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Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress
COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebr...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826090/ https://www.ncbi.nlm.nih.gov/pubmed/33484708 http://dx.doi.org/10.1016/j.taap.2021.115412 |
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author | Gregório, PauloC. da Cunha, Regiane S. Biagini, Gilson Bosquetti, Bruna Budag, Júlia Ortiz, Alberto Sánchez-Niño, Maria Dolores Barreto, Fellype C. Stinghen, Andréa E.M. |
author_facet | Gregório, PauloC. da Cunha, Regiane S. Biagini, Gilson Bosquetti, Bruna Budag, Júlia Ortiz, Alberto Sánchez-Niño, Maria Dolores Barreto, Fellype C. Stinghen, Andréa E.M. |
author_sort | Gregório, PauloC. |
collection | PubMed |
description | COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebroid deposits reminiscent of Fabry disease (α-galactosidase A deficiency) and endothelial cells are key targets of COVID-19. We have explored the effect of chloroquine on cultured endothelial cells and its modulation by recombinant α-galactosidase A (agalsidase). Following dose-response studies, 0.5 μg/mL chloroquine was added to cultured human endothelial cells. Neutral red and Lysotracker were used to assess lysosomes. Cytotoxicity was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) - MTT assay and cell stress by assessing reactive oxygen species (ROS) and nitric oxide (NO). In endothelial cells, chloroquine induced dose-dependent cytotoxicity at in vitro test concentrations for COVID-19 therapy. At a sublethal concentration, chloroquine significantly induced the accumulation of acid organelles (P < 0.05), increased ROS levels, and decreased NO production (P < 0.05). These adverse effects of chloroquine on endothelial cell biology were decreased by agalsidase-β (P < 0.05). Chloroquine-induced endothelial cell cytotoxicity and stress is attenuated by agalsidase-β treatment. This suggests that endothelial cell injury may contribute to the failure of chloroquine as therapy for COVID-19 and may be at least in part related to causing dysfunction of the lysosomal enzyme α-galactosidase A. |
format | Online Article Text |
id | pubmed-7826090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78260902021-01-25 Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress Gregório, PauloC. da Cunha, Regiane S. Biagini, Gilson Bosquetti, Bruna Budag, Júlia Ortiz, Alberto Sánchez-Niño, Maria Dolores Barreto, Fellype C. Stinghen, Andréa E.M. Toxicol Appl Pharmacol Article COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes. Chloroquine causes zebroid deposits reminiscent of Fabry disease (α-galactosidase A deficiency) and endothelial cells are key targets of COVID-19. We have explored the effect of chloroquine on cultured endothelial cells and its modulation by recombinant α-galactosidase A (agalsidase). Following dose-response studies, 0.5 μg/mL chloroquine was added to cultured human endothelial cells. Neutral red and Lysotracker were used to assess lysosomes. Cytotoxicity was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) - MTT assay and cell stress by assessing reactive oxygen species (ROS) and nitric oxide (NO). In endothelial cells, chloroquine induced dose-dependent cytotoxicity at in vitro test concentrations for COVID-19 therapy. At a sublethal concentration, chloroquine significantly induced the accumulation of acid organelles (P < 0.05), increased ROS levels, and decreased NO production (P < 0.05). These adverse effects of chloroquine on endothelial cell biology were decreased by agalsidase-β (P < 0.05). Chloroquine-induced endothelial cell cytotoxicity and stress is attenuated by agalsidase-β treatment. This suggests that endothelial cell injury may contribute to the failure of chloroquine as therapy for COVID-19 and may be at least in part related to causing dysfunction of the lysosomal enzyme α-galactosidase A. Elsevier Inc. 2021-03-01 2021-01-21 /pmc/articles/PMC7826090/ /pubmed/33484708 http://dx.doi.org/10.1016/j.taap.2021.115412 Text en © 2021 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Gregório, PauloC. da Cunha, Regiane S. Biagini, Gilson Bosquetti, Bruna Budag, Júlia Ortiz, Alberto Sánchez-Niño, Maria Dolores Barreto, Fellype C. Stinghen, Andréa E.M. Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
title | Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
title_full | Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
title_fullStr | Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
title_full_unstemmed | Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
title_short | Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
title_sort | chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826090/ https://www.ncbi.nlm.nih.gov/pubmed/33484708 http://dx.doi.org/10.1016/j.taap.2021.115412 |
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