Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells
- Autores
- Ramirez, Dario; Gomez-Mejiba, Sandra Esther
- Año de publicación
- 2023
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Irritation causes the recruitment and activation of neutrophils in the stressed airways. This process is known as neutrophilic inflammation. This process results in myeloperoxidase (MPO), an enzyme contained inside neutrophil azurophilic granules, being released as neutrophil extracellular traps (NETs), which also contain genomic DNA, modified histones, and other proteins. In the airways, released MPO can be taken up by bystander tissue epithelial cells. MPO is the only mammalian peroxidase enzyme that under physiological conditions produces hypochlorite (HOCl). Intracellularly produced HOCl may damage the cell genome, with the intermediacy of DNA-centered free radicals, which upon reaction with molecular oxygen decay to mutagenic end-oxidation products, such as 8-oxo-7,8-dihydro-2' –deoxyguanosine (8-oxodGuo). Herein, we aimed to test whether HOCl-induced DNA-centered radicals precede the oxidation of DNA and mutagenesis in A549 human lung epithelial cells as an in vitro model that resembles neutrophilic inflammation in irritated airways. Interestingly, by trapping HOCl-induced DNA-centered radicals, the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) blocks the formation of 8-oxo-dGuo and possibly other end-oxidation products, forming DNA-DMPO nitrone adducts, thus reducing mutagenesis in the hypoxanthine phosphoribosyl transferase (hrpt) gene, one of the most sensitive genes to oxidative damage. P53 is a transcription factor known as the master regulator of the cell response to genomic damage. By trapping DNAcentered radicals, DMPO also blocks the translocation of p53 to the cell nucleus, suggesting that by trapping DNA-centered radicals with DMPO, end-oxidation products are prevented, and the cell response to genomic damage is not sensed. DMPO traps DNA-centered radicals, reduces 8-oxo-dGuo accumulation, and blocks hrpt gene mutation. Trapping DNA-centered radicals to reduce the accumulation of HOCl-induced mutagenic end-oxidation products in the genome of bystander cells, which have taken MPO from the inflammatory milieu, will provide new therapeutic avenues to reduce genotoxic damage at sites of neutrophilic inflammation, such as in the irritated airways.
Fil: Ramirez, Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Gomez-Mejiba, Sandra Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina - Materia
-
AIRWAY IRRITATION
NEUTROPHILIC INFLAMMATION,
DNA-CENTERED RADICA
8-OXO-DGUO,
DMPO
DNA-DMPO NITRONE ADDUCT
HRPT GENE MUTATION - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/247621
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Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cellsRamirez, DarioGomez-Mejiba, Sandra EstherAIRWAY IRRITATIONNEUTROPHILIC INFLAMMATION,DNA-CENTERED RADICA8-OXO-DGUO,DMPODNA-DMPO NITRONE ADDUCTHRPT GENE MUTATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Irritation causes the recruitment and activation of neutrophils in the stressed airways. This process is known as neutrophilic inflammation. This process results in myeloperoxidase (MPO), an enzyme contained inside neutrophil azurophilic granules, being released as neutrophil extracellular traps (NETs), which also contain genomic DNA, modified histones, and other proteins. In the airways, released MPO can be taken up by bystander tissue epithelial cells. MPO is the only mammalian peroxidase enzyme that under physiological conditions produces hypochlorite (HOCl). Intracellularly produced HOCl may damage the cell genome, with the intermediacy of DNA-centered free radicals, which upon reaction with molecular oxygen decay to mutagenic end-oxidation products, such as 8-oxo-7,8-dihydro-2' –deoxyguanosine (8-oxodGuo). Herein, we aimed to test whether HOCl-induced DNA-centered radicals precede the oxidation of DNA and mutagenesis in A549 human lung epithelial cells as an in vitro model that resembles neutrophilic inflammation in irritated airways. Interestingly, by trapping HOCl-induced DNA-centered radicals, the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) blocks the formation of 8-oxo-dGuo and possibly other end-oxidation