Oxidative stress-mediated retinal pigment epithelium (RPE) degeneration plays a vital role in retinal degeneration with irreversible visual impairment, most notably in age-related macular degeneration (AMD), but a key pathogenic factor and the targeted medical control remain controversial and unclear. In this work, by sophisticated high-throughput sequencing and biochemistry investigations, the major pathologic processes during RPE degeneration in the sodium iodate-induced oxidative stress model has been identified to be heme oxygenase-1 (HO-1)-regulated ferroptosis, which is controlled by the Nrf2–SLC7A11–HO-1 hierarchy, through which ferrous ion accumulation and lethal oxidative stress cause RPE death and subsequently photoreceptor degeneration. By direct knockdown of HO-1 or using HO-1 inhibitor ZnPP, the specific inhibition of HO-1 overexpression has been determined to significantly block RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and achieved superior therapeutic effects: substantial recovery of the retinal structure and visual function. These findings highlight that targeting HO-1-mediated RPE ferroptosis could serve as an effectively retinal-protective strategy for retinal degenerative diseases prevention, including AMD.
Retinal degeneration is a main class of ocular diseases. So far, retinal progenitor cell (RPC) transplantation has been the most potential therapy for it, in which promoting RPCs neuronal differentiation remains an unmet challenge. To address this issue, innovatively designed L/ d - phenylalanine based chiral nanofibers (LPG and DPG) are employed and it finds that chirality of fibers can efficiently regulate RPCs differentiation. qPCR, western blot, and immunofluorescence analysis show that right-handed helical DPG nanofibers significantly promote RPCs neuronal differentiation, whereas left-handed LPG nanofibers decrease this effect. These effects are mainly ascribed to the stereoselective interaction between chiral helical nanofibers and retinol-binding protein 4 (RBP4, a key protein in the retinoic acid (RA) metabolic pathway). The findings of chirality-dependent neuronal differentiation provide new strategies for treatment of neurodegenerative diseases via optimizing differentiation of transplanted stem cells on chiral nanofibers.
Background and Purpose Retinal photodamage is a high‐risk factor for age‐related macular degeneration (AMD), the leading cause of irreversible blindness worldwide. However, both the pathogenesis and effective therapies for retinal photodamage are still unclear and debated. Experimental Approach The anti‐inflammatory effects of thrombospondin‐1 on blue light‐induced inflammation in ARPE‐19 cells and in retinal inflammation were evaluated. Furthermore, the anti‐angiogenic effects of thrombospondin‐1 on human microvascular endothelial cells (hMEC‐1 cells) and a laser‐induced choroidal neovascularisation (CNV) mouse model were evaluated. in vitro experiments, including western blotting, immunocytochemistry, migration assays and tube formation assays, as well as in vivo experiments, including immunofluorescence, visual electrophysiology, spectral‐domain optical coherence tomography, and fluorescein angiography, were employed to evaluate the anti‐inflammatory and anti‐angiogenic effects of thrombospondin‐1. Key Results Specific effects of blue light‐induced retinal inflammation and pathological angiogenesis were reflected by up‐regulation of pro‐inflammatory factors and activation of angiogenic responses, predominantly regulated by the NF‐κB and VEGFR2 pathways respectively. During the blue light‐induced pathological progress, THBS‐1 derived from retinal pigment epithelium down‐regulated proteomics and biological assays. Thrombospondin‐1 treatment also suppressed inflammatory infiltration and neovascular leakage. The protective effect of Thrombospondin‐1 was additionally demonstrated by a substantial rescue of visual function. Mechanistically, thrombospondin‐1 reversed blue light‐induced retinal inflammation and angiogenesis by blocking the activated NF‐κB and VEGFR2 pathways, respectively. Conclusion and Implications Thrombospondin‐1, with dual anti‐inflammatory and anti‐neovascularisation properties, is a promising agent for protection against blue light‐induced retinal damage and retinal degenerative disorders which are pathologically associated with inflammatory and angiogenic progress. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc
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