{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T18:02:43Z","timestamp":1787767363136,"version":"build-2784847793"},"reference-count":69,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["20K07075"],"award-info":[{"award-number":["20K07075"]}]},{"name":"JSPS KAKENHI","award":["22K08318"],"award-info":[{"award-number":["22K08318"]}]},{"name":"JSPS KAKENHI","award":["2021-YNG-002"],"award-info":[{"award-number":["2021-YNG-002"]}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","award":["20K07075"],"award-info":[{"award-number":["20K07075"]}],"id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","award":["22K08318"],"award-info":[{"award-number":["22K08318"]}],"id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016573","name":"Japan Association for Diabetes Education and Care","doi-asserted-by":"publisher","award":["2021-YNG-002"],"award-info":[{"award-number":["2021-YNG-002"]}],"id":[{"id":"10.13039\/100016573","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs\u2013RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe\u2212\/\u2212) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe\u2212\/\u2212 mice ex vivo. Although administration of SMTP-44D to Apoe\u2212\/\u2212 mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE,\u00a0cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe\u2212\/\u2212 mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe\u2212\/\u2212 mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.<\/jats:p>","DOI":"10.3390\/ijms24076505","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T02:30:20Z","timestamp":1680229820000},"page":"6505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["SMTP-44D Inhibits Atherosclerotic Plaque Formation in Apolipoprotein-E Null Mice Partly by Suppressing the AGEs-RAGE Axis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-7419","authenticated-orcid":false,"given":"Michishige","family":"Terasaki","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Shinagawa, Tokyo 142-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3935-8742","authenticated-orcid":false,"given":"Keita","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Department of Pharmacology, Toxicology and Therapeutics, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan"},{"name":"Pharmacological Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1734-0605","authenticated-orcid":false,"given":"Yusaku","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Anti-Glycation Research Section, Showa University School of Medicine, 1-5-8 Shinagawa, Tokyo 142-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Shinagawa, Tokyo 142-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9506-7571","authenticated-orcid":false,"given":"Takanori","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Shinagawa, Tokyo 142-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyasu","family":"Fukui","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, 1-5-8 Shinagawa, Tokyo 142-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3340-7312","authenticated-orcid":false,"given":"Keiji","family":"Hasumi","sequence":"additional","affiliation":[{"name":"TMS Co., Ltd., KeioFuchu1chome Bldg. 11F, 1-9 Fuchucho, Fuchu-shi, Tokyo 183-0055, Japan"},{"name":"Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-5-8 Fuchu-shi, Tokyo 183-8509, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-8598","authenticated-orcid":false,"given":"Yuichiro","family":"Higashimoto","sequence":"additional","affiliation":[{"name":"Department of Chemistry, 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