advancements in molecular biology, immunology, and AI techniques, through a detailed exploration of these molecular mechanisms, we aim to shed light on their distinct and overlapping regulatory functions in GBM and AD. The review culminates with a discussion on how insights into NF-κB, miRNAs, and TREM2 signaling may inform novel therapeutic approaches targeting microglia and macrophages in these neurodegenerative and neoplastic conditions. This comparative analysis underscores the potential for new, targeted treatments, offering a roadmap for future research aimed at mitigating the progression of these complex diseases.

Astrocytes, one of the most prevalent cell types in the central nervous system (CNS), are critically involved in neural function. Genetically manipulating astrocytes is an essential tool in understanding and affecting their roles. Adeno-associated viruses (AAVs) enable rapid genetic manipulation; however, astrocyte specificity of AAVs can be limited, with high off-target expression in neurons and sparsely in endothelial cells. Here, we report the development of a cassette of four copies of six miRNA targeting sequences (4x6T) which triggers transgene degradation specifically in neurons and endothelial cells. In combination with the GfaABC1D promoter, 4x6T increases astrocytic specificity of Cre with a viral reporter from 99% in multiple serotypes in mice, and confers astrocyte specificity in multiple recombinases and reporters. We also present empty vectors to add 4x6T to other cargo, independently and in Cre/Dre-dependent forms. This toolbox of AAVs allows rapid manipulation of astrocytes throughout the CNS, is compatible with different AAV serotypes, and demonstrates the efficacy of using multiplexed miRNA targeting sequences to decrease expression in multiple off-target cell populations simultaneously.

Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of β-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment.

Pathogenic Th17 cells are critical drivers of multiple autoimmune diseases, including uveitis and its animal model, experimental autoimmune uveitis (EAU). However, how innate immune signals modulate pathogenic Th17 responses remains largely unknown. Here, we showed that miR-338-3p endowed dendritic cells (DCs) with an increased ability to activate interphotoreceptor retinoid-binding protein (IRBP)1-20 -specific Th17 cells by promoting the production of IL-6, IL-1β, and IL-23. In vivo administration of LV-miR-338-infected DCs promoted pathogenic Th17 responses and exacerbated EAU development. Mechanistically, dual-specificity phosphatase 16 (Dusp16) was a molecular target of miR-338-3p. miR-338-3p repressed Dusp16 and therefore strengthened the mitogen-activated protein kinase (MAPK) p38 signaling, resulting in increased production of Th17-polarizing cytokines and subsequent pathogenic Th17 responses. In addition, methyltransferase like 3 (Mettl3), a key m6A methyltransferase, mediated the upregulation of miR-338-3p in activated DCs. Together, our findings identify a vital role for Mettl3/miR-338-3p/Dusp16/p38 signaling in DCs-driven pathogenic Th17 responses and suggest a potential therapeutic avenue for uveitis and other Th17 cell-related autoimmune disorders.

Abstract In Burkitt's lymphoma (BL), Epstein–Barr virus-encoded microRNAs (EBV miRNAs) are emerging as crucial regulatory agents that impact cellular and viral gene regulation. This review investigates the multifaceted functions of EBV miRNAs in the pathogenesis of Burkitt lymphoma. EBV miRNAs regulate several cellular processes that are essential for BL development, such as apoptosis, immune evasion, and cellular proliferation. These small, non-coding RNAs target both viral and host mRNAs, finely adjusting the cellular environment to favor oncogenesis. Prominent miRNAs, such as BART (BamHI-A rightward transcript) and BHRF1 (BamHI fragment H rightward open reading frame 1), are emphasized for their roles in tumor growth and immune regulation. For example, BART miRNAs prevent apoptosis by suppressing pro-apoptotic proteins, whereas BHRF1 miRNAs promote viral latency and immunological evasion. Understanding the intricate connections among EBV miRNAs and their targets illuminates BL pathogenesis and suggests novel treatment approaches. Targeting EBV miRNAs or their specific pathways offers a feasible option for developing innovative therapies that aim to disrupt the carcinogenic processes initiated by these viral components. future studies should focus on precisely mapping miRNA‒target networks and developing miRNA-based diagnostic and therapeutic tools. This comprehensive article highlights the importance of EBV miRNAs in Burkitt lymphoma, indicating their potential as biomarkers and targets for innovative treatment strategies. Graphical Abstract

Fenfen Guo,1 Hong Li,1 Jingjing Wang,1 Jiangfeng Wang,1 Jinling Zhang,1 Fanfang Kong,1 Zemin Zhang,2 Jinbao Zong1 1Departments of Clinical Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, People’s Republic of China; 2Departments of Infectious Disease, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of ChinaCorrespondence: Jinbao Zong, Email sdjinbaozong@163.comAbstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transformation (EMT), invasion, metastasis, metabolism, and drug resistance are the main factors affecting the development and treatment of tumors. MiRNAs play crucial roles in almost all major cellular biological processes. Studies have been carried out on miRNAs as biomarkers and therapeutic targets. Their dysregulation contributes to the progression and prognosis of HCC. This review aims to explore the molecular cascades and corresponding phenotypic changes caused by aberrant miRNA expression and their regulatory mechanisms, summarize and analyze novel biomarkers from somatic fluids (plasma/serum/urine), and highlight the latent capacity of miRNAs as therapeutic targets.Keywords: hepatocellular carcinoma, microRNAs, regulatory mechanisms, biomarker, targeted therapy

Tinghua Zhang,1 Bo Yuan,2 Shaofu Yu3 1Department of Clinical Laboratory, the Second People’s Hospital of Huaihua City, Huaihua, Hunan, People’s Republic of China; 2Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Guangdong, Shenzhen, People’s Republic of China; 3Department of Clinical Pharmacy, the Second People’s Hospital of Huaihua, Huaihua, Hunan, People’s Republic of ChinaCorrespondence: Shaofu Yu, Department of Clinical Pharmacy, the Second People’s Hospital of Huaihua, Huaihua, Hunan, People’s Republic of China, Tel +86-13974531958, Email yushaofuanjing@163.comObjective: Thyroid cancer is the most common malignant endocrine tumor, with papillary thyroid carcinoma (PTC) being the most prevalent type, accounting for 85% of thyroid cancer cases. Here, we conducted a bibliometric analysis of the literature in the field of microRNAs in PTC research to demonstrate current trends and research hotspots, and present a visual map of past and emerging trends.Methods: We searched the Web of Scientific Core Collection (WoSCC) database for publications from 1999 to 2023 centered on this field. Next, we employed visualization tools such as VOSviewer, CiteSpace, and Microsoft Excel 2019 to present co-occurrence and co-citation analyses, trends, hotspots, and visual representations of contributions from authors, institutions, journals, and countries/regions.Results: The bibliometric analysis encompassed the period from 1999 to 2023, with 994 papers from 54 countries/regions. The country with the most publications and highest total citations was the People’s Republic of China, but the United States held the highest average citation rate. Among the top ten productive institutions, the Ohio State University (Ohio State Univ) was the most prominent contributor to this field. The JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (J Clin Endocrinol Metab) ranked first in terms of citation counts and average citations among the top ten productive journals. In terms of keywords, “circular RNAs”, “promotes”, and “progression” have become prominent research areas.Conclusion: This study elucidates current trends, hotspots, and emerging frontiers in miRNA research within PTC, and provides new insights and guidance for future identification of new PTC biomarkers and clinical trials.Keywords: microRNAs, papillary thyroid cancer, bibliometric, VOSviewer, CiteSpace

Abstract Background Oral lichen planus (OLP) is a chronic inflammatory condition that can impact patients’ quality of life. While its exact etiology remains unclear, it is associated with an increased risk of malignant transformation. Currently, the diagnosis of OLP relies on clinical examination and histopathological analysis, which can be invasive. Therefore, there is an urgent need for non-invasive and accurate diagnostic biomarkers. This systematic review and meta-analysis aims to investigate the potential of salivary microRNAs as promising candidates for OLP diagnosis. This meta-analysis seeks to identify specific microRNAs that are differentially expressed and could serve as reliable biomarkers for OLP diagnosis. Methods Our strategy involved searching for pertinent keywords in multiple academic databases including Cochrane Library, Embase, LIVIVO, MEDLINE, Ovid, ProQuest, Scopus, Web of Science, Espacenet, and Google Scholar search engine. Upon identification, articles were screened and data extracted from the eligible studies. Split component synthesis method was utilized to assess specificity, sensitivity, likelihood and diagnostic odds ratios. The random-effects meta-analysis approach was used to combine study findings and develop pooled diagnostic performance metrics. Hierarchical summary receiver operating characteristic (ROC) plots were generated to determine area under the curve. Subgroup analyses concerning the type of saliva and control groups were also performed. Results Among the fourteen studies included in our systematic review, five were eligible for meta-analysis. Salivary microRNAs showed the pooled sensitivity of 0.80 (95% Confidence Interval (95% CI): 0.68–0.88), specificity of 0.89 (95% CI: 0.82–0.94), diagnostic odds ratio of 28.45 (95% CI: 10.40–77.80), and area under the curve (AUC) of 0.93 for OLP diagnosis. Unstimulated saliva had higher sensitivity and specificity than oral swirl samples as the biomarker medium for OLP diagnosis. Meta-analysis uncovered that miR-27a, miR-137, miR-1290, miR-27b, miR-4484, miR-142, and miR-1246 had the highest diagnostic odds ratio for OLP. Conclusions Our systematic review and meta-analysis demonstrate that salivary microRNAs can serve as valuable biomarkers for the diagnosis of OLP. The findings highlight the exceptional accuracy of salivary microRNAs in differentiating OLP patients from healthy controls and assessing the risk of malignant transformation.

Wojciech Jelski,1 Barbara Mroczko1,2 1Department of Biochemical Diagnostics, Medical University, Bialystok, Poland; 2Department of Neurodegeneration Diagnostics, Medical University, Bialystok, PolandCorrespondence: Wojciech Jelski, Department of Biochemical Diagnostics, Medical University, Waszyngtona 15 A, Bialystok, 15-269, Poland, Tel +48 85 746 8587, Fax +48 85 746 8585, Email wjelski@umb.edu.plAbstract: Brain tumors have been deadly cancers for years, and in most cases they are difficult to diagnose in their early stages. For this reason, researchers need to develop low-cost, sensitive methods for examining cancer biomarkers. Such biomarkers include microRNA. MicroRNA expression in various body fluids shows a high correlation with cancer. A number of studies have demonstrated changes in microRNA expression in cerebrospinal fluid and blood samples from patients with brain tumors. New biomarkers such as microRNAs may help diagnose brain tumors at the very beginning of the disease, enabling early treatment and increasing the chances of survival. This review describes the diagnostic role of microRNAs and the prospects for their use as biomarkers in patients with brain tumors.Keywords: microRNAs, brain tumor

Abstract Aims This study aims to investigate miR‐486‐5p and miR‐novel‐chr1_40444 expressions in dysglycemic individuals. Validating RNA‐sequencing findings in a larger sample via reverse transcription qPCR (RT‐qPCR), we aim to address global diagnostic and screening limitations, using an African cohort as an example. Materials and Methods This cross‐sectional study involved 1,271 individuals [normoglycemic (n = 974), prediabetic (n = 206), screen‐detected type 2 diabetes (n = 91)] from the ongoing Vascular and Metabolic Health (VMH) study in Cape Town, South Africa. Whole blood miRNA expression was assessed using TaqMan‐based RT‐qPCR, with data normalized to an endogenous control (miR‐16‐5p). Results Significant underexpression was observed in prediabetes vs normoglycemia for miR‐486‐5p (P = 0.038), whilst both miRNAs demonstrated significant upregulation in screen‐detected type 2 diabetes vs normoglycemia (miR‐486‐5p, P = 0.009; miR‐novel‐chr1_40444, P

Background/purpose: Tooth development, or odontogenesis, is a complex process in which several molecular pathways play a key role. Recently, microRNAs, a class of approximately 20-nucleotide small RNA molecules that regulate gene expression, have been implicated in the odontogenesis process. This study aimed to assess the role of miRNAs in odontogenesis anomalies, specifically agenesis and impaction. Materials and methods: We analyzed a manually curated list of 82 miRNAs associated with human odontogenesis, sourced from literature data. Employing two different approaches to validate findings, we conducted functional enrichment analysis to evaluate the cell pathways, diseases, and phenotypes enriched for those miRNAs. Results: Our findings indicate that the analyzed miRNAs regulate pathways linked to tooth anomalies, including the TGFꞵ and Wnt signaling pathways, and those governing the pluripotency of stem cells, known to mediate various cellular processes, and interconnected with odontogenesis-related pathways. Furthermore, the analysis disclosed several pathways associated with tumors, including small cell lung and gastric cancer. These results were confirmed also by diseases and phenotypes enrichment evaluation. Moreover, cell network analysis disclosed that miRNAs are embedded and interconnected in networks associated with dental diseases and cancer development, thus confirming the functional enrichment analyses. Conclusion: In summary, our results offer a quantitative measure of the potential involvement of miRNAs in regulating pathways crucial for developmental processes, notably odontogenesis, and provide results suggesting potential association with oncogenesis processes as well.

