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1.
Stem Cell Res Ther ; 14(1): 188, 2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37507770

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study. METHODS: Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency. RESULTS: FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages. CONCLUSION: These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.


Assuntos
Senescência Celular , Células-Tronco Mesenquimais , Animais , Humanos , Camundongos , Diferenciação Celular/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Histona Desacetilases/genética , Células-Tronco Mesenquimais/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
3.
Development ; 149(7)2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35297993

RESUMO

Beige adipocytes have a discrete developmental origin and possess notable plasticity in their thermogenic capacity in response to various environmental cues, but the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, forkhead box P4 (FOXP4), that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis capacity upon cold exposure. Of note, the outcome of Foxp4 deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we suggest that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program.


Assuntos
Adipócitos Bege , Adipócitos Marrons , Animais , Diferenciação Celular/genética , Regulação da Expressão Gênica , Camundongos , Termogênese/genética
4.
J Bone Miner Res ; 36(10): 2017-2026, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34131944

RESUMO

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism. © 2021 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Tecido Adiposo , Metabolismo Energético , Tecido Adiposo/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Osteoblastos/metabolismo
5.
Nat Commun ; 10(1): 5070, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699980

RESUMO

ß-Adrenergic receptor (ß-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the ß3-adrenergic receptor (ß3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses ß3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.


Assuntos
Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Adipogenia/genética , Metabolismo Energético/genética , Fatores de Transcrição Forkhead/genética , Receptores Adrenérgicos beta 3/genética , Proteínas Repressoras/genética , Termogênese/genética , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Camundongos , Obesidade/genética , Obesidade/metabolismo , Omento/metabolismo , Feocromocitoma/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteínas Repressoras/metabolismo
6.
Virology ; 518: 202-209, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29525670

RESUMO

Classical swine fever virus (CSFV) nonstructural protein NS5A is a multifunctional protein functioning in regulation of viral genome replication, protein translation and assembly by interaction with viral or host proteins. Here, heat shock protein 27 (Hsp27) has been identified as a novel binding partner of NS5A by using His tag "pull down" coupled with shotgun LC-MS/MS, with interaction of both proteins further confirmed by co-immunoprecipitation and laser confocal assays. In PK-15 cells, silencing of Hsp27 expression by siRNA enhanced CSFV replication, and upregulation of Hsp27 inhibited viral proliferation. Additionally, we have shown that overexpression of Hsp27 increased NF-κB signaling induced by TNFα. Blocking NF-κB signaling in PK-15 cells overexpressing Hsp27 by ammonium pyrrolidinedithiocarbamate (PDTC) eliminated the inhibition of CSFV replication by Hsp27. These findings clearly demonstrate that the inhibition of CSFV replication by Hsp27 is mediated via the NF-κB signaling pathway.


Assuntos
Vírus da Febre Suína Clássica/imunologia , Vírus da Febre Suína Clássica/fisiologia , Proteínas de Choque Térmico HSP27/metabolismo , Interações Hospedeiro-Patógeno , NF-kappa B/metabolismo , Proteínas não Estruturais Virais/metabolismo , Replicação Viral , Animais , Linhagem Celular , Cromatografia Líquida , Imunoprecipitação , Microscopia Confocal , Ligação Proteica , Mapeamento de Interação de Proteínas , Suínos , Espectrometria de Massas em Tandem
7.
Artigo em Inglês | MEDLINE | ID: mdl-26999624

RESUMO

INTRODUCTION: Hypertension has shown to be an important risk factor for the decline in cognitive function. Aim of our study is to investigate the presence of cognitive impairment of the elders with hypertension and other confounding factors. METHODS: This study was conducted on 400 veterans who were matched one-to-one with the confounding factors for assessing the presence of mild cognitive impairment using both MMSE and Montreal Cognitive Assessment (MoCA). The 13 related factors of patient data were studied. RESULTS: The prevalence rate of cognitive impairment was 29.25%. Age (OR 2.679, 95%CI 1.663-6.875), sleep impairment (OR 1.117, 95%CI 1.754-7.422), uncontrolled hypertension (OR 1.522, 95%CI 1.968-4.454), type 2 diabetes (OR 2.464, 95%CI 1.232-4.931), and hyperlipidaemia (OR 1.411, 95%CI 1.221-8.988) are the risk factors for the cognitive deterioration, while the protective factors are high level of education (OR 0.032, 95%CI 0.007-0.149) and regular exercise (OR 0.307, 95%CI 0.115-0.818). DISCUSSION: Because some vascular disease risk factors, such as hypertension, can be treated effectively, cognitive decline related to these risk factors, and vascular disease per se, may be prevented or its course modified through more aggressive treatment and improved compliance.


Assuntos
Disfunção Cognitiva/epidemiologia , Hipertensão/epidemiologia , Veteranos , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/epidemiologia , Ingestão de Líquidos , Escolaridade , Exercício Físico , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Prevalência , Fatores de Risco , Fatores Sexuais , Fumar , Veteranos/psicologia
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