镰状细胞病(SCD)是一种以严重贫血为特征的单基因遗传性疾病,溶血增加,和经常性的,由于血红蛋白S(HbS)产生的氧化应激的聚合,痛苦的血管闭塞危机。直到现在,在美国,只有四种药物被批准用于SCD。然而,这些药物中的每一种仅影响有限的SCD病理。重要的是,治愈疗法,比如基因治疗,或者造血干细胞移植并不是每个病人都能接受的,因为它们的成本很高,捐赠者匹配的可用性,及其严重的不良影响。因此,针对更广泛的SCD后遗症的新型治疗策略尚未满足医学需求.SCD表型严重程度可通过增加胎儿血红蛋白(HbF)表达来减轻。这导致抑制HbS聚合,从而导致镰状反应,和减少氧化应激。HbF的功效是由于其将HbS水平稀释至低于聚合所需的阈值并影响HbS聚合物在RBC中的稳定性的能力。核因子E2相关因子2(Nrf2)/Kelch样ECH相关蛋白1(Keap1)复合物信号是控制氧化应激的最重要的细胞保护信号之一。Nrf2存在于大多数器官中,从Keap1解离后,它在细胞质中积累,然后转位到细胞核,在那里它与抗氧化反应元件(ARE)序列结合,并增加各种细胞保护性抗氧化基因的表达。记住这一点,各种研究人员提出了多种主体的作用,更重要的是叔丁基对苯二酚(tBHQ),姜黄素,等。,(具有亲电子特性)在抑制keap1活性,所以Nrf2可以转移到细胞核来激活γ珠蛋白基因,从而维持α-血红蛋白稳定蛋白(AHSP)和HbF水平。这导致减少的氧化应激,因此减少SCD相关并发症。在这次审查中,我们将讨论Keap-1-Nrf2复合物在血红蛋白病中的作用,尤其是在SCD中,以及这种复合物如何代表更有效治疗方案的更好目标。
Sickle cell disease (SCD) is a monogenic inheritable disease characterized by severe anemia, increased hemolysis, and recurrent, painful vaso-occlusive crises due to the polymerization of hemoglobin S (HbS)-generated oxidative stress. Up until now, only four drugs are approved for SCD in the US. However, each of these drugs affects only a limited array of SCD pathologies. Importantly, curative therapies, such as gene therapy, or hematopoietic stem cell transplantation are not available for every patient because of their high costs, availability of donor matching, and their serious adverse effects. Therefore, there is an unmet medical need for novel therapeutic strategies that target broader SCD sequelae. SCD phenotypic severity can be alleviated by increasing fetal hemoglobin (HbF) expression. This results in the inhibition of HbS polymerization and thus sickling, and a reduction in oxidative stress. The efficacy of HbF is due to its ability to dilute HbS levels below the threshold required for polymerization and to influence HbS polymer stability in RBCs. Nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)-complex signaling is one of the most important cytoprotective signaling controlling oxidative stress. Nrf2 is present in most organs and, after dissociation from Keap1, it accumulates in the cytoplasm, then translocates to the nucleus where it binds to the antioxidant response element (ARE) sequences and increases the expression of various cytoprotective antioxidant genes. Keeping this in mind, various researchers have proposed a role of multiple agents, more importantly tert-Butylhydroquinone (tBHQ), curcumin, etc., (having electrophilic properties) in inhibiting keap1 activity, so that Nrf2 can translocate to the nucleus to activate the gamma globin gene, thus maintaining alpha-hemoglobin-stabilizing protein (AHSP) and HbF levels. This leads to reduced oxidative stress, consequently minimizing SCD-associated complications. In this review, we will discuss the role of the Keap-1-Nrf2 complex in hemoglobinopathies, especially in SCD, and how this complex might represent a better target for more effective treatment options.