{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:45:48Z","timestamp":1792291548056,"version":"4.4.0"},"reference-count":128,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Silesia","award":["BNW-2-002\/N\/5\/F"],"award-info":[{"award-number":["BNW-2-002\/N\/5\/F"]}]},{"name":"Medical University of Silesia","award":["BNW-1-093\/N\/4\/F"],"award-info":[{"award-number":["BNW-1-093\/N\/4\/F"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes mellitus and chronic venous disease (CVD) are multifactorial, long-lasting diseases. Although usually considered separately, they often coexist, and individuals with diabetes are more prone to CVD development. Despite different etiology, CVD and diabetic vascular complications share several pathomechanisms, and oxidative stress is one of them. In this study the antioxidative potential of two venoactive flavonoids\u2014diosmin and hesperidin\u2014in the course of type 1 diabetes was compared for the first time. Type 1 diabetic rats were treated with diosmin or hesperidin, each at two doses, 50 and 100 mg\/kg, for four weeks. In order to evaluate the antioxidative potential of tested compounds, the antioxidative enzyme activity (superoxide dismutase, catalase and glutathione peroxidase), thiols homeostasis, oxidative status markers (total antioxidative response\u2014TAR, total oxidative status and oxidative stress index\u2014OSI), and oxidative damage markers (advanced oxidation protein products and malondialdehyde) in the serum were measured. Diabetes caused disturbance in the serological redox homeostasis, especially by decreasing enzyme activity and TAR while increasing levels of oxidative damage markers and OSI, increasing advanced glycation end products (AGEs) levels, as well as altering carbohydrate and lipid metabolism. Flavonoids improved the majority of lipid metabolism markers and reduced AGEs with no effect on glycemia. In the context of oxidative stress, their effect was moderate and dose-dependent, and better potency of hesperidin over diosmin was noted, both in individual and multivariate analyses of the parameters. The collective analysis of all parameters led to the conclusion that both diosmin and hesperidin can be considered complementary agents averting negative impact of diabetes due to their multi-faceted actions, including antioxidative properties.<\/jats:p>","DOI":"10.3390\/ijms262311252","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T09:50:26Z","timestamp":1763718626000},"page":"11252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Diosmin or Hesperidin? Comparison of Antioxidative Action of Two Venoactive Flavonoids in Type 1 Diabetic Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3013-7564","authenticated-orcid":false,"given":"Weronika","family":"Borymska","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiello\u0144ska 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-2381","authenticated-orcid":false,"given":"S\u0142awomir","family":"Borymski","sequence":"additional","affiliation":[{"name":"Faculty of Natural Sciences, Institute of Biology, Biotechnology and Environmental Protection, University of Silesia in Katowice, Jagiello\u0144ska 28, 40-032 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-0505","authenticated-orcid":false,"given":"Maria","family":"Zych","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiello\u0144ska 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6283-9771","authenticated-orcid":false,"given":"S\u0142awomir","family":"Dudek","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiello\u0144ska 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3137-1694","authenticated-orcid":false,"given":"Ilona","family":"Kaczmarczyk-\u017bebrowska","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiello\u0144ska 4, 41-200 Sosnowiec, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.jdiacomp.2015.12.018","article-title":"Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications","volume":"30","author":"Domingueti","year":"2016","journal-title":"J. Diabetes Complicat."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Guo, H., Wu, H., and Li, Z. (2023). The pathogenesis of diabetes. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24086978"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1080\/03007995.2024.2333440","article-title":"Diabetes: A review of its pathophysiology, and advanced methods of mitigation","volume":"40","author":"Gupta","year":"2024","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1111\/imj.16455","article-title":"Preventing diabetes complications","volume":"54","author":"Templer","year":"2024","journal-title":"Intern. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"457","DOI":"10.23736\/S0392-9590.21.04664-2","article-title":"Chronic venous disease and diabetic microangiopathy: Pathophysiology and commonalities","volume":"40","author":"Gastaldi","year":"2021","journal-title":"Int. Angiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ortega, M.A., Fraile-Mart\u00ednez, O., Garc\u00eda-Montero, C., \u00c1lvarez-Mon, M.A., Chaowen, C., Ruiz-Grande, F., Pekarek, L., Monserrat, J., As\u00fansolo, A., and Garc\u00eda-Honduvilla, N. (2021). Understanding chronic venous disease: A critical overview of its pathophysiology and medical management. J. Clin. Med., 10.","DOI":"10.3390\/jcm10153239"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.avsg.2017.06.131","article-title":"The role of endothelial dysfunction and inflammation in chronic venous disease","volume":"46","author":"Cardoso","year":"2018","journal-title":"Ann. Vasc. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez, P., Lozano, P., Ros, G., and Solano, F. (2023). Hyperglycemia and oxidative stress: An integral, updated and critical overview of their metabolic interconnections. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119352"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Black, H.S. (2022). A synopsis of the associations of oxidative stress, ROS, and antioxidants with diabetes mellitus. Antioxidants, 11.","DOI":"10.3390\/antiox11102003"},{"key":"ref_10","first-page":"280","article-title":"Chronic venous disease and its intersections with diabetes mellitus","volume":"72","year":"2023","journal-title":"Physiol. Res."},{"key":"ref_11","first-page":"74","article-title":"Systemic phlebotropic drugs in pharmacotherapy of chronic venous insufficiency of the lower extremities","volume":"4","author":"Okley","year":"2015","journal-title":"News Farm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e15238","DOI":"10.1111\/dth.15238","article-title":"Treatment of chronic venous disorder: A comprehensive review","volume":"35","author":"Chaitidis","year":"2022","journal-title":"Dermatol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1007\/s10787-025-01688-z","article-title":"Therapeutic applications of natural products in the management of venous diseases: A comprehensive review","volume":"33","author":"Mostafa","year":"2025","journal-title":"Inflammopharmacology"},{"key":"ref_14","first-page":"CD003229","article-title":"Phlebotonics for venous insufficiency","volume":"3","author":"Vernooij","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.4236\/ijcm.2025.166019","article-title":"Comparative efficacy and safety of a horse chestnut formulation vs. diosmin-hesperidin in chronic venous insufficiency: Randomized double-blind trial","volume":"16","author":"Gama","year":"2025","journal-title":"Int. J. Clin. Med."},{"key":"ref_16","first-page":"25","article-title":"Hesperidin and diosmin\u2014A novel drugs","volume":"10","author":"Roy","year":"2020","journal-title":"Int. J. Pharm. Res. Technol."},{"key":"ref_17","first-page":"141","article-title":"Simultaneous determination of diosmin and hesperidin in pharmaceuticals by RPLC using ionic liquids as mobile phase modifiers","volume":"15","year":"2016","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"42","DOI":"10.15587\/2519-4852.2019.182412","article-title":"Studies of physico-chemical and pharmaco-technological parameters of bioflavonoids diosmin and hesperidin","volume":"5","author":"Borko","year":"2019","journal-title":"Sci. J. ScienceRise Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hassan, M.A., Elmageed, G.M.A., El-Qazaz, I.G., El-Sayed, D.S., El-Samad, L.M., and Abdou, H.M. (2023). The synergistic influence of polyflavonoids from Citrus aurantifolia on diabetes treatment and their modulation of the PI3K\/AKT\/FOXO1 signaling pathways: Molecular docking analyses and in vivo investigations. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15092306"},{"key":"ref_20","first-page":"29","article-title":"Pharmacokinetics and metabolism of oral diosmin in healthy volunteers","volume":"30","author":"Cova","year":"1992","journal-title":"Int. J. Clin. Parmacol. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/sj.ejcn.1602543","article-title":"Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects","volume":"61","author":"Kanaze","year":"2007","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/0891-5849(95)02227-9","article-title":"Structure-antioxidant activity relationships of flavonoids and phenolic acids","volume":"20","author":"Miller","year":"1996","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100122","DOI":"10.1016\/j.crphar.2022.100122","article-title":"Plant metabolite diosmin as the therapeutic agent in human diseases","volume":"3","author":"Mustafa","year":"2022","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Huwait, E., and Mobashir, M. (2022). Potential and therapeutic roles of diosmin in human diseases. