title: A tetrahydroisoquinoline alkaloid THI-28 reduces LPS-induced HMGB1 and diminishes organ injury in septic mice through p38 and PI3K/Nrf2/HO-1 signals.
abstract: We investigated whether THI-28 [1-4-(hydroxyphenylethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits release of high mobility group box 1 (HMGB1), a late phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated RAW264.7 cells through heme oxygenase (HO)-1 induction so that it shows beneficial effects in the cecal ligation and puncture (CLP)-induced septic mouse model. Silencing of target genes (HO-1, Nrf-2) or pharmacological signal inhibitors was exploited to investigate the HO-1 induction by THI-28. The dependency of HO-1 by THI-28 on survival rate and circulating HMGB1 level was tested in CLP-induced septic mice. Results showed that a time- and concentration-dependent HO-1 induction by THI-28 was significantly reduced by transfection with siNrf2 RNA. The reduction of iNOS/NO and HMGB1 expression by THI-28 was significantly reversed by silencing HO-1 RNA or treatment with SB203580, a p38 MAPK inhibitor, or LY294002, a PI3K inhibitor in LPS-activated cells. Decreasing p-IκBα by THI-28 resulted in inhibition of NF-κB activity which was reversed by silencing HO-1 RNA in LPS-activated cells. Most importantly, increased survival and reduction of liver and kidney injury and circulating HMGB1 levels by THI-28 in CLP-mice were reversed by ZnPPIX, HO-1 inhibitor. Taken together, these findings suggest that the novel compound THI-28 induces the expression of HO-1 by activating the PI3K and p38 MAPK pathways and suppressed HMGB1 and iNOS production in LPS-treated macrophages and septic mice, which may be useful in treating organ injury due to sepsis.
authors.affiliation: Department of Pharmacology, School of Medicine, Gyeongsang National University and Institute of Health Sciences, Jinju 660-772, Republic of Korea.
authors.forename: Hee Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000591710:1-(4-hydroxyphenylethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; D000893:Anti-Inflammatory Agents; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D007546:Isoquinolines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
keywords: HMGB1; Heme oxygenase; Inflammation; Sepsis