Chhunchha Bhavana, Kubo Eri, Krueger Ronald R, Singh Dhirendra P
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Ophthalmology, Kanazawa Medical University, Kanazawa 9200293, Japan.
Antioxidants (Basel). 2023 Jan 6;12(1):140. doi: 10.3390/antiox12010140.
A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2's activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.
衰老相关疾病的一个主要标志是无法引发细胞防御反应。转录蛋白Nrf2（核因子红细胞衍生2相关因子）在氧化应激反应、细胞内稳态和健康寿命中起关键作用。Nrf2的激活已被确定为恢复衰老过程中抗氧化防御的治疗靶点。在此，我们证明美国食品药品监督管理局（FDA）批准的药物肼屈嗪（Hyd）在体外/体内对不同年龄和类型的小鼠（m）或人（h）晶状体上皮细胞（LEC）以及小鼠晶状体而言，是Nrf2/抗氧化反应元件（ARE）途径的再激活剂。这导致Hyd驱动羰基减少活性氧（ROS）降低，4-羟基壬烯醛/丙二醛加合物减少，并具有细胞保护作用，通过延迟/预防晶状体因衰老/氧化应激而混浊，延长了晶状体的健康寿命。我们阐明Hyd通过诱导Nrf2从细胞质转移到细胞核来激活保护信号，并通过Nrf2与启动子的ARE序列直接相互作用增强ARE反应。功能丧失研究以及Hyd与抗氧化剂N-乙酰半胱氨酸（NAC）或过氧化物酶（Prdx）6的联合处理表明，Nrf2/ARE驱动的启动子活性增加依赖于Hyd。我们的研究提供了概念验证证据，从而为将Hyd重新用作延迟/预防衰老和氧化相关疾病的治疗药物铺平了道路。
