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1.
Biochemistry (Mosc) ; 84(10): 1197-1203, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694515

RESUMO

Here, we suggested that the epigenetic mechanism of benzo(a)pyrene (BP) action might be based on the aryl hydrocarbon receptor (AhR)-mediated transcription of the target genes, including miRNAs, that have the dioxin response element (DRE) in their promoters. The effect of BP on the expression of the oncogenic miR-483-3p, its host gene IGF2, and target gene IGF1 in primary hepatocytes and in the liver of Wistar female rats was investigated. The activation of AhR was confirmed using selective AhR inhibitor CH-223191 and by evaluating expression of the target CYP1A1 gene. The lack of coordination between the expression of miR-483-3p and its host gene IGF2 was revealed, which may be due to the presence of the binding site for the estrogen receptor alpha (ERα), which is a negative expression regulator. Our results confirm the existence of the AhR-mediated pathway in the regulation of expression of miR-483-3p, IGF1, and IGF2 under BP exposure, which is of considerable interest for understanding the epigenetic mechanisms of the carcinogenic effect of BP.


Assuntos
Benzo(a)pireno/farmacologia , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , Animais , Células Cultivadas , Biologia Computacional , Feminino , Hepatócitos/metabolismo , Fígado/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar
2.
Life Sci ; 235: 116842, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494170

RESUMO

MicroRNAs plays important role in the development of myocardial infarction (MI). The aim of this study was to analyze whether miR-429 has effect on the process of autophagy in myocardial anoxia/reoxygenation (AR) or ischemia/reperfusion (IR) injury and explore the underlying mechanism. The results showed that miR-429 was significantly decreased in MI mouse hearts and AR treated cardiomyocytes. Dual luciferase activity assay proved that MO25 was the direct target of miR-429. MO25 was dramatically decreased in AR treated cardiomyocytes. Overexpression of miR-429 dramatically decreased the expression of MO25, whereas inhibition of miR-429 noticeably increased the expression of MO25. In addition, overexpression of miR-429 reduced GFP-LC3B labelled cells, decreased the number of vesicle and autophagosome in each cardiomyocyte, and induced cell apoptosis in AR treated cardiomyocytes. In contrast, inhibition of miR-429 had the opposite effect. The further in vivo study showed that when mouse in IR group were injected with antagomiR-429, the weight of left ventricular was increased and infarct size was significantly decreased. Finally, both the in vitro and in vivo study showed that the expression of MO25, LKB1, pAMPKa, ATG13, p62 and LC3BI/II was noticeably increased by antagomiR-429. In conclusion, our results suggested that antagonism of miR-429 ameliorates anoxia/reoxygenation injury in cardiomyocytes by enhancing MO25/LKB1/AMPK mediated autophagy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Hipóxia/metabolismo , MicroRNAs/antagonistas & inibidores , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagossomos/efeitos dos fármacos , Contagem de Células , Vesículas Citoplasmáticas/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Camundongos , MicroRNAs/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Traumatismo por Reperfusão Miocárdica , Miocárdio/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
3.
Life Sci ; 235: 116862, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31513814

RESUMO

Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3'-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis.


Assuntos
Angiotensina II/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Hipertensão/genética , Hipertensão/prevenção & controle , MicroRNAs/antagonistas & inibidores , Adipocinas/sangue , Angiotensina II/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo/efeitos dos fármacos , Endotelina-1/sangue , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , L-Lactato Desidrogenase/metabolismo , Masculino , MicroRNAs/agonistas , MicroRNAs/biossíntese , MicroRNAs/genética , Óxido Nítrico/sangue , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
4.
Curr Top Med Chem ; 19(21): 1918-1947, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393249

