title: 3,3'-Diindolylmethane ameliorates experimental hepatic fibrosis via inhibiting miR-21 expression.
abstract: OBJECTIVE
  Hepatic fibrosis is a type of liver disease characterized by excessive collagen deposition produced by activated hepatic stellate cells (HSCs), and no appropriate drug treatment is available clinically. The microRNA, miR-21 exhibits an important role in the pathogenesis and progression of hepatic fibrosis. 3,3'-Diindolylmethane (DIM) is a natural autolytic product in plants and can down-regulate miR-21 expression. Here we have assessed the therapeutic effects of DIM against hepatic fibrosis and investigated the underlying mechanisms.
  
  
  METHODS
  The effects of DIM on HSC activation were measured by analysing the expression of α-smooth muscle actin and collagen I in both HSC-T6 cell line and primary HSCs. Expression of miR-21 was also measured after DIM treatment and the therapeutic effect of DIM was further studied in vivo, using the model of hepatic fibrosis induced by thioacetamide in mice. The antagonist oligonucleotide, antagomir-21, was also used to suppress the effects of miR-21.
  
  
  RESULTS
  DIM suppressed the central TGF-β signalling pathway underlying HSC activation by down-regulating the expression of miR-21. The decreased miR-21 expression was achieved by inhibiting the activity of the transcription factor, AP-1. Moreover, DIM blunted the activation phenotype of primary HSCs. Administration of DIM in vivo attenuated liver fibrosis induced by thioacetamide, as assessed by collagen deposition and profiles of profibrogenic markers.
  
  
  CONCLUSIONS
  DIM shows potential as a therapeutic agent for the treatment of hepatic fibrosis.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhongfei
authors.initials: Z
authors.lastname: Gao
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Shan
authors.initials: S
authors.lastname: Yin
authors.forename: Chunming
authors.initials: C
authors.lastname: Wang
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Zang
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D019610:Cytoprotection; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000378:metabolism*; D009841:Oligonucleotides / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D013853:Thioacetamide; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D007211:Indoles; D035683:MicroRNAs; D009841:Oligonucleotides; D051896:Smad Proteins, Receptor-Regulated; D013853:Thioacetamide; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; C558396:Acta2 protein, mouse; C531950:MIRN21 microRNA, mouse; C546082:mirn21 microRNA, rat; C498862:Acta2 protein, rat; C016392:3,3'-diindolylmethane
keywords: 3; 3′-Diindolylmethane; AP-1; Liver fibrosis; Smad; TGF-β; hepatic stellate cells; miR-21
references.citation: J Surg Res. 2006 May 15;132(2):208-13
references.pmid: 16580691
references.citation: Gastroenterology. 2003 Jul;125(1):178-91
references.pmid: 12851882
references.citation: Cell. 2012 Mar 16;148(6):1172-87
references.pmid: 22424228
references.citation: Mol Ther. 2013 Feb;21(2):388-98
references.pmid: 23207693
references.citation: Cancer Res. 2009 May 15;69(10):4468-75
references.pmid: 19435906
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2345-9
references.pmid: 10051644
references.citation: Mol Pharmacol. 2006 Feb;69(2):430-9
references.pmid: 16267208
references.citation: Inflamm Bowel Dis. 2009 Aug;15(8):1164-73
references.pmid: 19334074
references.citation: Gastroenterology. 2010 Jan;138(1):347-59
references.pmid: 19782079
references.citation: Oncogene. 2011 Jan 20;30(3):275-86
references.pmid: 20956945
references.citation: Lab Invest. 2010 Dec;90(12):1727-36
references.pmid: 20625373
references.citation: Nature. 2008 Dec 18;456(7224):980-4
references.pmid: 19043405
references.citation: N Engl J Med. 1993 Jun 24;328(25):1828-35
references.pmid: 8502273
references.citation: Gastroenterology. 2008 May;134(6):1655-69
references.pmid: 18471545
references.citation: Hepatology. 2000 Aug;32(2):247-55
references.pmid: 10915731
references.citation: World J Gastroenterol. 2004 Jun 1;10(11):1634-8
references.pmid: 15162539
references.citation: Biochem Pharmacol. 2010 Mar 1;79(5):715-21
references.pmid: 19854159
references.citation: Mol Cell Biol. 1990 Apr;10(4):1492-7
references.pmid: 2108318
references.citation: J Exp Med. 2010 Aug 2;207(8):1589-97
references.pmid: 20643828
references.citation: Gastroenterology. 2011 Mar;140(3):1052-62
references.pmid: 21134374
references.citation: Clin Cancer Res. 2008 Jan 15;14(2):419-27
references.pmid: 18223217
references.citation: Cancer Prev Res (Phila). 2009 Mar;2(3):251-6
references.pmid: 19223575
references.citation: Nat Rev Mol Cell Biol. 2007 Dec;8(12):970-82
references.pmid: 18000526
references.citation: Gastroenterology. 2012 Jun;142(7):1431-43
references.pmid: 22504185
references.citation: Annu Rev Pathol. 2011;6:425-56
references.pmid: 21073339
references.citation: J Am Soc Nephrol. 2011 Sep;22(9):1668-81
references.pmid: 21852586
references.citation: Free Radic Res. 2009 Oct;43(10):899-912
references.pmid: 19670067
references.citation: Oncogene. 2009 Jan 8;28(1):73-84
references.pmid: 18850008
references.citation: Cell. 1987 Jun 19;49(6):741-52
references.pmid: 3034433
references.citation: Methods Mol Med. 2005;117:99-113
references.pmid: 16118448
references.citation: Br J Pharmacol. 2010 Aug;160(7):1577-9
references.pmid: 20649561
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: Hepatology. 2001 Jul;34(1):89-100
references.pmid: 11431738
references.citation: Mol Cell Biochem. 2011 Dec;358(1-2):345-54
references.pmid: 21761201
references.citation: RNA. 2003 Feb;9(2):175-9
references.pmid: 12554859
references.citation: Carcinogenesis. 2010 Feb;31(2):252-8
references.pmid: 19748927
references.citation: Br J Pharmacol. 2010 Aug;160(7):1573-6
references.pmid: 20649560
references.citation: J Mol Biol. 2008 May 2;378(3):492-504
references.pmid: 18384814
references.citation: J Cell Mol Med. 2009 Jan;13(1):39-53
references.pmid: 19175699
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12719-24
references.pmid: 10535989
references.citation: Hepatology. 2002 Apr;35(4):762-71
references.pmid: 11915021
references.citation: J Lipid Res. 2000 Jun;41(6):882-93
references.pmid: 10828080
references.citation: J Hepatol. 2011 Sep;55(3):612-625
references.pmid: 21251937