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However, the effects of eumelanin on oxidative stress, hyperglycemia and depression in diabetic mice have not been extensively studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our study employed an enzymatic approach to extract eumelanin from squid ink and characterized it using spectroscopic techniques. Remarkably, eumelanin extracted with alkaline\u2010neutral\u2010flavor protease (ANF) displayed superior inhibitory activity against <jats:italic>\u03b1<\/jats:italic>\u2010glucosidase and <jats:italic>\u03b1<\/jats:italic>\u2010amylase, while enhancing glucose utilization and hepatic glycogen synthesis in human hepatocellular carcinoma cell line (HepG2) insulin resistance model. Further evaluation of ANF in a T2DM ICR mouse model demonstrated its significant potential in alleviating hyperglycemia, reducing glycosylated serum protein levels, improving glucose tolerance and modulating total cholesterol and low\u2010density lipoprotein levels, as well as antioxidant indices at a dosage of 0.04\u2009g\u2009kg<jats:sup>\u22121<\/jats:sup>. Additionally, ANF exhibited positive effects on energy levels and reduced immobility time in antidepressant behavioral experiments. Moreover, ANF positively influenced the density and infiltration state of renal cells, while mitigating inflammatory enlargement and deformation of liver cells, without inducing any adverse effects in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Overall, these findings underscore the significant therapeutic potential of ANF in the treatment of T2DM and its associated complications. By augmenting lipid and glucose metabolism, mitigating oxidative stress and alleviating depression, ANF emerges as a promising candidate for multifaceted intervention. \u00a9 2023 Society of Chemical Industry.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jsfa.12986","type":"journal-article","created":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T04:37:03Z","timestamp":1694839023000},"page":"993-1007","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Therapeutic potential of enzymatically extracted eumelanin from squid ink in type 2 diabetes mellitus <scp>ICR<\/scp> mice: Multifaceted intervention against hyperglycemia, oxidative stress and depression"],"prefix":"10.1002","volume":"104","author":[{"given":"Wen","family":"Song","sequence":"first","affiliation":[{"name":"CAS and Shandong Province Key laboratory of Experimental Marine Biology, Center for Ocean Mega\u2010Science Institute of Oceanology, Chinese Academy of 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