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We investigated the function and molecular mechanism of long non-coding RNA (lncRNA) small nucleolar RNA host gene 16 (Snhg16) in modifying ozone treatment for neuropathic pain (NP) in a mouse model of chronic constriction injury (CCI). Pain-related behavioral responses were evaluated using paw withdrawal threshold (PWT), paw lifting number (PLN), and paw withdrawal latency (PWL) tests. Interleukin (IL)-1β, IL-10, IL-6, and tumor necrosis factor-alpha (TNF-α) were measured by ELISA and qRT-PCR to evaluate neuroinflammation. qRT-PCR was performed to detect expressions of Snhg16, microRNA (miR)-719, sodium voltage-gated channel alpha subunit 1 (SCN1A), and inflammatory factors. Bioinformatics, dual-luciferase reporter assay, and RNA pull-down verified the underlying molecular mechanisms. Snhg16 expression increased in CCI mice. Snhg16 overexpression retarded the curative effect of ozone and induced NP. miR-719 was sponged by Snhg16. SCN1A was a target of miR-719. Inhibition of miR-719 markedly reversed the effects of Snhg16 on pain-related behavioral responses and neuroinflammation. Upregulation of SCN1A partly abrogated the effects of elevated miR-719 levels on the occurrence of NP. The findings demonstrate that lncRNA Snhg16 promotes NP progression in CCI mice by binding to miR-719 to increase SCN1A expression. The Snhg16/miR-719/SCN1A axis may influence the curative effects of ozone therapy in treating NP., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

MicroRNAs (miRNA) are endogenous non-coding RNAs, typically around 23 nucleotides in length. Many miRNAs have been founded to play crucial roles in gene regulation though post-transcriptional repression in animals. Existing studies suggest that the dysregulation of miRNA is closely associated with many human diseases. Discovering novel associations between miRNAs and diseases is essential for advancing our understanding of disease pathogenesis at molecular level. However, experimental validation is time-consuming and expensive. To address this challenge, numerous computational methods have been proposed for predicting miRNA-disease associations. Unfortunately, most existing methods face difficulties when applied to large-scale miRNA-disease complex networks. In this paper, we present a novel subgraph learning method named SGLMDA for predicting miRNA-disease associations. For miRNA-disease pairs, SGLMDA samples K-hop subgraphs from the global heterogeneous miRNA-disease graph. It then introduces a novel subgraph representation algorithm based on Graph Neural Network (GNN) for feature extraction and prediction. Extensive experiments conducted on benchmark datasets demonstrate that SGLMDA can effectively and robustly predict potential miRNA-disease associations. Compared to other state-of-the-art methods, SGLMDA achieves superior prediction performance in terms of Area Under the Curve (AUC) and Average Precision (AP) values during 5-fold Cross-Validation (5CV) on benchmark datasets such as HMDD v2.0 and HMDD v3.2. Additionally, case studies on Colon Neoplasms and Triple-Negative Breast Cancer (TNBC) further underscore the predictive power of SGLMDA.

Background: Inguinal hernia is a relatively common condition. Most patients with inguinal hernia require surgery. At present, mesh repair is one of the most effective methods to treat inguinal hernia, but insertion of the mesh can cause inflammation. Dexamethasone (DEX) can treat inflammation, but the mechanism by which DEX alleviates inflammation caused by inguinal hernia mesh placement remains unclear., Method: We randomly divided rats into groups: negative control (NC), inguinal hernia (IH), polypropylene mesh (PM), DEX treatment, and miR-155 treatment groups. RT-qPCR was performed to determine the expression of miR-155. ELISA was implemented to determine the secretion of IL-1β, IL-6, and IL-18. Western blotting was used to detect caspase-1, JAK1, p-JAK1, STAT3, and p-STAT3 expression. A dual-luciferase reporter gene array identified a connection between miR-155 and JAK1., Results: The results revealed that the expression of miR-155, IL-1β, IL-6, and IL-18 was upregulated in the PM group. After DEX treatment, the secretion of miR-155, caspase-1, IL-1β, IL-6, and IL-18 decreased. Dual luciferase results confirmed that miR-155 induced the targeted downregulation of JAK1, while a miR-155 mimic reversed the therapeutic effect of DEX, and the expression levels of p-JAK1 and p-STAT3 increased., Conclusion: DEX regulates the JAK1/STAT3 signaling pathway through miR-155 to relieve inflammation caused by inguinal hernia meshes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Differential activation of macrophages is associated with poor progression of breast cancer (BC). Many reports have elucidated the important involvement of exosomes produced by cancer cells in remodeling the macrophage activation phenotype to promote tumor expansion and invasion. However, the underlying mechanisms by which exosomes secreted by BC cells facilitate macrophage M2 polarization remain enigmatic and worth exploring. In this study, quantitative real-time PCR (RT-qPCR) was used to investigate miR-191-5p expression in BC tumor tissues and cells. Cell counting kit 8 (CCK-8), transwell, and flow cytometry were applied to assess the functional role of miR-191-5p in BC. Isolated nano-vesicles were identified using transmission electron microscopy and western blotting. We also observed that miR-191-5p was significantly elevated in BC clinical samples and that inhibition of miR-191-5p hindered the growth and metastasis of BC cells. Importantly, BC cells successfully accelerated macrophage M2-like polarization by directly transferring exosomes to macrophages, resulting in increased miR-191-5p levels in macrophages. Mechanistically, exosomal miR-191-5p directly inhibited the suppressors of cytokine signaling 3 (SOCS3) expression in macrophages and aggravated macrophage M2 polarization. Similarly, si-SOCS3 transfected macrophages boosted BC cell migration and invasion in a positive feedback manner. Overall, our results manifested a pro-growth and pro-metastatic role between the two cells by elucidating the crucial role of exosomal miR-191-5p in stimulating M2 macrophage polarization and mediating communication between BC cells and macrophages. These findings opened up new horizons for the development of BC therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Idiopathic Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilize human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA, are components of a single gene regulatory pathway. Our findings indicate that dysregulation of this pathway leads to the upregulation of glucocerebrosides (GluCer), which triggers a cellular senescence-like phenotype in dopaminergic neurons. Specifically, we discovered that downregulation of the transcriptional repressor SATB1 results in the derepression of the microRNA miR-22-3p, leading to decreased GBA expression and subsequent accumulation of GluCer. Furthermore, our results demonstrate that an increase in GluCer alone is sufficient to impair lysosomal and mitochondrial function, thereby inducing cellular senescence. Dysregulation of the SATB1-MIR22-GBA pathway, observed in both PD patients and normal aging, leads to lysosomal and mitochondrial dysfunction due to the GluCer accumulation, ultimately resulting in a cellular senescence-like phenotype in dopaminergic neurons. Therefore, our study highlights a novel pathway involving three genetic risk factors for PD and provides a potential mechanism for the senescence-induced neuroinflammation and reactive gliosis observed in both PD and normal aging., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Triple-negative breast cancer (TNBC) is a subtype of breast cancer, and its mechanisms of occurrence and development remain unclear. In this study, we aim to investigate the role and molecular mechanisms of the demethylase FTO (fat mass and obesity-associated protein) in TNBC. Through analysis of public databases, we identify that FTO may regulate the maturation of miR-17-5p and subsequently influence the expression of zinc finger and BTB domain-containing protein 4 (ZBTB4), thereby affecting the occurrence and progression of TNBC. We screen for relevant miRNAs and mRNAs from the GEO and TCGA databases and find that the FTO gene may play a crucial role in TNBC. In vitro cell experiments demonstrate that overexpression of FTO can suppress the proliferation, migration, and invasion ability of TNBC cells and can regulate the maturation of miR-17-5p through an m 6 A-dependent mechanism. Furthermore, we establish a xenograft nude mouse model and collect clinical samples to further confirm the role and impact of the FTO/miR-17-5p/ZBTB4 regulatory axis in TNBC. Our findings unveil the potential role of FTO and its underlying molecular mechanisms in TNBC, providing new perspectives and strategies for the research and treatment of TNBC.

