RESUMEN
Diagnostic strategies for symptomatic transthyretin (ATTR) cardiac amyloidosis showing typical morphological features such as increased ventricular wall thickness and myocardial injury such as an elevation in serum troponin T level have been established, but those for subclinical cardiac amyloidosis are limited. In the era when effective therapies to suppress/delay progression of ATTR cardiac amyloidosis are available, early detection of cardiac involvement plays a crucial role in appropriate decision-making for treatment in TTR mutation carriers who have a family history of heart failure and death due to ATTR amyloidosis. Findings of three cases with known pathogenic transthyretin (TTR) mutations (p.Ser70Arg, p.Phe53Val, and p.Val50Met) and family histories of death for amyloidosis were presented. Two cases were asymptomatic, and a case carrying p.Phe53Val had gastrointestinal symptoms and autonomic neuropathy. Levels of plasma N-terminal fragment of pro-B-type natriuretic peptide and troponin T were within normal ranges in all cases, but results of cardiac magnetic resonance (CMR) and bone scintigraphy clearly revealed the presence of cardiac involvement in all cases, even in a case without echocardiographic abnormalities including left ventricular hypertrophy and relative apical sparing of longitudinal strain shown by two-dimensional speckle-tracking echocardiography. Electrocardiography revealed modest abnormalities including reduced R wave amplitude in V2 and a trend toward left axis deviation in all cases. In conclusion, CMR, bone scintigraphy, and electrocardiography are useful for early detection of ATTR cardiac amyloidosis in TTR mutation carriers. The role of comprehensive cardiac assessment in the early detection of cardiac amyloidosis in TTR mutation carriers is discussed.
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Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/genética , Cardiopatías/diagnóstico , Cardiopatías/genética , Mutación/genética , Prealbúmina/genética , Adulto , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
SIRT1 is involved in the regulation of a variety of biological processes such as metabolism, stress response, autophagy and differentiation. Although progenitor cells of oligodendrocytes (OPCs) express high level of SIRT1, its function on differentiation is unknown. Because we have shown that SIRT1 plays a pivotal role in differentiation of neural precursor cells, we hypothesized that SIRT1 may also participate in the differentiation of oligodendrocytes (OLGs). We examined whether SIRT1 was expressed in two human oligodendrocyte cell lines: KG-1-C and MO 3.13 OLG. Transfection of cell lines with SIRT1-siRNA and SIRT2-siRNA promoted the extension of cellular processes. SIRT1-siRNA and SIRT2-siRNA increased acetyl-α-tubulin level, conversely, over expression of SIRTs resulted in decreased the ratio of acetyl-α-tubulin to α-tubulin. We also found knockdown of SIRT1 and SIRT2 induced overexpression of ßIV-tubulin and tubulin polymerization promoting protein (TPPP) (OLG-specific cytoskeleton-related molecules) that distributed widely in cell bodies. Taken together, SIRT1 may play a role in oligodenroglial differentiation and myelinogenesis.
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Forma de la Célula , Citoesqueleto/metabolismo , Regulación de la Expresión Génica , Oligodendroglía/citología , Oligodendroglía/metabolismo , Sirtuina 1/metabolismo , Acetilación , Diferenciación Celular/genética , Línea Celular , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , ARN Interferente Pequeño/genética , Sirtuina 1/deficiencia , Sirtuina 1/genética , Sirtuina 2/genética , Sirtuina 2/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMEN
Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating epithelioid granulomas. Multiple organs, including the lung, eyes, and skin, are involved in this disorder, and cardiac involvement is a major cause of morbidity and mortality in patients with this disorder. We present the case history of a 22-year-old man with neurosarcoidosis complicated by abrupt onset of cardiac tamponade. Cardiac tamponade is a rare but potentially fatal manifestation of sarcoidosis, which is treatable with glucocorticoid therapy. Including the present case, previously reported cases of sarcoidosis with cardiac tamponade are reviewed to delineate its clinical characteristics.
