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Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo
P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418395/ https://www.ncbi.nlm.nih.gov/pubmed/37569745 http://dx.doi.org/10.3390/ijms241512370 |
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author | Kozlovskiy, Sergei Pislyagin, Evgeny Menchinskaya, Ekaterina Chingizova, Ekaterina Kaluzhskiy, Leonid Ivanov, Alexis S. Likhatskaya, Galina Agafonova, Irina Sabutski, Yuri Polonik, Sergey Manzhulo, Igor Aminin, Dmitry |
author_facet | Kozlovskiy, Sergei Pislyagin, Evgeny Menchinskaya, Ekaterina Chingizova, Ekaterina Kaluzhskiy, Leonid Ivanov, Alexis S. Likhatskaya, Galina Agafonova, Irina Sabutski, Yuri Polonik, Sergey Manzhulo, Igor Aminin, Dmitry |
author_sort | Kozlovskiy, Sergei |
collection | PubMed |
description | P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate U-556, derived from 1,4-naphthoquinone thioglucoside, to inhibit ATP-induced Ca(2+) influx and YO-PRO-1 dye uptake, which indicates blocking P2X7R in RAW 264.7 macrophages. This process was accompanied by the inhibition of ATP-induced reactive oxygen species production in macrophages, as well as the macrophage survival strengthening under ATP toxic effects. Nevertheless, U-556 had no noticeable antioxidant capacity. Naphthoquinone-thioglucoside conjugate U-556 binding to the extracellular part of the P2X7R was confirmed by SPR analysis, and the kinetic characteristics of this complex formation were established. Computer modeling predicted that U-556 binds the P2X7R allosteric binding site, topographically similar to that of the specific A438079 blocker. The study of biological activity in in vivo experiments shows that tetracylic conjugate significantly reduces inflammation provoked by carrageenan. The data obtained points out that the observed physiological effects of U-556 may be due to its ability to block the functioning of the P2X7R. |
format | Online Article Text |
id | pubmed-10418395 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104183952023-08-12 Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo Kozlovskiy, Sergei Pislyagin, Evgeny Menchinskaya, Ekaterina Chingizova, Ekaterina Kaluzhskiy, Leonid Ivanov, Alexis S. Likhatskaya, Galina Agafonova, Irina Sabutski, Yuri Polonik, Sergey Manzhulo, Igor Aminin, Dmitry Int J Mol Sci Article P2X7 receptors (P2X7Rs) are ligand-gated ion channels that play a significant role in inflammation and are considered a potential therapeutic target for some inflammatory diseases. We have previously shown that a number of synthetic 1,4-naphthoquinones are capable of blocking P2X7Rs in neuronal and macrophage cells. In the present investigation, we have demonstrated the ability of the tetracyclic quinone-thioglucoside conjugate U-556, derived from 1,4-naphthoquinone thioglucoside, to inhibit ATP-induced Ca(2+) influx and YO-PRO-1 dye uptake, which indicates blocking P2X7R in RAW 264.7 macrophages. This process was accompanied by the inhibition of ATP-induced reactive oxygen species production in macrophages, as well as the macrophage survival strengthening under ATP toxic effects. Nevertheless, U-556 had no noticeable antioxidant capacity. Naphthoquinone-thioglucoside conjugate U-556 binding to the extracellular part of the P2X7R was confirmed by SPR analysis, and the kinetic characteristics of this complex formation were established. Computer modeling predicted that U-556 binds the P2X7R allosteric binding site, topographically similar to that of the specific A438079 blocker. The study of biological activity in in vivo experiments shows that tetracylic conjugate significantly reduces inflammation provoked by carrageenan. The data obtained points out that the observed physiological effects of U-556 may be due to its ability to block the functioning of the P2X7R. MDPI 2023-08-02 /pmc/articles/PMC10418395/ /pubmed/37569745 http://dx.doi.org/10.3390/ijms241512370 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kozlovskiy, Sergei Pislyagin, Evgeny Menchinskaya, Ekaterina Chingizova, Ekaterina Kaluzhskiy, Leonid Ivanov, Alexis S. Likhatskaya, Galina Agafonova, Irina Sabutski, Yuri Polonik, Sergey Manzhulo, Igor Aminin, Dmitry Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo |
title | Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo |
title_full | Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo |
title_fullStr | Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo |
title_full_unstemmed | Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo |
title_short | Tetracyclic 1,4-Naphthoquinone Thioglucoside Conjugate U-556 Blocks the Purinergic P2X7 Receptor in Macrophages and Exhibits Anti-Inflammatory Activity In Vivo |
title_sort | tetracyclic 1,4-naphthoquinone thioglucoside conjugate u-556 blocks the purinergic p2x7 receptor in macrophages and exhibits anti-inflammatory activity in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418395/ https://www.ncbi.nlm.nih.gov/pubmed/37569745 http://dx.doi.org/10.3390/ijms241512370 |
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