Background: Bariatric surgery (BS) is an effective approach in treating obesity and ameliorating T2DM with obesity. Our previous studies demonstrated that duodenal-jejunal bypass (DJB) altered long non-coding RNAs (lncRNAs) in the gastrointestinal system, which is associated with modulation of lipid metabolism, and glycemic control through entero-pancreatic axis and gut-brain axis. The adipose non-coding RNA expression profile and the underlying competing endogenous RNA (ceRNA) regulatory network pattern post DJB needs further research and investigation., Results: In this study, we compared the lncRNAs, circular RNAs (circRNAs) and messenger RNAs (mRNAs) expression in adipose tissues between the sham group and the DJB group. 2219 differentially expressed mRNAs (DEmRNAs), 722 differential expression of lncRNAs (DElncRNAs) and 425 differential expression of circRNAs (DEcircRNAs) were identified. GO terms and KEGG pathways analysis of the DEmRNAs implied that the dysregulated adipose mRNAs were associated with lipid, amino acid metabolism, insulin resistance, and extra cellular matrix (ECM)-related pathways. Moreover, via analyzing ceRNA regulatory networks of DElncRNAs and DEcircRNAs, 31 hub DE mRNAs, especially Mpp7, 9330159F19Rik, Trhde. Trdn, Sorbs2, were found on these pathways., Conclusions: The role of DJB in adipose tends to remodel ECM and improve the energy metabolism through the ceRNA regulatory network., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The strength and duration of the NF-κB signaling response must be tightly modulated to avoid an inadequate or excessive immune response. Relish, a core NF-κB transcription factor of the Drosophila Imd pathway, can control the expression of antimicrobial peptides, including Dpt and AttA, to defend against Gram-negative bacterial infections, but whether Relish may regulate miRNA expression to participate in the immune response remains unclear. In this study, taking advantage of Drosophila S2 cells and different overexpression/knockout/knockdown flies, we first found that Relish could directly activate the expression of miR-308 to negatively regulate the immune response and promote the survival of Drosophila during Enterobacter cloacae infection. Second, our results demonstrated that Relish-mediated expression of miR-308 could suppress target gene Tab2 to attenuate the Drosophila Imd pathway signal during the middle and late stages of the immune response. Third, we detected the dynamic expression patterns of Dpt, AttA, Relish, miR-308, and Tab2 in wild-type flies after E. coli infection, which further revealed that the feedback regulatory loop of Relish-miR-308-Tab2 plays a crucial role in the immune response and homeostasis maintenance of the Drosophila Imd pathway. Overall, our present study not only illustrates an important mechanism by which this Relish-miR-308-Tab2 regulatory axis can negatively control the Drosophila immune response and participate in homeostasis maintenance but also provides new insights into the dynamic regulation of the NF-κB/miRNA expression network of animal innate immunity., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Enzalutamide (Enz) is a next-generation androgen receptor (AR) antagonist used to treat castration-resistant prostate cancer (CRPC). Unfortunately, the relapsing nature of CRPC results in the development of Enz resistance in many patients. Non-coding RNAs (ncRNAs) are RNA molecules that do not encode proteins, which include microRNAs (miRNA), long ncRNAs (lncRNAs), circular RNAs (circRNAs), and other ncRNAs with known and unknown functions. Recently, dysregulation of ncRNAs in CRPC, particularly their regulatory function in drug resistance, has attracted more and more attention. Herein, we introduce the roles of dysregulation of different ncRNAs subclasses in the development of CRPC progression and Enz resistance. Recently determined mechanisms of Enz resistance are discussed, focusing mainly on the role of AR-splice variant-7 (AR-V7), mutations, circRNAs and lncRNAs that act as miRNA sponges. Also, the contributions of epithelial-mesenchymal transition and glucose metabolism to Enz resistance are discussed. We summarize the different mechanisms of miRNAs, lncRNAs, and circRNAs in the progression of CRPC and Enz resistance, and highlight the prospect of future therapeutic strategies against Enz resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Osteoporosis (OP) and periodontal disease (PD) are two common health issues that threaten the older population and potentially connected each other in the context of type 2 diabetes mellitus (T2DM). Dysregulated expression of microRNAs (miRNAs) may contribute to the development and progression of both OP and PD among elderly T2DM patients. The present study aimed to evaluate the accuracy of miR-25-3p expression for the detection of OP and PD when compared to a mixed group of patients with T2DM., Methods: The study recruited 45 T2DM patients with normal bone mineral density (BMD) and healthy periodontium, 40 type 2 diabetic osteoporosis patients coexistent with PD, 50 type 2 diabetic osteoporosis patients with healthy periodontium, and 52 periodontally healthy individuals. miRNA expression measurements in the saliva were determined by real-time PCR., Results: The salivary expression of miR-25-3p was higher in type 2 diabetic osteoporosis patients than patients with T2DM only and healthy individuals (P < 0.05). Among type 2 diabetic osteoporosis patients, those with PD exhibited a higher salivary expression of miR-25-3p than those with healthy periodontium (P < 0.05). Among type 2 diabetic patients with healthy periodontium, a higher salivary expression of miR-25-3p was noted in those with OP than those without (P < 0.05). We also found a higher salivary expression of miR-25-3p in T2DM patients than healthy individuals (P < 0.05). It was revealed that the salivary expression of miR-25-3p was increased as the T scores of BMD of patients were lowered, the PPD and CAL values of patients were enhanced. The salivary expression of miR-25-3p used as a test to predict a diagnosis of PD among type 2 diabetic osteoporosis patients, a diagnosis of OP among type 2 diabetic patients, and a diagnosis of T2DM among healthy individuals produced AUC of 0.859. 0.824, and 0.886, respectively., Conclusion: The findings obtained from the study support salivary miR-25-3p confers non-invasive diagnostic potential for PD and OP among a cohort of elderly T2DM patients., (© 2023. The Author(s).)

Tissue-resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)-expressing macrophages have phenotypical similarities to M1-polarized macrophages, are pro-inflammatory, and recruit CCR2 + circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2 ̶ macrophages, which phenotypically resemble M2-polarized macrophages, promote anti-inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage-derived sEV (M2 EV ) from M2-polarized bone-marrow-derived macrophages for intramyocardial injection and recapitulation of sEV-mediated anti-inflammatory activity in ischemic-reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2 EV treatment. M2 EV rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2 EV inhibited CCR2 + macrophage numbers, reduced monocyte-derived CCR2 + macrophage recruitment to infarct sites, induced M1-to-M2 macrophage switching and promoted neovascularization. Analysis of M2 EV microRNA content revealed abundant miR-181b-5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR-181b-5p is detrimental to beneficial M2 EV actions and resulted in failure to inhibit CCR2 + macrophage numbers and infarct size. Taken together, this investigation showed that M2 EV rescued myocardial function, improved myocardial repair, and regulated CCR2 + macrophages via miR-181b-5p-dependent mechanisms, indicating an option for cell-free therapy for AMI., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

LINC00467 was reported as an oncogenic gene in different types of human cancers. In this study, we investigated the molecular mechanisms of LINC00467 in the tumorigenesis of laryngeal squamous cell cancer (LSCC). RT-qPCR was utilized to detect the mRNA expression of genes, and western blot assay was used to determine the protein levels of TNF alpha-induced protein 3 (TNFAIP3). The cell viability was detected by CCK-8 assay. Transwell assays were conducted to determine the cell migration and invasion of LSCC cells, and the cell cycle was assessed by flow cytometry. The association between paired box 5 (PAX5), LINC00467, miR-4735-3p, and TNFAIP3 was verified using ChIP, RNA pull-down, or luciferase reporter assays. In our study, we found that LINC00467 was upregulated in LSCC, and knockdown of LINC00467 suppressed cell viability and metastasis of LSCC. Besides, LINC00467 transcription could be activated by PAX5 in LSCC. Furthermore, LINC00467 acted as competitive endogenous RNA (ceRNA) for miR-4735-3p to accelerate LSCC progression. In the meantime, TNFAIP3 was identified as a downstream gene of miR-4735-3p. Finally, TNFAIP3 overexpression could overturn the effects of miR-4735-3p mimic on LSCC cellular activities. In conclusion, our results demonstrated that PAX5-induced LINC00467 facilitated LSCC progression by inhibiting miR-4735-3p to increase TNFAIP3 expression., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The transformation of nonmuscle-invasive bladder cancer (BLCa) to muscle-invasive type and distant metastasis are the two major threats to patients after surgery. Thus, it is important to identify the key genes of BLCa cell invasion and metastasis. Long noncoding RNA (lncRNA) is a potential clinical tool for cancer diagnosis and treatment. Herein, we verified that lncRNA SNHG3 is upregulated in human BLCa specimens and is proportional to poor clinical prognosis via a combination of bioinformatic analyses and wet bench experiments. Then, we constructed SNHG3 knockdown and overexpression cell models via lentiviral packaging and CRISPR-Cas9 technique. Fluorescence in situ hybridization assay showed that SNHG3 is distributed in both the nucleus and cytoplasm of BLCa cell lines. In vitro assays including CCK-8, EdU, colony formation, wound healing, transwell, and tube formation demonstrated that SNHG3 knockdown and overexpression potently inhibited and enhanced BLCa cell proliferation, migration, invasion, and angiogenesis. In addition, IVIS imaging revealed that SNHG3 knockdown could significantly inhibit M-NSG mice xenograft tumor growth. Next, RNA sequencing, bioinformatics analyses and western blots indicated that SNHG3 could promote c-MYC expression. RNA immunoprecipitation, actinomycin D assay and western blot assays suggested that SNHG3 could also bind c-MYC protein which subsequently facilitate the stabilization of BMI1 mRNA, thus enhancing BMI1 protein level. However, SNHG3 knockdown had a slightly weaker inhibitory effect on BMI1 expression than c-MYC knockdown. Further, in vitro assays demonstrated that BMI1 knockdown could suppress the SNHG3 activation-induced tumor promoting effect in BLCa cells. Overall, this study has provided new insights into the potential implication of lncRNA SNHG3 in the pathogenesis of BLCa. Importantly, SNHG3/c-MYC/BMI1 axis may be a novel target for regulating tumor growth and metastasis in BLCa patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Current clinical tools for breast cancer (BC) diagnosis are insufficient but liquid biopsy of different bodily fluids has recently emerged as a minimally invasive strategy that provides a real-time snapshot of tumour biomarkers for early diagnosis, active surveillance of progression, and post-treatment recurrence. Extracellular vesicles (EVs) are nano-sized membranous structures 50-1000 nm in diameter that are released by cells into biological fluids. EVs contain proteins, nucleic acids, and lipids which play pivotal roles in tumourigenesis and metastasis through cell-to-cell communication. Proteins and miRNAs from small EVs (sEV), which range in size from 50-150 nm, are being investigated as a potential source for novel BC biomarkers using mass spectrometry-based proteomics and next-generation sequencing. This review covers recent developments in sEV isolation and single sEV analysis technologies and summarises the sEV protein and miRNA biomarkers identified for BC diagnosis, prognosis, and chemoresistance. The limitations of current sEV biomarker research are discussed along with future perspective applications., (© 2023. The Author(s).)

