{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:13:01Z","timestamp":1791925981015,"version":"4.3.4"},"reference-count":166,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-SUMMIT-109"],"award-info":[{"award-number":["AS-SUMMIT-109"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001869","name":"Academia Sinica","doi-asserted-by":"publisher","award":["AS-KPQ-109-BioMed"],"award-info":[{"award-number":["AS-KPQ-109-BioMed"]}],"id":[{"id":"10.13039\/501100001869","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-0210-01-18-02"],"award-info":[{"award-number":["MOST 109-0210-01-18-02"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["109-M4565"],"award-info":[{"award-number":["109-M4565"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["109-07"],"award-info":[{"award-number":["109-07"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Advanced glycation end products (AGEs) are generated by nonenzymatic modifications of macromolecules (proteins, lipids, and nucleic acids) by saccharides (glucose, fructose, and pentose) via Maillard reaction. The formed AGE molecules can be catabolized and cleared by glyoxalase I and II in renal proximal tubular cells. AGE-related diseases include physiological aging, neurodegenerative\/neuroinflammatory diseases, diabetes mellitus (DM) and its complications, autoimmune\/rheumatic inflammatory diseases, bone-degenerative diseases, and chronic renal diseases. AGEs, by binding to receptors for AGE (RAGEs), alter innate and adaptive immune responses to induce inflammation and immunosuppression via the generation of proinflammatory cytokines, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI). These pathological molecules cause vascular endothelial\/smooth muscular\/connective tissue-cell and renal mesangial\/endothelial\/podocytic-cell damage in AGE-related diseases. In the present review, we first focus on the cellular and molecular bases of AGE\u2013RAGE axis signaling pathways in AGE-related diseases. Then, we discuss in detail the modes of action of newly discovered novel biomolecules and phytochemical compounds, such as Maillard reaction and AGE\u2013RAGE signaling inhibitors. These molecules are expected to become the new therapeutic strategies for patients with AGE-related diseases in addition to the traditional hypoglycemic and anti-hypertensive agents. We particularly emphasize the importance of \u201cmetabolic memory\u201d, the \u201cFrench paradox\u201d, and the pharmacokinetics and therapeutic dosing of the effective natural compounds associated with pharmacogenetics in the treatment of AGE-related diseases. Lastly, we propose prospective investigations for solving the enigmas in AGE-mediated pathological effects.<\/jats:p>","DOI":"10.3390\/molecules25235591","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T03:51:16Z","timestamp":1606535476000},"page":"5591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":286,"title":["The Development of Maillard Reaction, and Advanced Glycation End Product (AGE)-Receptor for AGE (RAGE) Signaling Inhibitors as Novel Therapeutic Strategies for Patients with AGE-Related Diseases"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3218-0689","authenticated-orcid":false,"given":"Chieh-Yu","family":"Shen","sequence":"first","affiliation":[{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4794-9438","authenticated-orcid":false,"given":"Cheng-Hsun","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Han","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4544-4620","authenticated-orcid":false,"given":"Ko-Jen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Min","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Chou","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4988-0400","authenticated-orcid":false,"given":"Chia-Li","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan"},{"name":"Department of Internal Medicine, Kaohsiung Medical University College of Medicine, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s10522-004-3189-0","article-title":"Glucose, glycation and aging","volume":"5","author":"Suji","year":"2004","journal-title":"Biogerontology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1093\/gerona\/glq074","article-title":"Does accumulation of advanced glycation end products contribute to the aging phenotype?","volume":"65","author":"Semba","year":"2010","journal-title":"J. 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