title: Novel guggulsterone derivative GG-52 inhibits NF-kappaB signaling in intestinal epithelial cells and attenuates acute murine colitis.
abstract: We already showed that the plant sterol guggulsterone has been reported to inhibit nuclear factor-kappaB (NF-kappaB) signaling in intestinal epithelial cells (IECs) and to attenuate dextran sulfate sodium (DSS)-induced colitis. This study investigates the anti-inflammatory effects of novel guggulsterone derivatives on IEC and preventive and therapeutic murine models of DSS-induced colitis. Novel guggulsterone derivates with high lipophilicity were designed and four derivates, including GG-46, GG-50B, GG-52, and GG-53, were synthesized. Two guggulsterone derivatives, GG-50B and GG-52, significantly inhibited the activated NF-kappaB signals and the upregulated expression of interleukin-8 (IL-8) in COLO 205 cells stimulated with tumor necrosis factor-alpha (TNF-alpha). Pretreatment with GG-50B and GG-52 attenuated the increased IkappaB kinase (IKK) and IkappaBalpha phsophorylation induced by TNF-alpha. In preventive and therapeutic models of murine colitis, administration of GG-52 significantly reduced the severity of DSS-induced colitis, as assessed by disease activity index, colon length, and histology. In contrast, GG-50B did not show a significant reduction in the colitis severity. Moreover, the efficacy on attenuating colitis by GG-52 was comparable to that by sulfasalazine or prednisolone. These results indicate that the novel guggulsterone derivative GG-52 blocks NF-kappaB activation in IEC and ameliorates DSS-induced acute murine colitis, which suggests that GG-52 is a potential therapeutic agent for the treatment of inflammatory bowel diseases.
authors.affiliation: Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea.
authors.forename: Jung Mogg
authors.initials: JM
authors.lastname: Kim
authors.forename: Hyoun Woo
authors.initials: HW
authors.lastname: Kang
authors.forename: Mi Yeon
authors.initials: MY
authors.lastname: Cha
authors.forename: Doyoung
authors.initials: D
authors.lastname: Yoo
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: In-Kyoung
authors.initials: IK
authors.lastname: Kim
authors.forename: Jeounghun
authors.initials: J
authors.lastname: Ku
authors.forename: Sunil
authors.initials: S
authors.lastname: Kim
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Ma
authors.forename: Hyun Chae
authors.initials: HC
authors.lastname: Jung
authors.forename: In Sung
authors.initials: IS
authors.lastname: Song
authors.forename: Joo Sung
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011239:Prednisolone / Q000627:therapeutic use; D011282:Pregnenediones / Q000737:chemistry* / Q000494:pharmacology; D011283:Pregnenes / Q000494:pharmacology / Q000627:therapeutic use*; D012460:Sulfasalazine / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C550855:GG-50B compound; C550854:GG-52 compound; D016209:Interleukin-8; D016328:NF-kappa B; D011282:Pregnenediones; D011283:Pregnenes; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D011239:Prednisolone; C023617:pregna-4,17-diene-3,16-dione; D051550:I-kappa B Kinase