miRNA Function Research Articles

Effect of exosomes from nasopharyngeal carcinoma on endothelium pyroptosis and metastasis.

93 Background: Nasopharyngeal carcinoma (NPC) is a malignant tumor occurring in the epithelium of nasopharyngeal mucosa. Radiotherapy can achieve a good therapeutic effect for NPC in situ. However, there is no effective treatment once distant metastasis occurring. Epstein-Barr virus (EBV) is an important pathogenic factor of NPC and also promotes tumor metastasis. The passage of circulating tumor cells through the vascular barrier is one of the rate-limiting steps of tumor distant metastasis, and vascular endothelial cells are an important component. Exosomes are an important way of information transmission between cells. And some small molecules in exosomes involve in tumor metastasis. How the exosomes of NPC cells affect vascular endothelial cells and promote metastasis has not been studied. Therefore, it is of great significance to explore the effect of the NPC exosomes with EBV component on the vascular endothelial cells of metastatic foci and the mechanism of promoting tumor metastasis, in order to find effective therapeutic targets and molecular markers indicating distant metastasis. Methods: 1. Immunohistochemical analysis was used to analyze the vascular endothelium of liver and lung tissues with NPC metastasis compared with that of non-tumor liver and lung in pathological sections; 2. Using transmission electron microscope, cells and dye molecules through vascular endothelial cell monolayer experiment, immunofluorescence and animal tumorigenesis experiment to detect the effect of NPC exosomes on vascular endothelial cells and NPC metastasis; 3. Using CRISPR-Cas9 knockout EBNA1, cell function test and miRNA sequencing technology to analyze to analyze molecular types that induce vascular endothelial cell pyroptosis in NPC exosomes; 4. Using bioinformatics prediction, luciferase reporter gene, immunofluorescence and animal tumorigenesis experiment to further clarify the molecular pathway of molecules in the NPC exosomes that induce endothelial cell pyroptosis. Results: 1. Immunohistochemistry showed that P20 and NT-GSDMD were significantly higher in vascular endothelial cells of liver and lung tissues with NPC metastasis than in non-tumor liver and lung; 2. NPC exosomes can promote the increase of molecules related to vascular endothelial cell pyroptosis (P20, NT-GSDMD and IL-1 β), the formation of vesicular protrusion of cell membrane and the destruction of vascular endothelial monolayer barrier. And vascular endothelial cell pyroptosis can promote the migration of circulating tumor cells out of blood vessels to form metastatic foci; 3. BART2-5p in NPC exosomes is the main effector molecule that induces vascular endothelial cell pyroptosis; 4. MRE11A is the target molecule of BART2-5p to induce vascular endothelial cell pyroptosis. Conclusions: 1. It was found for the first time that the vascular endothelial cell pyroptosis in liver and lung metastasis of NPC; 2. It is proved that BART2-5p in NPC exosomes is involved in regulating the vascular endothelial cell pyroptosis, and promoting NPC cells to go through blood vessels and form metastatic foci; 3. MRE11A mediates BART2-5p to induce the vascular endothelial cell pyroptosis.

High specific microRNA detection based on G-quadruplex sensitive fluorescence under isothermal amplification

MicroRNAs (miRNAs) are crucial for various basic cellular processes and have been regarded as an important indicator for pathogenesis and development of cancer. While miRNAs are characterized by short sequence length, large single cell copy number variation, low abundance in vivo, and high homologous sequence similarity. The development of miRNA detection methods with high sensitivity, good selectivity and low cost is the key to study the function of miRNA. In this article, a method combining isothermal chain replacement amplification and G-quadruplex (G4) specific detection is developed for highly specific and sensitive detection of miRNA. By designing proper DNA sequences, a three-stranded DNA complex was formed and produced a lot of G4 structure sequences, which can be stained by specific fluorescence dye and quantified. In the experiment, the fluorescence dye shows extremely high specificity, which brings excellent signal discrimination, so that the target miRNAs can be accurately detected. Experiments under high background noise also verified this method is highly selective for target miRNAs. This method holds great imagination in expanding the detection methods to more platforms, such as nanopore sensors, because it alters the secondary structure of DNA sequences.

