Abstract：
Hemophilic arthropathy (HA) is a condition caused by recurrent intra-articular bleeding in patients with hemophilia. Pro-inflammatory cytokines play a crucial role in the pathogenesis of HA. Our previous research demonstrated that a novel compound, piperazino-enaminone (JODI), effectively inhibited pro-inflammatory cytokines, including IL-6, MCP-1, MIP-1α, and MIP-1β, in a mouse model of hemarthrosis. This study aims to enhance the anti-inflammatory effect of JODI by employing nanoparticle delivery systems, which could potentially improve its poor water solubility. Here, we developed liposomes modified with polyethylene glycol (PEG) for the delivery of JODI (JODI-LIP), and found that JODI-LIP exhibited uniform size, morphology, good stability and in vitro release degree. JODI-LIP mitigated cytotoxicity of JODI, and significantly suppressed the production of pro-inflammatory cytokines (TNF-α and IL-1β) and nitric oxide (NO) release in RAW 264.7 cells stimulated by lipopolysaccharide (LPS), as well as the proliferation of human fibroblast-like synovial (HFLS) cells. In a murine model of HA, JODI-LIP demonstrated superior efficacy in ameliorating joint swelling and synovitis, compared to JODI. Importantly, JODI-LIP markedly reduced pro-inflammatory cytokines (TNF-α, IFN-γ, IL-33, and MCP-1) in injured joints. No hepatic or hematological toxicity was observed in mice treated with JODI-LIP. In summary, our results suggest that JODI-LIP holds promise as a therapeutic intervention for HA by attenuating pro-inflammatory cytokine levels.
摘要：
血友病性关节病（HA）是由血友病患者的关节内复发性出血引起的疾病。促炎细胞因子在HA的发病机制中起着至关重要的作用。我们之前的研究表明，一种新的化合物，哌嗪-烯胺酮（JODI），有效抑制促炎细胞因子，包括IL-6、MCP-1、MIP-1α、和MIP-1β，在小鼠关节积血模型中。本研究旨在通过使用纳米颗粒递送系统来增强JODI的抗炎作用。这可能会改善其不良的水溶性。这里,我们开发了聚乙二醇（PEG）修饰的脂质体用于递送JODI（JODI-LIP），发现JODI-LIP表现出均匀的大小，形态学,良好的稳定性和体外释放度。JODI-LIP减轻了JODI的细胞毒性，并显着抑制脂多糖（LPS）刺激的RAW264.7细胞中促炎细胞因子（TNF-α和IL-1β）的产生和一氧化氮（NO）的释放，以及人成纤维细胞样滑膜（HFLS）细胞的增殖。在HA的鼠模型中，JODI-LIP在改善关节肿胀和滑膜炎方面表现出优异的疗效，与Jodi相比。重要的是,JODI-LIP显着降低促炎细胞因子（TNF-α，IFN-γ，IL-33和MCP-1）在受伤的关节中。在用JODI-LIP处理的小鼠中未观察到肝或血液学毒性。总之,我们的结果表明,JODI-LIP有望通过降低促炎细胞因子水平作为HA的治疗干预措施.
