{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:30:26Z","timestamp":1786365026891,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Skin ageing is associated with oxidative stress, mitochondrial dysfunction, extracellular matrix alterations, and impaired barrier function, supporting interest in antioxidant cosmeceuticals for mature skin. This study investigated the antioxidant activity of melatonin and N-acetylcysteine, the in vitro permeation of melatonin from different cream formulations, and their preliminary clinical performance in women aged 55\u201365 years. Antioxidant activity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2\u2032-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)\/Trolox equivalent antioxidant capacity (ABTS\/TEAC) assays. Melatonin permeation across Strat-M\u00ae membranes was evaluated using Franz diffusion cells and quantified by a validated high-performance liquid chromatography method coupled with a photodiode-array detection (HPLC-PDA) method. Clinical changes were assessed over 28 days using the Glogau wrinkle scale and a lower facial ptosis scale. N-acetylcysteine exhibited greater antioxidant activity than melatonin in the DPPH assay, with half-maximal inhibitory concentration (IC50) values of 5.96 \u00b1 1.02 and 530.11 \u00b1 48.63 \u00b5g\/mL, respectively. Melatonin permeation varied according to formulation composition, with cumulative amounts after 24 h ranging from 81.27 \u00b1 17.47 to 1043.48 \u00b1 33.43 \u00b5g\/cm2. Reductions in periocular wrinkle and lower facial ptosis scores were observed after 28 days. These preliminary findings support further investigation of melatonin\u2013N-acetylcysteine creams for mature skin. However, the present membrane model did not assess cutaneous retention, and the clinical observations require confirmation in larger, controlled studies.<\/jats:p>","DOI":"10.3390\/antiox15080991","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:09Z","timestamp":1786361889000},"page":"991","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A New Cosmeceutical Approach for Mature Skin: Antioxidant Activity, In Vitro Permeation, and Preliminary Clinical Efficacy of Melatonin\u2013N-Acetylcysteine Creams"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0749-8545","authenticated-orcid":false,"given":"Magdalena","family":"B\u00eersan","sequence":"first","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3346-3867","authenticated-orcid":false,"given":"Ruxandra","family":"\u0218tef\u0103nescu","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Phytotherapy, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38 Gheorghe Marinescu Street, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela-Lucia","family":"Muntean","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7751-2766","authenticated-orcid":false,"given":"Robert-Alexandru","family":"Vlad","sequence":"additional","affiliation":[{"name":"Pharmaceutical Technology and Cosmetology Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38th Gheorghe Marinescu Street, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3963-8376","authenticated-orcid":false,"given":"Alin-Viorel","family":"Foc\u0219a","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0202-5475","authenticated-orcid":false,"given":"Cristina-Elena","family":"Iancu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u0218adiye-Ioana","family":"Scripcariu","sequence":"additional","affiliation":[{"name":"Grigore T. Popa University of Medicine and Pharmacy Iasi, 16 Universitatii Street, 700115 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Ciurba","sequence":"additional","affiliation":[{"name":"Pharmaceutical Technology and Cosmetology Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38th Gheorghe Marinescu Street, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e70268","DOI":"10.1111\/exd.70268","article-title":"Interfollicular stem cells of human epidermis exhibit a distinct mechanical signature that deteriorates with aging","volume":"35","author":"Miny","year":"2026","journal-title":"Exp. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.jtv.2016.03.002","article-title":"Introduction to skin aging","volume":"26","author":"Tobin","year":"2017","journal-title":"J. Tissue Viability"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zheng, J., Wang, S., Sun, J., and Lv, J. (2026). Dermal fibroblast senescence: The central hub of skin aging\u2014From intrinsic dysfunction to microenvironmental remodeling. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27041653"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3390\/biom5020545","article-title":"Oxidative stress in aging human skin","volume":"5","author":"Rinnerthaler","year":"2015","journal-title":"Biomolecules"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Brown, A., Simonetto, C., and L\u00f3pez-Ot\u00edn, C. (2026). Homeodynamic rejuvenation: An adaptive framework for resetting skin aging. Front. Aging, 7.","DOI":"10.3389\/fragi.2026.1840035"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lephart, E.D., and Draelos, Z.D. (2026). Overview of aging, skin health, estrogen, menopause and HRT. Life, 16.","DOI":"10.3390\/life16030401"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1590\/abd1806-4841.20175697","article-title":"Antioxidants in dermatology","volume":"92","author":"Addor","year":"2017","journal-title":"An. Bras. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"D\u2019Orazi, G., Neroni, L., and Verdina, A. (2026). The oxidative stress: Origin and role in aging and diseases. Antioxidants, 15.","DOI":"10.3390\/antiox15050597"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/j.jid.2024.11.012","article-title":"Melatonin and the Skin: Current Progress and Perspectives for Human Health","volume":"145","author":"Slominski","year":"2025","journal-title":"J. Investig. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e72010","DOI":"10.1096\/fj.202600440RR","article-title":"Melatonin Accelerates Diabetic Wound Repair via Modulation of Tenascin C and Interleukin-10 in Fibroblasts","volume":"40","author":"Sun","year":"2026","journal-title":"FASEB J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s43440-025-00699-5","article-title":"Exploring Melatonin\u2019s Signalling Pathways in the Protection against Age-Related Skin Deterioration","volume":"77","author":"Taheri","year":"2025","journal-title":"Pharmacol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1210\/en.2014-1980","article-title":"N1-acetyl-5-methoxykynuramine (AMK) is produced in the human epidermis and shows antiproliferative effects","volume":"156","author":"Kim","year":"2015","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1080\/10715762.2018.1468564","article-title":"N-Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why","volume":"52","author":"Aldini","year":"2018","journal-title":"Free Radic. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1684\/ejd.2026.5048","article-title":"N-Acetylcysteine: Reinventing Classic Pharmacology through Skin","volume":"36","year":"2026","journal-title":"Eur. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Reiter, R.J., Rosales-Corral, S.A., Tan, D.X., Acuna-Castroviejo, D., Qin, L., Yang, S.F., and Xu, K. (2017). Melatonin, a full service anti-cancer agent: Inhibition of initiation, progression and metastasis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040843"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2174\/1567201052772915","article-title":"Transdermal drug delivery: Penetration enhancement techniques","volume":"2","author":"Benson","year":"2005","journal-title":"Curr. Drug Deliv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/nbt.1504","article-title":"Transdermal drug delivery","volume":"26","author":"Prausnitz","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schagen, S.K. (2017). Topical peptide treatments with effective anti-aging results. Cosmetics, 4.","DOI":"10.3390\/cosmetics4020016"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.31925\/farmacia.2020.1.15","article-title":"Evaluation of miconazole nitrate permeability through biological membrane from dermal systems","volume":"68","author":"Cristofor","year":"2020","journal-title":"Farmacia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"786","DOI":"10.37358\/RC.17.4.5553","article-title":"On the role of chemical and molecular biology in inflammation research","volume":"68","author":"Macovei","year":"2017","journal-title":"Rev. Chim."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"800","DOI":"10.31925\/farmacia.2020.5.5","article-title":"Compatibility study of four binary combinations of active ingredients for dermal film-forming systems","volume":"68","author":"Rusu","year":"2020","journal-title":"Farmacia"},{"key":"ref_22","first-page":"20","article-title":"The potential uses of N-acetylcysteine in dermatology: A review","volume":"12","author":"Janeczek","year":"2019","journal-title":"J. Clin. Aesthet. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"111161","DOI":"10.1016\/j.biopha.2020.111161","article-title":"Natural components in sunscreens: Topical formulations with sun protection factor (SPF)","volume":"134","author":"He","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e70306","DOI":"10.1111\/jocd.70306","article-title":"Application of Antioxidant Mixture Prevents Cutaneous \u201cOxinflammaging\u201d in Subjects Exposed to Particulate Matter","volume":"24","author":"Ivarsson","year":"2025","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_25","first-page":"228","article-title":"How best to halt and\/or revert UV-induced skin ageing: Strategies, facts and fiction","volume":"17","author":"Berneburg","year":"2008","journal-title":"Exp. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zosimidou, S.S., Vouvoudi, E.C., Tsagkalias, I.S., Lykidou, S.S., and Nikolaidis, N.F. (2023). Preparation of cosmetic emulsions containing Hippophae oil isolated by various methods: Study of their antioxidant, sun-blocking and physicochemical properties. Antioxidants, 12.","DOI":"10.3390\/antiox12101829"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ni\u0219ca, A., \u0218tef\u0103nescu, R., Steg\u0103ru\u0219, D.I., Mare, A.D., Farczadi, L., and T\u0103nase, C. (2021). Comparative study regarding the chemical composition and biological activity of pine bark extracts. Antioxidants, 10.","DOI":"10.3390\/antiox10020327"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ni\u0219ca, A., \u0218tef\u0103nescu, R., Steg\u0103ru\u0219, D.I., Mare, A.D., Farczadi, L., and T\u0103nase, C. (2021). Phytochemical profile and biological effects of spruce bark subjected to ultrasound-assisted and microwave-assisted extractions. Plants, 10.","DOI":"10.3390\/plants10050870"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/fft2.10","article-title":"Guidelines for antioxidant assays for food components","volume":"1","author":"Xiao","year":"2020","journal-title":"Food Front."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/0891-5849(89)90066-X","article-title":"The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide and hypochlorous acid","volume":"6","author":"Aruoma","year":"1989","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.2527\/jas.2006-835","article-title":"N-Acetylcysteine is a safe and effective precursor of cysteine","volume":"85","author":"Dilger","year":"2007","journal-title":"J. Anim. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"B\u00eersan, M., Gore, E., Scripcariu, \u0218.I., Vlad, R.A., Antonoaea, P., Pintea, C., Pintea, A., Cotoi, C.T., Foc\u0219a, A.V., and Ciurba, A. (2025). Multi-active cosmeceutical formulations: Stability, sensory performance and skin tolerability. Cosmetics, 12.","DOI":"10.3390\/cosmetics12050195"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"875","DOI":"10.31925\/farmacia.2024.4.16","article-title":"Texture analysis and comparative screening of the sensory properties of new skincare products","volume":"72","author":"Scripcariu","year":"2024","journal-title":"Farmacia"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Joseph, T.T., Schuch, V., Hossack, D.J., Chakraborty, R., and Johnson, E.L. (2024). Melatonin: The placental antioxidant and anti-inflammatory. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1339304"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2100378","DOI":"10.1002\/ardp.202100378","article-title":"Up-to-date studies regarding the determination of melatonin by chromatographic methods","volume":"355","author":"Alessa","year":"2022","journal-title":"Arch. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.jpha.2017.05.007","article-title":"Application of a validated HPLC-PDA method for the determination of melatonin content and its release from poly(lactic acid) nanoparticles","volume":"7","author":"Martins","year":"2017","journal-title":"J. Pharm. Anal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ejps.2014.11.002","article-title":"Prediction of skin permeation by chemical compounds using the artificial membrane Strat-MTM","volume":"67","author":"Uchida","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_38","first-page":"547","article-title":"Validation of a chromatographic method for miconazole assay from oral sustained-release mucoadhesive tablets","volume":"62","author":"Cojocaru","year":"2014","journal-title":"Farmacia"},{"key":"ref_39","first-page":"219","article-title":"Development of a rapid capillary zone electrophoresis method to quantify levofloxacin and meloxicam from transdermal therapeutic systems","volume":"64","author":"Rusu","year":"2019","journal-title":"Stud. Univ. Babe\u0219-Bolyai Chem."},{"key":"ref_40","unstructured":"(2026, June 11). Glogau Classification Scale. Available online: https:\/\/sfderm.com\/staff\/dr-richard-glogau\/."},{"key":"ref_41","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (2026, July 14). M10 Bioanalytical Method Validation and Study Sample Analysis: Guidance for Industry, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/m10-bioanalytical-method-validation-and-study-sample-analysis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2147\/CCID.S153905","article-title":"Antiaging efficacy of melatonin-based day and night creams: A randomized, split-face, assessor-blinded proof-of-concept trial","volume":"11","author":"Milani","year":"2018","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_43","first-page":"966","article-title":"Assessing the potential role for topical melatonin in an antiaging skin regimen","volume":"17","author":"Day","year":"2018","journal-title":"J. Drugs Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"245","DOI":"10.4161\/derm.22344","article-title":"Melatonin and human skin aging","volume":"4","author":"Fischer","year":"2012","journal-title":"Dermato-Endocrinology"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Greco, G., Di Lorenzo, R., Ricci, L., Di Serio, T., Vardaro, E., and Laneri, S. (2024). Clinical studies using topical melatonin. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105167"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"957","DOI":"10.4103\/idoj.idoj_992_24","article-title":"Melatonin in dermatology","volume":"16","author":"Relhan","year":"2025","journal-title":"Indian Dermatol. Online J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"652","DOI":"10.4103\/ijdvl.IJDVL_33_18","article-title":"N-acetylcysteine in dermatology","volume":"84","author":"Adil","year":"2018","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7563","DOI":"10.3390\/ijms15057563","article-title":"Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC\/Stat3 pathway","volume":"15","author":"Tsai","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Simon, J.A., Serrano, C., Kumar, D., Anaya, B.J., Bautista, L., Torrado-Salmer\u00f3n, C., and Serrano, D.R. (2025). Beyond Sleeping Disorders, the Role of Melatonin in Skin Diseases and Emerging Applications in Dermatology and Topical Therapy. Gels, 11.","DOI":"10.3390\/gels11110860"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/j.1525-1470.2011.01375.x","article-title":"Successful Treatment with Topical N-Acetylcysteine in Urea in Five Children with Congenital Lamellar Ichthyosis","volume":"28","author":"Bassotti","year":"2011","journal-title":"Pediatr. Dermatol."},{"key":"ref_51","first-page":"245","article-title":"Topical N-Acetylcysteine Treatment in Neonatal Ichthyosis","volume":"45","author":"Sarici","year":"2003","journal-title":"Turk. J. Pediatr."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"bcr2013008688","DOI":"10.1136\/bcr-2013-008688","article-title":"Successful experimental treatment of congenital ichthyosis in an infant","volume":"2013","author":"Deffenbacher","year":"2013","journal-title":"BMJ Case Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000078822","article-title":"Percutaneous penetration of topically applied melatonin in a cream and an alcoholic solution","volume":"17","author":"Fischer","year":"2004","journal-title":"Ski. Pharmacol. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jdermsci.2016.08.007","article-title":"Dose-dependent sun-protective effect of topical melatonin: A randomized, placebo-controlled, double-blind study","volume":"84","author":"Scheuer","year":"2016","journal-title":"J. Dermatol. Sci."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/991\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:52:30Z","timestamp":1786362750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/991"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":54,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["antiox15080991"],"URL":"https:\/\/doi.org\/10.3390\/antiox15080991","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}