Imidazole-based alkaloid derivative LCB54-0009 suppresses ocular angiogenesis and lymphangiogenesis in models of experimental retinopathy and corneal neovascularization

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dc.contributor.authorKim, Byung-Hakko
dc.contributor.authorLee, Junyeopko
dc.contributor.authorChoi, Jun-Subko
dc.contributor.authorPark, Dae Youngko
dc.contributor.authorSong, Ho Youngko
dc.contributor.authorPark, Tae Kyoko
dc.contributor.authorCho, Chung-Hyunko
dc.contributor.authorYe, Sang-Kyuko
dc.contributor.authorJoo, Choun-Kiko
dc.contributor.authorKoh, Gou Youngko
dc.contributor.authorKim, Tae-Yoonko
dc.date.accessioned2015-11-20T07:23:05Z-
dc.date.available2015-11-20T07:23:05Z-
dc.date.created2015-08-10-
dc.date.created2015-08-10-
dc.date.issued2015-08-
dc.identifier.citationBRITISH JOURNAL OF PHARMACOLOGY, v.172, no.15, pp.3875 - 3889-
dc.identifier.issn0007-1188-
dc.identifier.urihttp://hdl.handle.net/10203/200638-
dc.description.abstractBackground and PurposeAbnormally induced angiogenesis and lymphangiogenesis are associated with human diseases, including neovascular eye disease. Substances that inhibit these processes may have potential as an attractive therapeutic strategy for these diseases. Experimental ApproachIn vitro and in vivo angiogenesis and/or lymphangiogenesis were assessed in VEGF- or hypoxia-stimulated endothelial and retinal cells and in animal models of oxygen-induced retinopathy (OIR), streptozotocin-induced diabetic retinopathy (SIDR), suture-induced inflammatory corneal neovascularization (SICNV) and silver nitrate-induced corneal neovascularization. HUVECs and retinal cells were cultured under hypoxic conditions or incubated with VEGF to identify the molecular mechanisms involved. Key ResultsThe imidazole-based alkaloid derivative LCB54-0009 inhibited capillary-like tube formation in VEGF-induced HUVECs without inducing cytotoxic effects. Intravitreal injection of LCB54-0009 into retinas suppressed the formation of the pathological neovascular tufts and increased vascular permeability in both OIR of mice and SIDR of rats. Furthermore, subconjunctival injection of LCB54-0009 into the cornea suppressed corneal inflammation and inflammation-associated angiogenesis and lymphangiogenesis in SICNV of mice and silver nitrate cauterization of rats. These pharmacological activities were associated with effects on HIF-1 protein stability and HIF-1/NF-B redox sensitivity through its antioxidant activities. LCB54-0009 also inhibited the hypoxia-induced expression of angiopoietin-2, and VEGF-induced VEGFR-2 activation and downstream signalling, resulting in the down-regulation of the expression of pro-angiogenic factors and pro-inflammatory mediators and an up-regulation of the expression of anti-angiogenic factors. Conclusions and ImplicationsLCB54-0009 is a potential candidate molecule for blocking pathological angiogenesis and lymphangiogenesis mediated by HIF-1- angiopoietin-2 expression and VEGFR-2 activation.-
dc.languageEnglish-
dc.publisherWILEY-BLACKWELL-
dc.subjectHYPOXIA-INDUCIBLE FACTORS-
dc.subjectSMOOTH-MUSCLE-CELLS-
dc.subjectENDOTHELIAL-CELLS-
dc.subjectARRIVE GUIDELINES-
dc.subjectTUMOR PROGRESSION-
dc.subjectEPITHELIAL-CELLS-
dc.subjectGENE-EXPRESSION-
dc.subjectFACTOR 1-ALPHA-
dc.subjectCONCISE GUIDE-
dc.subjectIN-VIVO-
dc.titleImidazole-based alkaloid derivative LCB54-0009 suppresses ocular angiogenesis and lymphangiogenesis in models of experimental retinopathy and corneal neovascularization-
dc.typeArticle-
dc.identifier.wosid000357952500014-
dc.identifier.scopusid2-s2.0-84936991254-
dc.type.rimsART-
dc.citation.volume172-
dc.citation.issue15-
dc.citation.beginningpage3875-
dc.citation.endingpage3889-
dc.citation.publicationnameBRITISH JOURNAL OF PHARMACOLOGY-
dc.identifier.doi10.1111/bph.13177-
dc.contributor.localauthorKoh, Gou Young-
dc.contributor.nonIdAuthorKim, Byung-Hak-
dc.contributor.nonIdAuthorChoi, Jun-Sub-
dc.contributor.nonIdAuthorPark, Dae Young-
dc.contributor.nonIdAuthorSong, Ho Young-
dc.contributor.nonIdAuthorPark, Tae Kyo-
dc.contributor.nonIdAuthorCho, Chung-Hyun-
dc.contributor.nonIdAuthorYe, Sang-Kyu-
dc.contributor.nonIdAuthorJoo, Choun-Ki-
dc.contributor.nonIdAuthorKim, Tae-Yoon-
dc.type.journalArticleArticle-
dc.subject.keywordPlusHYPOXIA-INDUCIBLE FACTORS-
dc.subject.keywordPlusSMOOTH-MUSCLE-CELLS-
dc.subject.keywordPlusENDOTHELIAL-CELLS-
dc.subject.keywordPlusARRIVE GUIDELINES-
dc.subject.keywordPlusTUMOR PROGRESSION-
dc.subject.keywordPlusEPITHELIAL-CELLS-
dc.subject.keywordPlusGENE-EXPRESSION-
dc.subject.keywordPlusFACTOR 1-ALPHA-
dc.subject.keywordPlusCONCISE GUIDE-
dc.subject.keywordPlusIN-VIVO-
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