Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yuan, Yun, Hu, Qiongying, Liu, Lu, Xie, Fan, Yang, Luyao, Li, Yuchen, Zhang, Chuantao, Chen, Hongqing, Tang, Jianyuan, Shen, Xiaofei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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
_version_ 1784672253550526464
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
work_keys_str_mv AT yuanyun dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT huqiongying dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT liulu dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT xiefan dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT yangluyao dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT liyuchen dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT zhangchuantao dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT chenhongqing dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT tangjianyuan dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways
AT shenxiaofei dehydrocostuslactonesuppressesdextransulfatesodiuminducedcolitisbytargetingtheikkabnfkbandkeap1nrf2signallingpathways