{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:46:34Z","timestamp":1790462794016,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,11]],"date-time":"2019-04-11T00:00:00Z","timestamp":1554940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["NSC102-2320-B-038-018-MY3"],"award-info":[{"award-number":["NSC102-2320-B-038-018-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["NSC102-2628-B-038-009-MY3"],"award-info":[{"award-number":["NSC102-2628-B-038-009-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST104-2811-B-038-024"],"award-info":[{"award-number":["MOST104-2811-B-038-024"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST106-2320- B-038-015-MY3"],"award-info":[{"award-number":["MOST106-2320- B-038-015-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>N-retinylidene-N-retinylethanolamine (A2E) and other bisretinoids are components of lipofuscin and accumulate in retinal pigment epithelial (RPE) cells\u2014these adducts are recognized in the pathogenesis of retinal degeneration. Further, blue light-emitting diode (LED) light (BLL)-induced retinal toxicity plays an important role in retinal degeneration. Here, we demonstrate that low-luminance BLL enhances phototoxicity in A2E-laden RPE cells and rats. RPE cells were subjected to synthetic A2E, and the effects of BLL on activation of apoptotic biomarkers were examined by measuring the levels of cleaved caspase-3. BLL modulates the protein expression of zonula-occludens 1 (ZO-1) and paracellular permeability in A2E-laden RPE cells. Early inflammatory and angiogenic genes were also screened after short-term BLL exposure. In this study, we developed a rat model for A2E treatment with or without BLL exposure for 21 days. BLL exposure caused fundus damage, decreased total retinal thickness, and caused neuron transduction injury in the retina, which were consistent with the in vitro data. We suggest that the synergistic effects of BLL and A2E accumulation in the retina increase the risk of retinal degeneration. These outcomes help elucidate the associations between BLL\/A2E and angiogenic\/apoptotic mechanisms, as well as furthering therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms20071799","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T03:46:37Z","timestamp":1555040797000},"page":"1799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Low-Luminance Blue Light-Enhanced Phototoxicity in A2E-Laden RPE Cell Cultures and Rats"],"prefix":"10.3390","volume":"20","author":[{"given":"Cheng-Hui","family":"Lin","sequence":"first","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-Ru","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Jan","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana Shu-Lian","family":"Chow","sequence":"additional","affiliation":[{"name":"Institute of Drug Education and Research, College of Pharmacy, University of Houston, Texas 77004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3714-0464","authenticated-orcid":false,"given":"Yu-Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7728","DOI":"10.1167\/iovs.15-17677","article-title":"A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1beta and Inhibition of PGE2","volume":"56","author":"Shi","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Stiles, M., Moiseyev, G.P., Budda, M.L., Linens, A., Brush, R.S., Qi, H., White, G.L., Wolf, R.F., Ma, J.-X., and Floyd, R. (2015). PBN (Phenyl-N-Tert-Butylnitrone)-Derivatives Are Effective in Slowing the Visual Cycle and Rhodopsin Regeneration and in Protecting the Retina from Light-Induced Damage. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145305"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2537","DOI":"10.1038\/cddis.2016.453","article-title":"Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration","volume":"8","author":"Golestaneh","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1136\/bjophthalmol-2015-306972","article-title":"Current therapeutic developments in atrophic age-related macular degeneration","volume":"100","author":"Hanus","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.exer.2005.01.007","article-title":"RPE lipofuscin and its role in retinal pathobiology","volume":"80","author":"Sparrow","year":"2005","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0014-4835(03)00023-X","article-title":"Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: A possible mechanism for RPE aging and age-related macular degeneration","volume":"76","author":"Liang","year":"2003","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/j.freeradbiomed.2012.06.024","article-title":"Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of inflammation-related genes in retinal pigment epithelial cells","volume":"53","author":"Bian","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/1521-3773(20020301)41:5<814::AID-ANIE814>3.0.CO;2-2","article-title":"Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement","volume":"41","author":"Itagaki","year":"2002","journal-title":"Angew. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"39732","DOI":"10.1074\/jbc.M504933200","article-title":"Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin","volume":"280","author":"Jang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1562\/0031-8655(2000)071<0225:TSOLTT>2.0.CO;2","article-title":"Transmission spectra of light to the mammalian retina","volume":"71","author":"Dillon","year":"2000","journal-title":"Photochem. Photobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/php.12200","article-title":"A2E-mediated photochemical modification to fibronectin and its implications to age-related changes in Bruch\u2019s membrane","volume":"90","author":"Thao","year":"2014","journal-title":"Photochem. Photobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1159\/000452282","article-title":"Involvement of XBP1s in Blue Light-Induced A2E-Containing Retinal Pigment Epithelium Cell Death","volume":"57","author":"Lu","year":"2017","journal-title":"Ophthalmic Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.jcrs.2008.10.052","article-title":"Cytoprotective effects of a blue light-filtering intraocular lens on human retinal pigment epithelium by reducing phototoxic effects on vascular endothelial growth factor-alpha, Bax, and Bcl-2 expression","volume":"35","author":"Kernt","year":"2009","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_15","first-page":"839","article-title":"The correlation between the concentrations of VEGF and PEDF and Ca2+-PKC signaling pathways in human retinal pigment epithelial cells cultured in vitro after exposuring to blue light","volume":"51","author":"Wang","year":"2015","journal-title":"[Zhonghua yan ke za zhi] Chin. J. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e781","DOI":"10.1038\/cddis.2013.303","article-title":"Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability","volume":"4","author":"Cachafeiro","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.preteyeres.2013.02.001","article-title":"Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions","volume":"34","author":"Klaassen","year":"2013","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00109-017-1506-8","article-title":"Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, alphaCT1, reduces VEGF-dependent RPE pathophysiology","volume":"95","author":"Obert","year":"2017","journal-title":"J. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1167\/iovs.13-12250","article-title":"Lack of Correlation Between the Spatial Distribution of A2E and Lipofuscin Fluorescence in the Human Retinal Pigment Epithelium","volume":"54","author":"Ablonczy","year":"2013","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1073\/pnas.1524774113","article-title":"Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration","volume":"113","author":"Ueda","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/aos.13011","article-title":"Drusen maculopathy: A risk factor for visual deterioration","volume":"94","author":"Algvere","year":"2016","journal-title":"Acta Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"a017194","DOI":"10.1101\/cshperspect.a017194","article-title":"The proteomics of drusen","volume":"4","author":"Crabb","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Anderson, O.A., Finkelstein, A., and Shima, D.T. (2013). A2E induces IL-1ss production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067263"},{"key":"ref_24","first-page":"2988","article-title":"A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture","volume":"40","author":"Sparrow","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_25","first-page":"285","article-title":"Multiple A2E treatments lead to melanization of rod outer segment\u2013challenged ARPE-19 cells","volume":"20","author":"Poliakov","year":"2014","journal-title":"Mol. Vis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/eye.2015.261","article-title":"Low-energy light bulbs, computers, tablets and the blue light hazard","volume":"30","author":"Khazova","year":"2016","journal-title":"Eye"},{"key":"ref_27","first-page":"61","article-title":"Effects of blue light on the circadian system and eye physiology","volume":"22","author":"Tosini","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10522-013-9463-2","article-title":"Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD)","volume":"14","author":"Tokarz","year":"2013","journal-title":"Biogerontology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1167\/iovs.06-0333","article-title":"Activation of Caspase-8 and Caspase-12 Pathways by 7-Ketocholesterol in Human Retinal Pigment Epithelial Cells","volume":"47","author":"Luthra","year":"2006","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1093\/toxsci\/kfx030","article-title":"Periodic exposure to smartphone-mimic low-luminance blue light induces retina damage through Bcl-2\/BAX-dependent apoptosis","volume":"157","author":"Lin","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_31","first-page":"1356","article-title":"Blue light-induced apoptosis of A2E-containing RPE: Involvement of caspase-3 and protection by