TY - JOUR
T1 - Prevention of TGF-β-induced early liver fibrosis by a maleic acid derivative antioxidant through suppression of ROS, inflammation and hepatic stellate cells activation
AU - Yang, Kun Lin
AU - Chang, Wen Teng
AU - Hong, Ming Yuan
AU - Hung, Kuo Chen
AU - Chuang, Chia Chang
N1 - Funding Information:
We are greatly indebted to Professor Maria Trojanowska of the Medical University of South Carolina for Col 1A2 promoter construct, Professor Wen-Chang Chang, Department of Pharmacology, College of Medicine, National Cheng Kung University, Taiwan, for Cox-2 promoter construct and Professor Paturu Kondaiah, Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, India, for pPk9a. We also gratefully acknowledge the kind provision of HSC-T6 cells by Dr. Scott L. Friedman, Division of Liver Diseases, the Mount Sinai School of Medicine, New York, NY, U. S. A. This work was partially supported by a grant from the National Science Council, Taiwan (NSC 93-2622-B-006-002-CC3). We thank also the Simpson Biotech Co. Ltd., Taiwan for providing compound 2.
Publisher Copyright:
© 2017 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/4
Y1 - 2017/4
N2 - Current anti-fibrotic effect of antioxidants in vivo is disappointing due probably to the fact that once liver fibrogenesis is established it is too advanced to be reversed by anti-oxidation mechanism. We consider antioxidant may only act on the early phase of fibrogenesis. Thus, we had previously established an early liver fibrosis animal model using an inducible expression vector (pPK9a), which contains TGF-β gene and was hydro-dynamically transferred into mice to induce a transient liver fibrosis. TGF-β1 has been well documented to up-regulate the expression of α2(1) collagen (Col 1A2) gene in the liver via the reactive oxygen species (ROS); the process triggers inflammation, leading to hepatic stellate cells (HSC) activation and liver fibrogenesis. Using our animal model and ROS, cyclooxygenase-2 (Cox-2) and Col 1A2 promoter assays as screening targets, we report here that a maleic acid derivative isolated from the Antrodia camphorata mycelium strongly decreases ROS production, promoter activity of Cox-2 and Col 1A2, intracellular calcium, expression of alpha-smooth muscle actin (α-SMA), Smad4-p-Smad2/3 co-localization in cell nucleus and the DNA binding activity of Sp1. Our results suggest that the maleic acid derivative prevents liver fibrosis at an early phase both in vitro and in vivo through the inhibition of ROS, inflammation and the activation of HSC.
AB - Current anti-fibrotic effect of antioxidants in vivo is disappointing due probably to the fact that once liver fibrogenesis is established it is too advanced to be reversed by anti-oxidation mechanism. We consider antioxidant may only act on the early phase of fibrogenesis. Thus, we had previously established an early liver fibrosis animal model using an inducible expression vector (pPK9a), which contains TGF-β gene and was hydro-dynamically transferred into mice to induce a transient liver fibrosis. TGF-β1 has been well documented to up-regulate the expression of α2(1) collagen (Col 1A2) gene in the liver via the reactive oxygen species (ROS); the process triggers inflammation, leading to hepatic stellate cells (HSC) activation and liver fibrogenesis. Using our animal model and ROS, cyclooxygenase-2 (Cox-2) and Col 1A2 promoter assays as screening targets, we report here that a maleic acid derivative isolated from the Antrodia camphorata mycelium strongly decreases ROS production, promoter activity of Cox-2 and Col 1A2, intracellular calcium, expression of alpha-smooth muscle actin (α-SMA), Smad4-p-Smad2/3 co-localization in cell nucleus and the DNA binding activity of Sp1. Our results suggest that the maleic acid derivative prevents liver fibrosis at an early phase both in vitro and in vivo through the inhibition of ROS, inflammation and the activation of HSC.
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U2 - 10.1371/journal.pone.0174008
DO - 10.1371/journal.pone.0174008
M3 - Article
C2 - 28384213
AN - SCOPUS:85017114124
SN - 1932-6203
VL - 12
JO - PloS one
JF - PloS one
IS - 4
M1 - e0174008
ER -