{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:59:53Z","timestamp":1791457193353,"version":"4.3.4"},"reference-count":117,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,5,25]],"date-time":"2018-05-25T00:00:00Z","timestamp":1527206400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>For years, clinical studies involving human volunteers and several known pre-clinical in vivo models (i.e., mice, guinea pigs) have demonstrated their reliability in evaluating the effectiveness of a number of depigmenting agents. Although these models have great advantages, they also suffer from several drawbacks, especially involving ethical issues regarding experimentation. At present, a new depigmenting model using zebrafish has been proposed and demonstrated. The application of this model for screening and studying the depigmenting activity of many bioactive compounds has been given great attention in genetics, medicinal chemistry and even the cosmetic industry. Depigmenting studies using this model have been recognized as noteworthy approaches to investigating the antimelanogenic activity of bioactive compounds in vivo. This article details the current knowledge of zebrafish pigmentation and its reliability as a model for the screening and development of depigmenting agents. Several methods to quantify the antimelanogenic activity of bioactive compounds in this model, such as phenotype-based screening, melanin content, tyrosinase inhibitory activity, other related proteins and transcription genes, are reviewed. Depigmenting activity of several bioactive compounds which have been reported towards this model are compared in terms of their molecular structure and possible mode of actions. This includes patented materials with regard to the application of zebrafish as a depigmenting model, in order to give an insight of its intellectual value. At the end of this article, some limitations are highlighted and several recommendations are suggested for improvement of future studies.<\/jats:p>","DOI":"10.3390\/medicina54030035","type":"journal-article","created":{"date-parts":[[2018,5,28]],"date-time":"2018-05-28T03:54:21Z","timestamp":1527479661000},"page":"35","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["A Zebrafish Embryo as an Animal Model for the Treatment of Hyperpigmentation in Cosmetic Dermatology Medicine"],"prefix":"10.3390","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2766-8986","authenticated-orcid":false,"given":"Ahmad Firdaus B.","family":"Lajis","sequence":"first","affiliation":[{"name":"Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia"},{"name":"Laboratory of Molecular Medicine, Institute of Bioscience, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia"},{"name":"Bioprocessing and Biomanufacturing Research Center, Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1152\/physrev.00044.2003","article-title":"Melanin pigmentation in mammalian skin and its hormonal regulation","volume":"84","author":"Slominski","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1034\/j.1600-0749.2003.00029.x","article-title":"Chemical and Instrumental Approaches to Treat Hyperpigmentation","volume":"16","author":"Briganti","year":"2003","journal-title":"Pigment Cell Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1271\/bbb.100878","article-title":"In vitro and in vivo melanogenesis inhibition by biochanin A from Trifolium pratense","volume":"75","author":"Lin","year":"2011","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2174\/2210289201405020011","article-title":"Depigmenting efficacy of commercially available skin-lightening creams: Comparative analysis and in vivo evaluation","volume":"5","author":"Mustafa","year":"2014","journal-title":"Open Conf. Proc. J."},{"key":"ref_5","first-page":"311","article-title":"Skin-whitening effects of Mediterranean herbal extracts by in vitro and in vivo models","volume":"63","author":"Rizza","year":"2012","journal-title":"J. Cosmet. Sci."},{"key":"ref_6","first-page":"259","article-title":"Depigmenting effects of gallic Acid: A novel skin lightening agent for hyperpigmentary skin diseases","volume":"39","author":"Wang","year":"2013","journal-title":"Int. Union Biochem. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lee, B., Moon, K.M., Kim, S.J., Kim, S.H., Kim, D.H., An, H.J., Jeong, J.W., Kim, Y.R., Son, S., and Kim, M.J. (2016). (Z)-5-(2,4-Dihydroxybenzylidene)thiazolidine-2,4-dione prevents UVB-induced melanogenesis and wrinkle formation through suppressing oxidative stress in HRM-2 hairless mice. Oxidtive Med. Cell. Longev., 2016.","DOI":"10.1155\/2016\/2761463"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1600-0749.2005.00246.x","article-title":"Changes in responses of UVB irradiated skin of brownish guinea pigs with aging","volume":"18","author":"Tobiishi","year":"2005","journal-title":"Pigment Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/j.1365-2443.2011.01498.x","article-title":"Cold exposure down-regulates zebrafish pigmentation","volume":"16","author":"Kulkeaw","year":"2011","journal-title":"Genes Cells"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R81","DOI":"10.1016\/j.cub.2014.11.013","article-title":"Review Zebrafish Stripes as a Model for Vertebrate Colour Pattern Formation","volume":"25","author":"Singh","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/j.1600-0749.2007.00365.x","article-title":"Zebrafish as a new model for phenotype-based screening of melanogenic regulatory compounds","volume":"20","author":"Choi","year":"2007","journal-title":"Pigment Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0167-4889(98)00176-1","article-title":"Effects of lithium on pigmentation in the embryonic zebrafish (Brachydanio rerio)","volume":"1449","author":"Jin","year":"1999","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00403-018-1804-1","article-title":"Skin depigmenting action of silkworm (Bombyx mori L.) droppings in zebrafish","volume":"310","author":"Lee","year":"2018","journal-title":"Arch. Dermatol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7995","DOI":"10.1038\/srep07995","article-title":"Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, Z., Ptak, D., Zhang, L., Walls, E.K., Zhong, W., and Leung, Y.F. (2012). Phenylthiourea specifically reduces zebrafish eye size. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040132"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1038\/sj.jid.5700710","article-title":"Cell death of melanophores in zebrafish trpm7 mutant embryos depends on melanin synthesis","volume":"127","author":"McNeill","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S99","DOI":"10.1016\/j.mod.2017.04.255","article-title":"Zebrafish nicastrin deficiency leads to a Tyrosinase-dependent depigmentation","volume":"145","author":"Hsu","year":"2017","journal-title":"Mech. Dev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wiznia, L.E., and Elbuluk, N. (2017). Differences in skin structure and function in ethnic populations. Dermatoanthropology of Ethnic Skin and Hair, Springer.","DOI":"10.1007\/978-3-319-53961-4_4"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1126\/science.1116238","article-title":"SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans","volume":"310","author":"Lamason","year":"2005","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1468-2494.2010.00616.x","article-title":"The melanogenesis and mechanisms of skin-lightening agents-existing and new approaches","volume":"33","author":"Gillbro","year":"2011","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1006\/dbio.2000.9840","article-title":"Genetic analysis of melanophore development in zebrafish embryos","volume":"225","author":"Kelsh","year":"2000","journal-title":"Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bin, B.-H., Bhin, J., Yang, S.H., Shin, M., Nam, Y.-J., Choi, D.-H., Shin, D.W., Lee, A.-Y., Hwang, D., and Cho, E.-G. (2015). Membrane-associated transporter protein (MATP) regulates melanosomal ph and influences tyrosinase activity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129273"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e97597","DOI":"10.15252\/embj.201797597","article-title":"STIM1 activation of adenylyl cyclase 6 connects Ca2+ and cAMP signaling during melanogenesis","volume":"37","author":"Motiani","year":"2018","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/cne.22171","article-title":"Characterization of two melanin-concentrating hormone genes in zebrafish reveals evolutionary and physiological links with the mammalian MCH system","volume":"517","author":"Berman","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S0888-7543(02)00037-X","article-title":"The structure and evolution of the melanocortin and MCH receptors in fish and mammals","volume":"81","author":"Logan","year":"2003","journal-title":"Genomics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/j.1600-0749.2006.00307.x","article-title":"Regulation of pigmentation in zebrafish melanophores","volume":"19","author":"Logan","year":"2006","journal-title":"Pigment Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1242\/dev.123.1.369","article-title":"Zebrafish pigmentation mutations and the processes of neural crest development","volume":"123","author":"Kelsh","year":"1996","journal-title":"Development"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/dvdy.20513","article-title":"Pigment cell distributions in different tissues of the zebrafish, with special reference to the striped pigment pattern","volume":"234","author":"Hirata","year":"2005","journal-title":"Dev. Dyn."