title: Dipotassium glycyrrhizate via HMGB1 or AMPK signaling suppresses oxidative stress during intestinal inflammation.
abstract: OBJECTIVE
  Oxidative stress and inflammation are always associated. Appropriate management of oxidative mediators may represent a therapeutic strategy to reduce inflammation, and use of antioxidant can be protective against inflammatory diseases. Glycyrrhizin (GL) plays an anti-inflammatory and antioxidant effect by inhibiting high mobility group box 1 (HMGB1) or 11-β-hydroxysteroid dehydrogenase type II (11βHSD2) enzyme. In this study, the potential role of dipotassium glycyrrhizate (DPG), a salt of GL, to reduce oxidative stress in intestinal inflammatory condition was investigated in vivo and the mechanism of action of DPG was studied in vitro.
  
  
  RESULTS
  In a colitis mouse model DPG affected oxidative stress reducing iNOS and COX-2 expression, as well as NO and PGE2 levels. By means of LPS-stimulated macrophages we found that DPG inhibited the expression of pro-inflammatory cytokines and reduced iNOS and COX-2 expression in a time dependent manner, through two different ways of signal. DPG reduced, at a later time, both iNOS and COX-2, through a mechanism HMGB1-dependent, and at an earlier time only COX-2, through a mechanism AMP-activated kinase (AMPK)-phosphorylation-mediated.
  
  
  CONCLUSIONS
  DPG has a protective effect on colitis and inflammation through the inhibition of oxidative stress. This study clarifies the two-ways mechanism by which DPG inhibits iNOS and COX-2 during inflammation and demonstrates for the first time that AMPK is a target of DPG. Uncovering this mechanism is significant to clarify the relationship between energy homeostasis and anti-oxidative responses and suggests that DPG could play a relevant role in the development of new therapy against inflammatory diseases associated to oxidative stress.
authors.affiliation: Department of Radiobiology and Human Health, ENEA CR Casaccia, Rome, Italy. Electronic address: roberta.vitali@enea.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Vitali
authors.affiliation: Department of Radiobiology and Human Health, ENEA CR Casaccia, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Palone
authors.affiliation: Department of Radiobiology and Human Health, ENEA CR Casaccia, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pierdomenico
authors.affiliation: Department of Radiobiology and Human Health, ENEA CR Casaccia, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Negroni
authors.affiliation: Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.affiliation: Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Aloi
authors.affiliation: Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliva
authors.affiliation: Department of Radiobiology and Human Health, ENEA CR Casaccia, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Stronati
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D019695:Glycyrrhizic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D019695:Glycyrrhizic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D055372:AMP-Activated Protein Kinases
keywords: AMPK; DPG; Dipotassium glycyrrhizate (PubChem CID: 656852); HMGB1; Oxidative stress; Two-ways mechanism