title: The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice.
abstract: Ulcerative colitis (UC) is a chronic intestinal inflammatory disease. Necroptosis plays an important role in the pathogenesis of UC. Celastrol, a triterpene from the root bark of the Chinese medicinal plant Tripterygium wilfordii, has been reported to have anti-oxidant and anti-inflammatory activities in colitis. It is not known, however, how celastrol exerts its beneficial effects. The aim of this study is to investigate the effects and possible mechanism of celastrol in UC. Colitis was induced in mice by administration of 5% dextran sulfate sodium (DSS) in drinking water for 4days. Celastrol was administered intraperitoneally (1mg/kg) for 7days after colitis was induced. Our results showed that celastrol treatment ameliorated the severity of colitis, decreased the level of interleukin (IL)-1β, IL-6 and myeloperoxidase (MPO) and upregulated the level of E-cadherin in colitis mice. Moreover, the TUNEL staining and cleaved caspase-3 immunohistochemistry staining proved decreased necrotic cell death after celastrol treatment. On the mechanism, decreased level of necroptosis factors RIP3 and MLKL, and increased level of active caspase-8 were detected after celastrol treatment. Taken together, our results demonstrated that celastrol exerted beneficial effects in colitis treatment via suppressing the RIP3/MLKL necroptosis pathway.
authors.affiliation: Department of Gastroenterology and Digestive Diseases, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou 215006, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Gastroenterology and Digestive Diseases, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou 215006, China.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Digestive Diseases, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou 215006, China.
authors.forename: Jiaqing
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology and Digestive Diseases, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou 215006, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xia
authors.affiliation: Ministry of Education Engineering Center of Hematological Disease, Soochow University, 199 Renai Rd, Suzhou 215006, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Yang
authors.affiliation: Ministry of Health Key Laboratory of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou 215006, China. Electronic address: heyang1963@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: He
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000188:drug therapy* / Q000473:pathology; D053978:Pentacyclic Triterpenes; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D029757:Tripterygium / Q000737:chemistry; D014315:Triterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000897:Anti-Ulcer Agents; D015850:Interleukin-6; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D016264:Dextran Sulfate; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8; C050414:celastrol
keywords: Celastrol; MLKL; Necroptosis; RIP3; Ulcerative colitis