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The relevance of HHcy in clinical and experimental settings has led to the development of various analytical techniques with varying sensitivity and sample volume requirements. This study uses a fit-for-purpose, small-volume LC-MS\/MS workflow to quantify plasma homocysteine (Hcy), methionine (Met), and cysteine (Cys) in a diet-induced HHcy mouse model. Using these assays that overcome limitations imposed by sample availability in small animals, our study evaluated circulating levels of these amino acids in C57BL\/6 mice fed a HHcy-inducing diet rich in Met and lacking vitamins B6, B9, and B12. The increased Hcy and decreased Cys plasma concentrations observed in these mice correlated with decreased glutathione concentrations in brain homogenates and concomitant increase in the activity of the antioxidant enzyme Glutathione-S-Transferase and in the levels of the lipid peroxidation marker malondialdehyde. Overall, our work links plasma HHcy to the induction of brain oxidative stress, supporting the role of dietary modifications as complementary therapeutic strategies for neurodegenerative conditions.<\/jats:p>","DOI":"10.3390\/antiox15091162","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:24:33Z","timestamp":1789129473000},"page":"1162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diet-Induced Hyperhomocysteinemia in C57BL\/6 Mice: Simultaneous Evaluation of Plasma Homocysteine, Methionine, and Cysteine by LC-MS\/MS and Assessment of Associated Oxidative Stress in Brain Homogenates"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5517-2772","authenticated-orcid":false,"given":"Maria Luisa","family":"Valle","sequence":"first","affiliation":[{"name":"Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, 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