title: Pomegranate polyphenolics reduce inflammation and ulceration in intestinal colitis-involvement of the miR-145/p70S6K1/HIF1α axis in vivo and in vitro.
abstract: This study investigated the potential role of the p70S6K1/HIF1α axis in the anti-inflammatory activities of pomegranate (Punica granatum L.) polyphenolics in dextran sodium sulfate (DSS)-induced colitis in Sprague-Dawley rats and in lipopolysaccharide (LPS)-treated CCD-18Co colon-myofibroblastic cells. Rats were administered either control (CT) or pomegranate beverage (PG), containing ellagic acid and ellagitannins, then exposed to three cycles of 3% DSS followed by a 2-week recovery period. PG protected against DSS-induced colon inflammation and ulceration (50% and 66.7%, P=.05 and .045, respectively), and decreased the Ki-67 proliferative index in the central and basal regions compared to the control. PG also significantly reduced the expression of proinflammatory cytokines (TNF-α and IL-1β), COX-2, and iNOS at mRNA and protein levels. In addition, the expression of p70S6K1 and HIF1α was reduced, while the tumor suppressor miR-145 was induced by PG. The intestinal microbiota of rats treated with PG showed a significant increase in Ruminococcaceae that include several butyrate producing bacteria (P=.03). In vitro, PG reduced the expression of p70S6K1 and HIF1α and induced miR-145 in a dose-dependent manner. The involvement of miR-145/p70S6K1 was confirmed by treating LPS-treated CCD-18Co cells with miR-145 antagomiR, where the pomegranate polyphenolics reversed the effects of the antagomiR for p70S6K1 mRNA and protein levels. These results suggest that pomegranate polyphenols attenuated DSS-induced colitis by modulating the miR-145/p70S6K/HIF1α axis, indicating potential use in therapeutic treatment of ulcerative colitis.
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA.
authors.forename: Hyemee
authors.initials: H
authors.lastname: Kim
authors.affiliation: Interdisciplinary Program of Toxicology, Texas A&M University, College Station, TX, USA.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Banerjee
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA.
authors.forename: Maritza A
authors.initials: MA
authors.lastname: Sirven
authors.affiliation: Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Minamoto
authors.affiliation: Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Markel
authors.affiliation: Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Suchodolski
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Talcott
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA. Electronic address: smtalcott@tmau.edu.
authors.forename: Susanne U
authors.initials: SU
authors.lastname: Mertens-Talcott
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000178:diet therapy* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D000067030:Fruit and Vegetable Juices; D000069196:Gastrointestinal Microbiome / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D029561:Lythraceae / Q000737:chemistry*; D035683:MicroRNAs / Q000378:metabolism; D059808:Polyphenols / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C542511:MIRN145 microRNA, rat; D035683:MicroRNAs; D059808:Polyphenols; D016264:Dextran Sulfate; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: Colitis; HIF1α; Pomegranate; Rat; miR-145