{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:13:09Z","timestamp":1790097189781,"version":"4.0.1"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005187","name":"National and Kapodistrian University of Athens","doi-asserted-by":"publisher","award":["SARG 70\/3\/16125"],"award-info":[{"award-number":["SARG 70\/3\/16125"]}],"id":[{"id":"10.13039\/501100005187","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SARG 70\/3\/16125"],"award-info":[{"award-number":["SARG 70\/3\/16125"]}],"id":[{"id":"https:\/\/ror.org\/04gnjpq42","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) not only improve glycemic control but also possess anti-inflammatory and antioxidant properties. In this study, the effects of semaglutide and liraglutide on oxidative stress and wound healing were examined in human dermal fibroblasts (NHDFs) and keratinocytes (NHEKs) under diabetes-mimicking conditions. Cells were exposed to high glucose and hydrogen peroxide, followed by treatment with semaglutide or liraglutide at concentrations of 22.5 and 45 pg\/mL for 48 h. We assessed cell viability, apoptosis, intracellular reactive oxygen species (ROS), Ki-67, and Pax-7. Advanced glycation end-products (AGEs) and their receptor (RAGE) were quantified via ELISA. Wound healing was evaluated by scratch assay, and the gene expression of antioxidants, cytokines, and matrix components was measured by real-time PCR. Semaglutide significantly improved NHDF viability and proliferation under diabetic conditions, reducing ROS production more effectively than liraglutide. Apoptosis decreased, evidenced by increased Bcl-2 alongside decreased Bax and cleaved caspase-3, particularly with semaglutide. Furthermore, semaglutide uniquely activated Pax-7 expression. While both agents upregulated antioxidants, semaglutide more effectively suppressed AGEs\/RAGE and inflammatory cytokines. Both drugs enhanced collagen expression and accelerated wound closure; however, semaglutide achieved near-complete healing within 48 h. Neither drug induced observable changes in NHEKs. Semaglutide exhibits strong antioxidative, cytoprotective, and pro-regenerative effects in diabetic NHDFs, outperforming liraglutide across multiple parameters. These findings highlight semaglutide\u2019s therapeutic potential for diabetic wound healing, warranting further in vivo investigation.<\/jats:p>","DOI":"10.3390\/ijms27156981","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:51:23Z","timestamp":1785772283000},"page":"6981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Semaglutide and Liraglutide Modulate Oxidative Stress and Wound Repair in Normal Human Skin Cells Exposed to an In Vitro Diabetic-like Environment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7560-0575","authenticated-orcid":false,"given":"Ioanna A.","family":"Anastasiou","sequence":"first","affiliation":[{"name":"1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, \u2018Laiko\u2019 General Hospital, 11527 Athens, Greece"},{"name":"Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Tentolouris","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4320-3388","authenticated-orcid":false,"given":"Athanasia","family":"Katsaouni","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-7905","authenticated-orcid":false,"given":"Panagiotis","family":"Sarantis","sequence":"additional","affiliation":[{"name":"Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iordanis","family":"Mourouzis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Rebelos","sequence":"additional","affiliation":[{"name":"1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, \u2018Laiko\u2019 General Hospital, 11527 Athens, Greece"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-2534","authenticated-orcid":false,"given":"Nikolaos","family":"Tentolouris","sequence":"additional","affiliation":[{"name":"1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, \u2018Laiko\u2019 General Hospital, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tegegne, B.A., Adugna, A., Yenet, A., Yihunie Belay, W., Yibeltal, Y., Dagne, A., Hibstu Teffera, Z., Amare, G.A., Abebaw, D., and Tewabe, H. (2024). A critical review on diabetes mellitus type 1 and type 2 management approaches: From lifestyle modification to current and novel targets and therapeutic agents. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1440456"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021","volume":"402","author":"Ong","year":"2023","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1056\/NEJMra1615439","article-title":"Diabetic Foot Ulcers and Their Recurrence","volume":"376","author":"Armstrong","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1080\/07853890.2016.1231932","article-title":"Global epidemiology of diabetic foot ulceration: A systematic review and meta-analysis\u2020","volume":"49","author":"Zhang","year":"2017","journal-title":"Ann. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/S0140-6736(05)67700-8","article-title":"Wound healing and its impairment in the diabetic foot","volume":"366","author":"Falanga","year":"2005","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1172\/JCI32169","article-title":"Cellular and molecular basis of wound healing in diabetes","volume":"117","author":"Brem","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.molmet.2019.09.010","article-title":"Glucagon-like peptide 1 (GLP-1)","volume":"30","author":"Finan","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3094642","DOI":"10.1155\/2016\/3094642","article-title":"Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control","volume":"2016","author":"Lee","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.tem.2009.11.007","article-title":"Insulin-like actions of glucagon-like peptide-1: A dual receptor hypothesis","volume":"21","author":"Tomas","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yamanouchi, D. (2025). The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review. Int. J. Mol. Sci., 27.","DOI":"10.20944\/preprints202511.1408.v2"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E1209","DOI":"10.1152\/ajpendo.00237.2004","article-title":"Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease","volume":"287","author":"Gutniak","year":"2004","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rroji, M., Spahia, N., Figurek, A., and Spasovski, G. (2025). Targeting Diabetic Atherosclerosis: The Role of GLP-1 Receptor Agonists, SGLT2 Inhibitors, and Nonsteroidal Mineralocorticoid Receptor Antagonists in Vascular Protection and Disease Modulation. Biomedicines, 13.","DOI":"10.3390\/biomedicines13030728"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1159\/000454919","article-title":"Skin Wound Healing: An Update on the Current Knowledge and Concepts","volume":"58","author":"Sorg","year":"2017","journal-title":"Eur. Surg. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1124\/jpet.111.191098","article-title":"The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob\/ob mice","volume":"342","author":"Linke","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, X., Tan, Y., Li, J., Sun, W., Wang, Y., and Zhang, Y. (2025). Treatment of diabetic wound based on hypoglycemic and antioxidant. Front. Bioeng. Biotechnol., 13.","DOI":"10.3389\/fbioe.2025.1706136"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107874","DOI":"10.1016\/j.burns.2026.107874","article-title":"The Adverse Effects of Persistent Wound Stress on Patients with Type 2 Diabetes-Part 1: Pathophysiological Mechanisms and Multi-Organ Impacts","volume":"52","author":"Chen","year":"2026","journal-title":"Burns"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Anastasiou, I.A., Tentolouris, A., Sarantis, P., Katsaouni, A., Rebelos, E., Mourouzis, I., Pantos, C., and Tentolouris, N. (2025). Semaglutide Enhances Cellular Regeneration in Skin and Retinal Cells In Vitro. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17091115"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1002\/stem.688","article-title":"Pax7 Expressing Cells Contribute to Dermal Wound Repair, Regulating Scar Size through a \u03b2-Catenin Mediated Process","volume":"29","author":"Glancy","year":"2011","journal-title":"Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"158","DOI":"10.4062\/biomolther.2016.034","article-title":"Hypericin, a Naphthodianthrone Derivative, Prevents Methylglyoxal-Induced Human Endothelial Cell Dysfunction","volume":"25","author":"Do","year":"2017","journal-title":"Biomol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e70406","DOI":"10.1002\/mco2.70406","article-title":"Diabetic Wound Repair: From Mechanism to Therapeutic Opportunities","volume":"6","author":"Wang","year":"2025","journal-title":"MedComm"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.2174\/0118715303369584241231141001","article-title":"Protective Effects of Hydrogen Treatment Against High Glucose-Induced Oxidative Stress and Apoptosis via Inhibition of the AGEs\/RAGE\/NF-\u03baB Signaling Pathway in Skin