{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:25:46Z","timestamp":1790951146944,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Diabetes mellitus is a severe metabolic disorder strongly linked to vascular complications driven by endothelial dysfunction, chronic inflammation, and oxidative stress. Novel strategies to mitigate endothelial activation are urgently needed. In this context, phenolic compounds derived from olive leaves, a byproduct of olive oil production, have shown promising potential in counteracting diabetes- associated endothelial inflammation. This study investigates the potential anti-inflammatory effect of polyphenol-rich extracts derived from two olive leaves Spanish monocultivars, Picual and Changlot Real, in human umbilical vein endothelial cells from healthy pregnancies (C-HUVEC) and gestational diabetes (GD-HUVEC), which serve as a relevant in vitro model of hyperglycemia-induced endothelial dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Olive leaf extracts were characterized by HPLC-ESI-TOF-MS. C-HUVEC and GD-HUVEC were treated with the extracts, and pro-inflammatory markers expression (NF-kB p65, MCP-1, and VCAM-1), NF-kB p65 phosphorylation, and monocyte adhesion were assessed under basal and TNF\u03b1-stimulated conditions using RT-PCR, flow cytometry, and adhesion assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both Picual and Changlot Real extracts showed no cytotoxicity at concentrations up to 50 mg\/mL. Treatment with 10 mg\/mL of both extracts significantly reduced NF-kB p65 and MCP-1 gene expression, as well as NF-kB p65 phosphorylation, particularly in GD-HUVEC. VCAM-1 protein expression and TNF\u03b1-induced monocyte adhesion were also significantly decreased following extract treatment. Notably, Changlot Real exhibited a broader anti-inflammatory effect across both cell types, while Picual exerted a more selective effect in GD-HUVEC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings support the anti-inflammatory activity of olive leaf polyphenols and highlight the potential of Changlot Real and Picual extracts in mitigating endothelial dysfunction associated with diabetes. By modulating the NF-kB\u2013VCAM-1 axis, these compounds may attenuate endothelial activation, warranting further investigation into their possible role in the prevention or mitigation of diabetes-related vascular complications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2025.1671932","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T04:16:20Z","timestamp":1760415380000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Unveiling the anti-inflammatory potential of olive leaf phenolic extracts in diabetes-related endothelial dysfunction"],"prefix":"10.3389","volume":"16","author":[{"given":"Ilaria","family":"Cappellacci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Di Pietrantonio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Viola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Formoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata El\u017cbieta","family":"Zujko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Mart\u00edn-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Gomez-Caravaca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Verardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assunta","family":"Pandolfi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Pipino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2337\/dc25-S010","article-title":"10. Cardiovascular disease and risk management: standards of care in diabetes-2025","volume":"48","year":"2025","journal-title":"Diabetes Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s12933-018-0728-6","article-title":"Prevalence of cardiovascular disease\u00a0in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017","volume":"17","author":"Einarson","year":"2018","journal-title":"Cardiovasc Diabetol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60484-9","article-title":"Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies","volume":"375","author":"Emerging Risk Factors","year":"2010","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad192","article-title":"2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes","volume":"44","author":"Marx","year":"2023","journal-title":"Eur Heart J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/eht149","article-title":"Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I","volume":"34","author":"Paneni","year":"2013","journal-title":"Eur Heart J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s11883-014-0419-z","article-title":"Insulin resistance, diabetes, and cardiovascular risk","volume":"16","author":"Paneni","year":"2014","journal-title":"Curr Atheroscler Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2014.06.005","article-title":"Features of endothelial dysfunction in umbilical cord vessels of women with gestational diabetes","volume":"24","author":"Di Fulvio","year":"2014","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"8184656","DOI":"10.1155\/2019\/8184656","article-title":"Anti-inflammatory role of carotenoids in endothelial cells derived from umbilical cord of women affected by gestational diabetes mellitus","volume":"2019","author":"Ucci","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"B9","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s12970-019-0279-6","article-title":"Physiological- and performance-related effects of acute olive oil supplementation at moderate exercise