Purpose of the study. Bioinformatic search for transcriptomic markers (based on metabolomic data) and their validation in the urine of serous ovarian adenocarcinoma patients.Materials and methods. The study included 70 patients with serous ovarian adenocarcinoma and 30 conditionally healthy individuals. The search for metabolite regulator genes and gene regulator microRNAs was performed using the Random forest machine learning method. Ribonucleic acid (RNA) was isolated using the RNeasy Plus Universal Kits. The level of microRNA transcripts in urine was determined by real-time PCR. Differences were assessed using the Mann-Whitney test with Bonferroni correction.Results. Using the Random forest method, metabolite-regulator gene (47 genes) and metabolite-regulator microRNA (613 unique microRNA) relationships were established. The identified microRNAs were validated by real-time PCR. Changes in the levels of microRNA transcripts were detected: miR-382-5p, miR-593-3p, miR-29a-5p, miR-2110, miR-30c-5p, miR-181a-5p, let-7b-5p, miR-27a-3p, miR-370-3p, miR-6529-5p, miR-653-5p, miR-4742-5p, miR-2467-3p, miR-1909-5p, miR-6743-5p, miR-875-3p, miR-19a-3p, miR-208a-5p, miR-330-5p, miR-1207-5p, miR-4668-3p, miR-3193, miR-23a-3p, miR-12132, miR-765, miR-181b-5p, miR-4529-3p, miR-33b-5p, miR-17-5p, miR-6866-3p, miR-4753-5p, miR-103a-3p, miR-423-5p, miR-491-5p, miR-196b-5p, miR-6843-3p, miR-423-5p and miR-3184-5p in the urine of patients compared to conditionally healthy individuals.Conclusion. Thus, urine transcriptome profiling allowed both to identify potential disease markers and to better understand the molecular mechanisms of changes underlying ovarian cancer development.

Abstract Background Coronavirus disease 2019 (COVID-19) has created a global pandemic with significant morbidity and mortality. SARS-CoV-2 primarily infects the lungs and is associated with various organ complications. Therapeutic approaches to combat COVID-19, including convalescent plasma and vaccination, have been developed. However, the high mutation rate of SARS-CoV-2 and its ability to inhibit host T-cell activity pose challenges for effective treatment. Mesenchymal stem cells (MSCs) and their extracellular vesicles (MSCs–EVs) have shown promise in COVID-19 therapy because of their immunomodulatory and regenerative properties. MicroRNAs (miRNAs) play crucial regulatory roles in various biological processes and can be manipulated for therapeutic purposes. Objective We aimed to investigate the role of lyophilized MSC–EVs and their microRNAs in targeting the receptors involved in SARS-CoV-2 entry into host cells as a strategy to limit infection. In silico microRNA prediction, structural predictions of the microRNA–mRNA duplex, and molecular docking with the Argonaut protein were performed. Methods Male Syrian hamsters infected with SARS-CoV-2 were treated with human Wharton’s jelly-derived Mesenchymal Stem cell-derived lyophilized exosomes (Bioluga Company)via intraperitoneal injection, and viral shedding was assessed. The potential therapeutic effects of MSCs–EVs were measured via histopathology of lung tissues and PCR for microRNAs. Results The results revealed strong binding potential between miRNA‒mRNA duplexes and the AGO protein via molecular docking. MSCs–EVs reduced inflammation markers and normalized blood indices via the suppression of viral entry by regulating ACE2 and TMPRSS2 expression. MSCs–EVs alleviated histopathological aberrations. They improved lung histology and reduced collagen fiber deposition in infected lungs. Conclusion We demonstrated that MSCs–EVs are a potential therapeutic option for treating COVID-19 by preventing viral entry into host cells.