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Neuhauss, S.C.F. (2010). Zebrafish vision: Structure and function of the zebrafish visual system. Fish Physiology: Zebrafish, Elsevier. [1st ed.].","DOI":"10.1016\/S1546-5098(10)02903-1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.devcel.2016.06.020","article-title":"Pigment cell progenitors in zebrafish remain multipotent through metamorphosis developmental cell article pigment cell progenitors in zebrafish remain multipotent through metamorphosis","volume":"38","author":"Singh","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7823541","DOI":"10.1155\/2016\/7823541","article-title":"Isolation of 4,5-O-dicaffeoylquinic acid as a pigmentation inhibitor occurring in Artemisia capillaris Thunberg and its validation in vivo","volume":"2016","author":"Tabassum","year":"2016","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"D\u2019Mello, S.A.N., Finlay, G.J., Baguley, B.C., and Askarian-Amiri, M.E. (2016). Signaling pathways in melanogenesis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071144"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1111\/j.1755-148X.2009.00614.x","article-title":"Pigmentary function and evolution of tyrp1 gene duplicates in fish","volume":"22","author":"Braasch","year":"2009","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7971","DOI":"10.1074\/jbc.M309714200","article-title":"Regulation of tyrosinase processing and trafficking by organellar pH and by proteasome activity","volume":"279","author":"Watabe","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/s004270000125","article-title":"Tyrosinase gene expression in zebrafish embryos","volume":"211","author":"Camp","year":"2001","journal-title":"Dev. Genes Evol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/pcmr.12568","article-title":"An ongoing role for Wnt signaling in differentiating melanocytes in vivo","volume":"30","author":"Vibert","year":"2016","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1017\/S0967199400002975","article-title":"Structure and macromolecular composition of the zebrafish egg chorion","volume":"4","author":"Bonsignorio","year":"1996","journal-title":"Zygote"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lee, J.-W., Na, D.-S., and Ju, B.-K. (2007). Zebrafish chorion as an extracellular matrix for cell culture. World Congress on Medical Physics and Biomedical Engineering 2006, Springer.","DOI":"10.1007\/978-3-540-36841-0_855"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.4014\/jmb.1505.05069","article-title":"Melanin Biosynthesis Inhibition Effects of Ginsenoside Rb2 Isolated from Panax ginseng Berry","volume":"25","author":"Lee","year":"2015","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lajis, A.F.B., Hamid, M., Ahmad, S., and Ariff, A. (2017). Lipase-catalyzed synthesis of kojic acid derivative in bioreactors and the analysis of its depigmenting and antioxidant activities. Cosmetics, 4.","DOI":"10.3390\/cosmetics4030022"},{"key":"ref_41","unstructured":"Huang, C.-C., and Monte, A.P. (2014). Skin Lightening Compounds. (WO2016014529A1), U.S. Patent."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.jgr.2017.03.005","article-title":"Melanogenesis inhibition activity of floralginsenoside A from Panax ginseng berry","volume":"41","author":"Lee","year":"2017","journal-title":"J. Ginseng Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.15616\/BSL.2017.23.1.8","article-title":"p-coumaric acid potently down-regulates zebrafish embryo pigmentation: Comparison of in vivo assay and computational molecular modeling with phenylthiourea","volume":"23","author":"Kim","year":"2017","journal-title":"Biomed. Sci. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"32854","DOI":"10.1038\/srep32854","article-title":"Extract of Ganoderma formosanum mycelium as a highly potent tyrosinase inhibitor","volume":"6","author":"Hsu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Guillot, R., Muriach, B., Rocha, A., Rotllant, J., Kelsh, R.N., and Cerd\u00e1-Reverter, J.M. (2016). Thyroid Hormones regulate zebrafish melanogenesis in a gender-specific manner. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166152"},{"key":"ref_46","unstructured":"Shang, J., Zhou, L., Wu, H., Zhou, J., Jin, Y., and Liao, S. (2017). Application of fluoxetine to treatment of depigmentation disease. (9,833,424), U.S. Patent."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1089\/zeb.2008.0541","article-title":"mc1r pathway regulation of zebrafish melanosome dispersion","volume":"5","author":"Richardson","year":"2008","journal-title":"Zebrafish"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1755-148X.2007.00420.x","article-title":"Mitf contributes to melanosome distribution and melanophore dendricity","volume":"21","author":"Kawasaki","year":"2008","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mueller, K.P., and Neuhauss, S.C.F. (2014). Sunscreen for Fish: Co-option of UV light protection for camouflage. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087372"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1039\/c0pp00199f","article-title":"Light-induced body color change in developing zebrafish","volume":"9","author":"Shiraki","year":"2010","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chaita, E., Lambrinidis, G., Cheimonidi, C., Agalou, A., Beis, D., Trougakos, I., Mikros, E., Skaltsounis, A.-L., and Aligiannis, N. (2017). Anti-melanogenic properties of greek plants. A novel depigmenting agent from Morus alba wood. Molecules, 22.","DOI":"10.3390\/molecules22040514"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.2147\/DDDT.S137550","article-title":"Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies","volume":"11","author":"Abbas","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/exd.12915","article-title":"Omeprazole inhibits melanin biosynthesis in melan-a cells and zebrafish","volume":"25","author":"Baek","year":"2016","journal-title":"Exp. Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chae, J.K., Subedi, L., Jeong, M., Park, Y.U., Kim, C.Y., Kim, H., and Kim, S.Y. (2017). Gomisin N Inhibits melanogenesis through regulating the PI3K\/Akt and MAPK\/ERK signaling pathways in melanocytes. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020471"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1111\/pcmr.12272","article-title":"A dominant mutation in tyrp1A leads to melanophore death in zebrafish","volume":"27","author":"Krauss","year":"2014","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_56","first-page":"1178","article-title":"The active component screening of Anoectochilus roxburghii and the functional study on inhibition of melanogenesis in zebrafish","volume":"39","author":"Xu","year":"2017","journal-title":"Yi Chuan"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"952452","DOI":"10.1155\/2012\/952452","article-title":"Depigmenting effect of kojic acid esters in hyperpigmented B16F1 melanoma cells","volume":"2012","author":"Lajis","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"965312","DOI":"10.1155\/2013\/965312","article-title":"Inhibitory effect of arctigenin from Fructus arctii extract on melanin synthesis via repression of tyrosinase expression","volume":"2013","author":"Park","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ishak, N., Lajis, A.F.B., Mohamad, R., Ariff, A.B., Mohamed, M.S., Halim, M., and Wasoh, H. (2018). Kinetics and optimization of lipophilic kojic acid derivative synthesis in polar aprotic solvent using lipozyme RMIM and its rheological study. Molecules, 23.","DOI":"10.3390\/molecules23020501"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.3390\/ijms12084819","article-title":"Evaluation of in vitro and in vivo depigmenting activity of raspberry ketone from Rheum officinale","volume":"12","author":"Lin","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_61","first-page":"31","article-title":"Zebrafish model based biological activity evaluation for melanin inhibition of Vc and Sodium erythorbate","volume":"27","author":"Chen","year":"2014","journal-title":"Shandong Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.saa.2016.06.008","article-title":"Inhibitory mechanisms of glabridin on tyrosinase","volume":"168","author":"Chen","year":"2016","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/exd.12765","article-title":"Sesamol decreases melanin biosynthesis in melanocyte cells and zebrafish: Possible involvement of MITF via the intracellular cAMP and p38\/JNK signalling pathways","volume":"24","author":"Baek","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00403-015-1543-5","article-title":"Melanogenesis inhibition of \u03b2-lapachone, a natural product from Tabebuia avellanedae, with effective in vivo lightening potency","volume":"307","author":"Kim","year":"2015","journal-title":"Arch. Dermatol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.3390\/md11061899","article-title":"The extract of Rhodobacter sphaeroides inhibits melanogenesis through the MEK\/ERK signaling pathway","volume":"11","author":"Liu","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_66","first-page":"31","article-title":"Inhibitor effect of flavonoid from Blumea balsamifera (L.) dc. leaves extract on melanin synthesis in cultured B16F10 cell line and zebrafish","volume":"5","author":"Thach","year":"2017","journal-title":"Eur. J. Res. Med. Sci."