The First Affiliated Hospital of Chongqing Medical University, Ophthalmology, Chongqing 400016, PR China; Key Laboratory of Prevention and Treatment on major blinding diseases, Chongqing Eye Institute, Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing 400016, PR China.
Chongqing General Hospital, Endocrinology, Chongqing 400013, PR China.
Phytomedicine. 2024 Nov;134:155982. doi: 10.1016/j.phymed.2024.155982. Epub 2024 Aug 30.
Aging-induced decline in ciliary muscle function is an important factor in visual accommodative deficits in elderly adults. With this study, we provide an innovative investigation of the interaction between ciliary muscle aging and oxidative stress.
Tricolor guinea pigs were used for the experiments in vivo and primary guinea pig ciliary smooth muscle cells were used for the experiments in vitro.
We enriched for genes associated with muscle-aging-lutein relationship using bioinformatics, including Nuclear factor-erythroid 2-related factor-2 (Nrf2), Glutathione Peroxidase (GPx) gene family, Superoxide Dismutase (SOD) gene family, NAD(P)H: Quinone Oxidoreductase 1 (NQO1) and Heme Oxygenase-1 (HO-1). After gavage to aged guinea pigs, lutein reduced Reactive Oxygen Species (ROS) and P21 levels in senescent ciliary muscle; lutein decreased refractive error and restored accommodation of the eye. In addition, lutein increased GPx, SOD, and Catalase (CAT) levels in serum; lutein increased GPx and CAT levels in ciliary bodies. Lutein regulated the expression of proteins such as Nrf2, Kelch-like ECH-associated protein 1 (Keap1), and downstream proteins in senescent ciliary bodies. Similarly, guinea pig ciliary muscle cell senescence was associated with oxidative stress. In vitro, 100 μM lutein reversed the damage caused by 800 μM HO; it reduced Senescence-Associated β-galactosidase (SA-β-Gal) and ROS activites, cell apoptosis and cell migration. Also, lutein increased the expression of smooth muscle contractile proteins. Lutein also increased the expression of Nrf2, GPx2, NQO1 and HO-1, decreased the expression of Keap1. A reduction in Nrf2 activity led to a reduction in the ability of lutein to activate antioxidant enzymes in the cells, thus reducing its inhibitory effect on cell senescence.
lutein improved resistance to oxidative stress in senescent ciliary muscle in vivo and in vitro by regulating the Keap1/Nrf2/Antioxidant Response Element pathway. We have innovatively demonstrated the molecular pharmacological mechanism by which lutein reverse age-related ciliary muscle systolic and diastolic deficits.
睫状肌功能随年龄增长而下降是老年人视觉调节功能障碍的一个重要因素。本研究创新性地探讨了睫状肌衰老与氧化应激的相互作用。
三色豚鼠用于体内实验，原代豚鼠睫状平滑肌细胞用于体外实验。
我们使用生物信息学方法富集了与肌肉衰老-叶黄素关系相关的基因，包括核因子-红细胞 2 相关因子 2（Nrf2）、谷胱甘肽过氧化物酶（GPx）基因家族、超氧化物歧化酶（SOD）基因家族、NAD（P）H：醌氧化还原酶 1（NQO1）和血红素加氧酶-1（HO-1）。叶黄素灌胃给衰老豚鼠后，可降低衰老睫状肌中的活性氧（ROS）和 P21 水平；叶黄素可降低屈光度并恢复眼睛的调节力。此外，叶黄素可提高血清中 GPx、SOD 和过氧化氢酶（CAT）水平；叶黄素可提高睫状体中的 GPx 和 CAT 水平。叶黄素调节衰老睫状体内 Nrf2、Kelch 样 ECH 相关蛋白 1（Keap1）和下游蛋白等蛋白的表达。同样，豚鼠睫状肌细胞衰老与氧化应激有关。在体外，100μM 叶黄素可逆转 800μM HO 引起的损伤；降低衰老相关β-半乳糖苷酶（SA-β-Gal）和 ROS 活性、细胞凋亡和细胞迁移。此外，叶黄素增加了平滑肌收缩蛋白的表达。叶黄素还增加了 Nrf2、GPx2、NQO1 和 HO-1 的表达，降低了 Keap1 的表达。Nrf2 活性降低导致叶黄素激活细胞内抗氧化酶的能力降低，从而降低其对细胞衰老的抑制作用。
叶黄素通过调节 Keap1/Nrf2/抗氧化反应元件通路，改善衰老睫状肌的体内和体外抗氧化应激能力。本研究创新性地揭示了叶黄素逆转与年龄相关的睫状肌收缩和舒张功能障碍的分子药理学机制。
