PMID- 37004347 OWN - NLM STAT- MEDLINE DCOM- 20230425 LR - 20230705 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 118 DP - 2023 May TI - Tanshinone IIA analogue 15a inhibits NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate acute tubular necrosis. PG - 110065 LID - S1567-5769(23)00386-7 [pii] LID - 10.1016/j.intimp.2023.110065 [doi] AB - BACKGROUND: Acute tubular necrosis (ATN) is a common type of acute renal failure. Recent studies have shown that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in macrophages plays a crucial role in the progression of ATN. Previously, we synthesized an anti-inflammatory compound 15a based on Tanshinone IIA (Tan IIA). In the present study, we found that compound 15a exhibited a greater inhibitory effect on NLRP3-mediated pyroptosis than Tan IIA in vitro. METHODS: C57BL/6 and NLRP3-knockout (NLRP3-KO) mice were intraperitoneally injected with LPS or folic acid (FA) to develop ATN. In vitro, bone marrow-derived macrophages (BMDMs) were treated with LPS for 3 h and then treated with ATP for 0.5 h. RESULTS: We explored the mechanism by which compound 15a inhibited NLRP3 inflammasome in BMDMs as well as its renal protective effect against ATN in mice. We found that compound 15a exhibited a protective effect on mitochondria and reduced the production of mitochondrial reactive oxygen species (mtROS). Moreover, we revealed that compound 15a remarkably reduced the production of mtROS by promoting mitophagy, which resulted in the inhibition of NLRP3 inflammasome to alleviates ATN in mice. CONCLUSION: In summary, compound 15a inhibited NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate ATN. Our results identified compound 15a as a promising candidate for the treatment of NLRP3-driven ATN. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Chen, Jiahao AU - Chen J AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Luo, Wu AU - Luo W AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Hu, Chenghong AU - Hu C AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Ren, Miao AU - Ren M AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Xu, Haowen AU - Xu H AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Xu, Xiangwei AU - Xu X AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China. FAU - Li, Weifeng AU - Li W AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Chen, Yue AU - Chen Y AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Shao, Jingjing AU - Shao J AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. FAU - Xiao, Zhongxiang AU - Xiao Z AD - Affiliated Yueqing Hospital,Wenzhou Medical University, Yueqing, Wenzhou, Zhejiang, 325035, China. FAU - Lv, Xinting AU - Lv X AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China. Electronic address: yklvxinting@163.com. FAU - Liang, Guang AU - Liang G AD - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310012, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: wzmcliangguang@163.com. LA - eng PT - Journal Article DEP - 20230331 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 03UUH3J385 (tanshinone) RN - 0 (Lipopolysaccharides) RN - 0 (Reactive Oxygen Species) RN - 0 (Nlrp3 protein, mouse) SB - IM EIN - Int Immunopharmacol. 2023 Aug;121:110575. PMID: 37407366 MH - Mice MH - Animals MH - *Inflammasomes MH - *NLR Family, Pyrin Domain-Containing 3 Protein MH - Mitophagy MH - Lipopolysaccharides/pharmacology MH - Mice, Inbred C57BL MH - Macrophages MH - Reactive Oxygen Species MH - Mice, Knockout MH - Inflammation/drug therapy MH - Necrosis/drug therapy OTO - NOTNLM OT - Acute tubular necrosis OT - Macrophage OT - Mitophagy OT - NLRP3 OT - Tanshinone IIA OT - mtROS COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/04/03 06:00 MHDA- 2023/04/25 06:42 CRDT- 2023/04/02 18:05 PHST- 2023/01/28 00:00 [received] PHST- 2023/03/13 00:00 [revised] PHST- 2023/03/20 00:00 [accepted] PHST- 2023/04/25 06:42 [medline] PHST- 2023/04/03 06:00 [pubmed] PHST- 2023/04/02 18:05 [entrez] AID - S1567-5769(23)00386-7 [pii] AID - 10.1016/j.intimp.2023.110065 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 May;118:110065. doi: 10.1016/j.intimp.2023.110065. Epub 2023 Mar 31.