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Archives of Pharmacal Research

, Volume 40, Issue 9, pp 1071–1086 | Cite as

Tryptanthrin prevents oxidative stress-mediated apoptosis through AMP-activated protein kinase-dependent p38 mitogen-activated protein kinase activation

  • Eun Hye Jung
  • Ji Yun Jung
  • Hae Li Ko
  • Jae Kwang Kim
  • Sang Mi Park
  • Dae Hwa Jung
  • Chung A Park
  • Young Woo Kim
  • Sae Kwang Ku
  • Il Je ChoEmail author
  • Sang Chan KimEmail author
Research Article

Abstract

Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) has been reported to have a variety of pharmacological activities. Present study investigated the cytoprotective effects of tryptanthrin on arachidonic acid (AA) + iron-mediated oxidative stress and the molecular mechanisms responsible. In HepG2 cells, pretreatment with tryptanthrin inhibited the cytotoxic effect of AA + iron in a concentration-dependent manner. In addition, tryptanthrin prevented the changes in the levels of apoptosis-related proteins, and attenuated reactive oxygen species production, glutathione depletion, and mitochondrial membrane impairment induced by AA + iron. Mechanistic investigations showed that tryptanthrin increased the phosphorylations of AMP-activated protein kinase (AMPK) and of p38 mitogen-activated protein kinase (p38). Furthermore, inhibition of AMPK or p38 reduced the ability of tryptanthrin to prevent AA + iron-induced cell death and mitochondrial dysfunction. Transfection experiments using AMPK mutants indicated that p38 phosphorylation by tryptanthrin was dependent on AMPK activation. In a phenylhydrazine-induced acute liver injury model, tryptanthrin decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin in mice. Additionally, tryptanthrin reduced numbers of degenerating hepatocytes, infiltrating inflammatory cells, 4-hydroxynonenal-, and nitrotyrosine-positive cells in hepatic tissues. Thus, these results suggest tryptanthrin has therapeutic potential to protect cells from oxidative injury via AMPK-dependent p38 activation.

Keywords

Acute liver injury AMP-activated protein kinase Oxidative stress p38 mitogen-activated protein kinase Tryptanthrin 

Notes

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (No. 2012 R1A5A2A42671316) and by Korea Institute of Oriental Medicine (KIOM) (K16823).

Compliance with ethical standards

Conflict of interest

The authors declare that we have no conflict of interests.

Supplementary material

12272_2017_947_MOESM1_ESM.docx (991 kb)
Supplementary material 1 (DOCX 991 kb)

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Copyright information

© The Pharmaceutical Society of Korea 2017

Authors and Affiliations

  1. 1.College of Korean MedicineDaegu Haany UniversityGyeongsanRepublic of Korea
  2. 2.HaniBio Co., LtdGyeongsanRepublic of Korea

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