Astragaloside IV Synergizes with Ferulic Acid to Alleviate Hepatic Fibrosis in Bile Duct-Ligated Cirrhotic Rats
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ORIGINAL ARTICLE
Astragaloside IV Synergizes with Ferulic Acid to Alleviate Hepatic Fibrosis in Bile Duct‑Ligated Cirrhotic Rats Xue‑Mei Zhao1 · Jing Zhang2 · Yi‑Ni Liang1 · Ying‑Cai Niu1 Received: 2 August 2019 / Accepted: 17 December 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Background Due to the multi-factorial etiology of hepatic fibrosis, multi-target therapeutics based on combinatory drugs is known to be a promising strategy for the disease. Aims The present study attempted to test the hypothesis that astragaloside IV combined with ferulic acid synergistically inhibits activation of hepatic stellate cells in vivo. Methods Bile duct-ligated rats were treated with astragaloside IV or/and ferulic acid for 28 days. Liver fibrosis was measured by histological examination. The oxidative stress-related biomarkers were measured with spectrophotometry. Expressions of mRNA and protein were measured by real-time PCR and Western blotting. Results Bile duct-ligated rat treatment with astragaloside IV and ferulic acid in combination resulted in synergistic alleviation of hepatic fibrosis. Simultaneously, activation of hepatic stellate cells was significantly inhibited by the combination therapy when compared with astragaloside IV or ferulic acid alone. Interestingly, astragaloside IV, but not ferulic acid, induced accumulation of Nrf2 in the nucleus, synthesized antioxidant enzymes through negative regulation of glycogen synthase kinase-3β, scavenged reactive oxygen species, and, in turn, suppressed hepatic stellate cells activation in bile duct-ligated rats. Conversely, ferulic acid, but not astragaloside IV, suppressed TGF-β1 and its receptors expression, which resulted in downregulation of Smad3 and Smad4. Conclusions These findings suggest that the combination of astragaloside IV and ferulic acid synergistically induces deactivation of hepatic stellate cells through inhibition of the TGF-β pathway and activation of the Nrf2 pathway, and suggest that combination of astragaloside IV and ferulic acid is a promising candidate for the treatment of hepatic fibrosis. Keywords Ferulic acid · Astragaloside IV · Synergism · Hepatic fibrosis · Hepatic stellate cells
Xue-Mei Zhao and Jing Zhang have contributed equally to this work. * Ying‑Cai Niu [email protected] Xue‑Mei Zhao [email protected] Jing Zhang [email protected] Yi‑Ni Liang [email protected] 1
The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar 161006, Heilongjiang, People’s Republic of China
Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, Heilongjiang, People’s Republic of China
2
Abbreviations α-SMA α-Smooth muscle actin AsIV Astragaloside IV BDL Bile duct-ligated Col I Collagen α type I FA Ferulic acid GAPDH Glyceraldehyde-3-phosphate dehydrogenase GCL γ-Glutamylcysteine ligase GSH Glutathione GSK-3β Glycogen synthase kinase-3β H&E Hematoxylin–eosin HO-1 Heme oxygenase 1 LPO Lipid peroxidation
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