{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T06:00:08Z","timestamp":1771740008881,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["NRF-2022R1F1A1074560"],"award-info":[{"award-number":["NRF-2022R1F1A1074560"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002643","name":"Kwangwoon University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002643","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Korea Entrepreneurship Foundation","award":["20148427"],"award-info":[{"award-number":["20148427"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Spermidine (SPMD) is essential for numerous cellular functions and crucial for sustaining diverse biological activities. However, its antioxidant capabilities are relatively weak. In this study, we overcame this limitation by examining the antioxidant and cellular effects of ascorbic acid (AA)-conjugated spermidine (AA-SPMD) in human skin keratinocyte and fibroblast cells. AA-SPMD was successfully fabricated using an optimized design and synthetic approach, and its stability, antioxidant activity, cellular responses, and collagen I production were evaluated. In addition, we assessed the protective effects of AA-SPMD from hydrogen peroxide and UVA-induced oxidative damage in human skin cells. The AA-SPMD showed high stability under rigorous conditions and exhibited strong antioxidant activity. AA-SPMD showed no cytotoxic effect even at a concentration of 1 mM. In addition, it can increase the rate of cell proliferation and migration in skin cells without reducing the inhibition of human keratinocytes (HaCaT) and human dermal fibroblasts (HDF) at concentrations of 10 \u03bcM. Moreover, AA-SPMD can increase the amount of collagen I synthesized in HDF cells, thereby influencing cell proliferation and migration. Based on our in vitro study, AA-SPMD is expected to be more effective than AA or SPMD alone, indicating its potential utility in biomedical and cosmetic applications.<\/jats:p>","DOI":"10.3390\/molecules31040732","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T13:08:23Z","timestamp":1771592903000},"page":"732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Antioxidant and Cellular Activities of Functionalized Spermidine by Conjugating with Ascorbic Acid in Human Skin Cells"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0484-7845","authenticated-orcid":false,"given":"Ki Chang","family":"Nam","sequence":"first","affiliation":[{"name":"Department of Medical Engineering, Dongguk University College of Medicine, Goyang-si 10326, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wonchoul","family":"Park","sequence":"additional","affiliation":[{"name":"Institute of Technology, Capabioscience Co., Ltd., Seoul 01811, Republic of Korea"},{"name":"Institute of Technology, Biomax Co., Ltd., Guri-si 11901, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Jin","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Technology, Biomax Co., Ltd., Guri-si 11901, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bong Joo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Electrical & Biological Physics, Kwangwoon University, Seoul 01897, Republic of Korea"},{"name":"Institute of Biomaterials, Kwangwoon University, Seoul 01897, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14904","DOI":"10.1074\/jbc.R116.731661","article-title":"Functions of polyamines in mammals","volume":"291","author":"Pegg","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1016\/j.jid.2020.02.009","article-title":"The polyamine putrescine promotes human epidermal melanogenesis","volume":"140","author":"Sridharan","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1006\/bbrc.2000.2601","article-title":"Polyamines: Mysterious modulators of cellular functions","volume":"271","author":"Igarashi","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1146\/annurev.bi.53.070184.003533","article-title":"Polyamines","volume":"53","author":"Tabor","year":"1984","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.biocel.2009.07.009","article-title":"Modulation of cellular function by polyamines","volume":"42","author":"Igarashi","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41568-018-0050-3","article-title":"Polyamine metabolism and cancer: Treatments, challenges and opportunities","volume":"18","author":"Casero","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1080\/15548627.2018.1530929","article-title":"Spermidine: A physiology autophagy inducer acting as an anti-aging vitamin in humans?","volume":"15","author":"Bauera","year":"2019","journal-title":"Autophagy"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1079\/BJN19950087","article-title":"The importance of dietary polyamines in cell regeneration and growth","volume":"73","author":"Duguid","year":"1995","journal-title":"Br. J. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaan2788","DOI":"10.1126\/science.aan2788","article-title":"Spermidine in health and disease","volume":"359","author":"Madeo","year":"2018","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/nm.4222","article-title":"Cardioprotection and lifespan extension by the natural polyamine spermidine","volume":"22","author":"Eisenberg","year":"2016","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1007\/s10495-007-0758-0","article-title":"The mitochondrial pathway in yeast apoptosis","volume":"12","author":"Eisenberg","year":"2007","journal-title":"Apoptosis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/ncb1975","article-title":"Induction of autophagy by spermidine promotes