Nano- and micro-polystyrene plastics interfered the gut barrier function mediated by exosomal miRNAs in rats

Microplastics (MPs) are widely distributed in the global environment, entering and accumulating in organisms in various ways and posing health threats. MPs can damage intestine; however, the mechanism by which MPs cause intestinal damage in rats is unclear. Here, rats were exposed to 50 nm PS-NPs or 5 μm PS-MPs for 4 weeks to evaluate the possible effects on intestinal barrier function and exosomal miRNAs expressions. The results showed that PS-NPs or PS-MPs disrupted the gut microbiota and affected gut barrier function at the biological level. In addition, PS-NPs and PS-MPs altered the composition of exosomal miRNAs in the intestinal and serum. Both PS-NPs and PS-MPs decreased the expression of miR-126a-3p in the intestinal and serum exosomes, which is an important signalling molecule involved in MPs induced gut barrier function disorder. More importantly, both in vitro and in vivo experiments indicated that miR-126a-3p was closely related to oxidative damage of intestinal cells through the PI3K-Akt pathway and eventually promote cell apoptosis by regulating the target gene of PIK3R2. Our study suggested that PS-NPs and PS-MPs could affect rat intestinal barrier function through an exosomal miRNA mediated pathway.

MicroRNA Cargo in Wharton’s Jelly MSC Small Extracellular Vesicles: Key Functionality to In Vitro Prevention and Treatment of Premature White Matter Injury

SummaryPreterm birth is the leading cause of childhood morbidity and mortality and can result in white matter injury (WMI), leading to long-term neurological disabilities with global health burden. Mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEV) are a promising therapeutic agent for treating perinatal neurological injury. They carry microRNAs (miRNAs) predicted to be involved in the onset of premature WMI. We hypothesize that miRNAs have a key function in the beneficial effects of MSC-sEV. We isolated MSC from umbilical cord tissue, the Wharton’s jelly (WJ), and purified small extracellular vesicles (sEV) from WJ-MSC culture supernatant by ultracentrifugation and size exclusion chromatography. The miRNA content was quantified by real-time polymerase chain reaction. A luciferase gene assay validated silencing of TP53 and TAOK1, which we previously identified as predicted target genes of MSC-sEV miRNAs by Next Generation Sequencing and pathway enrichment analysis. The impact of sEV miRNAs on oligodendroglial maturation and neuronal apoptosis was evaluated using an in vitro oxygen-glucose deprivation model (OGD/R) by knocking-down DROSHA in WJ-MSC, which initiates miRNA processing. WJ-MSC-sEV contained miRNAs involved in WMI, namely hsa-miR-22-3p, hsa-miR-21-5p, hsa-miR-27b-3p, and the hsa-let-7 family. The luciferase assay strongly indicated an inhibitory effect of sEV miRNAs on the gene expression of TP53 and TAOK1. Small EV initiated oligodendrocyte maturation and reduced OGD/R-mediated neuronal apoptosis. Knocking-down DROSHA in WJ-MSC reduced the expression of sEV miRNAs and led to the loss of their beneficial effects. Our in vitro study strongly indicates the key function of miRNAs in the therapeutic potential of WJ-MSC-sEV in premature WMI.

Exosomal miR-184 in the aqueous humor of patients with central serous chorioretinopathy: a potential diagnostic and prognostic biomarker

BackgroundCentral serous chorioretinopathy (CSC) is the fourth most prevalent retinal disease leading to age-related macular degeneration (AMD) and retinal atrophy. However, CSC's pathogenesis and therapeutic target need to be better understood.ResultsWe investigated exosomal microRNA in the aqueous humor of CSC patients using next-generation sequencing (NGS) to identify potential biomarkers associated with CSC pathogenesis. Bioinformatic evaluations and NGS were performed on exosomal miRNAs obtained from AH samples of 62 eyes (42 CSC and 20 controls). For subgroup analysis, patients were divided into treatment responders (CSC-R, 17 eyes) and non-responders (CSC-NR, 25 eyes). To validate the functions of miRNA in CECs, primary cultured-human choroidal endothelial cells (hCEC) of the donor eyes were utilized for in vitro assays. NGS detected 376 miRNAs. Our results showed that patients with CSC had 12 significantly upregulated and 17 downregulated miRNAs compared to controls. miR-184 was significantly upregulated in CSC-R and CSC-NR patients compared to controls and higher in CSC-NR than CSC-R. In vitro assays using primary cultured-human choroidal endothelial cells (hCEC) demonstrated that miR-184 suppressed the proliferation and migration of hCECs. STC2 was identified as a strong candidate for the posttranscriptional down-regulated target gene of miR-184.ConclusionOur findings suggest that exosomal miR-184 may serve as a biomarker reflecting the angiostatic capacity of CEC in patients with CSC.

