{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T15:02:48Z","timestamp":1782658968447,"version":"3.54.5"},"reference-count":79,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004881","name":"Instituto Mexicano del Seguro Social","doi-asserted-by":"publisher","award":["R-2024-3601-203"],"award-info":[{"award-number":["R-2024-3601-203"]}],"id":[{"id":"10.13039\/501100004881","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background:\u00a0Annona cherimola Miller (A. cherimola) is traditionally used in Mexico to treat diabetes. Objectives: this study aimed to evaluate the antihyperglycemic activity of the aqueous leaf extracts (AEAcL) and stem (AEAcS) of A. cherimola alone and combined with oral antidiabetic drugs (OADs), as well as to determine their effect on % HbA1c, lipid parameters and toxicity. As well, the study aimed to isolate and identify some of its compounds to propose findings about its mode of action. Methods: Antihyperglycemic activity was evaluated using in vivo models with streptozotocin-induced experimental diabetes in Balb\/c mice. Computer tools were used to obtain the pharmacokinetic and toxicological properties of the identified flavonoids; to obtain findings on their potential as \u03b1-glucosidase and SGLT1 inhibitors, in vivo and in silico studies were carried out using oral sucrose tolerance (OSTT) and glucose (OGTT) tests and molecular coupling studies. Results: \u00c7AEs and aSAAcS administered alone at 200 mg\/kg showed a significant reduction in hyperglycemia. The best combination was AEAcL + Met (100\/500 mg\/kg), which significantly reduced hyperglycemic values and the % of HbA1c, TG, and LDL. The flavonoids isolated from AEAcL were identified as rutin, nicotiflorin, and narcissin. The molecular coupling assay and OSTT and OGTT tests showed that the flavonoids could inhibit \u03b1-glucosidase and SGLT1. Conclusions: AEAcL shows significant antihyperglycemic and antihyperlipidemic activity in murine models of diabetes, both alone (100 mg\/kg) and in combination with metformin (100\/500 mg\/kg). Isolated flavonoids (rutin, nicotiflorin, and narcissine) appear to be partly responsible for these effects, although they have pharmacokinetic limitations. In silico and in vivo studies suggest a possible mechanism of action by inhibition of \u03b1-glucosidase and SGLT1.<\/jats:p>","DOI":"10.3390\/ph18111754","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:58:42Z","timestamp":1763459922000},"page":"1754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Aqueous Extracts and Flavonoids Obtained from Annona cherimola Miller as Antidiabetic Treatments Alone and in Combination with Antidiabetic Drugs: In Vivo and In Silico Studies"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2673-4366","authenticated-orcid":false,"given":"Jesica","family":"Ram\u00edrez-Santos","sequence":"first","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Farmacolog\u00eda, UMAE Hospital de Especialidades, 2\u00b0 Piso CORSE, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauht\u00e9moc 330, Col. Doctores, Mexico City CP 06725, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1851-5988","authenticated-orcid":false,"given":"Fernando","family":"Calzada","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Farmacolog\u00eda, UMAE Hospital de Especialidades, 2\u00b0 Piso CORSE, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauht\u00e9moc 330, Col. Doctores, Mexico City CP 06725, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7355-9679","authenticated-orcid":false,"given":"Julita","family":"Mart\u00ednez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Farmacolog\u00eda, UMAE Hospital de Especialidades, 2\u00b0 Piso CORSE, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauht\u00e9moc 330, Col. Doctores, Mexico City CP 06725, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7401-303X","authenticated-orcid":false,"given":"Miguel","family":"Valdes","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n M\u00e9dica en Farmacolog\u00eda, UMAE Hospital de Especialidades, 2\u00b0 Piso CORSE, Centro M\u00e9dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauht\u00e9moc 330, Col. Doctores, Mexico City CP 06725, Mexico"},{"name":"Instituto Polit\u00e9cnico Nacional, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n S\/N, Col. Casco de Santo Tom\u00e1s, Miguel Hidalgo, Mexico City CP 11340, Mexico"},{"name":"Laboratorio de Inmunolog\u00eda, Departamento de Sistemas Biol\u00f3gicos, Universidad Aut\u00f3noma Metropolitana, Unidad Xochimilco, Calz. Del Hueso 1100, Col. Villa Quietud, Coyoac\u00e1n CP 04960, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7111-7922","authenticated-orcid":false,"given":"Elizabeth","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional, Secci\u00f3n de Estudios de Posgrado e Investigaci\u00f3n, Escuela Superior de Medicina, Plan de San Luis y Salvador D\u00edaz Mir\u00f3n S\/N, Col. Casco de Santo Tom\u00e1s, Miguel Hidalgo, Mexico City CP 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0546-5969","authenticated-orcid":false,"given":"Claudia","family":"Vel\u00e1zquez","sequence":"additional","affiliation":[{"name":"\u00c1rea Acad\u00e9mica de Farmacia, Instituto de Ciencias de la Salud, Universidad Aut\u00f3noma del Estado de Hidalgo, San Agustin Tlaxiaca CP 42076, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","unstructured":"(2025, April 07). World Health Organization. Available online: https:\/\/www.who.int\/es\/news-room\/fact-sheets\/detail\/diabetes."