Unraveling the multifaceted roles of peroxiredoxins in sickle cell anemia: implications in redox and inflammation adaptations.

IF 3 3区 医学 Q2 HEMATOLOGY Annals of Hematology Pub Date : 2025-03-14 DOI:10.1007/s00277-025-06294-1
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
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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.

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镰状细胞性贫血(SCA)是一个复杂的因素相互作用的过程,会产生大量活性氧(ROS),慢性炎症过程会导致慢性氧化应激。在这种情况下,抗氧化系统的有效作用就变得至关重要,而过氧化还原酶(PRDXs)因其丰富的数量和重要的作用而受到特别重视。我们的主要目的是建立 PRDXs 1、2 和 6 及其还原物 TRX1、TRXR1 和 SRX1 的基因和蛋白表达与 SCA 患者特有的高氧化状态之间的联系。与此同时,我们还评估了网织红细胞和红细胞中其他重要抗氧化酶(SOD1、CAT 和 GPX1)的生成情况,并探究了 NRF2/KEAP1/PKCδ 复合物的 mRNA 水平。我们的综合分析表明,与健康人相比,患者红细胞中的 ROS 水平升高了 3 倍。然而,NRF2/KEAP1/PKCδ复合体的基因表达量却显著减少,这表明可能有另一种转录因子在调节 SCA 患者的抗氧化反应。此外,SCA 患者体内抗氧化剂转录本水平的增加模式与其蛋白水平无关,这表明蛋白酶体可能会降解抗氧化剂。PRDX2的蛋白含量显著减少,表明这些细胞更容易受到氧化损伤。耐人寻味的是,PRDXs 1 和 2 在 SCA 患者的血浆中都显示出显著增加,这表明除了众所周知的细胞内抗氧化作用外,这些酶还可能在调节这些人的炎症中发挥重要的细胞外作用。我们的研究结果揭示了红细胞对同源性 HbS 存在的氧化还原代谢适应性的新见解,从而揭示了复杂的 SCA 病理生理学。此外,我们的研究还揭示了这些患者的血浆中同时存在 PRDXs 1 和 2,从而为潜在的预后和治疗途径提供了有价值的启示。
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来源期刊
Annals of Hematology
Annals of Hematology 医学-血液学
CiteScore
5.60
自引率
2.90%
发文量
304
审稿时长
2 months
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.
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