Sudipta Panja, Mi-Hyun Nam, Hanmant Gaikwad, Johanna Rankenberg, Ram H. Nagaraj
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引用次数: 0
Abstract
Presbyopia is the progressive loss of the ability of the lens to focus on nearby objects due to its increased stiffness. It occurs in the mid-40s and continues to worsen until the mid-60s. The age-associated increase in protein cross-linking in the lens leads to protein aggregation and water insolubility, especially in the nuclear region, contributing to lens stiffness. This study reports the development of aggrelyte-2A (methyl S -acetyl- N -(3,3-dimethylbutanoyl) cysteinate, a derivative of our previously reported aggrelyte-2) for reversing the stiffness of aged lenses. Aggrelyte-2A showed minimal toxicity in cultured mouse lens epithelial cells (up to 2000 µM) and human lens epithelial cells (up to 250 µM). Lenses from aged mice (age: 24-25 months) treated with 1 mM aggrelyte-2A for 24 h, and human lenses (age: 47-67 years) treated with 250 µM aggrelyte-2A for 48 h showed 11-14% reductions in stiffness, accompanied by an increase in acetyllysine in lens proteins, and free-thiols in the lens. Topical application of aggrelyte-2A (40 mM, 5 µl twice daily for 4 weeks) on mouse eyes significantly reduced lens stiffness. The topical application showed no toxicity to the lens, cornea, or retina, as revealed by morphological examination, H&E staining, and optical coherence tomography. These data suggest that aggrelyte-2A could be developed as a presbyopia-reversing therapeutic.
老花眼是由于晶状体的硬度增加而逐渐丧失聚焦附近物体的能力。它发生在40岁左右,并持续恶化,直到60岁左右。晶状体中与年龄相关的蛋白质交联增加导致蛋白质聚集和水不溶性,特别是在核区域,导致晶状体僵硬。本研究报告了aggrelyte-2A(甲基S -乙酰基- N -(3,3-二甲基丁烷基)半胱氨酸,我们之前报道的aggrelyte-2的衍生物)的发展,用于逆转老化镜片的僵硬。Aggrelyte-2A对培养的小鼠晶状体上皮细胞(高达2000µM)和人晶状体上皮细胞(高达250µM)的毒性很小。老龄小鼠(24-25个月)晶状体用1 mM aggrelyate - 2a处理24小时,人晶状体(47-67岁)用250µM aggrelyate - 2a处理48小时,晶状体硬度降低11-14%,晶状体蛋白中的乙酰赖氨酸和晶状体中的游离巯基增加。局部应用aggrelyte-2A (40 mM, 5µl,每天2次,持续4周)在小鼠眼睛上显著降低晶状体硬度。形态学检查、H&E染色和光学相干断层扫描显示,局部应用对晶状体、角膜或视网膜没有毒性。这些数据表明aggrelyte-2A可以作为一种逆转老花眼的治疗药物。