Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3 at linker regions in vivo and in vitro.

Abstract

AIM:

To investigate anti-liver fibrosis effects of Salvianolic acid B (Sal B) from Salvia miltiorrhiza Bunge involved mitogen-activated protein kinase (MAPK)-mediated transforming growth factor-beta (TGF-β) signaling.

MAIN METHODS:

Diethylnitrosamine (DEN)-induced liver fibrosis in mice and TGF-β1-activated hepatic stellate cells (HSCs) were established and treated with dosage/concentration-graded Sal B and/or MAPK activator (Vacquinol-1: MKK4-specific activator)/inhibitors (PD98059: ERK-specific inhibitor; SP600125: JNK-specific inhibitor; SB203580: p38-specific inhibitor). Histopathological characteristics and cell migration were assessed, α-SMA, Collagen I and members of TGF-β/MAPK/Smad signal transduction pathway were measured.

KEY FINDINGS:

Results in vivo showed that Sal B alleviated DEN-caused liver fibrosis embodied in ameliorative histopathological characteristics and decreased protein levels of hepatic fibrosis related markers (α-SMA, Collagen I, TGF-β1), its molecular mechanisms of action were correlative with inhibited activation of MAPK and phosphorylation of Smad2/3 at linker regions (P-Smad2/3L) and Smad2 at C-terminal (P-Smad2C) while increased phosphorylation of Smad3 at C-terminal (P-Smad3C). Results in vitro showed that Sal B restrained TGF-β1-induced HSCs activation, Collagen I production and cell migration; Sal B inhibited activation of MAPK and markedly decreased protein levels of P-Smad2/3L and P-Smad2C while slightly increased P-Smad3C in TGF-β1-stimulated HSCs, the expression of PAI-1 was inhibited by Sal B; activating MAPK receded inhibitory effects of Sal B on α-SMA, Collagen I, P-Smad2L and P-Smad3L expression while inhibited activation of MAPK reinforced those.

SIGNIFICANCE:

Sal B attenuates liver fibrosis via mediation of TGF-β/Smad and MAPK pathways, especially inhibition of MAPK-mediated P-Smad2/3L signaling, which maybe provides theoretical foundation of Sal B for treating clinically liver fibrosis.

• Authors: Chao Wu, Weiyang Chen, Hanyan Ding, Dong Li, Guanghua Wen, Chong Zhang, Wanpeng Lu, Ming Chen, Yan Yang
• Journal: Life sciences (Life Sci) Vol. 239 Pg. 116881 (Dec 15 2019) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 31678285 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Benzofurans
• SMAD2 protein, human
• SMAD3 protein, human
• Smad Proteins
• Smad2 Protein
• Smad3 Protein
• TGFB1 protein, human
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Diethylnitrosamine
• salvianolic acid B
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Benzofurans (metabolism, pharmacology)
• Diethylnitrosamine (pharmacology)
• Hepatic Stellate Cells
• Liver Cirrhosis (drug therapy, metabolism)
• Male
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphorylation
• Signal Transduction (drug effects)
• Smad Proteins (drug effects, metabolism)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1 (metabolism)