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Metab Brain Dis ; 33(4): 1327-1334, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29721772


The present study investigated the protective actions of telmisartan, an angiotensin II type 1 receptor blocker (ARBs), against the cell apoptosis induced by exposure to hydrogen peroxide (H2O2) in differentiated PC12 cells. Preincubation of PC12 cells with telmisartan prevented H2O2-induced cytotoxicity as indicated by increased MTT (3,(4,5-dimethylthiazole-2-yl)2,5-diphenyl-tetrazolium bromide) reduction, decreased lactate dehydrogenase (LDH) release, and improved morphological changes. Hoechst 33,258 staining showed that telmisartan markedly reduced shrunken nuclei of the cells, and Western blot analysis indicated that telmisartan significantly attenuated caspase-3 activity, as indicated by decreased ratio of cleaved Caspase-3 to its precursor and increased ratio of Bcl-2/Bax. The present findings showed that telmisartan protected against cellular oxidative damages by inhibiting apoptotic response.

Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Telmisartan/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células PC12 , Ratos
J Neurosci Res ; 95(12): 2409-2419, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28512996


New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.

Ácidos Aminossalicílicos/farmacologia , Benzilaminas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transplante de Células-Tronco/métodos , Acidente Vascular Cerebral/patologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley
Stem Cells Transl Med ; 5(5): 561-71, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27013738


UNLABELLED: The genetic correction of induced pluripotent stem cells (iPSCs) induced from somatic cells of patients with sensorineural hearing loss (caused by hereditary factors) is a promising method for its treatment. The correction of gene mutations in iPSCs could restore the normal function of cells and provide a rich source of cells for transplantation. In the present study, iPSCs were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T; P-iPSCs), the asymptomatic father of the patient (MYO7A c.1184G>A mutation; CF-iPSCs), and a normal donor (MYO7A(WT/WT); C-iPSCs). One of MYO7A mutation sites (c.4118C>T) in the P-iPSCs was corrected using CRISPR/Cas9. The corrected iPSCs (CP-iPSCs) retained cell pluripotency and normal karyotypes. Hair cell-like cells induced from CP-iPSCs showed restored organization of stereocilia-like protrusions; moreover, the electrophysiological function of these cells was similar to that of cells induced from C-iPSCs and CF-iPSCs. These results might facilitate the development of iPSC-based gene therapy for genetic disorders. SIGNIFICANCE: Induced pluripotent stem cells (iPSCs) were generated from a deaf patient with compound heterozygous MYO7A mutations (c.1184G>A and c.4118C>T). One of the MYO7A mutation sites (c.4118C>T) in the iPSCs was corrected using CRISPR/Cas9. The genetic correction of MYO7A mutation resulted in morphologic and functional recovery of hair cell-like cells derived from iPSCs. These findings confirm the hypothesis that MYO7A plays an important role in the assembly of stereocilia into stereociliary bundles. Thus, the present study might provide further insight into the pathogenesis of sensorineural hearing loss and facilitate the development of therapeutic strategies against monogenic disease through the genetic repair of patient-specific iPSCs.

Sistemas CRISPR-Cas , Forma Celular , Células Ciliadas Auditivas , Perda Auditiva Neurossensorial/genética , Células-Tronco Pluripotentes Induzidas , Mutação , Miosinas/genética , Reparo Gênico Alvo-Dirigido/métodos , Diferenciação Celular , Linhagem Celular , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/transplante , Células Ciliadas Auditivas/ultraestrutura , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/cirurgia , Hereditariedade , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Células-Tronco Pluripotentes Induzidas/ultraestrutura , Masculino , Potenciais da Membrana , Linhagem , Fenótipo , Recuperação de Função Fisiológica , Transfecção
J Neurosci ; 34(40): 13535-48, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25274829


Stroke is a major public health concern. The lack of effective therapies heightens the need for new therapeutic targets. Mammalian brain has the ability to rewire itself to restore lost functionalities. Promoting regenerative repair, including neurogenesis and dendritic remodeling, may offer a new therapeutic strategy for the treatment of stroke. Here, we report that interaction of neuronal nitric oxide synthase (nNOS) with the protein postsynaptic density-95 (PSD-95) negatively controls regenerative repair after stroke in rats. Dissociating nNOS-PSD-95 coupling in neurons promotes neuronal differentiation of neural stem cells (NSCs), facilitates the migration of newborn cells into the injured area, and enhances neurite growth of newborn neurons and dendritic spine formation of mature neurons in the ischemic brain of rats. More importantly, blocking nNOS-PSD-95 binding during the recovery stage improves stroke outcome via the promotion of regenerative repair in rats. Histone deacetylase 2 in NSCs may mediate the role of nNOS-PSD-95 association. Thus, nNOS-PSD-95 can serve as a target for regenerative repair after stroke.

Infarto da Artéria Cerebral Média/cirurgia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Células-Tronco Neurais/transplante , Óxido Nítrico Sintase Tipo I/metabolismo , Regeneração/fisiologia , Animais , Encéfalo/patologia , Encéfalo/ultraestrutura , Diferenciação Celular/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Embrião de Mamíferos , Glucose/deficiência , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Hipóxia/fisiopatologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Óxido Nítrico Sintase Tipo I/genética , Ratos , Ratos Sprague-Dawley
Zhonghua Yi Xue Za Zhi ; 88(31): 2201-3, 2008 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-19080672


OBJECTIVE: To evaluate the efficacy and adverse effects of 5-nitroimidazole derivatives in treatment of bacterial vaginosis (BV). METHODS: 278 BV patients were randomly divided into 8 groups to be treated with (1) oral metronidazole sustained release tablet 750 mg/day for 7 days, (2) oral metronidazole sustained release tablet 750 mg/day for 7 days and vaginal tinidazole 250 mg for 7 days, (3) oral tinidazole 1 g/day for 3 days (2 g for the first dose), (4) oral tinidazole 1 g/day for 3 days (2 g for the first dose), (5) oral ornidazole 2 x 500 mg/day for 3 days and vaginal tinidazole 250 mg for 7 days, (6) oral ornidazole 2 x 500 mg/day for 3 days, (7) oral secnidazole 2 g in a single dose and vaginal tinidazole 250 mg for 7 days, and (8) oral secnidazole 2 g in a single dose. RESULTS: The clinical cure rates of the oral administration groups were 56.76% - 62.50%, all significantly lower than those of the oral/vaginal combination groups (80.00% - 86.11%, all P < 0.05). There was nit significantly difference in efficacy level among the only oral treatment groups and the oral/vaginal combination groups (all P > 0.05). CONCLUSION: Combination of oral and vaginal administration of 5-nitroimidazole derivatives is more effective in treatment of BV than oral administration only.

Metronidazol/análogos & derivados , Nitroimidazóis/uso terapêutico , Ornidazol/uso terapêutico , Tinidazol/uso terapêutico , Vaginose Bacteriana/tratamento farmacológico , Administração Intravaginal , Administração Oral , Adulto , Preparações de Ação Retardada , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Nitroimidazóis/administração & dosagem , Ornidazol/administração & dosagem , Estudos Prospectivos , Comprimidos , Tinidazol/administração & dosagem , Resultado do Tratamento , Adulto Jovem