{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:19:33Z","timestamp":1790961573382,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"PROPG\/UNESP\/Brazil","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg\/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated \u03b2-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin\u2019s protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes.<\/jats:p>","DOI":"10.3390\/ijms26104652","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T06:40:23Z","timestamp":1747118423000},"page":"4652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Melatonin Improves Lipid Homeostasis, Mitochondrial Biogenesis, and Antioxidant Defenses in the Liver of Prediabetic Rats"],"prefix":"10.3390","volume":"26","author":[{"given":"Milena Cremer","family":"de Souza","sequence":"first","affiliation":[{"name":"Department of Parasitology, Immunology and General Pathology, State University of Londrina (UEL), Londrina 86057-970, Paran\u00e1, Brazil"},{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3988-9129","authenticated-orcid":false,"given":"Maria Luisa Gon\u00e7alves","family":"Agneis","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoliny Alves","family":"das Neves","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5867-6480","authenticated-orcid":false,"given":"Matheus Ribas","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5743-5182","authenticated-orcid":false,"given":"Ge\u00f3rgia da Silva","family":"Feltran","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2445-5598","authenticated-orcid":false,"given":"Ellen Mayara","family":"Souza Cruz","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Immunology and General Pathology, State University of Londrina (UEL), Londrina 86057-970, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9159-7313","authenticated-orcid":false,"given":"Jo\u00e3o Paulo Ferreira","family":"Schoffen","sequence":"additional","affiliation":[{"name":"Center of Biological Sciences, State University of Northern Paran\u00e1 (UENP), Bandeirantes 86360-000, Paran\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0199-3396","authenticated-orcid":false,"given":"Luiz Gustavo de Almeida","family":"Chuffa","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7461-8773","authenticated-orcid":false,"given":"F\u00e1bio Rodrigues Ferreira","family":"Seiva","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, S\u00e3o Paulo State University (UNESP), Botucatu 18618-693, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3390\/diabetology2020004","article-title":"Diabetes Mellitus: Insights from Epidemiology, Biochemistry, Risk Factors, Diagnosis, Complications and Comprehensive Management","volume":"2","author":"Alam","year":"2021","journal-title":"Diabetology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, Regional and Country-Level Diabetes Prevalence Estimates for 2021 and Projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","article-title":"Type 2 Diabetes Mellitus","volume":"1","author":"DeFronzo","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","unstructured":"World Health Organization (2024, March 01). Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia. Available online: https:\/\/www.who.int\/publications\/i\/item\/definition-and-diagnosis-of-diabetes-mellitus-and-intermediate-hyperglycaemia."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"(2014). American Diabetes Association Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 37, 81\u201390.","DOI":"10.2337\/dc14-S081"},{"key":"ref_6","unstructured":"Rosinger, A., Herrick, K., Gahche, J., and Park, S. (2024, March 01). Sugar-Sweetened Beverage Consumption Among U.S. Adults, 2011\u20132014; NCHS Data Brief No. 270, Available online: https:\/\/www.cdc.gov\/nchs\/products\/databriefs\/db270.htm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global Epidemiology and Pathogenesis","volume":"15","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1001\/jama.2023.4063","article-title":"Diagnosis and Management of Prediabetes: A Review","volume":"329","author":"Perreault","year":"2023","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3892\/mmr.2020.11175","article-title":"Diabetic-Induced Alterations in Hepatic Glucose and Lipid Metabolism: The Role of Type 1 and Type 2 Diabetes Mellitus (Review)","volume":"22","author":"Jiang","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41580-018-0092-0","article-title":"Mitochondrial Proteins: From Biogenesis to Functional Networks","volume":"20","author":"Pfanner","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4892","DOI":"10.1111\/jcmm.15194","article-title":"Mitochondrial Biogenesis: An Update","volume":"24","author":"Popov","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, L., Li, Y., Chen, G., and Chen, Q. (2023). Crosstalk between Mitochondrial Biogenesis and Mitophagy to Maintain Mitochondrial Homeostasis. J. Biomed. Sci., 30.","DOI":"10.1186\/s12929-023-00975-7"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41392-023-01547-9","article-title":"Mitochondrial Dynamics in Health and Disease: Mechanisms and Potential Targets","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.redox.2017.01.013","article-title":"Mitochondrial Dynamics in Type 2 Diabetes: Pathophysiological Implications","volume":"11","author":"Rocha","year":"2017","journal-title":"Redox Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Veluthakal, R., Esparza, D., Hoolachan, J.M., Balakrishnan, R., Ahn, M., Oh, E., Jayasena, C.S., and Thurmond, D.C. (2024). Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031504"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s10557-021-07250-7","article-title":"Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia\u2013Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis","volume":"37","author":"Maneechote","year":"2023","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4093\/dmj.2024.0796","article-title":"Overcoming \u03b2-Cell Dysfunction in Type 2 Diabetes Mellitus: CD36 Inhibition and Antioxidant System","volume":"49","author":"Park","year":"2025","journal-title":"Diabetes Metab. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18886","DOI":"10.3390\/molecules201018886","article-title":"Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism","volume":"20","author":"Tan","year":"2015","journal-title":"Molecules"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Souza Cruz, E.M., Bitencourt de Morais, J.M., Dalto da Rosa, C.V., da Silva Sim\u00f5es, M., Comar, J.F., de Almeida Chuffa, L.G., and Seiva, F.R.F. (2020). Long-Term Sucrose Solution Consumption Causes Metabolic Alterations and Affects Hepatic Oxidative Stress in Wistar Rats. Biol. Open, 9.","DOI":"10.1242\/bio.047282"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119048","DOI":"10.1016\/j.lfs.2021.119048","article-title":"Pterostilbene Influences Glycemia and Lipidemia and Enhances Antioxidant Status in the Liver of Rats That Consumed Sucrose Solution","volume":"269","author":"Cruz","year":"2021","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.biochi.2022.01.001","article-title":"Diabetes Mellitus and Melatonin: Where Are We?","volume":"202","author":"Patel","year":"2022","journal-title":"Biochimie"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/jpi.12360","article-title":"Melatonin as an Antioxidant: Under Promises but over Delivers","volume":"61","author":"Reiter","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1111\/j.1600-079X.2009.00720.x","article-title":"Melatonin Ameliorates High Fat Diet-Induced Diabetes and Stimulates Glycogen Synthesis via a PKCzeta-Akt-GSK3beta Pathway in Hepatic Cells","volume":"47","author":"Shieh","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12472","DOI":"10.1111\/jpi.12472","article-title":"Melatonin Increases Brown Adipose Tissue Mass and Function in Z\u00fccker Diabetic Fatty Rats: Implications for Obesity Control","volume":"64","author":"Reiter","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_25","first-page":"274","article-title":"Effect of Melatonin on Serum Glucose and Body Weights in Strptozotocin Induced Diabetes in Albino Rats","volume":"27","author":"Hidayat","year":"2015","journal-title":"J. Ayub Med. Coll. Abbottabad"},{"key":"ref_26","first-page":"453","article-title":"The Effect of Melatonin against Gastric Oxidative Stress and Dyslipidemia in Streptozotocin-Induced Diabetic Rats","volume":"14","author":"Hadjzadeh","year":"2018","journal-title":"Acta Endocrinol."},{"key":"ref_27","first-page":"117","article-title":"A Study on Effect of Melatonin in Dyslipidemia Caused by Experimentally Diabetes","volume":"21","author":"Keskin","year":"2019","journal-title":"Turk. J. Sport Exerc."},{"key":"ref_28","first-page":"524","article-title":"Modulation of Antioxidant Status, Carbohydrate and Lipid Metabolism by Melatonin on Streptozotocin Induced Diabetic Rats","volume":"4","author":"Mirunalini","year":"2012","journal-title":"J. Biochem. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41574-021-00627-6","article-title":"The Role of Sugar-Sweetened Beverages in the Global Epidemics of Obesity and Chronic Diseases","volume":"18","author":"Malik","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1159\/000320417","article-title":"The Effect of Sugar-Sweetened Beverage Intake on Energy Intake in an Ad Libitum 6-Month Low-Fat High-Carbohydrate Diet","volume":"57","author":"Munsters","year":"2010","journal-title":"Ann. Nutr. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/sj.ijo.0801229","article-title":"Liquid versus Solid Carbohydrate: Effects on Food Intake and Body Weight","volume":"24","author":"Dimeglio","year":"2000","journal-title":"Int. J. Obes."