Yang Shih-Chun, Chang Zi-Yu, Hsiao Chien-Yu, Alshetaili Abdullah, Wei Shih-Hsuan, Hsiao Yu-Tai, Fang Jia-You
Department of Microbiology, Soochow University, Taipei, Taiwan.
Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
Inflammation. 2025 Jan 14. doi: 10.1007/s10753-025-02236-1.
Atopic dermatitis (AD) is a multifaceted inflammatory skin condition characterized by the involvement of various cell types, such as keratinocytes, macrophages, neutrophils, and mast cells. Research indicates that flavonoids possess anti-inflammatory properties that may be beneficial in the management of AD. However, the investigation of the glycoside forms for anti-AD therapy is limited. We aimed to assess the ability of quercetin-3-O-glycosides in treating AD-like lesions through in silico-, cell-, and animal-based platforms. The glycosylated flavonols of quercitrin, isoquercitrin, and rutin were used in this study. We also tried to understand the influence of glycone type on the bioactivity and skin delivery of glycosides. The glycosides effectively reduced the overexpression of proinflammatory effectors such as interleukin (IL)-6, chemokine (C-X-C motif) ligand (CXCL)1, CXCL8, regulated upon activation normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC) in the activated keratinocytes. This reduction could be due to the inhibition of extracellular signal-regulated kinase (ERK) and p38 phosphorylation. Isoquercitrin (but not quercitrin and rutin) could arrest the upregulated IL-6 and CCL5 in the macrophage model. The glycosides significantly prevented histamine release from RBL-2H3 cells. The skin absorption examination showed a greater permeation of quercitrin and isoquercitrin than rutin with dual sugar moieties due to the smaller molecular volume and higher lipophilicity. The skin deposition of quercitrin and isoquercitrin was enhanced by about 11-fold in the stripped and delipidized skins, which mimicked AD lesions. The in vivo dinitrochlorobenzene (DNCB)-induced AD mouse model demonstrated less erosion, scaling, and epidermal hyperplasia after topical isoquercitrin treatment. The concentration of cytokines/chemokines in the lesion was decreased by isoquercitrin. These effects were similar to those of tacrolimus ointment. The immunohistochemistry (IHC) displayed the reduction of epidermal hyperproliferation and immune cell infiltration by topical isoquercitrin. The results indicated that the delivery of quercetin glycosides could provide an efficient and safe way to treat AD inflammation.
特应性皮炎（AD）是一种多方面的炎症性皮肤病，其特征是涉及多种细胞类型，如角质形成细胞、巨噬细胞、中性粒细胞和肥大细胞。研究表明，黄酮类化合物具有抗炎特性，可能对AD的治疗有益。然而，关于用于抗AD治疗的糖苷形式的研究有限。我们旨在通过计算机模拟、细胞和动物实验平台评估槲皮素-3-O-糖苷治疗类AD病变的能力。本研究使用了槲皮苷、异槲皮苷和芦丁的糖基化黄酮醇。我们还试图了解糖基类型对糖苷生物活性和皮肤递送的影响。这些糖苷有效降低了促炎效应因子如白细胞介素（IL）-6、趋化因子（C-X-C基序）配体（CXCL）1、CXCL8、活化正常T细胞表达和分泌的调节趋化因子（RANTES）以及胸腺和活化调节趋化因子（TARC）在活化角质形成细胞中的过表达。这种降低可能是由于细胞外信号调节激酶（ERK）和p38磷酸化的抑制。异槲皮苷（但不是槲皮苷和芦丁）可以阻止巨噬细胞模型中IL-6和CCL5的上调。这些糖苷显著抑制了RBL-2H3细胞中组胺的释放。皮肤吸收检查显示，由于分子体积较小和脂溶性较高，槲皮苷和异槲皮苷的渗透比具有双糖部分的芦丁更好。在模拟AD病变的去角质和脱脂皮肤中，槲皮苷和异槲皮苷的皮肤沉积增加了约11倍。在体内二硝基氯苯（DNCB）诱导的AD小鼠模型中，局部应用异槲皮苷后，糜烂和脱屑减少，表皮增生减轻。异槲皮苷降低了病变中细胞因子/趋化因子的浓度。这些作用与他克莫司软膏相似。免疫组织化学（IHC）显示局部应用异槲皮苷可减少表皮过度增殖和免疫细胞浸润。结果表明，槲皮素糖苷的递送可为治疗AD炎症提供一种有效且安全的方法。
