title: Enzymatically synthesized glycogen inhibits colitis through decreasing oxidative stress.
abstract: Inflammatory bowel diseases are a group of chronic inflammation conditions of the gastrointestinal tract. Disruption of the mucosal immune response causes accumulation of oxidative stress, resulting in the induction of inflammatory bowel disease. In this study, we investigated the effect of enzymatically synthesized glycogen (ESG), which is produced from starch, on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in C57BL/6 mice. Oral administration of ESG suppressed DSS- and TNBS-induced shortening of large intestine in female mice and significant decreased DSS-induced oxidative stress and TNBS-induced pro-inflammatory cytokine expression in the large intestine. ESG increase in the expression levels of heme oxygenase-1 (HO-1) and NF-E2-related factor-2 (Nrf2), a transcription factor for HO-1 expressed in the large intestine. Furthermore, ESG-induced HO-1 and Nrf2 were expressed mainly in intestinal macrophages. ESG is considered to be metabolized to resistant glycogen (RG) during digestion with α-amylase in vivo. In mouse macrophage RAW264.7 cells, RG, but not ESG decreased 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced reactive oxygen species (ROS). Knockdown of Nrf2 inhibited RG-induced HO-1 expression and negated the decrease in AAPH-induced ROS brought about by RG. RG up-regulated the protein stability of Nrf2 to decrease the formation of Nrf2-Keap1 complexes. RG-induced phosphorylation of Nrf2 at Ser40 was suppressed by ERK1/2 and JNK inhibitors. Our data indicate that ESG, digested with α-amylase to RG, suppresses DSS- and TNBS-induced colitis by increasing the expression of HO-1 in the large intestine of mice. Furthermore, we demonstrate that RG induces HO-1 expression by promoting phosphorylation of Nrf2 at Ser40 through activation of the ERK1/2 and JNK cascade in macrophages.
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan; Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 6578501, Japan.
authors.forename: Takakazu
authors.initials: T
authors.lastname: Mitani
authors.affiliation: Organization of Advanced Science and Technology, Kobe University, Kobe, Hyogo 6578501, Japan.
authors.forename: Yasukiyo
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Institute of Health Sciences, Ezaki Glico Co., Ltd., Osaka 5558502, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Furuyashiki
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo 6578501, Japan. Electronic address: ashida@kobe-u.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ashida
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006003:Glycogen / Q000008:administration & dosage* / Q000138:chemical synthesis; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects; D000067996:RAW 264.7 Cells; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D014302:Trinitrobenzenesulfonic Acid; D006003:Glycogen; D016264:Dextran Sulfate; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Glycogen; Heme oxygenase-1; Inflammatory bowel disease; Macrophage; Mitogen-activated protein kinase; NF-E2-related factor-2