{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:03:21Z","timestamp":1790744601348,"version":"4.1.0"},"reference-count":33,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:p>\n                    Diabetic foot ulceration (DFU) represents a common vascular complication of diabetes mellitus (DM) with high morbidity and disability resulting from amputation. Netrin-1 level was decreased in type 2 DM patients and has been identified as a protective regulator against diabetes-triggered myocardial infarction and nephropathy. Unfortunately, its role and molecular mechanism in DFU remain poorly elucidated. Here, netrin-1 levels were reduced in DM and DFU patients relative to healthy controls, with netrin-1 levels being the lowest in DFU patients. Moreover, exposure to high glucose (HG) also suppressed netrin-1 expression in human umbilical vein endothelial cells (HUVECs). Elevated netrin-1 expression by infection with Ad-netrin-1 adenovirus vector protected against HUVEC injury in response to HG by ameliorating the inhibitory effects on cell viability, lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, cell apoptotic rate and caspase-3 activity. Importantly, HG-impaired angiogenesis was improved after netrin-1 overexpression by elevating cell migration, capillary-like tube formation and VEGF production. Mechanism assay substantiated that netrin-1 elevation increased the phosphorylation levels of AKT and eNOS, and NO production, which was notably suppressed by HG, indicating that netrin-1 overexpression restored HG-triggered impairment of the PI3K\/AKT-eNOS pathway. More intriguingly, preconditioning with LY294002 (PI3K\/AKT antagonist) or\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>G<\/jats:sup>\n                    -monomethyl-\n                    <jats:sc>l<\/jats:sc>\n                    -arginine (eNOS inhibitor) antagonized netrin-1-induced activation of the PI3K\/AKT-eNOS pathway. Concomitantly, treatment with these antagonists also attenuated the protective role of netrin-1 in endothelial dysfunction upon HG stimulation. These results suggest that elevation of netrin-1 may restore HG-triggered impairment of HUVEC and angiogenesis by activating the PI3K\/AKT-eNOS pathway, indicating a potential agent for wound healing in DFU patients.\n                  <\/jats:p>","DOI":"10.1530\/jme-16-0239","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T20:31:18Z","timestamp":1488400278000},"page":"167-177","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":46,"title":["Netrin-1 restores cell injury and impaired angiogenesis in vascular endothelial cells upon high glucose by PI3K\/AKT-eNOS"],"prefix":"10.1530","volume":"58","author":[{"given":"Ying","family":"Xing","sequence":"first","affiliation":[{"name":"1Department of Endocrinology and Metabolism DiseaseXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingbo","family":"Lai","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism DiseaseXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism DiseaseXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism DiseaseXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ming","sequence":"additional","affiliation":[{"name":"1Department of Endocrinology and Metabolism DiseaseXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengxin","family":"Liu","sequence":"additional","affiliation":[{"name":"2Institute of Plastic and Reconstructive SurgeryXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[{"name":"2Institute of Plastic and Reconstructive SurgeryXijing Hospital, Forth Military Medical University, Xi\u2019an, Shaanxi, People\u2019s Republic of 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