Abstract Nuclear receptors (NRs) function as crucial transcription factors in orchestrating essential functions within the realms of development, host defense, and homeostasis of body. NRs have garnered increased attention due to their potential as therapeutic targets, with drugs directed at NRs demonstrating significant efficacy in impeding chronic disease progression. Consequently, these pharmacological agents hold promise for the treatment and management of various diseases. Accumulating evidence emphasizes the regulatory role of exosome-derived microRNAs (miRNAs) in chronic inflammation, disease progression, and therapy resistance, primarily by modulating transcription factors, particularly NRs. By exploiting inflammatory pathways such as protein kinase B (Akt)/mammalian target of rapamycin (mTOR), nuclear factor kappa-B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and Wnt/β-catenin signaling, exosomes and NRs play a pivotal role in the panorama of development, physiology, and pathology. The internalization of exosomes modulates NRs and initiates diverse autocrine or paracrine signaling cascades, influencing various processes in recipient cells such as survival, proliferation, differentiation, metabolism, and cellular defense mechanisms. This comprehensive review meticulously examines the involvement of exosome-mediated NR regulation in the pathogenesis of chronic ailments, including atherosclerosis, cancer, diabetes, liver diseases, and respiratory conditions. Additionally, it elucidates the molecular intricacies of exosome-mediated communication between host and recipient cells via NRs, leading to immunomodulation. Furthermore, it outlines the implications of exosome-modulated NR pathways in the prophylaxis of chronic inflammation, delineates current limitations, and provides insights into future perspectives. This review also presents existing evidence on the role of exosomes and their components in the emergence of therapeutic resistance.

Abstract There is little known about the contribution of exosomal microRNAs (exomiRs) in the children’s cardiac surgery-associated acute kidney injury (CSA-AKI). This study aimed to find diagnostic biomarkers for predicting CSA-AKI in children. A prospective observational study was conducted from April 2020 to March 2021.According to the changes of serum creatinine (SCr) value and urine volume within 48 h, the children were divided into acute kidney injury (AKI) group and non-AKI group. Serum samples were collected 4 h after cardiac surgery. Isolation of extracellular vesicles (EVs) and extraction of exomiRs from serum samples. Illumina high-throughput sequencing was used to quantify exomiRs and screen candidate microRNAs (miRNAs). Expression levels of candidate miRNAs were validated using droplet digital polymerase chain reaction (ddPCR). Normal and injuried rats’ kidney tissue were collected for tissue validation. In the pre-experimental stage (4 AKI vs. 4 non-AKI), hsa-miR-184, hsa-miR-4800-3p, hsa-miR-203a-3p and hsa-miR-6766-3p were selected as candidate genes. In the verification stage (8 AKI vs. 12 non-AKI), the expression of hsa-miR-184 in AKI group was significantly lower than that in non-AKI group (P = 0.031), and the expression of hsa-miR-4800-3p and hsa-miR-6766-3p in AKI group was significantly higher than that in non-AKI group (P = 0.01 and P = 0.047). There was no significant difference in the expression of hsa-miR-203a-3p between the two groups (P > 0.05). The expression of rats’ kidney tissue rno-miR-184 in AKI group was significantly lower than that in the normal group (P = 0.044). The area under the curve (AUC) of AKI predicted by hsa-miR-184 is 0.7865 and the AUC of hsa-miR-6766-3p is 0.7708. Combined with two kinds of miRNAs, the area under the curve of AKI is predicted to be 0.8646. The change of exomiRs level in circulatory system occurred in the early stage after cardiac operation, and the changes of hsa-miR-184 and hsa-miR-6766-3p content in circulatory system could predict CSA-AKI well.

Abstract Ovarian insufficiency is one of the common reproductive disorders affecting women with limited therapeutic aids. Mesenchymal stem cells have been investigated in such disorders before yet, the exact mechanism of MSCs in ovarian regeneration regarding their epigenetic regulation remains elusive. The current study is to investigate the role of the bone marrow-derived mesenchymal stem cells (BM-MSCs) lncRNA (Neat-1 and Hotair1) and miRNA (mir-21-5p, mir-144-5p, and mir-664-5p) in mitigating ovarian granulosa cell apoptosis as well as searching BM-MSCs in altering the expression of ovarian and hypothalamic IGF-1 – kisspeptin system in connection to HPG axis in a cyclophosphamide-induced ovarian failure rat model. Sixty mature female Sprague Dawley rats were divided into 3 equal groups; control group, premature ovarian insufficiency (POI) group, and POI + BM-MSCs. POI female rat model was established with cyclophosphamide. The result revealed that BM-MSCs and their conditioned media displayed a significant expression level of Neat-1, Hotair-1, mir-21-5p, mir-144-5p, and mir-664-5p. Moreover, BM-MSCs transplantation in POI rats improves; the ovarian and hypothalamic IGF-1 – kisspeptin, HPG axis, ovarian granulosa cell apoptosis, steroidogenesis, angiogenesis, energy balance, and oxidative stress. BM-MSCs expressed higher levels of antiapoptotic lncRNAs and microRNAs that mitigate ovarian insufficiency.

