Karen Simone Romanello, João Pedro Maia de Oliveira da Silva, Flaviene Felix Torres, Karina Kirschner Lopes Teixeira, Igor de Farias Domingos, Gabriela da Silva Arcanjo, Diego Antônio Pereira Martins, Aderson da Silva Araujo, Marcos André Cavalcanti Bezerra, Iran Malavazi, Danilo Grünig Humberto da Silva, Anderson Ferreira da Cunha
{"title":"Unraveling the multifaceted roles of peroxiredoxins in sickle cell anemia: implications in redox and inflammation adaptations.","authors":"Karen Simone Romanello, João Pedro Maia de Oliveira da Silva, Flaviene Felix Torres, Karina Kirschner Lopes Teixeira, Igor de Farias Domingos, Gabriela da Silva Arcanjo, Diego Antônio Pereira Martins, Aderson da Silva Araujo, Marcos André Cavalcanti Bezerra, Iran Malavazi, Danilo Grünig Humberto da Silva, Anderson Ferreira da Cunha","doi":"10.1007/s00277-025-06294-1","DOIUrl":null,"url":null,"abstract":"<p><p>Sickle cell anemia (SCA) presents a complex interplay of factors, with the production of high levels of reactive oxygen species (ROS) and the chronic inflammatory process leading to chronic oxidative stress. In this context, efficient action of antioxidant systems becomes crucial, with particular emphasis on peroxiredoxins (PRDXs) due to their abundance and vital roles. Our primary objective was to establish associations between gene and protein expression of PRDXs 1, 2, and 6, as well as their reducers TRX1, TRXR1, and SRX1, with the characteristic hyperoxidative status observed in SCA patients. Concomitantly, we assessed the production of other essential antioxidant enzymes (SOD1, CAT, and GPX1) in reticulocytes and erythrocytes and explored mRNA levels of the NRF2/KEAP1/PKCδ complex. Our comprehensive analysis revealed a ∼ 3-fold elevation in ROS levels in erythrocytes of patients compared to healthy individuals. However, the NRF2/KEAP1/PKCδ complex exhibited a significant reduction in gene expression, hinting that another transcription factor may regulate the antioxidant response among SCA patients. In addition, the pattern of increased transcript levels of antioxidants in SCA patients was not associated with their protein levels, indicating a possible degradation by proteasome. The protein content of PRDX2 showed a significant reduction, indicating an increased vulnerability of these cells to oxidative damage. Intriguingly, both PRDXs 1 and 2 exhibited significant increases in the plasma of SCA patients, indicating that, besides their well-known intracellular antioxidant role, these enzymes may also play a vital extracellular role in modulating inflammation in these individuals. Our findings unveil novel insights into the redox metabolism adaption of erythroid cells in response to the presence of HbS in homozygosity, thus, into the complex SCA pathophysiology. Moreover, our study reveals the simultaneous presence of both PRDXs 1 and 2 in the plasma of these patients, thereby offering valuable implications for potential prognostic and therapeutic avenues.</p>","PeriodicalId":8068,"journal":{"name":"Annals of Hematology","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Hematology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00277-025-06294-1","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Sickle cell anemia (SCA) presents a complex interplay of factors, with the production of high levels of reactive oxygen species (ROS) and the chronic inflammatory process leading to chronic oxidative stress. In this context, efficient action of antioxidant systems becomes crucial, with particular emphasis on peroxiredoxins (PRDXs) due to their abundance and vital roles. Our primary objective was to establish associations between gene and protein expression of PRDXs 1, 2, and 6, as well as their reducers TRX1, TRXR1, and SRX1, with the characteristic hyperoxidative status observed in SCA patients. Concomitantly, we assessed the production of other essential antioxidant enzymes (SOD1, CAT, and GPX1) in reticulocytes and erythrocytes and explored mRNA levels of the NRF2/KEAP1/PKCδ complex. Our comprehensive analysis revealed a ∼ 3-fold elevation in ROS levels in erythrocytes of patients compared to healthy individuals. However, the NRF2/KEAP1/PKCδ complex exhibited a significant reduction in gene expression, hinting that another transcription factor may regulate the antioxidant response among SCA patients. In addition, the pattern of increased transcript levels of antioxidants in SCA patients was not associated with their protein levels, indicating a possible degradation by proteasome. The protein content of PRDX2 showed a significant reduction, indicating an increased vulnerability of these cells to oxidative damage. Intriguingly, both PRDXs 1 and 2 exhibited significant increases in the plasma of SCA patients, indicating that, besides their well-known intracellular antioxidant role, these enzymes may also play a vital extracellular role in modulating inflammation in these individuals. Our findings unveil novel insights into the redox metabolism adaption of erythroid cells in response to the presence of HbS in homozygosity, thus, into the complex SCA pathophysiology. Moreover, our study reveals the simultaneous presence of both PRDXs 1 and 2 in the plasma of these patients, thereby offering valuable implications for potential prognostic and therapeutic avenues.
期刊介绍:
Annals of Hematology covers the whole spectrum of clinical and experimental hematology, hemostaseology, blood transfusion, and related aspects of medical oncology, including diagnosis and treatment of leukemias, lymphatic neoplasias and solid tumors, and transplantation of hematopoietic stem cells. Coverage includes general aspects of oncology, molecular biology and immunology as pertinent to problems of human blood disease. The journal is associated with the German Society for Hematology and Medical Oncology, and the Austrian Society for Hematology and Oncology.