The real-time imaging of low-abundance tumor-related microRNAs (miRNAs) in living cells holds great potential for early clinical diagnosis of cancers. However, the relatively low detection sensitivity and possible false-positive signals of a probe in complex cellular matrices remain critical challenges for accurate RNA detection. Herein, we developed a novel aptamer-functionalized cruciate DNA probe that enabled amplified multiple miRNA imaging in living cells via catalytic hairpin assembly (CHA). The cross-shaped design of the cruciate DNA probe improved the stability against nucleases and acted as a modular scaffold for CHA circuits for efficient delivery into tumor cells. The cruciate DNA probe allowed self-assembly through thermal annealing and displayed excellent performance for sensitive miRNA detection in vitro . The cruciate DNA probe could be internalized into nucleolin-overexpressed cells specifically via cell-targeting of the AS1411 aptamer, achieving amplified fluorescence imaging and quantitative evaluation of the expression of miRNAs in living cells. Through the simultaneous detection of intracellular multiple miRNAs, the developed cruciate DNA probe could provide more accurate information and reduce the chances of false positive signals for cancer diagnosis. This approach offers a new opportunity for promoting the development of miRNA-related biomedical research and tumor diagnostic applications.

Oxaliplatin (L-OHP) is a standard treatment drug for colorectal cancer (CRC), but acquired drug resistance limits the outcome of patients. We investigated the involvement of sirtuin 1 (SIRT1) in L-OHP resistance in the setting of CRC via microRNA-20b-3p/DEP domain containing 1 (miR-20b-3p/DEPDC1) axis. CRC tissues that were resistant or sensitive to L-OHP were harvested, in which SIRT1, miR-20b-3p, and DEPDC1 levels were tested. L-OHP-resistant-resistant CRC cells were transfected, subsequently, cellular proliferation, invasion, migration, and apoptosis were tested, and tumor resistance to L-OHP was observed. The binding of SIRT1 to miR-20b-3p promoter and the targeting relationship between miR-20b-3p and DEPDC1 were verified. An aberrant elevation in SIRT1 expression was seen in L-OHP-resistant CRC tissues and cells. Knockdown of SIRT1 sensitized CRC cells and xenografted CRC tumors to L-OHP. SIRT1 bound with miR-20b-3p promoter to regulate DEPDC1. Reducing miR-20b-3p or raising DEPDC1 levels weakened the effect of SIRT1 knockdown on L-OHP-resistant-CRC cells. SIRT1 enhances L-OHP resistance in CRC by mediating miR-20b-3p/DEPDC1 axis., (© 2022 International Federation for Cell Biology.)

Lung adenocarcinoma (LUAD) is the most common lung cancer with high incidence. The prognosis of LUAD is poor due to its aggressive behavior. Long non‑coding RNAs (lncRNAs) have been reported as a key modulator on LUAD progression. Therefore, the present study aimed to clarify the molecular mechanism of lncRNAs in LUAD development. The expression of lncRNA RP11‑805J14.5 (RP11‑805J14.5) in LUAD tissues and cells was quantified based on the data in The Cancer Genome Atlas (TCGA). Cell viability was determined using Cell Counting Kit‑8 method. Apoptotic cells were sorted and determined by flow cytometry. Cell migration and invasion abilities were detected by the Transwell assay. Luciferase reporter experiment and RNA pull‑down assay were utilized to determine the interactions between RP11‑805J14.5, microRNA (miR)‑34b‑3p, miR‑139‑5p, and cyclin D2 (CCND2). A xenograft tumor was established to determine tumor growth in vivo . RP11‑805J14.5 was highly expressed in LUAD and associated with poor survival of LUAD patients. Knockdown of RP11‑805J14.5 suppressed LUAD cell growth, invasion, migration and tumor growth, indicating that RP11‑805J14.5 is an important regulator of LUAD. Our study demonstrated that the regulation of RP11‑805J14.5 on LUAD was mediated by CCND2 whose expression was regulated by sponging miR‑34b‑3p and miR‑139‑5p. The expression of RP11‑805J14.5 was increased in LUAD, and the knockdown of RP11‑805J14.5 expression suppressed LUAD cell growth, invasion and migration by downregulating CCND2 by sponging miR‑34b‑3p and miR‑139‑5p, indicating that RP11‑805J14.5 could be a prospective target for LUAD therapy.

Development of theranostic nanosystems integrating cascaded surface-enhanced Raman scattering (SERS) imaging and gene silencing therapy for accurate cancer diagnosis and treatment is still a big challenge and rarely reported. Herein, a novel Au nanoparticles (AuNPs)-based theranostic nanosystem containing AuNP-Ys and AuNP-Ds for highly sensitive and specific cancer diagnosis and treatment was proposed for cascaded SERS imaging of intracellular cancer-related miR-106a and miR-106a-triggered DNAzyme-based dual gene-silencing therapy of cancer cells. The AuNP-Ys were prepared by modifying the AuNPs with specially designed Y-motifs, and the AuNP-Ds were obtained by colabeling Raman molecules and dsDNA linkers on AuNPs. When identifying the intracellular cancer-related miRNAs, the Y-motifs and dsDNA linkers undergoes miRNA-triggered ATP-driven conformational transitions and releases the miRNA for recycling, which results in the formation of AuNP network nanostructures to generate significantly enhanced SERS signals for sensitive identification of the cancer cells as well as the amplification and specific activation of DNAzymes to catalyze the Mg 2+ -assisted cleavage of the Survivin and c-Jun mRNAs for effective dual gene-silencing therapy of cancer cells. The AuNP-based theranostic nanosystem achieves the synergism of target-triggered SERS imaging and DNAzyme-based dual gene-silencing therapy with enhanced specificity, sensitivity, and curative effect, which can be a powerful tool for accurate diagnosis and efficient treatment of cancers.

MicroRNAs (miRNAs) are a class of non-coding RNAs that play critical role in many biological processes, such as cell growth, development, differentiation and aging. Increasing studies have revealed that miRNAs are closely involved in many human diseases. Therefore, the prediction of miRNA-disease associations is of great significance to the study of the pathogenesis, diagnosis and intervention of human disease. However, biological experimentally methods are usually expensive in time and money, while computational methods can provide an efficient way to infer the underlying disease-related miRNAs. In this study, we propose a novel method to predict potential miRNA-disease associations, called SVAEMDA. Our method mainly consider the miRNA-disease association prediction as semi-supervised learning problem. SVAEMDA integrates disease semantic similarity, miRNA functional similarity and respective Gaussian interaction profile (GIP) similarities. The integrated similarities are used to learn the representations of diseases and miRNAs. SVAEMDA trains a variational autoencoder based predictor by using known miRNA-disease associations, with the form of concatenated dense vectors. Reconstruction probability of the predictor is used to measure the correlation of the miRNA-disease pairs. Experimental results show that SVAEMDA outperforms other stat-of-the-art methods. AUC values of SVAEMDA of global leave-one-out cross validation (LOOCV) and 5-fold cross validation (5-fold CV) are 0.9464 and 0.9428 respectively. In addition, case studies of three common human diseases indicate that SVAEMDA obtains 100 percent of the top 50 predicted candidates in the benchmark databases. Therefore, SVAEMDA can efficiently and accurately predict the potential associations between diseases and miRNAs.

