{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T15:08:37Z","timestamp":1786201717889,"version":"build-2736575974"},"reference-count":53,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Endothelial dysfunction driven by senescent endothelial cells represents a pivotal mechanism underlying delayed wound healing in diabetic foot ulcers (DFU). Luteolin can enhance the angiogenesis of diabetic wounds, and improve cellular senescence. This study investigated its mechanism in DFU using advanced glycosylation end products (AGEs)\u2010treated HUVECs and streptozotocin (STZ) \u2010induced diabetic rats with surgical wounds. Integrin \u03b11 (ITGA1) was upregulated in wound tissues of diabetic patients and AGEs\u2010induced HUVECs. ITGA1 knockdown improved functional impairments and senescence in AGEs\u2010treated HUVECs, as demonstrated by the elevated abilities of proliferation, migration and tube\u2010formation, the decreased SA\u2010\u03b2\u2010galactosidase positive cells, and the reduced expression of senescence markers (P16, P21 and P53), where CCK\u20108, EdU, Transwell, and tube formation, and SA\u2010\u03b2\u2010galactosidase staining assay and Western blot were utilized. Luteolin significantly improved AGEs\u2010induced senescence and functional impairments of HUVECs, and accelerated wound healing in diabetic rats. Conversely, overexpression of ITGA1 abrogated these protective effects. Mechanistic studies revealed that Luteolin suppressed ITGA1 transcription by inhibiting lysine\u2010specific demethylase 4\u2009C (KDM4C)\u2010mediated demethylation of H3K9me3 at the ITGA1 promoter. Additionally, the epidermal growth factor receptor (EGFR)\/MEK\/ERK pathway was involved in Luteolin\u2032s therapeutic effects on DFU wound healing. In conclusion, Luteolin alleviated DFU through improving KDM4C\/ITGA1\u2010mediated functional impairments in AGEs\u2010induced senescent endothelial cell via the EGFR\/MEK\/ERK pathway, providing novel insights into the molecular mechanisms underlying Luteolin\u2032s therapeutic potential for DFU.<\/jats:p>","DOI":"10.1002\/jbt.70437","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T10:35:43Z","timestamp":1754649343000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Luteolin Alleviates Diabetic Foot Ulcers Through Improving KDM4C\/ITGA1\u2010mediated Functional Impairments of AGEs\u2010Induced Senescent Endothelial Cell"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8097-8027","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Vascular Surgery Shaanxi Provincial People\u2032s Hospital Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengxing","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Shaanxi Provincial People\u2032s Hospital Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1257-6684","authenticated-orcid":false,"given":"Feng","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery Shaanxi Provincial People\u2032s Hospital Xi\u2032an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.10578"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-021-01289-4"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12040542"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176660"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2024.1441196"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01725-2"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/burnst\/tkad010"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2022.147030"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118724"},{"issue":"3","key":"e_1_2_13_11_1","first-page":"311","article-title":"Inhibition of USP7 Suppresses Advanced Glycation End\u2010Induced Cell Cycle Arrest and Senescence of Human Umbilical Vein Endothelial Cells Through Ubiquitination of p53","volume":"54","author":"Li X.","year":"2022","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153437"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105939"},{"issue":"9","key":"e_1_2_13_14_1","first-page":"4145","article-title":"Luteolin Overcomes Acquired Resistance to Osimertinib in Non\u2010Small Cell Lung Cancer Cells by Targeting the HGF\u2010MET\u2010Akt Pathway","volume":"13","author":"Huang G.","year":"2023","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2021.05.019"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2FO03871D"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2018.11.034"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.03.073"},{"key":"e_1_2_13_19_1","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.2147\/DMSO.S450094","article-title":"Luteolin Alleviates Diabetic Nephropathy Fibrosis Involving AMPK\/NLRP3\/TGF\u2010\u03b2 Pathway[J]","volume":"17","author":"Huang R.","year":"2024","journal-title":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy"},{"key":"e_1_2_13_20_1","doi-asserted-by":"crossref","unstructured":"Y.Yang M.Zhou andH.LiuLuteolin an Aryl Hydrocarbon Receptor Antagonist Alleviates Diabetic Retinopathy by Regulating the NLRP\/NOX4 Signalling Pathway: Experimental and Molecular Docking study[J]. Physiol Int 2021.","DOI":"10.1556\/2060.2021.00148"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2021.104266"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9070761"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01193-5"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.4c04816"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09946-z"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03533-x"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-024-06109-4"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.615716"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30213"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.997880"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01476-06"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00892-09"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7135974"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0712239105"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114350"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.645200"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00765-3"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202012073"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2019.02.004"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-018-2215-z"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-14-0335"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-015-0669-5"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S372229"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0311922"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174317"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2010.10.016"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.201"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.4196\/kjpp.2021.25.4.297"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2014.29.2.265"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2022.01.013"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1350-9462(02)00043-5"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.031"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.12.008"},{"key":"e_1_2_13_54_1","doi-asserted-by":"crossref","unstructured":"J.Peng H.Zhu B.Ruan et al. miR\u2010155 Promotes m6A Modification of SOX2 mRNA Through Targeted Regulation of HIF\u20101\u03b1 And Delays Wound Healing in Diabetic Foot Ulcer In Vitro Models[J]. J Diabetes Investig 2024.","DOI":"10.1111\/jdi.14327"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70437","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbt.70437","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70437","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T18:55:45Z","timestamp":1776020145000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.70437"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":53,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/jbt.70437"],"URL":"https:\/\/doi.org\/10.1002\/jbt.70437","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2025-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70437"}}