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Taponamiento Cardíaco/etiología , Enfermedades del Sistema Nervioso Central/complicaciones , Derrame Pericárdico/cirugía , Pericardiocentesis/métodos , Sarcoidosis/complicaciones , Bloqueo de Rama/diagnóstico , Bloqueo de Rama/etiología , Taponamiento Cardíaco/diagnóstico , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/patología , Disnea/diagnóstico , Disnea/etiología , Electrocardiografía/métodos , Humanos , Masculino , Limitación de la Movilidad , Enfermedades Musculares/etiología , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/etiología , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/patología , Esteroides/administración & dosificación , Esteroides/uso terapéutico , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.
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Factor Activador de Células B/inmunología , Linfocitos B/inmunología , Clorhidrato de Fingolimod/uso terapéutico , Memoria Inmunológica/inmunología , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Antígeno de Maduración de Linfocitos B/inmunología , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Células Plasmáticas/inmunología , Células Precursoras de Linfocitos B/inmunología , Proteína Activadora Transmembrana y Interactiva del CAML/inmunología , Adulto JovenRESUMEN
BACKGROUND: Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. METHODS: We enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42-45° north), and 187 MS patients and 235 HCs from the southern half (33-35° north) of the Japanese archipelago (33-45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke's Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. RESULTS: The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (p (corr) = 0.0004 and p (corr) = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p = 0.0198). CONCLUSIONS: Living at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.
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Altitud , Susceptibilidad a Enfermedades/etiología , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/etiología , Esclerosis Múltiple/genética , Adulto , Alelos , Estudios Transversales , Evaluación de la Discapacidad , Femenino , Frecuencia de los Genes , Interacción Gen-Ambiente , Genotipo , Cadenas beta de HLA-DP/genética , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Análisis de Regresión , Índice de Severidad de la Enfermedad , Estadísticas no ParamétricasAsunto(s)
Autoanticuerpos/inmunología , Síndrome Miasténico de Lambert-Eaton/fisiopatología , Síndrome de Miller Fisher/fisiopatología , Conducción Nerviosa/fisiología , Potenciales de Acción/fisiología , Anciano , Enfermedades Asintomáticas , Ataxia/fisiopatología , Blefaroptosis/fisiopatología , Canales de Calcio Tipo P/inmunología , Canales de Calcio Tipo Q/inmunología , Diplopía/fisiopatología , Electrodiagnóstico , Electromiografía , Femenino , Gangliósidos/inmunología , Humanos , Hipoestesia/fisiopatología , Síndrome Miasténico de Lambert-Eaton/complicaciones , Síndrome Miasténico de Lambert-Eaton/inmunología , Nervio Mediano/fisiopatología , Síndrome de Miller Fisher/complicaciones , Síndrome de Miller Fisher/inmunología , Debilidad Muscular/fisiopatología , Midriasis/fisiopatología , Músculos Oculomotores/fisiopatología , Nervio Tibial/fisiopatología , Nervio Cubital/fisiopatologíaRESUMEN
BACKGROUND: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. OBJECTIVE: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. METHODS: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. RESULTS: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu (p < 0.0001 for both). Logistic regression analysis revealed that after adjusting for covariates that can be related to abnormal CSF IgG production, the geographic region (Hokkaido) showed odds ratios (ORs) of 4.08 and 2.57, whereas the HLA-DRB1*04:05 allele showed ORs of 0.36 and 0.30 for positive CSF findings and OCB positivity, respectively. CONCLUSIONS: The results indicate that latitude and HLA-DRB1 alleles independently affect the emergence of CSF IgG abnormalities in Japanese patients with MS.
