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Hydronidone induces apoptosis in activated hepatic stellate cells through endoplasmic reticulum stress-associated mitochondrial apoptotic pathway.
Sun, Zhongshang; Guo, Yuecheng; Xu, Xianjun; Zhou, Cui; Luo, Xin; Shen, Zhenyang; Shen, Bo; Wang, Junjun; Lu, Jingyi; Zhang, Qingqing; Shen, Feifei; Yu, Lou; Ye, Yanping; Zhang, Ling; Luo, Ying; Qu, Ying; Cai, Xiaobo; Dong, Hui; Lu, Lungen.
Afiliación
  • Sun Z; Department of Gastroenterology, Shanghai General Hospital of Nanjing Medical University, Shanghai, China.
  • Guo Y; Department of Gastroenterology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.
  • Xu X; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhou C; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Luo X; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Shen Z; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Shen B; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Wang J; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Lu J; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang Q; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Shen F; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Yu L; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Ye Y; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhang L; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Luo Y; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Qu Y; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Cai X; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Dong H; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Lu L; Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Gastroenterol Hepatol ; 39(8): 1695-1703, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38804845
ABSTRACT
BACKGROUND AND

AIM:

Hydronidone (HDD) is a novel pirfenidone derivative developed initially to reduce hepatotoxicity. Our previous studies in animals and humans have demonstrated that HDD treatment effectively attenuates liver fibrosis, yet the underlying mechanism remains unclear. This study aimed to investigate whether HDD exerts its anti-fibrotic effect by inducing apoptosis in activated hepatic stellate cells (aHSCs) through the endoplasmic reticulum stress (ERS)-associated mitochondrial apoptotic pathway.

METHODS:

The carbon tetrachloride (CCl4)- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver fibrosis models were used for in vivo studies. In vitro studies were conducted using the human hepatic stellate cell line LX-2. The apoptotic effect of HDD on aHSCs was examined using TUNEL and flow cytometry assays. The small interfering RNA (siRNA) technique was employed to downregulate the expression of interest genes.

RESULTS:

HDD treatment significantly promoted apoptosis in aHSCs in both the CCl4- and DDC-induced liver fibrosis in mice and LX-2 cells. Mechanistic studies revealed that HDD triggered ERS and subsequently activated the IRE1α-ASK1-JNK pathway. Furthermore, the influx of cytochrome c from the mitochondria into the cytoplasm was increased, leading to mitochondrial dysfunction and ultimately triggering apoptosis in aHSCs. Notably, inhibition of IRE1α or ASK1 by siRNA partially abrogated the pro-apoptotic effect of HDD in aHSCs.

CONCLUSIONS:

The findings of both in vivo and in vitro studies suggest that HDD induces apoptosis in aHSCs via the ERS-associated mitochondrial apoptotic pathway, potentially contributing to the amelioration of liver fibrosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / Células Estrelladas Hepáticas / Estrés del Retículo Endoplásmico / Cirrosis Hepática Límite: Animals / Humans / Male Idioma: En Revista: J Gastroenterol Hepatol Asunto de la revista: GASTROENTEROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / Células Estrelladas Hepáticas / Estrés del Retículo Endoplásmico / Cirrosis Hepática Límite: Animals / Humans / Male Idioma: En Revista: J Gastroenterol Hepatol Asunto de la revista: GASTROENTEROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia