Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Department of Pharmaceutical Sciences, University of Saint Joseph, School of Pharmacy and Physician Assistant Studies, Hartford, CT, USA.
Inflammation. 2019 Oct;42(5):1719-1729. doi: 10.1007/s10753-019-01032-y.
Hemarthrosis is the primary cause of hemophiliac arthropathy (HA). Pro-inflammatory cytokines are thought to play an important role in the pathogenesis of HA, and thus, anti-cytokine approaches may be used as an adjuvant therapy. A novel series of enaminone compounds (JODI), that contain the N-aryl piperazino motif, have been shown in vitro to reduce pro-inflammatory cytokines and thus may be efficacious in vivo. In this report, we will assess whether JODI can suppress multiple cytokines which might be potentially responsible for joint inflammation in a mouse model of hemarthrosis. The results showed that JODI significantly improved the survival after LPS treatment, and most pro-inflammatory cytokines/chemokines were decreased significantly after JODI administration. In the hemophilia mouse model, hemarthrosis resulted in local cytokine/chemokine changes, represented by elevated pro-inflammatory (IL-6, MCP-1, MIP-1α, MIP-1β) and pro-angiogenic (VEGF and IL-33) cytokines, and decreased anti-pro-inflammatory cytokines IL-4 and IL-10. The changes were reversed by administration of JODI, which can be used as a novel approach to manage hemophilia arthropathy.
关节积血是血友病性关节病（HA）的主要原因。促炎细胞因子被认为在 HA 的发病机制中起重要作用，因此，抗细胞因子方法可作为辅助治疗。一系列新型烯胺酮化合物（JODI），含有 N-芳基哌嗪基结构，已在体外证明可减少促炎细胞因子，因此在体内可能有效。在本报告中，我们将评估 JODI 是否可以抑制多种细胞因子，这些细胞因子可能在关节积血的小鼠模型中导致关节炎症。结果表明，JODI 显著提高了 LPS 处理后的存活率，并且 JODI 给药后大多数促炎细胞因子/趋化因子显著降低。在血友病小鼠模型中，关节积血导致局部细胞因子/趋化因子变化，表现为促炎（IL-6、MCP-1、MIP-1α、MIP-1β）和促血管生成（VEGF 和 IL-33）细胞因子升高，抗炎细胞因子 IL-4 和 IL-10 减少。JODI 的给药逆转了这些变化，可作为治疗血友病性关节病的新方法。