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051076"},{"key":"ref_25","first-page":"1235","article-title":"Promising influences of hesperidin and hesperetin against diabetes and its complications: A systematic review of molecular, cellular, and metabolic effects","volume":"22","author":"Mirzaei","year":"2023","journal-title":"EXCLI J."},{"key":"ref_26","first-page":"100419","article-title":"Revisiting diosmin for their potential biological properties and applications","volume":"7","author":"Rajasekar","year":"2024","journal-title":"Carbohydr. Polym. Technol. Appl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1080\/10408398.2014.906382","article-title":"Health-promoting effects of the citrus flavanone hesperidin","volume":"57","author":"Li","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12986-015-0057-7","article-title":"Antidiabetic properties of dietary flavonoids: A cellular mechanism review","volume":"12","author":"Vinayagam","year":"2015","journal-title":"Nutr. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13318-021-00731-y","article-title":"Pharmacology of diosmin, a citrus flavone glycoside: An updated review","volume":"47","author":"Gerges","year":"2022","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wdowiak, K., Walkowiak, J., Pietrzak, R., Bazan-Wo\u017aniak, A., and Cielecka-Piontek, J. (2022). Bioavailability of hesperidin and its aglycone hesperetin\u2014Compounds found in citrus fruits as a parameter conditioning the pro-health potential (neuroprotective and antidiabetic activity)\u2014Mini-review. Nutrients, 14.","DOI":"10.3390\/nu14132647"},{"key":"ref_31","first-page":"e13008","article-title":"Pharmacological treatment in diabetes mellitus type 1\u2014Insulin and what else ?","volume":"16","author":"Jainta","year":"2018","journal-title":"Int. J. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1080\/14740338.2021.1856813","article-title":"Improving the treatment of patients with diabetes using insulin analogues: Current findings and future directions","volume":"20","author":"Lefever","year":"2021","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_33","first-page":"195","article-title":"A review of the mechanisms of action and side effects of anti-diabetic agents","volume":"8","author":"Dahiru","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Dilworth, L., Stennett, D., Facey, A., Omoruyi, F., Mohansingh, S., and Omoruyi, F.O. (2024). Diabetes and the associated complications: The role of antioxidants in diabetes therapy and care. Biomed. Pharmacother., 181.","DOI":"10.1016\/j.biopha.2024.117641"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, W., Wang, X., Cao, S., Duan, Y., Xu, C., Gan, D., and He, W. (2022). Dietary antioxidant indices in relation to all-cause and cause-specific mortality among adults with diabetes: A prospective cohort study. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.849727"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hsu, C.C., Lin, M.H., Cheng, J.T., and Wu, M.C. (2017). Diosmin, a citrus nutrient, activates imidazoline receptors to alleviate blood glucose and lipids in type 1-like diabetic rats. Nutrients, 9.","DOI":"10.3390\/nu9070684"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/1440-1681.12739","article-title":"Antihyperglycaemic action of diosmin, a citrus flavonoid, is induced through endogenous \u03b2-endorphin in type I-like diabetic rats","volume":"44","author":"Hsu","year":"2017","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3164\/jcbn.09-82","article-title":"Hypoglycemic and hypolipidemic effects dietary hesperidin exerts in streptozotocin-induced marginal type 1 diabetic rats","volume":"46","author":"Akiyama","year":"2010","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"456","DOI":"10.5115\/acb.21.105","article-title":"The role of hesperidin in ameliorating retinal changes in rats with experimentally induced type 1 diabetes mellitus and the active role of vascular endothelial growth factor and glial fibrillary acidic protein","volume":"54","author":"Shehata","year":"2021","journal-title":"Anat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.etp.2017.01.008","article-title":"The ability of hesperidin compared to that of insulin for preventing osteoporosis induced by type I diabetes in young male albino rats: A histological and biochemical study","volume":"69","author":"Shehata","year":"2017","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/15569543.2017.1364268","article-title":"Preventive effects of hesperidin on diabetic nephropathy induced by streptozotocin via modulating TGF-\u03b21 and oxidative DNA damage","volume":"37","author":"Kandemir","year":"2018","journal-title":"Toxin Rev."