Azamollugin, a mollugin derivative, has inhibitory activity on MyD88- and TRIF-dependent pathways

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Journal of Natural Medicines Pub Date : 2024-09-16 DOI:10.1007/s11418-024-01842-x

Yuki Nakajima, Hitomi Nishino, Kazunori Takahashi, Alfarius Eko Nugroho, Yusuke Hirasawa, Toshio Kaneda, Hiroshi Morita

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Abstract

Previously, we reported that azamollugin, an aza-derivative of mollugin, exhibited potent inhibitory activity on NO production in LPS-stimulated RAW 264.7 cells. Further investigations in this study revealed that azamollugin not only suppressed iNOS gene expression regulated by NF-κB, but also inhibited LPS-induced IFN-β expression, which is known to be regulated by IRF3. Azamollugin exhibited an inhibitory activity on LPS-induced IRAK1 activation, suggesting inhibitory effect on the MyD88-dependent pathway. Furthermore, azamollugin inhibited LPS-induced phosphorylation of IRF3 and its upstream factor, TBK1/IKKε, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR4. In addition, azamollugin also suppressed poly(I:C)-induced phosphorylation of TBK1 and IRF3, suggesting an inhibitory effect on the TRIF-dependent pathway via TLR3. These results suggest that azamollugin has inhibitory activity against both the MyD88-dependent and TRIF-dependent pathways, respectively.

Graphical abstract

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棉隆素衍生物 Azamollugin 对 MyD88 和 TRIF 依赖性通路具有抑制活性

摘要以前，我们曾报道过棉隆素的杂环衍生物偶氮棉隆素对LPS刺激的RAW 264.7细胞中NO的产生具有强效抑制活性。本研究的进一步研究发现，氮杂毛蕊花素不仅能抑制受 NF-κB 调控的 iNOS 基因表达，还能抑制 LPS 诱导的 IFN-β 表达，而 IFN-β 是由 IRF3 调控的。棉隆素对 LPS 诱导的 IRAK1 激活有抑制作用，这表明它对 MyD88 依赖性途径有抑制作用。此外，氮卓谷蛋白还能抑制 LPS 诱导的 IRF3 及其上游因子 TBK1/IKKε 的磷酸化，这表明氮卓谷蛋白对通过 TLR4 的 TRIF 依赖性途径有抑制作用。此外，氮杂毛蕊花素还抑制了聚(I:C)诱导的TBK1和IRF3的磷酸化，这表明氮杂毛蕊花素通过TLR3对TRIF依赖性途径有抑制作用。这些结果表明，氮杂毛蕊花素分别对MyD88依赖性途径和TRIF依赖性途径具有抑制活性。图文摘要

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来源期刊

Journal of Natural Medicines 医学-药学

CiteScore

6.90

自引率

3.00%

发文量

审稿时长

1.7 months

期刊介绍： The Journal of Natural Medicines is an international journal publishing original research in naturally occurring medicines and their related foods and cosmetics. It covers: -chemistry of natural products -biochemistry of medicinal plants -pharmacology of natural products and herbs, including Kampo formulas and traditional herbs -botanical anatomy -cultivation of medicinal plants. The journal accepts Original Papers, Notes, Rapid Communications and Natural Resource Letters. Reviews and Mini-Reviews are generally invited.