MicroRNAs (miRNAs) are small non-coding RNAs that are related to a number of complicated biological processes, and numerous studies have demonstrated that miRNAs are closely associated with many human diseases. In this study, we present a matrix decomposition and similarity-constrained matrix factorization (MDSCMF) to predict potential miRNA-disease associations. First of all, we utilized a matrix decomposition (MD) algorithm to get rid of outliers from the miRNA-disease association matrix. Then, miRNA similarity was determined by utilizing similarity kernel fusion (SKF) to integrate miRNA function similarity and Gaussian interaction profile (GIP) kernel similarity, and disease similarity was determined by utilizing SKF to integrate disease semantic similarity and GIP kernel similarity. Furthermore, we added L 2 regularization terms and similarity constraint terms to non-negative matrix factorization to form a similarity-constrained matrix factorization (SCMF) algorithm, which was applied to make prediction. MDSCMF achieved AUC values of 0.9488, 0.9540, and 0.8672 based on fivefold cross-validation (5-CV), global leave-one-out cross-validation (global LOOCV), and local leave-one-out cross-validation (local LOOCV), respectively. Case studies on three common human diseases were also implemented to demonstrate the prediction ability of MDSCMF. All experimental results confirmed that MDSCMF was effective in predicting underlying associations between miRNAs and diseases.

There is increasing evidence that circular RNAs (circRNAs) can serve as microRNA (miRNA) sponges to regulate metastasis of multiple tumors, including pancreatic ductal adenocarcinoma (PDAC). However, the role of the circRNA/miRNA regulatory network in metastasis of PDAC has not been elucidated. The purpose of this study is to explore the role of circ&#95;0047744/miR-21/SOCS5 in the metastasis of PDAC. We found that circRNA&#95;0047744 was weakly expressed in PDAC tissues and cell lines. The expression of circ&#95;0047744 was negatively correlated with lymph node metastasis and positively correlated with overall survival in PDAC patients. Functionally, the overexpression of circ&#95;0047744 suppressed cell migration and invasion in vitro and in vivo. Mechanistically, circ&#95;0047744 could regulate SOCS5 expression by acting as a sponge of miR-21 to inhibit migration and invasion of PDAC cells. Our study demonstrates that circ&#95;0047744 acts as an anti-oncogene to inhibit PDAC metastasis by regulating the miR-21/SOCS5 axis, indicating that circ&#95;0047744 may be a potential novel therapeutic target for PDAC patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The identification of indeterminate pulmonary nodules (IPNs) following a low-dose computed tomography (LDCT) is a major challenge for early diagnosis of lung cancer. The inadequate assessment of IPNs' malignancy risk results in a large number of unnecessary surgeries or an increased risk of cancer metastases. However, limited studies on non-invasive diagnosis of IPNs have been reported., Methods: In this study, we identified and evaluated the diagnostic value of circulating small extracellular vesicle (sEV) microRNAs (miRNAs) in patients with IPNs that had been newly detected using LDCT scanning and were scheduled for surgery. Out of 459 recruited patients, 109 eligible patients with IPNs were enrolled in the training cohort (n = 47) and the test cohort (n = 62). An external cohort (n = 99) was used for validation. MiRNAs were extracted from plasma sEVs, and assessed using Small RNA sequencing. 490 lung adenocarcinoma samples and follow-up data were used to investigate the role of miRNAs in overall survival., Results: A circulating sEV miRNA (CirsEV-miR) model was constructed from five differentially expressed miRNAs (DEMs), showing 0.920 AUC in the training cohort (n = 47), and further identified in the test cohort (n = 62) and in an external validation cohort (n = 99). Among five DEMs of the CirsEV-miR model, miR-101-3p and miR-150-5p were significantly associated with better overall survival (p = 0.0001 and p = 0.0069). The CirsEV-miR scores were calculated, which significantly correlated with IPNs diameters (p < 0.05), and were able to discriminate between benign and malignant PNs (diameter ≤ 1 cm). The expression patterns of sEV miRNAs in the benign, adenocarcinoma in situ/minimally invasive adenocarcinoma, and invasive adenocarcinoma subgroups were found to gradually change with the increase in aggressiveness for the first time. Among all DEMs of the three subgroups, five miRNAs (miR-30c-5p, miR-30e-5p, miR-500a-3p, miR-125a-5p, and miR-99a-5p) were also significantly associated with overall survival of lung adenocarcinoma patients., Conclusions: Our results indicate that the CirsEV-miR model could help distinguish between benign and malignant PNs, providing insights into the feasibility of circulating sEV miRNAs in diagnostic biomarker development., Trial Registration: Chinese Clinical Trials: ChiCTR1800019877. Registered 05 December 2018, https://www.chictr.org.cn/showproj.aspx?proj=31346 ., (© 2022. The Author(s).)

Purpose: Circular RNAs (circRNAs) have emerged as a pivotal regulatory element in the progression of human cancers. Being an important member of circRNAs, circFOXO3 has been implicated in tumor invasion or metastasis of non-small cell lung cancer (NSCLC); however, the molecular mechanism underlying this promoting effect remains an enigma. The present study aims to study the function of circFOXO3 and dissect the relevant intracellular network in the progression and metastasis of NSCLC., Methods: Quantitative real time PCR (RT-qPCR) assay and Western blotting were used to quantify the levels of RNAs and proteins respectively. starBase v2.0 and luciferase assay were used to validate the target of circRNAs or miRNAs. Cell Counting Kit-8 (CCK-8) assay was adopted to examine cell viability. Transwell was used to determine cell invasion and migration. Xenograft model was established to detect tumor growth., Results: RT-qPCR showed that circFOXO3 was overexpressed in NSCLC cells and tissues. Knockdown of circFOXO3 not only inhibited NSCLC cell proliferation, migration and invasion in vitro but also suppressed tumor growth in vivo. starBase v2.0 and luciferase assay results collectively suggested that circFOXO3 sponged miR-545-3p and miR-506-3p. Dual-inhibition of circFOXO3 and its target miRNAs suppressed the reduction of cell proliferation, migration and invasion induced by siRNA of circFOXO3 (si-circFOXO3), demonstrating that the effect of circFOXO3 on NSCLC was dependent on sponging miR-545-3p and miR-506-3p. Further bioinformatic analysis and biochemistry experiments revealed that miR-545-3p and miR-506-3p regulated the expression of a family member of high-mobility group box, HMGB3., Conclusion: Here, we show thatcircFOXO3 in NSCLC promotes the proliferation, migration and invasion of NSCLC cells, thereby promoting tumor growth. We further find that circFOXO3 sponges miR-545-3p/miR-506-3p that bind to 3'-UTR of HMGB3 mRNA, which constitutes the major network fulfilling the circFOXO3's promoting effect. Therefore, we proposed that circFOXO3 could be a potential therapeutic target for NSCLC., (Copyright © 2021. Published by Elsevier Ltd.)

