Inhibitory Effect of Three Diketopiperazines from Marine-Derived Bacteria on HMGB1-Induced Septic Responses in Vitro and in Vivo

• Published in: The American journal of Chinese medicine (1979) Vol. 44; no. 6; p. 1145
• Main Authors: Lee, Wonhwa, Ku, Sae-Kwang, Park, Songhee, Kim, Kyung-Min, Choi, Hyukjae, Bae, Jong-Sup
• Format: Journal Article
• Language: English
• Published: Singapore 01.01.2016
• Subjects: Actinomycetales - chemistry; Actinomycetales - isolation & purification; Animals; Anti-Infective Agents, Local - chemistry; Anti-Infective Agents, Local - isolation & purification; Anti-Infective Agents, Local - pharmacology; Anti-Infective Agents, Local - therapeutic use; Bacillus - chemistry; Bacillus - isolation & purification; Cell Survival - drug effects; Diketopiperazines - chemistry; Diketopiperazines - isolation & purification; Diketopiperazines - pharmacology; Diketopiperazines - therapeutic use; Disease Models, Animal; Geologic Sediments - microbiology; HMGB1 Protein - adverse effects; HMGB1 Protein - physiology; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Inbred C57BL; Porifera - microbiology; Sepsis - drug therapy; Sepsis - genetics; Shock, Septic - drug therapy; Shock, Septic - genetics; HUVEC; Sepsis; Inflammation; HMGB1; Diketopiperazines
• ISSN: 0192-415X
• DOI: 10.1142/S0192415X16500646

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.