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Discovery of aspirin-triggered eicosanoid-like mediators in a Drosophila metainflammation blood tumor model.
Journal of Cell Science ( IF 3.3 ) Pub Date : 2019-10-28 , DOI: 10.1242/jcs.236141
Silvio Panettieri 1, 2 , Indira Paddibhatla 3, 4 , Jennifer Chou 4 , Roma Rajwani 4 , Rebecca S Moore 4 , Tamara Goncharuk 4 , George John 2, 5 , Shubha Govind 6, 7
Affiliation  

Epidemiologic studies have linked the use of aspirin to a decline in chronic inflammation that underlies many human diseases, including some cancers. Aspirin reduces the levels of cyclooxygenase-mediated pro-inflammatory prostaglandins, promotes the production of pro-resolution molecules, and triggers the production of anti-inflammatory electrophilic mono-oxygenated (EFOX) lipid mediators. We investigated the effects of aspirin in fruit fly models of chronic inflammation. Ectopic Toll/NF-κB and JAK/STAT signaling in mutant D. melanogaster results in overproliferation of hematopoietic blood progenitors resulting in the formation of granuloma-like tumors. Ectopic JAK-STAT signaling also leads to metabolic inflammation. We report that aspirin-treated mutant flies experience reduction in metabolic inflammation, mitosis, ectopic immune signaling, and macrophage infiltration. Moreover, these flies synthesize 13-HODE, and aspirin triggers 13-oxoODE (13-EFOX-L2) production. Providing the precursor of 13-HODE, linoleic acid, or performing targeted knockdown of the transcription factor STAT in inflammatory blood cells, boosts 13-EFOX-L2 levels while decreasing metabolic inflammation. Thus, hematopoietic cells regulate metabolic inflammation in flies, and their effects can be reversed by pharmaceutical or dietary intervention, suggesting deep phylogenetic conservation in the ability of animals to resolve inflammation and repair tissue damage. These findings can help identify novel treatment targets in humans.

中文翻译:

在果蝇元炎性血液肿瘤模型中发现了阿司匹林触发的类花生酸样介质。

流行病学研究已将阿司匹林的使用与慢性炎症的减少联系在一起,而慢性炎症是许多人类疾病(包括某些癌症)的基础。阿司匹林降低了环氧合酶介导的促炎性前列腺素的水平,促进了促分辨率分子的产生,并触发了抗炎性亲电子单加氧(EFOX)脂质介体的产生。我们研究了阿司匹林在慢性炎症果蝇模型中的作用。突变D. melanogaster中的异位Toll /NF-κB和JAK / STAT信号导致造血血祖细胞过度增殖,导致肉芽肿样肿瘤的形成。异位JAK-STAT信号转导也会导致代谢炎症。我们报告说,经阿司匹林治疗的突变体苍蝇在代谢性炎症,有丝分裂,异位免疫信号传导,和巨噬细胞浸润。此外,这些果蝇合成13-HODE,而阿司匹林触发13-氧代ODE(13-EFOX-L2)的生产。提供13-HODE的前体,亚油酸或在炎性血细胞中进行转录因子STAT的靶向敲低,可提高13-EFOX-L2水平,同时减少代谢性炎症。因此,造血细胞调节果蝇的代谢炎症,并且其作用可以通过药物或饮食干预来逆转,这表明动物在解决炎症和修复组织损伤的能力方面具有深厚的系统发育学保护意识。这些发现可以帮助确定人类的新型治疗目标。或在发炎的血细胞中进行转录因子STAT的靶向击倒,可提高13-EFOX-L2水平,同时减少代谢性炎症。因此,造血细胞调节果蝇的代谢炎症,并且其作用可以通过药物或饮食干预来逆转,这表明动物在解决炎症和修复组织损伤的能力方面具有深厚的系统发育学保护意识。这些发现可以帮助确定人类的新型治疗目标。或在发炎的血细胞中进行转录因子STAT的靶向击倒,可提高13-EFOX-L2水平,同时减少代谢性炎症。因此,造血细胞调节果蝇的代谢炎症,并且其作用可以通过药物或饮食干预来逆转,这表明动物在解决炎症和修复组织损伤的能力方面具有深厚的系统发育学保护意识。这些发现可以帮助确定人类的新型治疗目标。提示动物在解决炎症和修复组织损伤的能力上有较深的系统发育保护。这些发现可以帮助确定人类的新型治疗目标。提示动物在解决炎症和修复组织损伤的能力上有较深的系统发育保护。这些发现可以帮助确定人类的新型治疗目标。
更新日期:2020-03-16
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