title: Oridonin inhibits hepatic stellate cell proliferation and fibrogenesis.
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.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Bohanon
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Geetha L
authors.initials: GL
authors.lastname: Radhakrishnan
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Rastellini
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.|Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Radhakrishnan
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000032:analysis; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008103:Liver Cirrhosis / Q000517:prevention & control*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D045786:Diterpenes, Kaurane; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; C011959:oridonin
keywords: Apoptosis; Liver fibrosis; Oridonin; Stellate cells
references.citation: Org Lett. 2013 Jul 19;15(14):3718-21
references.pmid: 23834026
references.citation: J Bone Miner Res. 2010 Apr;25(4):706-15
references.pmid: 19821765
references.citation: Gut. 2005 Jan;54(1):142-51
references.pmid: 15591520
references.citation: Oncol Rep. 2010 Sep;24(3):647-51
references.pmid: 20664969
references.citation: Biol Pharm Bull. 2004 Oct;27(10):1527-31
references.pmid: 15467189
references.citation: Biochem Pharmacol. 2004 Dec 15;68(12):2367-78
references.pmid: 15548383
references.citation: EMBO J. 1998 Jun 1;17(11):3091-100
references.pmid: 9606191
references.citation: J Med Chem. 2013 Nov 14;56(21):8814-25
references.pmid: 24128046
references.citation: J Med Chem. 2013 Jun 27;56(12):5048-58
references.pmid: 23746196
references.citation: J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:94-8
references.pmid: 22320925
references.citation: J Biol Chem. 2001 Jun 1;276(22):19205-13
references.pmid: 11376010
references.citation: Acta Pharmacol Sin. 2006 Dec;27(12):1642-6
references.pmid: 17112421
references.citation: Acta Pharmacol Sin. 2007 Jul;28(7):1057-66
references.pmid: 17588343
references.citation: J Immunol Methods. 1998 Apr 15;213(2):157-67
references.pmid: 9692848
references.citation: J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:80-4
references.pmid: 22320922
references.citation: J Hepatol. 2011 Sep;55(3):612-625
references.pmid: 21251937
references.citation: Biochim Biophys Acta. 2013 Jul;1832(7):948-54
references.pmid: 23470555
references.citation: In Vitro Cell Dev Biol. 1989 Feb;25(2):217-22
references.pmid: 2466032
references.citation: Acta Pharmacol Sin. 2010 Jul;31(7):839-48
references.pmid: 20562900
references.citation: Gastroenterol Hepatol (N Y). 2011 Oct;7(10):661-71
references.pmid: 22298959
references.citation: Mol Biol Cell. 2002 Oct;13(10):3546-59
references.pmid: 12388756
references.citation: Blood. 2007 Apr 15;109(8):3441-50
references.pmid: 17197433
references.citation: Best Pract Res Clin Gastroenterol. 2011 Apr;25(2):195-206
references.pmid: 21497738
references.citation: Hepatology. 2009 Feb;49(2):533-44
references.pmid: 19115220
references.citation: Toxicol In Vitro. 2004 Oct;18(5):703-10
references.pmid: 15251189
references.citation: PLoS One. 2011;6(11):e28181
references.pmid: 22140539
references.citation: Biochim Biophys Acta. 2006 Nov;1760(11):1587-95
references.pmid: 17067743
references.citation: Int J Oncol. 2012 Jan;40(1):139-47
references.pmid: 21947421