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Cadenas HLA-DRB1/genética , Inmunoglobulina G/líquido cefalorraquídeo , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Bandas Oligoclonales/líquido cefalorraquídeo , Adulto , Alelos , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Focalización Isoeléctrica , Japón/epidemiología , Masculino , Esclerosis Múltiple/líquido cefalorraquídeo , Oportunidad Relativa , PrevalenciaRESUMEN
BACKGROUND: Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A/C gene mutations cause spinal muscular atrophy has not been established. CASE PRESENTATION: We report a man aged 65 years who presented with amyotrophy of lower limbs, arrhythmia and cardiac hypofunction. He showed gait disturbance since childhood, and his family showed similar symptoms. Neurological and electrophysiological findings suggested spinal muscular atrophy type 3. Gene analysis of lamin A/C gene showed a novel nonsense mutation p.Q353X (c.1057C > T). Further investigations revealed that he and his family members had cardiac diseases including atrioventricular block. CONCLUSIONS: We report the first Japanese case of spinal muscular atrophy phenotype associated with lamin A/C mutation. When a patient presents a spinal muscular atrophy phenotype and unexplained cardiac disease, especially when the family history is positive, gene analysis of lamin A/C gene should be considered.
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Arritmias Cardíacas/etiología , Lamina Tipo A/genética , Atrofia Muscular Espinal/genética , Anciano , Humanos , Masculino , Mutación , FenotipoRESUMEN
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial ß-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial ß-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial ß-oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed.
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Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Ejercicio Físico , Errores Innatos del Metabolismo Lipídico/complicaciones , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/genética , Enfermedades Musculares/complicaciones , Enfermedades Musculares/genética , Mutación Missense/genética , Rabdomiólisis/complicaciones , Rabdomiólisis/etiología , Acil-CoA Deshidrogenasa de Cadena Larga/sangre , Acil-CoA Deshidrogenasa de Cadena Larga/química , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Carnitina/análogos & derivados , Carnitina/sangre , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Heterocigoto , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/sangre , Errores Innatos del Metabolismo Lipídico/enzimología , Masculino , Enfermedades Mitocondriales/sangre , Enfermedades Mitocondriales/enzimología , Modelos Moleculares , Datos de Secuencia Molecular , Enfermedades Musculares/sangre , Enfermedades Musculares/enzimología , Estructura Terciaria de Proteína , Alineación de SecuenciaRESUMEN
We analyzed 20 patients diagnosed with autoimmune neurological diseases with seizure predominance. In these patients, we examined the usefulness of Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score and Antibodies Contributing to Focal Epilepsy Signs and Symptoms (ACES) score in autoimmune encephalitis (AE) for facilitating early treatment. APE2 score was positive in 19 of 20 patients. ACES score was positive in 15 of 20 patients, and 4 of 5 of the patients with negative ACES score did not have AE. Comprehensive assessment including the use of the above scores is desirable in the early stage of AE.
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Autoanticuerpos , Encefalitis , Convulsiones , Humanos , Autoanticuerpos/sangre , Masculino , Femenino , Persona de Mediana Edad , Encefalitis/inmunología , Encefalitis/diagnóstico , Encefalitis/terapia , Adulto , Anciano , Convulsiones/etiología , Convulsiones/inmunología , Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/complicaciones , Biomarcadores/sangre , Intervención Médica Temprana , Adulto Joven , Adolescente , Anciano de 80 o más Años , Índice de Severidad de la EnfermedadRESUMEN
Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS Criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative (did not meet criteria (n=16; 23.5%). At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusions We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.