3D Culture and Interferon-γ Priming Modulates Characteristics of Mesenchymal Stromal/Stem Cells by Modifying the Expression of Both Intracellular and Exosomal microRNAs.

Mesenchymal stromal/stem cells (MSCs) have emerged as a therapeutic tool in regenerative medicine. Recent studies have shown that exosome (EXO)-derived microRNAs (miRNAs) play a crucial role in mediating MSC functions. Additionally, intracellular miRNAs have been found to regulate MSC therapeutic capacities. However, the molecular mechanisms underlying miRNA-mediated MSC effects are not fully understood. We used 3D culture and IFN-γ to prime/enhance the MSC therapeutic effects in terms of functional miRNAs. After priming, our analysis revealed stable variations in intracellular miRNA among the MSC biological replicates. Conversely, a significant variability of miRNA was observed among EXOs released from biological replicates of the priming treatment. For each priming, we observed distinct miRNA expression profiles between the MSCs and their EXOs. Moreover, in both types of priming, gene ontology (GO) analysis of deregulated miRNAs highlighted their involvement in tissue repair/regeneration pathways. In particular, the 3D culture enhanced angiogenic properties in both MSCs and EXOs, while IFN-γ treatment enriched miRNAs associated with immunomodulatory pathways. These findings suggest that 3D culture and IFN-γ treatment are promising strategies for enhancing the therapeutic potential of MSCs by modulating miRNA expression. Additionally, the identified miRNAs may contribute to understanding the molecular mechanisms underlying the miRNA-mediated therapeutic effects of MSCs.

In silico analysis of serum miRNA profiles in seronegative and seropositive rheumatoid arthritis patients by small RNA sequencing.

Rheumatoid arthritis (RA) is a refractory autoimmune disease, affecting about 1% of the world's population. RA is divided into seronegative RA and seropositive RA. However, biomarkers for discriminating between seronegative and seropositive RA have not been reported. In this study, we profiled serum miRNAs in seronegative RA patients (N-RA), seropositive RA patients (P-RA) and healthy controls (HC) by small RNA sequencing. Results indicated that compared with HC group, there were one up-regulated and four downregulated miRNAs in N-RA group (fold change ≥ 2 and P value < 0.05); compared with P-RA group, there were two up-regulated and four downregulated miRNAs in N-RA group; compared with HC group, there were three up-regulated and four downregulated miRNAs in P-RA group. Among them, the level of hsa-miR-362-5p in N-RA group was up-regulated compared with that in HC group and P-RA group, and the level of hsa-miR-6855-5p and hsa-miR-187-3p in P-RA group was upregulated compared with that in N-RA group and HC group. Validation by qPCR confirmed that serum hsa-miR-362-5p level was elevated in N-RA group. Subsequently, by analyzing the target genes using RNAhybrid, PITA, Miranda and TargetScan and functions of differential miRNAs utilizing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), we found that the target genes and molecular pathways regulated by miRNAs in seronegative RA and seropositive RA were roughly the same, and miRNAs in these two diseases may participate in the occurrence and development of diseases by regulating the immune system. In conclusion, this study revealed the profiles of serum miRNAs in seronegative and seropositive RA patients for the first time, providing potential biomarkers and targets for the diagnosis and treatment of seronegative and seropositive RA.

Integrated analysis of lncRNA/circRNA-miRNA-mRNA in the proliferative phase of liver regeneration in mice with liver fibrosis.

