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Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response
BACKGROUND: Deep venous thrombosis (DVT) highly occurs in patients with severe COVID-19 and probably accounted for their high mortality. DVT formation is a time-dependent inflammatory process in which NETosis plays an important role. However, whether ginsenoside Rg5 from species of Panax genus could...
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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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411522/ https://www.ncbi.nlm.nih.gov/pubmed/36032109 http://dx.doi.org/10.3389/fimmu.2022.918476 |
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author | Chen, Ziyu Wang, Gaorui Xie, Xueqing Liu, Heng Liao, Jun Shi, Hailian Chen, Min Lai, Shusheng Wang, Zhengtao Wu, Xiaojun |
author_facet | Chen, Ziyu Wang, Gaorui Xie, Xueqing Liu, Heng Liao, Jun Shi, Hailian Chen, Min Lai, Shusheng Wang, Zhengtao Wu, Xiaojun |
author_sort | Chen, Ziyu |
collection | PubMed |
description | BACKGROUND: Deep venous thrombosis (DVT) highly occurs in patients with severe COVID-19 and probably accounted for their high mortality. DVT formation is a time-dependent inflammatory process in which NETosis plays an important role. However, whether ginsenoside Rg5 from species of Panax genus could alleviate DVT and its underlying mechanism has not been elucidated. METHODS: The interaction between Rg5 and P2RY(12) was studied by molecular docking, molecular dynamics, surface plasmon resonance (SPR), and molecular biology assays. The preventive effect of Rg5 on DVT was evaluated in inferior vena cava stasis–induced mice, and immunocytochemistry, Western blot, and calcium flux assay were performed in neutrophils from bone marrow to explore the mechanism of Rg5 in NETosis via P2RY(12). RESULTS: Rg5 allosterically interacted with P2RY(12), formed stable complex, and antagonized its activity via residue E188 and R265. Rg5 ameliorated the formation of thrombus in DVT mice; accompanied by decreased release of Interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in plasma; and suppressed neutrophil infiltration and neutrophil extracellular trap (NET) release. In lipopolysaccharide- and platelet-activating factor–induced neutrophils, Rg5 reduced inflammatory responses via inhibiting the activation of ERK/NF-κB signaling pathway while decreasing cellular Ca(2+) concentration, thus reducing the activity and expression of peptidyl arginine deiminase 4 to prevent NETosis. The inhibitory effect on neutrophil activity was dependent on P2RY(12). CONCLUSIONS: Rg5 could attenuate experimental DVT by counteracting NETosis and inflammatory response in neutrophils via P2RY(12), which may pave the road for its clinical application in the prevention of DVT-related disorders. |
format | Online Article Text |
id | pubmed-9411522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94115222022-08-27 Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response Chen, Ziyu Wang, Gaorui Xie, Xueqing Liu, Heng Liao, Jun Shi, Hailian Chen, Min Lai, Shusheng Wang, Zhengtao Wu, Xiaojun Front Immunol Immunology BACKGROUND: Deep venous thrombosis (DVT) highly occurs in patients with severe COVID-19 and probably accounted for their high mortality. DVT formation is a time-dependent inflammatory process in which NETosis plays an important role. However, whether ginsenoside Rg5 from species of Panax genus could alleviate DVT and its underlying mechanism has not been elucidated. METHODS: The interaction between Rg5 and P2RY(12) was studied by molecular docking, molecular dynamics, surface plasmon resonance (SPR), and molecular biology assays. The preventive effect of Rg5 on DVT was evaluated in inferior vena cava stasis–induced mice, and immunocytochemistry, Western blot, and calcium flux assay were performed in neutrophils from bone marrow to explore the mechanism of Rg5 in NETosis via P2RY(12). RESULTS: Rg5 allosterically interacted with P2RY(12), formed stable complex, and antagonized its activity via residue E188 and R265. Rg5 ameliorated the formation of thrombus in DVT mice; accompanied by decreased release of Interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in plasma; and suppressed neutrophil infiltration and neutrophil extracellular trap (NET) release. In lipopolysaccharide- and platelet-activating factor–induced neutrophils, Rg5 reduced inflammatory responses via inhibiting the activation of ERK/NF-κB signaling pathway while decreasing cellular Ca(2+) concentration, thus reducing the activity and expression of peptidyl arginine deiminase 4 to prevent NETosis. The inhibitory effect on neutrophil activity was dependent on P2RY(12). CONCLUSIONS: Rg5 could attenuate experimental DVT by counteracting NETosis and inflammatory response in neutrophils via P2RY(12), which may pave the road for its clinical application in the prevention of DVT-related disorders. Frontiers Media S.A. 2022-08-12 /pmc/articles/PMC9411522/ /pubmed/36032109 http://dx.doi.org/10.3389/fimmu.2022.918476 Text en Copyright © 2022 Chen, Wang, Xie, Liu, Liao, Shi, Chen, Lai, Wang and Wu 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 | Immunology Chen, Ziyu Wang, Gaorui Xie, Xueqing Liu, Heng Liao, Jun Shi, Hailian Chen, Min Lai, Shusheng Wang, Zhengtao Wu, Xiaojun Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response |
title | Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response |
title_full | Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response |
title_fullStr | Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response |
title_full_unstemmed | Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response |
title_short | Ginsenoside Rg5 allosterically interacts with P2RY(12) and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response |
title_sort | ginsenoside rg5 allosterically interacts with p2ry(12) and ameliorates deep venous thrombosis by counteracting neutrophil netosis and inflammatory response |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411522/ https://www.ncbi.nlm.nih.gov/pubmed/36032109 http://dx.doi.org/10.3389/fimmu.2022.918476 |
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