RESUMEN
To explore a novel therapy against Parkinson's disease through enhancement of α7 nicotinic acetylcholine receptor (nAChR), we evaluated the neuroprotective effects of 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA; GTS-21), a functionally selective α7 nAChR agonist, in a rat 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. Microinjection of 6-OHDA into the nigrostriatal pathway of rats destroys dopaminergic neurons selectively. DMXBA dose dependently inhibited methamphetamine-stimulated rotational behavior and dopaminergic neuronal loss induced by 6-OHDA. The protective effects were abolished by methyllycaconitine citrate salt hydrate, an α7 nAChR antagonist. Immunohistochemical study confirmed abundant α7 nAChR expression in the cytoplasm of dopaminergic neurons. These results indicate that DMXBA prevented 6-OHDA-induced dopaminergic neuronal loss through stimulating α7 nAChR in dopaminergic neurons. Injection of 6-OHDA elevated immunoreactivities to glial markers such as ionized calcium binding adaptor molecule 1, CD68, and glial fibrillary acidic protein in the substantia nigra pars compacta of rats. In contrast, these immunoreactivities were markedly inhibited by comicroinjection of DMXBA. Microglia also expressed α7 nAChR in both resting and activated states. Hence, we hypothesize that DMXBA simultaneously affects microglia and dopaminergic neurons and that both actions lead to dopaminergic neuroprotection. The findings that DMXBA attenuates 6-OHDA-induced dopaminergic neurodegeneration and glial activation in a rat model of Parkinson's disease raisethe possibility that DMXBA could be a novel therapeutic compound to prevent Parkinson's disease development.
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Compuestos de Bencilideno/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Oxidopamina/toxicidad , Enfermedad de Parkinson/prevención & control , Piridinas/uso terapéutico , Receptores Nicotínicos/metabolismo , Animales , Femenino , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/prevención & control , Oxidopamina/antagonistas & inhibidores , Enfermedad de Parkinson/patología , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/fisiología , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
We herein report a 68-year-old Japanese man with sporadic variant transthyretin (ATTRv) amyloidosis harboring the novel variant A97D (p.A117D) in TTR. He had slow development of asymmetric neuropathy, unintentional weight loss, mild autonomic failure and mild cardiomyopathy. TTR amyloid deposition on the gastric duodenal mucosa was detected. In silico analyses predicted that TTR A97D (p.A117D) altered the structure and function of the TTR protein. ATTRv amyloidosis is often difficult to diagnose in non-endemic regions due to its diverse phenotypes, such as atypical peripheral nerve involvement and a rare family history.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Masculino , Humanos , Prealbúmina/genética , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/genética , MutaciónRESUMEN
A 38-year-old man was taken to hospital with generalized clonic seizure. Brain magnetic resonance imaging (MRI) showed multiple ring-enhancing lesions centered in the left frontoparietal lobe. A histopathological examination of a brain biopsy sample revealed granulomatous lesions with caseous necrosis. We extracted DNA from a formalin-fixed paraffin-embedded (FFPE) brain specimen, and nested polymerase chain reaction (PCR) of the DNA sample detected the Mycobacterium tuberculosis-specific insertion sequence IS6110. The lesions worsened after anti-tuberculosis drugs were administered, which we considered to be a paradoxical response and continued treatment. A genetic diagnosis of M. tuberculosis using FFPE specimens is useful for diagnosing tuberculoma.
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Mycobacterium tuberculosis , Tuberculoma , Masculino , Humanos , Adulto , Adhesión en Parafina , Sensibilidad y Especificidad , ADN Bacteriano/genética , ADN Bacteriano/análisis , Mycobacterium tuberculosis/genética , Reacción en Cadena de la Polimerasa/métodos , Biopsia , Formaldehído , Encéfalo/diagnóstico por imagenRESUMEN
Muscular dystrophies are inherited myopathic disorders characterized by progressive muscle weakness. Recently, several gene therapies have been developed; however, the treatment options are still limited. Resveratrol, an activator of SIRT1, ameliorates muscular function in muscular dystrophy patients and dystrophin-deficient mdx mice, although its mechanism is still not fully elucidated. Here, we investigated the effects of resveratrol on membrane resealing. We found that resveratrol promoted membrane repair in C2C12 cells via the activation of SIRT1. To elucidate the mechanism by which resveratrol promotes membrane resealing, we focused on the reorganization of the cytoskeleton, which occurs in the early phase of membrane repair. Treatment with resveratrol promoted actin accumulation at the injured site. We also examined the role of cortactin in membrane resealing. Cortactin accumulated at the injury site, and cortactin knockdown suppressed membrane resealing and reorganization of the cytoskeleton. Additionally, SIRT1 deacetylated cortactin and promoted the interaction between cortactin and F-actin, thus possibly enhancing the accumulation of cortactin at the injury site. Finally, we performed a membrane repair assay using single fiber myotubes from control and resveratrol-fed mice, where the oral treatment with resveratrol promoted membrane repair ex vivo. These findings suggest that resveratrol promotes membrane repair via the SIRT1/cortactin axis.
