{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:49:21Z","timestamp":1762868961190,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:00:00Z","timestamp":1671408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Spanish Ministry of Science and Innovation-FEDER funds","award":["RTC2017-6089-1","RTI2018-098788-B-I00","PID2021-127741OB-I00","PI20\/00487","DTS 19\/00093"],"award-info":[{"award-number":["RTC2017-6089-1","RTI2018-098788-B-I00","PID2021-127741OB-I00","PI20\/00487","DTS 19\/00093"]}]},{"name":"Instituto de Salud Carlos III","award":["RTC2017-6089-1","RTI2018-098788-B-I00","PID2021-127741OB-I00","PI20\/00487","DTS 19\/00093"],"award-info":[{"award-number":["RTC2017-6089-1","RTI2018-098788-B-I00","PID2021-127741OB-I00","PI20\/00487","DTS 19\/00093"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>In diabetes, chronic hyperglycemia, dyslipidemia, inflammation and oxidative stress contribute to the progression of macro\/microvascular complications. Recently, benefits of the use of flavonoids in these conditions have been established. This study investigates, in two different mouse models of diabetes, the vasculoprotective effects of the synthetic flavonoid hidrosmin on endothelial dysfunction and atherogenesis. In a type 2 diabetes model of leptin-receptor-deficient (db\/db) mice, orally administered hidrosmin (600 mg\/kg\/day) for 16 weeks markedly improved vascular function in aorta and mesenteric arteries without affecting vascular structural properties, as assessed by wire and pressure myography. In streptozotocin-induced type 1 diabetic apolipoprotein E-deficient mice, hidrosmin treatment for 7 weeks reduced atherosclerotic plaque size and lipid content; increased markers of plaque stability; and decreased markers of inflammation, senescence and oxidative stress in aorta. Hidrosmin showed cardiovascular safety, as neither functional nor structural abnormalities were noted in diabetic hearts. Ex vivo, hidrosmin induced vascular relaxation that was blocked by nitric oxide synthase (NOS) inhibition. In vitro, hidrosmin stimulated endothelial NOS activity and NO production and downregulated hyperglycemia-induced inflammatory and oxidant genes in vascular smooth muscle cells. Our results highlight hidrosmin as a potential add-on therapy in the treatment of macrovascular complications of diabetes.<\/jats:p>","DOI":"10.3390\/antiox11122499","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T08:41:41Z","timestamp":1671439301000},"page":"2499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Synthetic Flavonoid Hidrosmin Improves Endothelial Dysfunction and Atherosclerotic Lesions in Diabetic Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Luna","family":"Jim\u00e9nez-Castilla","sequence":"first","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas","family":"Opazo-R\u00edos","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"},{"name":"Facultad de Ciencias de la Salud, Universidad de Las Am\u00e9ricas, Concepci\u00f3n-Talcahuano 4301099, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gema","family":"Marin-Royo","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Macarena","family":"Orejudo","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6348-1505","authenticated-orcid":false,"given":"Raquel","family":"Rodrigues-Diez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Universidad Aut\u00f3noma de Madrid, Instituto de Investigaci\u00f3n Hospital La Paz, 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Physiology, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4085-0459","authenticated-orcid":false,"given":"Constanza","family":"Ballesteros-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Universidad Aut\u00f3noma de Madrid, Instituto de Investigaci\u00f3n Hospital La Paz, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Soto-Catal\u00e1n","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5534-6821","authenticated-orcid":false,"given":"Teresa","family":"Caro-Ordieres","sequence":"additional","affiliation":[{"name":"Department of Research, Development, and Innovation, FAES Farma, 48940 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"Artaiz","sequence":"additional","affiliation":[{"name":"Department of Research, Development, and Innovation, FAES Farma, 48940 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Suarez-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Research, Development, and Innovation, FAES Farma, 48940 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Zazpe","sequence":"additional","affiliation":[{"name":"Department of Research, Development, and Innovation, FAES Farma, 48940 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Research, Development, and Innovation, FAES Farma, 48940 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcelino","family":"Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Cardiology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Tu\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Cardiology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana M.","family":"Briones","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Universidad Aut\u00f3noma de Madrid, Instituto de Investigaci\u00f3n Hospital La Paz, 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"Egido","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-5414","authenticated-orcid":false,"given":"Carmen","family":"G\u00f3mez-Guerrero","sequence":"additional","affiliation":[{"name":"Renal, Vascular and Diabetes Research Laboratory, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma de Madrid, 28040 Madrid, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1038\/s41598-021-82398-8","article-title":"A longitudinal study over 40 years to study the metabolic syndrome as a risk factor for cardiovascular diseases","volume":"11","author":"Lind","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12933-018-0728-6","article-title":"Prevalence of cardiovascular disease in type 2 diabetes: A systematic literature review of scientific evidence from across the world in 2007\u20132017","volume":"17","author":"Einarson","year":"2010","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrcardio.2011.154","article-title":"Cardiac remodeling at the population level--risk factors, screening, and outcomes","volume":"8","author":"Gjesdal","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1161\/CIRCULATIONAHA.116.022194","article-title":"Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus\u2014Mechanisms, Management, and Clinical Considerations","volume":"133","author":"Hess","year":"2016","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12933-016-0369-6","article-title":"Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes","volume":"15","author":"Odegaard","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2015.11.083","article-title":"Arterial stiffness, atherosclerosis and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications","volume":"77","author":"Palombo","year":"2016","journal-title":"Vascul Pharmacol."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2174\/1570161112666140423221319","article-title":"Small artery remodeling in obesity and insulin resistance","volume":"12","author":"Briones","year":"2014","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1042\/CS20140456","article-title":"Vascular injury in diabetic db\/db mice is ameliorated by atorvastatin: Role of Rac1\/2-sensitive Nox-dependent pathways","volume":"128","author":"Callera","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_10","first-page":"389","article-title":"Inflammation and its resolution in atherosclerosis: Mediators and therapeutic opportunities","volume":"16","author":"Yurdagul","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Poznyak, A., Grechko, A.V., Poggio, P., Myasoedova, V.A., Alfieri, V., and Orekhov, A.N. (2020). The Diabetes Mellitus\u2013Atherosclerosis Connection: The Role of Lipid and Glucose Metabolism and Chronic Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051835"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12944-020-01297-5","article-title":"Role of non-statin lipid-lowering therapy in coronary atherosclerosis regression: A meta-analysis and meta-regression","volume":"19","author":"Masson","year":"2020","journal-title":"Lipids Health Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7999","DOI":"10.1038\/s41598-021-87528-w","article-title":"The effects of lipid-lowering therapy on coronary plaque regression: A systematic review and meta-analysis","volume":"11","author":"Li","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/CIRCRESAHA.118.313129","article-title":"Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis","volume":"124","author":"Ridker","year":"2019","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1056\/NEJMoa1707914","article-title":"Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease","volume":"377","author":"Ridker","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1007\/s10067-022-06050-0","article-title":"Colchicine may become a new cornerstone therapy for coronary artery disease: A meta-analysis of randomized controlled trials","volume":"41","author":"Chen","year":"2022","journal-title":"Clin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wici\u0144ski, M., G\u00f3rski, K., W\u00f3dkiewicz, E., Walczak, M., Nowaczewska, M., and Malinowski, B. (2020). Vasculoprotective Effects of Vildagliptin. Focus on Atherogenesis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072275"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Caro-Ordieres, T., Mar\u00edn-Royo, G., Opazo-R\u00edos, L., Jim\u00e9nez-Castilla, L., Moreno, J.A., G\u00f3mez-Guerrero, C., and Egido, J. (2020). The Coming Age of Flavonoids in the Treatment of Diabetic Complications. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020346"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ullah, A., Munir, S., Badshah, S.L., Khan, N., Ghani, L., Poulson, B.G., Emwas, A.H., and Jaremko, M. (2020). Important Flavonoids and Their Role as a Therapeutic Agent. Molecules, 25.","DOI":"10.3390\/molecules25225243"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sajid, M., Channakesavula, C.N., Stone, S.R., and Kaur, P. (2021). Synthetic Biology towards Improved Flavonoid Pharmacokinetics. Biomolecules, 11.","DOI":"10.3390\/biom11050754"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143","DOI":"10.23736\/S0392-9590.18.03975-5","article-title":"Efficacy of micronized purified flavonoid fraction (Daflon\u00ae) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: A systematic review and meta-analysis of randomized double-blind placebo-controlled trials","volume":"37","author":"Kakkos","year":"2018","journal-title":"Int. Angiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Feldo, M., W\u00f3jciak-Kosior, M., Sowa, I., Kocki, J., Bogucki, J., Zubilewicz, T., K\u0119sik, J., and Bogucka-Kocka, A. (2019). Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules, 24.","DOI":"10.3390\/molecules24183316"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.amjms.2019.10.005","article-title":"The Potential Protective Effects of Diosmin on Streptozotocin-Induced Diabetic Cardiomyopathy in Rats","volume":"359","author":"Ali","year":"2020","journal-title":"Am. J. Med. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8472","DOI":"10.1039\/D0FO01598A","article-title":"Metabolism and pharmacological activities of the natural health-benefiting compound diosmin","volume":"11","author":"Zheng","year":"2020","journal-title":"Food Funct."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1007\/s10637-020-00905-6","article-title":"Combating atherosclerosis with targeted Diosmin nanoparticles-treated experimental diabetes","volume":"38","author":"Om","year":"2020","journal-title":"Investig. New Drugs"},{"key":"ref_26","first-page":"CD003229","article-title":"Phlebotonics for venous insufficiency","volume":"11","author":"Vernooij","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2S","DOI":"10.1016\/j.jvs.2011.01.079","article-title":"The care of patients with varicose veins and associated chronic venous diseases: Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum","volume":"53","author":"Gloviczki","year":"2011","journal-title":"J. Vasc. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.ejvs.2015.02.007","article-title":"Editor\u2019s Choice\u2014Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS)","volume":"49","author":"Wittens","year":"2015","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Paredes, M.D., Romec\u00edn, P., Atucha, N.M., O\u2019Valle, F., Castillo, J., Ortiz, M.C., and Garc\u00eda-Esta\u00f1, J. (2018). Moderate Effect of Flavonoids on Vascular and Renal Function in Spontaneously Hypertensive Rats. Nutrients, 10.","DOI":"10.20944\/preprints201807.0384.v1"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jim\u00e9nez-Castilla, L., Mar\u00edn-Royo, G., Orejudo, M., Opazo-R\u00edos, L., Caro-Ordieres, T., Artaiz, I., Su\u00e1rez-Cort\u00e9s, T., Zazpe, A., Hern\u00e1ndez, G., and G\u00f3mez-Guerrero, C. (2021). Nephroprotective Effects of Synthetic Flavonoid Hidrosmin in Experimental Diabetic Nephropathy. Antioxidants, 10.","DOI":"10.3390\/antiox10121920"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1161\/01.RES.0000266449.37396.1f","article-title":"Recipes for creating animal models of diabetic cardiovascular disease","volume":"100","author":"Hsueh","year":"2007","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3600","DOI":"10.2337\/db14-1926","article-title":"Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-\u03baB and STAT Signaling Pathways in Diabetic Mice","volume":"64","author":"Lazaro","year":"2015","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1161\/ATVBAHA.114.304144","article-title":"Suppressor of cytokine signaling 1-derived peptide inhibits Janus kinase\/signal transducers and activators of transcription pathway and improves inflammation and atherosclerosis in diabetic mice","volume":"34","author":"Recio","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1111\/bph.15776","article-title":"Microsomal prostaglandin E synthase-1 is involved in the metabolic and cardiovascular alterations associated with obesity","volume":"179","author":"Cachofeiro","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1161\/01.CIR.89.5.2462","article-title":"A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association","volume":"89","author":"Stary","year":"1994","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/9780470942390.mo100130","article-title":"Echocardiography in Mice","volume":"1","author":"Gao","year":"2011","journal-title":"Curr. Protoc. Mouse Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1038\/s41598-018-21087-5","article-title":"Vascular dysfunction in obese diabetic db\/db mice involves the interplay between aldosterone\/mineralocorticoid receptor and Rho kinase signaling","volume":"8","author":"Callera","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ferreira, N.S., Bruder-Nascimento, T., Pereira, C.A., Zanotto, C.Z., Prado, D.S., Silva, J.F., Rassi, D.M., Foss-Freitas, M.C., Alves-Filho, J.C., and Carlos, D. (2019). NLRP3 Inflammasome and Mineralocorticoid Receptors Are Associated with Vascular Dysfunction in