PDF(Pubmed)
Abstract：
Rheumatoid arthritis (RA) is a debilitating autoimmune condition characterized by chronic synovitis, joint damage, and inflammation, leading to impaired joint functionality. Existing RA treatments, although effective to some extent, are not without side effects, prompting a search for more potent therapies. Recent research has revealed the critical role of FAS-associated death domain protein (FADD) microvesicular shedding in RA pathogenesis, expanding its scope beyond apoptosis to include inflammatory and immune pathways. This study aimed to investigate the intricate relationship between mi-RNA 128a, autoimmune and inflammatory pathways, and adenosine levels in modulating FADD expression and microvesicular shedding in a Freund\'s complete adjuvant (FCA) induced RA rat model and further explore the antirheumatoid potency of trimetazidine (TMZ). The FCA treated model exhibited significantly elevated levels of serum fibrogenic, inflammatory, immunological and rheumatological diagnostic markers, confirming successful RA induction. Our results revealed that the FCA-induced RA model showed a significant reduction in the expression of FADD in paw tissue and increased microvesicular FADD shedding in synovial fluid, which was attributed to the significant increase in the expression of the epigenetic miRNA 128a gene in addition to the downregulation of adenosine levels. These findings were further supported by the significant activation of the TLR4/MYD88 pathway and its downstream inflammatory IkB/NFB markers. Interestingly, TMZ administration significantly improved, with a potency similar to methotrexate (MTX), the deterioration effect of FCA treatment, as evidenced by a significant attenuation of fibrogenic, inflammatory, immunological, and rheumatological markers. Our investigations indicated that TMZ uniquely acted by targeting epigenetic miRNA128a expression and elevating adenosine levels in paw tissue, leading to increased expression of FADD of paw tissue and mitigated FADD microvesicular shedding in synovial fluid. Furthermore, the group treated with TMZ showed significant downregulation of TLR4/MYD88 and their downstream TRAF6, IRAK and NF-kB. Together, our study unveils the significant potential of TMZ as an antirheumatoid candidate, offering anti-inflammatory effects through various mechanisms, including modulation of the FADD-epigenetic regulator mi-RNA 128a, adenosine levels, and the TLR4 signaling pathway in joint tissue, but also attenuation of FADD microvesicular shedding in synovial fluid. These findings further highlight the synergistic administration of TMZ and MTX as a potential approach to reduce adverse effects of MTX while improving therapeutic efficacy.
摘要：
类风湿性关节炎（RA）是一种以慢性滑膜炎为特征的衰弱性自身免疫性疾病，接头损伤,和炎症，导致关节功能受损。现有的RA治疗，虽然在某种程度上有效，不是没有副作用,促使人们寻找更有效的疗法。最近的研究揭示了FAS相关死亡结构域蛋白（FADD）微囊泡脱落在RA发病机制中的关键作用。将其范围扩大到细胞凋亡之外，包括炎症和免疫途径。本研究旨在探讨mi-RNA128a之间的复杂关系，自身免疫和炎症途径，和腺苷水平在弗氏完全佐剂（FCA）诱导的RA大鼠模型中调节FADD表达和微囊泡脱落，并进一步探讨曲美他嗪（TMZ）的抗类风湿功效。FCA处理的模型表现出显著升高的血清纤维化水平,炎症，免疫学和风湿病诊断标记，确认RA诱导成功。我们的结果表明，FCA诱导的RA模型显示，爪组织中FADD的表达显着降低，滑液中的微囊泡FADD脱落增加，这归因于除了腺苷水平下调外，表观遗传miRNA128a基因的表达显着增加。TLR4/MYD88途径及其下游炎性IkB/NFB标志物的显著激活进一步支持了这些发现。有趣的是,TMZ管理明显改善，具有类似于甲氨蝶呤（MTX）的效力，FCA治疗的恶化效应，如纤维化的显着衰减所证明的，炎症，免疫学，和风湿病标志物。我们的研究表明，TMZ通过靶向表观遗传miRNA128a表达和提高爪组织中的腺苷水平而独特地发挥作用。导致爪组织中FADD的表达增加，并减轻滑液中FADD微囊的脱落。此外，TMZ治疗组显示TLR4/MYD88及其下游TRAF6,IRAK和NF-kB显著下调.一起,我们的研究揭示了TMZ作为抗类风湿候选药物的巨大潜力，通过各种机制提供抗炎作用，包括调节FADD-表观遗传调节因子mi-RNA128a，腺苷水平，和关节组织中的TLR4信号通路，同时也减弱了滑液中FADD微囊的脱落。这些发现进一步突出了TMZ和MTX的协同施用作为减少MTX的副作用同时提高治疗功效的潜在方法。
