{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:56:47Z","timestamp":1788415007032,"version":"build-2803163510"},"reference-count":83,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T00:00:00Z","timestamp":1579564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Dexamethasone (Dex) is a synthetic glucocorticoid (GC) drug commonly used clinically for the treatment of several inflammatory and immune-mediated diseases. Despite its broad range of indications, the long-term use of Dex is known to be associated with specific abnormalities in several tissues and organs. In this study, the metabolomic effects on five different organs induced by the chronic administration of Dex in the Sprague\u2013Dawley rat model were investigated using the chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS) platform, which targets the amine\/phenol submetabolomes. Compared to controls, a prolonged intake of Dex resulted in significant perturbations in the levels of 492, 442, 300, 186, and 105 metabolites in the brain, skeletal muscle, liver, kidney, and heart tissues, respectively. The positively identified metabolites were mapped to diverse molecular pathways in different organs. In the brain, perturbations in protein biosynthesis, amino acid metabolism, and monoamine neurotransmitter synthesis were identified, while in the heart, pyrimidine metabolism and branched amino acid biosynthesis were the most significantly impaired pathways. In the kidney, several amino acid pathways were dysregulated, which reflected impairments in several biological functions, including gluconeogenesis and ureagenesis. Beta-alanine metabolism and uridine homeostasis were profoundly affected in liver tissues, whereas alterations of glutathione, arginine, glutamine, and nitrogen metabolism pointed to the modulation of muscle metabolism and disturbances in energy production and muscle mass in skeletal muscle. The differential expression of multiple dipeptides was most significant in the liver (down-regulated), brain (up-regulation), and kidney tissues, but not in the heart or skeletal muscle tissues. The identification of clinically relevant pathways provides holistic insights into the tissue molecular responses induced by Dex and understanding of the underlying mechanisms associated with their side effects. Our data suggest a potential role for glutathione supplementation and dipeptide modulators as novel therapeutic interventions to mitigate the side effects induced by Dex therapy.<\/jats:p>","DOI":"10.3390\/metabo10020042","type":"journal-article","created":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T11:01:00Z","timestamp":1579863660000},"page":"42","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Dexamethasone-Induced Perturbations in Tissue Metabolomics Revealed by Chemical Isotope Labeling LC-MS Analysis"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-7052","authenticated-orcid":false,"given":"Lina","family":"Dahabiyeh","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer","family":"Malkawi","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrook Street West, Montr\u00e9al, QC H4B 1R6, Canada"},{"name":"Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center (KFSHRC), Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-8768","authenticated-orcid":false,"given":"Dilek","family":"Colak","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Mujamammi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Biochemistry Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Essa","family":"Sabi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Biochemistry Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9347-2108","authenticated-orcid":false,"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majed","family":"Dasouki","sequence":"additional","affiliation":[{"name":"Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-9424","authenticated-orcid":false,"given":"Anas","family":"Abdel Rahman","sequence":"additional","affiliation":[{"name":"Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"},{"name":"Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"},{"name":"Department of Chemistry, College of Medicine, Memorial University of Newfoundland, St. John\u2019s, NL A1B 3V6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"j1415","DOI":"10.1136\/bmj.j1415","article-title":"Short term use of oral corticosteroids and related harms among adults in the United States: Population based cohort study","volume":"357","author":"Waljee","year":"2017","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/qjmed\/93.2.105","article-title":"Use of oral corticosteroids in the United Kingdom","volume":"93","author":"Leufkens","year":"2000","journal-title":"QJM"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ncprheum0898","article-title":"Genomic and nongenomic effects of glucocorticoids","volume":"4","author":"Stahn","year":"2008","journal-title":"Nat. Clin. Pract. Rheumatol."