TY - JOUR
T1 - Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis
AU - Bohanon, Fredrick J.
AU - Wang, Xiaofu
AU - Ding, Chunyong
AU - Ding, Ye
AU - Radhakrishnan, Geetha L.
AU - Rastellini, Cristiana
AU - Zhou, Jia
AU - Radhakrishnan, Ravi S.
N1 - Funding Information:
This work was supported by grants P50 CA097007 , P30 DA028821 , R21 MH093844 (J.Z.), and T32 DK007639 (F.J.B.) from the National Institutes of Health , R. A. Welch Foundation Chemistry , and Biology Collaborative Grant (J.Z.) from the Gulf Coast Consortia and John Sealy Memorial Endowment Fund , and the Center for Addiction Research (J.Z.) from the University of Texas Medical Branch . The authors would also like to thank Karen Martin for her generous help in preparing our data for publication.
PY - 2014/7
Y1 - 2014/7
N2 - Background Liver fibrosis is a common response to liver injury and, in severe cases, leads to cirrhosis. The hepatic stellate cells (HSCs) become activated after liver injury and play a significant role in fibrogenesis. The activated HSC is characterized by increased proliferation, overexpression of α smooth muscle actin, and excessive production of extracellular matrix (ECM) proteins. Oridonin, a naturally occurring diterpenoid, has been shown to induce apoptosis in liver and gastric cancer cells. However, its effects on the HSC are unknown. Methods We tested the effects of oridonin on the activated human and rat HSC lines LX-2 and HSC-T6, and the human hepatocyte cell line C3A. Transforming growth factor β1 (TGF-β1) was used to stimulate LX-2 cells. Results Oridonin significantly inhibited LX-2 and HSC-T6 proliferation. In contrast, oridonin had no antiproliferative effect on C3A cells at our tested range. Oridonin induced apoptosis and S-phase arrest in LX-2 cells. These findings were associated with an increase in p53, p21, p16, and cleaved Poly (ADP-ribose) Polymerase (PARP), and with a decrease in Cyclin-dependent kinase 4 (Cdk4). Oridonin markedly decreased expression of α smooth muscle actin and ECM protein type I collagen and fibronectin, blocked TGF-β1-induced Smad2/3 phosphorylation and type I collagen expression. Conclusions Oridonin induces apoptosis and cell cycle arrest involving the p53-p21 pathway in HSC and appears to be nontoxic to hepatocytes. In addition, oridonin suppressed endogenous and TGF-β1-induced ECM proteins. Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.
AB - Background Liver fibrosis is a common response to liver injury and, in severe cases, leads to cirrhosis. The hepatic stellate cells (HSCs) become activated after liver injury and play a significant role in fibrogenesis. The activated HSC is characterized by increased proliferation, overexpression of α smooth muscle actin, and excessive production of extracellular matrix (ECM) proteins. Oridonin, a naturally occurring diterpenoid, has been shown to induce apoptosis in liver and gastric cancer cells. However, its effects on the HSC are unknown. Methods We tested the effects of oridonin on the activated human and rat HSC lines LX-2 and HSC-T6, and the human hepatocyte cell line C3A. Transforming growth factor β1 (TGF-β1) was used to stimulate LX-2 cells. Results Oridonin significantly inhibited LX-2 and HSC-T6 proliferation. In contrast, oridonin had no antiproliferative effect on C3A cells at our tested range. Oridonin induced apoptosis and S-phase arrest in LX-2 cells. These findings were associated with an increase in p53, p21, p16, and cleaved Poly (ADP-ribose) Polymerase (PARP), and with a decrease in Cyclin-dependent kinase 4 (Cdk4). Oridonin markedly decreased expression of α smooth muscle actin and ECM protein type I collagen and fibronectin, blocked TGF-β1-induced Smad2/3 phosphorylation and type I collagen expression. Conclusions Oridonin induces apoptosis and cell cycle arrest involving the p53-p21 pathway in HSC and appears to be nontoxic to hepatocytes. In addition, oridonin suppressed endogenous and TGF-β1-induced ECM proteins. Thus, oridonin may act as a novel agent to prevent hepatic fibrosis.
KW - Apoptosis
KW - Liver fibrosis
KW - Oridonin
KW - Stellate cells
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U2 - 10.1016/j.jss.2014.03.036
DO - 10.1016/j.jss.2014.03.036
M3 - Article
C2 - 24742622
AN - SCOPUS:84902248209
SN - 0022-4804
VL - 190
SP - 55
EP - 63
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -