葡萄糖皮质类药物通过对15-氧酶异型的相互调节来调节脂质媒介网络,影响炎症解决
Zhigang Rao1, Elena Brunner1, Benjamin Giszas2
1Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena D-07743, Germany.
概括
葡萄糖皮质体 (GC) 调节免疫细胞中的15-氧酶 (LOX) 异型,影响专门的前溶解介质 (SPM) 生产. 这揭示了GC的机制.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 葡萄糖皮质醇 (GC) 是广泛使用的抗炎药物,但它们促进炎症解消的机制尚不清楚.
- 专门的预溶解媒介 (SPM) 对于解决炎症至关重要,它们的生物合成涉及氧化酶 (LOX) 酶.
- 单细胞/巨细胞系在炎症及其解决过程中发挥关键作用.
研究的目的:
- 研究人类单细胞/巨细胞中葡萄糖皮质类药物对15-LOX异型 (15-LOX-1和15-LOX-2) 的相互调节.
- 确定本条例对SPM和15-LOX衍生的单基化前体 (单-15-OH) 生物合成的后果.
- 探索这些发现在GC治疗COVID-19或炎症性肠病 (IBD) 的患者中的临床相关性.
主要方法:
- 对人类单细胞衍生的巨细胞 (MDM) 现型的甲治疗.
- 对ALOX15/ALOX15B (15-LOX-1/15-LOX-2) 基因和蛋白质表达的分析.
- 测量SPM和单一15-OH水平的测量.
- 葡萄糖皮质体受体 (GR) 抗剂 (RU486) 治疗和染色体免疫沉 (ChIP) 试验.
- 15-LOX-2的击倒实验.
- 来自GC治疗COVID-19或IBD的患者的单细胞的分析.
主要成果:
- 在炎症性M1-MDM中,甲调节了15-LOX-2的表达和增加了SPM/mono-15-OH的产生.
- 德甲降低了15-LOX-1表达的调节,并在预溶解M2-MDM时损害了SPM形成.
- 证实了GC受体 (GR) 与ALOX15B基因的增强子区域的结合.
- 15-LOX-2敲除取消了GC诱导的SPM和单-15-OH生产.
- 在GC治疗COVID-19和IBD患者的单细胞中观察到15-LOX-2的升调.
结论:
- 葡萄糖皮质类药物在人体单细胞/巨细胞中差异调节15-LOX异型,影响SPM生物合成.
- 通过GC对15-LOX-2的升调有助于炎症的解决.
- 这些发现为GC的解决前行动提供了洞察力,并提出了治疗机会.
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