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Thymocyte development requires precise control of PI3K-Akt signaling to promote proliferation and prevent leukemia and autoimmune disorders. Here, we show that ablating individual clusters of the miR-17∼92 family has a negligible effect on thymocyte development, while deleting the entire family severely impairs thymocyte proliferation and reduces thymic cellularity, phenocopying genetic deletion of Dicer. Mechanistically, miR-17∼92 expression is induced by Myc-mediated pre-T cell receptor (TCR) signaling, and miR-17∼92 promotes thymocyte proliferation by suppressing the translation of Pten. Retroviral expression of miR-17∼92 restores the proliferation and differentiation of Myc-deficient thymocytes. Conversely, partial deletion of the miR-17∼92 family significantly delays Myc-driven leukemogenesis. Intriguingly, thymocyte-specific transgenic miR-17∼92 expression does not cause leukemia or lymphoma but instead aggravates skin inflammation, while ablation of the miR-17∼92 family ameliorates skin inflammation. This study reveals intricate roles of the miR-17∼92 family in balancing thymocyte development, leukemogenesis, and autoimmunity and identifies those microRNAs (miRNAs) as potential therapeutic targets for leukemia and autoimmune diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The miR-17∼92 family microRNAs (miRNAs) play a key role in germinal center (GC) reaction through promoting T follicular helper (T FH ) cell differentiation. It remains unclear whether they also have intrinsic functions in B cell differentiation and function. Here we show that mice with B cell-specific deletion of the miR-17∼92 family exhibit impaired GC reaction, plasma cell differentiation, and antibody production in response to protein antigen immunization and chronic viral infection. Employing CRISPR-mediated functional screening, we identify Socs3 as a key functional target of miR-17∼92 in regulating plasma cell differentiation. Mechanistically, SOCS3, whose expression is elevated in miR-17∼92 family-deficient B cells, interacts with NIK and promotes its ubiquitination and degradation, thereby impairing NF-κB signaling and plasma cell differentiation. This moderate increase in SOCS3 expression has little effect on IL-21-STAT3 signaling. Our study demonstrates differential sensitivity of two key signaling pathways to alterations in the protein level of an miRNA target gene., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aberrant glucose metabolism is one of the most striking characteristics of metabolic reprogramming in cancer. Thus, clarifying the regulatory mechanism of glucose metabolism is crucial to understanding tumor progression and developing novel therapeutic strategies for cancer patients. Recent developments in circular RNAs have explained the regulatory mechanism of glucose metabolism from a new dimension. In this review, we briefly summarize the recent advances in circRNA research on cancer glucose metabolism and emphasize the different regulatory mechanisms, including acting as miRNA sponges, interacting with proteins and being translated into proteins. Additionally, we discuss the future research directions of circular RNAs in the field of glucose metabolism., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Chemically modified mRNA (CMmRNA) with selectively altered nucleotides are used to deliver transgenes, but translation efficiency is variable. We have transfected CMmRNA encoding human T-box transcription factor 18 (CMmTBX18) into heart cells or the left ventricle of rats with atrioventricular block. TBX18 protein expression from CMmTBX18 is weak and transient, but Acriflavine, an Argonaute 2 inhibitor, boosts TBX18 levels. Small RNA sequencing identified two upregulated microRNAs (miRs) in CMmTBX18-transfected cells. Co-administration of miR-1-3p and miR-1b antagomiRs with CMmTBX18 prolongs TBX18 expression in vitro and in vivo and is sufficient to generate electrical stimuli capable of pacing the heart. Different suppressive miRs likewise limit the expression of VEGF-A CMmRNA. Cells therefore resist translation of CMmRNA therapeutic transgenes by upregulating suppressive miRs. Blockade of suppressive miRs enhances CMmRNA expression of genes driving biological pacing or angiogenesis. Such counterstrategies constitute an approach to boost the efficacy and efficiency of CMmRNA therapies., Competing Interests: Declaration of interests The authors report no relevant conflicts., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is one of the most devastating cancers and is characterized by rapid cell proliferation and aggressive invasiveness. Legumain (LGMN), a substrate-specific protease, is associated with poor progression of GBM. Circular RNAs (circRNAs) are aberrantly expressed in various cancers and play crucial roles in tumor progression; however, the functional roles of circRNAs originating from LGMN remain largely unknown in GBM. Herein, we found that hsa_circ_0033009 (circLGMN) was the most abundantly expressed circRNA derived from LGMN. CircLGMN was upregulated in high-grade glioma (HGG), and high expression of circLGMN was associated with poor prognosis in patients with glioma. CircLGMN overexpression promoted GBM cell proliferation and enhanced cell invasion. Mechanistically, circLGMN acts as a sponge for miR-127-3p, and prevents miR-127-3p-mediated degradation of LGMN mRNA, ultimately leading to increased LGMN protein expression. Treatment with miR-127-3p mimic suppressed proliferation and reduced invasion of GBM cells overexpressing circLGMN. Moreover, circLGMN overexpression promoted GBM malignancy in vivo, while miR-127-3p overexpression alleviated this effect. Taken together, circLGMN is a novel tumor-promoting circRNA that acts by sponging miR-127-3p, which ultimately leads to LGMN upregulation. Thus, targeting the circLGMN/miR-127-3p/LGMN axis might be a promising strategy for GBM treatment. More importantly, the discovery of the self-regulatory mechanism of LGMN expression by circLGMN, will facilitate further research on LGMN., (Copyright © 2021. Published by Elsevier B.V.)

