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The intricate immunomodulatory mechanism underlying the onset and progression of chronic rhinosinusitis with nasal polyps (CRSwNP) in chronic sinusitis with nasal polyps remains poorly understood, particularly regarding the regulatory role of dendritic cells (DCs). MicroRNA has been identified as a modulator of DC function. Primary cells have a short time in vitro and their biological characteristics have not changed greatly which can better reflect the growth state of cells in the body, so as to obtain data closer to the physiological function in the body. Our research group has been engaged in the culture of human nasal epithelial progenitor cells (hNEPCs) for a long time, and in previous investigations, we observed downregulation of microRNA‐124 (miR‐124) in patients with chronic sinusitis and nasal polyps. Thus, our current study aims to elucidate the regulatory mechanism of DCs in chronic sinusitis with polyps by examining the impact of miR‐124 on DCs in this context. To accomplish this, we took the nasal mucosa of CRSwNP patients and normal nasal mucosa of non‐rhinitis patients for primary culture. We isolated exosomes from these cells for co‐culture experiments with DCs. Flow cytometry analysis was employed to assess the maturation phenotypes (MHC II, CD80 and CD86), cell cycle and apoptosis levels of DCs. Furthermore, enzyme‐linked immunosorbent assay was utilized to measure the levels of pro‐inflammatory cytokines (IL‐10, IL‐12 and IL‐23). The TLR4/NF‐κB signalling pathway in co‐cultured DCs was evaluated using the western blot assay. Through querying the Targetscan website, we predicted Rab27a as a target gene of miR‐124, which was subsequently validated through double luciferase assay, flow cytometry and other experimental approaches. Our findings demonstrate that MiR‐124 modulates the secretion of CRSwNP epithelial exosomes, thereby influencing DC function via its interaction with the target gene Rab27a. These results offer novel insights into potential therapeutic targets for the treatment of CRSwNP. [ABSTRACT FROM AUTHOR]

The article "RETRACTED: Mir-124 Attenuates STAT3-Mediated TH17 Differentiation in Colitis-Driven Colon Cancer" published in Frontiers in Oncology on December 17, 2020, discusses the role of miR-124 in inhibiting TH17 cell differentiation in colitis and colon cancer. The study demonstrates that miR-124 targets STAT3 to suppress TH17 cell polarization, potentially blocking the development of colitis-related cancer. The research highlights the importance of miR-124 in regulating adaptive immune responses and suggests it as a potential therapeutic target for colitis-related colon cancer. [Extracted from the article]

Introduction: Lupus nephritis (LN) is one of the most prevalent severe organ manifestations of systemic lupus erythematosus (SLE), impacting 70% of SLE patients. MicroRNAs (miRNAs), are small non-coding RNA molecules which influence the expression of approximately one-third of human genes after the process of transcription. Dysregulation of miRNAs was documented in numerous disorders, including SLE and LN. Cytokines are the orchestrators of the immune response in autoimmune diseases. Our study aims to explore the variation in the levels of circulating miRNAs and proinflammatory cytokines as potential diagnostic biomarkers among LN and SLE patients without LN in comparison to controls. Methods: The study involved 20 LN patients, 20 SLE patients without LN, and 10 healthy controls. Serum levels of IL-12 and IL-21 in addition to miR-124, miR-146a, miR-199a, and miR-21 were assessed using the enzyme-linked immunosorbent assay (ELISA) for cytokines and quantitative real-time PCR for miRNAs. Results: A significant downregulation in miR-124 (p<0.001) and a significant overexpression of miR-146a (p=0.005) were found in SLE patients without LN in comparison to controls. In comparison to SLE patients without LN and the control group, miR-199a, miR-21, and miR-146a were significantly upregulated in LN patients (p=<0.001) with high diagnostic values of these miRNAs in discriminating LN from SLE patients without LN according to Receiver operating curve (ROC) analysis. Logistic regression analysis revealed that only miR-199a is an independent predictor of LN (OR 1.69; 95% CI: 1.1-2.6). The expression of miR-124 was reduced in LN patients in comparison to the control but increased in LN patients in comparison to SLE patients without LN. However, there was no statistically significant difference in either scenario. In comparison to both SLE patients without LN and controls, LN patients exhibited the highest serum levels of IL-12 and IL-21, with no statistically significant difference. Regression analysis revealed that only miR-146a was associated with creatinine levels and SLEDAI score (p= 0.009 and 0.03, respectively), while miR-124 was associated with hemoglobin level (p=0.03). Conclusion: MiR-199a is an independent predictor for LN and might be used as a diagnostic biomarker for this disease. MiR-146a might play an important role in LN pathophysiology. [ABSTRACT FROM AUTHOR]

Background: In this study, Schisandrin B (SCHB), the main active component of Schisandra chinensis extract (SCE), was taken as the research object. From gene, microRNA (miR-124), and the level of protein expression system to study the influences of microglia phenotype to play the role of nerve inflammation. Methods: In this study, we investigated the role of miR-124 in regulating microglial polarization alteration and NF-κB/TLR4 signaling and MAPK signaling in the LPS-induced BV2 by PCR, western blot, ELISA, immunofluorescence, and cytometry. Results: SCE and SCHB significantly reduced the NO-releasing, decreased the levels of TNF-α, iNOS, IBA-1, and ratio of CD86+/CD206+, and increased the levels of IL-10, Arg-1. In addition, SCE and SCHB inhibited the nucleus translocation of NF-κB, decreased the expressions of IKK-α, and increased the expressions of IκB-α. Besides, the expressions of TLR4 and MyD88, and the ratios of p-p38/p38, p-ERK/ERK, and p-JNK/JNK were reduced by SCE and SCHB treatments. Furthermore, SCHB upregulated the mRNA levels of miR-124. However, the effects of SCHB were reversed by the miR-124 inhibitor. Conclusions: These findings suggested SCHB downregulated NF-κB/TLR4/MyD88 signaling pathway and MAPK signaling pathway via miR-124 to restore M1/M2 balance and alleviate depressive symptoms. [ABSTRACT FROM AUTHOR]

Abstract MicroRNAs (miRNAs) are 18–25 nucleotides long, single-stranded, non-coding RNA molecules that regulate gene expression. They play a crucial role in maintaining normal cellular functions and homeostasis in organisms. Studies have shown that miR-124-3p is highly expressed in brain tissue and plays a significant role in nervous system development. It is also described as a tumor suppressor, regulating biological processes like cancer cell proliferation, apoptosis, migration, and invasion by controlling multiple downstream target genes. miR-124-3p has been found to be involved in the progression of various kidney diseases, including diabetic kidney disease, calcium oxalate kidney stones, acute kidney injury, lupus nephritis, and renal interstitial fibrosis. It mediates these processes through mechanisms like oxidative stress, inflammation, autophagy, and ferroptosis. To lay the foundation for future therapeutic strategies, this research group reviewed recent studies on the functional roles of miR-124-3p in renal diseases and the regulation of its downstream target genes. Additionally, the feasibility, limitations, and potential application of miR-124-3p as a diagnostic biomarker and therapeutic target were thoroughly investigated.

