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1.
Cell ; 176(6): 1407-1419.e14, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827680

RESUMO

The function of somatic stem cells declines with age. Understanding the molecular underpinnings of this decline is key to counteract age-related disease. Here, we report a dramatic drop in the neural stem cells (NSCs) number in the aging murine brain. We find that this smaller stem cell reservoir is protected from full depletion by an increase in quiescence that makes old NSCs more resistant to regenerate the injured brain. Once activated, however, young and old NSCs show similar proliferation and differentiation capacity. Single-cell transcriptomics of NSCs indicate that aging changes NSCs minimally. In the aging brain, niche-derived inflammatory signals and the Wnt antagonist sFRP5 induce quiescence. Indeed, intervention to neutralize them increases activation of old NSCs during homeostasis and following injury. Our study identifies quiescence as a key feature of old NSCs imposed by the niche and uncovers ways to activate NSCs to repair the aging brain.


Assuntos
Encéfalo/fisiologia , Fatores Etários , Animais , Encéfalo/citologia , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Proliferação de Células/fisiologia , Senescência Celular/fisiologia , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Nervosa , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese , Nicho de Células-Tronco
2.
J Neurol ; 266(1): 57-67, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30377816

RESUMO

BACKGROUND: With ocrelizumab another drug is available for the treatment of multiple sclerosis (MS). Little is known on the long-term use of ocrelizumab on immune cell subsets, and no surrogate markers are available. Rituximab (RTX) has been in off-label use for the treatment of MS, neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) for > 10 years. OBJECTIVE: We evaluated the long-term depletion and repopulation rate of peripheral CD19+ B-cells as a potential surrogate for the clinical outcome, and whether it may serve for dosage and time-to-infusion decision making. METHODS: We evaluated the CD19+ and CD4+/8+ T-cell counts in n = 153 patients treated with RTX (132 MS, 21 NMO/NMOSD). The dosages ranged from 250 to 2000 mg RTX. Depletion/repopulation rates of CD19+ B-cells as well as long-term total lymphocyte cell counts, were assessed and corroborated with EDSS, ARR (annualized relapse rate), MRI, and time to reinfusion. RESULTS: CD19+ B-cells' repopulation rate significantly varied depending on the dosage applied leading to individualized application intervals (mean 9.73 ± 0.528 months). Low/absent CD19+ B-cell counts were associated with reduced ARR, EDSS, and GD+-MRI-lesions. Long-term B-cell-depleting therapy led to a transiently skewed CD4+/8+ T-cell ratio due to reduced CD4+ T-cells and absolute lymphocyte counts, which recovered after the second cycle. CONCLUSION: Our data suggest that CD19+ B-cell repopulation latency may serve as surrogate marker for individualized treatment strategies in MS and NMO/NMOSD, which proved clinically equally effective in our cohort as evaluated by previous studies.


Assuntos
Esclerose Múltipla/sangue , Esclerose Múltipla/terapia , Neuromielite Óptica/sangue , Neuromielite Óptica/terapia , Adulto , Antígenos CD19/metabolismo , Linfócitos B/imunologia , Relação Dose-Resposta Imunológica , Feminino , Seguimentos , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/imunologia , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/imunologia , Linfócitos T/imunologia
3.
J Neurol Sci ; 356(1-2): 193-5, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26104570

RESUMO

Hypereosinophilic syndrome represents a rare cause for cerebral infarctions and inflammatory neurological disorders. Various possible pathogenic mechanisms for cerebral infarctions have already been discussed. Complex mechanisms including a local hypercoagulability by eosinophilic granules as well as a direct damage to endothelial cells, leading to alterations of the microcirculation seem to be involved. The changing pattern of heroin use to inhalation/sniffing leading to an increasing abuse may cause a rise in the prevalence of Heroin induced eosinophilia, as it has been reported in a case of eosinophilic pneumonia associated with heroin inhalation. To our knowledge, the present case report displays the first description of stroke in the setting of heroin induced hypereosinophilia. Thus, besides usual vasoconstriction, HES should be considered in drug-induced cerebral infarctions.


Assuntos
Infarto Cerebral/etiologia , Heroína/efeitos adversos , Síndrome Hipereosinofílica/induzido quimicamente , Síndrome Hipereosinofílica/complicações , Adulto , Infarto Cerebral/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino
4.
PLoS One ; 9(4): e94772, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24722418

RESUMO

The tissue distribution and function of hemoglobin or myoglobin are well known; however, a newly found cytoglobin (CYGB), which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2'-, 7'-dichlorofluorescein diacetate (DCFH-DA), an indicator of reactive oxygen species (ROS), revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition.


Assuntos
Transformação Celular Neoplásica/patologia , Globinas/metabolismo , Melanócitos/patologia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Citoglobina , Metilação de DNA , Epigênese Genética , Humanos , Melanócitos/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo
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