International Immunopharmacology ( IF 4.8 ) Pub Date : 2019-11-13 , DOI: 10.1016/j.intimp.2019.105963 Sijia Peng , Jingjing Jia , Jingjing Sun , Qizhi Xie , Xiaoyun Zhang , Yuanfei Deng , Li Yi
Microglia activation is closely linked to ischemia, various chronic neurodegenerative diseases (e.g., Alzheimer′s disease, Parkinson′s disease, multiple sclerosis, amyotrophic lateral sclerosis), and many other central nervous system diseases. Accumulating evidence suggests that depressing the microglial inflammatory response could be an effective treatment for inflammatory disorders. The integrin αvβ3 inhibitor LXW7 has a neuroprotective effect; however, its anti-inflammatory effects and underlying mechanism remain unclear. Thus, we examined whether LXW7 would inhibit inflammatory cytokines and mediators, and we evaluated the potential mechanisms of its neuroprotective effects. Nitrite analysis revealed LXW7 reduced the nitric oxide (NO) level. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) suggested that LXW7 suppressed the expression of proinflammatory genes for tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and anti-inflammatory gene interleukin 10 (IL-10) at the messenger ribonucleic acid level. Enzyme-linked immunosorbent assay results demonstrated that LXW7 treatment reduced the expression of prostaglandin E2 (PGE2), TNF-α, IL-1β and IL-10 at the protein level. Western blotting was conducted to confirm the upregulation of inflammatory factors, including iNOS and COX-2 at the protein level. LXW7 inhibited major genes in the Akt/NF-κB and c-Jun NH2-terminal kinase/ mitogen-activated protein kinases (JNK/MAPK) signaling pathways. Immunofluorescence revealed that LXW7 inhibited the nuclear translocation of nuclear factor kappa B (NF-κB). Thus, LXW7 effectively alleviated LPS-induced inflammatory damage and had neuroprotective effects. The anti-inflammatory effects of LXW7 may be associated with the inhibition of microglial activation via Akt/NF-κB and JNK/MAPK signaling pathways by blocking integrin αvβ3 receptor. The present study′s findings suggest that LXW7 has a substantial therapeutic potential for treating inflammatory and neurodegenerative diseases.
中文翻译:
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LXW7通过抑制脂多糖刺激的BV2小胶质细胞中的Akt /核因子κB和丝裂原激活的蛋白激酶信号传导途径来减轻炎症
小胶质细胞活化与缺血,各种慢性神经退行性疾病(例如,阿尔茨海默氏病,帕金森氏病,多发性硬化症,肌萎缩性侧索硬化症)和许多其他中枢神经系统疾病密切相关。越来越多的证据表明,抑制小胶质细胞的炎症反应可能是治疗炎症性疾病的有效方法。整联蛋白αvβ3抑制剂LXW7具有神经保护作用。但是,其抗炎作用及其潜在机制尚不清楚。因此,我们检查了LXW7是否会抑制炎症细胞因子和介质,并评估了其神经保护作用的潜在机制。亚硝酸盐分析显示LXW7降低了一氧化氮(NO)含量。逆转录定量聚合酶链反应(RT-qPCR)表明,LXW7抑制了肿瘤坏死因子-α(TNF-α),白介素1-β(IL-1β),诱导型一氧化氮合酶(iNOS),信使核糖核酸水平的环氧化酶2(COX-2)和抗炎基因白介素10(IL-10)。酶联免疫吸附试验结果表明,LXW7处理可降低蛋白质水平上前列腺素E2(PGE2),TNF-α,IL-1β和IL-10的表达。进行蛋白质印迹分析以确认炎症因子在蛋白质水平上调,包括iNOS和COX-2。LXW7抑制了Akt /NF-κB和c-Jun NH2末端激酶/有丝分裂原激活的蛋白激酶(JNK / MAPK)信号通路中的主要基因。免疫荧光显示,LXW7抑制了核因子κB(NF-κB)的核易位。因此,LXW7有效减轻LPS引起的炎症损伤,并具有神经保护作用。LXW7的抗炎作用可能与通过阻断整联蛋白αvβ3受体抑制Akt /NF-κB和JNK / MAPK信号通路激活的小胶质细胞有关。本研究的发现表明,LXW7具有治疗炎性和神经退行性疾病的巨大治疗潜力。LXW7的抗炎作用可能与通过阻断整联蛋白αvβ3受体抑制Akt /NF-κB和JNK / MAPK信号通路激活的小胶质细胞有关。本研究的发现表明,LXW7具有治疗炎性和神经退行性疾病的巨大治疗潜力。LXW7的抗炎作用可能与通过阻断整联蛋白αvβ3受体抑制Akt /NF-κB和JNK / MAPK信号通路激活的小胶质细胞有关。本研究的发现表明,LXW7具有治疗炎性和神经退行性疾病的巨大治疗潜力。