RESUMO

microRNAs (miRNAs) are an evolutionarily conserved class of small single-stranded noncoding RNAs. The aberrant expression of specific miRNAs has been implicated in the development and progression of diverse cardiovascular diseases. For many decades, miRNA therapeutics has flourished, taking advantage of the fact that miRNAs can modulate gene expression and control cellular phenotypes at the posttranscriptional level. Genetic replacement or knockdown of target miRNAs by chemical molecules, referred to as miRNA mimics or inhibitors, has been used to reverse their abnormal expression as well as their adverse biological effects in vitro and in vivo in an effort to fully implement the therapeutic potential of miRNA-targeting treatment. However, the limitations of the chemical structure and delivery systems are hindering progress towards clinical translation. Here, we focus on the regulatory mechanisms and therapeutic trials of several representative miRNAs in the context of specific cardiovascular diseases; from this basic perspective, we evaluate chemical modifications and delivery vectors of miRNA-based chemical molecules and consider the underlying challenges of miRNA therapeutics as well as the clinical perspectives on their applications.


Assuntos
Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , MicroRNAs/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Bibliotecas de Moléculas Pequenas/química
5.
Bioengineered ; 10(1): 345-352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411110

RESUMO

This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Ontologia Genética , Histona Desacetilase 1/sangue , Histona Desacetilase 1/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Anotação de Sequência Molecular , Análise Multivariada , Proteínas de Neoplasias/sangue , Prognóstico , Curva ROC , Recidiva , Transdução de Sinais , Análise de Sobrevida , Quinases da Família src/sangue , Quinases da Família src/genética
6.
Cell Prolif ; 52(5): e12651, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31297902

RESUMO

OBJECTIVE: It is essential to characterize underlying molecular mechanism associated with head and neck squamous cell carcinoma (HNSCC) and identify promising therapeutic targets. Herein, we explored role of homeobox transcript antisense RNA (HOTAIR) in HNSCC to regulate stanniocalcin-2 (STC2) by sponging microRNA-206 (miR-206). METHODS: HNSCC-related differentially expressed genes and regulation network amongst HOTAIR, miR-206 and STC2 were identified. Next, effect of HOTAIR on cell biological functions of HNSCC was identified after transfection of cells with HOTAIR overexpressed plasmids or siRNA against HOTAIR. PI3K/AKT signalling pathway-related gene expression was measured after miR-206 and STC2 were suppressed. Cell invasion, migration and proliferation were assessed. Finally, tumour growth was assessed to determine the effects of HOTAIR/miR-206/STC2 axis in vivo. RESULTS: HOTAIR specifically bound to miR-206 and miR-206 targeted STC2. Downregulated HOTAIR or upregulated miR-206 suppressed HNSCC cell proliferation, invasion and migration. miR-206 inhibited PI3K/AKT signalling pathway by down-regulating STC2. Besides, silenced HOTAIR or overexpressed miR-206 repressed the tumour growth of nude mice with HNSCC. CONCLUSION: HOTAIR regulated HNSCC cell biological functions by binding to miR-206 through STC2.


Assuntos
Glicoproteínas/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo
7.
Cell Prolif ; 52(5): e12615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310044

RESUMO

OBJECTIVES: It has been widely reported that long non-coding RNAs (lncRNAs) can participate in multiple biological processes of human cancers. lncRNA HLA complex group 11 (HCG11) has been reported in human cancers as a tumour suppressor. This study focused on investigating the function and mechanism of HCG11 in glioma. MATERIALS AND METHODS: Based on The Cancer Genome Atlas (TCGA) data set and qRT-PCR analysis, the expression pattern of HCG11 was identified in glioma samples. The mechanism associated with HCG11 downregulation was determined by mechanism experiments. Gain-of-function assays were conducted for the identification of HCG11 function in glioma progression. Mechanism investigation based on the luciferase reporter assay, RIP assay and pull-down assay was used to explore the downstream molecular mechanism of HCG11. The role of molecular pathway in the progression of glioma was analysed in accordance with the rescue assays. RESULTS: HCG11 was expressed at low level in glioma samples compared with normal samples. FOXP1 could bind with HCG11 and transcriptionally inactivated HCG11. Overexpression of HCG11 efficiently suppressed cell proliferation, induced cell cycle arrest and promoted cell apoptosis. HCG11 was predominantly enriched in the cytoplasm of glioma cells and acted as a competing endogenous RNAs (ceRNAs) by sponging micro-496 to upregulate cytoplasmic polyadenylation element binding protein 3 (CPEB3). CEPB3 and miR-496 involved in HCG11-mediated glioma progression. CONCLUSIONS: HCG11 inhibited glioma progression by regulating miR-496/CPEB3 axis.


