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A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation

Sepsis is a dysregulated systemic response to infection, and no effective treatment options are available. Acacetin is a natural flavonoid found in various plants, including Sparganii rhizoma, Sargentodoxa cuneata and Patrinia scabiosifolia. Studies have revealed that acacetin potentially exerts ant...

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Autores principales: Ouyang, Yuanshuo, Rong, Yi, Wang, Yanming, Guo, Yanli, Shan, Liya, Yu, Xiushi, Li, Li, Si, Junqiang, Li, Xinzhi, Ma, Ketao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415621/
https://www.ncbi.nlm.nih.gov/pubmed/34483900
http://dx.doi.org/10.3389/fphar.2021.683645
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author Ouyang, Yuanshuo
Rong, Yi
Wang, Yanming
Guo, Yanli
Shan, Liya
Yu, Xiushi
Li, Li
Si, Junqiang
Li, Xinzhi
Ma, Ketao
author_facet Ouyang, Yuanshuo
Rong, Yi
Wang, Yanming
Guo, Yanli
Shan, Liya
Yu, Xiushi
Li, Li
Si, Junqiang
Li, Xinzhi
Ma, Ketao
author_sort Ouyang, Yuanshuo
collection PubMed
description Sepsis is a dysregulated systemic response to infection, and no effective treatment options are available. Acacetin is a natural flavonoid found in various plants, including Sparganii rhizoma, Sargentodoxa cuneata and Patrinia scabiosifolia. Studies have revealed that acacetin potentially exerts anti-inflammatory and antioxidative effects on sepsis. In this study, we investigated the potential protective effect of acacetin on sepsis and revealed the underlying mechanisms using a network pharmacology approach coupled with experimental validation and molecular docking. First, we found that acacetin significantly suppressed pathological damage and pro-inflammatory cytokine expression in mice with LPS-induced fulminant hepatic failure and acute lung injury, and in vitro experiments further confirmed that acacetin attenuated LPS-induced M1 polarization. Then, network pharmacology screening revealed EGFR, PTGS2, SRC and ESR1 as the top four overlapping targets in a PPI network, and GO and KEGG analyses revealed the top 20 enriched biological processes and signalling pathways associated with the therapeutic effects of acacetin on sepsis. Further network pharmacological analysis indicated that gap junctions may be highly involved in the protective effects of acacetin on sepsis. Finally, molecular docking verified that acacetin bound to the active sites of the four targets predicted by network pharmacology, and in vitro experiments further confirmed that acacetin significantly inhibited the upregulation of p-src induced by LPS and attenuated LPS-induced M1 polarization through gap junctions. Taken together, our results indicate that acacetin may protect against sepsis via a mechanism involving multiple targets and pathways and that gap junctions may be highly involved in this process.
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spelling pubmed-84156212021-09-04 A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation Ouyang, Yuanshuo Rong, Yi Wang, Yanming Guo, Yanli Shan, Liya Yu, Xiushi Li, Li Si, Junqiang Li, Xinzhi Ma, Ketao Front Pharmacol Pharmacology Sepsis is a dysregulated systemic response to infection, and no effective treatment options are available. Acacetin is a natural flavonoid found in various plants, including Sparganii rhizoma, Sargentodoxa cuneata and Patrinia scabiosifolia. Studies have revealed that acacetin potentially exerts anti-inflammatory and antioxidative effects on sepsis. In this study, we investigated the potential protective effect of acacetin on sepsis and revealed the underlying mechanisms using a network pharmacology approach coupled with experimental validation and molecular docking. First, we found that acacetin significantly suppressed pathological damage and pro-inflammatory cytokine expression in mice with LPS-induced fulminant hepatic failure and acute lung injury, and in vitro experiments further confirmed that acacetin attenuated LPS-induced M1 polarization. Then, network pharmacology screening revealed EGFR, PTGS2, SRC and ESR1 as the top four overlapping targets in a PPI network, and GO and KEGG analyses revealed the top 20 enriched biological processes and signalling pathways associated with the therapeutic effects of acacetin on sepsis. Further network pharmacological analysis indicated that gap junctions may be highly involved in the protective effects of acacetin on sepsis. Finally, molecular docking verified that acacetin bound to the active sites of the four targets predicted by network pharmacology, and in vitro experiments further confirmed that acacetin significantly inhibited the upregulation of p-src induced by LPS and attenuated LPS-induced M1 polarization through gap junctions. Taken together, our results indicate that acacetin may protect against sepsis via a mechanism involving multiple targets and pathways and that gap junctions may be highly involved in this process. Frontiers Media S.A. 2021-08-16 /pmc/articles/PMC8415621/ /pubmed/34483900 http://dx.doi.org/10.3389/fphar.2021.683645 Text en Copyright © 2021 Ouyang, Rong, Wang, Guo, Shan, Yu, Li, Si, Li and Ma. 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
Ouyang, Yuanshuo
Rong, Yi
Wang, Yanming
Guo, Yanli
Shan, Liya
Yu, Xiushi
Li, Li
Si, Junqiang
Li, Xinzhi
Ma, Ketao
A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation
title A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation
title_full A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation
title_fullStr A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation
title_full_unstemmed A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation
title_short A Systematic Study of the Mechanism of Acacetin Against Sepsis Based on Network Pharmacology and Experimental Validation
title_sort systematic study of the mechanism of acacetin against sepsis based on network pharmacology and experimental validation
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415621/
https://www.ncbi.nlm.nih.gov/pubmed/34483900
http://dx.doi.org/10.3389/fphar.2021.683645
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