Background

Treatment of chronic urticaria is challenging, the discovery of effective therapeutic drugs is urgently in demand.

Purpose

To study the effect and mechanism of Paeonol targeting mast cells and its therapeutic effect on chronic urticaria.

Study design: We developed a chronic urticaria model in vivo and mast cell model in vitro examined the effect of Paeonol in the treatment of chronic urticaria and its mechanism of action in mast cells.

Method

The anti-anaphylactoid effect of Paeonol was evaluated in PCA and systemic anaphylaxis models. The treatment role of Paeonol was studied in urticaria model. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate phosphorylation of Src, PI3K, and PLC. In vitro kinase assays were conducted to investigate the kinase activity of Lyn, PLC, PI3K and Src.

Results

In our study, Paeonol was able to attenuate evans blue leakage, serum histamine and chemokine release in a passive skin allergic reaction model. Simultaneously, Paeonol inhibited vasodilation and mast cell degranulation in C57BL/6 mice. Further research found that Paeonol alleviated symptoms such as erythema and rash in the Substance P-induced urticaria model, this is accompanied by inhibiting the release of related inflammatory factors. Validation experiments on mast cells in vitro found that Paeonol inhibited the activation of Src-PI3K/Lyn-PLC-NF-κB signaling pathway by crosslinking with Src kinase. Moreover, calcium influx, mast cell degranulation, cytokines generation and chemotaxis were reduced in LAD2 cells. Molecular docking experiments revealed that Paeonol is a specific antagonist targeting Src kinase in the treatment of skin diseases such as urticaria.

Conclusion

Paeonol, a herb-derived phenolic compound, can provide drug candidate for developing new drug in treatment of skin disease such as urticaria.

Significance statement

In this study, we primarily examined the effect of Paeonol in the treatment of chronic urticaria and its mechanism of action in mast cells. Interestingly, Paeonol was found to regulate Src kinase activity downstream of MRGPRX2 triggered signaling cascade in mast cells. Therefore, this plant-derived phenolic compound may provide a therapeutic option for the treatment of chronic urticaria.

中文翻译：

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丹皮酚通过抑制肥大细胞中 Src 激酶磷酸化来减轻 P 物质诱导的荨麻疹

背景

慢性荨麻疹的治疗具有挑战性，迫切需要发现有效的治疗药物。

目的

研究丹皮酚靶向肥大细胞的作用、机制及其对慢性荨麻疹的治疗作用。

研究设计：我们建立了慢性荨麻疹体内模型和肥大细胞体外模型，考察丹皮酚治疗慢性荨麻疹的效果及其在肥大细胞中的作用机制。

方法

在 PCA 和全身过敏反应模型中评估了丹皮酚的抗过敏作用。研究了丹皮酚在荨麻疹模型中的治疗作用。使用酶免疫测定试剂盒测量细胞因子和趋化因子的释放。进行蛋白质印迹分析以研究 Src、PI3K 和 PLC 的磷酸化。进行体外激酶测定以研究 Lyn、PLC、PI3K 和 Src 的激酶活性。

结果

在我们的研究中，丹皮酚能够在被动皮肤过敏反应模型中减少伊文思蓝渗漏、血清组胺和趋化因子释放。同时，丹皮酚抑制 C57BL/6 小鼠的血管舒张和肥大细胞脱颗粒。进一步研究发现，丹皮酚可减轻P物质诱导的荨麻疹模型中的红斑、皮疹等症状，同时抑制相关炎症因子的释放。肥大细胞体外验证实验发现，丹皮酚通过与Src激酶交联，抑制Src-PI3K/Lyn-PLC-NF-κB信号通路的激活。此外，LAD2细胞中的钙流入、肥大细胞脱颗粒、细胞因子产生和趋化性均减少。

结论

丹皮酚是一种源自草药的酚类化合物，可以为开发治疗荨麻疹等皮肤病的新药提供候选药物。

意义陈述

本研究主要探讨丹皮酚治疗慢性荨麻疹的效果及其对肥大细胞的作用机制。有趣的是，丹皮酚被发现可以调节肥大细胞中 MRGPRX2 触发的信号级联下游的 Src 激酶活性。因此，这种源自植物的酚类化合物可能为治疗慢性荨麻疹提供一种治疗选择。