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Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.
Hao, Yawen; Song, Shaohua; Li, Tao; Zai, Qiuhong; Ma, Ningning; Li, Yixin; Yang, Liu; Xiao, Peng; Xu, Tianyue; Ji, Longshan; Tan, Jiaxin; Ahmed, Yeni Ait; Xiang, Xiaogang; Wang, Xiaolin; Lafdil, Fouad; Xie, Qing; He, Yong.
Afiliación
  • Hao Y; Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • Song S; University of Chinese Academy of Sciences, Beijing, China.
  • Li T; Department of General Surgery or Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zai Q; Department of General Surgery or Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Ma N; Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • Li Y; University of Chinese Academy of Sciences, Beijing, China.
  • Yang L; Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • Xiao P; University of Chinese Academy of Sciences, Beijing, China.
  • Xu T; Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China.
  • Ji L; Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • Tan J; University of Chinese Academy of Sciences, Beijing, China.
  • Ahmed YA; Department of Hepatology, First Hospital of Jilin University, Jilin University, Changchun, Jilin, China.
  • Xiang X; Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
  • Wang X; Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Lafdil F; Laboratory of Cellular Immunity, Shanghai Key Laboratory of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Xie Q; Medizinische Klinik m. S. Hepatologie und Gastroenterologie Charité Universitätsmedizin Berlin, Germany.
  • He Y; Department of General Surgery or Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Int J Biol Sci ; 20(7): 2422-2439, 2024.
Article en En | MEDLINE | ID: mdl-38725842
ABSTRACT
Background &

Aims:

Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown.

Methods:

Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models.

Results:

In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis.

Conclusions:

Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Estrés Oxidativo / MicroARNs / Proteínas Quinasas p38 Activadas por Mitógenos / Células Estrelladas Hepáticas / Complejo Correpresor Histona Desacetilasa y Sin3 / Cirrosis Hepática Límite: Animals / Humans / Male Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Estrés Oxidativo / MicroARNs / Proteínas Quinasas p38 Activadas por Mitógenos / Células Estrelladas Hepáticas / Complejo Correpresor Histona Desacetilasa y Sin3 / Cirrosis Hepática Límite: Animals / Humans / Male Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia