Docosahexaenoic acid (DHA)是一种代表ω-3多不饱和脂肪酸的生物活性物质，它经过代谢可以生成生物活性的亲电性物质。其中，17-氧化-DHA是一种从DHA由环氧合酶-2和脱氢酶在活跃的巨噬细胞中产生的反应性代谢产物。本研究旨在探究17-氧化-DHA对紫外线B (UVB)诱导的小鼠皮肤氧化应激、炎症和癌变的影响。将17-氧化-DHA局部涂抹在无毛小鼠皮肤上可以改善UVB诱导的表皮细胞死亡。同时，17-氧化-DHA的局部应用可抑制UVB诱导的炎性转录因子STAT3在酪氨酸705上的磷酸化。此外，17-氧化-DHA的处理还可以降低氧化应激标记物4-羟基壬酸酰胺修饰的蛋白质、丙二醛和8-羟基-2'-去氧鸟嘌呤的水平。17-氧化-DHA对UVB辐射小鼠皮肤氧化损伤的保护作用与Nrf2的激活有关。17-氧化-DHA可以增强巨噬细胞吞噬凋亡JB6细胞的能力，这与清道夫受体CD36表达的增加有关。此外，在Nrf2的药物抑制或基因敲除下，17-氧化-DHA介导的巨噬细胞效应作用的增强被削弱。预处理小鼠皮肤可以减少UVB诱导的皮肤癌和肿瘤血管生成。同时，确认17-氧化-DHA处理显著抑制了STAT3酪氨酸705残基的磷酸化，并降低了其靶蛋白在皮肤乳头状瘤中的表达。总之，17-氧化-DHA可以保护皮肤免受UVB诱导的氧化细胞死亡、皮炎和癌变。这些效应与抑制STAT3介导的炎性信号传导以及激活Nrf2并随后上调抗氧化和抗炎基因表达有关。版权所有©2023年作者。已由Elsevier B.V.发表。

Docosahexaenoic acid (DHA), a representative omega-3 (ω-3) polyunsaturated fatty acids, undergoes metabolism to produce biologically active electrophilic species. 17-Oxo-DHA is one such reactive metabolite generated from DHA by cyclooxygenase-2 and dehydrogenase in activated macrophages. The present study was aimed to investigate the effects of 17-oxo-DHA on ultraviolet B (UVB)-induced oxidative stress, inflammation, and carcinogenesis in mouse skin. UVB-induced epidermal cell death was ameliorated by topically applied 17-oxo-DHA. Topical application of 17-oxo-DHA onto hairless mouse skin inhibited UVB-induced phosphorylation of the proinflammatory transcription factor, STAT3 on tyrosine 705 (Tyr705). The 17-oxo-DHA treatment also reduced the levels of oxidative stress markers, 4-hydroxynonenal-modified protein, malondialdehyde, and 8-oxo-2'-deoxyguanosine. The protective effects of 17-oxo-DHA against oxidative damage in UVB-irradiated mouse skin were associated with activation of Nrf2. 17-Oxo-DHA enhanced the engulfment of apoptotic JB6 cells by macrophages, which was related to the increased expression of the scavenger receptor CD36. The 17-oxo-DHA-mediated potentiation of efferocytic activity of macrophages was attenuated by the pharmacologic inhibition or knockout of Nrf2. The pretreatment with 17-oxo-DHA reduced the UVB-induced skin carcinogenesis and tumor angiogenesis. It was also confirmed that 17-oxo-DHA treatment significantly inhibited the phosphorylation of the Tyr705 residue of STAT3 and decreased the expression of its target proteins in cutaneous papilloma. In conclusion, 17-oxo-DHA protects against UVB-induced oxidative cell death, dermatitis, and carcinogenesis. These effects were associated with inhibition of STAT3-mediated proinflammatory signaling and also activation of Nrf2 with subsequent upregulation of antioxidant and anti-inflammatory gene expression.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.