},{"key":"ref_42","first-page":"256","article-title":"The effect of flavonoid treatment on the glycation and antioxidant status in type 1 diabetic patients","volume":"12","author":"Keenoy","year":"1999","journal-title":"Diabetes Nutr. Metab."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Carballo-Villalobos, A.I., Gonz\u00e1lez-Trujano, M.-E., Pellicer, F., and L\u00f3pez-Mu\u00f1oz, F.J. (2016). Antihyperalgesic effect of hesperidin improves with diosmin in experimental neuropathic pain. BioMed Res. Int., 2016.","DOI":"10.1155\/2016\/8263463"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/(SICI)1097-0215(19971127)73:5<719::AID-IJC18>3.0.CO;2-0","article-title":"Chemopreventive effects of diosmin and hesperidin on n-butyl-n-(4-hydroxybutyl) nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice","volume":"73","author":"Yang","year":"1997","journal-title":"Int. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1093\/carcin\/18.5.957","article-title":"Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin","volume":"18","author":"Tanaka","year":"1997","journal-title":"Carcinogenesis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/carcin\/18.4.761","article-title":"Modulation of N-methyl-N-amylnitrosamine-induced rat oesophageal tumourigenesis by dietary feeding of diosmin and hesperidin, both alone and in combination","volume":"18","author":"Tanaka","year":"1997","journal-title":"Carcinogenesis"},{"key":"ref_47","first-page":"246","article-title":"Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperidin, each alone and in combination","volume":"57","author":"Tanaka","year":"1997","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"35151","DOI":"10.1007\/s11356-019-06660-3","article-title":"Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats","volume":"26","author":"Elhelaly","year":"2019","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bednarska, K., and Fecka, I. (2021). Potential of vasoprotectives to inhibit non-enzymatic protein glycation, and reactive carbonyl and oxygen species uptake. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810026"},{"key":"ref_50","first-page":"1","article-title":"Sex-specific activity of hesperidin, diosmin and genistein on human umbilical vein","volume":"4","author":"Pinna","year":"2019","journal-title":"Biomed. Res. Clin. Pract. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1080\/19390211.2022.2107138","article-title":"The effect of hesperidin and diosmin individually or in combination on metabolic profile and neuropathy among diabetic patients with metabolic syndrome: A randomized controlled trial","volume":"20","author":"Osama","year":"2023","journal-title":"J. Diet. Suppl."},{"key":"ref_52","unstructured":"Borymska, W., Borymski, S., Zych, M., and Kaczmarczyk-\u017bebrowska, I. (2024, January 21\u201328). Por\u00f3wnanie potencja\u0142u antyoksydacyjnego dw\u00f3ch flawonoid\u00f3w flebotropowych\u2014Diosminy i hesperydyny\u2014W przebiegu cukrzycy typu 1. Proceedings of the 7 \u015al\u0105skie Farmaceutyczne Spotkanie Naukowe \u201cOd Nauki do Pacjenta\u201d, Sosnowiec, Poland."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1021\/cr068287r","article-title":"Serum and plasma proteomics","volume":"107","author":"Issaq","year":"2007","journal-title":"Chem. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ab.2010.07.015","article-title":"Differences in metabolite profile between blood plasma and serum","volume":"406","author":"Liu","year":"2010","journal-title":"Anal. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"537","DOI":"10.33549\/physiolres.930111","article-title":"The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas","volume":"50","author":"Szkudelski","year":"2001","journal-title":"Physiol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s00125-007-0886-7","article-title":"The mechanisms of alloxan- and streptozotocin-induced diabetes","volume":"51","author":"Lenzen","year":"2008","journal-title":"Diabetologia"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Klasik-Ciszewska, S., Londzin, P., Grzywnowicz, K., Borymska, W., Zych, M., Kaczmarczyk-\u017bebrowska, I., and Folwarczna, J. (2025). Effect of chrysin, a flavonoid present in food, on the skeletal system in rats with experimental type 1 diabetes. Nutrients, 17.","DOI":"10.3390\/nu17020316"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.pharep.2017.04.005","article-title":"Diosmin ameliorates the effects of oxidative stress in lenses of streptozotocin-induced type 1 diabetic rats","volume":"69","author":"Wojnar","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1080\/15376516.2019.1646370","article-title":"Hesperidin, a citrus flavonoid ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats","volume":"29","author":"Sundaram","year":"2019","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.biopha.2010.02.001","article-title":"Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats","volume":"64","author":"Pari","year":"2010","journal-title":"Biomed. Pharmacother."