},{"key":"ref_67","first-page":"237","article-title":"Melanogenesis inhibition by a crude extract of Magnolia officinalis","volume":"5","author":"Ding","year":"2011","journal-title":"J. Med. Plants Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1016\/j.bmc.2017.09.021","article-title":"Potent anti-melanogenic activity and favorable toxicity profile of selected 4-phenyl hydroxycoumarins in the zebrafish model and the computational molecular modeling studies","volume":"25","author":"Davis","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm2258","article-title":"Melanosomes\u2014Dark organelles enlighten endosomal membrane transport","volume":"8","author":"Raposo","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1002\/dvdy.22743","article-title":"Embryonic expression of zebrafish MiT family genes tfe3b, tfeb, and tfec","volume":"240","author":"Lister","year":"2011","journal-title":"Dev. Dyn."},{"key":"ref_71","unstructured":"Hiu-Min, W., Chung-Yi, C., and Zhi-Hong, W. (2013). Compositiion for Inhibiting Melanogenesis and Use Thereof. (8455023B2), U.S. Patent."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/14756366.2016.1256882","article-title":"Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors","volume":"32","author":"Pillaiyar","year":"2017","journal-title":"J. Enzy. Inhib. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/j.1600-0625.2010.01161.x","article-title":"Identifying melanogenesis inhibitors from Cinnamomum subavenium with in vitro and in vivo screening systems by targeting the human tyrosinase","volume":"20","author":"Wang","year":"2011","journal-title":"Exp. Dermatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.bbrc.2017.07.008","article-title":"Inhibitory effect of 5-iodotubercidin on pigmentation","volume":"490","author":"Kim","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1248\/bpb.b15-00410","article-title":"Antimelanogenic Effects of Picrionoside A Isolated from the Leaves of Korean Ginseng","volume":"38","author":"Lee","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1038\/emm.2013.20","article-title":"Glyceollins, a novel class of soybean phytoalexins, inhibit SCF-induced melanogenesis through attenuation of SCF\/c-kit downstream signaling pathways","volume":"45","author":"Shin","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/sj.jid.5701177","article-title":"Downregulation of melanin synthesis by haginin a and its application to in vivo lightening model","volume":"128","author":"Kim","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"56868","DOI":"10.18632\/oncotarget.18097","article-title":"Oleoylethanolamide inhibits \u03b1-melanocyte stimulating hormone-stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16 melanoma cells","volume":"8","author":"Zhou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_79","unstructured":"Li, C., Zhu, X., and Zhu, F. (2013). Application of Suloctidil in Preparation of Cosmetics or Medicine. (Patent CN103181860A)."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.ydbio.2009.06.010","article-title":"Developmental Control Foxd3 controls melanophore specification in the zebrafish neural crest by regulation of Mitf","volume":"332","author":"Curran","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Santoriello, C., Gennaro, E., Anelli, V., Distel, M., Kelly, A., K\u00f6ster, R.W., Hurlstone, A., and Mione, M. (2010). Kita Driven expression of oncogenic HRAS leads to early onset and highly penetrant melanoma in zebrafish. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015170"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Seberg, H.E., Van Otterloo, E., Loftus, S.K., Liu, H., Bonde, G., Sompallae, R., Gildea, D.E., Santana, J.F., Manak, J.R., and Pavan, W.J. (2017). TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006636"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Van Otterloo, E., Li, W., Bonde, G., Day, K.M., Hsu, M.