title: DGAEE, a newly synthesized derivative of glycyrrhetinic acid, potently attenuates mouse septic shock via its main metabolite DGA in an IL-10-dependent manner.
abstract: Endotoxin can stimulate inflammatory cytokine release from monocytes/macrophages and result in septic shock. Glycyrrhetinic acid (GA), the main bioactive component of licorice, possesses substantial anti-inflammatory activity. Here, we explored effect of 11-deoxy-18α-glycyrrhetinic acid-30-ethyl ester (DGAEE), a newly synthesized derivative of GA, on septic shock. DGAEE and its main metabolite 11-deoxy-18α-glycyrrhetinic acid (DGA) significantly alleviated septic shock as evidenced by improvements of survival rates, lung histopathological changes and wet/dry ratio in lipopolysaccharide (LPS)/D-galactosamine-stimulated mice, and decreased blood pressure in LPS/D-galactosamine-stimulated rats. The two compounds decreased serum levels of NO, TNF-α, IL-6, IL-1β, and increased the level of IL-10 more potently in mice. In LPS-stimulated RAW 264.7 cells, DGA but not DGAEE showed marked regulation of NO, TNF-α, IL-6 and IL-10 levels, suggesting that DGAEE display anti-shock effect by DGA rather than itself. Moreover, the neutralizing antibody against IL-10 markedly prohibited the inhibitory effect of DGA on the production of cytokines from RAW 264.7 cells, and AS101 (an inhibitor of IL-10 biosynthesis) almost completely reversed the anti-shock effect of DGA in mice. In addition, DGA did not affect activation of NF-κB-p65 and p38 MAPK as well as IκBα degradation, but moderately reduced activation of ERK and JNK, and markedly increased phosphorylation of GSK3β in LPS-stimulated RAW 264.7 cells. LY294002 (an inhibitor of GSK3β phosphorylation) and LiCl (an inhibitor of GSK3β activity) diminished and potentiated increase of IL-10 levels by DGA, respectively. In conclusion, DGAEE alleviates septic shock through DGA in an IL-10-dependent manner, and the mechanism is related to inactivation of GSK3β.
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Jinque
authors.initials: J
authors.lastname: Luo
authors.affiliation: Chia-Tai Tianqing Pharmaceutical Group Co., Ltd., Xuanwu Ave, Nanjing 210023, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yannong
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: yuedaicpu@hotmail.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: zhifeng-wei@hotmail.com.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wei
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines / Q000494:pharmacology; D051381:Rats; D012772:Shock, Septic / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000611107:11-deoxy-18alpha-glycyrrhetinic acid; C000611106:11-deoxy-18alpha-glycyrrhetinic acid-30-ethyl ester; D057134:Antibodies, Neutralizing; D002867:Chromones; D009025:Morpholines; D016753:Interleukin-10; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D006034:Glycyrrhetinic Acid
keywords: DGA; DGAEE; GSK3β; IL-10; Septic shock