MicroRNAs (miRNAs) are 18–25 nucleotides long, single-stranded, non-coding RNA molecules that regulate gene expression. They play a crucial role in maintaining normal cellular functions and homeostasis in organisms. Studies have shown that miR-124-3p is highly expressed in brain tissue and plays a significant role in nervous system development. It is also described as a tumor suppressor, regulating biological processes like cancer cell proliferation, apoptosis, migration, and invasion by controlling multiple downstream target genes. miR-124-3p has been found to be involved in the progression of various kidney diseases, including diabetic kidney disease, calcium oxalate kidney stones, acute kidney injury, lupus nephritis, and renal interstitial fibrosis. It mediates these processes through mechanisms like oxidative stress, inflammation, autophagy, and ferroptosis. To lay the foundation for future therapeutic strategies, this research group reviewed recent studies on the functional roles of miR-124-3p in renal diseases and the regulation of its downstream target genes. Additionally, the feasibility, limitations, and potential application of miR-124-3p as a diagnostic biomarker and therapeutic target were thoroughly investigated. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. Although PD etiology is not fully understood, alpha (α)-synuclein is a key protein involved in PD pathology. MicroRNAs (miRNA), small gene regulatory RNAs that control gene expression, have been identified as biomarkers and potential therapeutic targets for brain diseases, including PD. In particular, miR-124 is downregulated in the plasma and brain samples of PD patients. Recently we showed that the brain delivery of miR-124 counteracts 6-hydroxydopamine-induced motor deficits. However, its role in α-synuclein pathology has never been addressed. Here we used paraquat (PQ)-induced rat PD model to evaluate the role of miR-124-3p in α-synuclein accumulation and dopaminergic neuroprotection. Our results showed that an intranigral administration of miR-124-3p reduced the expression and aggregation of α-synuclein in the substantia nigra (SN) of rats exposed to PQ. NADPH oxidases (NOX), responsible for reactive oxygen species generation, have been considered major players in the development of α-synuclein pathology. Accordingly, miR-124-3p decreased protein expression levels of NOX1 and its activator, small GTPase Rac1, in the SN of PQ-lesioned rats. Moreover, miR-124-3p was able to counteract the reduced levels of pituitary homeobox 3 (PITX3), a protein required for the dopaminergic phenotype, induced by PQ in the SN. This is the first study showing that miR-124-3p decreases PQ-induced α-synuclein levels and the associated NOX1/Rac1 signaling pathway, and impacts PITX3 protein levels, supporting the potential of miR-124-3p as a disease-modifying agent for PD and related α-synucleinopathies. [ABSTRACT FROM AUTHOR]

Stroke is a cerebrovascular disease that threatens human health. Developing safe and effective drugs and finding therapeutic targets has become an urgent scientific problem. The aim of this study was to investigate the effect of oxygen–glucose deprivation of the microglia-derived exosome on hippocampal neurons and its relationship to miR-124 in the exosome. We incubated hippocampal neurons with exosomes secreted by oxygen–glucose deprivation/ reoxygenation (OGD/R) microglia. The levels of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) in the culture supernatant were detected by ELISA. CCK-8 was used to measure neuronal survival rates. The mRNA levels of TNF-α and IL-6 were detected by RT-qPCR to evaluate the effect of exosomes on neurons. RT-qPCR was then used to detect miR-124 in microglia and their secreted exosomes. Finally, potential targets of miR-124 were analyzed through database retrieval, gene detection with dual luciferase reporters, and western blotting experiments. The results showed that the contents of GLU, TNF-α and IL-6 mRNA increased in the supernatant of cultured hippocampal neurons, the content of GABA decreased, and the survival rate of neurons decreased. Oxygen–glucose deprivation increases miR-124 levels in microglia and their released exosomes. miR-124 acts as a target gene on cytokine signaling suppressor molecule 1(SOCS1), while miR-124 inhibitors reduce the expression of TNF-α and IL-6 mRNA in neurons. These results suggest that oxygen- and glucose-deprived microglia regulate inflammatory cytokines leading to reduced neuronal survival, which may be achieved by miR-124 using SOCS1 as a potential target. [ABSTRACT FROM AUTHOR]

IntroductionLupus nephritis (LN) is one of the most prevalent severe organ manifestations of systemic lupus erythematosus (SLE), impacting 70% of SLE patients. MicroRNAs (miRNAs), are small non-coding RNA molecules which influence the expression of approximately one-third of human genes after the process of transcription. Dysregulation of miRNAs was documented in numerous disorders, including SLE and LN. Cytokines are the orchestrators of the immune response in autoimmune diseases. Our study aims to explore the variation in the levels of circulating miRNAs and proinflammatory cytokines as potential diagnostic biomarkers among LN and SLE patients without LN in comparison to controls.MethodsThe study involved 20 LN patients, 20 SLE patients without LN, and 10 healthy controls. Serum levels of IL-12 and IL-21 in addition to miR-124, miR-146a, miR-199a, and miR-21 were assessed using the enzyme-linked immunosorbent assay (ELISA) for cytokines and quantitative real-time PCR for miRNAs.ResultsA significant downregulation in miR-124 (p

Objective To investigate the effects of metformin combined with ethinylestradiol and cyproterone acetate tablets on serum miR-124 levels and Th1/Th2 cytokine balance shift in patients with polycystic ovary syndrome (PCOS). Methods A total of 200 PCOS patients treated at Panzhihua Maternal and Child Health Hospital from January 2022 to February 2023 were included and divided into an observation group (n = 100) and a control group (n = 100) . The observation group received metformin combined with ethinylestradiol and cyproterone acetate tablets, while the control group received ethinylestradiol and cyproterone acetate tablets alone. The treatment duration was 3 months. Clinical data, lipid levels [total cholesterol (TC), triglyceride (TG), low density lipoprotein C (LDL-C)], fasting plasma glucose (FPG), fasting serum insulin (FINS), and homeostasis model assessment-IR (HOMA-IR) were collected before and after treatment. Serum miR-124, interlenkin (IL)-2, IL-6, and interferon-γ (INF-γ) were also measured. Results After treatment, TG, TC, and LDL-C levels in the observation group significantly decreased (P<0.05). Post treatment TG, TC, and LDL-C levels in the observation group were lower than those in the control group (P < 0.05) . There were no statistically significant differences in FPG, FINS, and HOMA-IR between the two groups before treatment (P>0.05). After treatment, FPG, FINS, and HOMA IR levels in the observation group significantly decreased (P< 0.05), and these levels were lower than those in the control group (P < 0.05) . There were no significant differences in IL-2, IL-6, INF-γ, and miR-124 levels between the two groups before treatment (P > 0.05) . After treatment, IL-6 and INF-γ levels decreased, and IL-2 and miR-124 levels increased in the observation group (P < 0.05) . Post-treatment IL-6 and INF-γ levels were lower, while IL-2 and miR-124 levels were higher in the observation group compared to the control group (P < 0.05) Conclusion Metformin combined with ethinylestradiol and cyproterone acetate tablets can significantly improve insulin resistance, regulate glucolipid metabolism and improve the state of Th1/ Th2 cytokine balance s hift in PCOS patients. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) from ENS precursor cells of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNAs in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development. [ABSTRACT FROM AUTHOR]

As a high proportion of miRNA in the brain, miR⁃124 is widely involved in the physiological and pathological processes of the central nervous system. Recent studies have found that miR⁃124 participates in the pathological process of Alzheimer’s disease and Parkinson’s disease by targeting and regulating the signal pathways and proteins related to neurodegenerative diseases. Hence, this article reviews the research progress on the roles of miR⁃124 in neurodegenerative diseases, aiming to provide a reference for the research on the mechanism of neurodegenerative diseases, and provide a new idea for drug treatment targets. [ABSTRACT FROM AUTHOR]

Background Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV. Methods We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks. Results The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P =.008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers. Conclusions The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a well-known neurodegenerative disease that is usually caused by the progressive loss of dopamine neurons and the formation of Lewy vesicles. 3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause damage to human substantia nigra neurons and an increased risk of PD, but the exact molecular mechanisms need further investigation. Methods: MPTP- and MPP+-induced PD cells and animal models were treated with Nissl staining to assess neuronal damage in the substantia nigra (SN) area; immunohistochemistry to detect TH expression in the SN; TUNEL staining to detect apoptosis in the SN area; Western blotting to detect the inflammatory factors NF-κB, TNF-α, IL-6 and mitogen-activated protein kinase kinase kinase 3 (MEKK3); Griess assay for NO; RT‒qPCR for metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-124 expression; Cell proliferation was assessed by CCK-8. Dual luciferase reporter genes were used to verify targeting relationships. Results: MDMA promoted MALAT1 expression, and knockdown of MALAT1 alleviated the MDMA-induced inhibition of SH-SY5Y cell proliferation, inflammation, NO release, SN neuronal injury, and TH expression inhibition. Both inhibition of miR-124 and overexpression of MEKK3 reversed the neuroprotective effects exhibited by knockdown of MALAT1. Conclusion: MDMA promotes MALAT1 expression and inhibits the targeted downregulation of MEKK3 by miR-124, resulting in upregulation of the expression of MEKK3 and finally jointly promoting PD progression. [ABSTRACT FROM AUTHOR]

