Abstract：
Chronic pain has emerged as a significant public health issue, seriously affecting patients\' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain.
摘要：
慢性疼痛已经成为一个重要的公共卫生问题，严重影响患者的生活质量和心理健康，缺乏有效的药物治疗。大量研究表明，巨噬细胞在炎性疼痛中起着至关重要的作用，和靶向神经免疫相互作用的药物开发可能代表了疼痛管理的一个有希望的方向。Chilobrachysjinghao(C.jinghao)被用作黎族的民间药物，具有消肿的功效，解毒,缓解疼痛,相关产品在市场上得到广泛应用。然而,晶赵的化学成分尚未见报道，药效物质和确切的作用机制尚未揭示。在这里我们分离了一个环状二肽,cyclo(L-Pro-L-Trp)(CPT)首次从C.jingzhao.CPT可显着减轻福尔马林诱导的炎性疼痛并显着抑制炎症反应。在体内,CPT减轻了中性粒细胞浸润和足底组织水肿，并抑制了促炎分子的mRNA表达。体外，CPT在RAW264.7和iBMDM细胞中抑制由脂多糖（LPS）引发的炎症，减少诱导型一氧化氮合酶（iNOS）的表达，超氧化物,和促炎分子。一项机制研究表明，CPT通过阻断丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB）信号通路发挥抗炎活性，以及减轻肿瘤坏死因子受体相关因子6（TRAF6）的泛素化。我们的研究结果阐明了C.jingzhao的药效学物质基础，和CPT可以是缓解炎症和炎性疼痛的有希望的线索。