},{"key":"ref_2","unstructured":"(2025, April 07). Instituto Nacional de Estad\u00edstica y Geograf\u00eda. Available online: https:\/\/www.inegi.org.mx\/contenidos\/saladeprensa\/boletines\/2025\/edr\/edr2024_en-jun_RR.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.2337\/dc20-S002","article-title":"Classification and diagnosis of diabetes: Standards of medical care in diabetes\u20142020","volume":"43","author":"Zhong","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., and Mart\u00edn, C. (2020). Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176275"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"773","DOI":"10.2337\/db09-9028","article-title":"From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus","volume":"58","author":"DeFronzo","year":"2009","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.freeradbiomed.2022.03.019","article-title":"Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives","volume":"184","author":"Bhatti","year":"2022","journal-title":"Free Rad. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3390\/diabetology4030032","article-title":"Perfecting the Puzzle of Pathophysiology: Exploring Combination Therapy in the Treatment of Type 2 Diabetes","volume":"4","author":"Gudoor","year":"2023","journal-title":"Diabetology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.arteri.2022.08.004","article-title":"Dietary modulation of advanced glycation end products metabolism on carotid intima-media thickness in type 2 diabetes patients: From the CORDIOPREV study","volume":"35","year":"2023","journal-title":"Cl\u00edn. Investig. Arterioscler."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4196\/kjpp.2014.18.1.1","article-title":"Advanced glycation end products and diabetic complications","volume":"18","author":"Singh","year":"2014","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2832","DOI":"10.1210\/jc.2009-2433","article-title":"Utility of glycated hemoglobin in diagnosing type 2 diabetes mellitus: A community-based study","volume":"95","author":"Kumar","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dilworth, L., Facey, A., and Omoruyi, F. (2021). Diabetes mellitus and its metabolic complications: The role of adipose tissues. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147644"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"139","DOI":"10.5483\/BMBRep.2016.49.3.268","article-title":"The role of lipids in the pathogenesis and treatment of type 2 diabetes and associated co-morbidities","volume":"49","author":"Erion","year":"2016","journal-title":"BMB Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1001\/jama.292.10.1188","article-title":"Relationship of physical activity vs body mass index with type 2 diabetes in women","volume":"292","author":"Weinstein","year":"2004","journal-title":"JAMA"},{"key":"ref_14","first-page":"1764","article-title":"Effect of Physical activity on Insulin Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus","volume":"7","author":"Venkatasamy","year":"2013","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature18642","article-title":"The genetic architecture of type 2 diabetes","volume":"536","author":"Fuchsberger","year":"2016","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nrg.2016.56","article-title":"Type 2 diabetes: Genetic data sharing to advance complex disease research","volume":"17","author":"Flannick","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_17","first-page":"521","article-title":"Gastrointestial adverse effects of old and new antidiabetics: How do we deal with them in real life?","volume":"89","year":"2024","journal-title":"Rev. Gastroenterol. Mex. (Engl. Ed.)