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Central poststroke pain (CPSP) is a neuropathic pain syndrome that usually occurs after cerebrovascular accidents. Currently, the pathogenesis of CPSP is not fully understood. Purinergic P2X4 receptor (P2X4R) is implicated in neuropathic pain including CPSP. Herein, we demonstrated that the levels of microRNA-133b-3p (miR-133b-3p), which targets P2X4R transcripts, were significantly downregulated in the ventral posterolateral nucleus of the thalamus (VPL), cerebrospinal fluid (CSF), and plasma of CPSP rats. The expression levels of miR-133b-3p negatively correlated with the severity of allodynia. Genetic knockdown of P2X4R in the VPL protected CPSP rats against allodynia. Similarly, genetic overexpression of miR-133b-3p in the VPL reversed the allodynia established in CPSP rats via downregulation of P2X4R expression. Treatment using gabapentin in CPSP rats significantly restored the decreased miR-133b-3p expression in the VPL, CSF, and plasma and blocked allodynia in CPSP rats. The administration of an miR-133b-3p inhibitor into the VPL abolished the antiallodynic activity of gabapentin. This mechanism was associated with P2X4R expression and involved the endogenous opioid system. Human patients with CPSP showed decreased plasma levels of miR-133b-3p compared with those of control participants. Logistic regression analysis of our patient cohort showed that determining plasma levels of miR-133b-3p may be useful for CPSP diagnosis and treatment., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

MicroRNAs (miRNAs) are noncoding RNAs with 18-26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA-target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update's critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3' untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Congenital anomalies are increasingly becoming a global pediatric health concern, which requires immediate attention to its early diagnosis, preventive strategies, and efficient treatments. Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (Gnai3) gene mutation has been demonstrated to cause congenital small jaw deformity, but the functions of Gnai3 in the disease-specific microRNA (miRNA) upregulations and their downstream signaling pathways during osteogenesis have not yet been reported. Our previous studies found that the expression of Mir24-2-5p was significantly downregulated in the serum of young people with overgrowing mandibular, and bioinformatics analysis suggested possible binding sites of Mir24-2-5p in the Gnai3 3'UTR region. Therefore, this study was designed to investigate the mechanism of Mir24-2-5p-mediated regulation of Gnai3 gene expression and explore the possibility of potential treatment strategies for bone defects. Methods: Synthetic miRNA mimics and inhibitors were transduced into osteoblast precursor cells to regulate Mir24-2-5p expression. Dual-luciferase reporter assay was utilized to identify the direct binding of Gnai3 and its regulator Mir24-2-5p. Gnai3 levels in osteoblast precursor cells were downregulated by shRNA (shGnai3). Agomir, Morpholino Oligo (MO), and mRNA were microinjected into zebrafish embryos to control mir24-2-5p and gnai3 expression. Relevant expression levels were determined by the qRT-PCR and Western blotting. CCK-8 assay, flow cytometry, and transwell migration assays were performed to assess cell proliferation, apoptosis, and migration. ALP, ARS and Von Kossa staining were performed to observe osteogenic differentiation. Alcian blue staining and calcein immersions were performed to evaluate the embryonic development and calcification of zebrafish. Results: The expression of Mir24-2-5p was reduced throughout the mineralization process of osteoblast precursor cells. miRNA inhibitors and mimics were transfected into osteoblast precursor cells. Cell proliferation, migration, osteogenic differentiation, and mineralization processes were measured, which showed a reverse correlation with the expression of Mir24-2-5p. Dual-luciferase reporter gene detection assay confirmed the direct interaction between Mir24-2-5p and Gnai3 mRNA. Moreover, in osteoblast precursor cells treated with Mir24-2-5p inhibitor, the expression of Gnai3 gene was increased, suggesting that Mir24-2-5p negatively targeted Gnai3. Silencing of Gnai3 inhibited osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization. Promoting effects of osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization by low expression of Mir24-2-5p was partially rescued upon silencing of Gnai3. In vivo , mir24-2-5p Agomir microinjection into zebrafish embryo resulted in shorter body length, smaller and retruded mandible, decreased cartilage development, and vertebral calcification, which was partially rescued by microinjecting gnai3 mRNA. Notably, quite similar phenotypic outcomes were observed in gnai3 MO embryos, which were also partially rescued by mir24-2-5p MO. Besides, the expression of phospho-JNK (p-JNK) and p-p38 were increased upon Mir24-2-5p inhibitor treatment and decreased upon shGnai3-mediated Gnai3 downregulation in osteoblast precursor cells. Osteogenic differentiation and mineralization abilities of shGnai3-treated osteoblast precursor cells were promoted by p-JNK and p-p38 pathway activators, suggesting that Gnai3 might regulate the differentiation and mineralization processes in osteoblast precursor cells through the MAPK signaling pathway. Conclusions: In this study, we investigated the regulatory mechanism of Mir24-2-5p on Gnai3 expression regulation in osteoblast precursor cells and provided a new idea of improving the prevention and treatment strategies for congenital mandibular defects and mandibular protrusion., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To assess the role of micro ribonucleic acid 425 in colorectal carcinogenesis., Methods: The experimental study was conducted from December 2016 to July 2017 at the Xinjiang Dingju Medical Laboratory, China, and comprised sphere formation assay, wound healing assay, transwell assay, thiazolyl blue tetrazolium bromide cell proliferation assay, flow cytometric analysis, reverse transcription quantitative polymerase chain reaction and western blotting to analyse the proliferation and invasion capability of HCT116 cells transfected with a micro ribonucleic acid-425 mimic, micro ribonucleic acid-425 inhibitor, micro ribonucleic acid-425 mimic negative control, and micro ribonucleic acid-425 inhibitor negative control., Results: Micro ribonucleic acid-425 expression in HCT116 cells was up regulated after transfection, resulting in inhibition of sphere formation. Over-expression of micro ribonucleic acid-425 inhibited the proliferation of HCT116 cells and induced apoptosis along with inhibition of HCT116 cell migration and invasion., Conclusion: Over-expression of micro ribonucleic acid-425 was found to have the potential to inhibit sphere formation as well as migration and invasion of HCT116 cells by inhibiting proliferation and promoting apoptosis.

Bone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

Background: One of the microRNAs (miRNAs) known to be associated with cancer development is miR-607. The aim of this study is to investigate the clinical significance and diagnostic and prognostic value of miR-607 and to explore its potential role in pancreatic ductal adenocarcinoma (PDAC)., Methods: The expression levels of miR-607 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between miR-607 expression and clinical characteristics was analyzed by the Chi-square test. Overall survival (OS) and progression-free survival (PFS) were evaluated via the Kaplan-Meier method, and the association between miR-607 expression and OS was investigated by the Cox proportional hazard analysis. The diagnostic value was estimated via receiver operating characteristic (ROC) curve analysis. The effect of miR-607 overexpression on cell migration, invasion, and epithelial-mesenchymal transition (EMT) was determined by wound-healing, Transwell invasion, and Western blotting assays., Results: miR-607 levels were downregulated in PDAC tumor tissues compared with normal tissues. Also, low miR-607 levels were observed in serum samples from PDAC patients than that in healthy controls. The miR-607 level was found to be closely correlated with lymphatic metastasis and liver metastasis, perineural invasion, and OS and PFS, and the low miR-607 level was an independent prognostic factor for the poor OS of PDAC patients. Furthermore, the area under the curve (AUC) of serum miR-607 for discriminating PDAC patients was 0.785 with a sensitivity of 0.647 and a specificity of 0.772, which was better than those for CA19-9 (AUC: 0.702, sensitivity: 0.607, specificity: 0.736) and CEA (AUC: 0.648, sensitivity: 0.542, specificity: 0.670). The AUC (0.863), sensitivity (0.766), and specificity (0.831) of their combination in the diagnosis of PDAC were better than those for alone. Moreover, ectopic overexpression of miR-607 could inhibit cell migration and invasion of BxPc-3 and PANC-1 cells by decreasing EMT ability., Conclusions: Low serum miR-607 level may serve as a potential diagnostic and prognostic biomarker through regulation of tumor metastasis in PDAC patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Dawei Jiang et al.)

Background: Although lncRNA TP73-AS1 has been shown to play important roles in various human diseases, its function in atherosclerosis (AS) remains unclear., Methods: Human aortic endothelial cells (HAECs) were treated with 50 μg/ml oxidized low-density lipoprotein (ox-LDL) to establish an atherosclerotic cell model. The expression of TP73-AS1, miR-654-3p and AKT3 was detected by qRT-PCR. Cell functions were evaluated CCK-8 assay and flow cytometry. The protein levels of apoptosis-related proteins were evaluated by western blot. The binding relationship among TP73-AS1, miR-654-3p and AKT3 was determined by bioinformatics analysis and luciferase reporter assay., Results: TP73-AS1 was upregulated and miR-654-3p was downregulated in ox-LDL treated HAECs. TP73-AS1 silencing and miR-654-3p mimics decreased the viability and inhibited apoptosis of ox-LDL treated HAECs, decreased the expression levels of c-caspase-9, c-caspase-3 and Bax, and increased Bcl-2 expression. In addition, miR-654-3p inhibitor significantly reversed the inhibitory effects of si-TP73-AS1 on cell viability and apoptosis. TP73-AS1 could positively regulate AKT3 through directly sponging miR-654-3p., Conclusion: TP73-AS1 promoted apoptosis of ox-LDL stimulated endothelial cells by targeting the miR-654-3p/AKT3 axis, suggesting that TP73-AS1 might be a potential target for AS treatment.

