Department of Dermatology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology; Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University.
Department of Nephrology, Zhongnan Hospital, Wuhan University.
Phytomedicine. 2024 Nov;134:155966. doi: 10.1016/j.phymed.2024.155966. Epub 2024 Aug 15.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiorgan and tissue involvement. Lupus nephritis (LN), an inflammatory condition of the kidneys associated with SLE, represents a significant cause of morbidity and mortality in SLE patients. Current immunosuppressive therapies for LN have limited efficacy and can lead to significant side effects. Demethylzeylasteral (DML) has shown promise in the treatment of LN, but its precise mechanism of action remains unclear.
To assess the therapeutic effects and potential molecular mechanisms of DML in LN METHODS: The study evaluated the renal protective effects of DML in MRL/lpr mice through assessments of immune complex levels, renal function, and pathological changes. Network pharmacology and transcriptomics approaches were used to elucidate the underlying mechanisms. Molecular docking, biacore assay, monoclonal antibody blocking experiments, and in vitro studies were conducted to verify the mechanisms of action.
DML treatment reduced levels of anti-Sm and anti-dsDNA IgG antibodies, as well as serum creatinine and blood urea nitrogen levels. DML also mitigated glomerular damage and fibrosis. Mechanistically, DML alleviated podocyte damage by suppressing inflammation and enhancing autophagy through inhibition of the IL-17A/JAK2-STAT3 pathways. Additionally, DML exhibited high binding affinity with IL17A, JAK2, and STAT3.
These findings provide strong evidence for the beneficial effects of DML in LN, suggesting its potential as a novel therapeutic strategy for improving renal function in autoimmune kidney diseases.
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，可累及多个器官和组织。狼疮肾炎（LN）是一种与 SLE 相关的肾脏炎症性疾病，是 SLE 患者发病率和死亡率的重要原因。目前用于 LN 的免疫抑制疗法疗效有限，并可能导致严重的副作用。Demethylzeylasteral（DML）在 LN 的治疗中显示出良好的效果，但确切的作用机制尚不清楚。
评估 DML 在 LN 中的治疗效果和潜在的分子机制。
该研究通过评估免疫复合物水平、肾功能和病理变化，评估 DML 在 MRL/lpr 小鼠中的肾脏保护作用。采用网络药理学和转录组学方法来阐明潜在的机制。通过分子对接、生物层干涉法、单克隆抗体阻断实验和体外研究来验证作用机制。
DML 治疗降低了抗 Sm 和抗 dsDNA IgG 抗体以及血清肌酐和血尿素氮水平。DML 还减轻了肾小球损伤和纤维化。机制上，DML 通过抑制 IL-17A/JAK2-STAT3 通路来抑制炎症和增强自噬，从而减轻足细胞损伤。此外，DML 与 IL17A、JAK2 和 STAT3 具有高结合亲和力。
这些发现为 DML 在 LN 中的有益作用提供了有力证据，表明其作为改善自身免疫性肾病肾功能的新型治疗策略具有潜力。