Objective: The most prevalent brain‐specific microRNA, MicroRNA‐124, exhibits anti‐inflammatory properties. Luteolin nano‐formulation with Zn oxide in the form of L/ZnO NPs may boost anti‐diabetic properties; however, its beneficial effect on miRNAs is yet unknown in diabetes. The effectiveness of L/ZnONPs supplements in preventing diabetic neurodegeneration by modulating inflammatory responses in a diabetic model was investigated. Methods: A diabetic rat model was induced by a high‐fat diet and streptozotocin (30 mg/kg I.P.). Plasma glucose, insulin, and HOMR‐IR levels, as well as cytokines, lipid peroxidation, GSH/GSSG, and glucose transporter 1, were determined along with the tight junction proteins occludin (OCLN) and zona occludens 1 (ZO‐1). Moreover, the expressions of brain CCAAT/enhancer‐binding protein (C/EBPA mRNA), miR‐124, glial fibrillary acidic protein (GFAP), and NF‐kBp65 were measured alongside the histological investigation. Results: The results revealed that L/ZnO NPs were able to diminish lipid peroxidation, increase the activity of antioxidant enzymes, and reduce inflammation under oxidative stress. Consequently, it was able to reduce hyperglycemia, elevate insulin levels, and improve insulin resistance. Besides, L/ZnO NPs upregulate miR‐124, reduce C/EBPA mRNA, increase BCl‐2, and inhibit apoptosis. The results indicate that diabetes raises BBB permeability via tight junction protein decline, which is restored following L/ZnO NPs treatment. Luteolin/ZnO NPs regulate miR‐124 and microglia polarization by targeting C/EBPA and are expected to alleviate inflammatory injury via modulation of the redox‐sensitive signal transduction pathways. Luteolin/ZnO NPs have a novel target for the protection of the BBB and the prevention of neurological complications in diabetes. [ABSTRACT FROM AUTHOR]

Metabolic rewiring of tumor cells leads to an enrichment of lactate in the tumor microenvironment (TME). This lactaterich environment of solid tumors has been reported to support tumor-infiltrating regulatory T (Treg) cells. Therefore, agents that modify the lactate metabolism of Treg cells have therapeutic potential. Monocarboxylate transporter 1 (MCT1), which Treg cells predominantly express, plays an essential role in the metabolism of tumor-infiltrating Treg cells. In this study, we show that miR-124 directly targets MCT1 and reduces lactate uptake, eventually impairing the immune-suppressive capacity of Treg cells. Particularly, exosomal miR-124 derived from bone marrow mesenchymal stromal cells (BM-MSCs) slows tumor growth and increases response to PD-1 blockade therapy. These data indicate a potential treatment strategy for improving immune checkpoint blockade therapy using miR-124-carried BM-MSCs-derived exosomes. [ABSTRACT FROM AUTHOR]

Objective: To explore the mechanism of LINC01410 involved in the immune escape of acute myeloid leukemia by regulating microRNA-124 （miR-124）/signaling and activator of transcription 3 （stat3） axis. Methods: Bone marrow samples were gathered from 21 AML patients, and the bone marrow samples and peripheral blood samples were gathered from 25 patients with nonmalignant hematological diseases during the same period, and leukocytes in bone marrow samples and natural killer cells （NK） in peripheral blood were collected; qRT-PCR method was used to detect the expressions of LINC01410 and miR-124; Western blot was used to detect the expression of stat3 protein; ELISA method was used to detect the content of IFN-γ; LDH kit was used to detect the NK cell toxicity; dual luciferase reporter gene was used to detect the targeting relationship among LINC01410, miR-124 and stat3. Results: Compared with patients with non-malignant hematological diseases, the expression of LINC01410 in the bone marrow of AML patients was significantly increased, and the expression of miR-124 was significantly decreased （P<0.05）; compared with the control group, the expressions of LINC01410 and p-stat3/stat3 in NK cells in the IL-2 group were significantly reduced （P<0.05）, and the expression of miR-124, content of IFN-γ and NK cell toxicity were significantly increased （P<0.05）; compared with IL-2 group, the expressions of LINC01410 and p-stat3/stat3 in NK cells in the sh-LINC01410 group were significantly reduced （P<0.05）, and the expression of miR-124, content of IFN-γ and NK cell toxicity were significantly increased （P<0.05）; silencing of miR-124 expression could reverse the inhibitory effect of LINC01410 down-expression on AML immune escape; compared with IL-2 group, the IFN-γ content and NK cytotoxicity of miR-124 mimics group were significantly increased （P<0.05）; stat3 overexpression reversed the inhibitory effect of miR-124 on AML immune escape. Conclusion: LINC01410 silence inhibits immune escape of AML by activating the miR-124/stat3 axis. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most common extracranial solid tumor that affects developing nerve cells in the fetus, infants, and children. miR-124 is a microRNA (miRNA) enriched in neuronal tissues, and VAMP3 (vesicle-associated membrane protein 3) has been reported to be an miR-124 target, although the relationship between NB and miR-124 or VAMP3 is unknown. Our current work identified that miR-124 levels are high in NB cases and that elevated miR-124 correlates with worse NB outcomes. Conversely, depressed VAMP3 correlates with worse NB outcomes. To investigate the mechanisms by which miR-124 and VAMP3 regulate NB, we altered miR-124 or VAMP3 expression in human NB cells and observed that increased miR-124 and reduced VAMP3 stimulated cell proliferation and suppressed apoptosis, while increased VAMP3 had the opposite effects. Genome-wide mRNA expression analyses identified gene and pathway changes which might explain the NB cell phenotypes. Together, our studies suggest that miR-124 and VAMP3 could be potential new markers of NB and targets of NB treatments. [ABSTRACT FROM AUTHOR]

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs' expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming. [ABSTRACT FROM AUTHOR]

Each year, more than 790 000 people in the United States suffer from a stroke. Although progress has been made in diagnosis and treatment of ischemic stroke (IS), new therapeutic interventions to protect the brain during an ischemic insult is highly needed. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally. Growing evidence suggests that miRNAs have a profound impact on ischemic stroke progression and are potential targets of novel treatments. Notably, inflammatory pathways play an important role in the pathogenesis of ischemic stroke and its pathophysiologic progression. Experimental and clinical studies have illustrated that inflammatory molecular events collaboratively contribute to neuronal and glial cell survival, edema formation and regression, and vascular integrity. In the present review, we examine recent discoveries regarding miRNAs and their roles in post-ischemic stroke neuropathogenesis. [ABSTRACT FROM AUTHOR]

Background: ABX464 (obefazimod) is a small molecule that upregulates a single microRNA (miR-124) in immune cells and reduces the production of various inflammatory cytokines and chemokines. Objective: We assessed the efficacy and safety of the standard of care (SoC) plus oral obefazimod (SoC plus ABX464), 50 mg once daily, versus the SoC plus placebo for prevention of severe acute respiratory syndrome in patients with coronavirus disease 2019 (COVID-19) who are at risk for severe disease. Methods: Eligible patients for this phase 2/3 double-blind, placebo-controlled miR-AGE study were randomized (2:1) into 2 groups: SoC-ABX464 (n = 339) and SoC-placebo (n = 170). The primary end point was the percentage of patients who did not require use of high-flow oxygen or invasive or noninvasive mechanical ventilation within 28 days. The safety analyses included patients who had been randomly assigned and had received at least 1 dose of the study treatment. Results: At the time of the interim analysis, obefazimod showed no benefit over placebo when added to the SoC; the study enrollment was stopped for futility. The evaluation of the safety of obefazimod in 505 patients showed significantly more treatment-emergent adverse events in the SoC-ABX464 group than in the SoC-placebo group (P = .007). Frequently reported AEs in the SoC-ABX464 group included headache (14.6%), abdominal pain (9.6%), diarrhea (9.0%), back pain (6.9%), and nausea (6.0%). No treatment-related changes in laboratory parameters were reported. Conclusion: For patients who have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and are at risk for severe COVID-19, obefazimod, 50 mg, provided no benefit over placebo when added to the SoC, although it did have a good safety profile (comparable to that reported in many therapeutic areas).

