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2.
CNS Neurosci Ther ; 23(8): 686-697, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28695670

RESUMO

AIMS: Accumulated evidence indicates that cerebral metabolic features, evaluated by proton magnetic resonance spectroscopy (1 H-MRS), are sensitive to early mitochondrion dysfunction associated with mitochondrial encephalomyopathy (ME). The metabolite ratios of lactate (lac)/Cr, N-acetyl aspartate (NAA)/creatine (Cr), total choline (tCho)/Cr, and myoinositol (mI)/Cr are measured in the infarct-like lesions by 1 H-MRS and may reveal metabolic changes associated with ME. However, the application of this molecular imaging technique in the investigation of the pathology of ME subtypes is unknown. METHODS: In this study, cerebral metabolic features of pathologically diagnosed ME cases, that is, 19 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); nine chronic progressive external ophthalmoplegia (CPEO); and 23 healthy controls, were investigated using 1 H-MRS. Receiver operating characteristics (ROC) analysis was used to evaluate the diagnostic power of the cerebral metabolites. Histochemical evaluation was carried out on muscle tissues derived from biopsy to assess the abnormal mitochondrial proliferation. The association between cerebral metabolic and mitochondrial cytopathy was examined by correlation analysis. RESULTS: Patients with MELAS or CPEO exhibited a significantly higher Lac/Cr ratio and a lower NAA/Cr ratio compared with controls. The ROC curve of Lac/Cr ratio indicated prominent discrimination between MELAS or CPEO and healthy control subjects, whereas the NAA/Cr ratio may present diagnostic power in the distinction of MELAS from CPEO. Lower NAA/Cr ratio was associated with higher Lac/Cr in MELAS, but not in CPEO. Furthermore, higher ragged-red fibers (RRFs) percentages were associated with elevated Lac/Cr and reduced NAA/Cr ratios, notably in MELAS. This association was not noted in the case of mI/Cr ratio. CONCLUSIONS: Mitochondrial cytopathy (lactic acidosis and RRFs on muscle biopsy) was associated with neuronal viability but not glial proliferation, notably in MELAS. Mitochondrial neuronopathy and neuronal vulnerability are considered significant causes in the pathogenesis of MELAS, particularly with regard to stroke-like episodes.


Assuntos
Encéfalo/metabolismo , Síndrome MELAS/metabolismo , Mitocôndrias/metabolismo , Oftalmoplegia Externa Progressiva Crônica/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Síndrome MELAS/diagnóstico por imagem , Síndrome MELAS/patologia , Masculino , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/diagnóstico por imagem , Oftalmoplegia Externa Progressiva Crônica/patologia , Espectroscopia de Prótons por Ressonância Magnética , Curva ROC
3.
Zhongguo Dang Dai Er Ke Za Zhi ; 19(4): 405-409, 2017 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-28407826

RESUMO

OBJECTIVE: To analyze the clinical features of 6 children with Duchenne muscular dystrophy (DMD) and review related literature, and to provide a basis for early diagnosis and effective treatment of this disease. METHODS: A retrospective analysis was performed on the clinical data of 6 children with DMD who were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to October 2015. RESULTS: All the 6 cases were boys without a family history of DMD, and the age of diagnosis of DMD was 1.2-11.5 years. All patients had insidious onset and increases in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase, creatine kinase (CK), and creatine kinase-MB, particularly CK, which was 3.3-107.2 times the normal level. Their gene detection results all showed DMD gene mutation. The gene detection results of two children's mothers showed that they carried the same mutant gene. The muscle biopsy in one case showed that the pathological changes confirmed the diagnosis of DMD. The level of CK in one case declined by 77.0% 5 days after umbilical cord blood mesenchymal stem cell transplantation. CONCLUSIONS: For boys with abnormal serum enzyme levels and motor function, DMD should be highly suspected. It should be confirmed by CK and DMD gene detection as soon as possible. And the progression of the disease could be delayed by early intervention for protecting the remaining normal muscle fibers.


