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Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC
BACKGROUND: Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic str...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318668/ https://www.ncbi.nlm.nih.gov/pubmed/37400760 http://dx.doi.org/10.1186/s10020-023-00671-0 |
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author | Zhao, Jia Liu, Hongbin Hong, Zhixian Luo, Wei Mu, Wenqing Hou, Xiaorong Xu, Guang Fang, Zhie Ren, Lutong Liu, Tingting Wen, Jincai Shi, Wei Wei, Ziying Yang, Yongping Zou, Wenjun Zhao, Jun Xiao, Xiaohe Bai, Zhaofang Zhan, Xiaoyan |
author_facet | Zhao, Jia Liu, Hongbin Hong, Zhixian Luo, Wei Mu, Wenqing Hou, Xiaorong Xu, Guang Fang, Zhie Ren, Lutong Liu, Tingting Wen, Jincai Shi, Wei Wei, Ziying Yang, Yongping Zou, Wenjun Zhao, Jun Xiao, Xiaohe Bai, Zhaofang Zhan, Xiaoyan |
author_sort | Zhao, Jia |
collection | PubMed |
description | BACKGROUND: Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. METHODS: IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. RESULTS: Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. CONCLUSIONS: Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00671-0. |
format | Online Article Text |
id | pubmed-10318668 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-103186682023-07-05 Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC Zhao, Jia Liu, Hongbin Hong, Zhixian Luo, Wei Mu, Wenqing Hou, Xiaorong Xu, Guang Fang, Zhie Ren, Lutong Liu, Tingting Wen, Jincai Shi, Wei Wei, Ziying Yang, Yongping Zou, Wenjun Zhao, Jun Xiao, Xiaohe Bai, Zhaofang Zhan, Xiaoyan Mol Med Research Article BACKGROUND: Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. METHODS: IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. RESULTS: Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. CONCLUSIONS: Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00671-0. BioMed Central 2023-07-03 /pmc/articles/PMC10318668/ /pubmed/37400760 http://dx.doi.org/10.1186/s10020-023-00671-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Zhao, Jia Liu, Hongbin Hong, Zhixian Luo, Wei Mu, Wenqing Hou, Xiaorong Xu, Guang Fang, Zhie Ren, Lutong Liu, Tingting Wen, Jincai Shi, Wei Wei, Ziying Yang, Yongping Zou, Wenjun Zhao, Jun Xiao, Xiaohe Bai, Zhaofang Zhan, Xiaoyan Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC |
title | Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC |
title_full | Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC |
title_fullStr | Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC |
title_full_unstemmed | Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC |
title_short | Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC |
title_sort | tanshinone i specifically suppresses nlrp3 inflammasome activation by disrupting the association of nlrp3 and asc |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318668/ https://www.ncbi.nlm.nih.gov/pubmed/37400760 http://dx.doi.org/10.1186/s10020-023-00671-0 |
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