CCM111 prevents hepatic fibrosis via cooperative inhibition of TGF-β, Wnt and STAT3 signaling pathways

In-Yu Lin; Yi-Shiou Chiou; Li-Ching Wu; Chen-Yu Tsai; Chiung-Tong Chen; Wu-Chang Chuang; Ming-Chung Lee; Ching-Che Lin; Ting-Ting Lin; Ssu-Ching Chen; Min-Hsiung Pan; Nianhan Ma

doi:10.1016/j.jfda.2018.09.008

CCM111 prevents hepatic fibrosis via cooperative inhibition of TGF-β, Wnt and STAT3 signaling pathways

J Food Drug Anal. 2019 Jan;27(1):184-194. doi: 10.1016/j.jfda.2018.09.008. Epub 2018 Oct 25.

Authors

In-Yu Lin¹, Yi-Shiou Chiou², Li-Ching Wu¹, Chen-Yu Tsai², Chiung-Tong Chen³, Wu-Chang Chuang⁴, Ming-Chung Lee⁴, Ching-Che Lin⁴, Ting-Ting Lin¹, Ssu-Ching Chen⁵, Min-Hsiung Pan^{2

6

7}, Nianhan Ma¹

Affiliations

¹ Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University, Taoyuan, Taiwan.
² Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan.
³ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
⁴ Brion Research Institute of Taiwan, New Taipei City, Taiwan.
⁵ Department of Life Sciences, National Central University, Taoyuan, Taiwan.
⁶ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.
⁷ Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.

Abstract

CCM111 is an aqueous extract of Antrodia cinnamomea (AC) that has exhibited anti-liver fibrosis functions. However, the detailed mechanisms of AC action against liver fibrosis have not been elucidated yet. The present research showed that CCM111 significantly lowered the levels of the hepatic enzyme markers glutamate oxaloacetate transaminase (GOT) and glutamic pyruvic transaminase (GPT), prevented liver damage and collagen deposition, and downregulated TGF-β/Smad signaling in a dose-dependent manner compared with CCl₄ treatment alone. CCM111 markedly inhibited TGF-β, Wnt and STAT3 signaling pathway-regulated downstream genes in the liver by next-generation sequencing. The antifibrotic mechanisms of CCM111 were further demonstrated in HSC-T6 cells. Our data demonstrated for the first time that CCM111 can protect against CCl₄-induced liver fibrosis by the cooperative inhibition of TGF-β-, Wnt- and STAT3-dependent proinflammatory and profibrotic mediators, suggesting that CCM111 might be a candidate for preventing and treating chronic fibrotic liver diseases.

Keywords: Antrodia cinnamomea; Liver fibrosis; STAT3 pathway; TGF-β pathway; Wnt pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antrodia / chemistry*
Drugs, Chinese Herbal / administration & dosage*
Humans
Liver / drug effects
Liver / metabolism
Liver Cirrhosis / genetics
Liver Cirrhosis / metabolism
Liver Cirrhosis / prevention & control*
Male
Mice
Mice, Inbred ICR
NF-kappa B / genetics
NF-kappa B / metabolism*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Signal Transduction / drug effects
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*
Wnt Proteins / genetics
Wnt Proteins / metabolism*

Substances

Drugs, Chinese Herbal
NF-kappa B
STAT3 Transcription Factor
Stat3 protein, mouse
Transforming Growth Factor beta
Wnt Proteins

Grants and funding

This work was supported by the following programs: the Ministry of Science and Technology, Taiwan (MOST106-2320-B-008-005-MY3), the National Central University-Landseed Hospital United Research Center (NCU-LSH-105-A-006, NCU-LSH-106-A-004).