目的　观察老年动脉瘤性蛛网膜下腔出血(SAH)患者介入栓塞术治疗前后血清miR-124, miR-27a-3p水 平变化，并探讨其与患者预后的关系。方法　选取老年动脉瘤性SAH经颅内动脉瘤介入栓塞术治疗患者200例，根 据术后28 d生存情况分为生存组182例和死亡组18例。采用实时荧光定量PCR法检测两组术前及术后3, 7 d的血 清miR-124, miR-27a-3p。绘制术后3, 7 d血清miR-124, miR-27a-3p预测患者死亡的受试者工作特征(ROC)曲线，分 析其预测价值。根据临界值，比较术后3, 7 d不同血清miR-124, miR-27a-3p水平患者的28 d生存率，多因素Logistic 回归分析其对患者预后的影响。结果　与术前比较，两组术后 3, 7 d血清 miR-124水平均升高, miR-27a-3p水平均 降低，且死亡组变化更明显(P均<0. 05)。术后3 d血清miR-124, miR-27a-3p预测患者死亡的AUC均小于术后7 d, 术后7 d血清miR-124, miR-27a-3p联合预测患者死亡的AUC为0. 906(95% CI：0. 834～0. 954)，敏感度及特异度分 别为 94. 44%, 76. 67%。根据临界值，术后 3 d不同血清 miR-124, miR-27a-3p水平者 28 d生存率比较差异无统计学 意义(P 均>0. 05)，术后 7 d 血清 miR-124>10. 31, miR-27a-3p≤0. 06 者 28 d 生存率均低于血清 miR-124≤10. 31, miR27a-3p>0. 06 者(P 均<0. 05)。术后 3, 7 d miR-124 水平升高, miR-27a-3p 水平降低均是患者死亡的独立影响因素 (P 均<0. 05)。结论　老年动脉瘤性 SAH 患者介入栓塞术后血清 miR-124水平升高, miR-27a-3p水平降低，且死亡 患者变化更明显，二者联合检测有助于评估患者的生存情况。 [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important regulatory miRNAs by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed custom panels of fifteen major oncogenes and five major tumor suppressor genes. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules which target the majority of these panels that have been reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific. Their expression patterns, verified targets, and the signaling pathways affected by their dysregulation in OSCC are thoroughly discussed. [ABSTRACT FROM AUTHOR]

Despite advances in non-small cell lung cancer (NSCLC) research, this is still the most common cancer type that has been diagnosed up to date. microRNAs have emerged as useful clinical biomarkers in both tissue and liquid biopsy. However, there are no reliable predictive biomarkers for clinical use. We evaluated the preclinical use of seven candidate miRNAs previously identified by our group. We collected a total of 120 prospective samples from 88 NSCLC patients. miRNA levels were analyzed via qRT-PCR from tissue and blood samples. miR-124 gene target prediction was performed using RNA sequencing data from our group and interrogating data from 2952 NSCLC patients from two public databases. We found higher levels of all seven miRNAs in tissue compared to plasma samples, except for miR-124. Our findings indicate that levels of miR-124, both free-circulating and within exosomes, are increased throughout the progression of the disease, suggesting its potential as a marker of disease progression in both advanced and early stages. Our bioinformatics approach identified KPNA4 and SPOCK1 as potential miR-124 targets in NSCLC. miR-124 levels can be used to identify early-stage NSCLC patients at higher risk of relapse. [ABSTRACT FROM AUTHOR]

Simple Summary: MicroRNA-124 (miR-124) is a small non-coding RNA that regulates gene expression and is abundantly expressed in the brain and immune system. Dysregulated expression of miR-124 is associated with several cancer types, making it a potential therapeutic target in oncology. We demonstrate the potential of miR-124 as a target in various cancer types. MicroRNA (miR) are a class of small non-coding RNA that are involved in post-transcriptional gene regulation. Altered expression of miR has been associated with several pathological conditions. MicroRNA-124 (miR-124) is an abundantly expressed miR in the brain as well as the thymus, lymph nodes, bone marrow, and peripheral blood mono-nuclear cells. It plays a key role in the regulation of the host immune system. Emerging studies show that dysregulated expression of miR-124 is a hallmark in several cancer types and it has been attributed to the progression of these malignancies. In this review, we present a comprehensive summary of the role of miR-124 as a promising therapeutic gateway in oncology. [ABSTRACT FROM AUTHOR]

Cyprinid herpesvirus 2 (CyHV‐2), the etiological agent of herpesvirus haematopoietic necrosis (HVHN) in carp and goldfish, has caused significant economic losses in the aquaculture industry. During viral infection, the host initiates a series of active or passive defences to regulate the process of virus infection. Apoptosis is a key component of active cellular defence, and members of the Bcl‐2 family have been shown to play a critical role in the apoptotic process. However, the mechanism of action of the Bcl‐2 family in inducing apoptosis during CyHV‐2 infection remains unclear. In this study, we revealed the molecular mechanism of miRNA‐mediated silver crucian carp BAX (ccBax) in CyHV‐2‐induced apoptosis for the first time and demonstrated that the overexpression of miR‐124 suppressed ccBax expression and significantly down‐regulated apoptosis in caudal fin cells of Carassius auratus gibelio (GiCF), while miR‐124 inhibitors were the opposite. These studies indicated that miR‐124 inhibits CyHV‐2‐induced apoptosis by reducing the expression of ccBax. Furthermore, the fact that transfection of miR‐124 mimics promoted CyHV‐2 replication, whereas miR‐124 inhibitors inhibited CyHV‐2 replication, indicated that miR‐124 inhibited CyHV‐2‐induced apoptosis and contributed to viral replication. All these results suggested that miR‐124 suppresses virus‐induced apoptosis and promotes viral replication by targeting and regulating ccBax expression. [ABSTRACT FROM AUTHOR]

miR-124 is a miRNA predominantly expressed in the nervous system and accounts for more than a quarter of the total miRNAs in the brain. It regulates neurogenesis, neuronal differentiation, neuronal maturation, and synapse formation and is the most important miRNA in the brain. Furthermore, emerging evidence has suggested miR-124 may be associated with the pathogenesis of various neurodevelopmental and neuropsychiatric disorders. Here, we provide an overview of the role of miR-124 in neurodevelopment and the underling mechanisms, and finally, we prospect the significance of miR-124 research to the field of neuroscience. [ABSTRACT FROM AUTHOR]