Assuntos
Glioma/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Antagomirs/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Progressão da Doença , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo
8.
Cell Prolif ; 52(5): e12661, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31318114

RESUMO

OBJECTIVES: Circular RNAs (circRNAs) are non-coding RNAs, some of which are thought to be involved in gastric cancer development. Here, we examined the functions of circRNA hsa_circ_006100 in gastric cancer cells and an animal model of gastric cancer. MATERIALS AND METHODS: The expression of hsa_circ_006100, miR-195 and various functional genes was determined by quantitative RT-PCR. Cell viability, clone formation, apoptosis and cell migration/invasion abilities were analysed by the CCK-8 assay, crystal violet staining, Hoechst staining and Transwell assay, respectively. A tumour model was established by subcutaneously injecting tumour cells into nude mice. Levels of protein expression were analysed by Western blotting and immunohistochemistry. RESULTS: A bioinformatics analysis showed that miR-195 was negatively co-expressed with hsa_circ_006100. Patients with a high hsa_circ_006100 level or low miR-195 level had tumours with a high TNM stage, poor cellular differentiation and lymph node metastasis. miR-195 was targeted and inhibited by hsa_circ_006100. Overexpression of hsa_circ_006100 enhanced cellular viability and proliferation, while miR-195 suppressed hsa_circ_006100-enhanced cell growth and induced apoptosis in MGC-803 and AGS cells. Forced hsa_circ_006100 expression promoted the migration and invasion of MGC-803 and AGS cells, while those activities were inhibited by miR-195. Mechanistically, GPRC5A was predicted as a target of miR-195 and was upregulated in gastric cancer. A miR-195 inhibitor restored cell viability, proliferation, migration and invasion, and repressed apoptosis via GPRC5A. In vivo studies showed that knockdown of hsa_circ_006100 delayed tumour growth, reduced PCNA expression and upregulated miR-195 and BCL-2 expression which was restored by miR-195 inhibition due to GPRC5A/EGFR signalling, and changed the EMT phenotype in vivo. CONCLUSIONS: Hsa_circ_006100 functions as an oncogene in gastric cancer and exerts its effects via miR-195/GPRC5A signalling.


Assuntos
MicroRNAs/metabolismo , RNA/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Neoplasias Gástricas/patologia , Animais , Antagomirs/metabolismo , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA/antagonistas & inibidores , RNA/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Neoplasias Gástricas/metabolismo
9.
Cell Prolif ; 52(5): e12635, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31334580

RESUMO

OBJECTIVES: MicroRNAs are powerful regulators in hepatocellular carcinoma (HCC) tumorigenesis. MicoRNA-191 (miR-191) has been reported to play an important role in HCC, However, the regulatory mechanism is still unclear. In this study, we investigated the role of miR-191 in HCC and studied its underlying mechanisms of action. MATERIALS AND METHODS: The expression of miR-191 in HCC tissues was determined by quantitative real-time PCR (qRT-PCR). The role of miR-191 in HCC cells was examined by using both in vitro and in vivo assays. Downstream targets of miR-191 were determined by qRT-PCR and Western blot analysis. Dual-luciferase assays were performed to validate the interaction between miR-191 and its targets. RESULTS: The expression of miR-191 was significantly higher in HCC patients and a higher miR-191 expression predicted poorer prognosis. Analysis of The Cancer Genome Atlas data sets suggested that miR-191 positively correlated with cell cycle progression. Gain and loss of function assays showed that miR-191 promoted cell cycle progression and proliferation. Luciferase reporter assay showed that miR-191 directly targeted the 3'-untranslated region of KLF6 mRNA. Furthermore, circular RNA has_circ_0000204 could sponge with miR-191, resulting in inactivation of miR-191. CONCLUSIONS: Our study sheds light on the novel underlying mechanism of miR-191 in HCC, which may accelerate the development of cancer therapy.


