Introduction

Arctigenin, derived from Arctium lappa L., has multiple pharmacological activities, including immunoregulatory, anti-diabetic, anti-tumor, and neuroprotective effects. Nevertheless, the potential therapeutic target of arctigenin in modulating inflammation remains undefined.

Objectives

In the present study, we identified that arctigenin was a phosphodiesterase-4 (PDE4) selective inhibitor for the first time. Further investigations were performed to fully uncover the effects and mechanism of arctigenin on experimental murine psoriasis model.

Methods

Crystal structure determination, PDEs enzyme assay, and isothermal titration calorimetry were included to illustrate the binding specialty, inhibitory effects, and selectivity of arctigenin on PDE4D. The anti-inflammatory effects were conducted in LPS-activated human peripheral blood mononuclear cells (PBMCs) and RAW264.7 cells. Imiquimod-induced murine psoriasis was performed to uncover the therapeutic effects and mechanism of arctigenin in vivo.

Results

Arctigenin could bind to the catalytic domain of PDE4D via formation of hydrogen bonds as well as π-π stacking interactions between the dibenzyl butyrolactone of arctigenin and several residues of PDE4D. Accordingly, arctigenin showed prominent anti-inflammation in human PBMCs and murine RAW264.7 cells. PDE4 inhibition by arctigenin resulted in elevation of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylation of cAMP-response element binding protein (CREB), which were largely blocked through intervention of protein kinase A (PKA) activity by H89 treatment or reduction of protein expression by siRNA transfection. Moreover, we first identified that a topical application of arctigenin ameliorated experimental psoriatic manifestations in imiquimod-induced murine psoriasis model by decreasing adhesion and chemotaxis of several inflammatory cells. Further proteomics analysis revealed that arctigenin could rectify the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, which might be largely related to the expression of Keratins.

Conclusion

The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis.

中文翻译：

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磷酸二酯酶4作为牛蒡子苷元缓解银屑病皮肤炎症的治疗靶点的鉴定

介绍

牛蒡子苷衍生自牛蒡子，具有多种药理活性，包括免疫调节、抗糖尿病、抗肿瘤和神经保护作用。然而，牛蒡子苷元调节炎症的潜在治疗靶点仍未确定。

目标

在本研究中，我们首次发现牛蒡子苷元是一种磷酸二酯酶 4 (PDE4) 选择性抑制剂。进一步研究以充分揭示牛蒡子苷元对实验性小鼠银屑病模型的影响和机制。

方法

包括晶体结构测定、PDEs 酶测定和等温滴定量热法，以说明牛蒡子苷元对 PDE4D 的结合特性、抑制作用和选择性。在 LPS 激活的人外周血单个核细胞 (PBMC) 和 RAW264.7 细胞中进行抗炎作用。对咪喹莫特诱导的小鼠银屑病进行了研究，以揭示牛蒡子苷元的体内治疗效果和机制。

结果

牛蒡子苷元可以通过氢键的形成以及牛蒡子苷元的二苄基丁内酯与 PDE4D 的几个残基之间的 π-π 堆积相互作用与 PDE4D 的催化结构域结合。因此，牛蒡子苷元在人 PBMC 和鼠 RAW264.7 细胞中显示出显着的抗炎作用。牛蒡子苷元对 PDE4 的抑制导致细胞内环磷酸腺苷 (cAMP) 升高和 cAMP 反应元件结合蛋白 (CREB) 磷酸化，这在很大程度上通过 H89 治疗干预蛋白激酶 A (PKA) 活性或降低蛋白质表达而被阻断通过 siRNA 转染。而且，我们首先发现牛蒡子苷元的局部应用通过减少几种炎症细胞的粘附和趋化性来改善咪喹莫特诱导的小鼠银屑病模型中的实验性银屑病表现。进一步的蛋白质组学分析表明，牛蒡子苷元可以纠正炎症皮肤微环境中角质形成细胞的免疫功能障碍和过度活化，这可能在很大程度上与角蛋白的表达有关。

结论

该研究提供了可信的线索，即牛蒡子苷元对 PDE4 的抑制可能作为治疗银屑病的潜在治疗方法。