longevity","volume":"11","author":"Eisenberg","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1158\/0008-5472.CAN-16-3462","article-title":"Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy","volume":"77","author":"Yue","year":"2017","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1038\/nn.3512","article-title":"Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner","volume":"16","author":"Gupta","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15024","DOI":"10.1073\/pnas.1206362109","article-title":"Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43","volume":"109","author":"Wang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1038\/cdd.2016.71","article-title":"Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages","volume":"23","author":"Yang","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ccell.2016.05.016","article-title":"Caloric restriction mimetics enhance anticancer immunosurveillance","volume":"30","author":"Pietrocola","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"91","DOI":"10.15698\/mic2015.03.195","article-title":"New roles for autophagy and spermidine in T cells","volume":"2","author":"Puleston","year":"2015","journal-title":"Microb. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e03706","DOI":"10.7554\/eLife.03706","article-title":"Autophagy is a critical regulator of memory CD8+ T cell formation","volume":"3","author":"Puleston","year":"2014","journal-title":"eLife"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.cell.2011.07.030","article-title":"Autophagy and aging","volume":"146","author":"Rubinsztein","year":"2011","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.arr.2016.04.009","article-title":"The crucial impact of lysosomes in aging and longevity","volume":"32","author":"Hughes","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"588","DOI":"10.15698\/mic2016.12.546","article-title":"Autophagy: Machinery and regulation","volume":"3","author":"Yin","year":"2016","journal-title":"Microb. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41598-018-36682-9","article-title":"Ascorbic acid encapsulated into negatively charged liposomes exhibits increased skin permeation, retention and enhances collagen synthesis by fibroblasts","volume":"9","author":"Nascimento","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12995","DOI":"10.1021\/bi0263210","article-title":"Vitamin C suppresses TNF alpha-induced NF kappa B activation by inhibiting I kappa B alpha phosphorylation","volume":"41","author":"Pedraza","year":"2002","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1111\/j.1524-4725.2005.31725","article-title":"Topical vitamin C: A useful agent for treating photoaging and other dermatologic conditions","volume":"31","author":"Farris","year":"2005","journal-title":"Dermatol. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s12272-011-0515-3","article-title":"Inhibition of UVA-mediated melanogenesis by ascorbic acid through modulation of antioxidant defense and nitric oxide system","volume":"34","author":"Panich","year":"2011","journal-title":"Arch. Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/jocd.12006","article-title":"Stability, transdermal penetration, and cutaneous effects of ascorbic acid and its derivatives","volume":"11","author":"Stamford","year":"2012","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_28","first-page":"1091","article-title":"Use of topical ascorbic acid and its effects on photo damaged skin topography","volume":"125","author":"Traikovich","year":"1999","journal-title":"Arch. Otorhinol. Head Neck Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0738-081X(95)00158-C","article-title":"Topical vitamin C in aging","volume":"14","author":"Colven","year":"1996","journal-title":"Clin. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4103\/2229-5178.110593","article-title":"Vitamin C in dermatology","volume":"4","author":"Telang","year":"2013","journal-title":"Indian. Dermatol. Online J."},{"key":"ref_31","first-page":"14","article-title":"Topical vitamin C and the skin: Mechanisms of action and clinical applications","volume":"10","author":"Chiang","year":"2017","journal-title":"J. Clin. Aesthet. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ravetti, S., Clemente, C., Brignone, S., Hergert, L., Allemandi, D., and Palma, S. (2019). Ascorbic acid in skin health. Cosmetics, 6.","DOI":"10.3390\/cosmetics6040058"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0039-9140(99)00243-X","article-title":"The use of stabilizers in the UV assay of ascorbic acid","volume":"51","author":"Kwakye","year":"2000","journal-title":"Talanta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/jssc.200700570","article-title":"Hydrophilic interaction liquid chromatography method for the determination of ascorbic acid","volume":"31","author":"Solich","year":"2008","journal-title":"J. Sep. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1742-4658.2006.05607.x","article-title":"Vitamin C. Biosynthesis, recycling and degradation in mammals","volume":"274","author":"Linster","year":"2007","journal-title":"FEBS J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"146416","DOI":"10.1016\/j.cej.2023.146416","article-title":"Spermidine-functionalized biomaterials to modulate implant-induced immune response and enhance wound healing","volume":"476","author":"Wang","year":"2023","journal-title":"Chem. Eng. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2310162","DOI":"10.1002\/advs.202310162","article-title":"Spermidine-functionalized injectable hydrogel reduces inflammation and enhances healing of acute and diabetic wounds in situ","volume":"11","author":"Wu","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_38","first-page":"299","article-title":"Spermidine-functionalized Janus hydrogel microneedles inhibit ferroptosis and promote healing of oral ulcers","volume":"60","author":"Yu","year":"2026","journal-title":"Bioact. Mater."