title: 13-Ethylberberine reduces HMGB1 release through AMPK activation in LPS-activated RAW264.7 cells and protects endotoxemic mice from organ damage.
abstract: High mobility group box 1 (HMGB1), a highly conserved non-histone DNA-binding protein, plays an important role in the pathogenesis of sepsis. Previously, the authors reported 13-ethylberberine (13-EBR) has anti-inflammatory and antibacterial effects. However, the effect of 13-EBR on HMGB1 release was not investigated. In the present study, it was hypothesized 13-EBR might reduce HMGB1 release by activating AMPK under septic conditions. The results obtained showed 13-EBR significantly reduced HMGB1 release from LPS-activated RAW264.7 cells, and that this reduction was reversed by silencing p38, or AMPK, or by co-treating cells with p38 MAPKinase inhibitor. 13-EBR increased the phosphorylations of p38 and AMPK, and the phosphorylation of p38 by 13-EBR was inhibited by AMPK-siRNA, indicating AMPK acted upstream of p38. In the lung tissues of LPS-treated mice, 13-EBR administration significantly increased p-AMPK but reduced inducible nitric oxide synthase (iNOS) protein levels. Hematoxylin and eosin staining revealed 13-EBR significantly reduced LPS-induced lung and liver damage. In addition, 13-EBR inhibited NF-kB in LPS-activated RAW264.7 cells, and in LPS-treated mice, 13-EBR administration significantly increased survival. Furthermore, co-administration of 13-EBR plus LPS prevented LPS-induced aortic rings hypocontractile response to phenylephrine in vitro. Taken together, these results indicate 13-EBR might offer a means of treating sepsis through AMPK activation.
authors.affiliation: Division of Bioscience, Dongguk University, Gyeongju 780-714, Republic of Korea.
authors.forename: Dong Ung
authors.initials: DU
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University and Institute of Health Sciences, Jinju 52527, Republic of Korea.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University and Institute of Health Sciences, Jinju 52527, Republic of Korea; Department of Convergence of Biomedical Sciences (BK21 PLUS Program), Gyeongsang National University and Institute of Health Sciences, Jinju 52527, Republic of Korea.
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine Gyeongsang National University and Institute of Health Sciences, Jinju 52527, Republic of Korea; Department of Convergence of Biomedical Sciences (BK21 PLUS Program), Gyeongsang National University and Institute of Health Sciences, Jinju 52527, Republic of Korea. Electronic address: kcchang@gnu.kr.
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001599:Berberine / Q000494:pharmacology / Q000627:therapeutic use*; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D011494:Protein Kinases / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D001599:Berberine; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases
keywords: AMPK; HMGB1; Inflammation; Sepsis; Vascular reactivity; p38MAPK