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Theranostics ; 12(2): 657-674, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34976206

RESUMEN

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-ß (TGF-ß)-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.


Asunto(s)
Neovascularización de la Córnea , Endotelio Vascular , Lactonas , Quinasas Quinasa Quinasa PAM , Resorcinoles , Animales , Humanos , Masculino , Ratones , Administración Oftálmica , Cápsulas , Ciclo Celular/efectos de los fármacos , Línea Celular , Neovascularización de la Córnea/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Replicación del ADN/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Endotelio Vascular/efectos de los fármacos , Gelatina , Lactonas/administración & dosificación , Lactonas/farmacología , Lactonas/uso terapéutico , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Ratones Endogámicos C57BL , Nanopartículas , Soluciones Oftálmicas , Resorcinoles/administración & dosificación , Resorcinoles/farmacología , Resorcinoles/uso terapéutico , RNA-Seq
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