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

Autor: Yan Yang, Dong Li, Guanghua Wen, Ming Chen, Chong Zhang, Weiyang Chen, Chao Wu, Hanyan Ding, Wanpeng Lu
Rok vydání: 2019
Předmět:
0301 basic medicine
MAPK/ERK pathway
Liver Cirrhosis
Male
Smad Proteins
Smad2 Protein
030226 pharmacology & pharmacy
Salvia miltiorrhiza
General Biochemistry
Genetics and Molecular Biology
Transforming Growth Factor beta1
03 medical and health sciences
Mice
0302 clinical medicine
Fibrosis
Transforming Growth Factor beta
parasitic diseases
medicine
Hepatic Stellate Cells
Animals
Diethylnitrosamine
Smad3 Protein
General Pharmacology
Toxicology and Pharmaceutics
Phosphorylation
Protein kinase A
Benzofurans
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
biology
Chemistry
Activator (genetics)
General Medicine
Transforming growth factor beta
medicine.disease
Molecular biology
030104 developmental biology
biology.protein
Hepatic stellate cell
Mitogen-Activated Protein Kinases
Hepatic fibrosis
Signal Transduction
Zdroj: Life sciences. 239
ISSN: 1879-0631
Popis: 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.
Databáze: OpenAIRE
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