Effects of exercise on microRNA expression in young males peripheral blood mononuclear cells

MicroRNAs are increasingly seen as targets of drug discovery because they influence gene function acting both to silence and subtly modulate protein translation. Little is known about effects of dynamic physiological states on microRNA regulation in humans. We hypothesized that microRNA expression in peripheral blood mononuclear cells (PBMCs) would be affected by brief exercise. Twelve young men performed brief bouts of heavy exercise. PBMC microRNA was analyzed before and immediately after exercise using the Agilent Human microRNA V2 Microarray. Exercise altered expression level of 34 microRNAs (FDR < 0.05). Many of them play roles in inflammatory processes (e.g., miR-125b[↓], down-regulated by proinflammatory factor LPS; and miR-132[↑], 125b[↓] and let-7e[↓] involved inTLR4 signaling). Using previous exercise data in PBMCs, we linked the microRNA changes to specific gene pathways. This analysis identified 12 pathways including the TGF-β and MAPK signaling. We also compared exercise-associated microRNA changes in PBMCs with the exercise-associated microRNAs previously identified in neutrophils. Nine microRNAs were affected in both PBMCs and neutrophils, but only six changed in the same direction. A commonly occurring physiologic perturbation, brief heavy exercise, changes microRNA profiles in PBMCs, many of which are related to inflammatory processes. The pattern of change suggests that exercise differentially influences microRNAs in leukocyte subtypes.     

Regulation of circadian behavioural output via clock-responsive miR-276b

Growing evidence indicates that microRNAs play numerous important roles. However, the roles of some microRNAs involved in regulation of circadian rhythm and sleep are still not well understood. In this study, we show that the miR-276b is essential for maintaining both sleep and circadian rhythm by targeting tim, npfr1 and DopR1 genes, with miR-276b deleted mutant flies sleeping more, and vice versa in miR-276b overexpressing flies. Through analysing its promoter, we found that mir-276b is responsive to CLOCK and regulates circadian rhythm through the negative feedback loop of the CLK/CYC-TIM/PER. Furthermore, miR-276b is broadly expressed in the clock neurons and the central complexes such as the mushroom body and the fan-shape body of Drosophila brain, in which up-regulation of miR-276b in tim, npfr1 and DopR1 expressing tissues significantly causes sleep decreases. This study clarifies that the mir-276b is very important for participating in regulation of circadian rhythm and sleep.     

Three new circulating microRNAs may be associated with wet age-related macular degeneration

Abstract

This study investigates the circulating microRNA (miRNA) expression profiles in patients with age-related macular degeneration (AMD) and the role of miRNA in wet AMD and its pathways. Exosomes were extracted from serum samples of AMD patients (n?=?70) and a control group (n?=?50). After isolating miRNA from the exosomes, miRNAs were transformed into cDNA. In the control and AMD samples, the expression was compared with a panel including 175 genes using the PCR array method. Target genes and pathways of miRNAs were detected by KEGG and Biocarta signaling pathway enrichments. Comparing the serum samples between groups revealed that the expression levels of 15 microRNAs within 175 genes had significantly changed. In the validation studies, miR-129-3p and miR-132-3p had no significant expression in AMD group compared to the controls. miR-486-5p and miR-626 had higher expression in AMD patients compared to the control group, while miR-885-5p showed significantly lower expression. Pathway analysis revealed that these miRNAs may have critical roles in the apoptosis and neovascularization pathways. The data suggest that some miRNAs within the serum may have a role in the pathogenesis of wet AMD. Further studies are needed to examine the use of these miRNAs as biomarkers.     

