Keap1-Nrf2 Heterodimer: A Therapeutic Target to Ameliorate Sickle Cell Disease.
Keap1-Nrf2 Heterodimer: A Therapeutic Target to Ameliorate Sickle Cell Disease.
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KEAP1-NRF2异二聚体：改善镰状细胞疾病的治疗靶点。
DOI：
10.3390/antiox12030740
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发表时间：
2023-03-17
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影响因子：
--
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中科院分区：
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镰状细胞病 (SCD) 是一种单基因遗传性疾病，其特征是严重贫血、溶血增加以及由于血红蛋白 S (HbS) 聚合产生的氧化应激而导致反复出现疼痛性血管闭塞危象。到目前为止，美国只有四种药物被批准用于治疗 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，基因治疗或造血干细胞移植等治疗方法由于成本高昂、供体匹配的可用性及其严重的副作用，并非适合每个患者。因此，针对更广泛的 SCD 后遗症的新型治疗策略的医疗需求尚未得到满足。 SCD 表型严重程度可以通过增加胎儿血红蛋白 (HbF) 表达来缓解。这会抑制 HbS 聚合，从而抑制镰状化，并减少氧化应激。 HbF 的功效在于其能够将 HbS 水平稀释至聚合所需的阈值以下，并影响红细胞中 HbS 聚合物的稳定性。核因子 E2 相关因子 2 (Nrf2)/Kelch 样 ECH 相关蛋白 1 (Keap1) 复合物信号传导是控制氧化应激的最重要的细胞保护信号传导之一。 Nrf2 存在于大多数器官中，从 Keap1 解离后，它在细胞质中积累，然后转移到细胞核，在细胞核中与抗氧化反应元件 (ARE) 序列结合，并增加各种细胞保护性抗氧化基因的表达。考虑到这一点，各种研究人员提出了多种药物的作用，更重要的是叔丁基氢醌（tBHQ）、姜黄素等（具有亲电特性）抑制keap1活性，使Nrf2可以转位到细胞核激活γ珠蛋白基因，从而维持α-血红蛋白稳定蛋白（AHSP）和HbF水平。这会减少氧化应激，从而最大限度地减少 SCD 相关并发症。在这篇综述中，我们将讨论 Keap-1-Nrf2 复合物在血红蛋白病（尤其是 SCD）中的作用，以及该复合物如何代表更有效治疗方案的更好靶标。
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.
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影响因子：
29
作者：
Drakesmith H;Nemeth E;Ganz T
通讯作者：
Ganz T
影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
64.8
作者：
BOOKCHIN, RM;NAGEL, RL;BALAZS, T
通讯作者：
BALAZS, T
影响因子：
8
作者：
Chowdhry, S.;Zhang, Y.;McMahon, M.;Sutherland, C.;Cuadrado, A.;Hayes, J. D.
通讯作者：
Hayes, J. D.