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.cmet.2014.08.005","article-title":"Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes","volume":"20","author":"Soccio","year":"2014","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"437","DOI":"10.2174\/18756417MTExfMTQ1z","article-title":"Herbal medicines for diabetes management and its secondary complications","volume":"17","author":"Kumar","year":"2021","journal-title":"Curr. Diabetes Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"184","DOI":"10.3390\/ddc3010011","article-title":"Plant-derived natural products: A source for drug discovery and development","volume":"3","author":"Chaachouay","year":"2024","journal-title":"Drugs Drug Candidates"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Al Kazman, B.S., Harnett, J.E., and Hanrahan, J.R. (2022). Traditional uses, phytochemistry and pharmacological activities of annonacae. Molecules, 27.","DOI":"10.3390\/molecules27113462"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mannino, G., Gentile, C., Porcu, A., Agliassa, C., Caradonna, F., and Bertea, C.M. (2020). Chemical profile and biological activity of cherimoya (Annona cherimola Mill.) and atemoya (Annona atemoya) leaves. Molecules, 25.","DOI":"10.3390\/molecules25112612"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vasarri, M., Barletta, E., Vinci, S., Ramazzotti, M., Francesconi, A., Manetti, F., and Degl\u2019Innocenti, D. (2020). Annona cherimola Miller fruit as a promising candidate against diabetic complications: An in vitro study and preliminary clinical results. Foods, 9.","DOI":"10.3390\/foods9101350"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.jep.2018.06.014","article-title":"Potential therapeutic applications of the genus Annona: Local and traditional uses and pharmacology","volume":"225","year":"2018","journal-title":"J. Ethnopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jep.2011.10.033","article-title":"Antidepressant-like effects of an alkaloid extract of the aerial parts of Annona cherimolia in mice","volume":"139","author":"Araujo","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_26","first-page":"365","article-title":"The pro-apoptotic effect of a Terpene-rich Annona cherimola leaf extract on leukemic cell lines. BMC Complement","volume":"19","author":"Ammoury","year":"2019","journal-title":"Altern. Med."},{"key":"ref_27","first-page":"63","article-title":"Pharmacological Screening of Annona cherimola for Antihyperlipidemic Potential","volume":"2","author":"Verma","year":"2011","journal-title":"J. Basic. Clin. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1007\/s00216-018-1051-5","article-title":"Characterization of bioactive compounds of Annona cherimola L. leaves using a combined approach based on HPLC-ESI-TOF-MS and NMR","volume":"410","author":"Verardo","year":"2018","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/0974-8490.199781","article-title":"Antihyperglycemic activity of the leaves from Annona cherimola miller and rutin on alloxan-induced diabetic rats","volume":"9","author":"Calzada","year":"2017","journal-title":"Pharmacogn. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Sol\u00eds, J., Calzada, F., Barbosa, E., and Vald\u00e9s, M. (2021). Antihyperglycemic and antilipidemic properties of a tea infusion of the leaves from Annona cherimola miller on streptozocin-induced type 2 diabetic mice. Molecules, 26.","DOI":"10.3390\/molecules26092408"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Sol\u00eds, J., Calzada, F., Barbosa, E., and Guti\u00e9rrez-Meza, J.M. (2022). Antidiabetic and Toxicological Effects of the Tea Infusion of Summer Collection from Annona cherimola Miller Leaves. Plants, 11.","DOI":"10.3390\/plants11233224"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Valdes, M., Calzada, F., Mart\u00ednez-Sol\u00eds, J., and Mart\u00ednez-Rodr\u00edguez, J. (2023). Antihyperglycemic effects of Annona cherimola miller and the flavonoid rutin in combination with oral antidiabetic drugs on streptozocin-induced diabetic mice. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010112"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Calzada, F., Valdes, M., Mart\u00ednez-Sol\u00eds, J., Vel\u00e1zquez, C., and Barbosa, E. (2023). Annona cherimola Miller and Its Flavonoids, an Important Source of Products for the Treatment of Diabetes Mellitus: In Vivo and In Silico Evaluations. Pharmaceuticals, 16.","DOI":"10.3390\/ph16050724"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110896","DOI":"10.1016\/j.scienta.2022.110896","article-title":"Botanical, genetic, phytochemical and pharmaceutical aspects of Annona cherimola Mill","volume":"296","author":"Perrone","year":"2022","journal-title":"Sci. Hortic."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1080\/14656566.2019.1672660","article-title":"Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes","volume":"20","author":"Hedrington","year":"2019","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.2147\/DDDT.S418321","article-title":"SGLT1: A potential drug target for cardiovascular disease","volume":"17","author":"Zhao","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"174","DOI":"10.4103\/ajm.ajm_53_20","article-title":"Pathophysiology of diabetes: An overview","volume":"10","author":"Banday","year":"2020","journal-title":"Avicenna J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0891-8422(03)00082-X","article-title":"Diabetes mellitus","volume":"19","author":"Schuster","year":"2002","journal-title":"Clin. Podiatr. Med. