title: Bis-N-norgliovictin, a small-molecule compound from marine fungus, inhibits LPS-induced inflammation in macrophages and improves survival in sepsis.
abstract: Sepsis is a highly lethal disorder characterized by systemic inflammation, and Toll-like receptor 4 (TLR4) in macrophages plays a crucial role in modulating innate immune response and outcome of sepsis. During the screening of natural products against inflammation, we identified bis-N-norgliovictin, a small-molecule compound isolated from marine-derived fungus, significantly inhibited lipopolysaccharide (LPS, ligand of TLR4)-induced tumor necrosis factor-α (TNF-α) production in RAW264.7 cells. In this study, we evaluated the effect of bis-N-norgliovictin on TLR4-mediated inflammation in mouse macrophages and LPS-induced sepsis model. In RAW264.7 and mouse peritoneal macrophages, bis-N-norgliovictin dose-dependently inhibited LPS-induced production of TNF-α, interleukin-6 (IL-6), interferon-β (IFN-β) and monocyte chemoattractant protein (MCP-1), but without suppressing cell viability. The anti-inflammatory effect was attributed to the down-regulation of TLR4-triggered myeloid differentiation primary response protein 88 (MyD88)-dependent and TIR-containing adapter inducing interferon-β (TRIF)-dependent signaling pathways, including p38 and c-Jun N-terminal kinase (JNK) of mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) cascades. Importantly, bis-N-norgliovictin also protected mice against LPS-induced endotoxic shock. Intravenous injection of bis-N-norgliovictin 1h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-α, IL-6, MCP-1 and IL-10, attenuated liver and lung injury and diminished M1 macrophage polarization in liver. Our results demonstrate that bis-N-norgliovictin exhibit potent anti-inflammatory effect both in vitro and in vivo. These findings suggest that bis-N-norgliovictin can be a useful therapeutic candidate for the treatment of sepsis and other inflammatory diseases.
authors: Immunology and Reproductive Biology Lab & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, PR China.
authors: Yuxian
authors: Y
authors: Song
authors: Huan
authors: H
authors: Dou
authors: Wei
authors: W
authors: Gong
authors: Xianqin
authors: X
authors: Liu
authors: Zhiguo
authors: Z
authors: Yu
authors: Erguang
authors: E
authors: Li
authors: Renxiang
authors: R
authors: Tan
authors: Yayi
authors: Y
authors: Hou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D054659:Diketopiperazines / Q000494:pharmacology / Q000627:therapeutic use*; D005658:Fungi / Q000737:chemistry; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D054659:Diketopiperazines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013440:Sulfides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C584130:bis-N-norgliovictin; D020928:Mitogen-Activated Protein Kinases