intensity","volume":"16","author":"Esquius","year":"2019","journal-title":"J Int Soc Sports Nutr"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jada.2009.02.023","article-title":"Position of the American Dietetic Association: functional foods","volume":"109","author":"Hasler","year":"2009","journal-title":"J Am Diet Assoc"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.repc.2021.05.011","article-title":"Oral administration of oleuropein and olive leaf extract has cardioprotective effects in rodents: A systematic review","volume":"41","author":"Menezes","year":"2022","journal-title":"Rev Port Cardiol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/S0378-8741(02)00332-X","article-title":"Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Olea europaea, subspecies africana leaves","volume":"84","author":"Somova","year":"2003","journal-title":"J Ethnopharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2006.11.016","article-title":"Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress","volume":"42","author":"Andreadou","year":"2007","journal-title":"J Mol Cell Cardiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2006.01.008","article-title":"Safety assessment of aqueous olive pulp extract as an antioxidant or antimicrobial agent in foods","volume":"44","author":"Soni","year":"2006","journal-title":"Food Chem Toxicol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1308606","article-title":"Oleanolic acid rescues critical features of umbilical vein endothelial cells permanently affected by hyperglycemia","volume":"14","author":"Stelling-Ferez","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2005.07.029","article-title":"Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits","volume":"78","author":"Al-Azzawie","year":"2006","journal-title":"Life Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.22038\/AJP.2021.18989","article-title":"(olive) leaf extract ameliorates learning and memory deficits in streptozotocin-induced diabetic rats","volume":"12","author":"Asghari","year":"2022","journal-title":"Avicenna J Phytomed"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1021\/jf901280r","article-title":"Antidiabetic and antioxidant effects of hydroxytyrosol and oleuropein from olive leaves in alloxan-diabetic rats","volume":"57","author":"Jemai","year":"2009","journal-title":"J Agric Food Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1021\/jf072589s","article-title":"Lipid-lowering and antioxidant effects of hydroxytyrosol and its triacetylated derivative recovered from olive tree leaves in cholesterol-fed rats","volume":"56","author":"Jemai","year":"2008","journal-title":"J Agric Food Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2003.12.010","article-title":"Oleuropein prevents oxidative myocardial injury induced by ischemia and reperfusion","volume":"15","author":"Manna","year":"2004","journal-title":"J Nutr Biochem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2018.e00805","article-title":"In vitro antioxidant activity of olive leaf extract (Olea europaea L.) and its protective effect on oxidative damage in human erythrocytes","volume":"4","author":"Lins","year":"2018","journal-title":"Heliyon"},{"key":"B22","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3390\/nu11081776","article-title":"Health effects of phenolic compounds found in extra-virgin olive oil, by-products, and leaf of olea europaea L","volume":"11","author":"Romani","year":"2019","journal-title":"Nutrients"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.3390\/molecules22071056","article-title":"Solvent-free microwave-assisted extraction of polyphenols from olive tree leaves: antioxidant and antimicrobial properties","volume":"22","author":"Sahin","year":"2017","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.5455\/OVJ.2024.v14.i10.15","article-title":"Neurotoxic effects of type II-diabetes mellitus and the possible preventive effects of olive leaves supplement in male rats","volume":"14","author":"Al-Hafidh","year":"2024","journal-title":"Open Vet J"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/adbi.202300172","article-title":"Role of epigenetics and metabolomics in predicting endothelial dysfunction in type 2 diabetes","volume":"7","author":"Di Pietrantonio","year":"2023","journal-title":"Adv Biol (Weinh)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae688","article-title":"The inflammatory and oxidative phenotype of gestational diabetes is epigenetically transmitted to the offspring: role of methyltransferase MLL1-induced H3K4me3","volume":"45","author":"Di Pietrantonio","year":"2024","journal-title":"Eur Heart J"},{"key":"B27","doi-asserted-by":"publisher","first-page":"7225","DOI":"10.3390\/ijms24087225","article-title":"Essential oils from mediterranean plants inhibit in vitro monocyte adhesion to\u00a0endothelial cells from umbilical cords of females with gestational diabetes mellitus","volume":"24","author":"Schiavone","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1021\/jf5058205","article-title":"Chemometric analysis for the evaluation of phenolic patterns in olive\u00a0leaves from six cultivars at different growth stages","volume":"63","author":"Talhaoui","year":"2015","journal-title":"J Agric Food Chem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2337\/dc22-S002","article-title":"2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022","volume":"45","year":"2022","journal-title":"Diabetes Care"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.854845","article-title":"Effect