KITENIN-targeting MicroRNA-124 Suppresses Colorectal Cancer Cell Motility and Tumorigenesis

MicroRNAs are increasingly implicated in the modulation of the progression of various cancers. We previously observed that KAI1 C-terminal interacting tetraspanin (KITENIN) is highly expressed in sporadic human colorectal cancer (CRC) tissues and hence the functional KITENIN complex acts to promote progression of CRC. However, it remains unknown that microRNAs target KITENIN and whether KITENIN-targeting microRNAs modulate CRC cell motility and colorectal tumorigenesis. Here, through bioinformatic analyses and functional studies, we showed that miR-124, miR-27a, and miR-30b negatively regulate KITENIN expression and suppress the migration and invasion of several CRC cell lines via modulation of KITENIN expression. Through in vitro and in vivo induction of mature microRNAs using a tetracycline-inducible system, miR-124 was found to effectively inhibit the invasion of CT-26 colon adenocarcinoma cells and tumor growth in a syngeneic mouse xenograft model. Constitutive overexpression of precursor miR-124 in CT-26 cells suppressed in vivo tumorigenicity and resulted in decreased expression of KITENIN as well as that of MYH9 and SOX9, which are targets of miR-124. Thus, our findings identify that KITENIN-targeting miR-124, miR-27a, and miR-30b function as endogenous inhibitors of CRC cell motility and demonstrate that miR-124 among KITENIN-targeting microRNAs plays a suppressor role in colorectal tumorigenesis.     

Expression profile of plasma microRNAs in nonsyndromic cleft lip and their clinical significance as biomarkers

ObjectiveThe aim of this study was to determine the expression profile of plasma microRNAs in nonsyndromic cleft lip (NSCL) and their clinical significance as biomarkers.MethodsAgilent human miRNA microarray chips were used to analyze three NSCL plasma samples (mixed as CL group) and three normal plasma samples (mixed as Control group). Six selected plasma miRNAs were validated using qRT-PCR between another 13 CL and 11 healthy children. The receiver operating characteristic (ROC) curve analysis was applied for three elevated miRNAs, miR-16-2-3p, miR-365a-3p and miR-877-5p. Their target genes were further assessed using gene ontology and pathway analysis.ResultsThe plasma miRNA differentially expressed (fold change ≥2) amounted to 305. In particular, it had been validated that miR-16-2-3p, miR-365a-3p and miR-877-5p were elevated in NSCL plasma samples. ROC curve analysis revealed that each microRNA was able to significantly discriminate NSCL subjects from normal controls. Gene ontology and pathway analysis revealed that many processes over-represented in CL are related to system development process, regulation of nitrogen compound metabolic process, FoxO signaling pathway and the ErbB signaling pathway.ConclusionOur study demonstrated that plasma miR-16-2-3p, miR-365a-3p and miR-877-5p might become biomarkers to diagnose NSCL and dysregulation of these miRNAs might be involved in the progression of NSCL.     

肝癌转移和预后相关的miRNA

microRNA(miRNA)是近年来发现的一类长度约为20～25个核苷酸的具有转录后调节功能的非编码单链的小分子RNA.研究发现miR-21、miR-34a、miR-9、miR-151与肝癌转移密切相关,而miR-122、miR-221和miR-125等影响肝癌预后.     

MicroRNAs as potential target gene in cancer gene therapy of gastrointestinal tumors

Introduction: MicroRNA (miRNA) is a small non-coding RNA, which negatively regulates the expression of many target genes, thereby contributing to the modulation of diverse cell fates. Recent advances in molecular biology have revealed the potential role of miRNAs in tumor initiation, progression and metastasis. Aberrant regulation of miRNAs has been frequently reported in a variety of cancers, including gastrointestinal tumors, suggesting that cancer-related miRNAs are promising as novel biomarkers for tumor diagnosis and are potential target genes for cancer gene therapy against gastrointestinal tumors.

Areas covered: The review focuses on the role of specific miRNAs (miR-192/194/215 and miR-7) in the differentiation of gastrointestinal epithelium and on the role of tumor-suppressive (miR-34, miR-143, miR-145) and oncogenic miRNAs (miR-21, miR-17-92 cluster) in gastrointestinal tumors. Furthermore, the potential role of miRNAs as novel biomarkers and target genes for cancer gene therapy against gastrointestinal tumors are discussed. We will also outline the potential clinical application of miRNAs for tumor diagnosis and cancer gene therapy against gastrointestinal tumors.