Assuntos
Distrofia Muscular de Duchenne/genética , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Creatina Quinase/genética , Distrofina/genética , Humanos , Lactente , Masculino , Distrofia Muscular de Duchenne/terapia , Estudos Retrospectivos
4.
CNS Neurosci Ther ; 20(6): 509-14, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24674659

RESUMO

AIMS: The purpose of this study was to evaluate the energy metabolism and mitochondrial function in skeletal muscle from patients with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) or chronic progressive external ophthalmoplegia (CPEO) using phosphorus magnetic resonance spectroscopy ((31)P-MRS), to determine whether abnormally increasing cytochrome c oxidase (COX), as detected in muscle biopsy, could be a cause for MELAS. METHODS: (31)P-MRS was performed on the quadriceps femoris muscle of 12 healthy volunteers and 11 patients diagnosed as MELAS or CPEO by muscle biopsy and genetic analysis. All subjects experienced a state of rest, 5-min exercise, and 5-min recovery protocol in a supine position. RESULTS: Compared to CPEO, MELAS patients typically exhibited COX-positive ragged-red fibers (RRFs) as well as strongly SDH-positive blood vessels (SSVs). However, based on (31)P-MRS results, MELAS showed a higher inorganic phosphate (Pi)/phosphocreatine (PCr) ratio and lower ATP/PCr ratio during exercise and delayed Pi/PCr and ATP/PCr recovery to normal. CONCLUSIONS: This study suggests that high COX expression contributes to severe skeletal energy failure by (31)P-MRS spectroscopy in MELAS.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Síndrome MELAS/patologia , Músculo Esquelético/enzimologia , Adolescente , Adulto , Análise de Variância , Estudos de Casos e Controles , Feminino , Humanos , Contração Isométrica/fisiologia , Síndrome MELAS/genética , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Isótopos de Fósforo , Adulto Jovem
5.
Int J Neurosci ; 123(2): 93-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23002909

RESUMO

Due to the complicated clinical features of mitochondrial encephalomyopathy, simplified mitochondrial disease criteria (MDC) have recently been established in Europe. This study evaluated the sensitivity and specificity of this scoring system in Chinese patients. Seventy-eight patients with suspected mitochondrial encephalomyopathy were recruited to be scored by the simplified MDC and were further classified into "possible" (2-4), "probable" (5-7), or "definite" categories (≥8). Significant differences were observed between the total scores in the mitochondrial encephalomyopathy group and the other myopathy group. In the mitochondrial encephalomyopathy group, 73.5% of patients had a score above 8, whereas in the other myopathy group, the "definite" percentage was only 3.2%, suggesting the proposed MDC scoring system has a high sensitivity for diagnosis of mitochondrial encephalomyopathy in China. Moreover, there were significant differences in the clinical scores and imaging portions of the MDC, suggesting that the simplified MDC may distinguish mitochondrial disorder from other multisystem disorders to aid in early diagnosis prior to a muscle biopsy.


Assuntos
/etnologia , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/etnologia , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/classificação , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/etnologia , Encefalomiopatias Mitocondriais/classificação , Adulto Jovem
6.
Brain Behav Immun ; 26(1): 61-71, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21802508

