Kabe Yasuaki, Takemoto Daisuke, Kanai Ayaka, Hirai Miwa, Ono Yoshiko, Akazawa Sota, Horikawa Manabu, Kitagawa Yoshinori, Handa Hiroshi, Rogi Tomohiro, Shibata Hiroshi, Suematsu Makoto
1Department of Biochemistry, Keio University School of Medicine, Tokyo, 160-8582 Japan.
2Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
NPJ Sci Food. 2020 Feb 20;4:4. doi: 10.1038/s41538-020-0064-6. eCollection 2020.
Sesamin [(7α,7'α,8α,8'α)-3,4:3',4'-bis(methylenedioxy)-7,9':7',9-diepoxylignane] is a major lignan in sesame seeds. Sesamin is converted to the catechol metabolite, SC1 [(7α,7'α,8α,8'α)-3',4'-methylenedioxy-7,9':7',9-diepoxylignane-3,4-diol] with anti-inflammatory effects after oral administration. However, its molecular target remains unknown. Analysis using high-performance affinity nanobeads led to the identification of annexin A1 (ANX A1) as an SC1-binding protein. SC1 was found to bind to the annexin repeat 3 region of ANX A1 with a high-affinity constant (Kd = 2.77 μmol L). In U937 cells, SC1 exhibited an anti-inflammatory effect dependent on ANX A1. Furthermore, administration of sesamin or SC1 attenuated carbon tetrachloride-induced liver damage in mice and concurrently suppressed inflammatory responses dependent on ANX A1. The mechanism involved SC1-induced ANX A1 phosphorylation at serine 27 that facilitates extracellular ANX A1 release. Consequently, the ANX A1 released into the extracellular space suppressed the production of tumor necrosis factor α. This study demonstrates that ANX A1 acts as a pivotal target of sesamin metabolites to attenuate inflammatory responses.
芝麻素[（7α，7'α，8α，8'α）-3,4:3'，4'-双亚甲二氧基-7,9':7'，9-二环氧木脂素]是芝麻籽中的一种主要木脂素。口服后，芝麻素会转化为具有抗炎作用的儿茶酚代谢产物SC1[（7α，7'α，8α，8'α）-3'，4'-亚甲二氧基-7,9':7'，9-二环氧木脂素-3,4-二醇]。然而，其分子靶点仍然未知。使用高性能亲和纳米珠进行分析后，确定膜联蛋白A1（ANX A1）为SC1结合蛋白。发现SC1以高亲和力常数（Kd = 2.77 μmol/L）与ANX A1的膜联蛋白重复3区域结合。在U937细胞中，SC1表现出依赖于ANX A1的抗炎作用。此外，给予芝麻素或SC1可减轻小鼠四氯化碳诱导的肝损伤，并同时抑制依赖于ANX A1的炎症反应。其机制涉及SC1诱导ANX A1在丝氨酸27处磷酸化，从而促进细胞外ANX A1释放。因此，释放到细胞外空间的ANX A1抑制了肿瘤坏死因子α的产生。这项研究表明，ANX A1作为芝麻素代谢产物的关键靶点，可减轻炎症反应。
