{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T03:38:34Z","timestamp":1793936314258,"version":"4.8.0"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union","award":["I34I19007170007"],"award-info":[{"award-number":["I34I19007170007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a disease characterized by a prolonged hyperglycemic condition caused by insulin resistance mechanisms in muscle and liver, reduced insulin production by pancreatic \u03b2 cells, and a chronic inflammatory state with increased levels of the pro-inflammatory marker semaphorin 3E. Phytochemicals present in several foods have been used to complement oral hypoglycemic drugs for the management of T2DM. Notably, dipeptidyl peptidase IV (DPPIV) inhibitors have demonstrated efficacy in the treatment of T2DM. Our study aimed to investigate, in in vitro models of insulin resistance, the ability of the flavanones naringenin and hesperetin, used alone and in combination with the anti-inflammatory natural molecules curcumin, polydatin, and quercetin, to counteract the insulin resistance and pro-inflammatory molecular mechanisms that are involved in T2DM development. Our results show for the first time that the combination of naringenin, hesperetin, curcumin, polydatin, and quercetin (that mirror the nutraceutical formulation GliceFen\u00ae, Mivell, Italy) synergistically decreases expression levels of the pro-inflammatory gene SEMA3E in insulin-resistant HepG2 cells and synergistically decreases DPPIV activity in insulin-resistant Hep3B cells, indicating that the combination of these five phytochemicals is able to inhibit pro-inflammatory and insulin resistance molecular mechanisms and could represent an effective innovative complementary approach to T2DM pharmacological treatment.<\/jats:p>","DOI":"10.3390\/ijms24098071","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:54:46Z","timestamp":1682949286000},"page":"8071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The Combination of Natural Molecules Naringenin, Hesperetin, Curcumin, Polydatin and Quercetin Synergistically Decreases SEMA3E Expression Levels and DPPIV Activity in In Vitro Models of Insulin Resistance"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-0790","authenticated-orcid":false,"given":"Emanuele-Salvatore","family":"Scarpa","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1733-654X","authenticated-orcid":false,"given":"Chiara","family":"Giordani","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences (DISCLIMO), Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5931-4616","authenticated-orcid":false,"given":"Antonella","family":"Antonelli","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Petrelli","sequence":"additional","affiliation":[{"name":"Clinic of Endocrinology and Metabolic Diseases, Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1286-1521","authenticated-orcid":false,"given":"Giancarlo","family":"Balercia","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Silvetti","sequence":"additional","affiliation":[{"name":"Clinic of Endocrinology and Metabolic Diseases, Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Pieroni","sequence":"additional","affiliation":[{"name":"Clinic of Endocrinology and Metabolic Diseases, Department of Clinical and Molecular Sciences, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9947-6778","authenticated-orcid":false,"given":"Jacopo","family":"Sabbatinelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences (DISCLIMO), Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"},{"name":"Laboratory Medicine Unit, Azienda Ospedaliero Universitaria delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3024-3495","authenticated-orcid":false,"given":"Maria Rita","family":"Rippo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences (DISCLIMO), Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Olivieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences (DISCLIMO), Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"},{"name":"Clinic of Laboratory and Precision Medicine, IRCCS Istituto Nazionale di Ricovero e Cura per Anziani, 60121 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1840-3903","authenticated-orcid":false,"given":"Giulia","family":"Matacchione","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences (DISCLIMO), Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155332","DOI":"10.1016\/j.metabol.2022.155332","article-title":"Pharmacotherapy of type 2 diabetes: An update and future directions","volume":"137","author":"DeMarsilis","year":"2022","journal-title":"Metabolism"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Su\u00e1rez, R., Chapela, S.P., \u00c1lvarez-C\u00f3rdova, L., Bautista-Valarezo, E., Sarmiento-Andrade, Y., Verde, L., Frias-Toral, E., and Sarno, G. 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