RESUMO

Inflammation is an important contributing mechanism in ischemic brain injury. The current study elucidates a previously unexplored role of Fas ligand (FasL) in post-stroke inflammatory responses that is independent of its well-known effect in triggering apoptosis. Focal cerebral ischemia was induced for 2 h by right middle cerebral artery occlusion (MCAO) in FasL mutant (gld) and wild-type mice. FasL mutation profoundly reduced brain damage and improved neurological performance from 6 to 72 h after ischemic stroke. The production of inflammatory cytokines in the brain was attenuated in gld mice after ischemia in the absence of dramatic change in inflammatory cell apoptosis. FasL mutation attenuated the recruitment of peripheral inflammatory cells (neutrophil) and inhibited the activation of residential glial cells (microglia and astrocyte). FasL mutation reduced CD8(+) T cells and turned the Th1/Th2 balance towards Th2 in the brain and peripheral blood after cerebral ischemia. In contrast to cerebral ischemia, the molecular and cellular inflammatory changes induced by intracerebroventricular injection of lipopolysaccharide (LPS) were also attenuated in gld mice. Moreover, the soluble FasL (sFasL) and phospho-SAPK/JNK were decreased in gld mice, suggesting that the inflammatory role of FasL in experimental stroke might relate to sFasL and the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our data suggest a novel role of FasL in the damaging inflammatory responses associated with cerebral ischemia. Neutralization of FasL may be a novel therapeutic strategy to suppress post-stroke inflammation and improve the long-term outcomes of stroke.


Assuntos
Encéfalo/patologia , Proteína Ligante Fas/genética , Inflamação/genética , Inflamação/patologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Edema Encefálico/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Contagem de Células , Infarto Cerebral/patologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Marcação de Genes , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/patologia , Injeções Intraventriculares , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/fisiologia , Proteínas Proto-Oncogênicas c-jun/genética , Reação em Cadeia da Polimerase em Tempo Real
7.
J Cereb Blood Flow Metab ; 30(7): 1356-65, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20179726

RESUMO

The purpose of this study is to investigate the possible mechanism and the neuroprotective effect of human urinary kallidinogenase (HUK) in cerebral ischemia. The mouse middle cerebral artery occlusion (MCAO) model was used. Mice were treated with HUK (20 PNAU/g per day, intravenous) or saline as control, from the beginning of reperfusion to 72 h. Neurological deficits, infarct size, and BWC were measured at 6, 24, 48, and 72 h after MCAO, respectively. Pathological changes of brain were observed by TUNEL assay. Inflammatory factors were measured by real-time PCR and western blotting. Activation of MAPKs, Akt, and nuclear factor-kappaB (NF-kappaB) was detected by western blotting. Our results indicated that HUK significantly improved neurofunction, decreased infarct size, and suppressed edema, as well as inflammatory mediators as compared with the vehicle group. Furthermore, HUK inhibited the NF-kappaB pathway and activated the MAPK/ERK pathway in this neuroprotection.


Assuntos
Isquemia Encefálica , Coagulantes , Inflamação , Calicreínas , NF-kappa B/metabolismo , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Animais , Comportamento/fisiologia , Biomarcadores/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Coagulantes/uso terapêutico , Coagulantes/urina , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Calicreínas/uso terapêutico , Calicreínas/urina , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/urina , Testes Neuropsicológicos , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
8.
Neuroreport ; 19(12): 1209-12, 2008 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-18628666

RESUMO

Histone deacetylases (HDAC) inhibitors have been emerging as neuroprotective agents by acting on neurons and microglia. In this study, we found trichostatin A (TSA), a HDAC inhibitor, could inhibit the elevation of glutamate in 150 microM 1-methyl-4-phenylpyridinium (MPP+)-treated primary cultured astrocytes medium when its concentration reached 132 nM. TSA of 132 nM or more could promote the uptake of [3H]-D, L-glutamate by astrocytes. Further study showed the downregulation of glutamate transporter 1 and glutamate/aspartate transporter induced by MPP+ were prevented by TSA. Therefore, these findings suggested TSA could alleviate MPP+-induced impairment of astrocytic glutamate uptake, which might be a novel mechanism contributing to neuroprotection by HDAC inhibitors.


Assuntos
1-Metil-4-fenilpiridínio/farmacologia , Astrócitos/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Ácidos Hidroxâmicos/farmacologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Western Blotting , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/análise , Ácido Glutâmico/farmacocinética , Histona Desacetilases/metabolismo , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos
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