Assuntos
Carcinoma Hepatocelular/patologia , Fator 6 Semelhante a Kruppel/metabolismo , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , RNA/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados Factuais , Progressão da Doença , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Fator 6 Semelhante a Kruppel/química , Fator 6 Semelhante a Kruppel/genética , Neoplasias Hepáticas/genética , Masculino , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Prognóstico , RNA/genética , Transplante Heterólogo
10.
Cell Prolif ; 52(5): e12664, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343104

RESUMO

OBJECTIVES: Low back pain becomes a common orthopaedic disease today. It is mainly induced by the degeneration of the intervertebral disc. In this study, we tried to reveal the pathogenesis of the degeneration and the relative therapeutic strategy, which are still elusive. MATERIALS AND METHODS: We collected 15 degenerative intervertebral tissues and five healthy donors. Nucleus pulposus and annulus fibrosus cells were subcultured. miR-640 expression was determined by qPCR. Computer analysis and luciferase reporter assay were used to confirm miR-640 target genes. Immunohistochemical and immunocytochemical staining was used to trace the proinflammatory cytokines and key transductor of signalling pathways. We also used ß-galactosidase staining, flow cytometry, and cell viability assay to monitor the degenerative index. RESULTS: miR-640 overexpressed in patients derived degenerative nucleus pulposus tissues and cells. The inflammatory environment promoted miR-640 expression via NF-κB signalling pathway. In addition, miR-640 targeted to LRP1 and enhances NF-κB signal activity, which built a positive feedback loop. miR-640 inhibited the expression of ß-catenin and EP300, therefore, restrained WNT signal and induced the degeneration in nucleus pulposus cells. miR-640 inhibitor treatment exhibited the effects of anti-inflammation, reverse WNT signalling pathway exhaustion, and remission of degenerative characteristics in vitro. CONCLUSIONS: miR-640 plays an important role in the degeneration of intervertebral disc and the relative inflammatory microenvironment. It is a promising potential therapeutic target for the low back pain biotherapy.


Assuntos
Degeneração do Disco Intervertebral/patologia , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Adolescente , Adulto , Anel Fibroso/citologia , Anel Fibroso/metabolismo , Antagomirs/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Proteína p300 Associada a E1A/metabolismo , Humanos , Interleucina-1beta/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Núcleo Pulposo/citologia , Núcleo Pulposo/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Adulto Jovem , beta Catenina/metabolismo
11.
Oncol Rep ; 42(4): 1459-1466, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31322270

RESUMO

The expression of CDR1­AS, a representative circular RNA, is closely linked with poor prognosis in gastrointestinal cancers, such as colon, liver, and pancreatic cancers. Although it is well known that CDR1­AS antagonizes microRNA­7 function through its sequence similarities in the brain, its biological function and link with the malignant potential of cancer cells remain unclear, partly due to the difficulties of ectopic expression of circular RNAs. In the present study, SW620, a colon cancer cell line that stably expresses CDR1­AS RNA circularized, was established using the laccase 2 gene cassette, and its biological function associated with malignant behavior was determined. In contrast to previous studies, cell growth or invasion ability was not altered by CDR1­AS expression. However, the expression levels of CMTM4 and CMTM6, which were recently recognized as critical regulators of PD­L1 protein expression at the cell surface, were significantly increased. Accordingly, the cell surface PD­L1 protein levels were increased in CDR1­AS­expressing cells. Notably, the effects were not canceled out by overexpressing microRNA­7, indicating that the increase in cell surface PD­L1 in CDR1­AS­expressing cells was not dependent on microRNA­7 function. These results indicated that expression of this circular RNA in cancer cells may lead to poor prognosis by increasing cell surface PD­L1 levels through microRNA­7­independent mechanisms.