Reproductive transition of grasses is characterized by switching the pattern of lateral branches, featuring the suppression of outgrowth of the subtending leaves (bracts) and rapid formation of higher-order branches in the inflorescence (panicle). However, the molecular mechanisms underlying such changes remain largely unknown. Here, we show that bract suppression is required for the reproductive branching in rice. We identified a pathway involving the intrinsic time ruler microRNA156/529, their targets SQUAMOSA PROMOTER BINDING PROTEIN LIKE (SPL) genes, NECK LEAF1 (NL1), and PLASTOCHRON1 (PLA1), which regulates the bract outgrowth and thus affects the pattern switch between vegetative and reproductive branching. Suppression of the bract results in global reprogramming of transcriptome and chromatin accessibility following the reproductive transition, while these processes are largely dysregulated in the mutants of these genes. These discoveries contribute to our understanding of the dynamic plant architecture and provide novel insights for improving crop yields., (Copyright © 2021 The Author. Published by Elsevier Inc. All rights reserved.)

Background: Esophageal cancer (EC) is a common malignancy of the digestive tract, with high incidence. The objective of this study was to investigate the effect of miR-630 expression on esophageal cancer (EC) cell invasion and migration., Methods: The study group comprised 58 EC patients admitted to our hospital from April 2014 to 2016, and the control group comprised 60 healthy people visiting the hospital during the same period. miR-630 levels in the peripheral blood of the two groups were compared, and the diagnostic value of miR-630 for EC was analyzed. EC cell lines were used to evaluate the influence of miR-630 expression on EC cell invasion and migration., Results: miR-630 expression was low in EC (p < 0.050). A receiver operating characteristic curve analysis showed that miR-630 expression had a good diagnostic value for EC (p < 0.050) and was associated with disease course, pathological stage, differentiation degree, tumor metastasis, and patient prognosis and survival (p < 0.05). The ROC curve analysis showed that when cutoff value was 5.38, the diagnostic sensitivity and specificity of miR-630 for EC were 73.33% and 76.67%, respectively; area under the ROC curve was 0.778 (95%CI 0.695-0.861). Transfection of miR-630 into EC cells indicated that miR-630 overexpression can reduce EC cell invasion and migration (p < 0.05). miR-630 expression is low in EC and has good diagnostic value for EC., Conclusion: miR-630 overexpression can reduce EC cell invasion and migration, showing a possible key role of miR-630 in EC diagnosis and treatment in the future., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

MicroRNA (miR)‑744‑5p serves a pivotal role in the progression of multiple cancers; however, the function of miR‑744‑5p in colorectal cancer (CRC) remains largely unknown. In the present study, the effects of miR‑744‑5p on the progression of CRC were analyzed and the mechanisms involved were investigated. It was revealed that miR‑744‑5p was frequently downregulated in CRC tissues and cell lines. Overexpression of miR‑744‑5p significantly inhibited the proliferation, colony formation, and promoted the apoptosis of CRC cells. Bioinformatics analysis revealed that Septin 2 (SEPT2) was a potential target of miR‑744‑5p. miR‑744‑5p bound the 3'‑untranslated region (UTR) of SEPT2 and reduced the level of SEPT2 in CRC cells. A negative correlation between the expression of miR‑744‑5p and SEPT2 was observed in CRC tissues. Overexpression of SEPT2 counteracted the suppressive effect of miR‑744‑5p on the proliferation and apoptosis of CRC cells. Collectively, these data demonstrated the functional mechanism of miR‑744‑5p by targeting SEPT2, which suggested miR‑744‑5p as a potential target for the treatment of patients with CRC.

