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8-Chloroadenosine Alters the Metabolic Profile and Downregulates Antioxidant and DNA Damage Repair Pathways in Macrophages.
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2019-12-16 , DOI: 10.1021/acs.chemrestox.9b00334 Jessica L Macer-Wright 1, 2 , Inga Sileikaite 3 , Benjamin S Rayner 1, 2 , Clare L Hawkins 1, 2, 3
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2019-12-16 , DOI: 10.1021/acs.chemrestox.9b00334 Jessica L Macer-Wright 1, 2 , Inga Sileikaite 3 , Benjamin S Rayner 1, 2 , Clare L Hawkins 1, 2, 3
Affiliation
The exposure of RNA and DNA nucleobases to the oxidant hypochlorous acid (HOCl) results in the generation of different stable chlorinated products. These chlorinated nucleobases are formed in vivo, particularly in chronic inflammatory pathologies, which are characterized by the overproduction of HOCl by myeloperoxidase. As such, chlorinated nucleosides are used as biomarkers of inflammation. However, these compounds have also attracted attention as potential chemotherapeutic agents with 8-chloro-adenosine (8ClA), for example, currently in clinical trials for the treatment of hematological cancers, including chronic lymphocytic leukemia. 8ClA has mainly RNA-directed effects in malignant cells, with exposure resulting in ATP depletion and apoptotic cell death. Whether 8ClA has significant reactivity with nonmalignant cells has not been widely studied. Here we show that prolonged incubation of J774A.1 macrophage-like cells with 8ClA results in the perturbation of cellular metabolism and apoptotic cell death. These effects are associated with an accumulation of 8-chloroadenosine triphosphate (8Cl-ATP), an effect not seen in experiments utilizing other chlorinated nucleosides. Exposure of the macrophages to 8ClA did not significantly change basal mitochondrial respiration or glycolysis but resulted in an increase in maximal mitochondrial respiration as well as spare respiratory capacity within these cells. Additionally, 8ClA exposure also altered the mRNA expression of a range of antioxidant and DNA damage repair genes in the macrophages in a manner consistent with a reduction in the capacity of the cells to cope with oxidative stress and repair DNA damage. Taken together, these results provide new insight into pathways by which the production of HOCl during chronic inflammation could perturb immune cell function and may also have implications for the use of 8ClA as a chemotherapeutic drug.
中文翻译:
8-Chloroadenosine改变巨噬细胞的代谢谱并下调抗氧化剂和DNA损伤修复途径。
将RNA和DNA核碱基暴露于氧化剂次氯酸(HOCl)会导致生成不同的稳定氯化产物。这些氯化的核碱基是在体内形成的,特别是在慢性炎性病理中,其特征在于髓过氧化物酶过量产生HOCl。这样,氯化核苷被用作炎症的生物标记。但是,这些化合物作为与8-氯腺苷(8ClA)的潜在化学治疗剂也引起了人们的关注,例如,目前正在临床试验中治疗血液学癌症,包括慢性淋巴细胞性白血病。8ClA在恶性细胞中主要具有RNA定向作用,暴露导致ATP耗竭和凋亡性细胞死亡。8ClA是否与非恶性细胞具有显着反应性尚未得到广泛研究。在这里,我们显示J774A.1巨噬细胞样细胞与8ClA的长时间孵育会导致细胞代谢紊乱和凋亡性细胞死亡。这些作用与8氯腺苷三磷酸(8Cl-ATP)的积累有关,这种作用在利用其他氯化核苷的实验中未见到。巨噬细胞暴露于8ClA不会显着改变基础线粒体呼吸或糖酵解,但会导致最大线粒体呼吸增加以及这些细胞内的备用呼吸能力增加。此外,8ClA暴露还改变了巨噬细胞中一系列抗氧化剂和DNA损伤修复基因的mRNA表达,其方式与降低细胞应对氧化应激和修复DNA损伤的能力相一致。综上所述,这些结果为慢性炎症期间HOCl的产生可能扰乱免疫细胞功能的途径提供了新的见解,也可能对8ClA作为化学治疗药物的使用产生影响。
更新日期:2019-12-17
中文翻译:
8-Chloroadenosine改变巨噬细胞的代谢谱并下调抗氧化剂和DNA损伤修复途径。
将RNA和DNA核碱基暴露于氧化剂次氯酸(HOCl)会导致生成不同的稳定氯化产物。这些氯化的核碱基是在体内形成的,特别是在慢性炎性病理中,其特征在于髓过氧化物酶过量产生HOCl。这样,氯化核苷被用作炎症的生物标记。但是,这些化合物作为与8-氯腺苷(8ClA)的潜在化学治疗剂也引起了人们的关注,例如,目前正在临床试验中治疗血液学癌症,包括慢性淋巴细胞性白血病。8ClA在恶性细胞中主要具有RNA定向作用,暴露导致ATP耗竭和凋亡性细胞死亡。8ClA是否与非恶性细胞具有显着反应性尚未得到广泛研究。在这里,我们显示J774A.1巨噬细胞样细胞与8ClA的长时间孵育会导致细胞代谢紊乱和凋亡性细胞死亡。这些作用与8氯腺苷三磷酸(8Cl-ATP)的积累有关,这种作用在利用其他氯化核苷的实验中未见到。巨噬细胞暴露于8ClA不会显着改变基础线粒体呼吸或糖酵解,但会导致最大线粒体呼吸增加以及这些细胞内的备用呼吸能力增加。此外,8ClA暴露还改变了巨噬细胞中一系列抗氧化剂和DNA损伤修复基因的mRNA表达,其方式与降低细胞应对氧化应激和修复DNA损伤的能力相一致。综上所述,这些结果为慢性炎症期间HOCl的产生可能扰乱免疫细胞功能的途径提供了新的见解,也可能对8ClA作为化学治疗药物的使用产生影响。