Long non-coding RNA CRNDE and DNA methylation play a vital role in the occurrence and development of chronic lymphocytic leukemia (CLL). This study attempted to investigate the biological role of CRNDE methylation in CLL. The expression and methylation levels of CRNDE in CLL cell lines (MEC-1 and HG3) before or after methylation inhibitor (5-Aza-2'-deoxycytidine, 5-Aza-CdR) treatment was detected by quantitative real-time PCR or methylation-Specific PCR. The relationship among CRNDE, miR-28 and NDRG2 was verified by luciferase reporter assay. The effect of CRNDE overexpression and 5-Aza-CdR treatment on cell proliferation and apoptosis of MEC-1 and HG3 cells were assessed by CCK8 and flow cytomery. Compared with normal B lymphocytes, CRNDE was down-regulated and the methylation level of CRNDE was increased in MEC-1 and HG3 cells. Then, 5-Aza-CdR treatment caused an increase of CRNDE expression in MEC-1 and HG3 cells by demethylation. The overexpression or demethylation of CRNDE inhibited cell proliferation and promoted apoptosis in MEC-1 and HG3 cells by up-regulating CRNDE expression. Moreover, CRNDE functioned as a competing endogenous RNA to repress miR-28, which controlled its down-stream target NDRG2. CRNDE overexpression inhibited cell proliferation and promoted apoptosis via miR-28/NDRG2 axis in CLL. In conclusion, our data elaborated that CRNDE expression was regulated by DNA methylation, and the protective effect of CRNDE on CLL was attributed to the inhibition of proliferation in CLL via miR-28/NDRG2 axis. Thus, this work highlights a novel competing endogenous RNA circuitry involving key regulators of CLL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have been found to enhance fracture healing. In addition, microRNAs contributing to the healing of various bone fractures have attracted widespread attention in recent years, but knowledge of the mechanisms by which they act is still very limited. In this study, we clarified the function of altered microRNA-19b (miR-19b) expression in BMSCs in fracture healing. We modulated miR-19b expression via mimics/inhibitors in BMSCs and via agomirs in mice to explore the effects of these changes on osteogenic factors, bone cell mineralization and the healing status of modeled fractures. Through gain- and loss-of function assays, the binding affinity between miR-19b and WWP1/Smurf2 was identified and characterized to explain the underlying mechanism involving the KLF5/β-catenin signaling pathway. miR-19b promoted the differentiation of human BMSCs into osteoblasts by targeting WWP1 and Smurf2. Overexpression of WWP1 or Smurf2 degraded the target protein KLF5 in BMSCs through ubiquitination to inhibit fracture healing. KLF5 knockdown delayed fracture healing by modulating the Wnt/β-catenin signaling pathway. Furthermore, miR-19b enhanced fracture healing via the KLF5/β-catenin signaling pathway by targeting WWP1 or Smurf2. Moreover, miR-19b was found to be enriched in BMSC-derived exosomes, and treatment with exosomes promoted fracture healing in vivo. Collectively, these results indicate that mesenchymal stem cell-derived exosomal miR-19b represses the expression of WWP1 or Smurf2 and elevates KLF5 expression through the Wnt/β-catenin signaling pathway, thereby facilitating fracture healing.

Background : Epigenetic regulation by promoter methylation-mediated silencing of cancer-related microRNAs plays vital roles in tumorigenesis. MiR-192-5p promotes tumor progression in various human cancers with conflicting biological effects. However, its expression levels and biological functions in endometrial carcinoma (EC) have not been reported. Methods : The methylation status of miR-192-5p in tissue samples and cell lines, was examined using bisulfite sequencing PCR. miR-192-5p expression was also measured. EC cell lines transfected with specifically designed vectors overexpressing miR-192-5p, its target gene ALX1 or both, were constructed. Tumorigenicity of these cell lines were examined by in vitro and in vivo experiments. Dual-luciferase reporter assay were employed to verify the target of miR-192-5p. Results : The promoter region of miR-192-5p gene was highly methylated and its expression significantly repressed in EC samples. Moreover, a higher level of promoter methylation as well as a lower expression of miR-192-5p, was significantly associated with advanced Federation of Gynecology and Obstetrics stage and shorter disease-free survival in patients with curatively resected EC. Functional studies demonstrated that miR-192-5p overexpression inhibited in vitro tumor progression, in vivo tumorigenicity and the expression of several oncoproteins that was highly related to epithelial-to-mesenchymal transition. ALX1 was verified as a direct target of miR-192-5p and demonstrated to mediate the tumor-suppressive function of miR-192-5p. Conclusion : miR-192-5p is a tumor suppressor miRNA that is epigenetically silenced by promoter methylation and may serve as a potential prognostic biomarker in EC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cancer cells-secreted extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in local and distant microenvironment. Our initial GEO database analysis identified the presence of differentially-expressed microRNA-1246 (miR-1246) in acute myeloid leukemia (AML) cell-derived EVs. Consequently, the current study set out to investigate the role of AML-derived EVs-packaged miR-1246 in leukemia stem cells (LSCs) bioactivities. The predicted binding between miR-1246 and LRIG1 was verified using dual luciferase reporter assay. Then, gain- and loss-of-function assays were performed in LSCs, where LSCs were co-cultured with AML cell-derived EVs to characterize the effects of miR-1246-containing EVs, miR-1246, LRIG1 and STAT3 pathway in LSCs. Our findings revealed, in AML cell-derived EVs, miR-1246 was highly-expressed and directly-targeted LRIG1 to activate the STAT3 pathway. MiR-1246 inhibitor or EV-encapsulated miR-1246 inhibitor was found to suppress the viability and colony formation abilities but promoted the apoptosis and differentiation of LSCs through inactivation of STAT3 pathway by up-regulating LRIG1. In addition, the inhibitory effects of AML cell-derived EVs carrying miR-1246 inhibitor on LSCs were substantiated by in vivo experiments. Collectively, our findings reveal that the repression of AML cell-derived EVs containing miR-1246 inhibitor alters the survival of LSCs by inactivating the LRIG1-mediated STAT3 pathway.

Motivation: MicroRNAs (miRNAs) are a class of non-coding RNAs that play critical roles in various biological processes. Many studies have shown that miRNAs are closely related to the occurrence, development and diagnosis of human diseases. Traditional biological experiments are costly and time consuming. As a result, effective computational models have become increasingly popular for predicting associations between miRNAs and diseases, which could effectively boost human disease diagnosis and prevention., Results: We propose a novel computational framework, called AEMDA, to identify associations between miRNAs and diseases. AEMDA applies a learning-based method to extract dense and high-dimensional representations of diseases and miRNAs from integrated disease semantic similarity, miRNA functional similarity and heterogeneous related interaction data. In addition, AEMDA adopts a deep autoencoder that does not need negative samples to retrieve the underlying associations between miRNAs and diseases. Furthermore, the reconstruction error is used as a measurement to predict disease-associated miRNAs. Our experimental results indicate that AEMDA can effectively predict disease-related miRNAs and outperforms state-of-the-art methods., Availability and Implementation: The source code and data are available at https://github.com/CunmeiJi/AEMDA., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: An estimated 5-10 % of healthy vaccinees lack adequate antibody response following receipt of a standard three-dose hepatitis B vaccination regimen. The cellular mechanisms responsible for poor immunological responses to hepatitis B vaccine have not been fully elucidated to date., Methods: There were 61 low responders and 56 hyper responders involved in our study. Peripheral blood samples were mainly collected at D7, D14 and D28 after revaccinated with a further dose of 20 µg of recombinant hepatitis B vaccine., Results: We found low responders to the hepatitis B vaccine presented lower frequencies of circulating follicular helper T (cTfh) cells, plasmablasts and a profound skewing away from cTfh2 and cTfh17 cells both toward cTfh1 cells. Importantly, the skewing of Tfh cell subsets correlated with IL-21 and protective antibody titers. Based on the key role of microRNAs involved in Tfh cell differentiation, we revealed miR-19b-1 and miR-92a-1 correlated with the cTfh cell subsets distribution and antibody production., Conclusions: Our findings highlighted a decrease in cTfh cells and specific subset skewing contribute to reduced antibody responses in low responders.

This study intends to address the function of miR-301b/nuclear receptor subfamily 3 group C member 2 (NR3C2) in breast cancer. The Cancer Genome Atlas database was processed to investigate the expression of miR-301b/NR3C2 in breast cancer samples, as well as the relationship between their expression and the prognosis of the patients. Cox regression analysis was performed to determine whether miR-301b/NR3C2 was an independent predictor of the patient's prognosis. Associations between miR-301b and NR3C2 were analyzed by prediction website, dual-luciferase assay, and Pearson correlation coefficient. Quantitative polymerase chain reaction and Western blot analyses were implemented to detect gene expression. The relevant biological characteristics of MCF7 and BCAP-37 cells were tested by cell counting kit-8, colony formation, and transwell assays. Lower expression of NR3C2, which was closely related to the bad prognosis of breast cancer patients, was presented in breast cancer samples and can be used as an independent predictor. miR-301b, as an upstream regulator of NR3C2, was highly expressed in breast cancer samples and can be used as an independent predictor as well. Notably, a higher level of miR-301b and lower level of NR3C2 were related to the reduced overall survival in patients with breast cancer. The proliferative and migratory behaviors of cells were elevated or blocked after overexpression of miR-301b or NR3C2, respectively. However, the above situation was attenuated after together upregulation of miR-301b and NR3C2. The present data afforded evidence that miR-301b may be a tumor-promoting miRNA in breast cancer, and that miR-301b/NR3C2 axis mediated tumor development from cell proliferation and migration., (© 2020 Wiley Periodicals LLC.)

