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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.
AuthorsJinque Luo, Mei Liu, Xin Wu, Yannong Dou, Yufeng Xia, Yue Dai, Zhifeng Wei
JournalInternational immunopharmacology (Int Immunopharmacol) Vol. 29 Issue 2 Pg. 583-590 (Dec 2015) ISSN: 1878-1705 [Electronic] Netherlands
PMID26456500 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier B.V. All rights reserved.
Chemical References
  • 11-deoxy-18alpha-glycyrrhetinic acid
  • 11-deoxy-18alpha-glycyrrhetinic acid-30-ethyl ester
  • Antibodies, Neutralizing
  • Chromones
  • Morpholines
  • Interleukin-10
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3
  • Glycyrrhetinic Acid
Topics
  • Animals
  • Antibodies, Neutralizing
  • Cell Line
  • Chromones (pharmacology)
  • Gene Expression Regulation (drug effects, physiology)
  • Glycogen Synthase Kinase 3 (genetics, metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Glycyrrhetinic Acid (analogs & derivatives, chemistry, pharmacology)
  • Inflammation (metabolism, prevention & control)
  • Interleukin-10 (genetics, metabolism)
  • Macrophages (drug effects)
  • Mice
  • Molecular Structure
  • Morpholines (pharmacology)
  • Rats
  • Shock, Septic (prevention & control)
  • Signal Transduction (drug effects)

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