Tetrandrine, Selleckchem Dasatinib
an alkaloid used in Chinese medicine, ameliorated liver fibrosis in animal models (Hsu et?al., 2007; Yin et?al., 2007). However, tetrandrine has multiple pharmacological effects, including a natrium channel-blocking effect (Chen et?al., 2009) and anti-proliferative effects on several cancer cell lines (Dong et?al., 1997; Yoo et?al., 2002). Thus, tetrandrine is not merely a non-selective calcium blocker. Additionally, tetrandrine is a potential hepatotoxin that induces multiple apoptogenic signals (Yan et?al., 2006). The pharmacokinetic and toxicokinetic characteristics of tetrandrine have not been well established (Song et?al., 2008), and further research is necessary before it can be considered for clinical use. In summary, we revealed that azelnidipine inhibited TGF-��1- or Ang II-induced HSC activation in vitro, attenuated CCl4- or TAA-induced liver fibrosis, and accelerated the regression of CCl4-induced liver fibrosis when administered at a clinically relevant dose. Furthermore, we have elucidated the mechanism of the anti-fibrotic effect of azelnidipine. Because azelnidipine is widely used in clinical practice without serious adverse effects, it may provide an effective new strategy for anti-fibrotic therapy. We are very grateful to Prof Scott L Friedman, Division of Liver Diseases, Mount Sinai Oxygenase
School of Medicine, New York, New York 10029-6574, USA, for generous provision of the human HSC cell line, LX-2. We appreciate Daiichi Sankyo Co., Ltd, Tokyo, Japan, for providing azelnidipine (racemate), (R)-(?)-azelnidipine and (S)-(+)-azelnidipine. None. Figure S1 (A) The effects of azelnidipine on LX-2 cell viability. The cells were incubated with azelnidipine at various concentrations for 24 hours. (B) The effects of each calcium blocker on the TGF-��1-induced stimulation of COL1A1 mRNA expression in LX-2 cells. (C) The effects of each calcium blocker on the TGF-��1-induced increase of intracellular ROS in LX-2 cells. The concentration of each calcium blocker and TGF-��1 were 100 nM and 5 ng��mL?1, respectively. **P < 0.01 versus control. Figure S2 (A) The roles of MAPK signal transduction pathways in TGF-��1-induced activation of this website
LX-2 cells. Time courses of TGF-��1-induced phosphorylation of MAPK signal transduction molecules. The effects of TGF-��1 on phosphorylation of JNK (a) p38 (b) or ERK1/2 (c) at different time points after adding TGF-��1. LX-2 cells activated by TGF-�� were used as a positive control. (B) The effect of 100 nM azelnidipine without TGF-��1 on phosphorylation of ERK1/2 in LX-2 cells. Time course of phosphorylation of ERK1/2 at different time points after adding azelnidipine. (C) Time course of TGF-��1-induced phosphorylation of Smad3. (D) The effect of azelnidipine (Azel) on TGF-��1-induced phosphorylation of Smad3 in LX-2 cells. The concentration of TGF-��1 was 5 ng��mL?1.