Non-coding RNAs play important roles in liver regeneration; however, their functions and mechanisms of action in the regeneration of fibrotic liver have not been elucidated. We aimed to clarify the expression patterns and regulatory functions of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration. Based on a mouse model of liver fibrosis with 70% hepatectomy, whole-transcriptome profiling was performed using high-throughput sequencing on samples collected at 0, 12, 24, 48, and 72h after hepatectomy. Hub genes were selected by weighted gene co-expression network analysis and subjected to enrichment analysis. Integrated analysis was performed to reveal the interactions of differentially expressed (DE) lncRNAs, circRNAs, miRNAs, and mRNAs, and to construct lncRNA-mRNA cis- and trans-regulatory networks and lncRNA/circRNA-miRNA-mRNA ceRNA regulatory networks. Real-Time quantitative PCR was used to validate part of the ceRNA network. A total of 1,329 lncRNAs, 48 circRNAs, 167 miRNAs, and 6,458 mRNAs were differentially expressed, including 812 hub genes. Based on these DE RNAs, we examined several mechanisms of ncRNA regulatory networks, including lncRNA cis and trans interactions, circRNA parental genes, and ceRNA pathways. We constructed a cis-regulatory core network consisting of 64 lncRNA-mRNA pairs (53 DE lncRNAs and 58 hub genes), a trans-regulatory core network consisting of 103 lncRNA-mRNA pairs (18 DE lncRNAs and 85 hub genes), a lncRNA-miRNA-mRNA ceRNA core regulatory network (20 DE lncRNAs, 12 DE miRNAs, and 33 mRNAs), and a circRNA-miRNA-mRNA ceRNA core regulatory network (5 DE circRNAs, 5 DE miRNAs, and 39 mRNAs). These results reveal the expression patterns of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration, as well as core regulatory networks of mRNAs and non-coding RNAs underlying liver regeneration. The findings provide insights into molecular mechanisms that may be useful in developing new therapeutic approaches to ameliorate diseases that are characterized by liver fibrosis, which would be beneficial for the prevention of liver failure and treatment of liver cancer.

Schisandrol A, a bioactive constituent from Schisandrae Chinensis Fructus, alleviates drug-induced liver injury by autophagy activation via exosomes

ObjectiveTo investigate the bioactive compounds of Schisandrae Chinensis Fructus (SCF) and their mechanisms of action in the treatment of drug-induced liver injury (DILI), specifically Acetaminophen (APAP)-induced DILI. MethodChemical components in SCF were identified using the UPLC-Q-TOF-MS method. Active components were then screened using HotMap, combined with SCF efficacy results concerning the prevention and treatment of drug-induced liver injury. Its direct target was elucidated using a comprehensive chemical-pharmacodynamic-exosome approach. ResultWe identified Schisandrol A, is a lignan component, as a key active compound that improved the symptoms DILI in mouse liver tissue; specifically, reducing oxidative stress and thereby the inflammatory response. To further understand the biological function of miRNAs in mouse liver exosomes, we used TargetScan (v5.0) and Miranda (v3.3a) to predict the target genes of MicroRNAs (miRNAs), where changes in the expression of mmu-let-7 family miRNAs were closely related to autophagy. This revealed differential miRNA target genes that were involved in 20 Kyoto Encyclopedia of Genes and Genomes pathways, including glycerol phosphate metabolism, inositol phosphate metabolism, phospholipase D signaling pathway, Rap1 signaling pathway, and Ras signaling pathway. ConclusionSchisandrol A alleviated the symptoms of DILI in mice by inhibiting oxidative stress and inflammation, whereas, it alleviated DILI by activating autophagy in the exosomes.

Identification of target hub genes and construction of a novel miRNA regulatory network in autism spectrum disorder by integrated analysis.

The incidence of autism spectrum disorder (ASD) is increasing year by year in children. The aim of the study was to find possible biomarkers for ASD diagnosis as well as examine MicroRNA (miRNA) signatures and crucial pathways. We conducted a two-stage study to explore potential target genes and functional miRNAs. Peripheral blood samples of children with ASD were enrolled and performed RNA sequencing analysis. The overlapped candidate genes were further screened in combination with differentially expressed genes (DEGs) of GSE77103 datasets. STRING established a protein-protein interaction network comprising DEGs. The hub genes were filtered out using the CytoHubba. Then, we set up a miRNA-mRNA regulatory network. Correlational analyses between hub genes and immune cells associated with ASD were carried out using the CIBERSORT software to assess the diversity of immune cell types in ASD. RNA-sequencing analysis was used to confirm the differential expression of 3 hub genes. Briefly, after blood samples were sequenced interrogating 867 differential genes in our internal screening dataset. After screening GEO databases, 551 DEGs obtained from GSE77103. Fourteen common genes were overlapped through DEGs of GEO datasets and internal screening dataset. Among protein-protein interaction network, 10 hub genes with high degree algorithm were screened out and 3 hub genes of them - ADIPOR1, LGALS3, and GZMB - that were thought to be most associated with the emergence of ASD. Then, we developed a network of miRNA-mRNA regulatory interactions by screening miRNAs (such as hsa-miR-20b-5p, hsa-miR-17-5p, and hsa-miR-216b-5p) that were closely associated to 3 hub genes. Additionally, we discovered 18 different immune cell types associated with ASD using the CIBERSORT algorithm, and we discovered that mononuclear macrophages differed considerably between the 2 groups. Overall, 3 hub genes (ADIPOR1, LGALS3, and GZMB) and 15 candidates miRNAs-target 3 genes regulatory pathways representing potentially novel biomarkers of ASD diseases were revealed. These findings could enhance our knowledge of ASD and offer possible therapeutic targets of ASD patients in the future.