},{"key":"ref_4","first-page":"1","article-title":"Genomic and non-genomic effects of glucocorticoids: Implications for breast cancer","volume":"8","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1196\/annals.1351.028","article-title":"Oral pulsed dexamethasone therapy in early rheumatoid arthritis: A pilot study","volume":"1069","author":"Kroot","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/j.1365-2249.2009.04010.x","article-title":"Mechanisms and clinical implications of glucocorticosteroids in the treatment of allergic rhinitis","volume":"158","author":"Okano","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.2147\/COPD.S172240","article-title":"Inhaled corticosteroids for chronic obstructive pulmonary disease: What is their role in therapy?","volume":"13","author":"Tashkin","year":"2018","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/978-1-4939-2895-8_14","article-title":"Glucocorticoids and Cancer","volume":"872","author":"Pufall","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Malkawi, A.K., Masood, A., Shinwari, Z., Jacob, M., Benabdelkamel, H., Matic, G., Almuhanna, F., Dasouki, M., Alaiya, A.A., and Rahman, A.M.A. (2019). Proteomic Analysis of Morphologically Changed Tissues after Prolonged Dexamethasone Treatment. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133122"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1097\/00004836-200110000-00006","article-title":"Side effects of corticosteroid therapy","volume":"33","author":"Buchman","year":"2001","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1016\/j.clinthera.2017.09.011","article-title":"Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review","volume":"39","author":"Rice","year":"2017","journal-title":"Clin. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1039\/C1AN15605E","article-title":"Modern analytical techniques in metabolomics analysis","volume":"137","author":"Zhang","year":"2012","journal-title":"Analyst"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/mas.21548","article-title":"Metabolomics toward personalized medicine","volume":"38","author":"Jacob","year":"2019","journal-title":"Mass Spectrom. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1021\/acs.jproteome.7b00750","article-title":"Tissue Level Diet and Sex-by-Diet Interactions Reveal Unique Metabolite and Clustering Profiles Using Untargeted Liquid Chromatography\u2013Mass Spectrometry on Adipose, Skeletal Muscle, and Liver Tissue in C57BL6\/J Mice","volume":"17","author":"Wells","year":"2018","journal-title":"J. Proteome Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1002\/mds.27173","article-title":"Profiling novel metabolic biomarkers for Parkinson\u2019s disease using in-depth metabolomic analysis","volume":"32","author":"Han","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.aca.2018.10.060","article-title":"Development of chemical isotope labeling LC-MS for tissue metabolomics and its application for brain and liver metabolome profiling in Alzheimer\u2019s disease mouse model","volume":"1050","author":"Wang","year":"2019","journal-title":"Anal. Chim Acta"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1021\/acs.chemrestox.8b00082","article-title":"A Study of NMR-Based Hepatic and Serum Metabolomics in a Liver Injury Sprague-Dawley Rat Model Induced by Psoralen","volume":"31","author":"Zhang","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Xia, T.S., Dong, X., Jiang, Y.P., Lin, L.Y., Dong, Z.M., Shen, Y., Xin, H.L., Zhang, Q.Y., and Qin, L.P. (2019). Metabolomics Profiling Reveals Rehmanniae Radix Preparata Extract Protects against Glucocorticoid-Induced Osteoporosis Mainly via Intervening Steroid Hormone Biosynthesis. Molecules, 24.","DOI":"10.3390\/molecules24020253"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1002\/bmc.3194","article-title":"Kidney tissue targeted metabolic profiling of glucocorticoid-induced osteoporosis and the proposed therapeutic effects of Rhizoma Drynariae studied using UHPLC\/MS\/MS","volume":"28","author":"Huang","year":"2014","journal-title":"Biomed. Chromatogr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1165\/rcmb.2012-0246OC","article-title":"Metabolomics Reveals Altered Metabolic Pathways in Experimental Asthma","volume":"48","author":"Ho","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.aca.2018.03.058","article-title":"A targeted metabolomics approach for clinical diagnosis of inborn errors of metabolism","volume":"1025","author":"Jacob","year":"2018","journal-title":"Anal. Chim Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3389\/fphar.2018.00046","article-title":"Metabolomics Based Profiling of Dexamethasone Side Effects in Rats","volume":"9","author":"Malkawi","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12108","DOI":"10.1021\/acs.analchem.9b03431","article-title":"Metabolomic Coverage of Chemical-Group-Submetabolome Analysis: Group Classification and Four-Channel Chemical Isotope Labeling LC-MS","volume":"91","author":"Zhao","year":"2019","journal-title":"Anal. Chem."