{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:19:44Z","timestamp":1791415184635,"version":"4.3.3"},"reference-count":30,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T00:00:00Z","timestamp":1643414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900753"],"award-info":[{"award-number":["81900753"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2021MH376"],"award-info":[{"award-number":["ZR2021MH376"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016694","name":"Science and Technology Development Plan of Shandong Province","doi-asserted-by":"publisher","award":["2017G006041"],"award-info":[{"award-number":["2017G006041"]}],"id":[{"id":"10.13039\/100016694","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Major special projects of the Ministry of science and technology","award":["2012ZX09303016-003"],"award-info":[{"award-number":["2012ZX09303016-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Low-grade inflammation is one of the characteristics of metabolic disorders induced by diabetes mellitus. The present study explores the underlying mechanism of milk fat globule epidermal growth factor 8 (MFG-E8) on necroptosis-induced intestinal inflammation and intestinal epithelial endocrine cell dysfunction in diabetes. Compared with the normal control group, pathological changes such as blunt and shortened villus and denuded villus tips were observed in ileum tissue of streptozotocin (STZ) induced senescence-resistant 1 (SAMR1) and senescence-accelerated prone 8 (SAMP8) diabetic mice under light microscope. Western blotting and immunohistochemistry (IHC) displayed significantly decreased protein expression of MFG-E8 in SAMR1 and SAMP8 diabetic mice, accompanied by an increased expression of phosphorylated mixed lineage kinase domain-like (p-MLKL) and HMGB1. In addition, advanced glycation end products (AGEs) significantly increased the pro-inflammatory mediators (TNF-\u03b1, IL-1\u03b2, IL-6) and HMGB1 by activating the receptor-interacting protein kinase 3 (RIPK3)\/MLKL signaling pathway in enteroendocrine STC-1 cells. D-pinitol pretreatment markedly attenuated the release of pro-inflammatory mediators and increased the expression of MFG-E8. MFG-E8 small interfering RNA (siRNA) promoted, while MFG-E8 overexpression inhibited, the activation of receptor-interacting proteins (RIPs) pathway and pro-inflammatory factors. Our study demonstrated that downregulation of MFG-E8 is an important phenomenon in the pathogenesis of diabetes-related intestinal inflammatory damage. MFG-E8 overexpression and D-pinitol intervention could protect against necroptosis-induced intestinal inflammation and maintain the function of enteroendocrine STC-1 cells in diabetes.<\/jats:p>","DOI":"10.3390\/nu14030604","type":"journal-article","created":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:12:56Z","timestamp":1643501576000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Protective Effect of MFG-E8 on Necroptosis-Induced Intestinal Inflammation and Enteroendocrine Cell Function in Diabetes"],"prefix":"10.3390","volume":"14","author":[{"given":"Xiaomin","family":"Hua","sequence":"first","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Department of Geriatric Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoying","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Jinan Aixinzhuoer Medical Laboratory, Jinan 250100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunli","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqing","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-122X","authenticated-orcid":false,"given":"Mei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17737","DOI":"10.3748\/wjg.v20.i47.17737","article-title":"Intestinal microbiota and type 2 diabetes: From mechanism insights to therapeutic perspective","volume":"20","author":"Han","year":"2014","journal-title":"World J. 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