Assuntos
Antígeno B7-H1/biossíntese , Neoplasias Colorretais/metabolismo , RNA Longo não Codificante/biossíntese , Animais , Antígeno B7-H1/genética , Células CACO-2 , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HEK293 , Humanos , Imuno-Histoquímica , Proteínas com Domínio MARVEL/biossíntese , Proteínas com Domínio MARVEL/genética , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , Prognóstico , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Cancer Sci ; 110(9): 2760-2772, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325400

RESUMO

Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. TP53TG1 is a recently identified lncRNA and several studies have shown that TP53TG1 may play the role of tumor suppressor gene or oncogene in different tumors. Nevertheless, the involvement of TP53TG1 in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has not been characterized. In our studies, we identified that TP53TG1 was highly expressed in PDAC and was a novel regulator of PDAC development. Knockdown of TP53TG1 inhibited proliferation, induced apoptosis, and decreased migration and invasion in PDAC cells, whereas enhanced expression of TP53TG1 had the opposite effects. Mechanistically, TP53TG1 could directly bind to microRNA (miR)-96 and effectively function as a sponge for miR-96, thus antagonizing the functions of miR-96 and leading to derepression of its endogenous target KRAS, which is a core oncogene in the initiation and maintenance of PDAC. Taken together, these observations imply that TP53TG1 contributes to the growth and progression of PDAC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR-96 and regulate KRAS expression, which highlights the importance of the complicated miRNA-lncRNA network in modulating the progression of PDAC.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteínas de Ligação a DNA/metabolismo , MicroRNAs/antagonistas & inibidores , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Longo não Codificante/metabolismo , Carcinogênese/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Longo não Codificante/genética
13.
Nucleic Acids Res ; 47(15): 7753-7766, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31340025

RESUMO

MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.


Assuntos
Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/terapia , RNA Neoplásico/genética , Biologia de Sistemas/métodos , Antagomirs/genética , Antagomirs/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Quimioterapia Adjuvante/métodos , Redes Reguladoras de Genes , Humanos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/agonistas , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Proteínas Supressoras de Tumor/agonistas , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
14.
Zhonghua Zhong Liu Za Zhi ; 41(7): 508-515, 2019 Jul 23.
Artigo em Chinês | MEDLINE | ID: mdl-31357837

RESUMO

Objective: To investigate the expression levels and the mechanism of miR-126 and insulin like growth factor 1 receptor (IGF1R) in gastric cancer tissues and cells. Methods: The expression levels of miR-126 and IGF1R in 60 gastric cancer tissues and matched normal gastric tissues were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot, respectively. The association of miR-126 expression with clinicopathology and prognosis of gastric cancer patients was further analyzed. CCK-8, soft agar assay, transwell assay were used to analyze the proliferation and invasion capacity of gastric cancer cells, respectively, while the dual luciferase reporter assay was used to determine the direct target of miR-126. Results: The expression of miR-126 was obviously correlated with lymphatic metastasis, distant metastasis and TNM stage of gastric cancer (all P<0.05). Cox multivariate analysis revealed that lymphatic metastasis, TNM stage, miR-126 and IGF-1R expression were independent risk factors for prognosis of gastric cancer patients (all P<0.05). The expression level of miR-126 in gastric cancer tissues was 2.01±0.23 significantly lower than 10.12±2.15 of normal gastric tissues (P<0.05). CCK-8 result showed that the absorbance values of MKN28 and BGC823 cells at 72 hours after transfected with miR-126 mimics were 1.06±0.05 and 1.01±0.09, respectively, significantly lower than 1.55±0.12 and 1.36±0.12 of the control group (all P<0.05). The clone numbers of MKN28 and BGC823 cells transfected with miR-126 mimics formed in the soft agar were 33±9 and 29±8, respectively, significantly lower than 76±13 and 71±11 of the control group (all P<0.05). Transwell assay showed that the invasived number of MKN28 and BGC823 cells transfected by miR-126 mimics was 98±12 and 89±8, respectively, significantly lower than 154±18 and 161±17 of the control group (all P<0.05). Double luciferase assay further clarified that miR-126 the 3'-untranslated region (3'-UTR) of IGF-1R, and inhibited its protein expression. CCK-8 results showed that overexpression of IGF-1R partially reversed the miR-126 induced proliferation inhibition in MKN28 (1.65±0.14 v. s. 0.98±0.11, P=0.003) and BGC823 cells (1.44 ±0.15 v. s. 0.89±0.10; P=0.006). Likewise, overexpression of IGF-1R partially reversed the miR-126-inhibited invasion of MKN28 (176±19 v. s. 101±14, P=0.005) and BGC823 cells (186±21 v. s. 92±9, P=0.002). Moreover, the inhibitory effects of miR-126 on proliferation were aggravated by silencing of IGF-1R in MKN28 (0.67±0.09 v. s. 0.99±0.12, P=0.021) and BGC823 cells (0.57±0.07 v. s. 0.92±0.12, P=0.012). Conclusion: miR-126 suppresses the proliferation and invasion of gastric cancer cells through targeting the 3'-UTR of IGF-1R and inhibiting its expression.


