Department of TCM, Changzhou Cancer Hospital, Changzhou, China.
Chem Biol Drug Des. 2024 Mar;103(3):e14472. doi: 10.1111/cbdd.14472.
Brucine is a weak alkaline indole alkaloid with wide pharmacological activities and has been identified to protect against rheumatoid arthritis (RA) process. Circular RNAs (circRNAs) are also reported to be involved in the pathogenesis of RA. Here, we aimed to probe the role and mechanism of Brucine and circ_0139658 in RA progression. The fibroblast-like synoviocytes of RA (RA-FLSs) were isolated for functional analysis. Cell proliferation, apoptosis, invasion, migration, as well as inflammatory response were evaluated by CCK-8 assay, EdU assay, flow cytometry, transwell assay, and ELISA analysis, respectively. qRT-PCR and western blotting analyses were utilized to measure the levels of genes and proteins. The binding between miR-653-5p and circ_0139658 or Yin Yang 1 (YY1), was verified using dual-luciferase reporter and RNA pull-down assays. Brucine suppressed the proliferation, migration, and invasion of RA-FLSs, and alleviated inflammation by reducing the release of pro-inflammatory factors and macrophage M1 polarization. RA-FLSs showed increased circ_0139658 and YY1 levels and decreased miR-653-5p levels. Circ_0139658 is directly bound to miR-653-5p to regulate YY1 expression. Brucine treatment suppressed circ_0139658 and YY1 expression but increased YY1 expression in RA-FLSs. Functionally, circ_0139658 overexpression reversed the suppressing effects of Brucine on RA-FLS dysfunction and inflammation. Moreover, circ_0139658 silencing alleviated the dysfunction and inflammation in RA-FLSs, which were reverted by YY1 overexpression. Brucine suppressed the proliferation, migration, invasion, and inflammation in RA-FLSs by decreasing YY1 via circ_0139658/miR-653-5p axis.
苦参碱是一种弱碱性吲哚生物碱，具有广泛的药理活性，已被证实可预防类风湿关节炎（RA）进程。环状 RNA（circRNA）也被报道参与 RA 的发病机制。在这里，我们旨在探讨苦参碱和 circ_0139658 在 RA 进展中的作用和机制。分离类风湿关节炎成纤维样滑膜细胞（RA-FLSs）进行功能分析。通过 CCK-8 测定、EdU 测定、流式细胞术、Transwell 测定和 ELISA 分析分别评估细胞增殖、凋亡、侵袭、迁移和炎症反应。qRT-PCR 和 Western blot 分析用于测量基因和蛋白水平。使用双荧光素酶报告和 RNA 下拉测定验证 miR-653-5p 与 circ_0139658 或 Yin Yang 1（YY1）之间的结合。苦参碱抑制 RA-FLSs 的增殖、迁移和侵袭，并通过减少促炎因子的释放和巨噬细胞 M1 极化来减轻炎症。RA-FLSs 显示 circ_0139658 和 YY1 水平升高，miR-653-5p 水平降低。Circ_0139658 直接与 miR-653-5p 结合以调节 YY1 表达。苦参碱处理抑制 circ_0139658 和 YY1 表达，但增加 RA-FLSs 中的 YY1 表达。功能上，circ_0139658 过表达逆转了苦参碱对 RA-FLS 功能障碍和炎症的抑制作用。此外，circ_0139658 沉默减轻了 RA-FLSs 的功能障碍和炎症，而过表达 YY1 则逆转了这一作用。苦参碱通过 circ_0139658/miR-653-5p 轴降低 YY1 表达来抑制 RA-FLSs 的增殖、迁移、侵袭和炎症。