Abstract Background MicroRNA isoforms (isomiRs), tRNA-derived fragments (tRFs), and rRNA-derived fragments (rRFs) represent most of the small non-coding RNAs (sncRNAs) found in cells. Members of these three classes modulate messenger RNA (mRNA) and protein abundance and are dysregulated in diseases. Experimental studies to date have assumed that the subcellular distribution of these molecules is well-understood, independent of cell type, and the same for all isoforms of a sncRNA. Results We tested these assumptions by investigating the subcellular distribution of isomiRs, tRFs, and rRFs in biological replicates from three cell lines from the same tissue and same-sex donors that model the same cancer subtype. In each cell line, we profiled the isomiRs, tRFs, and rRFs in the nucleus, cytoplasm, whole mitochondrion (MT), mitoplast (MP), and whole cell. Using a rigorous mathematical model we developed, we accounted for cross-fraction contamination and technical errors and adjusted the measured abundances accordingly. Analyses of the adjusted abundances show that isomiRs, tRFs, and rRFs exhibit complex patterns of subcellular distributions. These patterns depend on each sncRNA’s exact sequence and the cell type. Even in the same cell line, isoforms of the same sncRNA whose sequences differ by a few nucleotides (nts) can have different subcellular distributions. Conclusions SncRNAs with similar sequences have different subcellular distributions within and across cell lines, suggesting that each isoform could have a different function. Future computational and experimental studies of isomiRs, tRFs, and rRFs will need to distinguish among each molecule’s various isoforms and account for differences in each isoform’s subcellular distribution in the cell line at hand. While the findings add to a growing body of evidence that isomiRs, tRFs, rRFs, tRNAs, and rRNAs follow complex intracellular trafficking rules, further investigation is needed to exclude alternative explanations for the observed subcellular distribution of sncRNAs.

Abstract Background Coronavirus-19 disease (COVID-19) frequently causes coagulation disturbances. Data remains limited on the effects of microRNAs (miRNAs) on coagulation during COVID-19 infection. We aimed to analyze the comprehensive miRNA profile as well as coagulation markers and blood count in hospitalized COVID-19 patients. Methods Citrated plasma samples from 40 patients (24 men and 16 women) hospitalized for COVID-19 were analyzed. Basic coagulation tests, von Willebrand factor (VWF), ADAMTS13, blood count, C-reactive protein, and 27 miRNAs known to associate with thrombosis or platelet activation were analyzed. MiRNAs were analyzed using quantitative reverse transcription polymerase chain reaction (RT qPCR), with 10 healthy controls serving as a comparator. Results Among the patients, 15/36 (41%) had platelet count of over 360 × 109/L and 10/36 (28%) had low hemoglobin of

Na Yang,1,2,&ast; Yong-Bo Hou,2,3,&ast; Tian-Hao Cui,2 Jun-Ma Yu,2 Shu-Fang He,4,5 Hai-Juan Zhu1 1Department of Anesthesiology, Maternal and Child Medical Center of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Anesthesiology, The Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, People’s Republic of China; 3Department of Anesthesiology, Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 4Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 5Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shu-Fang He; Hai-Juan Zhu, Email sfhe@ahmu.edu.cn; 35880762@qq.comBackground: Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism.Methods: Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI.Results: IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-β (TGF-β) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-β 1in MI rats.Conclusion: IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-β pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair. Keywords: ischemic preconditioning, myocardial infarction, Exosomes, MicroRNAs, cardiac function, myocardial fibrosis