Pseudogenes, which are long noncoding RNAs that originate from protein-coding genes, have been suggested to play important roles in disease. Although studies have revealed high expression of legumain (LGMN) in many types of tumors, the regulation of LGMN remains largely unknown. Here, we found that a novel LGMN pseudogene (LGMNP1) was upregulated in glioblastoma (GBM) tissues and high LGMNP1 expression in GBM cells enhanced proliferation and invasion. Biochemical analysis showed that cytoplasmic LGMNP1 functionally targeted miR-495-3p in a manner involving an RNA-induced silencing complex. Dual-luciferase reporter assays demonstrated that LGMN was a target of miR-495-3p, and LGMN was upregulated and positively correlated with LGMNP1 in GBM. Moreover, miR-495-3p was downregulated and negatively correlated with LGMNP1 in GBM tissues. Notably, the tumor-promoting effects of LGMNP1 upregulation could be alleviated by miR-495-3p mimics. Furthermore, GBM cells overexpressing LGMNP1 exhibited more aggressive tumor progression and elevated LGMN expression in vivo. Thus, our data illustrate that LGMNP1 exerts its oncogenic activity, at least in part, as a competitive endogenous RNA (ceRNA) that elevates LGMN expression by sponging miR-495-3p. CeRNA-mediated miRNA sequestration might be a novel therapeutic strategy in GBM., (Copyright © 2020. Published by Elsevier B.V.)

Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR-138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7 -/- mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV-loaded anti-miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers., Competing Interests: The authors declare no competing financial interests in relation to the work described., (© 2020 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Although combination antiretroviral therapy (cART) has improved the health of millions of those living with HIV-1 (Human Immunodeficiency Virus, Type 1), the penetration into the central nervous system (CNS) of many such therapies is limited, thereby resulting in residual neurocognitive impairment commonly referred to as NeuroHIV. Additionally, while cART has successfully suppressed peripheral viremia, cytotoxicity associated with the presence of viral Transactivator of transcription (Tat) protein in tissues such as the brain, remains a significant concern. Our previous study has demonstrated that both HIV-1 Tat as well as opiates such as morphine, can directly induce synaptic alterations via independent pathways. Herein, we demonstrate that exposure of astrocytes to HIV-1 protein Tat mediates the induction and release of extracellular vesicle (EV) microRNA-7 (miR-7) that is taken up by neurons, leading in turn, to downregulation of neuronal neuroligin 2 (NLGN2) and ultimately to synaptic alterations. More importantly, we report that these impairments could be reversed by pretreatment of neurons with a neurotrophic factor platelet-derived growth factor-CC (PDGF-CC). Graphical Abstract.

Gastric cancer is the most commonly occurring cancer with a rapidly increasing incidence rate worldwide. The underlying molecular mechanisms of gastric cancer require further investigation. MicroRNAs exhibit tissue sensitivity as tumor biomarkers that play a role by promoting tumor growth as oncogenes or tumor suppressor genes. We evaluated the effects of microRNA-12129 on gastric cancer and identified the underlying mechanisms of microRNA-12129. Quantitative real-time polymerase chain reaction was conducted to determine the expression levels of microRNA-12129 and sirtuin 1 in vivo and in vitro , and Western blot analysis was performed to detect sirtuin 1 at the protein level in gastric cancer cell lines. Cell proliferation and cell cycle progression were detected by Cell Counting Kit-8 assay and flow cytometry analysis, respectively. The potential targets of microRNA-12129 were predicted by bioinformatics analysis. The targets of microRNA-12129 were confirmed by luciferase reporter assay and rescue assay. We found that microRNA-12129 was downregulated in gastric cancer tissues and gastric cancer cell lines and was significantly associated with the prognosis of patients with gastric cancer. In addition, microRNA-12129 overexpression suppressed tumor cell proliferation and blocked cell cycle progression. Bioinformatics analysis and luciferase reporter assay suggested that sirtuin 1 was a target of microRNA-12129, and sirtuin 1 expression was negatively related to microRNA-12129. Restoration of sirtuin 1 partly reduced the inhibition of cell proliferation and cell cycle progression induced by microRNA-144. Our results collectively suggested that microRNA-12129 suppressed cell proliferation and cell cycle progression in gastric cancer by targeting sirtuin 1. These findings indicated that manipulation of microRNA-12129 expression could help develop a novel therapeutic strategy for gastric cancer.

