{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:21:03Z","timestamp":1790659263293,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,30]],"date-time":"2017-05-30T00:00:00Z","timestamp":1496102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,30]],"date-time":"2017-05-30T00:00:00Z","timestamp":1496102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Oxidative stress is the major cause of skin aging that includes wrinkles, pigmentation, and weakened wound healing ability. Application of antioxidants in skin care is well accepted as an effective approach to delay the skin aging process. Methylene blue (MB), a traditional mitochondrial-targeting antioxidant, showed a potent ROS scavenging efficacy in cultured human skin fibroblasts derived from healthy donors and from patients with progeria, a genetic premature aging disease. In comparison with other widely used general and mitochondrial-targeting antioxidants, we found that MB was more effective in stimulating skin fibroblast proliferation and delaying cellular senescence. The skin irritation test, performed on an\n                    <jats:italic>in vitro<\/jats:italic>\n                    reconstructed 3D human skin model, indicated that MB was safe for long-term use, and did not cause irritation even at high concentrations. Application of MB to this 3D skin model further demonstrated that MB improved skin viability, promoted wound healing and increased skin hydration and dermis thickness. Gene expression analysis showed that MB treatment altered the expression of a subset of extracellular matrix proteins in the skin, including upregulation of elastin and collagen 2A1, two essential components for healthy skin. Altogether, our study suggests that MB has a great potential for skin care.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-02419-3","type":"journal-article","created":{"date-parts":[[2017,5,23]],"date-time":"2017-05-23T04:16:46Z","timestamp":1495513006000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Anti-Aging Potentials of Methylene Blue for Human Skin Longevity"],"prefix":"10.1038","volume":"7","author":[{"given":"Zheng-Mei","family":"Xiong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"O\u2019Donovan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Young","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,30]]},"reference":[{"key":"2419_CR1","doi-asserted-by":"publisher","unstructured":"Binic, I., Lazarevic, V., Ljubenovic, M., Mojsa, J. & Sokolovic, D. Skin ageing: natural weapons and strategies. Evid Based Complement Alternat Med. 827248, doi:10.1155\/2013\/827248 (2013).","DOI":"10.1155\/2013\/827248"},{"key":"2419_CR2","doi-asserted-by":"publisher","unstructured":"Jadoon, S. et al. Anti-Aging Potential of Phytoextract Loaded-Pharmaceutical Creams for Human Skin Cell Longetivity. Oxid Med Cell Longev 709628, doi:10.1155\/2015\/709628 (2015).","DOI":"10.1155\/2015\/709628"},{"key":"2419_CR3","first-page":"s12","volume":"7","author":"J Uitto","year":"2008","unstructured":"Uitto, J. The role of elastin and collagen in cutaneous aging: intrinsic aging versus photoexposure. J Drugs Dermatol \n                           7, s12\u201316 (2008).","journal-title":"J Drugs Dermatol"},{"key":"2419_CR4","doi-asserted-by":"publisher","unstructured":"Poljsak, B., Milisav, I., Lampe, T. & Ostan, I. Reproductive benefit of oxidative damage: an oxidative stress \u201cmalevolence\u201d? Oxid Med Cell Longev 760978, doi:10.1155\/2011\/760978 (2011).","DOI":"10.1155\/2011\/760978"},{"key":"2419_CR5","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3390\/biom5020545","volume":"5","author":"M Rinnerthaler","year":"2015","unstructured":"Rinnerthaler, M., Bischof, J., Streubel, M. K., Trost, A. & Richter, K. Oxidative stress in aging human skin. Biomolecules \n                           5, 545\u2013589, doi:10.3390\/biom5020545 (2015).","journal-title":"Biomolecules"},{"key":"2419_CR6","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.jdermsci.2010.03.003","volume":"58","author":"H Masaki","year":"2010","unstructured":"Masaki, H. Role of antioxidants in the skin: anti-aging effects. J Dermatol Sci. \n                           58, 85\u201390, doi:10.1016\/j.jdermsci.2010.03.003 (2010).","journal-title":"J Dermatol Sci."