鉴定出 1-乙基丙二酰基辅酶 A 是一种 NOD、LRR 和富含亮氨酸重复蛋白 3（NLRP3）炎症小体抑制剂，它能维持线粒体的完整性。
Identification of ethyl pyruvate as a NLRP3 inflammasome inhibitor that preserves mitochondrial integrity.
机构信息
Department of Hematology and Key Laboratory of non-resolving inflammation and cancer of Human Province, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan province, 410000, People's Republic of China.
Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
出版信息
Mol Med. 2018 Mar 15;24(1):8. doi: 10.1186/s10020-018-0006-9.
BACKGROUND
The NLRP3 inflammasome, a cytosolic complex that mediates the maturation of IL-1β and IL-18 as well as the release of high mobility group box 1 (HMGB1), contributes to the lethality of endotoxic shock. Ethyl pyruvate (EP) was previously shown to inhibit HMGB1 release and promote survival during endotoxemia and experimental sepsis. However, the underlying protective mechanism remains elusive.
RESULT
EP dose-dependently inhibited the ATP-, nigericin-, alum-, and silica-induced caspase-1 activation and HMGB1 release in mouse macrophages. EP failed to inhibit DNA transfection- or Salmonella Typhimurium-induced caspase-1 activation and HMGB1 release. Mechanistically, EP significantly attenuated mitochondrial damage and cytoplasmic translocation of mitochondrial DNA, a known NLRP3 ligand, without influencing the potassium efflux, the lysosomal rupture or the production of mitochondrial reactive oxygen species (mtROS).
CONCLUSION
Ethyl pyruvate acts as a novel NLRP3 inflammasome inhibitor that preserves the integrity of mitochondria during inflammation.
背景
NLRP3 炎性小体是一种胞质复合物，可介导 IL-1β 和 IL-18 的成熟以及高迁移率族蛋白 B1（HMGB1）的释放，有助于内毒素性休克的致死性。先前已表明，丙酮酸乙酯（EP）可抑制内毒素血症和实验性败血症期间的 HMGB1 释放并促进存活。然而，潜在的保护机制仍难以捉摸。
结果
EP 剂量依赖性地抑制了 ATP、 Nigericin、明矾和二氧化硅诱导的小鼠巨噬细胞中 caspase-1 的激活和 HMGB1 的释放。EP 不能抑制 DNA 转染或鼠伤寒沙门氏菌诱导的 caspase-1 激活和 HMGB1 的释放。从机制上讲，EP 显著减轻了线粒体损伤和已知的 NLRP3 配体线粒体 DNA 的细胞质易位，而不影响钾外流，溶酶体破裂或线粒体活性氧物质（mtROS）的产生。
结论
丙酮酸乙酯作为一种新型的 NLRP3 炎性小体抑制剂，可在炎症过程中保持线粒体的完整性。
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