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Войти в исследования Experimental eye research · 2025
Dihydromyricetin mitigates oxidative damage induced by mixed phthalates via Nrf2 activation in experimental models of glaucoma.
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Xiao Duncheng, Yang Fan, Li Mohan, Lu Zhe, Xing Shouxin, Wang Song, Tao Tianchang, Jiang Zhengxuan, Tao Liming
Аннотация
PURPOSE: To evaluate the impact of combined Di(2-ethylhexyl) phthalate (DEHP) and Di-isodecyl phthalate (DiDP) exposure on retinal oxidative stress, and to assess the protective role of dihydromyricetin (DMY) via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling.
METHODS: This study integrated epidemiological analysis from the National Health and Nutrition Examination Survey (NHANES) with in vitro and in vivo experiments. Generalized additive models and SHapley Additive exPlanations (SHAP) were used to assess the association between phthalate metabolites and glaucoma risk. Human primary retinal ganglion cells (RGCs) were exposed to DEHP/DiDP mixtures, and oxidative stress markers-reactive oxygen species (ROS), glutathione (GSH), and superoxide dismutase 1 (SOD1)-were measured. Nrf2 and mitogen-activated protein kinase (MAPK) pathway proteins were evaluated by Western blot. The effect of DMY was tested with and without the Nrf2 inhibitor ML385. Visual Evoked Potential (VEP) assessed retinal function in a mouse model of phthalate and ischemic injury.
RESULTS: DEHP and DiDP induced concentration-dependent cytotoxicity and oxidative stress by suppressing Nrf2/heme oxygenase-1 (HO-1) and activating MAPK signaling. DMY significantly restored antioxidant defenses and suppressed MAPK activation; these effects were abolished by Nrf2 inhibition. In vivo, DMY preserved visual evoked potential (VEP) responses, reflecting its protective effect on the optic nerve and post-retinal visual pathway. NHANES data supported a non-linear association between phthalate exposure and glaucoma risk.
CONCLUSIONS: DEHP and DiDP contribute to retinal neurodegeneration through oxidative stress and MAPK activation. DMY offers neuroprotection by activating Nrf2/HO-1 and suppressing MAPK signaling, suggesting therapeutic potential in environmentally induced glaucoma.
METHODS: This study integrated epidemiological analysis from the National Health and Nutrition Examination Survey (NHANES) with in vitro and in vivo experiments. Generalized additive models and SHapley Additive exPlanations (SHAP) were used to assess the association between phthalate metabolites and glaucoma risk. Human primary retinal ganglion cells (RGCs) were exposed to DEHP/DiDP mixtures, and oxidative stress markers-reactive oxygen species (ROS), glutathione (GSH), and superoxide dismutase 1 (SOD1)-were measured. Nrf2 and mitogen-activated protein kinase (MAPK) pathway proteins were evaluated by Western blot. The effect of DMY was tested with and without the Nrf2 inhibitor ML385. Visual Evoked Potential (VEP) assessed retinal function in a mouse model of phthalate and ischemic injury.
RESULTS: DEHP and DiDP induced concentration-dependent cytotoxicity and oxidative stress by suppressing Nrf2/heme oxygenase-1 (HO-1) and activating MAPK signaling. DMY significantly restored antioxidant defenses and suppressed MAPK activation; these effects were abolished by Nrf2 inhibition. In vivo, DMY preserved visual evoked potential (VEP) responses, reflecting its protective effect on the optic nerve and post-retinal visual pathway. NHANES data supported a non-linear association between phthalate exposure and glaucoma risk.
CONCLUSIONS: DEHP and DiDP contribute to retinal neurodegeneration through oxidative stress and MAPK activation. DMY offers neuroprotection by activating Nrf2/HO-1 and suppressing MAPK signaling, suggesting therapeutic potential in environmentally induced glaucoma.