Objective: type 2 diabetes, metabolic disorder, is one of the main risk factors for cardiovascular disease, leading to angiogenesis injury. The present study wanted to discover the effect of sodium butyrate (NaB) and voluntary exercise, alone or together, on miR-126 and related proteins in rats with type 2 diabetes. Methods: thirty-five male Wistar rats (200–250 g) were randomly divided into five groups: control, diabetes, diabetes-NaB, diabetes-exercise, and diabetes-NaB-exercise. Type 2 diabetes was induced by intraperitoneal injection of streptozotocin (35 mg/kg) and high-fat diet. The rats were then administrated NaB (200 mg/kg. ip) or were subjected to voluntary exercise, or combined NaB and voluntary exercise for 8 weeks. MiR-126 expression in the cardiac tissue was determined by real-time PCR, and the SPRED-1 and RAF proteins expression levels were measured by western blot. Results: NaB and voluntary exercise up-regulated cardiac miR-126 and RAF expression levels and down-regulated SPRED-1 in cardiac tissue of type 2 diabetic rats. Moreover, the combination of NaB and voluntary exercise amplified their effects on those parameters. Both NaB and voluntary exercise or together markedly modulated serum glucose and HbA1c. Conclusion: The present findings demonstrated that NaB combined with exercise could improve cardiac angiogenesis by increasing miR-126 and affecting related proteins. Thus, NaB together with voluntary exercise might be a promising intervention for the treatment and prevention of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Spinal cord injury often leads to severe motor and sensory deficits, and prognosis using the currently available therapies remains poor. Therefore, we aimed to explore a novel therapeutic approach for improving the prognosis of spinal cord injury. In this study, we implanted oscillating field stimulation devices and transplanted neural stem cells into the thoracic region (T9–T10) of rats with a spinal cord contusion. Basso-Beattie-Bresnahan scoring revealed that oscillating field stimulation combined with neural stem cells transplantation promoted motor function recovery following spinal cord injury. In addition, we investigated the regulation of oscillating field stimulation on the miR-124/Tal1 axis in neural stem cells. Transfection of lentivirus was performed to investigate the role of Tal1 in neurogenesis of neural stem cells induced by oscillating field stimulation. Quantitative reverse transcription-polymerase chain reaction, immunofluorescence and western blotting showed that oscillating field stimulation promoted neurogenesis of neural stem cells in vitro and in vivo. Hematoxylin and eosin staining showed that oscillating field stimulation combined with neural stem cells transplantation alleviated cavities formation after spinal cord injury. Taking the results together, we concluded that oscillating field stimulation decreased miR-124 expression and increased Tal1 content, thereby promoting the neurogenesis of neural stem cells. The combination of oscillating field stimulation and neural stem cells transplantation improved neurogenesis, and thereby promoted structural and functional recovery after spinal cord injury.

The central nervous system (CNS) consists of neuron and non-neuron cells including neural stem/precursor cells (NSPCs), neuroblasts, glia cells (mainly astrocyte, oligodendroglia and microglia), which thereby form a precise and complicated network and exert diverse functions through interactions of numerous bioactive ingredients. MicroRNAs (miRNAs), with small size approximately ~ 21nt and as well-documented post-transcriptional key regulators of gene expression, are a cluster of evolutionarily conserved endogenous non-coding RNAs. More than 2000 different miRNAs has been discovered till now. MicroRNA-124(miR-124), the most brain-rich microRNA, has been validated to possess important functions in the central nervous system, including neural stem cell proliferation and differentiation, cell fate determination, neuron migration, synapse plasticity and cognition, cell apoptosis etc. According to recent studies, herein, we provide a review of this conversant miR-124 to further understand the potential functions and therapeutic and clinical value in brain diseases. [ABSTRACT FROM AUTHOR]

The activation of hepatic stellate cells is the primary function of facilitating liver fibrosis. Interfering with the coordinators of different signaling pathways in activated hepatic stellate cells (aHSCs) could be a potential approach in ameliorating liver fibrosis. Regarding the illustrated anti‐fibrotic effect of imatinib in liver fibrosis, we investigated the imatinib′s potential role in inhibiting HSC activation through miR‐124 and its interference with the STAT3/hepatic leukemia factor (HLF)/IL‐6 circuit. The anti‐fibrotic effect of imatinib was investigated in the LX‐2 cell line and carbon tetrachloride (CCl4)‐induced Sprague‐Dawley rat. The expression of IL‐6, STAT3, HLF, miR‐124, and α‐smooth muscle actin (α‐SMA) were quantified by quantitative real‐time PCR (qRT‐PCR) and the protein level of α‐SMA and STAT3 was measured by western blot analysis both in vitro and in vivo. The LX‐2 cells were subjected to immunocytochemistry (ICC) for α‐SMA expression. After administering imatinib in the liver fibrosis model, histopathological examinations were done, and hepatic function serum markers were checked. Imatinib administration alleviated mentioned liver fibrosis markers. The expression of miR‐124 was downregulated, while IL‐6/HLF/STAT3 circuit agents were upregulated in vitro and in vivo. Notably, imatinib intervention decreased the expression of IL‐6, STAT3, and HLF. Elevated expression of miR‐124 suppressed the expression of STAT3 and further inhibited HSCs activation. Our results demonstrated that imatinib not only ameliorated hepatic fibrosis through tyrosine kinase inhibitor (TKI) activity but also interfered with the miR‐124 and STAT3/HLF/IL‐6 pathway. Considering the important role of miR‐124 in regulating liver fibrosis and HSCs activation, imatinib may exert its anti‐fibrotic activity through miR‐124. [ABSTRACT FROM AUTHOR]

Background. Parkinson's disease (PD) is characterized as a neurodegenerative disease; however, the mechanisms regarding its pathogenesis have not been fully explored. Objectives. To explore the role of circular RNA homeodomain interacting protein kinase 3 (circHIPK3) in the progression of PD. Materials and methods. The circHIPK3 and microRNA-124 (miR-124) expression in human serum and cerebral fluid was detected using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 92 PD patients and 95 controls. The circHIPK3 was overexpressed and/or silenced in cells to explore its molecular mechanisms and effects on neuroinflammation. The production of intracellular reactive oxygen species (ROS) was assessed using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Interleukin 6 (IL-6), IL-1β and tumor necrosis factor alpha (TNF-α) production in BV2 cells after the indicated treatment was measured using enzyme-linked immunosorbent assay (ELISA). The protein expression of microglia markers (cluster of differentiation molecule 11b (CD11b) and ionized calcium-binding adapter molecule 1 (Iba-1)), pyroptosis-related factors, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC), and caspase-1, signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) were examined using western blot analysis. Furthermore, the interaction between circHIPK3, miR-124 and STAT3 was predicted with bioinformatics and examined using fluorescence in situ hybridization (FISH), luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation (RIP). Results. The expression of circHIPK3 in human serum and cerebral fluids was significantly higher than in controls, whereas miR-124 expression was drastically reduced. In addition, lipopolysaccharide (LPS)- treated BV2 cells exhibited higher expression of circHIPK3 and lower miR-124 expression. The SH-SY5Y cells exhibited a significantly impaired viability and elevated apoptotic rate, along with an upregulation of circHIPK3 and a downregulation of miR-124 expression after being treated with supernatants collected from LPS-treated BV2 cells. The upregulation of circHIPK3 increased IL-6, IL-1β and TNF-α secretion in BV2 cells. The protein expressions of microglia markers (CD11b and Iba-1), as well as pyroptosis-related factors, NLRP3, caspase-1, and ASC, were also increased following the expression of circHIPK3. All these effects were reversed by the addition of miR-124. Conclusions. The circHIPK3 enhances neuroinflammation by sponging miR-124 and regulating the miR-124. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) from ENS precursor cells of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNAs in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development.

Introduction In this study, we aimed to investigate the role of rs531564 and the underlying signaling pathways. Material and methods Five hundred and twenty-eight spinal cord injury (SCI) patients were genotyped for the analysis of the effect of rs531564 upon the miR-124 expression. Results By luciferase assays, we validated Bcl-2-like protein 11 (BIM) as a target gene of miR-124 with a negative regulatory relationship between them. We also observed that miR-124 suppressed cell viability and accelerated cell apoptosis. Conclusions rs531564 could affect the expression of BIM by reducing the expression of miR-124, and it could be a bio-marker for the length of recovery after SCI.

Objective To explore the effect of microRNA-124 (miR-124) on the improvement of neurological function in mice with cerebral ischemia injury and its underlying mechanism. Methods ① A total of 32 C57 mice were randomly divided into sham group and cerebral ischemia group (n=16). The cerebral infarction area was detected by TTC staining and motor status of the mice was evaluated with neurobehavioral scoring in 3 d after brain injury. The expression change of miR-124 was detected by RT-qPCR and compared between the 2 groups. ② Primary neurons were isolated from fetal mice and cultured, and ischemia-reperfusion injury was simulated by oxygen glucose deprivation. The changes of miR-124 at 0 and 72 h after oxygen glucose deprivation were observed. ③ Another 32 C57 mice were randomly divided into cerebral ischemia group and cerebral ischemia+miR-124 group (n=16). TTC staining, rotating rod test and limb placement test were performed respectively to detect whether the motor function of the mice was improved. ④ The primary neurons were divided into oxygen-glucose deprivation group and oxygen-glucose deprivation+miR-124 group. The neurite elongation in the 2 groups was detected by immunofluorescence assay. The downstream target gene of miR-124 was predicted with Targetscan database. Double luciferase gene reporter assay and Western blotting were used to verify the effectiveness of miR-124 regulation on phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the control and miR-124 groups. Then, the effect of PTEN up-regulation on neurite elongation was observed in the oxygen glucose deprivation+miR-124 cells and oxygen glucose deprivation+miR-124+PTEN groups. ⑤ Rotating rod test and limb placement test were performed again for motor functions in the mice of cerebral ischemia+miR-124 group and cerebral ischemia+miR-124+PTEN group (n=8). Results Cerebral ischemia-reperfusion resulted in the area of cerebral infarction about 40% (P < 0.001) and significantly reduced neurocognitive function in mice (P < 0.001), reaching the condition of severe cognitive impairment. The expression of miR-124 was significantly higher in the cerebral ischemia group than the control group (P < 0.05). Overexpression of miR-124 could promote the growth of neuronal axons after oxygen glucose deprivation (P < 0.05), reduce the area of cerebral infarction (P < 0.05), and thus promote the recovery and improvement of animal motor ability (P < 0.05). With the aid of Targetscan database, PTEN was predicted as the downstream target of miR-124, and double luciferase gene reporter assay and Western blotting confirmed that miR-124 could effectively down-regulate the expression of PTEN (P < 0.05); Finally, up-regulation of PTEN reversed the effect of miR-124 on promoting the growth of neuronal axons and improving the motor ability of mice (P < 0.05). Conclusion MiR-124 promotes neuronal axonal growth and contributes to the recovery of motor function in mice with cerebral ischemia by down-regulating PTEN.

Ping Zhao,1 Erdong Xu,1 Rui Yuan,1 Ruhai Zhou,1 Jianlian Pan2 1Department of Ultrasound Medicine, Affiliated People’s Hospital of Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of China; 2Clinical Application Department, Shenzhen Mindray Bio-Medical Electronics Co, Ltd, Shenzhen, Guangzhou, 518057, People’s Republic of ChinaCorrespondence: Ping Zhao, Department of Ultrasound Medicine, Affiliated People’s Hospital of Ningbo University, No. 251 Baizhang East Road, Ningbo, Zhejiang, 315040, People’s Republic of China, Email zhaoping4578@126.comObjective: To investigate the predictive value of contrast-enhanced ultrasound (CEUS) combined with serum miR-124 level in acute cerebral infarction (ACI) and their association with the contrast enhancement of carotid atherosclerotic plaque.Methods: Totally 60 patients diagnosed with ACI and 60 controls were included in the study. All the subjects had carotid atherosclerotic plaques, and all of them were examined by CEUS and were tested for serum miR-124 levels.Results: Time to peak (TTP) and mean transit time (MTT) in the ACI group were significantly shorter than those in the control group (P < 0.05), but the peak intensity ratio (PIR), the area under the curve (AUC), and relative expression levels of serum miR-124 were notably greater in the ACI group (P < 0.05). There were statistically significant differences in TTP, MTT, PIR, AUC, and serum miR-124 expression in patients with different cerebral infarct areas in the ACI group (P < 0.05). Besides, the sensitivity and specificity of serum miR-124 levels for the prediction of ACI were 71.67% and 90.00%, respectively, with a cut-off value of 1.52, and the sensitivity was 86.67% and specificity was 93.33% of CEUS combined with serum miR-124 in the prediction of ACI. The ACI group showed a higher proportion of grades 2 and 3 (P < 0.001). Pearson correlation analysis showed that the intraplaque contrast enhancement was negatively related to TTP and MTT but had a positive correlation with PIR, AUC, and serum miR-124 levels.Conclusion: Grades 2 and 3 intraplaque contrast enhancement and serum miR-124 level of 1.52 had high sensitivity and specificity to predict ACI. Moreover, the CEUS parameters combined with serum miR-124 level could improve the performance in predicting ACI and had auxiliary value in evaluating the stability of carotid atherosclerotic plaques.Keywords: contrast-enhanced ultrasound, miR-124, acute cerebral infarction, carotid atherosclerotic plaque

Abstract Background Conventionally, breast cancer (BC) prognosis and prediction of response to therapy are based on TNM staging, histological and molecular subtype, as well as genetic alterations. The role of various epigenetic factors has been elucidated in carcinogenesis. However, it is still unknown to what extent miRNAs affect the response to neoadjuvant chemotherapy (NACT). This pilot study is focused on evaluating the role of miR-34a, miR-124a, miR-155, miR-137 and miR-373 in response to NACT. Methods That was a prospective study enrolling 34 patients with histologically confirmed BC of II-III stages. The median age of patients was 53 (47–59.8) years old, 70.6% of whom were HR-positive. MiRs levels were measured in the primary tumor before and after NACT. The response to therapy was assessed after surgery using the Miller-Payne scoring system. To establish the role of miRs in modulating response to NACT the Cox model was applied for analysis. Results BC demonstrated a great variability of miRs expression before and after NACT with no strong links to tumor stage and molecular subtype. Only miR-124a and miR-373 demonstrated differential expression between malignant and normal breast tissues before and after therapy though these distinctions did not impact response to NACT. Besides miR-124a and miR-137 levels after NACT were found to be dependent on HR status. While miR-124a levels increased (p = 0.021) in the tumor tissue, the expression of miR-137 was downregulated (p = 0.041) after NACT in HR positive BC. Conclusions The study revealed differences in miR-124a and miR-373 expression after NACT in primary BC tissues. Although miRs levels did not impact the response to NACT, we found miR-124a and miR-137 levels to be related to hormonal sensitivity of BC.

The retina is among the highest organized tissues of the central nervous system. To achieve such organization, a finely tuned regulation of developmental processes is required to form the retinal layers that contain the specialized neurons and supporting glial cells to allow precise phototransduction. MicroRNAs are a class of small RNAs with undoubtful roles in fundamental biological processes, including neurodevelopment of the brain and the retina. This review provides a short overview of the most important findings regarding microRNAs in the regulation of retinal development, from the developmental-dependent rearrangement of the microRNA expression program to the key roles of particular microRNAs in the differentiation and maintenance of retinal cell subtypes. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is characterized by vasoregression and glial activation. miRNA-124 (miR-124) reduces retinal microglial activation and alleviates vasoregression in a neurodegenerative rat model. Our aim was to determine whether miR-124 affects vascular and neural damage in the early diabetic retina. Diabetes was induced in 8-week-old Wistar rats by streptozotocin (STZ) injection. At 16 and 20 weeks, the diabetic rats were intravitreally injected with miR-124 mimic, and retinae were analyzed at 24 weeks. Microvascular damage was identified by evaluating pericyte loss and acellular capillary (AC) formation. Müller glial activation was assessed by glial fibrillary acidic protein (GFAP) immunofluorescence staining. Microglial activation was determined by immunofluorescent staining of ionized calcium-binding adaptor molecule 1 (Iba1) in whole mount retinae. The neuroretinal function was assessed by electroretinography. The expression of inflammation-associated genes was evaluated by qRT-PCR. A wound healing assay was performed to quantitate the mobility of microglial cells. The results showed that miR-124 treatment alleviated diabetic vasoregression by reducing AC formation and pericyte loss. miR-124 blunted Müller glial- and microglial activation in diabetic retinae and ameliorated neuroretinal function. The retinal expression of inflammatory factors including Tnf-α, Il-1β, Cd74, Ccl2, Ccl3, Vcam1, Tgf-β1, Arg1, and Il-10 was reduced by miR-124 administration. The elevated mobility of microglia upon high glucose exposure was normalized by miR-124. The expression of the transcription factor PU.1 and lipid raft protein Flot1 was downregulated by miR-124. In rat DR, miR-124 prevents vasoregression and glial activation, improves neuroretinal function, and modulates microglial activation and inflammatory responses. [ABSTRACT FROM AUTHOR]