Objective: Emerging evidence has revealed that exosomal microRNAs (miRNAs) are implicated in human diseases. However, role of exosomal miR-125b-5p in sepsis-induced acute lung injury (ALI) remains further explored. We focused on the effect of exosomal miR-125b-5p on ALI progression via targeting topoisomerase II alpha (TOP2A)., Methods: The ALI mouse models were established by cecal ligation and perforation, which were then treated with miR-125b-5p agomir or overexpressed TOP2A. Next, the pathological structure of ALI mouse lung tissues were observed, miR-125b-5p, TOP2A and vascular endothelial growth factor (VEGF) expression was determined, and the lung water content, inflammatory response, protein content in bronchoalveolar lavage fluid (BALF) and cell apoptosis in ALI mouse lung tissues were assessed. Exosomes were extracted from endothelial cells (ECs) and identified, which were then injected into the modeled mice to observe their roles in ALI. The targeting relationship between miR-125b-5p and TOP2A was confirmed., Results: MiR-125b-5p was downregulated while TOP2A was upregulated in ALI mice. MiR-125b-5p elevation or ECs-derived exosomes promoted VEGF expression, improved pathological changes and restrained lung water content, inflammatory response, protein content in BALF and cell apoptosis in lung tissues ALI mice. TOP2A overexpression reversed the repressive role of miR-125b-5p upregulation in ALI, while downregulated miR-125b-5p abrogated the effect of ECs-derived exosomes on ALI. TOP2A was confirmed as a direct target gene of miR-125b-5p., Conclusion: Our study indicates that ECs-derived exosomes overexpressed miR-125b-5p to protect from sepsis-induced ALI by inhibiting TOP2A, which may contribute to ALI therapeutic strategies.

Background: MicroRNAs are endogenous small noncoding RNAs, which play a critical role in regulating various biological and pathologic processes. Furthermore, miR-301a has been detected to be overly expressed in tumorigenic progression of ovarian cancer. However, the effects of miR-301a on ovarian cancer are still unclear., Objective: The objective of this study is to investigate the molecular mechanisms of miR-301a in epithelial ovarian cancer cells., Methods: The miR-301a expression in ovarian cancer cells was detected. Then, cell proliferation, cell cycle, and apoptosis of the miR-301a-mimic-transfected ovarian cancer cells were determined, as well as the effects of the miR-301a mimic on the PTEN/phosphoinositide 3-kinase (PI3K) signaling pathway were explored., Results: We found that the miR-301a expression levels were markedly upregulated in ovarian cancer tissues and cells, and upregulation of miR-301a-promoted cell viability and proliferation. Our results also showed that the miR-301a-mimic accelerated cell cycle progression of ovarian cancer cells by targeting the CDK4/Cyclin-D1 pathway but not the CDK2/Cyclin-E pathway. Moreover, transfection of the miR-301a mimic into ovarian cancer cells could decrease the PTEN expression while increasing the PI3K and Akt phosphorylation, as compared with the miR-301a inhibitor group and the negative control group., Conclusion: Therefore, miR-301a should be an oncogene in ovarian cancer, and overexpression of miR-301a promoted proliferation of ovarian cancer cells by modulating the PTEN/PI3K/Akt signaling pathway., (© 2021 S. Karger AG, Basel.)

Objective: To illustrate the role of microRNA-1231 (miR-1231) in regulating malignant proliferative potential and DTX sensitivity to gallbladder carcinoma (GBC) by regulating FOXC2 level., Patients and Methods: Expression levels of miR-1231 in GBC tissues and paracancerous ones were detected. The relationship between miR-1231 level and clinical parameters of GBC patients was analyzed. After overexpression of miR-1231, changes in proliferative and apoptotic potentials in GBC-SD and NOZ cells were examined by Cell Counting Kit-8 (CCK-8), colony formation assay and flow cytometry, respectively. Regulatory effects of miR-1231 on its downstream gene FOXC2 were determined by Luciferase assay. Finally, the role of miR-1231 in regulating DTX sensitivity to GBC cells was assessed., Results: MiR-1231 was downregulated in GBC tissues compared to paracancerous ones. GBC patients expressing lower level of miR-1231 had worse tumor staging and larger tumor size. Overexpression of miR-1231 attenuated proliferative potential, and induced apoptosis in GBC cells. FOXC2 was upregulated in GBC and negatively linked to miR-1231. Luciferase activity confirmed that FOXC2 was the target gene binding miR-1231. DTX treatment dose-dependently suppressed viability in GBC cells and overexpression of miR-1231 could enhance DTX sensitivity in GBC. Notably, overexpression of FOXC2 abolished regulatory effects of overexpressed miR-1231 on proliferative and apoptotic potentials in GBC cells., Conclusions: MiR-1231 is downregulated in GBC species. Its level is closely linked to tumor staging and tumor size in GBC patients. By downregulating FOXC2, miR-1231 enhances DTX sensitivity to GBC cells and thus alleviates the malignant development of GBC.

Alcoholic liver disease greatly affects human health. Previous studies have identified that microRNAs (miRNAs) are associated with the pathogenesis of alcoholic liver fibrosis (ALF). Therefore, the present study explored the regulatory mechanism of miR‑148a‑3p in ALF. An ALF model was established in rats by alcohol gavage, followed by treatment with miR‑148a‑3p. Reverse transcription‑quantitative (RT‑q) PCR was performed to detect miR‑148a‑3p expression in the rat liver tissues. The levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were determined by enzyme‑labeled colorimetry. Liver damage was evaluated by liver indices and histology. The direct target gene of miR‑148a‑3p was predicted by a dual luciferase reporter assay. The effects of miR‑148a‑3p and miR‑148a‑3p in combination with receptor tyrosine‑protein kinase erbB‑3 (ERBB3) on HSC‑T6 cell viability and apoptosis were detected by MTT and flow cytometry assays, respectively. Western blotting and RT‑qPCR assays were performed to detect the expression levels of proteins and mRNA associated with fibrosis and apoptosis. The data showed that miR‑148a‑3p mimics inhibited the expression levels of AST, ALT, ALP, LDH, α‑SMA and type I collagen in the model, decreased the liver indices, and improved the liver damage caused by alcohol. ERBB3, which was predicted as the direct target gene of miR‑148a‑3p, reversed the effects of ERBB3 on promoting cell viability and inhibiting apoptosis. Concomitantly, miR‑148a‑3p reversed the increased expression of Bcl‑2 and inhibited the expression levels of Bax and c‑cleaved‑3 caused by ERBB3. These data suggested that miR‑148a‑3p regulated ALF and the viability and apoptosis of hepatic stellate cells through targeting ERBB3.

MicroRNAs (miRNAs/miRs) are small noncoding RNAs 19‑24 nucleotides in length, which can play an important role in tumor development. However, the influence of miRNAs on the tumorigenicity of ovarian cancer cells has not been fully elucidated. Previously, DEAD box protein (DDX) 1 has been shown to play a role in tumor suppression of ovarian cancer progression. However, the functions of other DDX members in ovarian cancer development remain largely unknown. In the present study, it was demonstrated that overexpression of miR‑196a promoted ovarian cancer cell proliferation. In addition, DDX3 was significantly downregulated in ovarian cancer cell lines relative to the normal ovarian cell line. Moreover, DDX3 was identified as a direct target of miR‑196a in ovarian cancer cells. In addition, a preliminary mechanistic investigation indicated that downregulation of DDX3 promoted ovarian cancer cell proliferation through the PTEN/PI3K/AKT pathway. Taken together, this confirmed an association between DDX3 and miR‑196a in ovarian cancer, and showed that miR‑196a promoted the proliferation of ovarian cancer cells and attenuated apoptosis by downregulating the expression of DDX3 through the PTEN/PI3K/AKT pathway. Overall, the results of the present study suggested that DDX3 could be a novel target for ovarian cancer treatment.