Assuntos
Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Receptor IGF Tipo 1/metabolismo , Neoplasias Gástricas/patologia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Invasividade Neoplásica , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética
15.
Cell Prolif ; 52(5): e12640, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250518

RESUMO

OBJECTIVE: We aimed to investigate the roles of the lncRNA MALAT1 in renal cell carcinoma (RCC) progression. METHODS: qRT-PCR was used for the assessment of BIRC5, miRNA-203 and MALAT1 expression. Furthermore, the targeted relationships between miR-203 and BIRC5, as well as MALAT1 and miR-203, were predicted by the miRanda/starBase database and verified by dual-luciferase reporter gene assay. The effects of MALAT1, miRNA-203 and BIRC5 on cell proliferation, cell cycle, cell apoptosis, cell invasion and cell migration were studied by using CCK-8, flow cytometry, transwell and wound healing assays, respectively. In addition, the effects of MALAT1 on RCC tumorigenesis were evaluated in vivo by nude mouse tumorigenesis. RESULTS: The expression levels of BIRC5 and MALAT1 were higher in RCC tissues and cell lines than in adjacent normal tissues and a normal renal cortex proximal tubule epithelial cell line. In contrast, the expression of miRNA-203 in RCC tissues and cell lines was higher than that in adjacent normal tissues and a normal renal cortex proximal tubule epithelial cell line. BIRC5 and MALAT1 promoted cell proliferation yet decreased the percentage of RCC cells at G0/G1 phase. CONCLUSIONS: Our study demonstrated that MALAT1 functions as a miR-203 decoy to increase BIRC5 expression in RCC.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Survivina/metabolismo , Idoso , Animais , Antagomirs/metabolismo , Apoptose , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Masculino , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Survivina/antagonistas & inibidores , Survivina/genética
16.
Int J Oncol ; 55(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180529

RESUMO

The present study investigated the effects of the combined treatment of two peptide nucleic acids (PNAs), directed against microRNAs involved in caspase­3 mRNA regulation (miR­155­5p and miR­221­3p) in the temozolomide (TMZ)­resistant T98G glioma cell line. These PNAs were conjugated with an octaarginine tail in order to obtain an efficient delivery to treated cells. The effects of singularly administered PNAs or a combined treatment with both PNAs were examined on apoptosis, with the aim to determine whether reversion of the drug­resistance phenotype was obtained. Specificity of the PNA­mediated effects was analyzed by reverse transcription­quantitative polymerase­chain reaction, which demonstrated that the effects of R8­PNA­a155 and R8-PNA-a221 anti­miR PNAs were specific. Furthermore, the results obtained confirmed that both PNAs induced apoptosis when used on the temozolomide­resistant T98G glioma cell line. Notably, co­administration of both anti­miR­155 and anti­miR­221 PNAs was associated with an increased proapoptotic activity. In addition, TMZ further increased the induction of apoptosis in T98G cells co­treated with anti­miR­155 and anti­miR­221 PNAs.


