{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:27:57Z","timestamp":1786426077740,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T00:00:00Z","timestamp":1786233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"General Program of Natural Science Foundation of Qinghai Province","award":["2022-ZJ-917"],"award-info":[{"award-number":["2022-ZJ-917"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Impaired endothelial function, excessive oxidative stress, and persistent bacterial infection collectively contribute to delayed healing of diabetic chronic wounds. Methylglyoxal (MGO)-induced metabolic stress is a critical driver of endothelial injury; however, effective multifunctional strategies capable of restoring vascular function and maintaining cellular homeostasis remain limited. In this study, the endothelial protective potential of an amphibian-derived Bowman\u2013Birk inhibitor (BBI)-type peptide, OSTI-1872, and its rationally designed structural analogues were investigated using an MGO-induced injury model in human umbilical vein endothelial cells (HUVECs). Among the tested peptides, the optimised analogue OSTI-2337 exhibited superior protective activity. OSTI-2337 markedly attenuated MGO-induced oxidative stress, restored nitric oxide bioavailability, enhanced VEGF expression, promoted endothelial migration and tube formation, and reduced oxidative DNA damage. Mechanistically, these effects were associated with coordinated regulation of MGO detoxification and redox homeostasis, as evidenced by enhanced GLO1 expression and modulation of the PI3K\/AKT\/GSK3\u03b2\/Nrf2 axis, accompanied by increased expression of downstream antioxidant proteins HO-1 and NQO1. In addition, OSTI-1872 and OSTI-2337 displayed antibacterial activity against representative bacterial strains, suggesting their potential advantages for complex diabetic wound environments. Collectively, these findings demonstrate that structural optimisation significantly enhances the biological activity of amphibian BBI-type peptides and identify OSTI-2337 as a multifunctional peptide candidate capable of integrating endothelial protection, MGO detoxification, redox regulation, and antibacterial activity for the management of diabetes-associated vascular injury and chronic wound complications.<\/jats:p>","DOI":"10.3390\/biom16081157","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:20:03Z","timestamp":1786324803000},"page":"1157","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Optimisation of an Amphibian BBI-Type Peptide Enhances Endothelial Protection Against Methylglyoxal-Induced Injury Through Coordinated Regulation of Glyoxalase-Mediated Detoxification and Redox Homeostasis"],"prefix":"10.3390","volume":"16","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[{"name":"Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi\u2019an 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Wu","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wudi","family":"Wang","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weichang","family":"Li","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenggang","family":"Yue","sequence":"additional","affiliation":[{"name":"Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi\u2019an 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengbang","family":"Ma","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8811-8489","authenticated-orcid":false,"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2576-0252","authenticated-orcid":false,"given":"Mei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F.","family":"Burrows","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8011-9260","authenticated-orcid":false,"given":"Tianbao","family":"Chen","sequence":"additional","affiliation":[{"name":"Natural Drug Discovery Group, School of Pharmacy, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanxing","family":"Xu","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s12933-020-01159-5","article-title":"Global Trend of Diabetes Mortality Attributed to Vascular Complications, 2000\u20132016","volume":"19","author":"Ling","year":"2020","journal-title":"Cardiovasc. 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