Protective effects of an electrophilic metabolite of docosahexaenoic acid on UVB-induced oxidative cell death, dermatitis, and carcinogenesis

Seong Hoon Kim; So Eui Lee; Su-Jung Kim; Xizhu Fang; Jihyeon Hur; Erdi Sozen; Nesrin Kartal Özer; Kwang Pyo Kim; Young-Joon Surh

doi:10.1016/j.redox.2023.102666

Protective effects of an electrophilic metabolite of docosahexaenoic acid on UVB-induced oxidative cell death, dermatitis, and carcinogenesis

Redox Biol. 2023 Jun:62:102666. doi: 10.1016/j.redox.2023.102666. Epub 2023 Mar 9.

Authors

Seong Hoon Kim¹, So Eui Lee², Su-Jung Kim³, Xizhu Fang¹, Jihyeon Hur⁴, Erdi Sozen⁵, Nesrin Kartal Özer⁶, Kwang Pyo Kim⁷, Young-Joon Surh⁸

Affiliations

¹ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
² Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
³ 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.
⁴ Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, South Korea.
⁵ Department of Biochemistry, Faculty of Medicine, Marmara University, Maltepe, Istanbul, Turkey.
⁶ Department of Biochemistry, Faculty of Medicine, Uskudar University, Altunizade, Istanbul, Turkey.
⁷ Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, South Korea; Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, South Korea. Electronic address: kimkp@khu.ac.kr.
⁸ 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; Cancer Research Institute, Seoul National University, Seoul, South Korea. Electronic address: surh@snu.ac.kr.

Abstract

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.

Keywords: 17-Oxo-DHA; Dermatitis; Efferocytosis; Photocarcinogenesis; Resolution of inflammation; UVB-induced inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Cell Death
Dermatitis*
Docosahexaenoic Acids / pharmacology
Fatty Acids, Omega-3* / pharmacology
Mice
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism
Oxidative Stress
Ultraviolet Rays / adverse effects

Substances

Docosahexaenoic Acids
NF-E2-Related Factor 2
Fatty Acids, Omega-3