Fredrick J Bohanon1, Xiaofu Wang1, Chunyong Ding2, Ye Ding2, Geetha L Radhakrishnan3, Cristiana Rastellini1, Jia Zhou2, Ravi S Radhakrishnan1,3. 1. Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA. 2. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA. 3. Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
Abstract
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.
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.
Authors: Grant A Ramm; Ross W Shepherd; Anita C Hoskins; Sonia A Greco; Agnieszka D Ney; Tamara N Pereira; Kim R Bridle; James D Doecke; Peter J Meikle; Bruno Turlin; Peter J Lewindon Journal: Hepatology Date: 2009-02 Impact factor: 17.425
Authors: Ye Ding; Chunyong Ding; Na Ye; Zhiqing Liu; Eric A Wold; Haiying Chen; Christopher Wild; Qiang Shen; Jia Zhou Journal: Eur J Med Chem Date: 2016-06-13 Impact factor: 6.514