miR-124 is a significantly up-regulated miRNA in peripheral blood collected from piglets infected with Salmonella Typhimurium, suggesting that it may play an important role in Salmonella pathogenesis. This study focused on the transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) isolated from miR-124 sponge and Salmonella Typhimurium-treated piglets, and trying to investigate the function of miR-124 in Salmonella infection. The transcriptome profiling analysis revealed that 2778 genes in miR-124 sponge + Salmonella Typhimurium treatment versus control, 2271 genes in Salmonella Typhimurium treatment versus control, and 1301 genes in miR-124 sponge + Salmonella Typhimurium versus Salmonella Typhimurium treatment, were differentially expressed, respectively (FDR < 0.05 and fold change > 2.0). Pathway analysis indicated that the MAPK signaling pathway, Ribosome pathway, and T-cell receptor signaling pathway were the most significantly enriched pathway in differentially expressed genes between miR-124 sponge + Salmonella Typhimurium and Salmonella Typhimurium along treatment (FDR < 0.05). Reporter assays and electrophoretic mobility shift assays showed that miR-124 is a crucial regulatory factor that targets IQ motif containing GTPase-activating protein 2 (IQGAP2). Cell culture experiment indicated that miR-124 attenuated the Salmonella Typhimurium-mediated activation of CDC42 and RAC1 (P < 0.05). Cultured PBMCs treated with miR-124 and IQGAP2-siRNA had higher intracellular Salmonella count than control samples, particularly 12 h post-infection (P < 0.05). Immunofluorescence analysis revealed that miR-124 treatment reduced the percentage of LAMP-1-positive phagosomes. The miR-124 could be an important regulator for IQGAP2/Rho GTPase pathway in Salmonella Typhimurium-infected PBMCs, and this pathway could be a target for Salmonella that support its infection in PBMCs in piglets. [ABSTRACT FROM AUTHOR]

Introduction: Neuroinflammation contributes to secondary injury after traumatic brain injury (TBI), which has been mainly mediated by the microglia. MiR-124 was reported to play an important role in the polarization of microglia by targeting TLR4 signaling pathway. However, the role and mechanism of miR-124 in neuroinflammation mediated by microglia after TBI is unclear. To clarify this, we performed this research. Methods: The expression of miR-124 was first measured by RT-PCR in the injured brain at 1/3/7 days post-TBI. Then, miR-124 mimics or inhibitors administration was used to interfere the expression of miR-124 at 24 h post-TBI. Subsequently, the microglia polarization markers were detected by RT-PCR, the expression of inflammatory cytokines was detected by ELISA, the expression of TLR4/MyD88/IRAK1/TRAF6/NF-κB was measured by WB, and the neurological deficit was evaluated by NSS and MWM test. At last, in vitro experiments were performed to explore the exact target molecule of miR-124 on TLR4 signaling pathway. Results: Animal research indicated that the expression of miR-124 was downregulated after TBI. Upregulation of miR-124 promoted the M2 polarization of microglia and inhibited the activity of TLR4 pathway, as well as reduced neuroinflammation and neurological deficit after TBI. In vitro experiments indicated that miR-124 promoted the M2 polarization of microglia and reduced neuroinflammation by inhibiting TRAF6. Conclusion: This study demonstrated that upregulation of miR-124 promoted the M2 polarization of microglia and reduced neuroinflammation after TBI by inhibiting TRAF6. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRs) are involved in the autoimmune and neurological diseases, including multiple sclerosis (MS), through modulating post-transcriptional gene regulation. Accumulating evidence indicates that miR-10, miR-24a, miR-124, and miR-21 play an imperative role in MS pathogenesis. Therefore, the current research aimed to analyze the expression of the selected miRNAs for MS in Iranian population. Methods and Results: Blood sample of 75 relapsing-remitting MS (RRMS) patients and 75 healthy individuals suffering no neurodegenerative illness was collected. Subsequently, the isolation of peripheral blood mononuclear cells (PBMCs) was performed by employing Ficoll-Hypaque density gradient method. Afterward, total RNA was extracted and subjected to qRT-PCR analysis. The obtained results evidenced that the relative expression of miR-10 (P = 0.0002), miR-21 (P = 0.0014), and miR-124 (P = 0.0091) significantly decreased in RRMS patients compared to healthy participants. On the contrary, no notable change was observed between the studies groups regarding miR-24a expression levels (P = 0.107). ROC curve analysis estimated an area under the curve (AUC) value equal to 0.75 with P = 0.0006 for miR-10, while it was decreased for miR-21 (AUC = 0.67 and P = 0.0054) and miR-124 (AUC = 0.66 and P = 0.012). Conclusion: The change in miR-10, miR-124, and miR-21 expression patterns was implied to participate in MS development. Further large scale observational studies are recommended. [ABSTRACT FROM AUTHOR]

The dysregulation of microRNA expression is significantly associated with the initiation and development of CRC. miR-124 is markedly downregulated in colorectal cancer. In the present study, the effects of methylation, over expression and downregulation of miR-124 and its target gene DNMT3B on the proliferation, migration and invasion of colorectal cell line were investigated. The promoter methylation status of miR-124 in the CRC was investigated by methylation specific PCR (MSP). The potential role of miR-124 expression in CRC cells was investigated using the demethylation reagent 5-Aza-CdR and transfection of miR-124 mimic/antimir. MSP revealed that miR-124 promoter region was hypermethylated, result in its significant downregulation in tumour tissues. We showed miR-124 expression was upregulated following 5-AZA-CdR treatment. Transfected Hct-116 cell line with miR-124 leads to decreased DNMT3B expression, cell proliferation, migration and invasion of HCT-116. In conclusion, our data indicate that miR-124 suppress colorectal cancer proliferation, migration and invasion through downregulating DNMT3B level. [ABSTRACT FROM AUTHOR]

Objectives: Atherosclerosis is a dominant cardiovascular disease. Curcumin has protective effect on atherosclerosis. However, the mechanisms remain to be explored. Methods: Atherosclerosis was induced by feeding mice with high-fat diet (HFD) and ox-low-density lipoprotein (LDL)-induced human umbilical vein endothelial cells (HUVECs) were structured. Oil Red O staining was used to evaluate the plaques in the artery. Quantitative real-time PCR (qRT-PCR) was conducted to detect the level of myocardial infarction associated transcript (MIAT), miR-124, and enhancer of zeste homolog 2 (EZH2). We performed western blotting and enzyme linked immunosorbent assay to examine the expression of EZH2 and cytokines including IL-1β, TNFα, IL-6, and IL-8, respectively. RNA immunoprecipitation and chromatin immunoprecipitation (ChIP) were used to validate the interaction between myocardial infarction associated transcript and EZH2. Flow cytometry and CCK-8 assay were used to examine cell apoptosis and proliferation, respectively. Results: Curcumin suppressed inflammation in atherosclerosis mouse model and ox-LDL-induced cell model. MIAT overexpression and miR-124 inhibition relieved the anti-inflammation effect of curcumin in ox-LDL-induced cell. MIAT regulated miR-124 by interacting with EZH2. Curcumin relieved ox-LDL-induced cell inflammation via regulating MIAT/miR-124 pathway. Conclusion: MIAT/miR-124 axis mediated the effect of curcumin on atherosclerosis and altered cell apoptosis and proliferation, both in vivo and in vitro. These data further support the application of curcumin in control of atherosclerosis advancement. [ABSTRACT FROM AUTHOR]