Cells","volume":"25","author":"Yu","year":"2025","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8852759","DOI":"10.1155\/2021\/8852759","article-title":"The Role of Oxidative Stress and Antioxidants in Diabetic Wound Healing","volume":"2021","author":"Deng","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1007\/s12020-025-04293-w","article-title":"GLP-1RA and the possible skin aging","volume":"89","author":"Paschou","year":"2025","journal-title":"Endocrine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Karimi, M.A., Gholami Chahkand, M.S., Dadkhah, P.A., Sheikhzadeh, F., Yaghoubi, S., Esmaeilpour Moallem, F., Deyhimi, M.S., Arab Bafrani, M., Shahrokhi, M., and Nasrollahizadeh, A. (2025). Comparative effectiveness of semaglutide versus liraglutide, dulaglutide or tirzepatide: A systematic review and meta-analysis. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1438318"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1001\/jama.2021.23619","article-title":"Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults with Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial","volume":"327","author":"Rubino","year":"2022","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Xuan, Y.H., Huang, B.B., Tian, H.S., Chi, L.S., Duan, Y.M., Wang, X., Zhu, Z.X., Cai, W.H., Zhu, Y.T., and Wei, T.M. (2014). High-glucose inhibits human fibroblast cell migration in wound healing via repression of bFGF-regulating JNK phosphorylation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108182"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"43","DOI":"10.2478\/afpuc-2024-0008","article-title":"Impact of Glucagon-like Peptide-1 Receptor Agonists on Intestinal Epithelial Cell Barrier","volume":"71","author":"Takizawa","year":"2024","journal-title":"Eur. Pharm. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1021\/acsmedchemlett.4c00303","article-title":"Novel Glucagon-like Peptide 1 Receptor Agonists for Treating Type II Diabetes","volume":"15","author":"Sabnis","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e23099","DOI":"10.1002\/jbt.23099","article-title":"Low concentrations of bisphenol A promote the activation of the mitochondrial apoptotic pathway on Beta-TC-6 cells via the generation of intracellular reactive oxygen species and mitochondrial superoxide","volume":"36","author":"Anastasiou","year":"2022","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1177\/15347346231212332","article-title":"Effects of Hypericin on Cultured Primary Normal Human Dermal Fibroblasts Under Increased Oxidative Stress","volume":"25","author":"Anastasiou","year":"2026","journal-title":"Int. J. Low. Extrem. Wounds"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e70036","DOI":"10.1002\/jbt.70036","article-title":"l-Securinine Induces ROS-Dependent Apoptosis on Pancreatic Cancer Cells via the PI3K\/AKT\/mTOR Signaling Pathway","volume":"38","author":"Anastasiou","year":"2024","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/978-1-60761-629-0_18","article-title":"Primer design for RT-PCR","volume":"630","author":"Li","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Letsiou, S., Kalliampakou, K., Gardikis, K., Mantecon, L., Infante, C., Chatzikonstantinou, M., Labrou, N.E., and Flemetakis, E. (2017). Skin protective effects of Nannochloropsis gaditana extract on H2O2-stressed human dermal fibroblasts. Front. Mar. Sci., 4.","DOI":"10.3389\/fmars.2017.00221"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cca.2007.07.003","article-title":"Actin, a reliable marker of internal control?","volume":"385","author":"Ruan","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115891","DOI":"10.1016\/j.taap.2022.115891","article-title":"Oleanolic acid-loaded nanoparticles attenuate activation of hepatic stellate cells via suppressing TGF-\u03b21 and oxidative stress in PM2.5-exposed hepatocytes","volume":"437","author":"Leilei","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Suarez-Arnedo, A., Torres Figueroa, F., Clavijo, C., Arbel\u00e1ez, P., Cruz, J.C., and Mu\u00f1oz-Camargo, C. (2020). An image J plugin for the high throughput image analysis of in vitro scratch wound healing assays. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232565"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6981\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:18:04Z","timestamp":1785921484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":36,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156981"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156981","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]}}}