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Malmstr\u00f6m, H., Walldius, G., Grill, V., Jungner, I., Gudbj\u00f6rnsdottir, S., and Hammar, N. (2014). Fructosamine is a useful indicator of hyperglycaemia and glucose control in clinical and epidemiological studies\u2014Cross-sectional and longitudinal experience from the AMORIS cohort. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111463"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/bcp.14120","article-title":"Hesperidin supplementation has no effect on blood glucose control: A systematic review and meta-analysis of randomized controlled clinical trials","volume":"86","author":"Mohammadi","year":"2020","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Takeuchi, M., Sakasai-Sakai, A., Takata, T., Takino, J., and Koriyama, Y. (2022). Effects of toxic AGEs (TAGE) on human health. Cells, 11.","DOI":"10.3390\/cells11142178"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Kuzan, A. (2021). Toxicity of advanced glycation end products (Review). Biomed. Rep., 14.","DOI":"10.3892\/br.2021.1422"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Khalid, M., Petroianu, G., and Adem, A. (2022). Advanced glycation end products and diabetes mellitus: Mechanisms and perspectives. Biomolecules, 12.","DOI":"10.3390\/biom12040542"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Hafizur, R.M., Momin, S., and Fatima, N. (2017). Prevention of advanced glycation end-products formation in diabetic rats through beta-cell modulation by Aegle marmelos. BMC Complement. Altern. Med., 17.","DOI":"10.1186\/s12906-017-1743-y"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Li, L., Song, Q., Zhang, X., Yan, Y., and Wang, X. (2022). Allicin alleviates diabetes mellitus by inhibiting the formation of advanced glycation end products. Molecules, 27.","DOI":"10.3390\/molecules27248793"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s00210-019-01700-8","article-title":"Effects of diosmin and crocin on metabolic syndrome-associated cardio-vascular complications in rats","volume":"392","author":"Mahmoud","year":"2019","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2016.01.015","article-title":"Role of dietary flavonoids in amelioration of sugar induced cataractogenesis","volume":"593","author":"Patil","year":"2016","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s12013-021-00997-8","article-title":"Bioflavonoid (hesperidin) restrains protein oxidation and advanced glycation end product formation by targeting AGEs and glycolytic enzymes","volume":"79","author":"Khan","year":"2021","journal-title":"Cell Biochem. Biophys."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3923\/ijp.2019.604.615","article-title":"Hesperidin exerts the gestational diabetes mellitus via AGEs-RAGE signalling pathway","volume":"15","author":"Wang","year":"2019","journal-title":"Int. J. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"12868","DOI":"10.3390\/molecules171112868","article-title":"Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats","volume":"17","author":"Shi","year":"2012","journal-title":"Molecules"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Lee, J., Yun, J.S., and Ko, S.H. (2022). Advanced glycation end products and their effect on vascular complications in type 2 diabetes mellitus. Nutrients, 14.","DOI":"10.3390\/nu14153086"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"188","DOI":"10.4093\/dmj.2017.0105","article-title":"The role of advanced glycation end products in diabetic vascular complications","volume":"42","author":"Rhee","year":"2018","journal-title":"Diabetes Metab. J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1152\/physiol.00031.2016","article-title":"Central role of metabolism in endothelial cell function and vascular disease","volume":"32","author":"Bierhansl","year":"2017","journal-title":"Physiology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.2119\/molmed.2015.00067","article-title":"Advanced glycation end products: A molecular target for vascular complications in diabetes","volume":"21","author":"Yamagishi","year":"2015","journal-title":"Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.tem.2020.01.015","article-title":"Dyslipidemia