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1.
Mol Ther Nucleic Acids ; 18: 16-23, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31479921

RESUMO

Among the large number of known microRNAs (miRNAs), some miRNAs play negligible roles in cell regulation. Therefore, selecting essential miRNAs is an important initial step for a deeper understanding of miRNAs and their functions. In this study, we generated 60 classification models by combining 12 representative feature extraction methods and 5 commonly used classification algorithms. The optimal model for essential miRNA classification that we obtained is based on the Mismatch feature extraction method combined with the random forest algorithm. The F-Measure, area under the curve, and accuracy values of this model were 93.2%, 96.7%, and 93.0%, respectively. We also found that the distribution of the positive and negative examples of the first few features greatly influenced the classification results. The feature extraction methods performed best when the differences between the positive and negative examples were obvious, and this led to better classification of essential miRNAs. Because each classifier's predictions for the same sample may be different, we employed a novel voting method to improve the accuracy of the classification of essential miRNAs. The performance results showed that the best classification results were obtained when five classification models were used in the voting. The five classification models were constructed based on the Mismatch, pseudo-distance structure status pair composition, Subsequence, Kmer, and Triplet feature extraction methods. The voting result was 95.3%. Our results suggest that the voting method can be an important tool for selecting essential miRNAs.

2.
Gene ; 711: 143948, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31255737

RESUMO

The incidence of atherosclerosis is greatly increased, which becomes the leading cause for the death and disability worldwide. Endothelial cells dysfunction plays a substantial role in the pathogenesis of atherosclerosis. MicroRNA-148a-3p (miR-148a-3p) and circular RNA 0003575 (circ_0003575) modulated lipid metabolism and proliferative function of endothelial cells, respectively. However, the role of them in modulation of endothelial cell function and progression of atherosclerosis remains unknown. Endothelial cells were isolated from the aorta of Apoe-/- mice. miR-148a-3p in atherosclerosis patients and healthy controls were measured by qRT-PCR. Overexpression and knockdown of miR-148a-3p in endothelial cells were established. The proliferation, migration and apoptosis of endothelial cells were measured by MTT, Transwell, and fluorescence microscope, respectively. Online software (miRWalk 2.0 and RegRNA2.0) and databases (miRWalk, miRanda, RNA22, and Targetscan) were used to predict potential target genes of miR-148a-3p and circ_0003575. The expression of target genes was detected through western blotting. The expression of miR-148a-3p was significantly upregulated in patients with atherosclerosis as relative to healthy people. Overexpression of miR-148a-3p exhibited stimulatory effects on endothelial cell proliferation and migration and inhibited programmed cell death. Six intersection target genes, c-MAF, FOXO4, FOXO3, MITF, ETV7, and CRX, were predicted between miR-148a-3p and circ_0003575. The opposite effects of circ_0003575 and miR-148a-3p on the expression of FOXO4 and FOXO3, which are essential for lipid metabolism. We demonstrate that miR-148a-3p suppresses FOXO4 and FOXO3 expression via interruption of circ_0003575 function, which in turn impairs the proliferative and migratory function of endothelial cells, eventually exacerbating the atherosclerosis.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/genética , Células Endoteliais/citologia , Proteína Forkhead Box O3/metabolismo , MicroRNAs/genética , RNA/genética , Fatores de Transcrição/metabolismo , Regulação para Cima , Animais , Apolipoproteínas E/genética , Apoptose , Aterosclerose/metabolismo , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Proteína Forkhead Box O3/genética , Redes Reguladoras de Genes , Humanos , Metabolismo dos Lipídeos , Camundongos , Fatores de Transcrição/genética
3.
Metab Brain Dis ; 34(5): 1355-1363, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31134481

RESUMO

Accumulation of extracellular amyloid-ß (Aß) in hippocampal subregions is a hallmark of Alzheimer's disease (AD), which promotes neuronal apoptosis, potentiates cognitive decline and play a causative role in AD pathogenesis. However, whether this process is controlled by distinct miRNAs at the posttranscriptional level remain fascinating but poorly understood. Using post mortem hippocampal samples from human AD patients and 3xTg-AD mouse, we demonstrate that miR-342-3p expression was significantly induced during the AD development. With the aid of intrahippocampal injection of miR-342-3p antagomir, we further show that in vivo miR-342-3p inhibition synergistically improved cognitive deficits in 3xTg-AD mice. The hippocampal Aß-plaque burden in 3xTg-AD mice, as revealed by immunohistochemical analysis with 4G8 antibody, was attenuated also. Mechanistically, the upregulation of neuronal miR-342-3p is linked to an increase in the activation of the stress kinase c-Jun N-terminal kinase with the subsequent death of the neurons in Aß-challenged HT22 hippocampal neuronal cells. These findings support the model that derangement of hippocampus signal transduction and subsequent neuronal apoptosis in AD arises as a consequence of increased Aß burden and chronic activation of the JNK MAPK cascade in a miR-342-3p-dependent manner. Overall, we described for the first time the regulatory activity of miR-342-3p on relevant Aß metabolism pathways in Alzheimer's disease.

4.
J Cell Biochem ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485526

RESUMO

Bone morphogenetic protein (BMP)2/7 heterodimer shows greater efficacy in enhancing bone regeneration. However, the precise mechanism and the role of mitogen-activated protein kinase (MAPK) signaling network in BMP2/7-driven osteogenesis remain ambiguous. In this study, we evaluated the effects of BMP2/7 heterodimers on osteoblastic differentiation in rat bone marrow mesenchymal stem cells (BMSCs), with the aim to elaborate how MAPKs might be involved in this cellular process by treatment of rat BMSCs with BMP2/-7 with a special signal-pathway inhibitor. We found that BMP2/7 heterodimer induced a much stronger osteogenic response in rat BMSCs compared with either homodimer. Most interestingly, extracellular signal-regulated kinase (ERK) demonstrated a highly sustained phosphorylation and activation in the BMP2/7 heterodimer treatment groups, and inhibition of ERK cascades using U0126 special inhibitor that significantly reduced the activity of ALP and calcium mineralization to a substantial degree in rat BMSCs treated with BMP2/7 heterodimers. Collectively, we demonstrate that BMP2/7 heterodimer shows a potent ability to stimulate osteogenesis in rat BMSCs. The activated ERK signaling pathway involved in this process may contribute partially to an increased osteogenic potency of heterodimeric BMP2/7 growth factors.

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