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      Novel Activity of ODZ10117, a STAT3 Inhibitor, for Regulation of NLRP3 Inflammasome Activation.

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          Abstract

          The NLRP3 inflammasome serves as a host defense mechanism against various pathogens, but there is growing evidence linking its activation in sterile condition to diverse inflammatory diseases. Therefore, the identification of specific inhibitors that target NLRP3 inflammasome activation is meaningful and important for novel therapies for NLRP3 inflammasome-associated diseases. In this study, we identified a chemical compound, namely ODZ10117 (ODZ), that showed NLRP3 inflammasome-targeting anti-inflammatory effects during the screening of a chemical library for anti-inflammatory activity. Although ODZ was initially discovered as a STAT3 inhibitor, here we found it also has inhibitory activity on NLRP3 inflammasome activation. ODZ inhibited the cleavage of caspase-1 and IL-1β-induced canonical NLRP3 inflammasome triggers, but had no effect on those induced by AIM2 or NLRC4 triggers. Mechanistically, ODZ impairs NLRP3 inflammasome activation through the inhibition of NLRP3-NEK7 interaction that is required for inflammasome formation. Moreover, the results obtained from the in silico docking experiment suggested that ODZ targets NLRP3 protein, which provides evidence for the specificity of ODZ to the NLRP3 inflammasome. Furthermore, ODZ administration significantly reduced MSU-induced IL-1β release and the mortality rate of mice with LPS-induced sepsis. Collectively, these results demonstrate a novel effect of ODZ10117 in regulating NLRP3 inflammasome activation both in vitro and in vivo, making it a promising candidate for the treatment of NLRP3-inflammasome-associated immune disorders and cancer.

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          Author and article information

          Journal
          Int J Mol Sci
          International journal of molecular sciences
          MDPI AG
          1422-0067
          1422-0067
          Mar 23 2023
          : 24
          : 7
          Affiliations
          [1 ] BK21 Project Team, Department of Applied Life Science, Graduate School, Konkuk University, Chungju 27478, Republic of Korea.
          [2 ] Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
          [3 ] Department of Biotechnology, Research Institute of Inflammatory Diseases, Research Institute (RIBHS), College of Biomedical and Health Science, Konkuk University, Chungju 27478, Republic of Korea.
          Article
          ijms24076079
          10.3390/ijms24076079
          10094431
          37047051
          90739d0a-0cf9-4417-9580-b6daccc4b3af
          History

          MSU-induced peritonitis,NLRP3 inflammasome,ODZ10117,LPS-induced sepsis

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