Type 2 Diabetes Mellitus. Cells, 8.","DOI":"10.3390\/cells8121595"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1177\/1479164119865885","article-title":"Hypermetabolism and impaired endothelium-dependent vasodilation in mesenteric arteries of type 2 diabetes mellitus db\/db mice","volume":"16","author":"Arildsen","year":"2019","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/ehjcvp\/pvv035","article-title":"Cardiovascular safety of anti-diabetic drugs","volume":"2","author":"Kumar","year":"2016","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1161\/CIRCULATIONAHA.118.038771","article-title":"Cardiovascular Safety Trials for All New Diabetes Mellitus Drugs?","volume":"139","author":"Everett","year":"2019","journal-title":"Circulation"},{"key":"ref_42","first-page":"656795","article-title":"Updating experimental models of diabetic cardiomyopathy","volume":"2015","author":"Picatoste","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"H934","DOI":"10.1152\/ajpheart.00238.2018","article-title":"Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction","volume":"315","author":"Alex","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_44","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-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e12527","DOI":"10.1002\/rth2.12527","article-title":"Micronized purified flavonoid fraction for the treatment of chronic venous insufficiency, with a focus on postthrombotic syndrome: A narrative review","volume":"5","author":"Li","year":"2021","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ejphar.2011.12.040","article-title":"Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats","volume":"679","author":"Silambarasan","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1039\/C4FO00144C","article-title":"Modulation of nitric oxide by flavonoids","volume":"5","author":"Duarte","year":"2014","journal-title":"Food Funct."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e286","DOI":"10.1038\/nutd.2017.34","article-title":"Metabolites of flavonoid compounds preserve indices of endothelial cell nitric oxide bioavailability under glucotoxic conditions","volume":"7","author":"Qian","year":"2017","journal-title":"Nutr. Diabetes"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12933-019-0948-4","article-title":"Glucose and insulin levels are associated with arterial stiffness and concentric remodeling of the heart","volume":"18","author":"Markus","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1097\/00005344-200111002-00005","article-title":"Endothelial factors and microvascular hypertensive disease","volume":"38","author":"Rizzoni","year":"2001","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1161\/01.CIR.103.9.1238","article-title":"Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus","volume":"103","author":"Rizzoni","year":"2001","journal-title":"Circulation"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Souza-Smith, F.M., Katz, P.S., Trask, A.J., Stewart, J.A., Lord, K.C., Varner, K.J., Vassallo, D.V., and Lucchesi, P.A. (2011). Mesenteric resistance arteries in type 2 diabetic db\/db mice undergo outward remodeling. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023337"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1042\/CS20140758","article-title":"Mineralocorticoid receptor blockade prevents vascular remodelling in a rodent model of type 2 diabetes mellitus","volume":"129","author":"Silva","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1515\/cclm-2020-0601","article-title":"The emerging role of cell senescence in atherosclerosis","volume":"59","author":"Wu","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.carpath.2005.05.006","article-title":"Activation of telomerase and expression of human telomerase reverse transcriptase in coronary atherosclerosis","volume":"14","author":"Liu","year":"2005","journal-title":"Cardiovasc. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kang, G.G., Francis, N., Hill, R., Waters, D., Blanchard, C., and Santhakumar, A.B. (2019). Dietary Polyphenols and Gene Expression in Molecular Pathways Associated with Type 2 Diabetes Mellitus: A Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010140"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1007\/s10753-016-0413-4","article-title":"Diosmin Modulates the NF-kB Signal Transduction Pathways and Downregulation of Various Oxidative Stress Markers in Alloxan-Induced Diabetic Nephropathy","volume":"39","author":"Ahmed","year":"2016","journal-title":"Inflammation"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/12\/2499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:44:15Z","timestamp":1760147055000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/12\/2499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,19]]},"references-count":57,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["antiox11122499"],"URL":"https:\/\/doi.org\/10.3390\/antiox11122499","relation":{},"ISSN":["2076-3921"],"issn-type":[{"type":"electronic","value":"2076-3921"}],"subject":[],"published":{"date-parts":[[2022,12,19]]}}}