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Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways
Dehydrocostus lactone (DCL) is a major sesquiterpene lactone isolated from Aucklandia lappa Decne, a traditional Chinese herbal medicine that used to treat gastrointestinal diseases. This study aimed to examine the therapeutic effects of DCL on dextran sulfate sodium (DSS)-induced colitis with a foc...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936814/ https://www.ncbi.nlm.nih.gov/pubmed/35321327 http://dx.doi.org/10.3389/fphar.2022.817596 |
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author | Yuan, Yun Hu, Qiongying Liu, Lu Xie, Fan Yang, Luyao Li, Yuchen Zhang, Chuantao Chen, Hongqing Tang, Jianyuan Shen, Xiaofei |
author_facet | Yuan, Yun Hu, Qiongying Liu, Lu Xie, Fan Yang, Luyao Li, Yuchen Zhang, Chuantao Chen, Hongqing Tang, Jianyuan Shen, Xiaofei |
author_sort | Yuan, Yun |
collection | PubMed |
description | Dehydrocostus lactone (DCL) is a major sesquiterpene lactone isolated from Aucklandia lappa Decne, a traditional Chinese herbal medicine that used to treat gastrointestinal diseases. This study aimed to examine the therapeutic effects of DCL on dextran sulfate sodium (DSS)-induced colitis with a focus on identifying the molecular mechanisms involved in DCL-mediated anti-inflammatory activity in macrophages. First, oral administration of DCL (5–15 mg/kg) not only ameliorated symptoms of colitis and colonic barrier injury, but also inhibited the expression of proinflammatory cytokines and myeloperoxidase in colon tissues in DSS-challenged mice. Furthermore, DCL also exhibited significant anti-inflammatory activity in LPS/IFNγ-stimulated RAW264.7 macrophages. Importantly, DCL significantly suppressed the phosphorylation and degradation of IκBα and subsequent NF-κB nuclear translocation, and enhanced the nuclear accumulation of Nrf2 in LPS/IFNγ-treated RAW264.7 cells. Mechanistically, DCL could directly interact with IKKα/β and Keap1, thereby leading to the inhibition of NF-κB signalling and the activation of Nrf2 pathway. Furthermore, DCL-mediated actions were abolished by dithiothreitol, suggesting a thiol-mediated covalent linkage between DCL and IKKα/β or Keap1. These findings demonstrated that DCL ameliorates colitis by targeting NF-κB and Nrf2 signalling, suggesting that DCL may be a promising candidate in the clinical treatment of colitis. |
format | Online Article Text |
id | pubmed-8936814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89368142022-03-22 Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways Yuan, Yun Hu, Qiongying Liu, Lu Xie, Fan Yang, Luyao Li, Yuchen Zhang, Chuantao Chen, Hongqing Tang, Jianyuan Shen, Xiaofei Front Pharmacol Pharmacology Dehydrocostus lactone (DCL) is a major sesquiterpene lactone isolated from Aucklandia lappa Decne, a traditional Chinese herbal medicine that used to treat gastrointestinal diseases. This study aimed to examine the therapeutic effects of DCL on dextran sulfate sodium (DSS)-induced colitis with a focus on identifying the molecular mechanisms involved in DCL-mediated anti-inflammatory activity in macrophages. First, oral administration of DCL (5–15 mg/kg) not only ameliorated symptoms of colitis and colonic barrier injury, but also inhibited the expression of proinflammatory cytokines and myeloperoxidase in colon tissues in DSS-challenged mice. Furthermore, DCL also exhibited significant anti-inflammatory activity in LPS/IFNγ-stimulated RAW264.7 macrophages. Importantly, DCL significantly suppressed the phosphorylation and degradation of IκBα and subsequent NF-κB nuclear translocation, and enhanced the nuclear accumulation of Nrf2 in LPS/IFNγ-treated RAW264.7 cells. Mechanistically, DCL could directly interact with IKKα/β and Keap1, thereby leading to the inhibition of NF-κB signalling and the activation of Nrf2 pathway. Furthermore, DCL-mediated actions were abolished by dithiothreitol, suggesting a thiol-mediated covalent linkage between DCL and IKKα/β or Keap1. These findings demonstrated that DCL ameliorates colitis by targeting NF-κB and Nrf2 signalling, suggesting that DCL may be a promising candidate in the clinical treatment of colitis. Frontiers Media S.A. 2022-03-07 /pmc/articles/PMC8936814/ /pubmed/35321327 http://dx.doi.org/10.3389/fphar.2022.817596 Text en Copyright © 2022 Yuan, Hu, Liu, Xie, Yang, Li, Zhang, Chen, Tang and Shen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Yuan, Yun Hu, Qiongying Liu, Lu Xie, Fan Yang, Luyao Li, Yuchen Zhang, Chuantao Chen, Hongqing Tang, Jianyuan Shen, Xiaofei Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways |
title | Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways |
title_full | Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways |
title_fullStr | Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways |
title_full_unstemmed | Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways |
title_short | Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways |
title_sort | dehydrocostus lactone suppresses dextran sulfate sodium-induced colitis by targeting the ikkα/β-nf-κb and keap1-nrf2 signalling pathways |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936814/ https://www.ncbi.nlm.nih.gov/pubmed/35321327 http://dx.doi.org/10.3389/fphar.2022.817596 |
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