-Y., and Cornell, R.A. (2010). Differentiation of zebrafish melanophores depends on transcription factors AP2 Alpha and AP2 Epsilon. PLoS Genet, 6.","DOI":"10.1371\/journal.pgen.1001122"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"448","DOI":"10.4014\/jmb.1409.09033","article-title":"Whitening effect of octaphlorethol A isolated from Ishige foliacea in an in vivo zebrafish model","volume":"25","author":"Kim","year":"2015","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2306\/scienceasia1513-1874.2017.43.163","article-title":"Phenotype-based screening of selected mangrove methanolic crude extracts with anti-melanogenic activity using zebrafish (Danio rerio) as a model","volume":"43","author":"Andre","year":"2017","journal-title":"ScienceAsia"},{"key":"ref_86","unstructured":"Xue, H., Pan, Y., Xu, J.-J., Zhang, W., Yao, Li., and Li, X. (2017). One Kind Anoectochilus Extract and Its Preparation Method and Application. (Patent CN107308087A)."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Kim, M.K., Bang, C.Y., Kim, M.Y., Lee, J.-H., Ro, H., Choi, M.-S., Kim, D.-I., Jang, Y.P., and Choung, S.Y. (2016). Traditional herbal prescription LASAP-C inhibits melanin synthesis in B16F10 melanoma cells and zebrafish. BMC Complement. Altern. Med., 16.","DOI":"10.1186\/s12906-016-1209-7"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"144","DOI":"10.5021\/ad.2011.23.2.144","article-title":"Whitening Effects of Marine Pseudomonas Extract","volume":"23","author":"Kang","year":"2011","journal-title":"Ann. Dermatol."},{"key":"ref_89","first-page":"1005","article-title":"Alcohol extracts of Narcissus bulb inhibits melanogenesis in zebrafish embryos","volume":"25","author":"Zhang","year":"2017","journal-title":"Acta Lab. Anim. Sci. Sin."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/s41598-017-18720-0","article-title":"Tyrosinase-based TLC Autography for anti-melanogenic drug screening","volume":"8","author":"Hsu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"719","DOI":"10.4314\/tjpr.v13i5.10","article-title":"Methanol Partition Fraction of ethanol extract of discorea nipponica makino inhibits melanogenesis","volume":"13","author":"Ding","year":"2014","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_92","unstructured":"Chen, J., and Yu, X. (2015). A Skin-Whitening Ingredient Safety and Efficacy of the Detection Method. (Patent CN104977399B)."},{"key":"ref_93","unstructured":"Wen, Z.-H., Wu, P.-S., Liu, W.-S., Chang, F.-H., and Chen, T.-W. (2013). Method and System for Screening of a To-Be-Analyzed Candidate as a Skin-Whitening Agent. (8494269B2), U.S. Patent."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5228","DOI":"10.1021\/acs.jpcb.7b02914","article-title":"Predicting a drug\u2019s membrane permeability: A computational model validated with in vitro permeability assay data","volume":"121","author":"Bennion","year":"2017","journal-title":"J. Phys. Chem. B"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/nature07163","article-title":"Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes","volume":"454","author":"Setty","year":"2008","journal-title":"Nature"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.ydbio.2010.12.004","article-title":"Mitfa is required at multiple stages of melanocyte differentiation but not to establish the melanocyte stem cell","volume":"350","author":"Johnson","year":"2011","journal-title":"Dev. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"51640","DOI":"10.18632\/oncotarget.10540","article-title":"Effect of JNK inhibitor SP600125 on hair cell regeneration in zebrafish (Danio rerio) larvae","volume":"7","author":"He","year":"2016","journal-title":"Oncotarget"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1089\/zeb.2016.1261","article-title":"Screening of toxic effects of bisphenol A and products of its degradation: zebrafish (Danio rerio) embryo test and molecular docking","volume":"13","author":"Makarova","year":"2016","journal-title":"Zebrafish"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1152\/physiol.00043.2011","article-title":"Mechanisms of protein delivery to melanosomes in pigment cells","volume":"27","author":"Sitaram","year":"2012","journal-title":"Physiology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1111\/pcmr.12535","article-title":"Fluorescent quantification of melanin","volume":"29","author":"Fernandes","year":"2016","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1111\/pcmr.12140","article-title":"Raman spectroscopy as a non-invasive technique for the quantification of melanins in