RESUMO
BACKGROUND: Stroke is a leading cause of mortality worldwide. Rac-MAPK kinase 6 (Map2k6) plays important roles in cell proliferation and apoptosis. However, the role played by Map2k6 in stroke injury and the underlying mechanism of action remain unknown. METHODS: Mice received cerebral ischemia/reperfusion (I/R) injuries by transient middle cerebral artery occlusion. HT22 cells were subjected to oxygen glucose deprivation and reoxygenation (OGD/R) to simulate an I/R injury. Subsequently, the levels of circ_016719, miR-29c and Map2k6 expression were determined, and their interactions were examined by luciferase assays. Circ_016719 knockdown, miR-29c inhibition or Map2k6 overexpression was induced in HT22â¯cells; after which, the cells were examined for their viability, apoptosis, autophagy and proliferation, as well their levels of Map2k6, p38, p53, LC3B-I, LC3B-II, Beclin 1, and p62 expression. RESULTS: Significantly increased levels of circ_016719 and Map2k6, and decreased levels of miR-29c were observed in both in vivo and in vitro I/R injury models. In HT22â¯cells, circ_016719 knockdown significantly increased miR-29c expression and cell proliferation, but decreased Map2k6 expression and cell apoptosis. Additionally, significant increases in LC3B-I and p62 levels and decreased LC3B-II levels were observed, indicating that circ_016719 knockdown had significantly inhibited autophagy. Furthermore, additional inhibition of miR-29c markedly suppressed the effects of circ_016719 knockdown; however, that suppression was significantly attenuated by Map2k6 overexpression. Additionally, Map2k6 was identified as a direct target of miR-29c, which in turn, might be sponged by circ_016719. CONCLUSIONS: Our results suggest that circ_016719 directly targets miR-29c, and thereby regulates the expression and functions of Map2k6, which significantly contributes to the pro-apoptotic role of circ_016719.
Assuntos
Apoptose , MAP Quinase Quinase 6/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Animais , Autofagia , Sequência de Bases , Linhagem Celular , Sobrevivência Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glucose , MAP Quinase Quinase 6/genética , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/ultraestrutura , Oxigênio , RNA Circular , Acidente Vascular Cerebral/genéticaRESUMO
Ischemic stroke is the leading cause of disability and deaths worldwide. MiRNAs have been shown to play an important role in development and pathogenesis of the nervous system. However, the precise function and mechanism of miRNAs are not fully understood in the brain injury induced by ischemia/reperfusion (I/R). Herein, our study showed that miR-375 expression was significantly down-regulated in the rat I/R brain. With the in vivo and in vitro I/R stroke models, we found that miR-375 mimic provides significant protection from injury to cerebral I/R, which is reflected by reduced infarct volumes and cell apoptosis, and increased proliferation and migration of PC12 cells. Mechanistically, our findings showed that miR-375 binds to 3'-UTR region of Ctgf mRNA, subsequently leading to the decreased expression of Ctgf in the I/R brain. Furthermore, we showed that miR-375/Ctgf-mediated protective effects are associated with p21/PI3K/Akt signaling pathways. Our findings thus provide a new insight into the mechanism of cerebral I/R injury and pave a potential new way for the therapy of cerebral I/R injury.
Assuntos
Isquemia Encefálica/genética , Fator de Crescimento do Tecido Conjuntivo/genética , MicroRNAs/genética , Traumatismo por Reperfusão/genética , Acidente Vascular Cerebral/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Isquemia Encefálica/fisiopatologia , Movimento Celular , Proliferação de Células/genética , Regulação da Expressão Gênica , Humanos , Células PC12 , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/genética , Acidente Vascular Cerebral/fisiopatologia , Quinases Ativadas por p21/genéticaRESUMO
Pseudobulbar affect (PBA) is a common complication of central nervous system diseases such as stroke, multiple sclerosis, and other neurological diseases, but it remains under-recognized and under-treated in the clinic. PBA caused by acute disseminated encephalomyelitis (ADEM) has rarely been reported. Here, we report a 30-year-old Chinese woman who has experienced PBA from ADEM for 7 years. The patient's principal manifestations were extreme emotions or tears when she saw, heard, or spoke about sad news or other sad things; the durations of these unmanageable emotions were often less than 30 sec, and they occurred at frequencies that ranged from one to several times a day. Occasionally, she laughed uncontrollably while people were talking despite a lack of funny or sad stimuli in the conversation or the surrounding environment. Thus, her social functioning was impaired. This case indicates that the long-term PBA can occur secondarily to ADEM, and this possibility should be considered clinically to ensure timely identification and treatment.