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Weinberg Sibony, R., Segev, O., Dor, S., and Raz, I. (2023). Drug therapies for diabetes. Inter. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242417147"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.coph.2021.08.013","article-title":"Dyslipidemia and diabetes mellitus: Role of lipoprotein species and interrelated pathways of lipid metabolism in diabetes mellitus","volume":"61","author":"Kane","year":"2021","journal-title":"Curr. Opin. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Salehi, B., Ata, A., Anil Kumar, N.V., Sharopov, F., Ramirez-Alarcon, K., Ruiz-Ortega, A., Ayatollahi, S.A., Fokou, P.V.T., Kobarfard, F., and Zakaria, Z.A. (2019). Antidiabetic potential of medicinal plants and their active components. Biomolecules, 9.","DOI":"10.3390\/biom9100551"},{"key":"ref_42","unstructured":"(2025, April 07). Encuesta Nacional de Salud y Nutrici\u00f3n. Available online: https:\/\/ensanut.insp.mx."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S2221-6189(13)60126-2","article-title":"A review: Anti diabetic medicinal plants used for diabetes mellitus","volume":"2","author":"Arumugam","year":"2013","journal-title":"J. Acute Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108846","DOI":"10.1016\/j.jdiacomp.2024.108846","article-title":"The optimal dose of metformin to control conversion to diabetes in patients with prediabetes: A meta-analysis","volume":"38","author":"Yi","year":"2024","journal-title":"J. Diabetes Complicat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/s42255-023-00796-w","article-title":"Inactivation of the antidiabetic drug acarbose by human intestinal microbial-mediated degradation","volume":"5","author":"Tian","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"179","DOI":"10.12944\/CRNFSJ.13.Special-Issue-July.11","article-title":"Comprehensive in vivo Antidiabetic Investigations and antioxidant potential of Caralluma edulis whole Plant","volume":"13","author":"Hadi","year":"2025","journal-title":"Curr. Res. Nutr. Food Sci. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13098-017-0254-9","article-title":"Interactions between antidiabetic drugs and herbs: An overview of mechanisms of action and clinical implications","volume":"9","author":"Gupta","year":"2017","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jep.2013.09.029","article-title":"Evaluation of cholesterol absorption and biosynthesis by decoctions of Annona cherimola leaves","volume":"150","author":"Ferreira","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_50","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. Met."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"100981","DOI":"10.1016\/j.focha.2025.100981","article-title":"Systematic review on effectiveness of flavonoids against hypercholesterolemia: Insights from in-silico, in-vitro, and in-vivo studies","volume":"7","author":"Hanis","year":"2025","journal-title":"Food Chem. Adv."},{"key":"ref_52","unstructured":"Ahmed, O.M., Moneim, A.A., Yazid, I.A., and Mahmoud, A.M. (2010). Antihyperglycemic, antihyperlipidemic and antioxidant effects and the probable mechanisms of action of Ruta graveolens infusion and rutin in nicotinamide-streptozotocin-induced diabetic rats. Diabetol. Croat., 15\u201335."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.biopha.2017.10.001","article-title":"Mechanisms of antidiabetic effects of flavonoid rutin","volume":"96","author":"Ghorbani","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9095504","DOI":"10.1155\/2022\/9095504","article-title":"In vivo and in silico assessment of diabetes ameliorating potentiality and safety profile of Gynura procumbens leaves","volume":"2022","author":"Tahsin","year":"2022","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Lam, T.-P., Tran, N.-V.N., Pham, L.-H.D., Lai, N.V.-T., Dang, B.-T.N., Truong, N.-L.N., Nguyen-Vo, S.-K., Hoang, T.-L., Mai, T.T., and Tran, T.-D. (2024). Flavonoids as dual-target inhibitors against \u03b1-glucosidase and \u03b1-amylase: A systematic review of in vitro studies. Nat. Prod. Bioprospecting, 14.","DOI":"10.1007\/s13659-023-00424-w"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.fshw.2014.11.003","article-title":"\u03b1-Glucosidase inhibitors isolated from medicinal plants","volume":"3","author":"Yin","year":"2014","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"67","DOI":"10.21705\/mcbs.v3i2.60","article-title":"Antioxidant, \u03b1-glucosidase inhibitory activity and molecular docking study of gallic acid, quercetin and rutin: A comparative study","volume":"3","author":"Limanto","year":"2019","journal-title":"Mol. Cell Biomed. Sci."