{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T18:54:57Z","timestamp":1793904897036,"version":"4.8.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"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. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Chrysin (5,7-dihydroxyflavone) is a natural flavonoid that has been reported as a potential treatment for non-alcoholic fatty liver disease (NAFLD). However, extensive phase II metabolism and poor aqueous solubility led to a decrease in the chrysin concentration in the blood after oral administration, limiting its pharmacological development <jats:italic>in vivo<\/jats:italic>.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In the present study, we synthesized a novel chrysin derivative prodrug (C-1) to address this issue. We introduced a hydrophilic prodrug group at the 7-position hydroxyl group, which is prone to phase II metabolism, to improve water solubility and mask the metabolic site. Further, we evaluated the ameliorative effects of C-1 on NAFLD <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> by NAFLD model cells and db\/db mice.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold><jats:italic>In vitro<\/jats:italic> studies indicated that C-1 has the ability to ameliorate lipid accumulation, cellular damage, and oxidative stress in NAFLD model cells. <jats:italic>In vivo<\/jats:italic> experiments showed that oral administration of C-1 at a high dose (69.3\u00a0mg\/kg) effectively ameliorated hyperlipidemia and liver injury and reduced body weight and liver weight in db\/db mice, in addition to alleviating insulin resistance. Proteomic analysis showed that C-1 altered the protein expression profile in the liver and particularly improved the expression of proteins associated with catabolism and metabolism. Furthermore, in our preliminary pharmacokinetic study, C-1 showed favorable pharmacokinetic properties and significantly improved the oral bioavailability of chrysin.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our data demonstrated that C-1 may be a promising agent for NAFLD therapy.<\/jats:p>","DOI":"10.3389\/fphar.2024.1336232","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T04:46:47Z","timestamp":1713502007000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthesis and biological evaluation of the novel chrysin prodrug for non-alcoholic fatty liver disease treatment"],"prefix":"10.3389","volume":"15","author":[{"given":"Ruiming","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanyue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxing","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuoyuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenmei","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xifei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongmei","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.ejmech.2016.10.061","article-title":"Prodrug approach: an overview of recent cases","volume":"127","author":"Abet","year":"2017","journal-title":"Eur. 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