Gallic acid selectively induces the necrosis of activated hepatic stellate cells via a calcium-dependent calpain i activation pathway

Shu Chung Hsieh, Chi Hao Wu, Chun Chi Wu, Jung Hsing Yen, Mei Chun Liu, Chi Mei Hsueh, Shih Lan Hsu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Aims The activation of hepatic stellate cells (HSCs) in response to liver injury is critical to the development of liver fibrosis, thus, the blockage of the activation of HSCs is considered as a rational approach for anti-fibrotic treatment. In this report, we investigated the effects and the underlying mechanisms of gallic acid (GA) in interfering with the activation of HSCs. Main methods The primary cultured rat HSCs were treated with various doses of GA for different time intervals. The morphology, viability, caspase activity, calcium ion flux, calpain I activity, reactive oxygen species generation and lysosomal functions were then investigated. Key findings GA selectively killed HSCs in both dose- and time-dependent manners, while remained no harm to hepatocytes. Besides, caspases were not involved in GA-induced cell death of HSCs. Further results showed that GA toxicity was associated with a rapid burst of reactive oxygen species (ROS) and a subsequent increase of intracellular Ca2 + and calpain activity. Addition of calpain I but not calpain II inhibitor rescued HSCs from GA-induced death. In parallel, pretreatment with antioxidants or an intracellular Ca2 + chelator eradicated GA responses, implying that GA-mediated cytotoxicity was dependent on its pro-oxidative properties and its effect on Ca2 + flux. Furthermore, application of ROS scavengers also reversed Ca2 + release and the disruption of lysosomal membranes in GA-treated HSCs. Significance These results provide evidence for the first time that GA causes selective HSC death through a Ca2 +/calpain I-mediated necrosis cascade, suggesting that GA may represent a potential therapeutic agent to combat liver fibrosis.

Original languageEnglish
Pages (from-to)55-64
Number of pages10
JournalLife Sciences
Volume102
Issue number1
DOIs
Publication statusPublished - Apr 25 2014

Keywords

  • Calcium
  • Calpain
  • Gallic acid
  • Hepatic stellate cells
  • Necrosis

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Gallic acid selectively induces the necrosis of activated hepatic stellate cells via a calcium-dependent calpain i activation pathway'. Together they form a unique fingerprint.

  • Cite this