Cargando…
Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin
The excessive release of heme during hemolysis contributes to the severity of sickle cell anemia (SCA) by exacerbating hemoglobin S (HbS) autoxidation, inflammation and systemic tissue damage. The present study investigated the effect of hydroxyurea (HU) on free radical neutralization and its stimul...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380266/ https://www.ncbi.nlm.nih.gov/pubmed/32765515 http://dx.doi.org/10.3389/fimmu.2020.01488 |
_version_ | 1783562819271131136 |
---|---|
author | Santana, Sânzio Silva Pitanga, Thassila Nogueira de Santana, Jeanne Machado Zanette, Dalila Lucíola Vieira, Jamile de Jesus Yahouédéhou, Sètondji Cocou Modeste Alexandre Adanho, Corynne Stéphanie Ahouefa Viana, Sayonara de Melo Luz, Nivea Farias Borges, Valeria Matos Goncalves, Marilda Souza |
author_facet | Santana, Sânzio Silva Pitanga, Thassila Nogueira de Santana, Jeanne Machado Zanette, Dalila Lucíola Vieira, Jamile de Jesus Yahouédéhou, Sètondji Cocou Modeste Alexandre Adanho, Corynne Stéphanie Ahouefa Viana, Sayonara de Melo Luz, Nivea Farias Borges, Valeria Matos Goncalves, Marilda Souza |
author_sort | Santana, Sânzio Silva |
collection | PubMed |
description | The excessive release of heme during hemolysis contributes to the severity of sickle cell anemia (SCA) by exacerbating hemoglobin S (HbS) autoxidation, inflammation and systemic tissue damage. The present study investigated the effect of hydroxyurea (HU) on free radical neutralization and its stimulation of antioxidant genes in human peripheral blood mononuclear cells (PBMC) and human umbilical vein endothelial cells (HUVEC) in the presence or absence of hemin. HU (100 and 200 μM) significantly reduced the production of intracellular reactive oxygen species (ROS) induced by hemin at 70 μM in HUVEC. HUVECs treated with HU+hemin presented significant increases in nitric oxide (NO) production in culture supernatants. HU alone or in combination with hemin promoted the induction of superoxide dismutase-1 (SOD1) and glutathione disulfide-reductase (GSR) in HUVECs and PBMCs, and glutathione peroxidase (GPX1) in PBMCs. Microarray analysis performed in HUVECs indicated that HU induces increased expression of genes involved in the antioxidant response system: SOD2, GSR, microsomal glutathione S-transferase (MGST1), glutathione S-transferase mu 2 (GSTM2), carbonyl reductase 1 (CBR1) and klotho B (KLB). Significant increases in expression were observed in genes with kinase activity: protein kinase C beta (PRKCB), zeta (PRKCZ) and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (PIK3C2B). HU also induced a significant increase in expression of the gene p62/sequestosome (p62/SQSTM1) and a significant decrease in the expression of the transcriptional factor BACH1 in HUVECs. Upstream analysis predicted the activation of Jun, miR-155-5p and mir-141-3p. These results suggest that HU directly scavenges free radicals and induces the expression of antioxidant genes via induction of the Nrf2 signaling pathway. |
format | Online Article Text |
id | pubmed-7380266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73802662020-08-05 Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin Santana, Sânzio Silva Pitanga, Thassila Nogueira de Santana, Jeanne Machado Zanette, Dalila Lucíola Vieira, Jamile de Jesus Yahouédéhou, Sètondji Cocou Modeste Alexandre Adanho, Corynne Stéphanie Ahouefa Viana, Sayonara de Melo Luz, Nivea Farias Borges, Valeria Matos Goncalves, Marilda Souza Front Immunol Immunology The excessive release of heme during hemolysis contributes to the severity of sickle cell anemia (SCA) by exacerbating hemoglobin S (HbS) autoxidation, inflammation and systemic tissue damage. The present study investigated the effect of hydroxyurea (HU) on free radical neutralization and its stimulation of antioxidant genes in human peripheral blood mononuclear cells (PBMC) and human umbilical vein endothelial cells (HUVEC) in the presence or absence of hemin. HU (100 and 200 μM) significantly reduced the production of intracellular reactive oxygen species (ROS) induced by hemin at 70 μM in HUVEC. HUVECs treated with HU+hemin presented significant increases in nitric oxide (NO) production in culture supernatants. HU alone or in combination with hemin promoted the induction of superoxide dismutase-1 (SOD1) and glutathione disulfide-reductase (GSR) in HUVECs and PBMCs, and glutathione peroxidase (GPX1) in PBMCs. Microarray analysis performed in HUVECs indicated that HU induces increased expression of genes involved in the antioxidant response system: SOD2, GSR, microsomal glutathione S-transferase (MGST1), glutathione S-transferase mu 2 (GSTM2), carbonyl reductase 1 (CBR1) and klotho B (KLB). Significant increases in expression were observed in genes with kinase activity: protein kinase C beta (PRKCB), zeta (PRKCZ) and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (PIK3C2B). HU also induced a significant increase in expression of the gene p62/sequestosome (p62/SQSTM1) and a significant decrease in the expression of the transcriptional factor BACH1 in HUVECs. Upstream analysis predicted the activation of Jun, miR-155-5p and mir-141-3p. These results suggest that HU directly scavenges free radicals and induces the expression of antioxidant genes via induction of the Nrf2 signaling pathway. Frontiers Media S.A. 2020-07-17 /pmc/articles/PMC7380266/ /pubmed/32765515 http://dx.doi.org/10.3389/fimmu.2020.01488 Text en Copyright © 2020 Santana, Pitanga, de Santana, Zanette, Vieira, Yahouédéhou, Adanho, Viana, Luz, Borges and Goncalves. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Santana, Sânzio Silva Pitanga, Thassila Nogueira de Santana, Jeanne Machado Zanette, Dalila Lucíola Vieira, Jamile de Jesus Yahouédéhou, Sètondji Cocou Modeste Alexandre Adanho, Corynne Stéphanie Ahouefa Viana, Sayonara de Melo Luz, Nivea Farias Borges, Valeria Matos Goncalves, Marilda Souza Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin |
title | Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin |
title_full | Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin |
title_fullStr | Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin |
title_full_unstemmed | Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin |
title_short | Hydroxyurea Scavenges Free Radicals and Induces the Expression of Antioxidant Genes in Human Cell Cultures Treated With Hemin |
title_sort | hydroxyurea scavenges free radicals and induces the expression of antioxidant genes in human cell cultures treated with hemin |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380266/ https://www.ncbi.nlm.nih.gov/pubmed/32765515 http://dx.doi.org/10.3389/fimmu.2020.01488 |
work_keys_str_mv | AT santanasanziosilva hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT pitangathassilanogueira hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT desantanajeannemachado hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT zanettedalilaluciola hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT vieirajamiledejesus hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT yahouedehousetondjicocoumodestealexandre hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT adanhocorynnestephanieahouefa hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT vianasayonarademelo hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT luzniveafarias hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT borgesvaleriamatos hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin AT goncalvesmarildasouza hydroxyureascavengesfreeradicalsandinducestheexpressionofantioxidantgenesinhumancellculturestreatedwithhemin |