2. Academic Validation
  3. Gigantol ameliorates CCl4-induced liver injury via preventing activation of JNK/cPLA2/12-LOX inflammatory pathway

Gigantol ameliorates CCl4-induced liver injury via preventing activation of JNK/cPLA2/12-LOX inflammatory pathway

  • Sci Rep. 2020 Dec 17;10(1):22265. doi: 10.1038/s41598-020-79400-0.
Yaru Xue 1 2,  Qiangqiang Deng 1,  Qingli Zhang 3,  Zhenghua Ma 4 5 6,  Binfan Chen 1 2,  Xiaolu Yu 1 2,  Huige Peng 1,  Sheng Yao 1 4 5,  Jia Liu 3,  Yang Ye 7 8 9 10,  Guoyu Pan 11 12
Affiliations

Affiliations

  • 1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Institutional Technology Service Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 State Key Laboratory of Drug Research and Natural Products Chemistry Department Shanghai, Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 SIMM-CUHK Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines, Shanghai, 201203, China.
  • 6 School of Life Science and Technology, Shanghai Tech University, Shanghai, 201203, China.
  • 7 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 8 State Key Laboratory of Drug Research and Natural Products Chemistry Department Shanghai, Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 9 SIMM-CUHK Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines, Shanghai, 201203, China. [email protected].
  • 10 School of Life Science and Technology, Shanghai Tech University, Shanghai, 201203, China. [email protected].
  • 11 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 12 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
PMID: 33335297 DOI: 10.1038/s41598-020-79400-0
Abstract

Arachidonic acid (AA) signaling pathway is an important constituent of inflammatory processes. In our previous study, it was found that dihydro-stilbene gigantol relieved hepatic inflammation in mice with CCl4-induced acute liver injury. This study aimed to investigate the involvement of arachidonate metabolic cascade in this process. Our results showed CCl4 activated AA metabolism with the evidence of cPLA2 phosphorylation, which was dependent on the MAPK/JNK activation. Pretreatment with JNK Inhibitor SU3327 or gigantol abolished the cPLA2 activation, along with the attenuation of liver damage. Besides, gigantol markedly decreased immune cells activation. Metabolomic analysis revealed that gigantol universally reversed the upregulation of major AA metabolites in injured mouse livers induced by CCl4, especially 12-hydroxyeicosatetraenoic acid (12-HETE). Gigantol also decreased the mRNA and protein expression of platelet-, and leukocyte-type 12-lipoxxygenase (LOX) in the liver. Furthermore, pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) and specific 12-LOX inhibitors baicalein and ML351 attenuated the liver injury to the same extent as gigantol. Overall, our study elucidated a comprehensive profile of AA metabolites during hepatic inflammation caused by CCl4, highlighting the role of 12-LOX-12-HETE pathway in this process. And gigantol alleviated liver inflammation partly through inhibiting the JNK/cPLA2/12-LOX pathway.

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