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Abstract：
Formononetin (FNT) is a plant-derived isoflavone natural product with anti-inflammatory, antioxidant, and anti-allergic properties. We showed previously that FNT inhibits immunoglobulin E (IgE)-dependent mast cell (MC) activation, but the effect of FNT on IgE-independent MC activation is yet unknown. Our aim was to investigate the effects and possible mechanisms of action of FNT on IgE-independent MC activation and pseudoallergic inflammation. We studied the effects of FNT on MC degranulation in vitro with a cell culture model using compound C48/80 to stimulate either mouse bone marrow-derived mast cells (BMMCs) or RBL-2H3 cells. We subsequently measured β-hexosaminase and histamine release, the expression of inflammatory factors, cell morphological changes, and changes in NF-κB signaling. We also studied the effects of FNT in several in vivo murine models of allergic reaction: C48/80-mediated passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), and 2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD). The results showed that FNT inhibited IgE-independent degranulation of MCs, evaluated by a decrease in the release of β-hexosaminase and histamine and a decreased expression of inflammatory factors. Additionally, FNT reduced cytomorphological elongation and F-actin reorganization and attenuated NF-κB p65 phosphorylation and NF-κB-dependent promoter activity. Moreover, the administration of FNT alleviated pseudoallergic responses in vivo in mouse models of C48/80-stimulated PCA and ASA, and DNCB-induced AD. In conclusion, we suggest that FNT may be a novel anti-allergic drug with great potential to alleviate pseudoallergic responses via the inhibition of IgE-independent MC degranulation and NF-κB signaling.
摘要：
Formononetin（FNT）是一种植物来源的异黄酮天然产物，具有抗炎作用，抗氧化剂，和抗过敏特性。我们以前表明，FNT抑制免疫球蛋白E（IgE）依赖性肥大细胞（MC）激活，但FNT对IgE非依赖性MC激活的影响尚不清楚。我们的目的是研究FNT对不依赖IgE的MC激活和假性过敏性炎症的影响和可能的作用机制。我们使用化合物C48/80刺激小鼠骨髓源性肥大细胞（BMMC）或RBL-2H3细胞的细胞培养模型，研究了FNT对MC脱颗粒的体外作用。我们随后测量了β-己糖胺酶和组胺释放，炎症因子的表达，细胞形态变化,和NF-κB信号的变化。我们还研究了FNT在几种体内小鼠过敏反应模型中的作用：C48/80介导的被动皮肤过敏反应（PCA），主动全身过敏反应（ASA），和2,4-二硝基苯（DNCB）诱导的特应性皮炎（AD）。结果表明，FNT抑制不依赖IgE的MC脱颗粒，通过β-己糖胺酶和组胺的释放减少以及炎症因子的表达减少来评估。此外,FNT降低了细胞形态伸长和F-肌动蛋白重组，并减弱了NF-κBp65磷酸化和NF-κB依赖性启动子活性。此外，在C48/80刺激的PCA和ASA的小鼠模型中，施用FNT减轻了体内假性过敏反应，和DNCB诱导的AD。总之,我们认为FNT可能是一种新型的抗过敏药物,具有通过抑制非IgE依赖性MC脱颗粒和NF-κB信号传导来减轻假性过敏反应的巨大潜力.