The three-host tick Haemaphysalis longicornis is an obligate blood-sucking ectoparasite. In life-stage transitions, microRNAs (miRNAs) show a variety of expression changes. To investigate these changes, deep sequencing technology was applied to identify the conserved and potentially novel miRNAs expressed during the different life stages of H. longicornis. Total RNA from eggs, unfed larvae, unfed nymphs and unfed adults was extracted for deep sequence analysis. Deep sequencing on a Hiseq 4000 generated a total of 111,192,069 reads, grouped into four small RNA (sRNA) libraries, one for each of the four developmental stages of H. longicornis. Among these sequences, 78 conserved and 55 potentially novel miRNAs were identified, including stage-specific and differentially expressed miRNAs. Gene ontology (GO) analysis indicated significantly enriched GO terms related to cell proliferation and differentiation, including specific terms for the processes of development, growth, metabolism, regulation of biological functions, reproduction, and membrane enzyme regular activity. Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis revealed a significant enrichment of the insulin, notch, Hippo, and Wnt signaling pathways for growth and development. Our data highlight the abundance of miRNA changes (conserved and potentially novel) in the different life stages of H. longicornis. In particular, stage-specific miRNAs, as observed, are essential regulators for the development of H. longicornis., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Osteosarcoma is a malignant bone tumour with the lowest survival rates out of all paediatric cancers and is primarily diagnosed in children and adolescents. MNAT1 is a subunit in the cyclin-dependent kinase-activating kinase complex. Abnormal up-regulation of MNAT1 has been associated with the poor prognosis of multiple cancers. Bioinformatics analysis showed that has-circ-0001146 and miR-26a-5p were involved in the regulation of MNAT1 in osteosarcoma. The present study investigated the regulatory effects of has-circ-0001146 and miR-26a-5p on MNAT1 expression using luciferase reporter and RNA-pull down assays. The effects of the has-circ-0001146/miR26a-5p/Mnat1 network on the proliferation and invasion of osteosarcoma were evaluated by cell viability, apoptosis, migration, and invasion assays. Osteosarcoma tissues showed higher MNAT1 and has-circ-0001146 expression than adjacent normal tissues, although the expression of MNAT1 was not significantly up-regulated in sarcomas according to TCGA databases. As indicated by luciferase reporter and RNA-pull down assays, miR-26a-5p was able to bind to both has-circ-0001146 and MNAT1 mRNA. The depletion of has-circ-0001146 as well as the increase of miR-26a-5p decreased MNAT1 expression in osteosarcoma cells, while the reduction of miR-26a-5p was associated with increased MNAT1 expression. These data suggested that has-circ-0001146 promoted MNAT1 expression by competitively binding to miR-26a-5p with MNAT1 mRNA. The depletion of has-circ-0001146 or MNAT1 or the increase of miR-26a-5p inhibited osteosarcoma cell viability and invasion, and increased apoptosis. Reduction of miR-26a-5p conversely promoted osteosarcoma cell viability and invasion. The present study confirmed that has-circ-0001146 blocked miR-26a-5p targeting MNAT1 in osteosarcoma cells, thereby promoting the malignant behaviours of osteosarcoma cells., (© 2020 The Author(s).)

Promoter methylation‑associated silencing of cancer‑associated microRNAs (miRNAs) is a common epigenetic mechanism during tumorigenesis in various types of human cancer. However, this has not been comprehensively examined in endometrial carcinoma (EC). In the present study, an miRNA microarray consisting of 1,347 common human miRNAs was used to select potential tumor suppressive miRNAs that were hyper‑methylated in EC. This led to the identification of miR‑638, miR‑210 and miR‑3665. The methylation status of miR‑638 was examined by bisulfite sequencing polymerase chain reaction and miR‑638 expression was measured by TaqMan miRNA assays. EC cell lines transfected with vectors overexpressing miR‑638, its target gene myocyte enhancer factor 2C (MEF2C) or both, were constructed. Dual‑luciferase reporter assays, a xenograft mouse model and rescue experiments were designed to study miR‑638 and its target gene MEF2C. The results indicated that the promoter region of miR‑638 was highly methylated and the expression of miR‑638 was significantly downregulated in cancerous tissues from 42 patients with EC who underwent surgical resection. Additionally, a low expression of miR‑638 was significantly associated with advanced Federation of Gynecology and Obstetrics stage and was demonstrated to indicate shorter disease‑free survival. Functional studies indicated that the overexpression of miR‑638 in EC cell lines inhibited in vitro tumor progression and in vivo tumorigenicity. MEF2C was verified as a direct target of miR‑638 and was demonstrated to mediate the tumor‑suppressive function of miR‑638 in EC.

The current research aimed to study the effects of dexmedetomidine (DEX) pretreatment on rats with sepsis-induced acute kidney injury (SAKI) and miR-146a expression. The model of SAKI was established through the tail vein injection of lipopolysaccharide (LSP). We used an automatic biochemical analyzer to detect serum urea nitrogen (BUN) and creatinine (Cre) levels. The expression levels of urine KIM-1 and NGAL and serum IL-1β and IL-6 were analyzed by enzyme-linked immunosorbent assay (ELISA). The content and activity of superoxide dismutase (SOD) were detected by the xanthine oxidase method. The content of malondialdehyde (MDA) was determined by the thiobarbituric acid (TBA) method. Reactive oxygen species (ROS) was detected by fluorescent probe DCFH-DA. Catalase (CAT) was detected by potassium permanganate titration. The expression level of miR-146a in the renal tissue and serum was detected by RT-PCR. The expression levels of Nrf2 and HO-1 proteins were detected by Western blot. Compared with those in the model group, rats in the DEX group had significantly lower expression levels of serum BUN, Cre, IL-1β, and IL-6, and oxidant markers MDA and ROS, but significantly higher expression levels of miR-146a and antioxidant markers SOD and CAT. DEX pretreatment could improve the kidney morphology, injury severity, and Nrf2 and HO-1 proteins of rats with SAKI. In conclusion, DEX can improve oxidative stress and inflammatory responses in rats with SAKI, reduce the severity of the renal injury, and up-regulate the expression level of miR-146a.

Objective: The present study aimed to determine the expression of long non-coding RNA (lncRNA) FOXD3 antisense RNA 1 (FOXD3-AS1) in lung cancer tissues and to explore its underlying mechanisms in mediating non-small cell lung cancer (NSCLC) progression., Materials and Methods: Gene expression levels were determined by quantitative real-time PCR; lung cancer cell proliferation and invasion were determined by in vitro functional assays; protein levels were determined by Western blot assay; xenograft nude mice model was used to evaluate the in vivo tumor growth of lung cancer cells; Luciferase reporter assay determined the interactions among FOXD3-AS1, miR-127-3p, and mediator complex subunit 28 (MED28)., Results: Data mining and analysis of the clinical sample showed that FOXD3-AS1 expression was significantly up-regulated in lung cancer tissues. In vitro functional assays demonstrated that FOXD3-AS1 overexpression promoted NSCLC cell proliferation and invasion, while FOXD3-AS1 knockdown exerted tumor-suppressive effects on NSCLC cells. Moreover, FOXD3-AS1 interacted with miR-127-3p by acting as a competing endogenous RNA to suppress miR-127-3p expression, while miR-127-3p repressed MED28 expression by targeting MED28 3' untranslated region in NSCLC cells. Mechanistically, the oncogenic effects of FOXD3-AS1 overexpression were significantly attenuated by miR-127-3p overexpression and MED28 knockdown in NSCLC cells. In the xenograft mice model, FOXD3-AS1 knockdown suppressed in vivo tumor growth of A549 cells, and also up-regulated miR-127-3p expression and repressed MED28 expression in the xenograft tumors. In the clinical aspect, the downregulation of miR-127-3p and up-regulation of MED28 were respectively detected in lung cancer tissues., Conclusions: Our findings provided new evidence that the FOXD3-AS1 regulated NSCLC progression via targeting the miR-127-3p/MED28 axis.

Previous studies showed that miR-124 had a protective role by reducing oxidant stress and preventing cell apoptosis and autophagy. However, its role in doxorubicin-induced cardiomyopathy was less known. In our study, we confirmed increased ROS and decreased expression of miR-124 in doxorubicin-treated heart tissues and primary cardiomyocytes. The oxidative stress and cell apoptosis were alleviated by overexpressing miR-124, characterized by decreased activity of MDA and increased activity of SOD. While inhibiting miR-124 generated opposed effects. Mechanistically, our bioinformatic prediction and luciferase assay confirmed that miR-124 inhibited the expression of p66Shc, a proapoptotic signaling pathway. Our results suggested that miR-124 was hopeful to become a therapeutic target in doxorubicin-related cardiomyopathy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)