title: Inhibitory Effect of Three Diketopiperazines from Marine-Derived Bacteria on HMGB1-Induced Septic Responses in Vitro and in Vivo.
abstract: The nucleosomal protein high-mobility group box-1 (HMGB1), which has recently been established as a late mediator of lethal systemic inflammation, has a relatively wide therapeutic window for pharmacological interventions. Compounds produced by marine-derived microbes have been widely investigated for their potential use as bioactive natural products. Cyclic dipeptides, which are also known as diketopiperazines, are molecules that are frequently found in marine-derived microorganisms. While their pharmacological potential has been well established, their biological activities against septic responses have not yet been reported. Here, three diketopiperazines (1-3) isolated from two strains of marine-derived bacteria were investigated for their potential activities against HMGB1-mediated septic responses. The data showed that 1-3 effectively inhibited the lipopolysaccharide (LPS)-induced release of HMGB1 and suppressed the HMGB1-mediated septic responses, including hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, 1-3 inhibited the HMGB1-mediated production of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text] and interleukin (IL)-6 and the activation of nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) and extracellular signal-regulated kinase (ERK) 1 and ERK2. Collectively, these results indicated that 1-3 might act as potential therapeutic agents for various severe vascular inflammatory diseases through the inhibition of the HMGB1 signaling pathway.
authors.affiliation: * College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Daegu 41566, Republic of Korea.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Lee
authors.affiliation: ‡ Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: § College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Songhee
authors.initials: S
authors.lastname: Park
authors.affiliation: † Division of Plant Biosciences, School of Applied BioSciences, College of Agriculture and Life Science, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Kim
authors.affiliation: § College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Hyukjae
authors.initials: H
authors.lastname: Choi
authors.affiliation: * College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Daegu 41566, Republic of Korea.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000192:Actinomycetales / Q000737:chemistry* / Q000302:isolation & purification; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001407:Bacillus / Q000737:chemistry* / Q000302:isolation & purification; D002470:Cell Survival / Q000187:drug effects; D054659:Diketopiperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D019015:Geologic Sediments / Q000382:microbiology; D024243:HMGB1 Protein / Q000009:adverse effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D011161:Porifera / Q000382:microbiology*; D018805:Sepsis / Q000188:drug therapy* / Q000235:genetics; D012772:Shock, Septic / Q000188:drug therapy / Q000235:genetics
chemical_list: D000891:Anti-Infective Agents, Local; D054659:Diketopiperazines; D024243:HMGB1 Protein
keywords: Diketopiperazines; HMGB1; HUVEC; Inflammation; Sepsis