Flavonoids with Inhibitory Effects on NLRP3 Inflammasome Activation from Millettia velutina,Journal of Natural Products

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Flavonoids with Inhibitory Effects on NLRP3 Inflammasome Activation from Millettia velutina
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-09-29 , DOI: 10.1021/acs.jnatprod.0c00478
Xu Ma ₁ , Min Zhao ₁ , Ming-Hai Tang ₁ , Lin-Lin Xue ₁ , Rui-Jia Zhang ₁ , Ling Liu ₂ , Heng-Fan Ni ₂ , Xiao-Ying Cai ₁ , Shuang Kuang ₁ , Feng Hong ₁ , Lun Wang ₁ , Kai Chen ₁ , Huan Tang ₁ , Yan Li _{1,

3} , Ai-Hua Peng ₁ , Jian-Hong Yang ₁ , He-Ying Pei ₁ , Hao-Yu Ye ₁ , Li-Juan Chen _{1,

2}

Affiliation

Eight new flavonoids, including two β-hydroxy/methoxychalcones, velutones A and B (1 and 2), two 1,3-diarylpropan-1-ols, velutols C and D (3 and 4), a dihydroxychalcone, velutone E (5), a chalcone, velutone F (6), a furanoflavanone, velutone G (7), and a furanoflavonol, velutone H (8), and 14 known compounds were isolated from Millettia velutina. Their structures were determined by high-resolution electrospray ionisation mass spectrometry (HR-ESIMS) and spectroscopic data analyses and time-dependent density functional theory electronic circular dichroism (TD-DFT–ECD) calculations. Among the isolated constituents, compound 6 exhibited the most potent inhibitory effect (IC₅₀: 1.3 μM) against nigericin-induced IL-1β release in THP-1 cells. The initial mechanism of action study revealed that compound 6 suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion. Most importantly, compound 6 exerted potent protective effects in the LPS-induced septic shock mice model by improving the survival rate of mice and suppressing serum IL-1β release. These results demonstrated that compound 6 had the potential to be developed as a broad-spectrum NLRP3 inflammasome inhibitor for the treatment of NLRP3-related disease.

中文翻译：

黄酮类化合物对鸡血藤 NLRP3 炎症小体激活的抑制作用

八种新的黄酮类化合物，包括两个 β-羟基/甲氧基查尔酮、velutones A 和 B（1和2）、两个 1,3-二芳基丙-1-醇、velutols C 和 D（3和4）、一个二羟基查尔酮、velutone E（5 )、查耳酮、velutone F ( 6 )、呋喃黄酮、velutone G ( 7 ) 和呋喃黄酮醇、 velutone H ( 8 ) 和 14 种已知化合物从Millettia velutina中分离. 它们的结构是通过高分辨率电喷雾电离质谱（HR-ESIMS）和光谱数据分析以及瞬态密度泛函理论电子圆二色性（TD-DFT-ECD）计算确定的。在分离的成分中，化合物6对 THP-1 细胞中尼日利亚菌素诱导的 IL-1β 释放表现出最有效的抑制作用 (IC ₅₀ : 1.3 μM)。最初的作用机制研究表明，化合物6通过阻断 ASC 寡聚化来抑制 NLRP3 炎症小体激活，而不影响引发步骤，随后抑制了 caspase-1 激活和 IL-1β 分泌。最重要的是，化合物6通过提高小鼠的存活率和抑制血清 IL-1β 的释放，在 LPS 诱导的脓毒性休克小鼠模型中发挥有效的保护作用。这些结果表明，化合物6有潜力开发为广谱 NLRP3 炎症小体抑制剂，用于治疗 NLRP3 相关疾病。

更新日期：2020-10-26

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