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The NRF2-LOC344887 signaling axis suppresses pulmonary fibrosis.
Liu, Pengfei; Luo, Gang; Dodson, Matthew; Schmidlin, Cody J; Wei, Yongyi; Kerimoglu, Baris; Ooi, Aikseng; Chapman, Eli; Garcia, Joe Gn; Zhang, Donna D.
Afiliação
  • Liu P; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • Luo G; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • Dodson M; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • Schmidlin CJ; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • Wei Y; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • Kerimoglu B; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • Ooi A; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ, 85721, USA.
  • Chapman E; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ, 85721, USA.
  • Garcia JG; Department of Medicine, University of Arizona Health Sciences, University of Arizona, Tucson, AZ, 85721, USA.
  • Zhang DD; Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA; University of Arizona Cancer Center, University of Arizona, Tucson, AZ, 85721, USA. Electronic address: dzhang@pharmacy.arizona.edu.
Redox Biol ; 38: 101766, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33126057
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by an increase in differentiation of fibroblasts to myofibroblasts and excessive accumulation of extracellular matrix in lung tissue. Pharmacological activation of NRF2 has proved to be a valuable antifibrotic approach, however the detailed mechanisms of how NRF2 mediates antifibrotic function remain unclear. In this study, we found that the antifibrotic function of sulforaphane (SFN), an NRF2 activator, was largely dependent on LOC344887, a long noncoding RNA. Two functional AREs were identified in both the promoter and intron 1 of LOC344887, which defines LOC344887 as a novel anti-fibrotic NRF2 target gene. RNA-seq analysis revealed that LOC344887 controls genes and signaling pathways associated with fibrogenesis. Deletion or downregulation of LOC344887 enhanced expression of CDH2/N-cadherin, as well as a number of other fibrotic genes and blunted the antifibrotic effects of SFN. Furthermore, LOC344887-mediated downregulation of fibrotic genes may involve the PI3K-AKT signaling pathway, as pharmacologic inhibition of PI3K activity blocked the effects of LOC344887 knockdown. Our findings demonstrate that NRF2-mediated LOC344887 upregulation contributes to the antifibrotic potential of SFN by repressing the expression of CDH2 and other fibrotic genes, providing novel insight into how NRF2 controls the regulatory networks of IPF. This study provides a better understanding of the molecular mechanisms of NRF2 activators against pulmonary fibrosis and presents a novel therapeutic axis for prevention and intervention of fibrosis-related diseases.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Revista: Redox Biol Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Revista: Redox Biol Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Estados Unidos