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Upregulation of BCL-2 by acridone derivative through gene promoter i-motif for alleviating liver damage of NAFLD/NASH.
Li, Xiaoya; Wang, Jing; Gong, Xue; Zhang, Meiling; Kang, Shuangshuang; Shu, Bing; Wei, Zuzhuang; Huang, Zhi-Shu; Li, Ding.
Afiliação
  • Li X; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Wang J; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Gong X; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Zhang M; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Kang S; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Shu B; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Wei Z; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Huang ZS; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
  • Li D; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, 132 Wai huan East Road, Guangzhou 510006, P. R. China.
Nucleic Acids Res ; 48(15): 8255-8268, 2020 09 04.
Article em En | MEDLINE | ID: mdl-32710621
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are global epidemic public health problems with pathogenesis incompletely understood. Hepatocyte excessive apoptosis is a significant symbol for NAFLD/NASH patients, and therefore anti-apoptosis therapy could be used for NAFLD/NASH treatment. Up-regulation of BCL-2 has been found to be closely related with anti-apoptosis. BCL-2 gene promoter region has a C-rich sequence, which can form i-motif structure and play important role in regulating gene transcription. In this study, after extensive screening and evaluation, we found that acridone derivative A22 could up-regulate BCL-2 transcription and translation in vitro and in cells through selective binding to and stabilizing BCL-2 gene promoter i-motif. Our further experiments showed that A22 could reduce hepatocyte apoptosis in NAFLD/NASH model possibly through up-regulating BCL-2 expression. A22 could reduce inflammation, endoplasmic reticulum stress and cirrhosis in high-fat diet-fed mice liver model. Our findings provide a potentially new approach of anti-apoptosis for NAFLD/NASH treatment, and A22 could be further developed as a lead compound for NAFLD/NASH therapy. Our present study first demonstrated that gene promoter i-motif could be targeted for gene up-regulation for extended treatment of other important diseases besides cancer.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação para Cima / Genes bcl-2 / Acridonas / Hepatopatia Gordurosa não Alcoólica Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação para Cima / Genes bcl-2 / Acridonas / Hepatopatia Gordurosa não Alcoólica Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article