Lin Xian, Lin Tengyu, Wang Xiaocheng, He Jiaxin, Gao Xu, Lyu Shuyan, Wang Qingwen, Chen Jian
Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen 518036, China; Institute of Immunology and Inflammatory Diseases, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China; Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen 518036, China.
Shenzhen Key Laboratory of Inflammatory and Immunology Diseases, Shenzhen 518036, China.
Phytomedicine. 2023 Dec;121:155109. doi: 10.1016/j.phymed.2023.155109. Epub 2023 Sep 21.
Rheumatoid arthritis (RA) is an autoimmune disease known as a leading cause of disability with considerable mortality. Developing alternative drugs and targets for RA treatment is an urgent issue. Sesamol is a phenolic compound isolated from natural food sesame (Sesamum indicum L.) with various biological activities.
The current research intended to illuminate the bioactivity and mechanisms of sesamol in RA fibroblast-like synoviocytes (FLS), and aimed to estimate the potential clinical application value of sesamol in RA treatment.
CCK-8, EdU, and flow cytometry assays, as well as transwell tests were applied to observe the effects of sesamol on the abnormal functions of RA-FLS. Moreover, synovial organoids and a collagen-induced arthritis (CIA) mouse model were constructed to further explore the therapeutic capacity of sesamol on RA. Furthermore, RNA sequencing combined with quantitative real-time PCR assay, Western blot as well as co-immunoprecipitation were employed to clarify the mechanism of sesamol in regulating RA progression.
Sesamol suppressed the proliferation through inhibiting DNA replication, triggering cell cycle arrest and apoptosis of RA-FLS. Besides, sesamol impaired RA-FLS migration and invasion. Interestingly, sesamol inhibited the growth of constructed synovial organoids and alleviated RA symptoms in CIA mice. Moreover, RNA sequencing further implicated p53 signaling as a downstream pathway of sesamol. Furthermore, sesamol was shown to decrease p53 ubiquitination and degradation, thereby activating p53 signaling. Finally, bioinformatics analyses also highlighted the importance of sesamol-regulated networks in the progression of RA.
Our investigation demonstrated that sesamol served as a novel p53 stabilizer to attenuate the abnormal functions of RA-FLS via facilitating the activation of p53 signaling. Moreover, our study highlighted that sesamol might be an effective lead compound or candidate drug and p53 could be a promising target for the therapy of RA.
类风湿关节炎（RA）是一种自身免疫性疾病，是导致残疾的主要原因之一，死亡率相当高。开发用于RA治疗的替代药物和靶点是一个紧迫的问题。芝麻酚是一种从天然食物芝麻（Sesamum indicum L.）中分离出的酚类化合物，具有多种生物活性。
当前研究旨在阐明芝麻酚在RA成纤维样滑膜细胞（FLS）中的生物活性及机制，并评估芝麻酚在RA治疗中的潜在临床应用价值。
采用CCK-8、EdU、流式细胞术检测以及Transwell试验观察芝麻酚对RA-FLS异常功能的影响。此外，构建滑膜类器官和胶原诱导性关节炎（CIA）小鼠模型以进一步探究芝麻酚对RA的治疗能力。此外，运用RNA测序结合定量实时PCR检测、蛋白质免疫印迹以及免疫共沉淀来阐明芝麻酚调节RA进展的机制。
芝麻酚通过抑制DNA复制、引发细胞周期阻滞和RA-FLS凋亡来抑制其增殖。此外，芝麻酚损害RA-FLS的迁移和侵袭能力。有趣的是，芝麻酚抑制构建的滑膜类器官生长并减轻CIA小鼠的RA症状。此外，RNA测序进一步表明p53信号通路是芝麻酚的下游通路。此外，芝麻酚可减少p53的泛素化和降解，从而激活p53信号通路。最后，生物信息学分析也强调了芝麻酚调节网络在RA进展中的重要性。
我们的研究表明，芝麻酚作为一种新型p53稳定剂，通过促进p53信号通路的激活来减弱RA-FLS的异常功能。此外，我们的研究强调芝麻酚可能是一种有效的先导化合物或候选药物，p53可能是RA治疗的一个有前景的靶点。