MicroRNA, a small non-coding RNA, how do you know?

MicroRNA (miRNA) has well been known as a kind of short non-coding RNAs that can regulate their target genes. Preciously, several studies have confirmed that miRNAs play varied biological function and regulate variant pathological processes. This study reviews the progress of miRNA and discuss their value as well as translational possibility. We input the keyword "miRNA" in PUBMED (https://pubmed.ncbi.nlm.nih.gov/) and acquired near 20000 papers. Of these, the main literature were categorized and summarized. We systematically addressed the synthesis, transport and location of miRNAs and focusedly discussed the function of miRNA and the associated possible mechanisms. These knowledge therefore provides important information to understand the role and current progress of miRNA, so as to explain the source and function of miRNA, and provide useful information for related research in future practice.

Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes.

As chondrocytes from osteoarthritic cartilage usually exhibit aging and senescent characteristics, targeting aging chondrocytes could be a potential therapeutic strategy. In this study, exosomes derived from umbilical cord-derived mesenchymal stem cells (UCMSC-EXOs) combined with the chondrocyte-targeting capacity and controlled-release system were proposed for osteoarthritis (OA) treatment via rejuvenating aging chondrocytes. The essential functional miRNAs within UCMSC-EXOs were investigated, with the p53 signaling pathway identified as the key factor. To improve the therapeutic efficiency and retention time of UCMSC-EXOs in vivo, the exosomes (EXOs) were engineered on membranes with a designed chondrocyte-targeting polymers, and encapsulated within thiolated hyaluronic acid microgels to form a "two-phase" releasing system, which synergistically facilitated the repair of OA cartilage in a rat model. Together, this study highlighted the rejuvenating effects of UCMSC-EXOs on OA chondrocytes and the potential to combine with chondrocyte-targeting and sustained-release strategies toward a future cell-free OA treatment.

Pluripotency-Associated microRNAs in Early Vertebrate Embryos and Stem Cells.

MicroRNAs (miRNAs), small non-coding RNA molecules, regulate a wide range of critical biological processes, such as proliferation, cell cycle progression, differentiation, survival, and apoptosis, in many cell types. The regulatory functions of miRNAs in embryogenesis and stem cell properties have been extensively investigated since the early years of miRNA discovery. In this review, we will compare and discuss the impact of stem-cell-specific miRNA clusters on the maintenance and regulation of early embryonic development, pluripotency, and self-renewal of embryonic stem cells, particularly in vertebrates.

An ensemble of stacking classifiers for improved prediction of miRNA–mRNA interactions

MicroRNAs (miRNAs) are small non-coding RNA molecules that play a crucial role in regulating gene expression at the post-transcriptional level by binding to potential target sites of messenger RNAs (mRNAs), facilitated by the Argonaute family of proteins. Selecting the conservative candidate target sites (CTS) is a challenging step, considering that most of the existing computational algorithms primarily focus on canonical site types, which is a time-consuming and inefficient utilization of miRNA target site interactions. We developed a stacking classifier algorithm that addresses the CTS selection criteria using feature-encoding techniques that generates feature vectors, including k-mer nucleotide composition, dinucleotide composition, pseudo-nucleotide composition, and sequence order coupling. This innovative stacking classifier algorithm surpassed previous state-of-the-art algorithms in predicting functional miRNA targets. We evaluated the performance of the proposed model on 10 independent test datasets and obtained an average accuracy of 79.77%, which is a significant improvement of 7.26 % over previous models. This improvement shows that the proposed method has great potential for distinguishing highly functional miRNA targets and can serve as a valuable tool in biomedical and drug development research.

