The cyanobacterial marine natural product honaucin A inhibits mammalian innate inflammation in vitro and in vivo. To decipher its mechanism of action, RNA sequencing was used to evaluate differences in gene expression of cultured macrophages following honaucin A treatment. This analysis led to the hypothesis that honaucin A exerts its anti-inflammatory activity through activation of the cytoprotective nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile response element (ARE/EpRE) signaling pathway. Activation of this pathway by honaucin A in cultured human MCF7 cells was confirmed using an Nrf2 luciferase reporter assay. In vitro alkylation experiments with the natural product and N-acetyl-l-cysteine suggest that honaucin A activates this pathway through covalent interaction with the sulfhydryl residues of the cytosolic repressor protein Keap1. Honaucin A presents a potential therapeutic lead for diseases with an inflammatory component modulated by Nrf2-ARE.

中文翻译：

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海洋天然产物柔红霉素A通过激活Nrf2-ARE途径减轻炎症

蓝藻海洋天然产物香豆素A在体外和体内抑制哺乳动物的先天性炎症。为了解释其作用机理，RNA测序被用来评估Honaucin A处理后培养的巨噬细胞基因表达的差异。该分析得出这样的假设，即大黄素A通过激活细胞保护性核红系2相关因子2（Nrf2）-抗氧化反应元件/亲电反应元件（ARE / EpRE）信号传导途径发挥其抗炎活性。使用Nrf2荧光素酶报告基因测定法证实了人源激素A在培养的人MCF7细胞中对该途径的激活。天然产物和N-乙酰基-l的体外烷基化实验-半胱氨酸表明，香豆素A通过与胞质阻遏蛋白Keap1的巯基残基共价相互作用来激活该途径。Honaucin A提出了具有由Nrf2-ARE调节的炎症成分的疾病的潜在治疗先导。