{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:37:58Z","timestamp":1780076278795,"version":"3.54.0"},"reference-count":108,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG054714"],"award-info":[{"award-number":["RF1AG054714"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG061296"],"award-info":[{"award-number":["RF1AG061296"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1AG069206"],"award-info":[{"award-number":["RO1AG069206"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG067331"],"award-info":[{"award-number":["R01AG067331"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>db\/db mice, which lack leptin receptors and exhibit hyperphagia, show disturbances in energy metabolism and are a model of obesity and type 2 diabetes. The geroneuroprotector drug candidate CMS121 has been shown to be effective in animal models of Alzheimer\u2019s disease and aging through the modulation of metabolism. Thus, the hypothesis was that CMS121 could protect db\/db mice from metabolic defects and thereby reduce liver inflammation and kidney damage. The mice were treated with CMS121 in their diet for 6 months. No changes were observed in food and oxygen consumption, body mass, or locomotor activity compared to control db\/db mice, but a 5% reduction in body weight was noted. Improved glucose tolerance and reduced HbA1c and insulin levels were also seen. Blood and liver triglycerides and free fatty acids decreased. Improved metabolism was supported by lower levels of fatty acid metabolites in the urine. Markers of liver inflammation, including NF-\u03baB, IL-18, caspase 3, and C reactive protein, were lowered by the CMS121 treatment. Urine markers of kidney damage were improved, as evidenced by lower urinary levels of NGAL, clusterin, and albumin. Urine metabolomics studies provided further evidence for kidney protection. Mitochondrial protein markers were elevated in db\/db mice, but CMS121 restored the renal levels of NDUFB8, UQCRC2, and VDAC. Overall, long-term CMS121 treatment alleviated metabolic imbalances, liver inflammation, and reduced markers of kidney damage. Thus, this study provides promising evidence for the potential therapeutic use of CMS121 in treating metabolic disorders.<\/jats:p>","DOI":"10.3390\/ijms24076828","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T05:21:23Z","timestamp":1680758483000},"page":"6828","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Geroprotective Drug Candidate CMS121 Alleviates Diabetes, Liver Inflammation, and Renal Damage in db\/db Leptin Receptor Deficient Mice"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1667-554X","authenticated-orcid":false,"given":"Saadia","family":"Zahid","sequence":"first","affiliation":[{"name":"Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA"},{"name":"Neurobiology Research Laboratory, Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8097-4611","authenticated-orcid":false,"given":"Alcir L.","family":"Dafre","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA"},{"name":"Biochemistry Department, Federal University of Santa Catarina, Florian\u00f3polis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4142-7054","authenticated-orcid":false,"given":"Antonio","family":"Currais","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingting","family":"Yu","sequence":"additional","affiliation":[{"name":"The Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Schubert","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-0610","authenticated-orcid":false,"given":"Pamela","family":"Maher","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","unstructured":"WHO World Health Organization (2023, January 05). 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