BACKGROUND AND PURPOSE: Oxidative stress plays a critical role in liver fibrogenesis. Reactive oxygen species (ROS) stimulate hepatic stellate cells (HSCs), and ROS‐mediated increases in calcium influx further increase ROS production. Azelnidipine is a calcium blocker that has been shown to have antioxidant effects in endothelial cells and cardiomyocytes. Therefore, we evaluated the anti‐fibrotic and antioxidative effects of azelnidipine on liver fibrosis.EXPERIMENTAL APPROACH: We used TGF‐β1‐activated LX‐2 cells (a human HSC line) and mouse models of fibrosis induced by treatment with either carbon tetrachloride (CCl₄) or thioacetamide (TAA).KEY RESULTS: Azelnidipine inhibited TGF‐β1 and angiotensin II (Ang II)‐activated α1(I) collagen mRNA expression in HSCs. Furthermore, TGF‐β1‐ and Ang II‐induced oxidative stress and TGF‐β1‐induced p38 and JNK phosphorylation were reduced in HSCs treated with azelnidipine. Azelnidipine significantly decreased inflammatory cell infiltration, pro‐fibrotic gene expressions, HSC activation, lipid peroxidation, oxidative DNA damage and fibrosis in the livers of CCl₄‐ or TAA‐treated mice. Finally, azelnidipine prevented a decrease in the expression of some antioxidant enzymes and accelerated regression of liver fibrosis in CCl₄‐treated mice.CONCLUSIONS AND IMPLICATIONS: Azelnidipine inhibited TGF‐β1‐ and Ang II‐induced HSC activationin vitroand attenuated CCl₄‐ and TAA‐induced liver fibrosis, and it accelerated regression of CCl₄‐induced liver fibrosis in mice. The anti‐fibrotic mechanism of azelnidipine against CCl₄‐induced liver fibrosis in mice may have been due an increased level of antioxidant defence. As azelnidipine is widely used in clinical practice without serious adverse effects, it may provide an effective new strategy for anti‐fibrotic therapy.

The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.

Spontaneous regression of hepatic inflammatory pseudotumor with primary biliary cirrhosis: Case report and literature review

MK-0626, a selective DPP-4 inhibitor, attenuates hepatic steatosis in ob/ob mice