feathers and hairs","volume":"26","author":"Jorge","year":"2013","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"14343","DOI":"10.1038\/ncomms14343","article-title":"Microenvironment-derived factors driving metastatic plasticity in melanoma","volume":"8","author":"Kim","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s10811-010-9565-z","article-title":"Protective effect of Ecklonia cava on UVB-induced oxidative stress: In vitro and in vivo zebrafish model","volume":"23","author":"Ko","year":"2011","journal-title":"J. Appl. Phycol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1365-3164.2011.01009.x","article-title":"Protective effects of phlorotannins against ultraviolet B radiation in zebrafish (Danio rerio)","volume":"23","author":"Cha","year":"2012","journal-title":"Vet. Dermatol."},{"key":"ref_105","first-page":"508","article-title":"Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage","volume":"6","author":"Feng","year":"2013","journal-title":"Dis. Model. Mech."},{"key":"ref_106","first-page":"162","article-title":"Vertebrate melanophores as potential model for drug discovery and development: A review","volume":"16","author":"Saima","year":"2011","journal-title":"Cell Mol. Biol. Lett."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"14176","DOI":"10.1073\/pnas.93.24.14176","article-title":"Transgenic mice carrying the dominant rhodopsin mutation P347S: Evidence for defective vectorial transport of rhodopsin to the outer segments","volume":"93","author":"Li","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1210\/me.2011-0046","article-title":"TSH receptor function is required for normal thyroid differentiation in zebrafish","volume":"25","author":"Opitz","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/j.1346-8138.2010.00983.x","article-title":"Screening of marine algae for potential tyrosinase inhibitor: Those inhibitors reduced tyrosinase activity and melanin synthesis in zebrafish","volume":"38","author":"Cha","year":"2011","journal-title":"J. Dermatol."},{"key":"ref_110","first-page":"505","article-title":"Screening of medicinal herbs against melanin biosynthesis inhibition in vivo zebrafish model","volume":"11","author":"Baek","year":"2013","journal-title":"Korea J. Aesth. Cosmetol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jep.2014.04.016","article-title":"Assessment of Cuscuta chinensis seeds\u2019 effect on melanogenesis: Comparison of water and ethanol fractions in vitro and in vivo","volume":"154","author":"Wang","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1401279","DOI":"10.1155\/2017\/1401279","article-title":"Isolation and Characterization of Isofraxidin 7-O-(6\u2032-O-p-Coumaroyl)-\u03b2-glucopyranoside from Artemisia capillaries Thunberg: A Novel, Nontoxic Hyperpigmentation Agent That Is Effective In Vivo","volume":"2017","author":"Yim","year":"2017","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1755-148X.2012.00977.x","article-title":"Small molecule screening identifies targetable zebrafish pigmentation pathways","volume":"25","author":"Colanesi","year":"2012","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.abb.2014.07.033","article-title":"Targeting melanocyte and melanoma stem cells by 8-hydroxy-2-dipropylaminotetralin","volume":"563","author":"Bonchak","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Garcia-Jimenez, A., Teruel-Puche, J.A., Berna, J., Rodriguez-Lopez, J.N., Tudela, J., and Garcia-Canovas, F. (2017). Action of tyrosinase on alpha and beta-arbutin: A kinetic study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177330"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Azam, M.S., Choi, J., Lee, M.-S., and Kim, H.-R. (2017). Hypopigmenting Effects of Brown Algae-Derived Phytochemicals: A Review on Molecular Mechanisms. Mar. Drugs, 15.","DOI":"10.3390\/md15100297"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e32036","DOI":"10.7554\/eLife.32036","article-title":"A zebrafish and mouse model for selective pruritus via direct activation of TRPA1","volume":"7","author":"Esancy","year":"2018","journal-title":"Elife"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/54\/3\/35\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:06:01Z","timestamp":1760195161000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/54\/3\/35"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,25]]},"references-count":117,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["medicina54030035"],"URL":"https:\/\/doi.org\/10.3390\/medicina54030035","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,25]]}}}