},{"issue":"2325","key":"2419_CR7","doi-asserted-by":"publisher","first-page":"e2327","DOI":"10.1016\/j.neurobiolaging.2010.12.012","volume":"32","author":"RH Schirmer","year":"2011","unstructured":"Schirmer, R. H., Adler, H., Pickhardt, M. & Mandelkow, E. Lest we forget you\u2013methylene blue\u2026. Neurobiol Aging \n                           32(2325), e2327\u20132316, doi:10.1016\/j.neurobiolaging.2010.12.012 (2011).","journal-title":"Neurobiol Aging"},{"key":"2419_CR8","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1592\/phco.30.7.702","volume":"30","author":"CA Paciullo","year":"2010","unstructured":"Paciullo, C. A., McMahon Horner, D., Hatton, K. W. & Flynn, J. D. Methylene blue for the treatment of septic shock. Pharmacotherapy \n                           30, 702\u2013715, doi:10.1592\/phco.30.7.702 (2010).","journal-title":"Pharmacotherapy"},{"issue":"Suppl 2","key":"2419_CR9","doi-asserted-by":"publisher","first-page":"S439","DOI":"10.3233\/JAD-2010-100414","volume":"20","author":"H Atamna","year":"2010","unstructured":"Atamna, H. & Kumar, R. Protective role of methylene blue in Alzheimer\u2019s disease via mitochondria and cytochrome c oxidase. J Alzheimers Dis. \n                           20(Suppl 2), S439\u2013452 (2010).","journal-title":"J Alzheimers Dis."},{"key":"2419_CR10","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1096\/fj.07-9610com","volume":"22","author":"H Atamna","year":"2008","unstructured":"Atamna, H. et al. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. Faseb j \n                           22, 703\u2013712, doi:10.1096\/fj.07-9610com (2008).","journal-title":"Faseb j"},{"key":"2419_CR11","doi-asserted-by":"publisher","first-page":"425","DOI":"10.18632\/aging.100038","volume":"1","author":"JJ Wu","year":"2009","unstructured":"Wu, J. J. et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Albany NY) \n                           1, 425\u2013437, doi:10.18632\/aging.100038 (2009).","journal-title":"Aging (Albany NY)"},{"key":"2419_CR12","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1080\/07391102.2004.10506960","volume":"21","author":"R Rohs","year":"2004","unstructured":"Rohs, R. & Sklenar, H. Methylene blue binding to DNA with alternating AT base sequence: minor groove binding is favored over intercalation. J Biomol Struct Dyn. \n                           21, 699\u2013711, doi:10.1080\/07391102.2004.10506960 (2004).","journal-title":"J Biomol Struct Dyn."},{"key":"2419_CR13","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1111\/acel.12434","volume":"15","author":"ZM Xiong","year":"2016","unstructured":"Xiong, Z. M. et al. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell \n                           15, 279\u2013290, doi:10.1111\/acel.12434 (2016).","journal-title":"Aging Cell"},{"key":"2419_CR14","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1111\/acel.12170","volume":"13","author":"DE Harrison","year":"2014","unstructured":"Harrison, D. E. et al. Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell \n                           13, 273\u2013282, doi:10.1111\/acel.12170 (2014).","journal-title":"Aging Cell"},{"key":"2419_CR15","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1054\/mehy.2000.1194","volume":"56","author":"MM Banaclocha","year":"2001","unstructured":"Banaclocha, M. M. Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases. Med Hypotheses \n                           56, 472\u2013477, doi:10.1054\/mehy.2000.1194 (2001).","journal-title":"Med Hypotheses"},{"key":"2419_CR16","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1111\/j.1749-6632.2010.05627.x","volume":"1201","author":"RA Smith","year":"2010","unstructured":"Smith, R. A. & Murphy, M. P. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci. \n                           1201, 96\u2013103, doi:10.1111\/j.1749-6632.2010.05627.x (2010).","journal-title":"Ann N Y Acad Sci."},{"key":"2419_CR17","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1016\/j.freeradbiomed.2011.06.033","volume":"51","author":"S Dikalov","year":"2011","unstructured":"Dikalov, S. Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med. \n                           51, 1289\u20131301, doi:10.1016\/j.freeradbiomed.2011.06.033 (2011).","journal-title":"Free Radic Biol Med."},{"key":"2419_CR18","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1016\/j.tiv.2013.08.006","volume":"27","author":"JW Casas","year":"2013","unstructured":"Casas, J. W. et al. In vitro human skin irritation test for evaluation of medical device extracts. Toxicology in vitro: an international journal published in association with BIBRA \n                           27, 2175\u20132183, doi:10.1016\/j.tiv.2013.08.006 (2013).","journal-title":"Toxicology in vitro: an international journal published in association with BIBRA"},{"key":"2419_CR19","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1038\/nrm2944","volume":"11","author":"CR Burtner","year":"2010","unstructured":"Burtner, C. R. & Kennedy, B. K. Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol. \n                           11, 567\u2013578, doi:10.1038\/nrm2944 (2010).","journal-title":"Nat Rev Mol Cell Biol."},{"key":"2419_CR20","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3233\/JAD-2007-12210","volume":"12","author":"PI Moreira","year":"2007","unstructured":"Moreira, P. I. et al. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis. \n                           12, 195\u2013206, doi:10.3233\/JAD-2007-12210 (2007).","journal-title":"J Alzheimers Dis."},{"key":"2419_CR21","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/cr.2011.55","volume":"21","author":"S Lee","year":"2011","unstructured":"Lee, S. et al. Mitochondrial H2O2 generated from electron transport chain complex I stimulates muscle differentiation. Cell Res. \n                           21, 817\u2013834, doi:10.1038\/cr.2011.55 (2011).","journal-title":"Cell Res."},{"key":"2419_CR22","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","volume":"53","author":"Q Ma","year":"2013","unstructured":"Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol \n                           53, 401\u2013426, doi:10.1146\/annurev-pharmtox-011112-140320 (2013).","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2419_CR23","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1016\/j.cell.2016.05.017","volume":"165","author":"N Kubben","year":"2016","unstructured":"Kubben, N. et al. Repression of the Antioxidant NRF2 Pathway in Premature. Aging. Cell \n                           165, 1361\u20131374, doi:10.1016\/j.cell.2016.05.017 (2016).","journal-title":"Aging. Cell"},{"key":"2419_CR24","doi-asserted-by":"publisher","first-page":"3716","DOI":"10.1093\/hmg\/ddu080","volume":"23","author":"C Stack","year":"2014","unstructured":"Stack, C. et al. Methylene blue upregulates Nrf2\/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet \n                           23, 3716\u20133732, doi:10.1093\/hmg\/ddu080 (2014).","journal-title":"Hum Mol Genet"},{"key":"2419_CR25","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1159\/000213172","volume":"36","author":"MC Branchet","year":"1990","unstructured":"Branchet, M. C., Boisnic, S., Frances, C. & Robert, A. M. Skin thickness changes in normal aging skin. Gerontology \n                           36, 28\u201335, doi:10.1159\/000213172 (1990).","journal-title":"Gerontology"},{"key":"2419_CR26","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1111\/j.0909-725X.2005.00151.x","volume":"11","author":"JM Waller","year":"2005","unstructured":"Waller, J. M. & Maibach, H. I. Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. Skin Res Technol \n                           11, 221\u2013235, doi:10.1111\/j.0909-725X.2005.00151.x (2005).","journal-title":"Skin Res Technol"},{"key":"2419_CR27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ijpharm.2012.06.005","volume":"435","author":"GK Menon","year":"2012","unstructured":"Menon, G. K., Cleary, G. W. & Lane, M. E. The structure and function of the stratum corneum. Int J Pharm \n                           435, 3\u20139, doi:10.1016\/j.ijpharm.2012.06.005 (2012).","journal-title":"Int J Pharm"},{"key":"2419_CR28","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1111\/1523-1747.ep12524316","volume":"75","author":"H Tagami","year":"1980","unstructured":"Tagami, H. et al. Evaluation of the skin surface hydration in vivo by electrical measurement. J Invest Dermatol \n                           75, 500\u2013507, doi:10.1111\/1523-1747.ep12524316 (1980).","journal-title":"J Invest Dermatol"},{"key":"2419_CR29","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1111\/1523-1747.ep12285424","volume":"86","author":"GC Sephel","year":"1986","unstructured":"Sephel, G. C. & Davidson, J. M. Elastin production in human skin fibroblast cultures and its decline with age. J Invest Dermatol \n                           86, 279\u2013285, doi:10.1111\/1523-1747.ep12285424 (1986).","journal-title":"J Invest Dermatol"},{"key":"2419_CR30","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3390\/pharmaceutics3010107","volume":"3","author":"KI Hulkower","year":"2011","unstructured":"Hulkower, K. I. & Herber, R. L. Cell migration and invasion assays as tools for drug discovery. Pharmaceutics \n                           3, 107\u2013124, doi:10.3390\/pharmaceutics3010107 (2011).","journal-title":"Pharmaceutics"},{"key":"2419_CR31","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s00268-003-7397-6","volume":"28","author":"A Gosain","year":"2004","unstructured":"Gosain, A. & DiPietro, L. A. Aging and wound healing. World J Surg. \n                           28, 321\u2013326, doi:10.1007\/s00268-003-7397-6 (2004).","journal-title":"World J Surg."