Shandong Jiang,1,2 Libin Hu,1,2 Hang Zhou,1,2 Jianan Wu,1,2 Jiayin Zhou,1,2 Xian Yu,1,2 Gao Chen1,2 1Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People’s Republic of China; 2Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People’s Republic of ChinaCorrespondence: Gao Chen, Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, 310009, People’s Republic of China, Email d-chengao@zju.edu.cnAbstract: Intracerebral hemorrhage (ICH) is a primary, non-traumatic cerebral event associated with substantial mortality and disability. Despite advancements in understanding its etiology and refining diagnostic techniques, a validated treatment to significantly improve ICH prognosis remains elusive. Exosomes, a subtype of extracellular vesicles, encapsulate bioactive components, predominantly microRNAs (miRNAs), facilitating and regulating intercellular communication. Currently, exosomes have garnered considerable interests in clinical transformation for their nanostructure, minimal immunogenicity, low toxicity, inherent stability, and the ability to traverse the blood-brain barrier. A wealth of studies has demonstrated that exosomes can improve the prognosis of ICH through anti-apoptosis, neurogenesis, angiogenesis, anti-inflammation, immunomodulation, and autophagy, primarily via the transportation or overexpression of selected miRNAs. More importantly, exosomes can be easily customized with specific miRNAs or bioactive compounds to establish delivery systems, broadening their potential applications. This review focuses on the therapeutic potential of exosomes in ICH, reviewing the mechanisms of molecular biology mediated by certain miRNAs, discussing the benefits, challenges, and future prospects in ICH treatment. We hope comprehensive understanding of exosomes based on miRNAs will provide new insights into the treatment of ICH and guide the translation of exosome’s research from laboratory to clinical practice. Keywords: intracerebral hemorrhage, exosomes, extracellular vesicles, microRNAs, stem cells

Background: Hypersensitivity pneumonitis (HP) is an inflammatory disorder affecting lung parenchyma and often evolves into fibrosis (fHP). The altered regulation of genes involved in the pathogenesis of the disease is not well comprehended, while the role of microRNAs in lung fibroblasts remains unexplored. Methods: We used integrated bulk RNA-Seq and enrichment pathway bioinformatic analyses to identify differentially expressed (DE)-miRNAs and genes (DEGs) associated with HP lungs. In vitro, we evaluated the expression and potential role of miR-155-5p in the phenotype of fHP lung fibroblasts. Loss and gain assays were used to demonstrate the impact of miR-155-5p on fibroblast functions. In addition, mir-155-5p and its target TP53INP1 were analyzed after treatment with TGF-β, IL-4, and IL-17A. Results: We found around 50 DEGs shared by several databases that differentiate HP from control and IPF lungs, constituting a unique HP lung transcriptional signature. Additionally, we reveal 18 DE-miRNAs that may regulate these DEGs. Among the candidates likely associated with HP pathogenesis was miR-155-5p. Our findings indicate that increased miR-155-5p in fHP fibroblasts coincides with reduced TP53INP1 expression, high proliferative capacity, and a lack of senescence markers compared to IPF fibroblasts. Induced overexpression of miR-155-5p in normal fibroblasts remarkably increases the proliferation rate and decreases TP53INP1 expression. Conversely, miR-155-5p inhibition reduces proliferation and increases senescence markers. TGF-β, IL-4, and IL-17A stimulated miR-155-5p overexpression in HP lung fibroblasts. Conclusion: Our findings suggest a distinctive signature of 53 DEGs in HP, including CLDN18, EEF2, CXCL9, PLA2G2D, and ZNF683, as potential targets for future studies. Likewise, 18 miRNAs, including miR-155-5p, could be helpful to establish differences between these two pathologies. The overexpression of miR-155-5p and downregulation of TP53INP1 in fHP lung fibroblasts may be involved in his proliferative and profibrotic phenotype. These findings may help differentiate and characterize their pathogenic features and understand their role in the disease.

Meningiomas, characterized primarily as benign intracranial or spinal tumors, present distinctive challenges due to their variable clinical behavior, with certain cases exhibiting aggressive features linked to elevated morbidity and mortality. Despite their prevalence, the underlying molecular mechanisms governing the initiation and progression of meningiomas remain insufficiently understood. MicroRNAs (miRNAs), small endogenous non-coding RNAs orchestrating post-transcriptional gene expression, have garnered substantial attention in this context. They emerge as pivotal biomarkers and potential therapeutic targets, offering innovative avenues for managing meningiomas. Recent research delves into the intricate mechanisms by which miRNAs contribute to meningioma pathogenesis, unraveling the molecular complexities of this enigmatic tumor. Meningiomas, originating from arachnoid meningothelial cells and known for their gradual growth, constitute a significant portion of intracranial tumors. The clinical challenge lies in comprehending their progression, particularly factors associated with brain invasion and heightened recurrence rates, which remain elusive. This comprehensive review underscores the pivotal role of miRNAs, accentuating their potential to advance our comprehension of meningioma biology. Furthermore, it suggests promising directions for developing diagnostic biomarkers and therapeutic interventions, holding the promise of markedly improved patient outcomes in the face of this intricate and variable disease.