Bcl-2","volume":"42","author":"Sparrow","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_32","first-page":"1222","article-title":"Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE","volume":"43","author":"Sparrow","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brain-from eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S1350-9462(01)00010-6","article-title":"An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch\u2019s membrane interface in aging and age-related macular degeneration","volume":"20","author":"Hageman","year":"2001","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/j.1460-2075.1982.tb01257.x","article-title":"Gene transfer into mouse lyoma cells by electroporation in high electric fields","volume":"1","author":"Neumann","year":"1982","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1085\/jgp.20028566","article-title":"Interaction of A2E with model membranes. Implications to the pathogenesis of age-related macular degeneration","volume":"120","author":"De","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29354","DOI":"10.1074\/jbc.M910191199","article-title":"The biosynthesis of A2E, a fluorophore of aging retina, involves the formation of the precursor, A2-PE, in the photoreceptor outer segment membrane","volume":"275","author":"Liu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bavik, C., Henry, S.H., Zhang, Y., Mitts, K., McGinn, T., Budzynski, E., Pashko, A., Lieu, K.L., Zhong, S., and Blumberg, B. (2015). Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124940"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jpba.2015.10.010","article-title":"A novel fluorescence-based assay for measuring A2E removal from human retinal pigment epithelial cells to screen for age-related macular degeneration inhibitors","volume":"117","author":"Jin","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4555","DOI":"10.1167\/iovs.12-11572","article-title":"Disruption of Cell-Cell Junctions and Induction of Pathological Cytokines in the Retinal Pigment Epithelium of Light-Exposed Mice","volume":"54","author":"Narimatsu","year":"2013","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1182\/blood.V96.1.34","article-title":"Human endothelial cells express CCR2 and respond to MCP-1: Direct role of MCP-1 in angiogenesis and tumor progression","volume":"96","author":"Salcedo","year":"2000","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/1742-2094-9-221","article-title":"Small interfering RNA-mediated suppression of Ccl2 in Muller cells attenuates microglial recruitment and photoreceptor death following retinal degeneration","volume":"9","author":"Rutar","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Nakaigawa, N., Kondo, K., Ueno, D., Namura, K., Makiyama, K., Kobayashi, K., Shioi, K., Ikeda, I., Kishida, T., and Kaneta, T. (2017). The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET\/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy. BMC Cancer, 17.","DOI":"10.1186\/s12885-016-3044-0"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1365-4632.2011.05299.x","article-title":"Glucose transporter member 1 is involved in UVB-induced epidermal hyperplasia by enhancing proliferation in epidermal keratinocytes","volume":"52","author":"Tochio","year":"2013","journal-title":"Int. J. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Weinkauf, B., Rukwied, R., Quiding, H., Dahllund, L., Johansson, P., and Schmelz, M. (2012). Local gene expression changes after UV-irradiation of human skin. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039411"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/jcp.21792","article-title":"A2E, a component of lipofuscin, is pro-angiogenic in vivo","volume":"220","author":"Iriyama","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1167\/iovs.09-3944","article-title":"Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina","volume":"50","author":"Maeda","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14609","DOI":"10.1073\/pnas.95.25.14609","article-title":"Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium","volume":"95","author":"Parish","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17551","DOI":"10.1073\/pnas.1008769107","article-title":"Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease","volume":"107","author":"Moiseyev","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/toxsci\/kfv132","article-title":"Long-term Fluorometholone Topical Use Induces Ganglion Cell Damage in Rats Analyzed With Optical Coherence Tomography","volume":"147","author":"Liao","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/j.1476-5381.2012.02227.x","article-title":"Silibinin inhibits VEGF secretion and age-related macular degeneration in a hypoxia-dependent manner through the PI-3 kinase\/Akt\/mTOR pathway","volume":"168","author":"Lin","year":"2013","journal-title":"Br. J. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1799\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:44:42Z","timestamp":1760186682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,11]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071799"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071799","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,11]]}}}