Objective : To develop an effective new method for early detection of pancreatic cancer biomarkers and to aid early clinical diagnosis. Methods : A DNA probe (Probe) capable of specifically recognizing the target miRNA was designed. The specific probe of miRNA 21 is designed first, and then mixed with the miRNA 21 sample to form a complex molecule, and the complex molecule is added to the nanochannels to detect the received signal. The probe is designed to detect the electrical signal by means of pre-matching and post-matching and observe the stability of the signal. The miRNA 21, miRNA 155, miRNA 196a were added to the nano-single channel to detect the characteristic signals and blocking time. The miRNA 21·probe 21 mixture was mixed with other five cancer-associated microRNAs, and the signal results of the detection were collected and compared. Results : The signal of miRNA 21 was successfully detected. Whether the probe is designed at the front or the back, there are two signal results. The Probe should be designed to match the middle region of the miRNA. The three microRNA complex molecules have different characteristic signals and blocking times, which can be effectively distinguished. Conclusion : Nanochannels can effectively detect pancreatic cancer-related microRNAs.

Objective: To investigate the effect of miR-425 on the proliferation and apoptosis of clear cell renal carcinoma (ccRCA) cells, and to explore the underlying mechanism., Patients and Methods: A total of 80 pairs of human clear cell renal carcinoma (ccRCA) and cancer-adjacent normal tissue samples were collected in this study. Human ccRCA cell line (786-O) and normal human kidney cell line (HK-2) were used in cellular research. The expression level of miR-425 was detected in ccRCA tissues and cells, respectively. Target genes of miR-425 were predicted by bioinformatics and verified by luciferase reporter gene assay. Moreover, the role of miR-425 in regulating E2F6 as well as its effect on the proliferation and apoptosis of ccRCA cells were detected., Results: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) results showed that the expression of miR-425 was significantly decreased in ccRCA tissues and cells. The proliferation ability and cell cycle of 786-O cells were significantly inhibited after miR-425 overexpression. The percentage of cells in G0/G1 phase was remarkably increased, while the percentage of cells in S and G2/M phases was significantly decreased. Besides, the number of apoptotic cells was significantly increased in the miR-425 intervention group. On-line target gene prediction software indicated that E2F6 was the potential downstream target gene of miR-425. RT-PCR, Western blotting and luciferase reporter gene assay demonstrated that the expression of E2F6 was negatively regulated by miR-425. In addition, subsequent experiments showed that the up-regulation of E2F6 could suppress the inhibitory effect of miR-425 on the proliferation and apoptosis of ccRCA cells., Conclusions: Our research demonstrated the inhibitory function of miR-425 in ccRCA. Therefore, the miR-425/E2F6 axis was expected to be one of the targets of ccRCA targeted therapy.

Chronic neuroinflammation still remains a common underlying feature of HIV-infected patients on combined anti-retroviral therapy (cART). Previous studies have reported that despite near complete suppression of virus replication by cART, cytotoxic viral proteins such as HIV trans-activating regulatory protein (Tat) continue to persist in tissues such as the brain and the lymph nodes, thereby contributing, in part, to chronic glial activation observed in HIV-associated neurological disorders (HAND). Understanding how the glial cells cross talk to mediate neuropathology is thus of paramount importance. MicroRNAs (miR) also known as regulators of gene expression, have emerged as key paracrine signaling mediators that regulate disease pathogenesis and cellular crosstalk, through their transfer via the extracellular vesicles (EV). In the current study we have identified a novel function of miR-9, that of mediating microglial migration. We demonstrate that miR-9 released from Tat-stimulated astrocytes can be taken up by microglia resulting in their migratory phenotype. Exposure of human astrocytoma (A172) cells to HIV Tat resulted in induction and release of miR-9 in the EVs, which, was taken up by microglia, leading in turn, increased migration of the latter cells, a process that could be blocked by both an exosome inhibitor GW4869 or a specific target protector of miR-9. Furthermore, it was also demonstrated that EV miR-9 mediated inhibition of the expression of target PTEN, via its binding to the 3'UTR seed sequence of the PTEN mRNA, was critical for microglial migration. To validate the role of miR-9 in this process, microglial cells were treated with EVs loaded with miR-9, which resulted in significant downregulation of PTEN expression with a concomitant increase in microglial migration. These findings were corroborated by transfecting microglia with a specific target protector of PTEN, that blocked miR-9-mediated downregulation of PTEN as well as microglial migration. In vivo studies wherein the miR-9 precursor-transduced microglia were transplanted into the striatum of mice, followed by assessing their migration in response to a stimulus administered distally, further validated the role of miR-9 in mediating microglial migration. Collectively, our findings provide evidence that glial crosstalk via miRs released from EVs play a vital role in mediating disease pathogenesis and could provide new avenues for development of novel therapeutic strategies aimed at dampening neuropathogenesis.

