{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:53:44Z","timestamp":1786978424058,"version":"build-2736575974"},"reference-count":67,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007706","name":"Ministero dello Sviluppo Economico","doi-asserted-by":"publisher","award":["F\/200052\/01\/X45"],"award-info":[{"award-number":["F\/200052\/01\/X45"]}],"id":[{"id":"10.13039\/501100007706","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Metabolic dysfunction\u2010associated fatty liver disease (MAFLD) and diabesity (diabetes related to obesity) are interrelated since glucose and lipid alterations play a vital role in the development of both disorders. Due to their multi\u2010variant metabolic features, more than one drug or natural product may be required to achieve proper therapeutic effects. This study aimed to evaluate the effectiveness of a formulation containing co\u2010micronized palmitoylethanolamide and rutin (PEA\u2010Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high\u2010fat diet (HFD)\u2010induced diabesity in mice. NORM3 decreased the body weight and fat mass of obese mice. The formulation improved HFD\u2010altered insulin sensitivity and hepatic glucose production and metabolism, as shown by glucose, insulin, pyruvate tolerance tests, Western blot, and real\u2010time PCR. In the liver, NORM3 limited macro\u2010 and micro\u2010vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. NORM3 counteracted lipid dysfunctions of HFD animals, activating AMPK, a key cellular energy sensor, and normalizing the expression of carnitine palmitoyl\u2010transferase (CPT)1, a rate\u2010limiting enzyme of fatty acid \u03b2\u2010oxidation, and other genes involved in lipid homeostasis. Relevantly, the hepatic antioxidant activity of NORM3 was proved (reduced ROS and increased detoxifying factors and enzymes). Finally, in\u00a0vitro synergistic protective effects of the components (PEA\u2010Rut and HT) on H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010induced oxidative challenge in HepG2 were determined (ROS production, inflammation, and antioxidant defense). Our results show the beneficial effect of NORM3 and its potential as an innovative phytotherapeutic combination in limiting hepatic damage progression and counteracting glucose and lipid dysmetabolism associated with diabesity.\n                  <\/jats:p>","DOI":"10.1002\/ptr.8361","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T10:54:27Z","timestamp":1730285667000},"page":"6035-6047","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Co\u2010Micronized Palmitoylethanolamide and Rutin Associated With Hydroxytyrosol Recover Diabesity\u2010Induced Hepatic Dysfunction in Mice: In\u00a0Vitro Insights Into the Synergistic Effect"],"prefix":"10.1002","volume":"38","author":[{"given":"S.","family":"Melini","sequence":"first","affiliation":[{"name":"Department of Pharmacy, School of Medicine University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3409-5744","authenticated-orcid":false,"given":"C.","family":"Pirozzi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Lama","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Comella","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Opallo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Del Piano","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine and Animal Productions University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Di Napoli","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine and Animal Productions University of Naples Federico II  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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