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Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization

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Wang, J-H, Tseng, C-L, Lin, F-L, Chen, J, Hsieh, E-H, Lama, S, Chuang, Y-F, Kumar, S, Zhu, L, McGuinness, MB, Hernandez, J, Tu, L, Wang, P-Y and Liu, G-S ORCID: 0000-0003-3379-724X 2022 , 'Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization' , Theranostics, vol. 12, no. 2 , pp. 657-674 , doi: 10.7150/thno.65098.

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Abstract

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV.Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model.Results: We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea.Conclusion: Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.

Item Type: Article
Authors/Creators:Wang, J-H and Tseng, C-L and Lin, F-L and Chen, J and Hsieh, E-H and Lama, S and Chuang, Y-F and Kumar, S and Zhu, L and McGuinness, MB and Hernandez, J and Tu, L and Wang, P-Y and Liu, G-S
Keywords: corneal neovascularization, eye drops, nanoparticle
Journal or Publication Title: Theranostics
Publisher: Ivyspring International Publisher
ISSN: 1838-7640
DOI / ID Number: 10.7150/thno.65098
Copyright Information:

© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

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