},{"key":"ref_24","first-page":"36","article-title":"Mechanisms of Muscle Atrophy Induced by Glucocorticoids","volume":"72","author":"Schakman","year":"2009","journal-title":"Horm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/0014-4827(84)90354-9","article-title":"Induction of Acute Phase Proteins by Dexamethasone in Rat Hepatocyte Primary Cultures","volume":"151","author":"Gross","year":"1984","journal-title":"Exp. Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/00004728-197801000-00003","article-title":"Steroids and Apparent Cerebral Atrophy on Computed Tomography Scans","volume":"2","author":"Bentson","year":"1978","journal-title":"J. Comput. Assist. Tomogr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1539S","DOI":"10.1093\/jn\/137.6.1539S","article-title":"Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain","volume":"137","author":"Fernstrom","year":"2007","journal-title":"J. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1600-0447.1990.tb06443.x","article-title":"Suppressant Effects of Dexamethasone on the Availability of Plasma L-Tryptophan and Tyrosine in Healthy Controls and in Depressed-Patients","volume":"81","author":"Maes","year":"1990","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1007\/BF01965327","article-title":"Control of Catecholamine Release and Degradation by Glucocorticoids","volume":"28","author":"Parvez","year":"1972","journal-title":"Experientia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1111\/j.1471-4159.1981.tb10834.x","article-title":"Glucocorticoids Increase Tyrosine-Hydroxylase Activity in Cultured Murine Neuro-Blastoma","volume":"36","author":"Williams","year":"1981","journal-title":"J. Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1152\/physrev.1983.63.2.484","article-title":"Role of Precursor Availability in Control of Monoamine Biosynthesis in Brain","volume":"63","author":"Fernstrom","year":"1983","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15954","DOI":"10.1038\/srep15954","article-title":"Glucocorticoid (dexamethasone)-induced metabolome changes in healthy males suggest prediction of response and side effects","volume":"5","author":"Bordag","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s10863-014-9551-2","article-title":"Effects of methylglyoxal and pyridoxamine in rat brain mitochondria bioenergetics and oxidative status","volume":"46","author":"Cardoso","year":"2014","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s00018-005-5082-7","article-title":"Pyridoxamine as a multifunctional pharmaceutical: Targeting pathogenic glycation and oxidative damage","volume":"62","author":"Voziyan","year":"2005","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"880","DOI":"10.14336\/AD.2017.1121","article-title":"Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging","volume":"9","author":"Fournet","year":"2018","journal-title":"Aging Dis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"McBean, G.J. (2017). Cysteine, Glutathione, and Thiol Redox Balance in Astrocytes. Antioxidants, 6.","DOI":"10.3390\/antiox6030062"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1093\/nar\/gkv047","article-title":"Regulation of mammalian nucleotide metabolism and biosynthesis","volume":"43","author":"Lane","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1021\/cr0301144","article-title":"DNA and RNA synthesis: Antifolates","volume":"105","author":"Kompis","year":"2005","journal-title":"Chem. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1531S","DOI":"10.1093\/jn\/135.6.1531S","article-title":"Brain amino acid requirements and toxicity: The example of leucine","volume":"135","author":"Yudkoff","year":"2005","journal-title":"J. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1515\/CCLM.2007.342","article-title":"Differential expression of gamma-aminobutyric acid receptor A (GABA(A)) and effects of homocysteine","volume":"45","author":"Tyagi","year":"2007","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/B978-0-444-64057-4.00013-2","article-title":"Gamma-aminobutyric acid (GABA): Biosynthesis, role, commercial production, and application","volume":"Volume 57","author":"Rahman","year":"2018","journal-title":"Study in Natural Products Chemistry"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ngo, D.H., and Vo, T.S. (2019). An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid. Molecules, 24.","DOI":"10.3390\/molecules24152678"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.3892\/ijmm.2012.1154","article-title":"Inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt in spontaneously hypertensive rat hearts","volume":"30","author":"Lin","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1210\/en.2012-1563","article-title":"Dual Role for Glucocorticoids in Cardiomyocyte Hypertrophy and Apoptosis","volume":"153","author":"Ren","year":"2012","journal-title":"Endocrinology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/ajcn\/79.2.185","article-title":"Renal metabolism of amino acids: Its role in interorgan amino acid exchange","volume":"79","author":"Soeters","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2791S","DOI":"10.1093\/jn\/134.10.2791S","article-title":"Renal arginine metabolism","volume":"134","author":"Brosnan","year":"2004","journal-title":"J. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1590\/S0100-879X2003000200002","article-title":"Glutamine and glutamate as vital metabolites","volume":"36","author":"Newsholme","year":"2003","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Jacob, M., Gu, X., Luo, X., Al-Mousa, H., Arnaout, R., Al-Saud, B., Lopata, A.L., Li, L., Dasouki, M., and Rahman, A.M.A. (2019). Metabolomics Distinguishes DOCK8 Deficiency from Atopic Dermatitis: Towards a Biomarker Discovery. Metabolites, 9.","DOI":"10.3390\/metabo9110274"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1046\/j.1523-1755.1999.055003778.x","article-title":"Role of glutamine in human carbohydrate metabolism in kidney and other tissues","volume":"55","author":"Stumvoll","year":"1999","journal-title":"Kidney Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"R1444","DOI":"10.1152\/ajpregu.00294.2007","article-title":"Glucocorticoids increase salt appetite by promoting water and sodium excretion","volume":"293","author":"Thunhorst","year":"2007","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11010-016-2688-z","article-title":"Mitochondrial defects associated with beta-alanine toxicity: Relevance to hyper-beta-alaninemia","volume":"416","author":"Shetewy","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0925-4439(02)00067-4","article-title":"Beta-alanine protection against hypoxic liver injury in the rat","volume":"1587","author":"Vairetti","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1194\/jlr.M034249","article-title":"Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation","volume":"54","author":"Le","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"455","DOI":"10.2131\/jts.42.455","article-title":"Dexamethasone-induced hepatomegaly and steatosis in larval zebrafish","volume":"42","author":"Yin","year":"2017","journal-title":"J. Toxicol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7569127","DOI":"10.1155\/2018\/7569127","article-title":"L-Arginine Enhances Protein Synthesis by Phosphorylating mTOR (Thr 2446) in a Nitric Oxide-Dependent Manner in C2C12 Cells","volume":"2018","author":"Wang","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.biocel.2013.05.036","article-title":"Glucocorticoid-induced skeletal muscle atrophy","volume":"45","author":"Schakman","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.metabol.2006.05.009","article-title":"The effect of glutamine on prevention of glucocorticoid-induced skeletal muscle atrophy is associated with myostatin suppression","volume":"55","author":"Salehian","year":"2006","journal-title":"Metabolism"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/jn\/134.3.489","article-title":"Glutathione metabolism and its implications for health","volume":"134","author":"Wu","year":"2004","journal-title":"J. Nutr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4912","DOI":"10.1046\/j.1432-1327.2000.01597.x","article-title":"Glutathione metabolism in brain\u2014Metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species","volume":"267","author":"Dringen","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.afos.2015.07.008","article-title":"The effect of glucocorticoids on bone and muscle","volume":"1","author":"Klein","year":"2015","journal-title":"Osteoporos. Sarcopenia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1007\/s00726-015-2045-7","article-title":"Intrinsic carnosine metabolism in the human kidney","volume":"47","author":"Peters","year":"2015","journal-title":"Amino Acids"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/0005-2736(94)90201-1","article-title":"Taurine And Beta-Alanine Transport In An Established Human Kidney-Cell Line Derived From The Proximal Tubule","volume":"1194","author":"Jessen","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s10545-017-0099-2","article-title":"Carnosinase, diabetes mellitus and the potential relevance of carnosinase deficiency","volume":"41","author":"Peters","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6521","DOI":"10.1074\/jbc.M209764200","article-title":"Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase","volume":"278","author":"Teufel","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1002\/cmdc.200800433","article-title":"Design, Synthesis, and Evaluation of Carnosine Derivatives as Selective and Efficient Sequestering Agents of Cytotoxic Reactive Carbonyl Species","volume":"4","author":"Vistoli","year":"2009","journal-title":"Chemmedchem"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"C26","DOI":"10.1159\/000106509","article-title":"Antiglycation and antioxidant effect of carnosine against glucose degradation products in peritoneal mesothelial cells","volume":"107","author":"Alhamdani","year":"2007","journal-title":"Nephron Clin. Pract."