Cocaine is known to activate microglia both in vitro and in vivo. High expression of microglial Toll-like receptors (TLRs) and their downstream signal transducers play critical roles in determining microglial activation status. Emerging reports have also demonstrated that cocaine can enhance the strength of TLR signaling. Detailed molecular mechanisms underlying this phenomenon, however, remain elusive. In this study, we investigated the role(s) of miR-124 in regulating microglial TLR4 signaling in the context of cocaine. Herein, we found a dose- and time-dependent upregulation of KLF4 in cocaine-exposed BV-2 cells and rat primary microglial cells (rPMs). KLF4 also identified as a novel 3'-UTR target directly regulated by miR-124. In parallel, miR-124 regulated multiple TLR4 signaling molecules including TLR4, MyD88, TRAF6, and IRAK1. Repeated doses of cocaine (20 mg/kg; i.p.) administration in mice for 7 days further validated the in vitro key findings. Also, miR-124 overexpression significantly blocked the cocaine-mediated upregulation of pro-inflammatory cytokines. In contrast, miR-124 overexpression notably increased the expression of anti-inflammatory mediators in cocaine-exposed microglial cells. Intriguingly, stereotactic administration of lentivirus-miR-124 in the striatum significantly inhibited cocaine-mediated microglial activation and locomotor hyperactivity in vivo. In summary, these findings implicate the role of miR-124 in regulating TLR4 signaling, thereby indicating a new pathway responsible for cocaine-mediated microglial activation.

SRY-box 9 (SOX9) is an important transcription factor required for development, which has additionally been reported to be an independent prognostic indicator for the survival of patients with non‑small cell lung cancer (NSCLC). Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs/miRs) may contribute to the initiation and progression of cancer. SOX9 may be regulated by a number of miRNAs in different types of cancer, including in NSCLC. The present study sought to identify novel candidate miRNAs associated with SOX9 in NSCLC using online tools, and investigated the detailed functions of miR‑185, which suppressed SOX9 mRNA expression most strongly out of the candidate miRNAs. It was observed that ectopic miR‑185 expression significantly suppressed NSCLC cell proliferation, invasion and migration. Using luciferase reporter gene and RNA immunoprecipitation assays, SOX9 was confirmed to be a direct target of miR‑185. In addition, the downstream Wnt signaling‑associated factors β‑catenin and c‑Myc proto‑oncogene protein (Myc) were demonstrated to be inhibited by miR‑185 overexpression. SOX9, β‑catenin and c‑Myc mRNA expression was significantly upregulated in NSCLC tissues, and was inversely correlated with miR‑185 expression. The results of the present study demonstrated that rescuing miR‑185 expression in NSCLC, thereby inhibiting SOX9 expression and the downstream Wnt signaling, and leading to the suppression of NSCLC cell proliferation, invasion and migration, may be a promising strategy for the treatment of NSCLC.

