{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:05:05Z","timestamp":1790813105331,"version":"4.1.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T00:00:00Z","timestamp":1696982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beverly Glen Laboratories, Inc."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Polyethylene glycol-23 glyceryl distearate (GDS-23), a diacylglycerol polyethylene glycol adduct, forms niosomes with a liposome-like structure and functions as an active ingredient in drug delivery systems. In addition, it upregulates antioxidant proteins such as heme oxygenase 1 and NAD(P)H-quinone dehydrogenase 1 in cells. However, the activation of nuclear factor E2-related factor-2 (Nrf2), which plays a role in inducing the expression of antioxidant proteins, and its protective effects induced by GDS-23 treatment against oxidative stress have not been elucidated. This study aimed at verifying the activation of Nrf2 by GDS-23 and clarifying its underlying mechanisms, and investigated whether GDS-23 protects against hydroquinone-induced cytotoxicity. Normal human epidermal keratinocytes were treated with GDS-23. Real-time reverse transcription-polymerase chain reaction, western blotting, and immunostaining were used to investigate the mechanism of Nrf2 activation, and neutral red assay was performed to evaluate cytotoxicity. GDS-23-treated cells showed an increase in antioxidant protein levels and stabilization of Nrf2 in the nucleus. During Nrf2 activation, p62, an autophagy-related adaptor protein, was phosphorylated at Ser349. Inhibition of the interaction between the phosphorylated p62 and Kelch-like ECH-associated protein 1 significantly suppressed the GDS-23-mediated induction of antioxidant protein expression. In addition, hydroquinone-induced cell toxicity was significantly attenuated by GDS-23. GDS-23 induced the intracellular antioxidant system by activating Nrf2 in a p62 phosphorylation-dependent manner without generating oxidative stress in the cells. GDS-23 may be applied as a multifunctional material for drug delivery system that enhances internal antioxidant systems.<\/jats:p>","DOI":"10.1371\/journal.pone.0291905","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T17:21:24Z","timestamp":1697044884000},"page":"e0291905","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Noncanonical mechanism of Nrf2 activation by diacylglycerol polyethylene glycol adducts in normal human epidermal keratinocytes"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6578-7709","authenticated-orcid":true,"given":"Tatsuro","family":"Miyoshi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ashino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Numazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,10,11]]},"reference":[{"key":"pone.0291905.ref001","first-page":"183","article-title":"Niosomes: novel sustained release nonionic stable vesicular systems\u2014an overview","author":"NB Mahale","year":"2012","journal-title":"Adv Colloid Interface Sci"},{"key":"pone.0291905.ref002","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0924-2244(01)00044-9","article-title":"Liposomes in nutrition.","volume":"12","author":"BC Keller","year":"2001","journal-title":"Trends in Food Science & Technology."},{"key":"pone.0291905.ref003","doi-asserted-by":"crossref","first-page":"12325","DOI":"10.1039\/C4CC04344H","article-title":"Spermidinium closo-dodecaborate-encapsulating liposomes as efficient boron delivery vehicles for neutron capture therapy","volume":"50","author":"S Tachikawa","year":"2014","journal-title":"Chem Commun (Camb)."},{"key":"pone.0291905.ref004","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1248\/bpb.b16-00857","article-title":"Innovations in liposomal DDS technology and its application for the treatment of various diseases","volume":"40","author":"N. 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