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.regpep.2008.12.004","article-title":"Carnosine inhibits high glucose-induced mesangial cell proliferation through mediating cell cycle progression","volume":"154","author":"Jia","year":"2009","journal-title":"Regul. Pept."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4348973","DOI":"10.1155\/2019\/4348973","article-title":"Carnosine Protects Mouse Podocytes from High Glucose Induced Apoptosis through PI3K\/AKT and Nrf2 Pathways","volume":"2019","author":"Zhao","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.2337\/db07-0128","article-title":"A CTG polymorphism in the CNDP1 gene determines the secretion of serum carnosinase in cos-7-transfected cells","volume":"56","author":"Riedl","year":"2007","journal-title":"Diabetes"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"32","DOI":"10.4103\/0971-5916.193280","article-title":"Association of CTG repeat polymorphism in carnosine dipeptidase 1 (CNDP1) gene with diabetic nephropathy in north Indians","volume":"143","author":"Yadav","year":"2016","journal-title":"Indian J. Med. Res."},{"key":"ref_71","unstructured":"Peters, V., Yard, B., and Schmitt, C. (2019). Carnosine and diabetic nephropathy. Curr. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Rezzani, R., Favero, G., Ferroni, M., Lonati, C., and Moghadasian, M.H. (2019). A carnosine analog with therapeutic potentials in the treatment of disorders related to oxidative stress. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0215170"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1080\/14756366.2017.1355793","article-title":"Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift","volume":"32","author":"Peters","year":"2017","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/bph.14070","article-title":"FL-926-16, a novel bioavailable carnosinase-resistant carnosine derivative, prevents onset and stops progression of diabetic nephropathy in db\/db mice","volume":"175","author":"Iacobini","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1023\/A:1027360207238","article-title":"Imprinting effects of proline containing dipeptides (proline glycine, proline-leucine, proline-valine and their retro variants) in Tetrahymena. Evolutionary conclusions","volume":"17","author":"Csaba","year":"1997","journal-title":"Biosci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1007\/s11596-007-0513-3","article-title":"Preventive effects of nitroglycerine on glucocorticoid-induced osteoporosis in growing rats","volume":"27","author":"Li","year":"2007","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1021\/ac900166a","article-title":"Differential C-12\/C-13-Isotope Dansylation Labeling and Fast Liquid Chromatography\/Mass Spectrometry for Absolute and Relative Quantification of the Metabolome","volume":"81","author":"Guo","year":"2009","journal-title":"Anal. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"10723","DOI":"10.1021\/ac3025625","article-title":"Determination of Total Concentration of Chemically Labeled Metabolites as a Means of Metabolome Sample Normalization and Sample Loading Optimization in Mass Spectrometry-Based Metabolomics","volume":"84","author":"Wu","year":"2012","journal-title":"Anal. Chem"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4675","DOI":"10.1021\/ac5009089","article-title":"IsoMS: Automated Processing of LC-MS Data Generated by a Chemical Isotope Labeling Metabolomics Platform","volume":"86","author":"Zhou","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1021\/ac5039994","article-title":"Counting Missing Values in a Metabolite-Intensity Data Set for Measuring the Analytical Performance of a Metabolomics Platform","volume":"87","author":"Huan","year":"2015","journal-title":"Anal. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nprot.2011.319","article-title":"Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst","volume":"6","author":"Xia","year":"2011","journal-title":"Nat. Protoc."},{"key":"ref_82","first-page":"92","article-title":"Multivariate Analysis in Metabolomics","volume":"1","author":"Worley","year":"2013","journal-title":"Curr. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3401","DOI":"10.1021\/ac400099b","article-title":"MyCompoundID: Using an Evidence-Based Metabolome Library for Metabolite Identification","volume":"85","author":"Li","year":"2013","journal-title":"Anal. Chem."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/10\/2\/42\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:20:26Z","timestamp":1760361626000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/10\/2\/42"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,21]]},"references-count":83,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["metabo10020042"],"URL":"https:\/\/doi.org\/10.3390\/metabo10020042","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,21]]}}}