Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the el...Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the elderly.However,an effective therapy for this disease is lacking.Here,we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate(SI)-induced oxidative cell death and prolonged their healthy survival.D609 effectively attenuated excessive reactive oxygen species(ROS)and prevented severe mitochondrial loss due to oxidative stress in the RPE cells.Surprisingly,the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein.The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model.These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609,which may ultimately have clinical applications for the treatment of AMD.展开更多
Forkhead box C1(FOXC1)is required for neural crest and ocular development,and mutations in FOXC1 lead to inherited Axenfeld-Rieger syndrome.Here,we find that FOXC1 and paired box 6(PAX6)are co-expressed in the human l...Forkhead box C1(FOXC1)is required for neural crest and ocular development,and mutations in FOXC1 lead to inherited Axenfeld-Rieger syndrome.Here,we find that FOXC1 and paired box 6(PAX6)are co-expressed in the human limbus and central corneal epithelium.Deficiency of FOXC1 and alternation in epithelial features occur in patients with corneal ulcers.FOXC1 governs the fate of the corneal epithelium by directly binding to lineage-specific open promoters or enhancers marked by H3K4me2.FOXC1 depletion not only activates the keratinization pathway and reprograms corneal epithelial cells into skin-like epithelial cells,but also disrupts the collagen metabolic process and interferon signaling pathways.Loss of interferon regulatory factor 1 and PAX6 induced by FOXC1 dysfunction is linked to the corneal ulcer.Collectively,our results reveal a FOXC1.mediated regulatory network responsible for corneal epithelial homeostasis and provide a potential therapeutic target for corneal ulcer.展开更多
基金The National Key Research and Development(R&D)Program of China(2016YFA0101700)National Natural Science Foundation of China(81700805,81622012 and 81870633)+1 种基金Fundamental Research Funds for the Central Universities(17ykjc28)Fundamental Research Funds of the State Key Laboratory of Ophthalmology.Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S029).
文摘Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the elderly.However,an effective therapy for this disease is lacking.Here,we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate(SI)-induced oxidative cell death and prolonged their healthy survival.D609 effectively attenuated excessive reactive oxygen species(ROS)and prevented severe mitochondrial loss due to oxidative stress in the RPE cells.Surprisingly,the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein.The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model.These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609,which may ultimately have clinical applications for the treatment of AMD.
基金We thank Dr.Tong Chen and his colleagues at EHBIO Gene Technology(Beijing)for providing technical support for our bioinformatics analysis.This work was supported by The National Key Research and Development(R&D)Program of China(2016YFA0101700)the National Natural Science Foundation of China(31771626,81622012)the Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S029).
文摘Forkhead box C1(FOXC1)is required for neural crest and ocular development,and mutations in FOXC1 lead to inherited Axenfeld-Rieger syndrome.Here,we find that FOXC1 and paired box 6(PAX6)are co-expressed in the human limbus and central corneal epithelium.Deficiency of FOXC1 and alternation in epithelial features occur in patients with corneal ulcers.FOXC1 governs the fate of the corneal epithelium by directly binding to lineage-specific open promoters or enhancers marked by H3K4me2.FOXC1 depletion not only activates the keratinization pathway and reprograms corneal epithelial cells into skin-like epithelial cells,but also disrupts the collagen metabolic process and interferon signaling pathways.Loss of interferon regulatory factor 1 and PAX6 induced by FOXC1 dysfunction is linked to the corneal ulcer.Collectively,our results reveal a FOXC1.mediated regulatory network responsible for corneal epithelial homeostasis and provide a potential therapeutic target for corneal ulcer.