},{"key":"ref_58","first-page":"2057333","article-title":"Hypoglycemic effects od plant flavonoids: A Review","volume":"2021","author":"Foo","year":"2021","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.3109\/13880209.2014.880486","article-title":"\u03b1-Glucosidase inhibition, 15-lipoxygenase inhibition, and brine shrimp toxicity of extracts and isolated compounds from Terminalia macroptera leaves","volume":"52","author":"Pham","year":"2014","journal-title":"Pharm. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"11463","DOI":"10.1021\/jf903083h","article-title":"Comparative evaluation of quercetin, isoquercetin and rutin as inhibitors of \u03b1-glucosidase","volume":"57","author":"Li","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_62","first-page":"5","article-title":"Bioavailability and metabolic pharmacokinetics of rutin and quercetin in rats","volume":"13","author":"Yang","year":"2005","journal-title":"J. Food Drug Anal."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1080\/10286020.2024.2337807","article-title":"Simultaneous assessment of absorption and pharmacokinetic characteristics of four active flavonoids from Chimonanthus nitens Leaf Granules using LC-MS determination: In vivo and in vitro","volume":"26","author":"Wang","year":"2024","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_64","first-page":"9","article-title":"Overview on the Rule of Five","volume":"49","author":"Pollastri","year":"2010","journal-title":"Curr. Prot. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Park, M.J., and Kang, Y.H. (2020). Isolation of Isocoumarins and Flavonoids as \u03b1-Glucosidase Inhibitors from Agrimonia pilosa L. Molecules, 25.","DOI":"10.3390\/molecules25112572"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zhu, H., and Zhong, X. (2022). Synthesis of activity evaluation of flavonoid derivatives as \u0251-glucosidase inhibitors. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.1041328"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Yi, X., Dong, M., Guo, N., Tian, J., Lei, P., Wang, S., Yang, Y., and Shi, Y. (2023). Flavonoids improve type 2 diabetes mellitus and its complications: A review. Front. Nutr., 10.","DOI":"10.3389\/fnut.2023.1192131"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Shamsudin, N.F., Ahmed, Q.U., Mahmood, S., Shah, S.A.A., Sarian, M.N., Khattak, M.M.A.K., Khatib, A., Sabere, A.S.M., Yusoff, Y.M., and Latip, J. (2022). Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012605"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e120720188794","DOI":"10.2174\/1573399817666201207200346","article-title":"Flavonoids in the Treatment of Diabetes: Clinical Outcomes and Mechanism to Ameliorate Blood Glucose Levels","volume":"17","author":"Dunya","year":"2021","journal-title":"Curr. Diabetes Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e29718","DOI":"10.1016\/j.heliyon.2024.e29718","article-title":"Clinical applications and mechanism insights of natural flavonoids against type 2 diabetes mellitus","volume":"10","author":"Abdelhakim","year":"2024","journal-title":"Heliyon"},{"key":"ref_71","unstructured":"Norma Oficial Mexicana (2024, February 05). NOM-062-ZOO-1999: Especificaciones T\u00e9cnicas Para la Producci\u00f3n, Cuidado y Uso de Los Animales de Laboratorio. Available online: https:\/\/www.fmvz.unam.mx\/fmvz\/principal\/archivos\/062ZOO.PDF."},{"key":"ref_72","unstructured":"OECD (2024, April 09). Guideline for Testing of Chemicals 423. Acute Oral Toxicity-Acute Toxic Class Method. Organizaci\u00f3n Para la Cooperaci\u00f3n y el Desarrollo Economicos, OECD\/OCDE. Available online: https:\/\/www.oecd.org\/chemicalsafety\/risk-assessment\/1948378.pdf."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.jfda.2016.03.009","article-title":"Myrciaria cauliflora extract improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-nicotinamide mice","volume":"24","author":"Hsu","year":"2016","journal-title":"J. Food Drug Anal."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"Autodock4 and AutodockTools4: Automated docking with selective receptor flexibility","volume":"16","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_76","unstructured":"Molinspiration Cheminformatics (2025, January 05). 2017 Calculation of Molecular Properties and Bioactivity Score. Available online: http:\/\/www.molinspiration.com\/services\/logp.html."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties","volume":"49","author":"Xiong","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"gkae303","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1754\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T10:09:17Z","timestamp":1763460557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1754"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,18]]},"references-count":79,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ph18111754"],"URL":"https:\/\/doi.org\/10.3390\/ph18111754","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,18]]}}}