Alterations of mast cells and TGF-β1 on the silymarin treatment for CCl4-induced hepatic fibrosis

Senescence marker protein 30 (SMP30), an important aging marker molecule that is highly expressed in the liver, has been known to protect hepatocytes from apoptosis by the synthesis of vitamin C. To explore the function of SMP30 in liver fibrosis, the effect of SMP30 deficiency on liver fibrosis was investigated in SMP30 knockout (KO) mice. Moreover, the in vivo results were further confirmed by way of hepatic stellate cell (HSC) isolation. We demonstrated that carbon tetrachloride (CCl4)-induced liver fibrosis and the nuclear translocation of p-Smad2/3, the immediate downstream of transforming growth factor beta (TGF-β), were significantly inhibited in the liver of SMP30 KO mice compared with wildtype (WT) mice. We also confirmed that both WT and SMP30 KO HSCs did not express SMP30. Finally, we further confirmed that up-regulation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) caused by a lack of vitamin C was the pivotal factor in the mechanisms for attenuated liver fibrosis of SMP30 KO mice, and feeding with vitamin C restored CCl4-induced liver fibrosis in SMP30 KO mice. Conclusion: Vitamin C deficiency by SMP30 depletion attenuated liver fibrosis by way of up-regulated PPAR-γ expression in SMP30 KO mice. Our results provide, for the first time, the possible mechanisms underlying inhibition of HSC activation associated with vitamin C and PPAR-γ up-regulation in liver fibrosis of SMP30 KO mice. (Hepatology 2010.)

Helicobacter pylori vacuolating cytotoxin A (VacA) has been considered as an apoptosis-inducing factor. Here, we investigated the mechanism of VacA-induced apoptosis in relation to the defense mechanism and MAP kinases pathway in gastric epithelial cells. AGS cells exposed to enriched VacA extracts affected the level of SOD-1 and villin. We further investigated the role of VacA in those inductions using a functional recombinant VacA (rVacA). Activation of p38 MAPK and Bax dimerization by rVacA were increased in a dose-dependent manner. rVacA-induced ERK1/2 MAPK activation was maximal at 30 min and 4 h and 1–4 μg/ml of rVacA. rVacA-induced SOD-1 expression was considerably diminished by inhibiting ERK1/2 MAPK and it was slightly increased by inhibiting p38 MAPK. rVacA increased or decreased villin expression depending on dose and exposure time and its expression was mainly appeared in the contractile actin ring of the dividing cells. Despite its cytoprotective effect, SB-203580, a p38 inhibitor, was unlikely to reduce VacA-induced Bax dimerization and rather inhibited villin and Bcl2 expression, indicating that p38 may also play a role in cell proliferation or differentiation for survival after VacA intoxication. Furthermore, p38 inhibitor accelerated rVacA-induced cell death after exposure of AGS cells to H₂O₂but ERK1/2 inhibitor protected cells from H₂O₂insult. These results suggest that SOD-1 and villin are expressed differentially upon VacA insult depending on dose and exposure time via ERK and p38 MAP kinases; decrease in SOD-1 and villin expression coupled with Bax dimerization leads to apoptosis of gastric epithelial cells.

Jeong WI, et al. J Vet Sci. 2006 Sep;7(3):299-301. http://dx.doi.org/10.4142/jvs.2006.7.3.299