{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:20:46Z","timestamp":1789993246945,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,1,12]],"date-time":"2015-01-12T00:00:00Z","timestamp":1421020800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Nuclear factor erythroid 2\u2010related factor 2 (<jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2) is a redox\u2010sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of the <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2 pathway seems protective for many organs, and although a well\u2010known <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2 activator, bardoxolone methyl, was evaluated clinically for treating chronic kidney disease, it was found to induce adverse events. Many bardoxolone methyl derivatives, mostly derived by chemical modifications, have already been studied. However, we adopted a biotransformation technique to obtain a novel Nrf2 activator.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The potent novel <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2 activator, <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>9, was obtained from microbial transformation products. Its <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2 activity was evaluated by determining <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content>:quinone oxidoreductase\u20101 induction activity in <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>epa1c1c7 cells. We also investigated the effects of <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>9 on oxygen\u2010induced retinopathy in rats and glycated albumin\u2010induced blood\u2013retinal barrier permeability in rabbits because many ocular diseases are associated with oxidative stress and inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Bardoxolone methyl doubled the specific activity of Nrf2 in <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>epa1c1c7 cells at a much higher concentration than <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>9. Moreover, the induction of <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2\u2010targeted genes was observed at a one\u2010tenth lower concentration of <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>9. Interestingly, the cytotoxicity of <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>9 was substantially reduced compared with bardoxolone methyl. Oral and intravitreal administration of <jats:styled-content style=\"fixed-case\">RS<\/jats:styled-content>9 ameliorated the pathological scores and leakage in the models of retinopathy in rats and ocular inflammation in rabbits respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2 activators are applicable for treating ocular diseases and novel <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>rf2 activators have potential as a unique method for prevention and treatment of retinovascular disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12999","type":"journal-article","created":{"date-parts":[[2014,11,3]],"date-time":"2014-11-03T11:06:33Z","timestamp":1415012793000},"page":"1237-1249","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Novel <scp>N<\/scp>rf2 activators from microbial transformation products inhibit blood\u2013retinal barrier permeability in rabbits"],"prefix":"10.1111","volume":"172","author":[{"given":"Yasuhiro","family":"Nakagami","sequence":"first","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  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