Nimbolide exerts protective effects in complete Freund's adjuvant induced inflammatory arthritis via abrogation of STAT-3/NF-κB/Notch-1 signaling
Nimbolide exerts protective effects in complete Freund's adjuvant induced inflammatory arthritis via abrogation of STAT-3/NF-κB/Notch-1 signaling
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DOI：
10.1016/j.lfs.2020.118911
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发表时间：
2021-02-01
期刊：
影响因子：
6.1
通讯作者：
Godugu, Chandraiah
中科院分区：
文献类型：
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作者：
Anchi, Pratibha;Swamy, Veerabhadra;Godugu, Chandraiah
目的：跨膜Notch-1受体通过炎性细胞因子的激活受到STAT-3和NF-κ B B磷酸化的高度调节。Nimbolide（NMB）通过靶向多种途径表现出有效的抗炎、抗纤维化、抗癌活性。本研究采用完全弗氏佐剂（CFA）诱导的大鼠炎症性关节炎（IA）模型，观察NMB对STAT-3/NF-κ B/Notch-1轴的调节作用。主要方法：采用IL-1 β刺激的HIG-82滑膜成纤维细胞模型和CFA诱导的大鼠IA模型，观察NMB的抗炎和抗关节炎活性。通过抗迁移作用评估体外抗关节炎活性，而通过放射学和组织学分析评估体内作用。采用Western blot、免疫组化和ELISA方法研究NMB对STAT-3、NF-κ B B、Notch-1信号通路和促炎细胞因子的影响。从关节炎大鼠的放射学和组织学异常的改善中可以证明，它减少了关节炎的进展。NMB显着抑制亚硝氧化应激和促炎细胞因子的水平。NMB对MAPK、STAT-3和NF-κ B B磷酸化介导的Notch-1信号通路的上调也表现出显著的保护活性。意义：NMB可能通过抑制STAT-3/NF-κ B B/ Notch-1轴和降低促炎细胞因子水平而对类风湿关节炎具有临床治疗价值。
Aim: Activation of transmembrane Notch-1 receptors through inflammatory cytokines is highly regulated by STAT-3 and NF-.B phosphorylation. Nimbolide (NMB) exhibits potent anti-inflammatory, anti-fibrotic, anticancer activities by targeting various pathways. Here, we have investigated the effect of NMB in regulation of STAT-3/NF-kappa B/Notch-1 axis in complete Freund's adjuvant (CFA) induced inflammatory arthritis (IA) model.Main methods: The anti-inflammatory and anti-arthritic activity of NMB was evaluated both in vitro (IL-1 beta stimulated HIG-82 synovial fibroblasts) and in vivo (CFA induced rat model of IA) models. In vitro anti-arthritic activity was assessed by anti-migratory effect, while in vivo effects were evaluated through radiological and histological analysis. The effect of NMB on STAT-3, NF-kappa B, Notch-1 signaling pathways and proinflammatory cytokines were studied using western blot, immunohistochemistry and ELISA methods.Key findings NMB attenuated the migration of synovial fibroblasts in vitro. It reduced the progression of arthritis as evidenced from the improved radiological and histological abnormalities in arthritic rats. NMB significantly suppressed the nitrosooxidative stress and levels of pro-inflammatory cytokines. NMB also exhibited remarkable protective activity against upregulation of MAPK, STAT-3 and NF-kappa B phosphorylation mediated Notch-1 signaling pathway in synovial tissue of arthritic rats.Significance: NMB may have clinical therapeutic value in rheumatoid arthritis by inhibiting STAT-3/NF-kappa B/ Notch-1 axis and also by reducing the levels of proinflammatory cytokines.