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1.
Antioxid Redox Signal ; 37(1-3): 208-228, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-34428933

RESUMO

Significance: Reactive species have been classically considered causative of age-related degenerative processes, but the scenario appears considerably more complex and to some extent counterintuitive than originally anticipated. The impact of reactive species in precocious aging syndromes is revealing new clues to understand and perhaps challenge the resulting degenerative processes. Recent Advances: Our understanding of reactive species has considerably evolved, including their hormetic effect (beneficial at a certain level, harmful beyond this level), the occurrence of diverse hormetic peaks in different cell types and organisms, and the extended type of reactive species that are relevant in biological processes. Our understanding of the impact of reactive species has also expanded from the dichotomic damaging/signaling role to modulation of gene expression. Critical Issues: These new concepts are affecting the study of aging and diseases where aging is greatly accelerated. We discuss how notions arising from the study of the underlying mechanisms of a progeroid disease, Cockayne syndrome, represent a paradigm shift that may shed a new light in understanding the role of reactive species in age-related degenerative processes. Future Issues: Future investigations urge to explore established and emerging notions to elucidate the multiple contributions of reactive species in degenerative processes linked to pathophysiological aging and their possible amelioration. Antioxid. Redox Signal. 37, 208-228.


Assuntos
Envelhecimento , Síndrome de Cockayne , Espécies Reativas de Nitrogênio , Espécies Reativas de Oxigênio , Enxofre , Animais , Antioxidantes/uso terapêutico , Síndrome de Cockayne/fisiopatologia , Síndrome de Down/fisiopatologia , Humanos , Mitocôndrias , Estresse Oxidativo , Progéria/fisiopatologia , Espécies Reativas de Nitrogênio/química , Espécies Reativas de Oxigênio/química , Transdução de Sinais , Enxofre/química , Síndrome de Werner/fisiopatologia
2.
Nat Commun ; 10(1): 5576, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811121

RESUMO

Cellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response. Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53-independent manner. This activity of CSB is independent of its role in the repair of UV-induced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress. These findings establish a CSB/p21 axis that acts as a barrier to replicative senescence, and link a progeroid factor with the process of regular ageing in human.


Assuntos
Senescência Celular/fisiologia , Síndrome de Cockayne/metabolismo , DNA Helicases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Histonas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Linhagem Celular , Senescência Celular/genética , Síndrome de Cockayne/genética , Síndrome de Cockayne/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , DNA/metabolismo , DNA/efeitos da radiação , Dano ao DNA , DNA Helicases/genética , Reparo do DNA , Enzimas Reparadoras do DNA/genética , Regulação para Baixo , Epigenômica , Fibroblastos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transcriptoma , Raios Ultravioleta/efeitos adversos
3.
J Pathol ; 242(2): 221-233, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28337746

RESUMO

Thymidylate synthase (TS) is a fundamental enzyme of nucleotide metabolism and one of the oldest anti-cancer targets. Beginning from the analysis of gene array data from the NCI-60 panel of cancer cell lines, we identified a significant correlation at both gene and protein level between TS and the markers of epithelial-to-mesenchymal transition (EMT), a developmental process that allows cancer cells to acquire features of aggressiveness, like motility and chemoresistance. TS levels were found to be significantly augmented in mesenchymal-like compared to epithelial-like cancer cells, to be regulated by EMT induction, and to negatively correlate with micro-RNAs (miRNAs) usually expressed in epithelial-like cells and known to actively suppress EMT. Transfection of EMT-suppressing miRNAs reduced TS levels, and a specific role for miR-375 in targeting the TS 3'-untranslated region was identified. A particularly relevant association was found between TS and the powerful EMT driver ZEB1, the shRNA-mediated knockdown of which up-regulated miR-375 and reduced TS cellular levels. The TS-ZEB1 association was confirmed in clinical specimens from lung tumours and in a genetic mouse model of pancreatic cancer with ZEB1 deletion. Interestingly, TS itself appeared to have a regulatory role in EMT in cancer cells, as TS knockdown could directly reduce the EMT phenotype, the migratory ability of cells, the expression of stem-like markers, and chemoresistance. Taken together, these data indicate that the TS enzyme is functionally linked with EMT and cancer differentiation, with several potential translational implications. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Transição Epitelial-Mesenquimal , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Timidilato Sintase/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , RNA Interferente Pequeno/genética , Timidilato Sintase/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
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