{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:44:14Z","timestamp":1789422254677,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["JO 395\/3-1"],"award-info":[{"award-number":["JO 395\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D). Previously, we have shown that combination with anti-TCR\/anti-TNF-\u03b1 antibody-based therapy re-established normoglycemia and increased proteinic arginine-dimethylation in the spleen, yet not in the pancreas. High blood glucose is often associated with elevated formation of advanced glycation end-products (AGEs) which act via their receptor (RAGE). Both anti-TCR and anti-TNF-\u03b1 are inhibitors of RAGE. The aim of the present work was to investigate potential biochemical changes of anti-TCR\/anti-TNF-\u03b1 therapy in the LEW.1AR1-iddm rat. We determined by stable-isotope dilution gas chromatography-mass spectrometry (GC-MS) the content of free and proteinic AGEs and the N\u03b5-monomethylation of lysine (Lys) residues in proteins of pancreas, kidney, liver, spleen and lymph nodes of normoglycemic control (ngCo, n = 6), acute diabetic (acT1D, n = 6), chronic diabetic (chT1D, n = 4), and cured (cuT1D, n = 4) rats after anti-TCR\/anti-TNF-\u03b1 therapy. Analyzed biomarkers included Lys and its metabolites N\u03b5-carboxymethyl lysine (CML), furosine and N\u03b5-monomethyl lysine (MML). Other amino acids were also determined. Statistical methods including ANOVA, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to evaluate the effects. Most statistical differences between the study groups were observed for spleen, pancreas and kidney, with liver and lymph nodes showing no such differences. In the pancreas, the groups differed with respect to proteinic furosine (p = 0.0289) and free CML (p = 0.0023). In the kidneys, the groups differed with respect to proteinic furosine (p = 0.0076) and CML (p = 0.0270). In the spleen, group differences were found for proteinic furosine (p = 0.0114) and free furosine (p = 0.0368), as well as for proteinic CML (p = 0.0502) and proteinic MML (p = 0.0191). The acT1D rats had lower furosine, CML and MML levels in the spleen than the rats in all other groups. This observation corresponds to the lower citrullination levels previously measured in these rats. PCA revealed diametric associations between PC1 and PC2 for spleen (r = \u22120.8271, p &lt; 0.0001) compared to pancreas (r = 0.5805, p = 0.0073) and kidney (r = 0.8692, p &lt; 0.0001). These findings underscore the importance of the spleen in this animal model of human T1D. OPLS-DA showed that in total sixteen amino acids differed in the experimental groups.<\/jats:p>","DOI":"10.3390\/ijms23031541","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T05:26:17Z","timestamp":1643433977000},"page":"1541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Advanced Glycation End-Products (AGEs) of Lysine and Effects of Anti-TCR\/Anti-TNF-\u03b1 Antibody-Based Therapy in the LEW.1AR1-iddm Rat, an Animal Model of Human Type 1 Diabetes"],"prefix":"10.3390","volume":"23","author":[{"given":"Svetlana","family":"Baskal","sequence":"first","affiliation":[{"name":"Core Unit Proteomics, Institute of Toxicology, Hannover Medical School, 30623 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanos A.","family":"Tsikas","sequence":"additional","affiliation":[{"name":"Dean of Studies Office, Academic Controlling, Hannover Medical School, 30623 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0004-4866","authenticated-orcid":false,"given":"Olga","family":"Begou","sequence":"additional","affiliation":[{"name":"Laboratory of Analytical Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"},{"name":"Biomic_Auth, Centre for Bioanalysis and Omics, Centre for Interdisciplinary Research of Aristotle University of Thessaloniki, Innovation Area of Thessaloniki, 57001 Thermi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Bollenbach","sequence":"additional","affiliation":[{"name":"Core Unit Proteomics, Institute of Toxicology, Hannover Medical School, 30623 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigurd","family":"Lenzen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0176-972X","authenticated-orcid":false,"given":"Anne","family":"J\u00f6rns","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6320-0956","authenticated-orcid":false,"given":"Dimitrios","family":"Tsikas","sequence":"additional","affiliation":[{"name":"Core Unit Proteomics, Institute of Toxicology, Hannover Medical School, 30623 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00726-021-02984-y","article-title":"Post-translational modifications (PTM): Analytical approaches, signaling, physiology and pathophysiology-part I","volume":"53","author":"Tsikas","year":"2021","journal-title":"Amino Acids"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1042\/BCJ20160117","article-title":"Protein lysine methylation by seven-beta-strand methyltransferases","volume":"473","author":"Falnes","year":"2016","journal-title":"Biochem. 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