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Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages

Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ(0) (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-i...

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Autores principales: Hseu, You-Cheng, Tseng, Yu-Fang, Pandey, Sudhir, Shrestha, Sirjana, Lin, Kai-Yuan, Lin, Cheng-Wen, Lee, Chuan-Chen, Huang, Sheng-Teng, Yang, Hsin-Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759827/
https://www.ncbi.nlm.nih.gov/pubmed/35035661
http://dx.doi.org/10.1155/2022/4266214
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author Hseu, You-Cheng
Tseng, Yu-Fang
Pandey, Sudhir
Shrestha, Sirjana
Lin, Kai-Yuan
Lin, Cheng-Wen
Lee, Chuan-Chen
Huang, Sheng-Teng
Yang, Hsin-Ling
author_facet Hseu, You-Cheng
Tseng, Yu-Fang
Pandey, Sudhir
Shrestha, Sirjana
Lin, Kai-Yuan
Lin, Cheng-Wen
Lee, Chuan-Chen
Huang, Sheng-Teng
Yang, Hsin-Ling
author_sort Hseu, You-Cheng
collection PubMed
description Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ(0) (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ(0)'s non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ(0) led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ(0) increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ(0) inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ(0), Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ(0) or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ(0)-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ(0) inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ(0) might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.
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spelling pubmed-87598272022-01-15 Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages Hseu, You-Cheng Tseng, Yu-Fang Pandey, Sudhir Shrestha, Sirjana Lin, Kai-Yuan Lin, Cheng-Wen Lee, Chuan-Chen Huang, Sheng-Teng Yang, Hsin-Ling Oxid Med Cell Longev Research Article Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ(0) (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ(0)'s non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ(0) led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ(0) increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ(0) inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ(0), Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ(0) or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ(0)-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ(0) inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ(0) might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties. Hindawi 2022-01-07 /pmc/articles/PMC8759827/ /pubmed/35035661 http://dx.doi.org/10.1155/2022/4266214 Text en Copyright © 2022 You-Cheng Hseu et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Hseu, You-Cheng
Tseng, Yu-Fang
Pandey, Sudhir
Shrestha, Sirjana
Lin, Kai-Yuan
Lin, Cheng-Wen
Lee, Chuan-Chen
Huang, Sheng-Teng
Yang, Hsin-Ling
Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
title Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
title_full Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
title_fullStr Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
title_full_unstemmed Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
title_short Coenzyme Q(0) Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages
title_sort coenzyme q(0) inhibits nlrp3 inflammasome activation through mitophagy induction in lps/atp-stimulated macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759827/
https://www.ncbi.nlm.nih.gov/pubmed/35035661
http://dx.doi.org/10.1155/2022/4266214
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