{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:01:37Z","timestamp":1790542897091,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Oxidative stress is identified as a major inducer of retinal pigment epithelium (RPE) cell dysregulation and is associated with age-related macular degeneration (AMD). The protection of RPE disorders plays an essential role in the pathological progress of retinal degeneration diseases. The pharmacological functions of fucoxanthin, a characteristic carotenoid, including anti-inflammatory and antioxidant properties, may ameliorate an outstanding bioactivity against premature senescence and cellular dysfunction. This study demonstrates that fucoxanthin protects RPE cells from oxidative stress-induced premature senescence and decreased photoreceptor cell loss in a sodium iodate-induced AMD animal model. Similarly, oxidative stress induced by hydrogen peroxide, nuclear phosphorylated histone (\u03b3H2AX) deposition and premature senescence-associated \u03b2-galactosidase staining were inhibited by fucoxanthin pretreatment in a human RPE cell line, ARPE-19 cells. Results reveal that fucoxanthin treatment significantly inhibited reactive oxygen species (ROS) generation, reduced malondialdehyde (MDA) concentrations and increased the mitochondrial metabolic rate in oxidative stress-induced RPE cell damage. Moreover, atrophy of apical microvilli was inhibited in cells treated with fucoxanthin after oxidative stress. During aging, the RPE undergoes well-characterized pathological changes, including amyloid beta (A\u03b2) deposition, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression and tight junction disruption, which were also reduced in fucoxanthin-treated groups by immunofluorescence. Altogether, pretreatment with fucoxanthin may protect against premature senescence and cellular dysfunction in retinal cells by oxidative stress in experimental AMD animal and human RPE cell models.<\/jats:p>","DOI":"10.3390\/md19020114","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T20:56:21Z","timestamp":1613681781000},"page":"114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Cytoprotective Potential of Fucoxanthin in Oxidative Stress-Induced Age-Related Macular Degeneration and Retinal Pigment Epithelial Cell Senescence In Vivo and In Vitro"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-527X","authenticated-orcid":false,"given":"Shiu-Jau","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Mackay Memorial Hospital, Taipei 10449, Taiwan"},{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzer-Bin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11049, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Yu","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiang-Jui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Optometry, Mackay Junior College of Medicine, Nursing, and Management, New Taipei 11260, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8176-3269","authenticated-orcid":false,"given":"An-Sheng","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Hsien","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4681-2939","authenticated-orcid":false,"given":"Kuang-Wen","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.redox.2015.03.004","article-title":"Redox theory of aging","volume":"5","author":"Jones","year":"2015","journal-title":"Redox Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.2147\/OPTH.S2151","article-title":"Age and disease-related structural changes in the retinal pigment epithelium","volume":"2","author":"Bonilha","year":"2008","journal-title":"Clin. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9358","DOI":"10.1038\/srep09358","article-title":"NHE8 is essential for RPE cell polarity and photoreceptor survival","volume":"5","author":"Xia","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_4","first-page":"171","article-title":"The toxicology of potassium and sodium iodates: Acute toxicity in mice","volume":"120","author":"Webster","year":"1957","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1167\/iovs.13-12477","article-title":"Assessing sodium iodate-induced outer retinal changes in rats using confocal scanning laser ophthalmoscopy and optical coherence tomography","volume":"55","author":"Yang","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16054","DOI":"10.1038\/cddiscovery.2016.54","article-title":"Retinal pigment epithelial cell necroptosis in response to sodium iodate","volume":"2","author":"Hanus","year":"2016","journal-title":"Cell Death Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0022-5320(79)80014-3","article-title":"The relationship of primate foveal cones to the pigment epithelium","volume":"67","author":"Anderson","year":"1979","journal-title":"J. Ultrastruct. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"802","DOI":"10.2174\/156652410793937813","article-title":"The retinal pigment epithelium in health and disease","volume":"10","author":"Sparrow","year":"2010","journal-title":"Curr. