Investigative ophthalmology & visual science · 2025
Targeted Activation of OGG1 Inhibits Paraptosis in Lens Epithelial Cells of Early Age-Related Cortical Cataract.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Geng Wenjing, Li Pengfei, Zhang Guowei, Zhong Renhao, Xu Linhui, Kang Lihua, Liu Xi, Wu Miaomiao, Ji Min, Guan Huaijin
Аннотация
PURPOSE: To investigate potential modes of programmed cell death in the lens epithelial cells (LECs) of patients with early age-related cortical cataract (ARCC) and to explore early-stage intervention strategies.
METHODS: Anterior lens capsules were collected from early ARCC patients for comprehensive analysis. Ultrastructural examination of LECs was performed using transmission electron microscopy. Cell death-associated protein markers were quantified via Western blot analysis, including those for paraptosis (ALIX, GRP78), apoptosis (cleaved caspase 3 and caspase 9), pyroptosis (N-GSDMD), and ferroptosis (GPX4). Intracellular vesicle-organelle colocalization was assessed through immunofluorescence. OGG1 protein expression and activity were evaluated through multiple methods, including Western blot, laser micro-irradiation, and immunofluorescence. The therapeutic potential of the OGG1 activator TH10785 on paraptosis was investigated using an ex vivo rat lens model.
RESULTS: Morphologic changes revealed significant endoplasmic reticulum (ER) swelling in ARCC patient LECs, with no characteristic apoptotic features. Paraptosis-related proteins exhibited significant alterations, while other cell death pathway markers (apoptosis, pyroptosis, and ferroptosis) remained unchanged. In the reactive oxygen species-induced paraptosis model, vesicular structures showed exclusive colocalization with ER-specific fluorescence. Elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine were observed concurrent with decreased OGG1 activity. The OGG1 activator TH10785 showed efficacy in suppressing LECs paraptosis in ex vivo rat lens cultures.
CONCLUSIONS: Paraptosis was identified in the LECs of patients with early ARCC. TH10785 activates OGG1 to suppress paraptosis in LECs, suggesting a novel therapeutic approach for early ARCC intervention.
METHODS: Anterior lens capsules were collected from early ARCC patients for comprehensive analysis. Ultrastructural examination of LECs was performed using transmission electron microscopy. Cell death-associated protein markers were quantified via Western blot analysis, including those for paraptosis (ALIX, GRP78), apoptosis (cleaved caspase 3 and caspase 9), pyroptosis (N-GSDMD), and ferroptosis (GPX4). Intracellular vesicle-organelle colocalization was assessed through immunofluorescence. OGG1 protein expression and activity were evaluated through multiple methods, including Western blot, laser micro-irradiation, and immunofluorescence. The therapeutic potential of the OGG1 activator TH10785 on paraptosis was investigated using an ex vivo rat lens model.
RESULTS: Morphologic changes revealed significant endoplasmic reticulum (ER) swelling in ARCC patient LECs, with no characteristic apoptotic features. Paraptosis-related proteins exhibited significant alterations, while other cell death pathway markers (apoptosis, pyroptosis, and ferroptosis) remained unchanged. In the reactive oxygen species-induced paraptosis model, vesicular structures showed exclusive colocalization with ER-specific fluorescence. Elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine were observed concurrent with decreased OGG1 activity. The OGG1 activator TH10785 showed efficacy in suppressing LECs paraptosis in ex vivo rat lens cultures.
CONCLUSIONS: Paraptosis was identified in the LECs of patients with early ARCC. TH10785 activates OGG1 to suppress paraptosis in LECs, suggesting a novel therapeutic approach for early ARCC intervention.