Expert opinion: Exploration of tumor-related miRNAs would provide important opportunities for the development of novel cancer gene therapies aimed at normalizing the critical miRNAs that are deregulated in gastrointestinal tumors.     

Therapeutic Effects of MicroRNA-582-5p and -3p on the Inhibition of Bladder Cancer Progression

Many reports have indicated that the abnormal expression of microRNAs (miRNAs) is associated with the progression of disease and have identified miRNAs as attractive targets for therapeutic intervention. However, the bifunctional mechanisms of miRNA guide and passenger strands in RNA interference (RNAi) therapy have not yet been clarified. Here, we show that miRNA (miR)-582-5p and -3p, which are strongly decreased in high-grade bladder cancer clinical samples, regulate tumor progression in vitro and in vivo. Significantly, the overexpression of miR-582-5p or -3p reduced the proliferation and invasion of UM-UC-3 human bladder cancer cells. Furthermore, transurethral injections of synthetic miR-582 molecule suppressed tumor growth and metastasis in an animal model of bladder cancer. Most interestingly, our study revealed that both strands of miR-582-5p and -3p suppressed the expression of the same set of target genes such as protein geranylgeranyltransferase type I beta subunit (PGGT1B), leucine-rich repeat kinase 2 (LRRK2) and DIX domain containing 1 (DIXDC1). Knockdown of these genes using small interfering RNA (siRNA) resulted in the inhibition of cell growth and invasiveness of UM-UC-3. These findings uncover the unique regulatory pathway involving tumor suppression by both strands of a single miRNA that is a potential therapeutic target in the treatment of invasive bladder cancer.     

MiR-522 contributes to cell proliferation of human glioblastoma cells by suppressing PHLPP1 expression

Previous studies have shown that microRNAs play essential roles in cancer growth and progression. Although a number of microRNAs were differentially expressed in glioblastoma (GBM). In this study, we evaluated the miR-522s role in cell proliferation in GBM. Expression of miR-522 is markedly upregulated in GBM tissues and GBM cells compared with the matched non-tumor adjacent brain tissues (TAT) and normal human astrocytes (NHAs). In functional assays, miR-522 promoted GBM cell proliferation, which could be reversed by inhibitor of miR-522. We further identified PH domain leucine-rich repeats protein phosphatase-1 (PHLPP1) as a putative target of miR-522, which is likely a main contributor to the promotion of tumor cell growth observed in our assays. Our results demonstrated that miR-522 promoted tumor cell proliferation and hence may represent a novel therapeutically relevant cellular target to treatment of GBM patients.     

MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell proliferation and migration

microRNAs (miRNA, miR) play an important role in cancer cell growth and migration; however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. By applying a miRNA microarray platform and unsupervised hierarchical clustering analysis, we found that several miRNAs have altered expression levels in osteosarcoma cell lines and tumor tissues when compared with normal human osteoblasts. Three miRNAs, miR-199a-3p, miR-127-3p, and miR-376c, were significantly decreased in osteosarcoma cell lines, whereas miR-151-3p and miR-191 were increased in osteosarcoma cell lines in comparison with osteoblasts. Transfection of precursor miR-199a-3p into osteosarcoma cell lines significantly decreased cell growth and migration, thus indicating that the inhibition effect is associated with an increase in the G(1)-phase and a decrease of the S-phase cell population. In addition, we observed decreased mTOR and Stat3 expression in miR-199a-3p transfected cells. This study provides new insights for miRNAs in osteosarcoma and suggests that miR-199a-3p may play a functional role in osteosarcoma cell growth and proliferation. Restoring miR-199a-3p's function may provide therapeutic benefits in osteosarcoma.     

