Astragaloside IV synergizes with ferulic acid to suppress hepatic stellate cells activationin vitro

Abstract

Because hepatic fibrosis usually involves more than one pathological process, combination therapy with modalities that target aberrant signaling cascade in activated hepatic stellate cells (HSCs) represents an alternative strategy. This study evaluates the hypothesis that astragaloside IV (AS-IV) and ferulic acid (FA) synergize to inhibit HSCs activation via simultaneous activating nuclear factor erythroid-2-related factor-2 (Nrf2) and blocking transforming growth factor-β (TGF-β) pathways. The combination of FA and AS-IV, hereafter referred to as the AS-IV/FA, at suboptimal concentrations synergistically inhibited HSCs activation, as measured by expressions of α-smooth muscle actin (α-SMA), collagen α type I (Col I) and fibronectin. Nrf2 nuclear accumulation, glutathione (GSH) increase, and reactive oxygen species (ROS) reduction by AS-IV were not potentiated by co-treatment with FA. Similarly, inhibition of TGF-β1 secretion and Smad activity by FA also was not enhanced by combined treatment with AS-IV. AS-IV/FA synergistically suppresses the p38 mitogen-activated protein kinase (MAPK) activity. Inhibition of HSCs activation by AS-IV/FA could be completely blocked by TGF-βs-neutralizing antibody plus shRNA-mediated knockdown of Nrf2. Dual blockade of the TGF-β1/Smad pathway by FA and activation of Nrf2/ARE pathway by AS-IV contributed to the synergistic effects of this combination treatment. These results suggest that combinatorial treatments that target different pathway may afford a more effective strategy to inhibit HSC activation.

Astragaloside IV Protects Against Oxidized Low-Density Lipoprotein (ox-LDL)-Induced Endothelial Cell Injury by Reducing Oxidative Stress and Inflammation

“…In HUVEC, endothelial senescence was caused by suppressed expression of Nrf2 at the transcriptional level [30], and this decreased expression was modulated by direct targeting of Nrf2 mRNA by several microRNAs (miRNAs) [31,32]. AS-IV demonstrates a broad range of anti-oxidative stress by activating the Nrf2 antioxidant pathway, thereby protecting cortical neurons against ischemia/reperfusion injury [33], inhibiting hepatic stellate cell activation [34], and protecting lipopolysaccharide-induced microglia [35]. In particular, activation of Nrf2 by AS-IV protects the integrity of the blood-brain barrier, which was destroyed by LPS [36].…”

Emodin suppresses activation of hepatic stellate cells through p38 mitogen‐activated protein kinase and Smad signaling pathways in vitro

“…Hepatic fibrosis is the pathological component of a variety of chronic liver diseases and can ultimately progress to cirrhosis (Martin, Weideman, Crook, & Brown, ). Although antifibrotic activity has been demonstrated for many compounds in vitro and in animal models (H. Dong, Guo, Liang, Wang, & Niu, ; Lu, Zou, Liu, & Niu, ; Y. B. Zhang et al, ), efficacious medical treatments for hepatic fibrosis are not currently available except for liver transplantation (reviewed by Koyama, Xu, Liu, & Brenner, ).…”

Hepatoprotective and immunomodulatory effects of copper-nicotinate complex against fatty liver in rat model

“…Many cytokines have been suggested to play an essential pathogenic [40]. In addition, lipid peroxidation end products are potent chemoattractants for inflammatory cells [41] and can activate hepatic stellate cells and hence stimulate hepatic fibrosis [42].…”