Zong Jiaxin, Cheng Jieyi, Fu Yuanfeng, Song Jing, Pan Weisong, Yang Li, Zhang Ting, Zhou Mingmei
Murad Research Center for Modernized Chinese Medicine, Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Center for Chinese Medicine Therapy and Systems Biology, Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Pharmacol. 2020 Nov 19;11:558629. doi: 10.3389/fphar.2020.558629. eCollection 2020.
The imiquimod (IMQ)-induced psoriasis mouse model has been used as a model for pathogenic mechanism research, and methotrexate (MTX) is widely employed to treat various clinical manifestations of psoriasis. We explored the underlying pathogenesis of psoriasis and the treatment mechanism of the conventional drugs from the metabolic perspective of the psoriasis mouse model.
Male BALB/c mice were smeared IMQ for 7 days to induce treatment-resistant psoriasis and intragastrically administered 1 mg/kg MTX. We evaluated inflammation of psoriasis-like lesions and therapeutic effects of MTX based on histological changes and immunohistochemistry. Based on gas chromatography-mass spectrometer detection of serum samples, a comprehensive metabolomics analysis was carried out to identify alterations of metabolites.
It was found that MTX ameliorated psoriatic lesions (representative erythema, scaling, and thickening) by inhibiting proliferation and differentiation of keratinocytes. Using multivariate statistical analysis to process metabolomics data, the results displayed alterations in serum metabolites among mice of the control group, IMQ group, and MTX group. Compared with group, psoriasis mice had the higher level of d-galactose and lower expression of myo-inositol, 9,12-octadecadienoic acid, and cholesterol. In contrast with the model set, serum levels of glycine, pyrrolidone carboxylic acid, d-galactose, and d-mannose were significantly decreased in the MTX group.
The differential metabolites, reflecting the perturbation in the pathways of inositol phosphate metabolism; galactose metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and glutathione metabolism, may lead to the pathogenesis of psoriasis, and they are also related to the pharmacological treatment effect of MTX on psoriasis. This study established the foundation for further research on the mechanism and therapeutic targets of psoriasis.
咪喹莫特（IMQ）诱导的银屑病小鼠模型已被用作致病机制研究的模型，甲氨蝶呤（MTX）被广泛用于治疗银屑病的各种临床表现。我们从银屑病小鼠模型的代谢角度探讨了银屑病的潜在发病机制和传统药物的治疗机制。
雄性BALB/c小鼠涂抹IMQ 7天以诱导难治性银屑病，并胃内给予1mg/kg MTX。我们基于组织学变化和免疫组织化学评估银屑病样病变的炎症和MTX的治疗效果。基于血清样本的气相色谱-质谱检测，进行了全面的代谢组学分析以鉴定代谢物的变化。
发现MTX通过抑制角质形成细胞的增殖和分化改善了银屑病病变（典型的红斑、鳞屑和增厚）。使用多变量统计分析处理代谢组学数据，结果显示对照组、IMQ组和MTX组小鼠的血清代谢物有变化。与对照组相比，银屑病小鼠的d-半乳糖水平较高，而肌醇、9,12-十八碳二烯酸和胆固醇的表达较低。与模型组相比，MTX组血清中的甘氨酸、吡咯烷酮羧酸、d-半乳糖和d-甘露糖水平显著降低。
差异代谢物反映了肌醇磷酸代谢、半乳糖代谢、乙醛酸和二羧酸代谢、甘氨酸、丝氨酸和苏氨酸代谢以及谷胱甘肽代谢途径的紊乱，可能导致银屑病的发病机制，并且它们也与MTX对银屑病的药理治疗效果有关。本研究为进一步研究银屑病的机制和治疗靶点奠定了基础。
