Karuppagounder Vengadeshprabhu, Arumugam Somasundaram, Thandavarayan Rajarajan A, Pitchaimani Vigneshwaran, Sreedhar Remya, Afrin Rejina, Harima Meilei, Suzuki Hiroshi, Nomoto Mayumi, Miyashita Shizuka, Suzuki Kenji, Nakamura Masahiko, Watanabe Kenichi
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
Exp Dermatol. 2015 Jun;24(6):418-23. doi: 10.1111/exd.12685. Epub 2015 Mar 25.
Quercetin, glycosylated form of flavonoid compound, has potent antioxidant and anti-inflammatory properties. In this study, we have investigated the effects of quercetin on skin lesion, high-mobility group box (HMGB)1 cascade signalling and inflammation in atopic dermatitis (AD) mouse model. AD-like lesion was induced by the application of house dust mite extract to the dorsal skin of NC/Nga transgenic mouse. After AD induction, quercetin (50 mg/kg, p.o) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for HMGB1, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)4, nuclear factor (NF)κB, nuclear factor erythroid-2-related factor (Nrf)2, kelch-like ECH-associated protein (Keap)1, extracellular signal-regulated kinase (ERK)1/2, cyclooxygenase (COX)2, tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-2Rα and other inflammatory markers in the skin of AD mice. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)γ, IL-4) were measured by enzyme-linked immunosorbent assay. Quercetin treatment attenuated the development of AD-like skin lesions. Histological analysis showed that quercetin inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells. Furthermore, quercetin treatment downregulated cytoplasmic HMGB1, RAGE, nuclear p-NFκB, p-ERK1/2, COX2, TNFα, IL-1β, IL-2Rα, IFNγ and IL-4 and upregulated nuclear Nrf2. Our data demonstrated that the HMGB1/RAGE/NFκB signalling might play an important role in skin inflammation, and quercetin treatment could be a promising agent for AD by modulating the HMGB1/RAGE/NFκB signalling and induction of Nrf2 protein.
槲皮素是一种黄酮类化合物的糖基化形式，具有强大的抗氧化和抗炎特性。在本研究中，我们调查了槲皮素对特应性皮炎（AD）小鼠模型皮肤损伤、高迁移率族蛋白B1（HMGB1）级联信号传导和炎症的影响。通过将屋尘螨提取物涂抹于NC/Nga转基因小鼠的背部皮肤来诱导AD样损伤。诱导AD后，每天口服给予槲皮素（50 mg/kg），持续2周。我们通过蛋白质印迹法评估了AD小鼠皮肤中HMGB1、晚期糖基化终末产物受体（RAGE）、Toll样受体（TLR）4、核因子（NF）κB、核因子红细胞2相关因子（Nrf）2、kelch样ECH相关蛋白（Keap）1、细胞外信号调节激酶（ERK）1/2、环氧化酶（COX）2、肿瘤坏死因子（TNF）α、白细胞介素（IL）-1β、IL-2Rα和其他炎症标志物的皮炎严重程度、组织病理学变化和蛋白质表达变化。此外，通过酶联免疫吸附测定法测量了辅助性T（Th）细胞因子（干扰素（IFN）γ、IL-4）的血清水平。槲皮素治疗减轻了AD样皮肤损伤的发展。组织学分析表明，槲皮素抑制了角化过度、不全角化、棘层肥厚、肥大细胞和炎症细胞浸润。此外，槲皮素治疗下调了细胞质HMGB1、RAGE、核p-NFκB、p-ERK1/2、COX2、TNFα、IL-1β、IL-2Rα、IFNγ和IL-4，并上调了核Nrf2。我们的数据表明，HMGB1/RAGE/NFκB信号传导可能在皮肤炎症中起重要作用，槲皮素治疗可能通过调节HMGB1/RAGE/NFκB信号传导和诱导Nrf2蛋白成为治疗AD的一种有前景的药物。
