title: Timosaponin AIII and its metabolite sarsasapogenin ameliorate colitis in mice by inhibiting NF-κB and MAPK activation and restoring Th17/Treg cell balance.
abstract: The rhizome of Anemarrhena asphodeloides (AA, family Liliaceae), which contains furostanol and spirostanol saponins, is a typical herbal medicine that improves learning and memory in rats and inhibits inflammation. In a preliminary study, timosaponin AIII, one of AA main constituents, was metabolized to sarsasapogenin by gut microbiota and inhibited NF-κB activation in lipopolysaccharide (LPS)-stimulated macrophages. Here we have investigated the anti-inflammatory effects of AIII and sarsasapogenin in vitro and in vivo. Both AIII and sarsasapogenin potently inhibited NF-κB and MAPK activation, as well as IRAK1, TAK1, and IκBα phosphorylation in LPS-stimulated macrophages. Further, AIII and sarsasapogenin inhibited the binding of LPS to macrophage Toll-like receptor 4, as well as polarization of M2 to M1 macrophages. Oral administration of AIII and sarsasapogenin inhibited 2,3,4-trinitrobenzene sulfonic acid (TNBS)-induced colon shortening and myeloperoxidase activity in mice, along with reducing NF-κB activation and interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels, while simultaneously increasing IL-10. Both compounds inhibited Th17 cell differentiation in colonic lamina propria, but induced Treg cell differentiation. Further, AIII and sarsasapogenin inhibited the differentiation of splenic CD4(+) T cells into Th17 cells in vitro. The vitro and in vivo anti-inflammatory effects of sarsasapogenin were more potent than AIII. These results suggest that orally administered AIII may be metabolized to sarsasapogenin by gut microbiota, which may ameliorate inflammatory diseases such as colitis by inhibiting TLR4-NF-κB/MAPK signaling pathway and restoring Th17/Treg cell balance.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Su-Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Jeong
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Geum-Dan
authors.initials: GD
authors.lastname: Kang
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
authors.affiliation: Dongwha Pharm Research Institute, 71, Tapsil-ro, 35beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 446-902, Republic of Korea.
authors.forename: Hyun-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: dhkim@khu.ac.kr.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use; D013150:Spirostans / Q000494:pharmacology / Q000627:therapeutic use; D013256:Steroids / Q000494:pharmacology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012503:Saponins; D013150:Spirostans; D013256:Steroids; C543146:timosaponin AIII; D014302:Trinitrobenzenesulfonic Acid; C046297:sarsasapogenin; D009195:Peroxidase; D020928:Mitogen-Activated Protein Kinases
keywords: Colitis; Inflammation; Macrophage; Sarsasapogenin; Th17 cell; Timosaponin AIII