Changhai Liu,1 Xiangsheng Ding,1 Cuie Wei,1 Yongdong Pei,1 Fanjun Meng,1 Yuren Zhong,1 Yi Liu2 1Department of Burn and Plastic Surgery, The First Affiliated of Hospital of Kangda College of Nanjing Medical University/The First People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China; 2Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Changhai Liu, Department of Burn and Plastic Surgery, The First Affiliated of Hospital of Kangda College of Nanjing Medical University/The First People’s Hospital of Lianyungang, No. 6 Zhenhua East Road, Haizhou District, Lianyungang City, 222000, People’s Republic of China, Email ChanghaiLiuNanjing@163.com Yi Liu, Department of Burn Plastic Surgery and Wound Repair, Second Hospital of Lanzhou University, No. 82 Cuiyingmen, Chengguan District, Lanzhou City, 730030, People’s Republic of China, Email bl9509@163.comBackground: A cascade of genes and pathways have been reported in the precise regulation of malignant melanoma (MM). Previous study has demonstrated that lncRNA LNCOC1 is an oncogenic factor in the pathogenesis and development of various cancers. The present study explored the functionalities of LNCOC1 and its interactions with miR-124 in MM.Methods: A total of 65 melanoma patients were enrolled in this study. The expression of LNCOC1 and miR-124 after cell transfection were detected by RT-qPCR. The migration rates of SK-MEL-3 and A375 cells after transient transfection with LNCOC1 expression vector and miR-124 mimic was detected by trans-well assay.Results: LNCOC1 was accumulated to high levels in melanoma, and it was significantly correlated with the low survival rate of melanoma patients. Our bioinformatics data showed that miR-124 could target LNCOC1. Overexpression of miR-124 could downregulate LNCOC1. However, up-regulated the expression of LNCOC1 did not affect the expression of miR-124. Our correlation analysis also revealed that the expression of LNCOC1 and miR-124 were inversely correlated in both melanoma tissues and non-tumor tissues. The trans-well invasion and migration assays indicated that overexpression of miR-124 inhibited the melanoma cell invasion and migration. However, overexpression of LNCOC1 promoted melanoma cell invasion and migration.Conclusion: LNCOC1 is upregulated in melanoma, which can be considered as a potential target of miR-124 in modulating melanoma cell invasion and migration. LNCOC1 may also be an interfering target of MM therapy.Keywords: LNCOC1, miR-124, melanoma, invasion, migration

Chemotherapy-induced neurodegeneration represents a significant challenge in cancer survivorship, manifesting in cognitive impairments that severely affect patients' quality of life. Emerging neuroregenerative therapies offer promise in mitigating these adverse effects, with miRNA-124 playing a pivotal role due to its critical functions in neural differentiation, neurogenesis, and neuroprotection. This review article delves into the innovative approach of using miRNA-124-loaded extracellular vesicles (EVs) encapsulated within hydrogel matrices as a targeted strategy for combating chemotherapy-induced neurodegeneration. We explore the biological underpinnings of miR-124 in neuroregeneration, detailing its mechanisms of action and therapeutic potential. The article further examines the roles and advantages of EVs as natural delivery systems for miRNAs and the application of hydrogel matrices in creating a sustained release environment conducive to neural tissue regeneration. By integrating these advanced materials and biological agents, we highlight a synergistic therapeutic strategy that leverages the bioactive properties of miR-124, the targeting capabilities of EVs, and the supportive framework of hydrogels. Preclinical studies and potential pathways to clinical translation are discussed, alongside the challenges, ethical considerations, and future directions in the field. This comprehensive review underscores the transformative potential of miR-124-loaded EVs in hydrogel matrices, offering insights into their development as a novel and integrative approach for addressing the complexities of chemotherapy-induced neurodegeneration. • Innovative use of miR-124-loaded EVs for neuroregenerative therapies. • Hydrogels enhance targeted delivery and sustained release of miR-124. • MiR-124 plays a crucial role in neural differentiation and neuroprotection. • Overcoming biological barriers in CNS for effective miR-124 delivery. • Ethical, regulatory, and scalability considerations for clinical translation. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most common extracranial solid tumor that affects developing nerve cells in the fetus, infants, and children. miR-124 is a microRNA (miRNA) enriched in neuronal tissues, and VAMP3 (vesicle-associated membrane protein 3) has been reported to be an miR-124 target, although the relationship between NB and miR-124 or VAMP3 is unknown. Our current work identified that miR-124 levels are high in NB cases and that elevated miR-124 correlates with worse NB outcomes. Conversely, depressed VAMP3 correlates with worse NB outcomes. To investigate the mechanisms by which miR-124 and VAMP3 regulate NB, we altered miR-124 or VAMP3 expression in human NB cells and observed that increased miR-124 and reduced VAMP3 stimulated cell proliferation and suppressed apoptosis, while increased VAMP3 had the opposite effects. Genome-wide mRNA expression analyses identified gene and pathway changes which might explain the NB cell phenotypes. Together, our studies suggest that miR-124 and VAMP3 could be potential new markers of NB and targets of NB treatments.

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs’ expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming.

A decrease in the miR-124 expression was observed in various epithelial cancers. Like a classical suppressor, miR-124 can inhibit the translation of multiple oncogenic proteins. Epigenetic mechanisms play a significant role in the regulation of miR-124 expression and involve hypermethylation of the MIR-124-1/-2/-3 genes and the effects of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) according to the model of competing endogenous RNAs (ceRNAs). More than 40 interactomes (lncRNA/miR-124/mRNA) based on competition between lncRNAs and mRNAs for miR-124 binding have been identified in various epithelial cancers. LncRNAs MALAT1, NEAT1, HOXA11-AS, and XIST are the most represented in these axes. Fourteen axes (e.g., SND1-IT1/miR-124/COL4A1) are involved in EMT and/or metastasis. Moreover, eight axes (e.g., OIP5-AS1/miR-124-5p/IDH2) are involved in key pathways, such as Wnt/b-catenin, E2F1, TGF-β, SMAD, ERK/MAPK, HIF-1α, Notch, PI3K/Akt signaling, and cancer cell stemness. Additionally, 15 axes impaired patient survival and three axes reduced chemo- or radiosensitivity. To date, 14 cases of miR-124 regulation by circRNAs have been identified. Half of them involve circHIPK3, which belongs to the exonic ecircRNAs and stimulates cell proliferation, EMT, autophagy, angiogenesis, and multidrug resistance. Thus, miR-124 and its interacting partners may be considered promising targets for cancer therapy. [ABSTRACT FROM AUTHOR]

Central nervous system injuries and diseases, such as ischemic stroke, spinal cord injury, neurodegenerative diseases, glioblastoma, multiple sclerosis, and the resulting neuroinflammation often lead to death or long-term disability. MicroRNAs are small, non-coding, single-stranded RNAs that regulate posttranscriptional gene expression in both physiological and pathological cellular processes, including central nervous system injuries and disorders. Studies on miR-124, one of the most abundant microRNAs in the central nervous system, have shown that its dysregulation is related to the occurrence and development of pathology within the central nervous system. Herein, we review the molecular regulatory functions, underlying mechanisms, and effective delivery methods of miR-124 in the central nervous system, where it is involved in pathological conditions. The review also provides novel insights into the therapeutic target potential of miR-124 in the treatment of human central nervous system injuries or diseases. [ABSTRACT FROM AUTHOR]