K313, a novel benzoxazole derivative, exhibits anti‐inflammatory properties via inhibiting GSK3β activity in LPS‐induced RAW264.7 macrophages

• Published in: Journal of cellular biochemistry Vol. 119; no. 7; pp. 5382 - 5390
• Main Authors: Zhao, Bo‐Bo, Guo, Hui‐Jie, Liu, Yang, Luo, Xing‐Yan, Yang, Shu‐Xia, Wang, Yan‐Tang, Leng, Xiao, Mo, Chun‐Fen, Zou, Qiang
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2018
• Subjects: AKT protein; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; anti‐inflammatory properties; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Biological properties; Cell activation; Cell proliferation; Cells, Cultured; Cytokines; Cytokines - metabolism; Deactivation; Extracellular signal-regulated kinase; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; glycogen synthase kinase‐3 beta; Immunosuppression; Indoles; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Inflammation - metabolism; Inflammatory response; Interleukins; K313; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lithium; Lithium chloride; LPS‐induced RAW264.7 macrophages; Lymphocytes T; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; MAP kinase; Mice; Molecular chains; NF-kappa B - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Nitrotyrosine; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Synergistic effect; Transcription; Tumor necrosis factor; Tumor necrosis factor-TNF; K313; LPS-induced RAW264.7 macrophages; glycogen synthase kinase-3 beta; anti-inflammatory properties
• DOI: 10.1002/jcb.26685
• ISSN: 0730-2312

Benzoxazole and its derivatives have been widely studied in recent years due to their various biological properties. A previous study has demonstrated that K313 (1H‐indole‐2,3‐dione 3‐(1,3‐benzoxazol‐2‐ylhydrazone)), a novel benzoxazole derivative, inhibits T cell proliferation to yield immunosuppressive effects. However, there are no related reports about its anti‐inflammatory effects. In the present study, we investigated the anti‐inflammatory properties and the underlying molecular mechanism of K313 in lipopolysaccharide (LPS)‐induced RAW264.7 macrophages. K313 dose‐dependently (5, 10, and 20 μM) inhibited LPS‐stimulated nitric oxide (NO), interleukin (IL)‐6, tumor necrosis factor (TNF)‐α, and 3‐nitrotyrosine (3‐NT) production and significantly decreased the gene transcription levels of inducible nitric oxide (iNOS), IL‐6, and TNF‐α. In addition, the results showed that the inflammatory cytokines suppressed by K313 were not regulated by p65 NF‐κB, ERK1/2, AKT, or p38 MAPK. Instead, K313 increased phosphorylation of glycogen synthase kinase‐3 beta (GSK‐3β) (Ser9) resulting in GSK‐3β deactivation. Moreover, in LPS‐stimulated RAW264.7 macrophages, K313 and lithium chloride (LiCl) had a synergistic effect on the anti‐inflammatory response. These results indicated that K313 exhibited anti‐inflammatory properties and revealed the potential mechanism. K313 can increase GSK‐3β (Ser9) phosphorylation to decrease GSK‐3β activation in LPS‐induced RAW264.7 macrophages. K313, a novel benzoxazole derivative, had anti‐inflammatory effects by decreasing GSK‐3β activation, that is, by increasing the Ser9 phosphorylation of GSK‐3β. And the anti‐inflammatory properties of K313 were not regulated by p65 NF‐κB, ERK1/2, AKT, or p38 MAPK.