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1023\/A:1002136712070","article-title":"Cellular mechanisms of blood-retinal barrier dysfunction in macular edema","volume":"97","author":"Vinores","year":"1999","journal-title":"Doc. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1159\/000320077","article-title":"Cystoid macular edema in uveitis","volume":"47","author":"Okada","year":"2010","journal-title":"Dev. Ophthalmol."},{"key":"ref_11","first-page":"184","article-title":"Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas","volume":"9","author":"Dentchev","year":"2003","journal-title":"Mol. Vis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Masuda, N., Tsujinaka, H., Hirai, H., Yamashita, M., Ueda, T., and Ogata, N. (2019). Effects of concentration of amyloid \u03b2 (A\u03b2) on viability of cultured retinal pigment epithelial cells. BMC Ophthalmol., 19.","DOI":"10.1186\/s12886-019-1076-3"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.preteyeres.2011.02.004","article-title":"Parallel findings in age-related macular degeneration and Alzheimer\u2019s disease","volume":"30","year":"2011","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1038\/s41598-017-03397-2","article-title":"Amyloid \u03b2 peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice","volume":"7","author":"Prasad","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"588050","DOI":"10.3389\/fcell.2020.588050","article-title":"Reversed Senescence of Retinal Pigment Epithelial Cell by Coculture with Embryonic Stem Cell via the TGF\u03b2 and PI3K Pathways","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1023\/A:1025643303914","article-title":"Epidemiology of age-related maculopathy: A review","volume":"18","author":"Klaver","year":"2003","journal-title":"Eur. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11900","DOI":"10.1073\/pnas.0503015102","article-title":"Apolipoprotein E allele-dependent pathogenesis: A model for agerelated retinal degeneration","volume":"102","author":"Malek","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.ajpath.2011.10.015","article-title":"A rat model for studying the biological effects of circulatng LDL in the choriocapillaris-BrM-RPE complex","volume":"180","author":"Yin","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.4161\/auto.36184","article-title":"Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD","volume":"10","author":"Mitter","year":"2014","journal-title":"Autophagy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ejphar.2010.05.057","article-title":"Systemic administration of a free radical scavenger, edaravone, protects against light-induced photoreceptor degeneration in the mouse retina","volume":"642","author":"Imai","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0731-7085(03)00055-4","article-title":"Topical formulations with superoxide dismutase: Influence of formulation composition on physical stability and enzymatic activity","volume":"32","author":"Borin","year":"2003","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1080\/02713680701363833","article-title":"L-Carnitine protects human retinal pigment epithelial cells from oxidative damage","volume":"32","author":"Shamsi","year":"2007","journal-title":"Curr. Eye Res."},{"key":"ref_24","first-page":"361","article-title":"Proton-donative antioxidant activity of fucoxanthin with 1,1-diphenyl-2-picrylhydrazyl (DPPH)","volume":"42","author":"Nomura","year":"1997","journal-title":"Biochem. Mol. Biol. Int."},{"key":"ref_25","first-page":"779","article-title":"Fucoxanthin in association with vitamin C acts as modulators of human neutrophil function","volume":"6","author":"Morandi","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jep.2018.06.023","article-title":"Alleviative effect of fucoxanthin-containing extract from brown seaweed Laminaria japonica on renal tubular cell apoptosis through upregulating Na+\/H+ exchanger NHE1 in chronic kidney disease mice","volume":"224","author":"Chen","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Karpi\u0144ski, T.M., and Adamczak, A. (2019). Fucoxanthin\u2015An Antibacterial Carotenoid. Antioxidants, 8.","DOI":"10.3390\/antiox8080239"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1615\/JEnvironPatholToxicolOncol.2019030301","article-title":"Anti-Inflammatory and Apoptotic Signaling Effect of Fucoxanthin on Benzo(A)Pyrene-Induced Lung Cancer in Mice","volume":"38","author":"Chen","year":"2019","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chen, S.J., Lee, C.J., Lin, T.B., Liu, H.J., Huang, S.Y., Chen, J.Z., and Tseng, K.W. (2016). Inhibition of Ultraviolet B-Induced Expression of the Proinflammatory Cytokines TNF-\u03b1 and VEGF in the Cornea by Fucoxanthin Treatment in a Rat Model. Mar. Drugs, 14.","DOI":"10.3390\/md14010013"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chen, S.J., Lee, C.J., Lin, T.B., Peng, H.Y., Liu, H.J., Chen, Y.S., and Tseng, K.W. (2019). Protective Effects of Fucoxanthin on Ultraviolet B-Induced Corneal Denervation and Inflammatory Pain in a Rat Model. Mar. Drugs, 17.","DOI":"10.3390\/md17030152"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neuron.2012.06.018","article-title":"Mechanisms of age-related macular degeneration","volume":"75","author":"Ambati","year":"2012","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gu, X., Neric, N.J., Crabb, J.S., Crabb, J.W., Bhattacharya, S.K., Rayborn, M.E., Hollyfield, J.G., and Bonilha, V.L. (2012). Age-related changes in the retinal pigment epithelium (RPE). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038673"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lu, Z., Lin, V., May, A., Che, B., Xiao, X., Shaw, D.H., Su, F., Wang, Z., Du, H., and Shaw, P.X. (2019). HTRA1 synergizes with oxidized phospholipids in promoting inflammation and macrophage infiltration essential for ocular VEGF expression. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0216808"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s10753-013-9757-1","article-title":"First evidence for the anti-inflammatory activity of fucoxanthin in high-fat-diet-induced obesity in mice and the antioxidant functions in PC12 cells","volume":"37","author":"Tan","year":"2014","journal-title":"Inflammation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2174\/1874205X01610010083","article-title":"Oxidative Stress Induces Senescence in Cultured RPE Cells","volume":"10","author":"Aryan","year":"2016","journal-title":"Open Neurol. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2019.02.005","article-title":"Sirt3 mediates the protective effect of hydrogen in inhibiting ROS-induced retinal senescence","volume":"135","author":"Li","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.preteyeres.2008.09.001","article-title":"Mitochondrial DNA damage and its potential role in retinal degeneration","volume":"27","author":"Jarrett","year":"2008","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_38","first-page":"644","article-title":"Increased mitochondrial DNA damage and down-regulation of DNA repair enzymes in aged rodent retinal pigment epithelium and choroid","volume":"14","author":"Wang","year":"2008","journal-title":"Mol. Vis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.3390\/ijms14022996","article-title":"Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration","volume":"14","author":"Blasiak","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1111\/acel.12650","article-title":"The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore","volume":"16","author":"Rottenberg","year":"2017","journal-title":"Aging Cell."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.redox.2017.05.015","article-title":"Altered bioenergetics and enhanced resistance to oxidative stress in human retinal pigment epithelial cells from donors with age-related macular degeneration","volume":"13","author":"Ferrington","year":"2017","journal-title":"Redox Biol."},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"101201","DOI":"10.1016\/j.redox.2019.101201","article-title":"Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors","volume":"24","author":"Brown","year":"2019","journal-title":"Redox Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/978-3-319-17121-0_95","article-title":"Live Imaging of LysoTracker-Labelled Phagolysosomes Tracks Diurnal Phagocytosis of Photoreceptor Outer Segment Fragments in Rat RPE Tissue Ex Vivo","volume":"85","author":"Mao","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.bbamem.2007.12.014","article-title":"Structural and functional associations of apical junctions with cytoskeleton","volume":"1778","author":"Miyoshi","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1749-6632.2012.06613.x","article-title":"Tight junctions on the move: Molecular mechanisms for epithelial barrier regulation","volume":"1258","author":"Shen","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3","DOI":"10.5301\/EJO.2010.6049","article-title":"Blood-retinal barrier","volume":"21","author":"Bernardes","year":"2011","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrm2101","article-title":"Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer\u2019s amyloid beta-peptide","volume":"8","author":"Haass","year":"2007","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e3115","DOI":"10.1038\/cddis.2017.502","article-title":"Cooperation of Rel family members in regulating A\u03b21-40-mediated proinflammatory cytokine secretion by retinal pigment epithelial cells","volume":"8","author":"Huang","year":"2017","journal-title":"Cell. Death Dis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"538","DOI":"10.4103\/1673-5374.205083","article-title":"The complexities underlying age-related macular degeneration: Could amyloid beta play an important role?","volume":"12","author":"Lynn","year":"2017","journal-title":"Neural. Regen. Res."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/2\/114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:25:47Z","timestamp":1760160347000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/19\/2\/114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,18]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["md19020114"],"URL":"https:\/\/doi.org\/10.3390\/md19020114","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,18]]}}}