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Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity

Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemo...

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Autores principales: Samoylova, Natalia A., Gureev, Artem P., Popov, Vasily N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094522/
https://www.ncbi.nlm.nih.gov/pubmed/37047089
http://dx.doi.org/10.3390/ijms24076118
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author Samoylova, Natalia A.
Gureev, Artem P.
Popov, Vasily N.
author_facet Samoylova, Natalia A.
Gureev, Artem P.
Popov, Vasily N.
author_sort Samoylova, Natalia A.
collection PubMed
description Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemotherapy. We showed that the exposure of mitochondria to cisplatin increased the level of lipid peroxidation products in the in vitro experiment. Cisplatin caused strong damage to renal mtDNA, both in the in vivo and in vitro experiments. Cisplatin injections induced oxidative stress by depleting renal antioxidants at the transcriptome level but did not increase the rate of H(2)O(2) production in isolated mitochondria. Methylene blue, on the contrary, induced mitochondrial H(2)O(2) production. We supposed that methylene blue-induced H(2)O(2) production led to activation of the Nrf2/ARE signaling pathway. The consequences of activation of this signaling pathway were manifested in an increase in the expression of some antioxidant genes, which likely caused a decrease in the amount of mtDNA damage. Methylene blue treatment induced an increase in the expression of genes that were involved in the base excision repair (BER) pathway: the main pathway for mtDNA reparation. It is known that the expression of these genes can also be regulated by the Nrf2/ARE signaling pathway. We can assume that the protective effect of methylene blue is related to the activation of Nrf2/ARE signaling pathways, which can activate the expression of genes related to antioxidant defense and mtDNA reparation. Thus, the protection of kidney mitochondria from cisplatin-induced damage using methylene blue can significantly expand its application in medicine.
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spelling pubmed-100945222023-04-13 Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity Samoylova, Natalia A. Gureev, Artem P. Popov, Vasily N. Int J Mol Sci Article Cisplatin is a platinum-based cytostatic drug that is widely used for cancer treatment. Mitochondria and mtDNA are important targets for platinum-based cytostatics, which mediates its nephrotoxicity. It is important to develop therapeutic approaches to protect the kidneys from cisplatin during chemotherapy. We showed that the exposure of mitochondria to cisplatin increased the level of lipid peroxidation products in the in vitro experiment. Cisplatin caused strong damage to renal mtDNA, both in the in vivo and in vitro experiments. Cisplatin injections induced oxidative stress by depleting renal antioxidants at the transcriptome level but did not increase the rate of H(2)O(2) production in isolated mitochondria. Methylene blue, on the contrary, induced mitochondrial H(2)O(2) production. We supposed that methylene blue-induced H(2)O(2) production led to activation of the Nrf2/ARE signaling pathway. The consequences of activation of this signaling pathway were manifested in an increase in the expression of some antioxidant genes, which likely caused a decrease in the amount of mtDNA damage. Methylene blue treatment induced an increase in the expression of genes that were involved in the base excision repair (BER) pathway: the main pathway for mtDNA reparation. It is known that the expression of these genes can also be regulated by the Nrf2/ARE signaling pathway. We can assume that the protective effect of methylene blue is related to the activation of Nrf2/ARE signaling pathways, which can activate the expression of genes related to antioxidant defense and mtDNA reparation. Thus, the protection of kidney mitochondria from cisplatin-induced damage using methylene blue can significantly expand its application in medicine. MDPI 2023-03-24 /pmc/articles/PMC10094522/ /pubmed/37047089 http://dx.doi.org/10.3390/ijms24076118 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
Samoylova, Natalia A.
Gureev, Artem P.
Popov, Vasily N.
Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
title Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
title_full Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
title_fullStr Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
title_full_unstemmed Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
title_short Methylene Blue Induces Antioxidant Defense and Reparation of Mitochondrial DNA in a Nrf2-Dependent Manner during Cisplatin-Induced Renal Toxicity
title_sort methylene blue induces antioxidant defense and reparation of mitochondrial dna in a nrf2-dependent manner during cisplatin-induced renal toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10094522/
https://www.ncbi.nlm.nih.gov/pubmed/37047089
http://dx.doi.org/10.3390/ijms24076118
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