Astrocyte activation is a hallmark of HIV infection and aging in the CNS. In chronically infected HIV patients, prolonged activation of astrocytes has been linked to accelerated aging including but not limited to neurocognitive impairment and frailty. The current study addresses the role of HIV protein Tat in inducing a set of small noncoding microRNAs (miRNA) that play critical role in astrogliosis. In our efforts to link astrocyte activation as an indicator of aging, we assessed the brains of both wild type and HIV transgenic rats for the expression of glial fibrillary acidic protein (GFAP). As expected, in the WT animals we observed age-dependent increase in astrogliosis in the older animals compared to the younger group. Interestingly, compared to the young WT group, young HIV Tg rats exhibited higher levels of GFAP in this trend was also observed in the older HIV Tg rats compared to the older WT group. Based on the role of SIRT1 in aging and the regulation of SIRT1 by miRNAs-34a and -138, we next assessed the expression levels of these miRs in the brains of both the young an old WT and HIV Tg rats. While there were no significant differences in the young WT versus the HIV Tg rats, in the older HIV Tg rats there was a significant upregulation in the expression of miRs-34a & -138 in the brains. Furthermore, increased expression of miRs-34a & -138 in the older Tg rats, correlated with a concomitant decrease in their common anti-aging target protein SIRT1, in the brains of these animals. To delineate the mechanism of action we assessed the role of HIV-Tat (present in the Tg rats) in inducing miRs-34a & -138 in both the primary astrocytes and the astrocytoma cell line A172, thereby leading to posttranscriptional suppression of SIRT1 with a concomitant up regulation of NF-kB driven expression of GFAP.

Neuroinflammation plays a critical role in the development of reward-related behavior in cocaine self-administration rodents. Cocaine, one of most commonly abused drugs, has been shown to activate microglia both in vitro and in vivo. Detailed molecular mechanisms underlying cocaine-mediated microglial activation remain poorly understood. microRNAs (miRs) belonging to a class of small noncoding RNA superfamily have been shown to modulate the activation status of microglia. miR-124, one of the microglia-enriched miRs, functions as an anti-inflammatory regulator that maintains microglia in a quiescent state. To date, the possible effects of cocaine on microglial miR-124 levels and the associated underlying mechanisms have not been explored. In the current study, we demonstrated that cocaine exposure decreased miR-124 levels in both BV-2 cells and rat primary microglia. These findings were further validated in vivo, wherein we demonstrated decreased abundance of miR-124 in purified microglia isolated from cocaine-administered mice brains compared with cells from saline administered animals. Molecular mechanisms underlying these effects involved cocaine-mediated increased mRNA and protein expression of DNMTs in microglia. Consistently, cocaine substantially increased promoter DNA methylation levels of miR-124 precursors (pri-miR-124-1 and -2), but not that of pri-miR-124-3, both in vitro and in vivo. In summary, our findings demonstrated that cocaine exposure increased DNA methylation of miR-124 promoter resulting into its downregulation, which, in turn, led to microglial activation. Our results thus implicate that epigenetic modulation of miR-124 could be considered as a potential therapeutic approach to ameliorate microglial activation and, possibly, the development of cocaine addiction.

The role of microRNAs (miRNAs) in regulating innate immune response to Candida albicans infection in Caenorhabditis elegans is still largely unclear. Using small RNA SOLiD deep sequencing technique, we profiled the miRNAs that were dysregulated by C. albicans infection. We identified 16 miRNAs that were up-regulated and 4 miRNAs that were down-regulated in nematodes infected with C. albicans. Bioinformatics analysis implied that these dysregulated miRNAs may be involved in the control of many important biological processes. Using available mutants, we observed that mir-251 and mir-252 loss-of-function mutants were resistant to C. albicans infection, whereas mir-360 mutants were hypersensitive to C. albicans infection. The expression pattern of antimicrobial genes suggested that mir-251, mir-252, and mir-360 played crucial roles in regulating the innate immune response to C. albicans infection. Fungal burden might be closely associated with altered lifespan and innate immune response in mir-251, mir-252, and mir-360 mutants. Moreover, mir-251 and mir-252 might function downstream of p38 mitogen activated protein kinase (MAPK) or IGF-1/insulin-like pathway to regulate the innate immune response to C. albicans infection. Our results provide an important molecular basis for further elucidating how miRNA-mRNA networks may control the innate immune response to C. albicans infection.

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate protein biosynthesis and participate in the pathogenesis of various tumours. Previous studies have shown that miR-210 is highly expressed in different types of human cancers, including glioblastoma multiforme (GBM). However, the role that miR-210 plays in GBM remains unclear. Here, we detected the expression and examined the function of miRNA-210 in GBM cells. Furthermore, we investigated the possible molecular mechanisms by which miRNA-210 mediates cell proliferation and apoptosis. Fifteen GBM and five normal brain tissues, in addition to the U87MG and U251 GBM cell lines, were analysed in this study. We found that miR-210 was upregulated in GBM tissues and cell lines when compared to normal brain tissue. Cell counting and flow cytometric assay results demonstrated that upregulation of miR-210 induced cell proliferation and decreased cell apoptosis, respectively. In addition, downregulation of miR-210 inhibited cell proliferation and induced apoptosis. We also detected a miR-210 target, regulator of differentiation 1 (ROD1), which is involved in GBM progression. Knockdown of ROD1 reversed the growth arrest and apoptosis that were originally induced by miR-210 inhibition. We propose that miR-210 regulates cell proliferation and apoptosis in GBM cells by targeting ROD1. Our findings may provide a new potential therapeutic target for the treatment of GBM.

