title: Anti-septic effects of dabrafenib on HMGB1-mediated inflammatory responses.
abstract: A nucleosomal protein, high mobility group box 1 (HMGB1) is known to be a late mediator of sepsis. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. Inhibition of HMGB1 and renewal of vascular integrity is appearing as an engaging therapeutic strategy in the administration of severe sepsis or septic shock. Here, we examined the effects of dabrafenib (DAB) on the modulation of HMGB1-mediated septic responses. DAB inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses by enhancing the expressions of cell adhesion molecules (CAMs) in human endothelial cells. In addition, treatment with DAB inhibited the HMGB1 secretion by CLP and sepsis-related mortality and pulmonary injury. This study demonstrated that DAB could be alternative therapeutic options for sepsis or septic shock via the inhibition of the HMGB1 signaling pathway. [BMB Reports 2016; 49(4): 214-219].
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
authors.forename: Byeongjin
authors.initials: B
authors.lastname: Jung
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Kang
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566; Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Noh
authors.affiliation: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Korea.
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Fatima Hospital, Daegu 41199, Korea.
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Han
authors.affiliation: Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Korea.
authors.forename: Moon-Chang
authors.initials: MC
authors.lastname: Baek
authors.affiliation: Department of Biochemistry, School of Medicine, Gachon University, Incheon 21999, Korea.
authors.forename: Jaehong
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D008026:Ligation; D008070:Lipopolysaccharides; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010091:Oximes / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology; D011677:Punctures; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000891:Anti-Infective Agents, Local; D015815:Cell Adhesion Molecules; D024243:HMGB1 Protein; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010091:Oximes; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; C561627:dabrafenib