Assuntos
Caspase 3/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , MicroRNAs/antagonistas & inibidores , Ácidos Nucleicos Peptídicos/farmacologia , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Glioma/enzimologia , Humanos , MicroRNAs/genética , Ácidos Nucleicos Peptídicos/genética
17.
Chem Biol Interact ; 309: 108705, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31199929

RESUMO

MicroRNAs have emerged as critical mediators of cerebral ischaemia/reperfusion injury. Recent studies have demonstrated that microRNA-302b-3p (miR-302b-3p) plays an important role in regulating apoptosis and oxidative stress in various cells. However, whether miR-302b-3p is involved in regulating cerebral ischaemia/reperfusion injury-induced neuronal apoptosis and oxidative stress remains unknown. In the present study, we explored the potential function and molecular mechanism of miR-302b-3p in oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal injury, using an in vitro model of cerebral ischaemia/reperfusion injury. We found that miR-302b-3p expression was up-regulated by OGD/R treatment in neurons. The inhibition of miR-302b-3p improved cell viability, and reduced apoptosis and the production of reactive oxygen species, showing a protective effect against OGD/R-induced injury. Interestingly, miR-302b-3p was shown to target and modulate murine fibroblast growth factor 15 (FGF15). Moreover, our results showed that miR-302b-3p down-regulation contributed to the promotion of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE)-mediated antioxidant signaling associated with the inactivation of glycogen synthase kinase-3ß. However, the knockdown of FGF15 significantly reversed the miR-302b-3p inhibition-mediated protective effect in OGD/R-treated neurons. Overall, these results demonstrated that miR-302b-3p inhibition confers a neuroprotective effect in OGD/R-treated neurons by up-regulating Nrf2/ARE antioxidant signaling via targeting FGF15, providing a novel target for neuroprotection in cerebral ischaemia/reperfusion injury.


Assuntos
Hipóxia Celular , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Elementos de Resposta Antioxidante/genética , Linhagem Celular , Sobrevivência Celular , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/genética , Glucose/deficiência , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neurônios/citologia , Neurônios/metabolismo , Neuroproteção , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Regulação para Cima
18.
Chem Biol Interact ; 309: 108716, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31207222

RESUMO

BACKGROUND: Neferine (NEF) is a major bisbenzylisoquinline alkaloid mainly exists in the seed embryo of Nelumbo nucifera (Gaertn.) that possesses anti-tumor effects. Our study designed to check the effect of NEF on breast cancer MDA-MB-231 cells and further explore the potential mechanism. METHODS: MDA-MB-231 cells were administrated with various dosages of NEF for 24 h after which cell viability was measured. The effects of NEF on cell proliferation, apoptosis, migration and invasion were assessed by BrdU staining, flow cytometry assay and Transwell assay. Western blot was utilized to assess the accumulation of proteins related with proliferation, apoptosis, metastasis, PI3K/AKT and MEK/ERK pathways. RESULTS: Viability was efficiently reduced by NEF in a dose-dependent manner. NEF (8 µM) significantly suppressed cell proliferation, migration and invasion but enhanced apoptosis in MDA-MB-213 cells. Interestingly, NEF suppressed miR-374a expression and miR-374a mediated the inhibitory effect of NEF. Moreover, miR-374a positively regulated FGFR-2 expression and FGFR-2 overexpression impeded the effect of NEF on MDA-MB-213 cells. FGFR-2 overexpression abolished the suppressive effect of NEF on PI3K/AKT and MEK/ERK pathways. CONCLUSION: We found that NEF possessed the anti-growth and anti-metastasis effect on MDA-MB-231 cells through regulating miR-374a/FGFR-2, which might provide new insight for breast cancer management.


