Abstract
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.