Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, China.
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, China.
J Ethnopharmacol. 2022 Aug 10;294:115348. doi: 10.1016/j.jep.2022.115348. Epub 2022 May 6.
With most of the anti-rheumatic drugs having severe adverse drug reactions and poor tolerance, the active components from natural herbs provides a repository for novel, safe, and effective drug development. Sanguisorba officinalis L. exhibits definite anti-inflammatory capacity, however, whether it has anti-rheumatic effects has not been revealed.
In the present study, the effect of Ziyuglycoside I (Ziyu I), one of the most important active components in Sanguisorba officinalis L., was investigated in treating collagen-induced arthritis (CIA), illuminating its potential pharmacological mechanisms.
CIA mice were treated with 5, 10, or 20 mg/kg of Ziyu I or 2 mg/kg of MTX, and clinical manifestations as well as pathological changes were observed. T and B cell viability was determined using cell counting kit-8, plasma autoantibodies and cytokines were tested with ELISA, T and B cell subsets were identified by flow cytometry, Blimp1 expression was detected by RT-qPCR and in situ immunofluorescence. The expression of activation-induced cytidine deaminase (AID) was detected by immunohistochemistry. ERK activation in B cells was verified through western blotting and immunofluorescence. Meanwhile, bioinformatics retrieval and molecular docking/molecular dynamics were used to predict the relationship between Blimp1, ERK and Ziyu I with the pharmacokinetics and toxicity of Ziyu I being evaluated in the ADMETlab Web platform.
Ziyu I treatment effectively alleviated the joint inflammatory manifestation including arthritis index, global scores, swollen joint count and body weight of CIA mice. It improved the pathological changes of joint and spleen of arthritic mice, especially in germinal center formation. Ziyu I displayed a moderate regulatory effect on T cell activation, the percentage of total T and helper T cells, and tumor necrosis factor-α, but transforming growth factor-β was not restored. Increased spleen index, B cell viability and plasma auto-antibody production in CIA mice were significantly reduced by Ziyu I therapy. Of note, we found that Ziyu I administration substantially inhibited the excessive expansion of plasma cells in spleen through preventing the expression of B lymphocyte induced maturation protein 1 (Blimp1) and AID in B cells. Ziyu I was predicted in silico to directly interact with ERK2, and reduce ERK2 activation, contributing to the depressed expression of Blimp1. Moreover, Ziyu I was predicted to have a favorable pharmacokinetic profile and low toxicity.
Ziyu I effectively ameliorates CIA in mice by inhibiting plasma cell generation through prevention of ERK2-mediated Blimp1 expression in B cells. Therefore, Ziyu I is a promising candidate for anti-arthritic drug development.
由于大多数抗风湿药物具有严重的不良反应和较差的耐受性，天然草药的活性成分为新型、安全和有效的药物开发提供了一个宝库。地榆具有明确的抗炎作用，但它是否具有抗风湿作用尚未揭示。
本研究旨在探讨地榆中最重要的活性成分之一紫珠苷 I（Ziyu I）治疗胶原诱导性关节炎（CIA）的作用，阐明其潜在的药理机制。
用 5、10 或 20mg/kg 的 Ziyu I 或 2mg/kg 的 MTX 治疗 CIA 小鼠，观察临床症状和病理变化。用细胞计数试剂盒-8 测定 T 和 B 细胞活力，用 ELISA 法检测血浆自身抗体和细胞因子，用流式细胞术鉴定 T 和 B 细胞亚群，用 RT-qPCR 和原位免疫荧光法检测 Blimp1 表达。用免疫组化法检测激活诱导的胞苷脱氨酶（AID）的表达。通过 Western blot 和免疫荧光法验证 B 细胞中 ERK 的激活。同时，通过生物信息学检索和分子对接/分子动力学，预测 Blimp1、ERK 与紫珠苷 I 的关系，并在 ADMETlab Web 平台上评估紫珠苷 I 的药代动力学和毒性。
紫珠苷 I 治疗可有效缓解 CIA 小鼠关节炎症表现，包括关节炎指数、总体评分、肿胀关节计数和体重。它改善了关节炎小鼠关节和脾脏的病理变化，特别是生发中心的形成。紫珠苷 I 对 T 细胞活化、总 T 细胞和辅助性 T 细胞的比例以及肿瘤坏死因子-α有中等调节作用，但转化生长因子-β未恢复。CIA 小鼠脾脏指数、B 细胞活力和血浆自身抗体产生的增加明显减少。值得注意的是，我们发现，通过抑制 B 细胞中 B 淋巴细胞诱导成熟蛋白 1（Blimp1）和 AID 的表达，紫珠苷 I 治疗可显著抑制脾脏中浆细胞的过度扩增。此外，预测紫珠苷 I 可直接与 ERK2 相互作用，降低 ERK2 的激活，从而导致 Blimp1 的表达下调。此外，预测紫珠苷 I 具有良好的药代动力学特性和低毒性。
紫珠苷 I 通过抑制 B 细胞中 ERK2 介导的 Blimp1 表达，有效改善 CIA 小鼠的病情，从而抑制浆细胞的生成。因此，紫珠苷 I 是一种有前途的抗关节炎药物候选物。
