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Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats

INTRODUCTION: Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damag...

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Autores principales: Hassanein, Emad H M, Abd El-Ghafar, Omnia A M, Ahmed, Marwa A, Sayed, Ahmed M, Gad-Elrab, Wail M, Ajarem, Jamaan S, Allam, Ahmed A, Mahmoud, Ayman M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721127/
https://www.ncbi.nlm.nih.gov/pubmed/33299300
http://dx.doi.org/10.2147/DDDT.S281854
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author Hassanein, Emad H M
Abd El-Ghafar, Omnia A M
Ahmed, Marwa A
Sayed, Ahmed M
Gad-Elrab, Wail M
Ajarem, Jamaan S
Allam, Ahmed A
Mahmoud, Ayman M
author_facet Hassanein, Emad H M
Abd El-Ghafar, Omnia A M
Ahmed, Marwa A
Sayed, Ahmed M
Gad-Elrab, Wail M
Ajarem, Jamaan S
Allam, Ahmed A
Mahmoud, Ayman M
author_sort Hassanein, Emad H M
collection PubMed
description INTRODUCTION: Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damage, emphasizing the role of PI3K/Akt/mTOR and Nrf2 signaling. MATERIALS AND METHODS: Rats received either AV (100 mg/kg) or ED (20 mg/kg) orally for 10 days and CP (200 mg/kg) on day 7. At day 11, the rats were sacrificed, and samples were collected for analysis. RESULTS: AV and ED ameliorated serum troponin I, CK-MB, LDH, AST and ALP, and prevented cardiac histological alterations in CP-intoxicated rats. Both treatments decreased cardiac lipid peroxidation and enhanced GSH, SOD and cytoglobin in CP-induced rats. AV and ED downregulated Keap1, whereas increased the expression of PI3K, Akt, mTOR and Nrf2 in the heart of rats received CP. Additionally, the binding modes of AV and ED to Keap1 were pinpointed in silico using molecular docking simulations. CONCLUSION: AV and ED prevent CP cardiotoxicity by attenuating oxidative stress and tissue injury, and modulating cytoglobin, and PI3K/Akt/mTOR and Keap1/Nrf2 signaling. Therefore, AV and ED may represent promising agents that can prevent cardiac injury in patients receiving CP.
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spelling pubmed-77211272020-12-08 Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats Hassanein, Emad H M Abd El-Ghafar, Omnia A M Ahmed, Marwa A Sayed, Ahmed M Gad-Elrab, Wail M Ajarem, Jamaan S Allam, Ahmed A Mahmoud, Ayman M Drug Des Devel Ther Original Research INTRODUCTION: Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damage, emphasizing the role of PI3K/Akt/mTOR and Nrf2 signaling. MATERIALS AND METHODS: Rats received either AV (100 mg/kg) or ED (20 mg/kg) orally for 10 days and CP (200 mg/kg) on day 7. At day 11, the rats were sacrificed, and samples were collected for analysis. RESULTS: AV and ED ameliorated serum troponin I, CK-MB, LDH, AST and ALP, and prevented cardiac histological alterations in CP-intoxicated rats. Both treatments decreased cardiac lipid peroxidation and enhanced GSH, SOD and cytoglobin in CP-induced rats. AV and ED downregulated Keap1, whereas increased the expression of PI3K, Akt, mTOR and Nrf2 in the heart of rats received CP. Additionally, the binding modes of AV and ED to Keap1 were pinpointed in silico using molecular docking simulations. CONCLUSION: AV and ED prevent CP cardiotoxicity by attenuating oxidative stress and tissue injury, and modulating cytoglobin, and PI3K/Akt/mTOR and Keap1/Nrf2 signaling. Therefore, AV and ED may represent promising agents that can prevent cardiac injury in patients receiving CP. Dove 2020-11-30 /pmc/articles/PMC7721127/ /pubmed/33299300 http://dx.doi.org/10.2147/DDDT.S281854 Text en © 2020 Hassanein et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Hassanein, Emad H M
Abd El-Ghafar, Omnia A M
Ahmed, Marwa A
Sayed, Ahmed M
Gad-Elrab, Wail M
Ajarem, Jamaan S
Allam, Ahmed A
Mahmoud, Ayman M
Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
title Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
title_full Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
title_fullStr Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
title_full_unstemmed Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
title_short Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats
title_sort edaravone and acetovanillone upregulate nrf2 and pi3k/akt/mtor signaling and prevent cyclophosphamide cardiotoxicity in rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721127/
https://www.ncbi.nlm.nih.gov/pubmed/33299300
http://dx.doi.org/10.2147/DDDT.S281854
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