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Marine bromophenols suppressed choroidal neovascularization by targeting HUWE1 through NF-κb signaling pathway
Kepeng Ou1, Youjian Li1, Yuwei Wang2
1College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing, China.
Insights
Marine bromophenols (BDB) reduce inflammation and suppress choroidal neovascularization by targeting HUWE1 via the NF-κB pathway. This suggests BDB as a potential therapy for chronic eye inflammation.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Chronic inflammation in the retina and choroid drives choroidal neovascularization (CNV) recurrence.
- Anti-VEGF treatments require regular injections due to persistent inflammation.
- Marine bromophenols (BDB) exhibit anti-inflammatory properties, but their mechanism is unclear.
Purpose of the Study:
- To investigate the mechanism by which BDB suppresses endothelial cell function and choroidal neovascularization.
- To identify the molecular targets of BDB in the context of inflammation.
Main Methods:
- In vitro and in vivo studies using endothelial cells and choroidal explants.
- Analysis of inflammatory cytokine levels (IL-1β, IL-6, TNF-α, IL-4, MMP-9).
- Investigation of the NF-κB pathway and protein-protein interactions using Co-IP assay to identify BDB targets.
Main Results:
- BDB restricted endothelial cell function and suppressed choroidal explants without affecting cell viability.
- BDB significantly reduced inflammatory cytokines and NF-κB p65 phosphorylation.
- HUWE1 was identified as a binding partner of BDB, and its overexpression enhanced BDB's suppressive effects.
Conclusions:
- BDB suppresses endothelial cell function and choroidal neovascularization by targeting HUWE1 through the NF-κB pathway.
- BDB shows potential as a therapeutic candidate for treating chronic inflammation in conditions like CNV.
Abstract:
Inflammation plays a key role in the progression of choroidal neovascularization (CNV). Regular intravitreal injection of anti-VEGF medication is required for many patients to sustain eye condition as CNV always recurs due to persistent chronic inflammation in the retina and choroid. Marine bromophenols (BDB) have been widely studied due to their diverse bioactivities, including anti-inflammatory effect, though the mechanism of which remained unclear. Our study demonstrated that BDB could restricted endothelial cells' function and suppressed choroidal explants both in vitro and in vivo without out affecting the cells viability. BDB also significantly reduced numerous inflammatory cytokines in both raw cells and choroidal tissue, including IL-1β, IL-6, TNF-α, IL-4 and MMP-9. Moreover, we demonstrated that BDB down regulated phosphorylation of NF-κB p65 in the raw cells. By Co-IP assay, HUWE1 was found to be bound with BDB and the binding location was at sequences position 4214. When overexpressed HUWE1 in HUVECs, the suppression of endothelial cells' function by BDB became more significant. Taken together, the findings in this study showed that BDB suppressed endothelial cells' function and choroidal neovascularization by targeting HUWE1 through NF-κB pathway, which suggested that BDB could be a potential therapeutic candidate in treating chronic inflammation in choroidal neovascularization.
