title: 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.
authors.affiliation: Faculté des Sciences Biologiques, Laboratoire de Biologie Cellulaire et Moléculaire, Université des Sciences et de la Technologie Houari Boumediene, Alger, Algeria.
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Bounaama
authors.forename: Bahia
authors.initials: B
authors.lastname: Djerdjouri
authors.forename: Audrey
authors.initials: A
authors.lastname: Laroche-Clary
authors.forename: Valérie
authors.initials: V
authors.lastname: Le Morvan
authors.forename: Jacques
authors.initials: J
authors.lastname: Robert
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019813:1,2-Dimethylhydrazine; D000975:Antioxidants; D001119:Arginase; D051792:Basic Helix-Loop-Helix Proteins; D003474:Curcumin; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; D053773:Transforming Growth Factor beta1; C489734:Hes1 protein, mouse