in type 1 diabetes: A masked danger","volume":"31","year":"2020","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s42000-018-0014-8","article-title":"Diabetes and lipid metabolism","volume":"17","author":"Athyros","year":"2018","journal-title":"Hormones"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1111\/liv.14827","article-title":"Liver chemistries in glycogenic hepatopathy associated with type 1 diabetes mellitus: A systematic review and pooled analysis","volume":"41","author":"Haffar","year":"2021","journal-title":"Liver Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00232-012-9503-x","article-title":"Therapeutic potential of some plant extracts used in turkish traditional medicine on streptozocin-induced type 1 diabetes mellitus in rats","volume":"246","author":"Ozkol","year":"2013","journal-title":"J. Membr. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7389864","DOI":"10.1155\/2016\/7389864","article-title":"Evaluation of antidiabetic and antihyperlipidemic effects of peganum harmala seeds in diabetic rats","volume":"2016","author":"Komeili","year":"2016","journal-title":"Cholesterol"},{"key":"ref_82","first-page":"192","article-title":"Antiatherogenic, hepatoprotective, and hypolipidemic effects of coenzyme Q10 in alloxan-induced type 1 diabetic rats","volume":"10","author":"Ahmadvand","year":"2014","journal-title":"ARYA Atheroscler."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jff.2012.12.004","article-title":"Antihyperlipidemic effect of diosmin: A citrus flavonoid on lipid metabolism in experimental diabetic rats","volume":"5","author":"Srinivasan","year":"2013","journal-title":"J. Funct. Foods"},{"key":"ref_84","first-page":"863","article-title":"Natural diosmin alleviating obesity and nonalcoholic fatty liver disease by regulating the activating the AMP-activated protein kinase (AMPK) pathway","volume":"23","author":"Liu","year":"2025","journal-title":"Chin. J. Nat. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1134\/S1607672924601215","article-title":"Effect of hesperidin on lipid profile, inflammation and apoptosis in experimental diabetes","volume":"521","author":"Bayir","year":"2025","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_86","first-page":"53","article-title":"Antidiabetic effects of hesperidin and naringin in type 2 diabetic rats","volume":"41","author":"Ahmed","year":"2012","journal-title":"Diabetol. Croat."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.1021\/jf9001445","article-title":"Low-Density-Lipoprotein (LDL)-bound flavonoids increase the resistance of LDL to oxidation and glycation under pathophysiological concentrations of glucose in vitro","volume":"57","author":"Wu","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"310","DOI":"10.19161\/etd.834331","article-title":"Higher serum Endocan levels are involved in the pathophysiology of chronic venous insufficiency","volume":"59","year":"2020","journal-title":"Ege T\u0131p Derg."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7489795","DOI":"10.1155\/2020\/7489795","article-title":"Association of glycemic indices (hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress and diabetic complications","volume":"2020","author":"Papachristoforou","year":"2020","journal-title":"J. Diabetes Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.cbi.2014.10.016","article-title":"Free radicals, reactive oxygen species, oxidative stresses and their classifications","volume":"224","author":"Lushchak","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1080\/00365510802658473","article-title":"Amelioration of streptozotocin-induced diabetes mellitus, oxidative stress and dyslipidemia in rats by tomato extract lycopene","volume":"69","author":"Ali","year":"2009","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"314","DOI":"10.25011\/cim.v32i5.6918","article-title":"Protective effects of vitamin E on central nervous system in streptozotocin-induced diabetic rats","volume":"32","author":"Kabay","year":"2009","journal-title":"Clin. Investig. Med."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Grabia, M., Socha, K., Soroczy\u0144ska, J., Bossowski, A., and Markiewicz-\u017bukowska, R. (2023). Determinants related to oxidative stress parameters in pediatric patients with type 1 diabetes mellitus. Nutrients, 15.","DOI":"10.3390\/nu15092084"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"198","DOI":"10.4103\/ijmbs.ijmbs_59_18","article-title":"Biomarkers of oxidative stress and antioxidant defense in patients with type 1 diabetes mellitus","volume":"10","author":"Alghazeer","year":"2018","journal-title":"Ibnosina J. Med. Biomed. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s12011-008-8258-9","article-title":"The evaluation of the oxidative stress parameters in nondiabetic and diabetic senile cataract patients","volume":"128","author":"Yildirim","year":"2009","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.diabres.2006.12.007","article-title":"AOPP and its relations with selected markers of oxidative\/antioxidative system in type 2 diabetes mellitus","volume":"77","author":"Piwowar","year":"2007","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_97","first-page":"863","article-title":"Effects of thymol supplementation against type 2 diabetes in streptozotocin-induced rat model","volume":"20","author":"Agarwal","year":"2020","journal-title":"Plant Arch."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"286","DOI":"10.11594\/jtls.07.03.15","article-title":"Correlation of interleukin-10, superoxide dismutase (SOD), and malondialdehyde (MDA) levels with HbA1c in pediatric type 1 diabetes mellitus","volume":"7","author":"Astari","year":"2017","journal-title":"J. Trop. Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"26","DOI":"10.15605\/jafes.039.01.14","article-title":"Fructosamine and HbA1c: A correlational study in a southeast asian population","volume":"39","author":"Chandran","year":"2024","journal-title":"J. ASEAN Fed. Endocr. Soc."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1139\/bcb-2016-0142","article-title":"Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-\u03b3 expression and hampering miR-17-5p-activated canonical Wnt-\u03b2-catenin signaling","volume":"95","author":"Hasan","year":"2017","journal-title":"Biochem. Cell Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1016\/j.biochi.2013.07.014","article-title":"Diosmin binding to human serum albumin and its preventive action against degradation due to oxidative injuries","volume":"95","author":"Barreca","year":"2013","journal-title":"Biochimie"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/1440-1681.13221","article-title":"Hesperidin attenuates altered redox homeostasis in an experimental hyperlipidaemic model of rat","volume":"47","author":"Kumar","year":"2020","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1007\/s10735-024-10272-8","article-title":"Serum biochemical evaluation following administration of imidazolyl thiazolidinedione in streptozotocin-induced diabetic rats","volume":"55","author":"Shakour","year":"2024","journal-title":"J. Mol. Histol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1089\/ars.2012.4964","article-title":"Low-molecular-weight thiols in thiol-disulfide exchange","volume":"18","author":"Hamilton","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1095-6433(03)00114-4","article-title":"Oxidative stress in streptozotocin-induced diabetic rats: Effects of garlic oil and melatonin","volume":"135","author":"Anwar","year":"2003","journal-title":"Comp. Biochem. Physiol.\u2014Part A"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"101014","DOI":"10.1016\/j.jaim.2024.101014","article-title":"Antidiabetic and antioxidant properties of Boswellia sacra oleo-gum in streptozotocin-induced diabetic rats","volume":"15","author":"Rashan","year":"2024","journal-title":"J. Ayurveda Integr. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/1735-5362.329921","article-title":"Chrysin ameliorates STZ-induced diabetes in rats: Possible impact of modulation of TLR4\/NF-\u03ba\u03b2 pathway","volume":"17","author":"Salama","year":"2022","journal-title":"Res. Pharm. Sci."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Shiming, Z., Mak, K.K., Balijepalli, M.K., Chakravarthi, S., and Pichika, M.R. (2021). Swietenine potentiates the antihyperglycemic and antioxidant activity of metformin in streptozotocin induced diabetic rats. Biomed. Pharmacother., 139.","DOI":"10.1016\/j.biopha.2021.111576"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"121","DOI":"10.26650\/IstanbulJPharm.2022.1011516","article-title":"Relationship of thiol\/disulphide homeostasis with oxidative stress parameters in non-diabetic, prediabetic and type 2 diabetic Turkish women","volume":"52","author":"Hamamcioglu","year":"2022","journal-title":"Istanbul J. Pharm."