Therapeutic strategies for human microsporidia infections

Over the past 20 years, microsporidia have emerged as a cause of infectious diseases in AIDS patients, organ transplant recipients, children, travelers, contact lens wearers and the elderly. Enterocytozoon bieneusi and the Encephalitozoon spp., Encephalitozoon cuniculi, Encephalitozoon hellem and Encephalitozoon intestinalis, are the most frequently identified microsporidia in humans, and are associated with diarrhea and systemic disease. The microsporidia are small, single-celled, obligately intracellular parasites that have been identified in water sources, as well as in wild, domestic and food-producing farm animals, thereby raising concerns for waterborne, foodborne and zoonotic transmission. Current therapies for microsporidiosis include albendazole, a benzimidazole that inhibits microtubule assembly and is effective against several microsporidia, including the Encephalitozoon spp., although it is less effective against Encephalitozoon bieneusi. Fumagillin, an antibiotic and antiangiogenic compound produced by Aspergillus fumigatus, is more broadly effective against Encephalitozoon spp. and E. bieneusi; however, is toxic when administered systemically to mammals. Recent studies are also focusing on compounds that target the microsporidia polyamines (e.g., polyamine analogs), methionine aminopeptidase 2 (e.g., fumagillin-related compounds), chitin inhibitors (e.g., nikkomycins), topoisomerases (e.g., fluoroquinolones) and tubulin (e.g., benzimidazole-related compounds).     

Clinical verification of a novel urinary microRNA panal: 133b, -342 and -30 as biomarkers for diabetic nephropathy identified by bioinformatics analysis

BackgroundBecause microvascular disease is one of the major drivers of diabetic complications, early detection of diabetic nephropathy (DN) by assessing the expression of exosomal microRNAs (miRNAs) in DN patients and healthy controls, may be of clinical value. The aim of this study wasto identify a novel miRNA panel of DN by combining bioinformatics analysis of miRNA databases and clinical verification to evaluate the significance of this panel as urine biomarkers for type 2 diabetic nephropathy (T2DN).Patients and MethodsPublic miRNA databases e.g miro-Ontology and miRWalk were analyzed and a novel panel of 3 microRNAs was retrieved. Meanwhile, combinatorial target prediction algorithms were applied. Multiple case-matched normal were examined by quantative RT-PCR for differential expression in urine exosomes from 210 participants, and the three identified miRNAs were validated as DN biomarkers.ResultsWe found urinary exosomalmiR-133b, miR-342, and miR-30a were expressed at significantly elevated levels in T2DN patients (P < 0.001) compared to normal. Furthermore, high-level expression of the 3 miRNAs was associated withHbA1c,systolic-diastolic blood pressure, LDL, serum creatinine, urinary albumin creatinine ratio and estimated glomerular filtration rate(eGFR). Moreover, 39.3%, 19.6% and 17.9% of patients with normo-albuminuria had positive (miR-133b, miR-342 and miR-30a, respectively); indicating the possibility of molecular changes in these patients before onset of albuminuria.ConclusionWe have identified novel urinary exosomal miRNA biomarkers of DN which were altered not only in micro and macroalbuminuric groups but also in some normoalbuminuria cases prior to albuminuria.     

Uncommon yeast infections in hematological patients: from diagnosis to treatment

Invasive fungal diseases have been recognized with increasing frequency as major pathogens in patients with cancer over the past few decades, as a result of new and more aggressive anticancer treatments and supportive care, and this has been especially reported for patients suffering from hematological malignancies. In these settings, typically uncommon yeasts and filamentous fungi have recently emerged as significant human pathogens, frequently as breakthrough infections in patients receiving empirical antifungal therapy or antifungal prophylaxis and with reported high crude mortality rates. The aim of this article is to discuss certain aspects of the approach to invasive fungal diseases due to uncommon yeasts (e.g., Trichosporon spp., Blastomyces spp. and Cryptococcus spp.) in patients with hematological malignancies, focusing on epidemiology, diagnosis, treatment outcomes and the role of novel antifungal drugs (i.e., new triazoles and echinocandins).