Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
Redox Biol. 2023 Jun;62:102666. doi: 10.1016/j.redox.2023.102666. Epub 2023 Mar 9.
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.
二十二碳六烯酸（DHA）是一种代表性的ω-3（ω-3）多不饱和脂肪酸，经过代谢可产生具有生物活性的亲电物质。17-氧代-DHA 是由环加氧酶-2 和活化巨噬细胞中的脱氢酶从 DHA 生成的一种反应性代谢物。本研究旨在探讨 17-氧代-DHA 对小鼠皮肤中紫外线 B（UVB）诱导的氧化应激、炎症和癌变的影响。17-氧代-DHA 可改善 UVB 诱导的表皮细胞死亡。将 17-氧代-DHA 局部应用于无毛小鼠皮肤可抑制 UVB 诱导的促炎转录因子 STAT3 酪氨酸 705（Tyr705）的磷酸化。17-氧代-DHA 处理还降低了氧化应激标志物 4-羟基壬烯醛修饰蛋白、丙二醛和 8-氧-2'-脱氧鸟苷的水平。17-氧代-DHA 对 UVB 照射小鼠皮肤氧化损伤的保护作用与 Nrf2 的激活有关。17-氧代-DHA 增强了巨噬细胞对凋亡 JB6 细胞的吞噬作用，这与清道夫受体 CD36 的表达增加有关。Nrf2 的药理学抑制或敲除减弱了 17-氧代-DHA 介导的巨噬细胞吞噬作用的增强。17-氧代-DHA 的预处理减少了 UVB 诱导的皮肤癌变和肿瘤血管生成。还证实，17-氧代-DHA 处理可显著抑制 STAT3 的 Tyr705 残基磷酸化，并降低皮肤乳头瘤中其靶蛋白的表达。总之，17-氧代-DHA 可防止 UVB 诱导的氧化细胞死亡、皮炎和癌变。这些作用与抑制 STAT3 介导的促炎信号以及随后激活 Nrf2 并随后上调抗氧化和抗炎基因表达有关。