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Distrofias Musculares , Sirtuina 1 , Actinas , Animales , Cortactina/metabolismo , Ratones , Ratones Endogámicos mdx , Resveratrol/farmacología , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
A 26-year-old Japanese woman developed a fever, myalgia and gait disturbance one day after receiving the second dose of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. A neurological examination revealed symmetrical weakness and myalgia in proximal lower limbs, and a blood examination showed prominent elevation of creatinine kinase. Magnetic resonance imaging (MRI) revealed a high signal intensity in the thigh muscles on short-tau inversion recovery images, and antibody testing revealed positive findings for anti-signal recognition particle (SRP) antibody. Thus, anti-SRP antibody-positive immune-mediated myopathy was diagnosed. We initiated immunotherapy, and she was ultimately able to walk stably.
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COVID-19 , Enfermedades Musculares , Femenino , Humanos , Adulto , Partícula de Reconocimiento de Señal , SARS-CoV-2 , Vacuna nCoV-2019 mRNA-1273 , Vacunas contra la COVID-19/efectos adversos , Mialgia , Autoanticuerpos , COVID-19/prevención & control , Enfermedades Musculares/etiología , Enfermedades Musculares/tratamiento farmacológico , VacunaciónRESUMEN
SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2-terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-ß (Aß), and overexpression of SIRT3ct suppressed the toxic function of Aß in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions.
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Sirtuina 3 , Animales , Peróxido de Hidrógeno/metabolismo , Ratones , Mitocondrias/metabolismo , Estrés Oxidativo , Células PC12 , Ratas , Sirtuina 3/genética , Sirtuina 3/metabolismo , Ubiquitina/metabolismoRESUMEN
Oxidative stress plays a pivotal role in chronic heart failure. SIRT1, an NAD(+)-dependent histone/protein deacetylase, promotes cell survival under oxidative stress when it is expressed in the nucleus. However, adult cardiomyocytes predominantly express SIRT1 in the cytoplasm, and its function has not been elucidated. The purpose of this study was to investigate the functional role of SIRT1 in the heart and the potential use of SIRT1 in therapy for heart failure. We investigated the subcellular localization of SIRT1 in cardiomyocytes and its impact on cell survival. SIRT1 accumulated in the nucleus of cardiomyocytes in the failing hearts of TO-2 hamsters, postmyocardial infarction rats, and a dilated cardiomyopathy patient but not in control healthy hearts. Nuclear but not cytoplasmic SIRT1-induced manganese superoxide dismutase (Mn-SOD), which was further enhanced by resveratrol, and increased the resistance of C2C12 myoblasts to oxidative stress. Resveratrol's enhancement of Mn-SOD levels depended on the level of nuclear SIRT1, and it suppressed the cell death induced by antimycin A or angiotensin II. The cell-protective effects of nuclear SIRT1 or resveratrol were canceled by the Mn-SOD small interfering RNA or SIRT1 small interfering RNA. The oral administration of resveratrol to TO-2 hamsters increased Mn-SOD levels in cardiomyocytes, suppressed fibrosis, preserved cardiac function, and significantly improved survival. Thus, Mn-SOD induced by resveratrol via nuclear SIRT1 reduced oxidative stress and participated in cardiomyocyte protection. SIRT1 activators such as resveratrol could be novel therapeutic tools for the treatment of chronic heart failure.