Microglia participate in innate inflammatory responses within the central nervous system. The highly conserved microRNA-9 (miR-9) plays critical roles in neurogenesis as well as axonal extension. Its role in microglial inflammatory responses, however, remains poorly understood. Here we identify a unique role of miR-9 in mediating the microglial inflammatory response via distinct signalling pathways. MiR-9-mediated regulation of cellular activation involved downregulated expression of the target protein, monocyte chemotactic protein-induced protein 1 (MCPIP1) that is crucial for controlling inflammation. Results indicate that miR-9-mediated cellular activation involved signalling via the NF-κB pathway, but not the β-catenin pathway.

MicroRNA-155 is highly expressed in many malignant tumors with poor prognosis, which regulates cell apoptosis, proliferation, invasion, metastasis, tumor angiogenesis, and metabolism. This study aims at investigating the clinical significance of miR-155 expression in human gliomas. Real-time quantitative PCR was used to detect the expression levels of miR-155 in 131 glioma and 16 normal brain tissues. The association of miR-155 expression with clinicopathological factors and prognosis of glioma patients were analyzed. The expression levels of miR-155 were significantly higher in glioma tissues than that in normal brain tissues (P < 0.001), which was associated with high pathological grade (P < 0.001) and low Karnofsky Performance Status score (P = 0.022). As a result of Kaplan-Meier survival and Cox regression analyses, overall survival (OS) rates and progression-free survival were significantly poorer in high-expression group relative to low-expression group (both P < 0.001). Furthermore, miR-155 expression was significantly associated with poor OS (P < 0.001) and PFS (P = 0.001) in glioma patients who had high pathological grades (III-IV) as calculated by subgroup analyses. These findings reveal that miR-155 expression might be an independent prognostic factor and a therapeutic target for human glioma.

Rongxin Zhang,1,2 Zhao Hou,2 Kexin Liao,2 Chao Yu,2 Rongrong Jing,1,2 Caixia Tu1,2 1Institute of Integrative Medicine, Dalian Medical University, Dalian, 116044, People’s Republic of China; 2Department of Dermatology, The Second Hospital of Dalian Medical University, Dalian, 116027, People’s Republic of ChinaCorrespondence: Caixia Tu, Department of Dermatology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian, 116027, People’s Republic of China, Tel +8617709872288, Fax +86 411 84672130, Email tucx2010@sina.comPurpose: Circular RNAs (circRNAs) are abundant, stable, and evolutionarily conserved noncoding RNAs with impacts on cell proliferation, differentiation, invasion, apoptosis, and immunity by acting as an miRNA sponge. This study aimed to investigate the expression of circRNAs in vitiligo and analyze the differentially expressed circRNAs (DEcircRNAs) bioinformatically.Patients and Methods: Biopsies of five lesional and five nonlesional skins of patients with vitiligo and five healthy skins (control) were harvested in this study. The expression profiles of circRNAs and DEcircRNAs were determined by microarray analysis and qRT-PCR. Bioinformatics analysis was used to predict target genes of DEcircRNAs binding to miRNAs and their underlying functions. Meanwhile, a competing endogenous RNA (ceRNA) network was constructed using Cytoscape.Results: A total of 817 and 508 DEcircRNAs were identified in lesional and nonlesional skins of patients with vitiligo, respectively. The results of hsa_circRNA_000957 and hsa_circRNA_101798 validation were consistent with our microarray analysis. Furthermore, 32 miRNA response elements (MREs) and related target genes of DEcircRNAs were identified, whose main functions were involved in the pathogenesis of vitiligo. Hsa_circRNA_000957 and hsa_circRNA_101798 might be candidate biomarkers for vitiligo.Conclusion: This study provides scientific clues for understanding the mechanism of vitiligo.Keywords: vitiligo, circular RNAs, microRNAs, miRNA response element, ceRNA