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"22954","DOI":"10.1039\/C7RA02447A","article-title":"Surface spermidine functionalized PEGylated poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery","volume":"7","author":"Li","year":"2017","journal-title":"RSC Adv."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"37482","DOI":"10.1039\/D5RA03825A","article-title":"Progress in the design of ascorbic acid derivative-mediated drug delivery","volume":"15","author":"Lamie","year":"2025","journal-title":"RSC Adv."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S0731-7085(96)01904-8","article-title":"Stability of vitamin C derivatives in solution and topical formulations","volume":"15","author":"Austria","year":"1997","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4706418","DOI":"10.1155\/2020\/4706418","article-title":"Rinsing with L-ascorbic acid exhibits concentration-dependent effects on human gingival fibroblast in vitro wound healing behavior","volume":"2020","author":"Chaitrakoonthong","year":"2020","journal-title":"Int. J. Dent."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wei, Z.-X., Cai, L., Zhao, X.-M., Jiang, X.-R., and Li, X.-L. (2022). Effects of spermidine on cell proliferation, migration, and inflammatory response in porcine enterocytes. Front. Biosci., 27.","DOI":"10.31083\/j.fbl2706194"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12964-021-00717-y","article-title":"Systemic and topical administration of spermidine accelerates skin wound healing","volume":"19","author":"Ito","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.mattod.2014.01.019","article-title":"Molecular biomechanics of collagen molecules","volume":"17","author":"Chang","year":"2014","journal-title":"Mater. Today"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e33302","DOI":"10.1016\/j.heliyon.2024.e33302","article-title":"Gold nanoparticles coated with collagen-I and their wound healing activity in human skin fibroblast cells","volume":"10","author":"Poomrattanangoon","year":"2024","journal-title":"Heliyon"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Mathew-Steiner, S.S., Roy, S., and Sen, C.K. (2021). Collagen in wound healing. Bioengineering, 8.","DOI":"10.3390\/bioengineering8050063"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.addr.2003.08.002","article-title":"Collagens\u2014Structure, function, and biosynthesis","volume":"55","author":"Gelse","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1056\/NEJM199909023411006","article-title":"Cutaneous wound healing","volume":"341","author":"Singer","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"539","DOI":"10.5483\/BMBRep.2020.53.10.120","article-title":"Human collagen alpha-2 type I stimulates collagen synthesis, wound healing, and elastin production in normal human dermal fibroblasts (HDFs)","volume":"53","author":"Hwang","year":"2020","journal-title":"BMB Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.bbrc.2012.11.110","article-title":"Ascorbic acid enhances the expression of type 1 and type 4 collagen and SVCT2 in cultured human skin fibroblasts","volume":"430","author":"Kishimoto","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1016\/j.jid.2025.03.040","article-title":"Vitamin C promotes epidermal proliferation by promoting DNA demethylation of proliferation-related genes in human epidermal equivalents","volume":"145","author":"Sato","year":"2025","journal-title":"J. Investig. Dermatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1046\/j.1523-1747.2002.01717.x","article-title":"Vitamin C regulates keratinocyte viability, epidermal barrier, and basement membrane in vitro, and reduces wound contraction after grafting of cultured skin substitutes","volume":"118","author":"Boyce","year":"2002","journal-title":"J. Investig. Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1111\/1523-1747.ep12286468","article-title":"L-ascorbic acid inhibits UVA-induced lipid peroxidation and secretion of IL-1\u03b1 and IL-6 in cultured human keratinocytes in vitro","volume":"108","author":"Tebbe","year":"1997","journal-title":"J. Investig. Dermatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.saa.2005.10.013","article-title":"Measurements of UV-generated free radicals\/reactive oxygen species (ROS) in skin","volume":"63","author":"Herrling","year":"2006","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ejphar.2011.11.013","article-title":"Anti-oxidative and anti-aging activities of 2-O-\u03b1-glucopyranosyl-L-ascorbic acid on human dermal fibroblasts","volume":"674","author":"Taniguchi","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s00403-017-1729-0","article-title":"Comparison of protective effect of ascorbic acid on redox and endocannabinoid systems interactions in in vitro cultured human skin fibroblasts exposed to UV radiation and hydrogen peroxide","volume":"309","author":"Bielawska","year":"2017","journal-title":"Arch. Dermatol. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13578-021-00614-4","article-title":"Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1\/p62 expression","volume":"11","author":"Yuan","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1166\/jbn.2015.2031","article-title":"Photodynamic anticancer activities of multifunctional cobalt ferrite nanoparticles in various cancer cells","volume":"11","author":"Park","year":"2015","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"16890","DOI":"10.1021\/acsami.7b03870","article-title":"In situ forming and H2O2-releasing hydrogels for treatment of drug-resistant bacterial infections","volume":"9","author":"Lee","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Choi, K.H., Nam, K.C., Cho, G., Jung, J.S., and Park, B.J. (2018). Enhanced photodynamic anticancer activities of multifunctional magnetic nanoparticles (Fe3O4) conjugated with chlorin e6 and folic acid in prostate and breast cancer cells. 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