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Cardiomiopatía Dilatada/metabolismo , Insuficiencia Cardíaca/metabolismo , Fibras Musculares Esqueléticas/enzimología , Miocitos Cardíacos/enzimología , Sirtuina 1/metabolismo , Superóxido Dismutasa/metabolismo , Adulto , Animales , Cardiomiopatía Dilatada/patología , Núcleo Celular/enzimología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Enfermedad Crónica , Cricetinae , Modelos Animales de Enfermedad , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Insuficiencia Cardíaca/patología , Humanos , Masculino , Mesocricetus , Ratones , Fibras Musculares Esqueléticas/citología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocitos Cardíacos/citología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Fenoles/farmacología , Extractos Vegetales/farmacología , Ratas , Resveratrol , Sirtuina 1/genética , Estilbenos/farmacologíaRESUMEN
Neural precursor cells (NPCs) differentiate into neurons, astrocytes, and oligodendrocytes in response to intrinsic and extrinsic changes. Notch signals maintain undifferentiated NPCs, but the mechanisms underlying the neuronal differentiation are largely unknown. We show that SIRT1, an NAD(+)-dependent histone deacetylase, modulates neuronal differentiation. SIRT1 was found in the cytoplasm of embryonic and adult NPCs and was transiently localized in the nucleus in response to differentiation stimulus. SIRT1 started to translocate into the nucleus within 10 min after the transfer of NPCs into differentiation conditions, stayed in the nucleus, and then gradually retranslocated to the cytoplasm after several hours. The number of neurospheres that generated Tuj1(+) neurons was significantly decreased by pharmacological inhibitors of SIRT1, dominant-negative SIRT1 and SIRT1-siRNA, whereas overexpression of SIRT1, but not that of cytoplasm-localized mutant SIRT1, enhanced neuronal differentiation and decreased Hes1 expression. Expression of SIRT1-siRNA impaired neuronal differentiation and migration of NPCs into the cortical plate in the embryonic brain. Nuclear receptor corepressor (N-CoR), which has been reported to bind SIRT1, promoted neuronal differentiation and synergistically increased the number of Tuj1(+) neurons with SIRT1, and both bound the Hes1 promoter region in differentiating NPCs. Hes1 transactivation by Notch1 was inhibited by SIRT1 and/or N-CoR. Our study indicated that SIRT1 is a player of repressing Notch1-Hes1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of NPCs.
Asunto(s)
Diferenciación Celular , Núcleo Celular/metabolismo , Histona Desacetilasas/metabolismo , Neuronas/citología , Sirtuinas/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Animales , Células Cultivadas , Citoplasma/metabolismo , Femenino , Ratones , Neuronas/metabolismo , Embarazo , Sirtuina 1RESUMEN
A 59-year-old woman presented with a 7-year history of facial numbness on the left side, and gradual worsening of symptoms. Over several years, facial muscle weakness, dysarthria, tongue atrophy and fasciculation had progressed. Then, she developed cerebellar ataxia affecting the left extremities, in addition to earlier symptoms. Brain MRI revealed cerebellar atrophy, and 99mTc-SPECT depicted cerebellar hypoperfusion. A repetitive nerve stimulation test (RNS) indicated abnormal decrement in the nasalis and trapezius muscles on the left side. Facial-onset sensory and motor neuronopathy (FOSMN) was diagnosed. Administration of intravenous immunoglobulin resulted in improvement of some symptoms. Although cerebellar ataxia is not a common symptom of FOSMN, a case showing TDP-43-positive glial cytoplasmic inclusions in cerebellar white matter has been reported. Therefore, it is possible that FOSMN may cause cerebellum impairment in some patients. Furthermore, RNS positive rate in the trapezius muscle is known to be high in amyotrophic lateral sclerosis (ALS) patients. It is speculated that RNS of the affected muscles in FOSMN may show abnormal decrement by the same mechanisms as ALS.