of the human amniotic membrane on the umbilical vein endothelial cells of gestational diabetic mothers: new insight on inflammation and angiogenesis","volume":"10","author":"Pipino","year":"2022","journal-title":"Front Bioeng Biotechnol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"329","DOI":"10.3390\/biom14030329","article-title":"High glucose promotes and aggravates the senescence and dysfunction of vascular endothelial cells in women with hyperglycemia in pregnancy","volume":"14","author":"Zheng","year":"2024","journal-title":"Biomolecules"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4449","DOI":"10.3390\/ijms26094449","article-title":"Non-thermal plasma attenuates TNF-alpha-induced endothelial inflammation via ROS modulation and NF-kappaB inhibition","volume":"26","author":"Kim","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202002072RR","article-title":"Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes","volume":"35","author":"Di Tomo","year":"2021","journal-title":"FASEB J"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2019.00056","article-title":"Olive leaf extract attenuates inflammatory activation and DNA damage in human arterial endothelial cells","volume":"6","author":"Burja","year":"2019","journal-title":"Front Cardiovasc Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.3390\/antiox12081509","article-title":"Anti-inflammatory effects of olive leaf extract and its bioactive compounds oleacin and oleuropein-aglycone on senescent endothelial and small airway epithelial cells","volume":"12","author":"Silvestrini","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s12986-025-00947-8","article-title":"The effects of the mediterranean diet supplemented with olive oils on pro-inflammatory biomarkers and soluble adhesion molecules: a systematic review and meta-analysis of randomized controlled trials","volume":"22","author":"Tehrani","year":"2025","journal-title":"Nutr Metab (Lond)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"8188","DOI":"10.1038\/s41598-021-87628-7","article-title":"Olive leaf extract supplementation improves the vascular and metabolic alterations associated with aging in Wistar rats","volume":"11","author":"Gonzalez-Hedstrom","year":"2021","journal-title":"Sci Rep"},{"key":"B38","doi-asserted-by":"publisher","first-page":"104487","DOI":"10.1016\/j.phrs.2019.104487","article-title":"The metabolic and vascular protective effects of olive (Olea europaea L.) leaf extract in diet-induced obesity in mice are related to the amelioration of gut microbiota dysbiosis and to its immunomodulatory properties","volume":"150","author":"Vezza","year":"2019","journal-title":"Pharmacol Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1177\/1091581815619764","article-title":"A comprehensive toxicological safety assessment of an extract of olea europaea L. Leaves (Bonolive)","volume":"35","author":"Clewell","year":"2016","journal-title":"Int J Toxicol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/nu14183773","article-title":"Metabolism and bioavailability of olive bioactive constituents based on in vitro, in vivo and human studies","volume":"14","author":"Nikou","year":"2022","journal-title":"Nutrients"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201200795","article-title":"Human absorption and metabolism of oleuropein and hydroxytyrosol ingested as olive (Olea europaea L.) leaf extract","volume":"57","author":"de Bock","year":"2013","journal-title":"Mol Nutr Food Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"325","DOI":"10.3390\/nu15020325","article-title":"Oral bioavailability and metabolism of hydroxytyrosol from food supplements","volume":"15","author":"Bender","year":"2023","journal-title":"Nutrients"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057622","article-title":"Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, placebo-controlled, crossover trial","volume":"8","author":"de Bock","year":"2013","journal-title":"PloS One"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1055\/a-0583-0543","article-title":"Potential herb-drug pharmacokinetic interactions between african wild olive leaf extract and selected antihypertensive drugs","volume":"84","author":"Mmopele","year":"2018","journal-title":"Planta Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1763","article-title":"Fetal sex and the natural history of maternal risk of diabetes during and after pregnancy","volume":"100","author":"Retnakaran","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/dme.12989","article-title":"Sex of the baby and future maternal risk of Type 2 diabetes in women who had gestational diabetes","volume":"33","author":"Retnakaran","year":"2016","journal-title":"Diabetes Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s41387-022-00203-5","article-title":"Sex-specific mediating effect of gestational weight gain between pre-pregnancy body mass index and gestational diabetes mellitus","volume":"12","author":"Zhang","year":"2022","journal-title":"Nutr Diabetes"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1671932\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T04:16:21Z","timestamp":1760415381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1671932\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":47,"alternative-id":["10.3389\/fendo.2025.1671932"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1671932","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]},"article-number":"1671932"}}