Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Immunol. 2019 Jan 8;9:3102. doi: 10.3389/fimmu.2018.03102. eCollection 2018.
Plumbago zeylanica L. (with plumbagin as its active ingredients) has been used for centuries to treat conditions such as joint swelling, fractures, and bacterial infections, suggesting that it possesses anti-inflammatory and immunosuppressive properties. In the present study, we evaluated the potential anti-arthritic activity and related mechanisms of plumbagin. Collagen-induced arthritis (CIA) was initiated in Wistar rats with collagen type II. Plumbagin (2 and 6 mg/kg) was orally administered to rats with CIA from day 12 to day 32 post immunization. The effects of plumbagin on arthritis progression were assessed by paw swelling, clinical scoring, and histologic analysis. The percentage of Treg and Th17 were defined by flow cytometry or immunofluorescence (IF) staining. Bone erosion and resorption were assessed by micro-CT and histomorphometric analysis. Osteoclast differentiation was further determined by osteoclastogenesis assay. The molecular docking assay was used to determine the potential binding site of plumbagin. Treatment with plumbagin significantly inhibited arthritis development, as well as suppressed the local and systemic inflammation. Plumbagin reciprocally regulated pro-inflammatory Th17 cell and immunosuppressive Treg cell populations. In addition, plumbagin protected inflammation-induced bone loss by inhibiting osteoclast formation and activity. Plumbagin markedly suppressed RANKL-stimulated osteoclast-specific gene expression by repressing NF-κB signaling activation and MAP kinase phosphorylation. Further study via molecular docking assay demonstrated that plumbagin bound to MET169 of JNK kinase and LYS138 and SER183 of p38 kinase. Plumbagin not only attenuates the immune-induced arthritis by inhibiting inflammation, but also protects bone erosion by directly inhibiting osteoclast formation and activity. These data suggest plumbagin is a promising new candidate drug for treating inflammatory joint diseases.
白花丹（以白花丹素为其活性成分）已被使用了几个世纪来治疗关节肿胀、骨折和细菌感染等疾病，这表明它具有抗炎和免疫抑制特性。在本研究中，我们评估了白花丹素的潜在抗关节炎活性及其相关机制。在 Wistar 大鼠中用 II 型胶原诱导关节炎。从免疫后第 12 天到第 32 天，给 CIA 大鼠口服给予白花丹素（2 和 6mg/kg）。通过爪肿胀、临床评分和组织学分析评估白花丹素对关节炎进展的影响。通过流式细胞术或免疫荧光（IF）染色定义 Treg 和 Th17 的百分比。通过微 CT 和组织形态计量分析评估骨侵蚀和吸收。通过破骨细胞生成试验进一步确定破骨细胞分化。分子对接试验用于确定白花丹素的潜在结合位点。 白花丹素治疗显著抑制关节炎发展，并抑制局部和全身炎症。白花丹素相互调节促炎 Th17 细胞和免疫抑制 Treg 细胞群。此外，白花丹素通过抑制破骨细胞形成和活性来保护炎症诱导的骨丢失。白花丹素通过抑制 NF-κB 信号激活和 MAP 激酶磷酸化，显著抑制 RANKL 刺激的破骨细胞特异性基因表达。通过分子对接试验的进一步研究表明，白花丹素结合到 JNK 激酶的 MET169 和 p38 激酶的 LYS138 和 SER183。 白花丹素不仅通过抑制炎症来减轻免疫诱导的关节炎，而且还通过直接抑制破骨细胞形成和活性来保护骨侵蚀。这些数据表明，白花丹素是一种有前途的治疗炎症性关节疾病的新型候选药物。
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