},{"key":"2419_CR32","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nprot.2007.30","volume":"2","author":"CC Liang","year":"2007","unstructured":"Liang, C. C., Park, A. Y. & Guan, J. L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc \n                           2, 329\u2013333, doi:10.1038\/nprot.2007.30 (2007).","journal-title":"Nat Protoc"},{"key":"2419_CR33","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1083\/jcb.201110034","volume":"197","author":"Y Kageyama","year":"2012","unstructured":"Kageyama, Y. et al. Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage. J Cell Biol. \n                           197, 535\u2013551, doi:10.1083\/jcb.201110034 (2012).","journal-title":"J Cell Biol."},{"key":"2419_CR34","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1002\/biof.197","volume":"38","author":"H Atamna","year":"2012","unstructured":"Atamna, H., Mackey, J. & Dhahbi, J. M. Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction. Biofactors \n                           38, 158\u2013166, doi:10.1002\/biof.197 (2012).","journal-title":"Biofactors"},{"key":"2419_CR35","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.redox.2015.09.004","volume":"6","author":"H Atamna","year":"2015","unstructured":"Atamna, H., Atamna, W., Al-Eyd, G., Shanower, G. & Dhahbi, J. M. Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue. Redox Biol. \n                           6, 426\u2013435, doi:10.1016\/j.redox.2015.09.004 (2015).","journal-title":"Redox Biol."},{"key":"2419_CR36","doi-asserted-by":"publisher","first-page":"e0167454","DOI":"10.1371\/journal.pone.0167454","volume":"11","author":"H Zhang","year":"2016","unstructured":"Zhang, H. et al. Loss of H3K9me3 Correlates with ATM Activation and Histone H2AX Phosphorylation Deficiencies in Hutchinson-Gilford Progeria Syndrome. PLoS One \n                           11, e0167454, doi:10.1371\/journal.pone.0167454 (2016).","journal-title":"PLoS One"},{"key":"2419_CR37","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1111\/srt.12132","volume":"20","author":"E Boireau-Adamezyk","year":"2014","unstructured":"Boireau-Adamezyk, E., Baillet-Guffroy, A. & Stamatas, G. N. Age-dependent changes in stratum corneum barrier function. Skin Res Technol. \n                           20, 409\u2013415, doi:10.1111\/srt.12132 (2014).","journal-title":"Skin Res Technol."},{"key":"2419_CR38","doi-asserted-by":"publisher","first-page":"288","DOI":"10.18632\/aging.100550","volume":"5","author":"ZM Xiong","year":"2013","unstructured":"Xiong, Z. M., LaDana, C., Wu, D. & Cao, K. An inhibitory role of progerin in the gene induction network of adipocyte differentiation from iPS cells. Aging (Albany NY) \n                           5, 288\u2013303, doi:10.18632\/aging.v5i4 (2013).","journal-title":"Aging (Albany NY)"},{"key":"2419_CR39","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1111\/bjd.12131","volume":"168","author":"R Noordam","year":"2013","unstructured":"Noordam, R. et al. Serum insulin-like growth factor 1 and facial ageing: high levels associate with reduced skin wrinkling in a cross-sectional study. Br J Dermatol \n                           168, 533\u2013538, doi:10.1111\/bjd.12131 (2013).","journal-title":"Br J Dermatol"},{"key":"2419_CR40","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1210\/jcem-73-5-1081","volume":"73","author":"A Iranmanesh","year":"1991","unstructured":"Iranmanesh, A., Lizarralde, G. & Veldhuis, J. D. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab \n                           73, 1081\u20131088, doi:10.1210\/jcem-73-5-1081 (1991).","journal-title":"J Clin Endocrinol Metab"},{"key":"2419_CR41","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1002\/bdrc.21016","volume":"96","author":"JF Almine","year":"2012","unstructured":"Almine, J. F., Wise, S. G. & Weiss, A. S. Elastin signaling in wound repair. Birth Defects Res C Embryo Today \n                           96, 248\u2013257, doi:10.1002\/bdrc.21016 (2012).","journal-title":"Birth Defects Res C Embryo Today"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02419-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02419-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02419-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T23:37:50Z","timestamp":1671752270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02419-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,30]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["2419"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-02419-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,30]]},"assertion":[{"value":"16 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2475"}}