Role of microRNA miR171 in plant development.

MicroRNAs (miRNAs) are endogenous non-coding small RNA with 19-24 nucleotides (nts) in length, which play an essential role in regulating gene expression at the post-transcriptional level. As one of the first miRNAs found in plants, miR171 is a typical class of conserved miRNAs. The miR171 sequences among different species are highly similar, and the vast majority of them have both "GAGCCG" and "CAAUAU" fragments. In addition to being involved in plant growth and development, hormone signaling and stress response, miR171 also plays multiple and important roles in plants through interactions with microbe and other small-RNAs. The miRNA functions by regulating the expression of target genes. Most of miR171's target genes are in the GRAS gene family, but also include some NSP, miRNAs, lncRNAs, and other genes. This review is intended to summarize recent updates on miR171 regarding its function in plant life and hopefully provide new ideas for understanding miR171 function and regulatory mechanisms.

Modern concepts in cervical carcinogenesis

The article discusses modern ideas about cervical carcinogenesis as a multi-stage process of multifactorial genesis. Currently, ideas about the pathogenesis of cervical cancer (CC) are based not only on understanding the role of high-risk oncogenic human papillomavirus (HPV) in this process and accumulation of genetic changes caused by it, but also on formation of a complex HPV interactome, or a network of intermolecular interactions of HPV oncoproteins with host cell proteins. Carcinogenesis also involves a wide range of epigenetic events and, above all, impairment of the regulatory function of miRNAs. An important role in cervical carcinogenesis is attributed to the concept of cancer stem cells (CSCs) formulated in recent years, which is closely related to the explanation of disease recurrence and treatment resistance, as well as to new approaches to treatment. The cervicovaginal microbiome and cervical microenvironment, which are responsible for natural clearance of HPV, regression of epithelial lesions, and modeling of the immune response, are becoming promising objects for research.The aim of the review was to present up-to-date information on the most important mechanisms of cervical carcinogenesis, as well as on new approaches to the treatment of CC, based, in particular, on the use of knowledge about regulatory miRNAs, CSC markers, and the state of the cervicovaginal microbiota.

Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression

Glutamate abnormalities in the medial prefrontal cortex (mPFC) are associated with cognitive deficits. We previously showed that homozygous deletion of CNS glutamate dehydrogenase 1 (Glud1), a metabolic enzyme critical for glutamate metabolism, leads to schizophrenia-like behavioral abnormalities and increased mPFC glutamate; mice heterozygous for CNS Glud1 deletion (C-Glud1+/− mice) showed no cognitive or molecular abnormalities. Here, we examined the protracted behavioral and molecular effects of mild injection stress on C-Glud1+/− mice. We found spatial and reversal learning deficits, as well as large-scale mPFC transcriptional changes in pathways associated with glutamate and GABA signaling, in stress-exposed C-Glud1+/− mice, but not in their stress-naïve or C-Glud1+/+ littermates. These effects were observed several weeks following stress exposure, and the expression levels of specific glutamatergic and GABAergic genes differentiated between high and low reversal learning performance. An increase in miR203-5p expression immediately following stress may provide a translational regulatory mechanism to account for the delayed effect of stress exposure on cognitive function. Our findings show that chronic glutamate abnormalities interact with acute stress to induce cognitive deficits, and resonate with gene x environment theories of schizophrenia. Stress-exposed C-Glud1+/− mice may model a schizophrenia high-risk population, which is uniquely sensitive to stress-related ‘trigger’ events.

Profiling of miRNAs and their interfering targets in peripheral blood mononuclear cells from patients with chronic myeloid leukaemia.

