Tanshinone IIA regulates the TGF-β1/Smad signaling pathway to ameliorate non-alcoholic steatohepatitis-related fibrosis

Lianjie Xu; Yurong Zhang; Nengbo Ji; Yan Du; Tao Jia; Shanshan Wei; Wei Wang; Shan Zhang; Wenhui Chen

doi:10.3892/etm.2022.11413

Tanshinone IIA regulates the TGF-β1/Smad signaling pathway to ameliorate non-alcoholic steatohepatitis-related fibrosis

Exp Ther Med. 2022 Jun 1;24(1):486. doi: 10.3892/etm.2022.11413. eCollection 2022 Jul.

Authors

Lianjie Xu¹, Yurong Zhang¹, Nengbo Ji¹, Yan Du¹, Tao Jia², Shanshan Wei¹, Wei Wang¹, Shan Zhang^{1

3

4}, Wenhui Chen^{1

3

4}

Affiliations

¹ Faculty of Basic Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 650500, P.R. China.
² Department of Orthopedics, First Clinical Medical College of Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 650021, P.R. China.
³ Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Kunming, Yunnan 450500, P.R. China.
⁴ Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan 450500, P.R. China.

Abstract

Tanshinone IIA (TIIA) is a major component extracted from the traditional herbal medicine Salvia miltiorrhiza and has been indicated to play a role in the treatment of organ fibrosis. However, the evidence supporting its antifibrotic effect is insufficient and the underlying mechanism is unclear. To investigate the therapeutic effect of TIIA on non-alcoholic steatohepatitis-related fibrosis (NASH-F), the present study used a methionine choline deficiency diet to induce NASH-F in rats, and explored the effect of TIIA on the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Wistar rats were randomly divided into control, NASH-F and TIIA groups. After 8 weeks of treatment, the levels of serum markers associated with liver function and fibrosis were measured, liver fat vacuoles and inflammation were assessed by haematoxylin and eosin staining, and liver fibrosis was assessed by Masson's trichrome staining. TGF-β1, Smad2, Smad3, Smad7 and α-smooth muscle actin (α-SMA) mRNA expression, and TGF-β1, Smad2/3, phosphorylated (p)-Smad2/3, Smad7 and α-SMA protein levels were determined. The results revealed that TIIA could remarkably ameliorate liver fat vacuoles and inflammation in NASH-F rats, and could decrease the levels of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, total bile acid, hyaluronic acid, type Ⅳ collagen, laminin and type III collagen, while increasing the levels of total cholesterol and triglycerides; however, this was not statistically significance. TIIA markedly suppressed the increased TGF-β1, Smad2, Smad3 and α-SMA mRNA expression levels observed in the liver of NASH-F rats, while it increased the mRNA expression level of Smad7. Similarly, TIIA suppressed the increased TGF-β1, p-Smad2/3 and α-SMA protein levels observed in the liver of NASH-F rats, while it increased the protein expression level of Smad7 in vitro and in vivo. TIIA had no significant cytotoxic effect at 10, 20, 40 and 80 µmol/l on human LX-2 cell. In conclusion, the findings of the present study indicated that TIIA alleviated NASH-F by regulating the TGF-β1/Smad signaling pathway. TIIA may be a useful tool in the prevention and treatment of NASH-F.

Keywords: TGF-β1/Smad; hepatic fibrosis; non-alcoholic steatohepatitis; tanshinone IIA.

Grants and funding

Funding: This work was supported by the National Natural Science Foundation of China (grant nos. 81960814, 81760818 and 82160898), Science and Technology Program of Yunnan Science and Technology Department [grant nos. 2018FF001(-006), 2019FF002(-079) and 202101AZ070001-042] and Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine (Yunnan University of Traditional Chinese Medicine; grant no. 2019DG016).