title: Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis.
abstract: Colon carcinogenesis is long known to be associated with ulcerative colitis (UC), a chronic gastrointestinal disorder. Various pre-clinical and clinical studies have shown that melatonin (MEL) has beneficial effects in cancer. However, elucidation of the detailed molecular mechanisms involved in MEL-mediated protection against the colon carcinogenesis deserves further investigation. The present study was aimed at deciphering the effect of MEL on autophagy and Nrf2 signaling pathways in a mouse model of colitis-associated colon carcinogenesis (CACC). For the induction of CACC, male Swiss Albino mice were administered a single ip injection of 20 mg 1, 2-dimethylhydrazine dihydrochloride (DMH)/kg bw, followed by 3 cycles of 3% w/v dextran sulfate sodium (DSS) in drinking water treatment initiated 1 wk after DMH injection. One week after the initiation of DSS treatment, MEL was administered at the dose of 1 mg/kg, bw, po for 8 and 18 wk. Mice were sacrificed at 10 and 20 wk after DMH injection. MEL treatment decreased the progression of CACC by down regulating the process of autophagy as revealed by the expression pattern of various autophagy markers such as Beclin-1, LC3B-II/LC3B-I ratio and p62. These findings were accompanied with the increased expression of Nrf2 and the associated antioxidant enzymes,
  quinone oxidoreductase (NQO-1) and heme oxygenase-1 (HO-1) in the colon of mice with CACC. MEL intervention reduced autophagy by ameliorating inflammation and oxidative stress in the colon of mice with CACC. We conclude that MEL treatment attenuates the progression of CACC in mice by modulating autophagy and Nrf2 signaling pathways.
authors.affiliation: Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors.forename: P P
authors.initials: PP
authors.lastname: Trivedi
authors.affiliation: Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors.forename: G B
authors.initials: GB
authors.lastname: Jena
authors.affiliation: Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors.forename: K B
authors.initials: KB
authors.lastname: Tikoo
authors.affiliation: Icon Analytical Equipment Pvt Ltd, Delhi, India.
authors.forename: V
authors.initials: V
authors.lastname: Kumar
mesh_terms: D019813:1,2-Dimethylhydrazine; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects*; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016264:Dextran Sulfate; D019813:1,2-Dimethylhydrazine; D008550:Melatonin
keywords: Nrf2; autophagy; colitis-associated colon carcinogenesis; inflammation; melatonin; oxidative stress