Astragaloside IV synergizes with ferulic acid to suppress hepatic stellate ce...
Astragaloside IV synergizes with ferulic acid to suppress hepatic stellate cells activation in vitroAbstract
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 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.
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