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Front. Pharmacol. | doi: 10.3389/fphar.2018.01469

Protective Effects of Costunolide against D-Galactosamine and Lipopolysaccharide-Induced Acute Liver Injury in Mice.

 Jingxin Mao1, Man Yi1, Rui Wang1, Yuanshe Huang1 and  Min Chen1*
  • 1College of Pharmaceutical Sciences, Southwest University, China

Costunolide, a sesquiterpene isolated from Vladimiria souliei (Franch.) Ling, is known to exhibit anti-inflammatory, anti-viral, and anti-tumor activities. However, the effects of costunolide on liver injury are poorly understood. The current study aimed to investigate the hepatoprotective effects of costunolide against lipopolysaccharide and D-galactosamine-induced acute liver injury in mice. The results indicated that costunolide (40 mg/kg) could significantly improve the pathological changes of hepatic tissue, reduced the lipopolysaccharide and D-galactosamine-induced increases of alanine aminotransferase (from 887.24±21.72 to 121.67±6.56 IU/L) and aspartate aminotransferase (from 891.01±45.24 to 199.94±11.53 IU/L) activities in serum. Further research indicated that costunolide significantly reduced malondialdehyde content (from 24.56±1.39 to 9.17±0.25 nmol/ml) and reactive oxygen species (from 203.34±7.68% to 144.23±7.12%), increased the activity of anti-oxidant enzymes superoxide dismutase (from 153.74±10.33 to 262.27±8.39 U/ml), catalase (from 6.12±0.30 to 12.44±0.57 U/ml) and total anti-oxidant capacity (from 0.64±0.06 to 6.29±0.11 U/ml) in hepatic tissues. Western blot results revealed that costunolide trigger the anti-oxidative defense system by inhibiting kelch-like ECH-associated protein 1 and nuclear factor-related factor 2 (cytosol), increasing nuclear factor-related factor 2 (nucleus), heme oxygenase-1 and NAD (P) H quinone oxidoreductase 1 activity. Moreover, costunolide significantly decreased the protein expression of pro-inflammatory cytokines including interleukin 1β, interleukin 6, and tumor necrosis factor. Pretreatment with costunolide could reduce the expression of toll-like receptor 4, myeloid differentiation factor 88, p65 (Nucleus), phosphorylated IκB kinase α/β, inhibitor of nuclear factor kappa-B kinase, inhibitor kappa Bα, and prevent the expression of phosphorylated inhibitor kappa B kinase which repressed translocation of p65 from cytoplasm to nucleus. In addition, pretreatment with costunolide also inhibited hepatocyte apoptosis by reducing the expression of B-cell lymphoma 2 associated X, cytochrome C, cysteinyl aspartate specific proteinase 3, cysteinyl aspartate specific proteinase 8 and cysteinyl aspartate specific proteinase 9, as well as is increased B-cell lymphoma 2. The protective effects of costunolide against lipopolysaccharide and D-galactosamine -induced acute liver injury might attributed to its anti-oxidative activity in nuclear factor-related factor 2 signaling pathways, anti-inflammatory suppression in nuclear factor-kappa B signaling pathways, and inhibition of hepatocyte apoptosis. Thus, costunolide may be a potential therapeutic agent in attenuating acute liver injury in the future.

Keywords: Acute liver injury, Costunolide, Vladimiria souliei; anti-oxidation, anti-inflammatory, anti-apoptosis

Received: 18 Dec 2017; Accepted: 30 Nov 2018.

Edited by:

DINKAR SAHAL, International Centre for Genetic Engineering and Biotechnology (India), India

Reviewed by:

Haoxing Zhang, Shenzhen University, China
Haihua Feng, Jilin University, China  

Copyright: © 2018 Mao, Yi, Wang, Huang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Min Chen, Southwest University, College of Pharmaceutical Sciences, Chongqing, 400715, China, mminchen@swu.edu.cn