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/j.1749-6632.2002.tb04690.x","article-title":"Glutathione in defense and signaling: Lessons from a small thiol","volume":"973","author":"Dickinson","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Ra\u021biu, S., Mari\u0219, M.I., Furdui-Lin\u021ba, A.V., Sima, L.V., Bratu, T.I., Sturza, A., Muntean, D.M., and Cre\u021bu, O.M. (2025). Oxidative stress in the pathophysiology of chronic venous disease: An overview. Antioxidants, 14.","DOI":"10.3390\/antiox14080989"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Geravandi, S., Emamgholipour, S., Pakdaman, M., Sari, A.A., and Esmaeili, A. (2025). Principal components of type 2 diabetes risk: An exploratory factor analysis in an Iranian cohort. BMC Public Health, 25.","DOI":"10.1186\/s12889-025-21814-4"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1039\/C3MB70618D","article-title":"An integrated metabonomic approach to studying metabolic profiles in rat models with insulin resistance induced by high fructose","volume":"10","author":"Yang","year":"2014","journal-title":"Mol. Biosyst."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"165541","DOI":"10.1016\/j.bbadis.2019.165541","article-title":"Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus","volume":"1865","author":"Gao","year":"2019","journal-title":"BBA\u2014Mol. Basis Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1186\/s40064-016-3364-1","article-title":"Multivariate analysis and molecular interaction of curcumin with PPAR\u03b3 in high fructose diet induced insulin resistance in rats","volume":"5","author":"Jayakumar","year":"2016","journal-title":"Springerplus"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Abdou, H.M., Elmageed, G.M.A., Hussein, H.K., Yamari, I., Chtita, S., El-Samad, L.M., and Hassan, M.A. (2025). Antidiabetic effects of quercetin and silk sericin in attenuating dysregulation of hepatic gluconeogenesis in diabetic rats through potential modulation of PI3K\/Akt\/FOXO1 signaling: In vivo and in silico studies. Xenobiotics, 15.","DOI":"10.3390\/jox15010016"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/s11418-025-01909-3","article-title":"A plasma metabolomic analysis revealed the metabolic regulatory mechanism of the water extract of Dendrobium huoshanense in improving streptozotocin\u2014Induced type 1 diabetes model rats","volume":"79","author":"Xu","year":"2025","journal-title":"J. Nat. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13098-024-01257-4","article-title":"Metabolomics analysis of serum and urine in type 1 diabetes patients with different time in range derived from continuous glucose monitoring","volume":"16","author":"Ma","year":"2024","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S2095-4964(14)60001-7","article-title":"Protective effect of diosmin against diabetic neuropathy in experimental rats","volume":"12","author":"Jain","year":"2014","journal-title":"J. Integr. Med."},{"key":"ref_120","first-page":"945","article-title":"Anti-depressant effect of hesperidin in diabetic rats","volume":"952","author":"Abdallah","year":"2014","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"814","DOI":"10.3109\/13880209.2013.870584","article-title":"Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions","volume":"52","author":"Visnagri","year":"2014","journal-title":"Pharm. Biol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/ki.1996.186","article-title":"Advanced oxidation protein products as a novel marker of oxidative stress in uremia","volume":"49","author":"Friedlander","year":"1996","journal-title":"Kidney Int."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.clinbiochem.2003.10.014","article-title":"A novel automated method to measure total antioxidant response against potent free radical reactions","volume":"37","author":"Erel","year":"2004","journal-title":"Clin. Biochem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.clinbiochem.2005.08.008","article-title":"A new automated colorimetric method for measuring total oxidant status","volume":"38","author":"Erel","year":"2005","journal-title":"Clin. Biochem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ijcard.2004.05.069","article-title":"Increased oxidative stress in children exposed to passive smoking","volume":"100","author":"Kosecik","year":"2005","journal-title":"Int. J. Cardiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.clinbiochem.2014.09.026","article-title":"A novel and automated assay for thiol\/disulphide homeostasis","volume":"47","author":"Erel","year":"2014","journal-title":"Clin. Biochem."},{"key":"ref_128","first-page":"1","article-title":"Past: Paleontological statistics software package for education and data analysis","volume":"4","author":"Hammer","year":"2001","journal-title":"Palaeontol. Electron."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11252\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T05:20:12Z","timestamp":1763875212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":128,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311252"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311252","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]}}}