MicroRNAs may be implicated in the acquisition of drug resistance in chronic myeloid leukemia as they regulate the expression of not only BCR-ABL1 but also genes associated with the activation of drug transfer proteins or essential signaling pathways. To understand the impact of specifically expressed miRNAs in chronic myeloid leukemia and their target genes, we collected peripheral blood mononuclear cells (PBMC) from patients diagnosed with chronic myeloid leukemia (CML) and healthy donors to determine whole miRNA expression by small RNA sequencing and screened out 31 differentially expressed microRNAs (DE-miRNAs) with high expression. With the utilization of miRNA set enrichment analysis tools, we present here a comprehensive analysis of the relevance of DE-miRNAs to disease and biological function. Furthermore, the literature-based miRNA-target gene database was used to analyze the overall target genes of the DE-miRNAs and to define their associated biological responses. We further integrated DE-miRNA target genes to identify CML miRNA targeted gene signature singscore (CMTGSS) and used gene-set enrichment analysis (GSEA) to analyze the correlation between CMTGSS and Hallmark gene-sets in PBMC samples from clinical CML patients. Finally, the association of CMTGSS stratification with multiple CML cell lineage gene sets was validated in PBMC samples from CML patients using GSEA. Although individual miRNAs have been reported to have varying degrees of impact on CML, overall, our results show that abnormally upregulated miRNAs are associated with apoptosis and aberrantly downregulated miRNAs are associated with cell cycle. The clinical database shows that our defined DE-miRNAs are associated with the prognosis of CML patients. CMTGSS-based stratification analysis presented a tendency for miRNAs to affect cell differentiation in the blood microenvironment. Collectively, this study defined differentially expressed miRNAs by miRNA sequencing from clinical samples and comprehensively analyzed the biological functions of the differential miRNAs in association with the target genes. The analysis of the enrichment of specific myeloid differentiated cells and immune cells also suggests the magnitude and potential targets of differentially expressed miRNAs in the clinical setting. It helps us to make links between the different results obtained from the multi-faceted studies to provide more potential research directions.

The role of extracellular vesicle-derived miRNAs in adipose tissue function and metabolic health.

Extracellular vesicles (EVs) are nanometer size lipid particles that are released from virtually every cell type. Recent studies have shown that miRNAs carried by EVs play important roles in intercellular and interorgan communication. In the context of obesity and insulin resistance, EV-derived miRNAs functionally bridge major metabolic organs, including the adipose tissue, skeletal muscle, liver, and pancreas, to regulate insulin secretion and signaling. As a result, many of these EV-derived miRNAs have been proposed as potential disease biomarkers and/or therapeutic agents. However, the field's knowledge of EV miRNA-mediated regulation of mammalian metabolism is still in its infancy. Here, we review the evidence indicating that EV-derived miRNAs provide cell-to-cell and organ-to-organ communication to support metabolic health, highlight the potential medical relevance of these discoveries, and discuss the most important knowledge gaps and future directions for this field.

Role of miRNA-99a-5p in Modulating the Function of Hepatocellular Carcinoma Cells: Bioinformatics Analysis and In Vitro Assay.

This study aimed to investigate the biological functions of miRNAs in hepatobiliary tumors as the focus of targeted therapy research. Hepatobiliary tumors are among the leading causes of cancer-related deaths worldwide. Many microRNAs (miRNAs) play an important regulatory role in tumor progression. Our study aims to explore some biologically functional miRNAs from different datasets of hepatobiliary tumors for disease diagnosis or treatment. In this study, we tried to filter out differentially expressed miRNAs in different tumor datasets from the GEO database. In this study, we first perform analyses in different GEO data sets. After taking the intersection, the initial scope is limited to several differential RNAs. Then, combined with the existing research results from Kaplan-Meier survival analysis and literature, the candidate molecule was finally identified to be studied. Furthermore, the biological characteristics analysis of the candidate molecule was performed on the basis of Cancermirnome online tool, including expression levels in tumors, KEGG and GO analysis, ROC analysis, and target gene prediction. Furthermore, the effect of the candidate molecule on the biological functions of liver cancer was verified by In Vitro assay. The preliminary analysis of bioinformatics shows that 16 differentially expressed miRNAs may play an important role in HCC or ICC. Ultimately, we identified miRNA-99a-5p as the only molecule to study. The results showed that miRNA-99a-5p is abnormally expressed in many tumors, and in liver cancer, its level of expression in tumor tissue is significantly lower than that in normal tissue. Then, the KEGG and GO analysis found that it functions in multiple pathways. At the same time, the ROC analysis found that it showed great potential for prognostic prediction in HCC and we also predicted that RUNDC3B is the most likely target to which it binds. Finally, the experimental results of overexpression and knockdown confirmed that miRNA-99a-5p could inhibit cell proliferation in HCC, which also suggested that it may be an important tumor suppressor in HCC. MiRNA-99a-5p was negatively correlated with HCC progression and could act as a novel therapeutic target for HCC.