Assuntos
Benzilisoquinolinas/farmacologia , Proliferação de Células/efeitos dos fármacos , MicroRNAs/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Antagomirs/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos
19.
Chem Biol Interact ; 308: 364-371, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158334

RESUMO

BACKGROUND: Notoginsenoside R1 (NGR1) is the main saponin isolated from the roots of Panax notoginseng (Burk.) F.H. Chen (Araliaceae). This study explored the protective effects of NGR1 on human renal proximal tubular epithelial cell inflammatory damage caused by lipopolysaccharide (LPS), as well as possible internal molecular mechanisms. METHODS: Cell viability and apoptosis were assessed using CCK-8 assay and Annexin V-FITC/PI Apoptosis Detection kit, respectively. Reactive oxygen species (ROS) level was tested using DCFH-DA staining. qRT-PCR was used to measure microRNA-26a (miR-26a), interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α) expressions. miRNA transfection was conducted to knock down miR-26a. The protein expression levels of key molecules related to cell apoptosis, inflammatory response and nuclear factor kappa B (NF-κB) pathway were detected using western blotting. RESULTS: LPS stimulation caused human renal proximal tubular epithelial cell viability reduction, apoptosis and inflammatory cytokines expression. NGR1 treatment protected human renal proximal tubular epithelial cells from LPS-caused viability reduction, ROS level elevation, apoptosis and inflammatory cytokines expression. Mechanistically, NGR1 enhanced miR-26a expression in LPS-treated human renal proximal tubular epithelial cells. Knockdown of miR-26a reversed the protective effect of NGR1 on LPS-treated cells. Besides, NGR1 inactivated NF-κB pathway in LPS-treated human renal proximal tubular epithelial cells via up-regulating miR-26a. CONCLUSION: NGR1 protected human renal proximal tubular epithelial cells from LPS-caused inflammatory damage at least partially via up-regulating miR-26a and then inactivating NF-κB pathway.


Assuntos
Ginsenosídeos/farmacologia , MicroRNAs/metabolismo , Regulação para Cima/efeitos dos fármacos , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-1beta/metabolismo , Túbulos Renais Proximais/citologia , Lipopolissacarídeos/farmacologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Chem Biol Interact ; 308: 332-338, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170386

RESUMO

BACKGROUND: Sevoflurane (sevo) has been reported to be an effective neuroprotective agent in cerebral ischemia/reperfusion injury (CIRI). However, the precise molecular mechanism underlying sevo preconditioning in CIRI remains largely unknown. METHODS: A middle cerebral artery occlusion (MCAO) rat model and primary cortical neurons after oxygen-glucose deprivation and reoxygenation (OGDR) were used as the in vivo and in vitro models of CIRI. The expression profiles of miR-181a and X chromosome-linked inhibitor-of-apoptosis protein (XIAP) in the cerebral cortex of rats and in cortical neurons were examined by qRT-PCR and Western blot, respectively. The infarct volumes were measured by TTC staining and neurological deficits in rats was determined by Zea-Longa scoring criteria. The cell viability, lactate dehydrogenase (LDH) release and apoptotic rate were detected in cortical neurons by MTT assay, LDH analysis and flow cytometry. Western blot analysis was performed to assess the expression of apoptosis-related protein. Luciferase reporter assay was used to confirm the interaction between miR-181a and XIAP. RESULTS: miR-181a was upregulated and XIAP was downregulated in rats after MCAO. Sevo preconditioning attenuated miR-181a expression and promoted XIAP level in a rat model of CIRI. Sevo preconditioning ameliorated anti-miR-181a-mediated protective effects on cerebral ischemia in rat model of CIRI, presented as the decrease of infarct volume, neurological deficit and apoptosis. Moreover, sevo pretreatment abated miR-181a-induced cellular injury in primary cortical neurons after OGD, embodied by the increase of cell viability, the reduction of LDH release and the decline of apoptosis. Furthermore, miR-181a suppressed XIAP expression by binding to its 3'UTR in cortical neurons, and sevo-mediated increase on XIAP expression was counteracted by miR-181 overexpression in OGDR-treated neurons. CONCLUSION: Sevo preconditioning protected against CIRI in vitro and in vivo possibly by inhibiting miR-181a and facilitating XIAP.


Assuntos
MicroRNAs/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Sevoflurano/uso terapêutico , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Sequência de Bases , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Proteínas Inibidoras de Apoptose/química , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Alinhamento de Sequência , Sevoflurano/farmacologia
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