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e20180314","DOI":"10.1590\/0001-3765201920180314","article-title":"High-Fat Diet and Streptozotocin in the Induction of Type 2 Diabetes Mellitus: A New Proposal","volume":"91","author":"Kume","year":"2019","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"von Kr\u00fcchten, R., Lorbeer, R., M\u00fcller-Peltzer, K., Rospleszcz, S., Storz, C., Askani, E., Kulka, C., Schuppert, C., Rathmann, W., and Peters, A. (2022). Association between Adipose Tissue Depots and Dyslipidemia: The KORA-MRI Population-Based Study. Nutrients, 14.","DOI":"10.3390\/nu14040797"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e06474","DOI":"10.1016\/j.heliyon.2021.e06474","article-title":"Melatonin Protects the Heart and Pancreas by Improving Glucose Homeostasis, Oxidative Stress, Inflammation and Apoptosis in T2DM-Induced Rats","volume":"7","author":"Abdulwahab","year":"2021","journal-title":"Heliyon"},{"key":"ref_35","first-page":"958","article-title":"Long-Term Melatonin Administration Improves Glucose Homeostasis and Insulin Resistance State in High-Fat-Diet Fed Rats","volume":"8","author":"Wan","year":"2013","journal-title":"Cent. Eur. J. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.biopha.2018.04.033","article-title":"Insulin Specifically Regulates Expression of Liver and Muscle Phosphofructokinase Isoforms","volume":"103","author":"Ausina","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Jang, M., Manz, A., Volk, T., and Kleber, A. (2018). Study of Melatonin-Mediated Effects on Various Hepatic Inflammatory Responses Stimulated by IL-6 in a New HepG2-on-a-Chip Platform. Biomed. Microdevices, 20.","DOI":"10.1007\/s10544-018-0300-x"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.bcp.2018.01.001","article-title":"Activation of Nuclear Receptor PXR Impairs Glucose Tolerance and Dysregulates GLUT2 Expression and Subcellular Localization in Liver","volume":"148","author":"Kummu","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/nm.4350","article-title":"Insulin Action and Resistance in Obesity and Type 2 Diabetes","volume":"23","author":"Czech","year":"2017","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121530","DOI":"10.1016\/j.lfs.2023.121530","article-title":"Melatonin Modulates the Warburg Effect and Alters the Morphology of Hepatocellular Carcinoma Cell Line Resulting in Reduced Viability and Migratory Potential","volume":"319","author":"Cruz","year":"2023","journal-title":"Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1177\/0885066618793385","article-title":"Review of Biguanide (Metformin) Toxicity","volume":"34","author":"Wang","year":"2019","journal-title":"J. Intensive Care Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.metabol.2015.10.014","article-title":"Metformin-Associated Lactic Acidosis: Current Perspectives on Causes and Risk","volume":"65","author":"Defronzo","year":"2016","journal-title":"Metabolism"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1053\/j.ackd.2019.08.004","article-title":"Toxicity of Metformin and Hypoglycemic Therapies","volume":"27","author":"Akhter","year":"2020","journal-title":"Adv. Chronic Kidney Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1152\/advan.00052.2006","article-title":"Staying Current PGC-1: A Key Regulator of Energy Metabolism","volume":"30","author":"Liang","year":"2006","journal-title":"Adv. Physiol. Educ."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1172\/JCI21752","article-title":"Mitochondrial Remodeling in Adipose Tissue Associated with Obesity and Treatment with Rosiglitazone","volume":"114","author":"Nicoloro","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_46","first-page":"284","article-title":"Melatonin Promotes Mitochondrial Biogenesis and Mitochondrial Degradation in Hepatocytes During Sepsis","volume":"29","author":"Hu","year":"2023","journal-title":"Altern. Ther. Health Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Cooper, I.D., Brookler, K.H., Kyriakidou, Y., Elliott, B.T., and Crofts, C.A.P. (2021). Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070800"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Quintana-Cabrera, R., Manjarr\u00e9s-Raza, I., Vicente-Guti\u00e9rrez, C., Corrado, M., Bola\u00f1os, J.P., and Scorrano, L. (2021). Opa1 Relies on Cristae Preservation and ATP Synthase to Curtail Reactive Oxygen Species Accumulation in Mitochondria. Redox Biol., 41.","DOI":"10.1016\/j.redox.2021.101944"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27905","DOI":"10.1074\/jbc.274.39.27905","article-title":"Hydrogen Peroxide Alters Mitochondrial Activation and Insulin Secretion in Pancreatic Beta Cells","volume":"274","author":"Maechler","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Hajam, Y.A., Rani, R., Ganie, S.Y., Sheikh, T.A., Javaid, D., Qadri, S.S., Pramodh, S., Alsulimani, A., Alkhanani, M.F., and Harakeh, S. (2022). Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells, 11.","DOI":"10.3390\/cells11030552"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.exger.2010.01.003","article-title":"The Sites and Topology of Mitochondrial Superoxide Production","volume":"45","author":"Brand","year":"2010","journal-title":"Exp. Gerontol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1007\/s00018-017-2615-9","article-title":"Melatonin and the Electron Transport Chain","volume":"74","author":"Hardeland","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s13105-014-0322-7","article-title":"Hepatoprotective Effects of Melatonin against Pronecrotic Cellular Events in Streptozotocin-Induced Diabetic Rats","volume":"70","author":"Grigorov","year":"2014","journal-title":"J. Physiol. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"588","DOI":"10.37212\/jcnos.334113","article-title":"Melatonin Reduces Lens Oxidative Stress Level in STZ-Induced Diabetic Rats through Supporting Glutathione Peroxidase and Reduced Glutathione Values","volume":"8","author":"Kahya","year":"2016","journal-title":"J. Cell. Neurosci. Oxidative Stress"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/s11094-011-0640-9","article-title":"Effects of Melatonin on the Activity of the Glutathione Antioxidant System and Various NADPH-Generating Enzymes in the Liver and Blood of Rats with Type 2 Diabetes Mellitus","volume":"45","author":"Agarkov","year":"2011","journal-title":"Pharm. Chem. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"115717","DOI":"10.1016\/j.ecoenv.2023.115717","article-title":"Melatonin Alleviates Particulate Matter-Induced Liver Fibrosis by Inhibiting ROS-Mediated Mitophagy and Inflammation via Nrf2 Activation","volume":"268","author":"Zhu","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/jpi.12008","article-title":"Therapeutic Efficacy of Melatonin in Reducing Retinal Damage in an Experimental Model of Early Type 2 Diabetes in Rats","volume":"54","author":"Salido","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_58","first-page":"5.47.1\u20135.47.20","article-title":"Streptozotocin-Induced Diabetic Models in Mice and Rats","volume":"70","author":"Furman","year":"2015","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Barri\u00e8re, D.A., Noll, C., Roussy, G., Lizotte, F., Kessai, A., Kirby, K., Belleville, K., Beaudet, N., Longpr\u00e9, J.M., and Carpentier, A.C. (2018). Combination of High-Fat\/High-Fructose Diet and Low-Dose Streptozotocin to Model Long-Term Type-2 Diabetes Complications. Sci. Rep., 8.","DOI":"10.1038\/s41598-017-18896-5"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1590\/1519-6984.221405","article-title":"Murinometric Measurements and Retroperitoneal Adipose Tissue in Young Rats Exposed to the High-Fat Diet: Is There Correlation?","volume":"81","author":"Cordeiro","year":"2021","journal-title":"Braz. J. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1055\/s-0030-1249651","article-title":"Energy Expenditure, Lipid Profile, Oxidative Stress, and Cardiac Energy Metabolism after Growth Hormone Treatment in Obese Young Rats","volume":"42","author":"Seiva","year":"2010","journal-title":"Horm. Metab. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.measurement.2017.08.013","article-title":"Measurement of the Total Protein in Serum by Biuret Method with Uncertainty Evaluation","volume":"112","author":"Zheng","year":"2017","journal-title":"Measurement"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1515\/labmed-2019-0098","article-title":"A Colorimetric Method to Measure Oxidized, Reduced and Total Glutathione Levels in Erythrocytes","volume":"43","author":"Alisik","year":"2019","journal-title":"J. Lab. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1365-2141.1973.tb01768.x","article-title":"Glutathione Peroxidase in Human Redcells in Health and Disease","volume":"25","author":"Hopkins","year":"1973","journal-title":"J. Haematol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6183","DOI":"10.1016\/S0021-9258(20)81842-0","article-title":"Mechanism for Several Activities of the Glutathione-S-Transferase","volume":"20","author":"Keen","year":"1976","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2337\/diab.30.3.235","article-title":"The Inhibition of Islet Superoxide Dismutase by Diabetogenic Drugs","volume":"30","author":"Crouch","year":"1981","journal-title":"Diabetes"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","article-title":"Catalase in Vitro","volume":"105","author":"Aebi","year":"1984","journal-title":"Methods Enzymol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:31:48Z","timestamp":1760031108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,13]]},"references-count":67,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26104652"],"URL":"https:\/\/doi.org\/10.3390\/ijms26104652","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,13]]}}}