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Short curcumin treatment modulates oxidative stress, arginase activity, aberrant crypt foci, and TGF-β1 and HES-1 transcripts in 1,2-dimethylhydrazine-colon carcinogenesis in mice.

Abstract
This study investigated the effect of short curcumin treatment, a natural antioxidant on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) in mice. The incidence of aberrant crypt foci (ACF) was 100%, with 54 ± 6 per colon, 10 weeks after the first DMH injection and reached 67 ± 12 per colon after 12 weeks. A high level of undifferentiated goblet cells and a weak apoptotic activity were shown in dysplastic ACF. The morphological alterations of colonic mucosa were associated to severe oxidative stress ratio with 43% increase in malondialdehyde vs. 36% decrease in GSH. DMH also increased inducible nitric synthase (iNOS) mRNA transcripts (250%), nitrites level (240%) and arginase activity (296%), leading to nitrosative stress and cell proliferation. Curcumin treatment, starting at week 10 post-DMH injection for 14 days, reduced the number of ACF (40%), iNOS expression (25%) and arginase activity (73%), and improved redox status by approximately 46%, compared to DMH-treated mice. Moreover, curcumin induced apoptosis of dysplastic ACF cells without restoring goblet cells differentiation. Interestingly, curcumin induced a parallel increase in TGF-β1 and HES-1 transcripts (42% and 26%, respectively). In conclusion, the protective effect of curcumin was driven by the reduction of arginase activity and nitrosative stress. The up regulation of TGF-β1 and HES-1 expression by curcumin suggests for the first time, a potential interplay between these signalling pathways in the chemoprotective mechanism of curcumin.
AuthorsAbdelkader Bounaama, Bahia Djerdjouri, Audrey Laroche-Clary, Valérie Le Morvan, Jacques Robert
JournalToxicology (Toxicology) Vol. 302 Issue 2-3 Pg. 308-17 (Dec 16 2012) ISSN: 1879-3185 [Electronic] Ireland
PMID22982865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Antioxidants
  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Transcription Factor HES-1
  • Transforming Growth Factor beta1
  • Arginase
  • Curcumin
  • 1,2-Dimethylhydrazine
Topics
  • 1,2-Dimethylhydrazine (toxicity)
  • Aberrant Crypt Foci (chemically induced, drug therapy)
  • Animals
  • Antioxidants (pharmacology)
  • Apoptosis (drug effects)
  • Arginase (antagonists & inhibitors, genetics, metabolism)
  • Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
  • Carcinogenesis (drug effects)
  • Cell Differentiation (drug effects)
  • Colonic Neoplasms (metabolism, pathology)
  • Curcumin (pharmacology)
  • Homeodomain Proteins (genetics, metabolism)
  • Intestinal Mucosa (drug effects)
  • Male
  • Mice
  • Oxidative Stress (drug effects)
  • Signal Transduction
  • Transcription Factor HES-1
  • Transforming Growth Factor beta1 (genetics, metabolism)
  • Up-Regulation

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