products, forming DNA-DMPO nitrone adducts, thus reducing mutagenesis in the hypoxanthine phosphoribosyl transferase (hrpt) gene, one of the most sensitive genes to oxidative damage. P53 is a transcription factor known as the master regulator of the cell response to genomic damage. By trapping DNAcentered radicals, DMPO also blocks the translocation of p53 to the cell nucleus, suggesting that by trapping DNA-centered radicals with DMPO, end-oxidation products are prevented, and the cell response to genomic damage is not sensed. DMPO traps DNA-centered radicals, reduces 8-oxo-dGuo accumulation, and blocks hrpt gene mutation. Trapping DNA-centered radicals to reduce the accumulation of HOCl-induced mutagenic end-oxidation products in the genome of bystander cells, which have taken MPO from the inflammatory milieu, will provide new therapeutic avenues to reduce genotoxic damage at sites of neutrophilic inflammation, such as in the irritated airways.Fil: Ramirez, Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Gomez-Mejiba, Sandra Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaCold Spring Harbor Laboratory Press2023-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/247621Ramirez, Dario; Gomez-Mejiba, Sandra Esther; Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells; Cold Spring Harbor Laboratory Press; Biorxiv; 6-2023; 1-242692-82052692-8205CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1101/2024.06.18.599657info:eu-repo/semantics/altIdentifier/url/https://www.biorxiv.org/content/10.1101/2024.06.18.599657v1info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:52:18Zoai:ri.conicet.gov.ar:11336/247621instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:52:19.27CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
title |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
spellingShingle |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells Ramirez, Dario AIRWAY IRRITATION NEUTROPHILIC INFLAMMATION, DNA-CENTERED RADICA 8-OXO-DGUO, DMPO DNA-DMPO NITRONE ADDUCT HRPT GENE MUTATION |
title_short |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
title_full |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
title_fullStr |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
title_full_unstemmed |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
title_sort |
Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells |
dc.creator.none.fl_str_mv |
Ramirez, Dario Gomez-Mejiba, Sandra Esther |
author |
Ramirez, Dario |
author_facet |
Ramirez, Dario Gomez-Mejiba, Sandra Esther |
author_role |
author |
author2 |
Gomez-Mejiba, Sandra Esther |
author2_role |
author |
dc.subject.none.fl_str_mv |
AIRWAY IRRITATION NEUTROPHILIC INFLAMMATION, DNA-CENTERED RADICA 8-OXO-DGUO, DMPO DNA-DMPO NITRONE ADDUCT HRPT GENE MUTATION |
topic |
AIRWAY IRRITATION NEUTROPHILIC INFLAMMATION, DNA-CENTERED RADICA 8-OXO-DGUO, DMPO DNA-DMPO NITRONE ADDUCT HRPT GENE MUTATION |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Irritation causes the recruitment and activation of neutrophils in the stressed airways. This process is known as neutrophilic inflammation. This process results in myeloperoxidase (MPO), an enzyme contained inside neutrophil azurophilic granules, being released as neutrophil extracellular traps (NETs), which also contain genomic DNA, modified histones, and other proteins. In the airways, released MPO can be taken up by bystander tissue epithelial cells. MPO is the only mammalian peroxidase enzyme that under physiological conditions produces hypochlorite (HOCl). Intracellularly produced HOCl may damage the cell genome, with the intermediacy of DNA-centered free radicals, which upon reaction with molecular oxygen decay to mutagenic end-oxidation products, such as 8-oxo-7,8-dihydro-2' –deoxyguanosine (8-oxodGuo). Herein, we aimed to test whether HOCl-induced DNA-centered radicals precede the oxidation of DNA and mutagenesis in A549 human lung epithelial cells as an in vitro model that resembles neutrophilic inflammation in irritated airways. Interestingly, by trapping HOCl-induced DNA-centered radicals, the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) blocks the formation of 8-oxo-dGuo and possibly other end-oxidation products, forming DNA-DMPO nitrone adducts, thus reducing mutagenesis in the hypoxanthine phosphoribosyl transferase (hrpt) gene, one of the most sensitive genes to oxidative damage. P53 is a transcription factor known as the master regulator of the cell response to genomic damage. By trapping DNAcentered radicals, DMPO also blocks the translocation of p53 to the cell nucleus, suggesting that by trapping DNA-centered radicals with DMPO, end-oxidation products are prevented, and the cell response to genomic damage is not sensed. DMPO traps DNA-centered radicals, reduces 8-oxo-dGuo accumulation, and blocks hrpt gene mutation. Trapping DNA-centered radicals to reduce the accumulation of HOCl-induced mutagenic end-oxidation products in the genome of bystander cells, which have taken MPO from the inflammatory milieu, will provide new therapeutic avenues to reduce genotoxic damage at sites of neutrophilic inflammation, such as in the irritated airways. Fil: Ramirez, Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Gomez-Mejiba, Sandra Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina |
description |
Irritation causes the recruitment and activation of neutrophils in the stressed airways. This process is known as neutrophilic inflammation. This process results in myeloperoxidase (MPO), an enzyme contained inside neutrophil azurophilic granules, being released as neutrophil extracellular traps (NETs), which also contain genomic DNA, modified histones, and other proteins. In the airways, released MPO can be taken up by bystander tissue epithelial cells. MPO is the only mammalian peroxidase enzyme that under physiological conditions produces hypochlorite (HOCl). Intracellularly produced HOCl may damage the cell genome, with the intermediacy of DNA-centered free radicals, which upon reaction with molecular oxygen decay to mutagenic end-oxidation products, such as 8-oxo-7,8-dihydro-2' –deoxyguanosine (8-oxodGuo). Herein, we aimed to test whether HOCl-induced DNA-centered radicals precede the oxidation of DNA and mutagenesis in A549 human lung epithelial cells as an in vitro model that resembles neutrophilic inflammation in irritated airways. Interestingly, by trapping HOCl-induced DNA-centered radicals, the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) blocks the formation of 8-oxo-dGuo and possibly other end-oxidation products, forming DNA-DMPO nitrone adducts, thus reducing mutagenesis in the hypoxanthine phosphoribosyl transferase (hrpt) gene, one of the most sensitive genes to oxidative damage. P53 is a transcription factor known as the master regulator of the cell response to genomic damage. By trapping DNAcentered radicals, DMPO also blocks the translocation of p53 to the cell nucleus, suggesting that by trapping DNA-centered radicals with DMPO, end-oxidation products are prevented, and the cell response to genomic damage is not sensed. DMPO traps DNA-centered radicals, reduces 8-oxo-dGuo accumulation, and blocks hrpt gene mutation. Trapping DNA-centered radicals to reduce the accumulation of HOCl-induced mutagenic end-oxidation products in the genome of bystander cells, which have taken MPO from the inflammatory milieu, will provide new therapeutic avenues to reduce genotoxic damage at sites of neutrophilic inflammation, such as in the irritated airways. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-06 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/247621 Ramirez, Dario; Gomez-Mejiba, Sandra Esther; Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells; Cold Spring Harbor Laboratory Press; Biorxiv; 6-2023; 1-24 2692-8205 2692-8205 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/247621 |
identifier_str_mv |
Ramirez, Dario; Gomez-Mejiba, Sandra Esther; Trapping DNA-radicals with DMPO reduced hypochlorous acid-induced 8-oxo-7,8-dihydro-2?-deoxyguanosine and mutagenesis in lung epithelial cells; Cold Spring Harbor Laboratory Press; Biorxiv; 6-2023; 1-24 2692-8205 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1101/2024.06.18.599657 info:eu-repo/semantics/altIdentifier/url/https://www.biorxiv.org/content/10.1101/2024.06.18.599657v1 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Cold Spring Harbor Laboratory Press |
publisher.none.fl_str_mv |
Cold Spring Harbor Laboratory Press |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613605443502080 |
score |
13.069144 |