Alleviation of hepatic fibrosis and autophagy via inhibition of transforming growth factor-β1/Smads pathway through shikonin.

Abstract

BACKGROUND AND AIM:

Liver fibrosis is a worldwide clinical challenge during the progression of chronic liver disease to liver cirrhosis. Shikonin is extracted from the root of Lithospermum erythrorhizon with antioxidant, anti-inflammatory, anticancer, and wound-healing properties. The study aims to investigate the protective effect of shikonin on liver fibrosis and its underlying mechanism.

METHODS:

Two liver fibrosis models were established in male C57 mice by intraperitoneal injection of CCl4 or bile duct ligation. Shikonin was administered orally three times weekly at a dose of 2.5 or 5 mg/kg. Protein and mRNA expressions were assayed by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining.

RESULTS:

Shikonin significantly inhibited activation of hepatic stellate cells and extracellular matrix formation by downregulating the transforming growth factor-β1 expression and maintaining the normal balance between metalloproteinase-2 and tissue inhibitor of metalloproteinase-1. Shikonin also decreased hepatic stellate cell energy production by inhibiting autophagy.

CONCLUSIONS:

The results confirmed that shikonin attenuated liver fibrosis by downregulating the transforming growth factor-β1/Smads pathway and inhibiting autophagy.

• Authors: Tong Liu, Ling Xu, Chengfen Wang, Kan Chen, Yujing Xia, Jingjing Li, Sainan Li, Liwei Wu, Jiao Feng, Shizan Xu, Wenwen Wang, Xiya Lu, Xiaoming Fan, Wenhui Mo, Yingqun Zhou, Yan Zhao, Chuanyong Guo
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 34 Issue 1 Pg. 263-276 (Jan 2019) ISSN: 1440-1746 [Electronic] Australia
• PMID: 29864192 (Publication Type: Journal Article)
• Copyright: © 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Naphthoquinones
• Smad Proteins, Receptor-Regulated
• Tgfb1 protein, mouse
• Timp1 protein, mouse
• Tissue Inhibitor of Metalloproteinase-1
• Transforming Growth Factor beta1
• shikonin
• Aspartate Aminotransferases
• Alanine Transaminase
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse

Topics

• Alanine Transaminase (blood)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Aspartate Aminotransferases (blood)
• Autophagy (drug effects)
• Disease Models, Animal
• Down-Regulation (drug effects)
• Extracellular Matrix (metabolism)
• Hepatic Stellate Cells (physiology)
• Liver Cirrhosis (metabolism, pathology, prevention & control)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mice, Inbred C57BL
• Naphthoquinones (pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Smad Proteins, Receptor-Regulated (antagonists & inhibitors)
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)
• Transforming Growth Factor beta1 (antagonists & inhibitors)