Ren Jing, Chen Xin, Wang Hao-Yu, Yang Tao, Zhang Kai-Rong, Lei Shu-Yue, Qi Lu-Yao, Feng Chun-Lan, Zhou Rong, Zhou Hu, Tang Wei
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Acta Pharmacol Sin. 2025 May;46(5):1361-1374. doi: 10.1038/s41401-024-01449-8. Epub 2025 Jan 8.
Psoriasis is a chronic, systemic immune-mediated skin disease. Although many new strategies for psoriasis treatment have been developed, there is great need in clinic for treating psoriasis. Gentiopicroside (GPS), derived from Gentiana manshurica Kitagawa, has multiple pharmacological activities including anti-inflammatory, anti-oxidative and antiviral activities. In this study, we investigated the potential effects of GPS in imiquimod (IMQ)-induced psoriasis mouse model and the underlying mechanisms. The mice were sensitized on their shaved back with IMQ cream for 7 days with or without topical application of 1% or 2% GPS cream. We showed that the application of GPS cream significantly ameliorated psoriasis-like skin lesions; GPS effect was better than that of calcipotriol. GPS rectified the immune cells infiltration and keratinocytes activation in the skin lesions, and significantly inhibited TNF-α/IFN-γ stimulated human keratinocyte (HaCaT) activation in vitro. Proteomic analysis from keratinocytes with and without GPS treatment prompted that GPS regulated the Keap1-Nrf2 pathway, which was the most important pathway in regulating oxidative stress and inflammation. We demonstrated that GPS regulated the protein expression of p62 and Keap1, induced Nrf2 nuclear translocation followed by transcription of Nrf2 downstream antioxidant genes in HaCaT cells. Furthermore, the antioxidant effects of GPS were abolished in Nrf2 keratinocytes. Simultaneously, Nrf2 mice showed increased psoriasiform symptoms with a diminished protective effect in response to GPS treatment. Collectively, the study discloses that GPS inhibits keratinocyte activation and ameliorates psoriasis-like skin lesions in an Nrf2-dependent manner.
银屑病是一种慢性、全身性免疫介导的皮肤病。尽管已经开发出许多治疗银屑病的新策略，但临床上对银屑病治疗仍有很大需求。来源于龙胆的龙胆苦苷（GPS）具有多种药理活性，包括抗炎、抗氧化和抗病毒活性。在本研究中，我们研究了GPS对咪喹莫特（IMQ）诱导的银屑病小鼠模型的潜在作用及其潜在机制。将小鼠背部剃毛后用IMQ乳膏致敏7天，同时局部应用1%或2%的GPS乳膏或不用。我们发现，应用GPS乳膏可显著改善银屑病样皮肤损伤；GPS的效果优于卡泊三醇。GPS纠正了皮肤损伤中的免疫细胞浸润和角质形成细胞活化，并在体外显著抑制肿瘤坏死因子-α/干扰素-γ刺激的人角质形成细胞（HaCaT）活化。对经GPS处理和未经处理的角质形成细胞进行蛋白质组学分析表明，GPS调节Keap1-Nrf2通路，这是调节氧化应激和炎症的最重要通路。我们证明，GPS调节p62和Keap1的蛋白表达，诱导Nrf2核转位，随后在HaCaT细胞中转录Nrf2下游抗氧化基因。此外，在Nrf2基因敲除的角质形成细胞中，GPS的抗氧化作用消失。同时，Nrf2基因敲除小鼠的银屑病样症状加重，对GPS治疗的保护作用减弱。总的来说，该研究表明，GPS以Nrf2依赖的方式抑制角质形成细胞活化并改善银屑病样皮肤损伤。
