title: Ethanol extract of Prunella vulgaris var. lilacina inhibits HMGB1 release by induction of heme oxygenase-1 in LPS-activated RAW 264.7 cells and CLP-induced septic mice.
abstract: The ethanol extract of the flower of P. vulgaris var. lilacina (EEPV) has been used traditionally as an antiinflammatory agent in many countries. Inducers of heme oxygenase-1 (HO-1) reduce high mobility group box 1 (HMGB1), a late phase cytokine, in sepsis. Although EEPV has been used as an antiinflammatory agent, no report is available as to whether it modifies HMGB1 in sepsis due to HO-1 induction. It was found that EEPV increased HO-1 protein expression in RAW 264.7 cells, which was significantly inhibited by LY294002, but not PD98059, SB203580 or SP600125. In addition, EEPV activated NF-E2-related factor (Nrf2) to move from the cytosol to the nucleus, and EEPV-induced HO-1 and activation of ARE-luciferase activity were significantly reduced by siNrf2 transfection and LY294002 but not SB203508. EEPV also significantly inhibited NF-κB luciferase activity, and decreased both iNOS/NO and COX-2/PGE(2) production in lipopolysaccharide (LPS)-stimulated macrophages which was reversed by siHO-1 RNA transfection. Importantly, EEPV inhibited HMGB1 release in LPS-activated macrophages in a PI3K-sensitive manner and reduced serum HMGB1 level and lung HMGB1 expression in cecal ligation and puncture (CLP)-induced septic mice. It is concluded that EEPV induces HO-1 expression through PI3K/Nrf2 signal pathways, which may be beneficial for the treatment of sepsis due to a reduction of HMGB1 release.
authors.affiliation: Department of Pharmacology, School of Medicine, and Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Jun
authors.forename: Hee Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Jae Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Kang Ro
authors.initials: KR
authors.lastname: Lee
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002432:Cecum / Q000293:injuries* / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D004790:Enzyme Induction; D000431:Ethanol; D005419:Flavonoids / Q000494:pharmacology; D035264:Flowers / Q000737:chemistry; D005822:Genetic Vectors; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D021381:Protein Transport; D031347:Prunella / Q000737:chemistry*; D011725:Pyridines / Q000494:pharmacology; D018805:Sepsis / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000873:Anthracenes; D002867:Chromones; D005419:Flavonoids; D024243:HMGB1 Protein; D007093:Imidazoles; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D011725:Pyridines; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one