PMID- 32989235 OWN - NLM STAT- MEDLINE DCOM- 20211007 LR - 20240226 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 42 IP - 6 DP - 2021 Jun TI - Pristimerin protects against inflammation and metabolic disorder in mice through inhibition of NLRP3 inflammasome activation. PG - 975-986 LID - 10.1038/s41401-020-00527-x [doi] AB - Excessive activation of NLRP3 inflammasome is associated with the pathogenesis of inflammatory diseases. Pristimerin (Pri) is a quinonoid triterpene derived from traditional Chinese medical herb Celastraceae and Hippocrateaceae. Pri has shown antifungal, antibacterial, antioxidant, and anticancer activities. In this study we investigated whether NLRP3 inflammasome was associated with the anti-inflammatory activity of Pri. We showed that Pri (0.1-0.4 muM) dose-dependently blocked caspase-1 activation and IL-1beta maturation in LPS-primed mouse bone-marrow-derived macrophages (BMDMs). Pri specifically inhibited NLRP3 inflammasome activation, had no visible effects on NLRC4 and AIM2 inflammasome activation. Furthermore, we demonstrated that Pri blocked the assembly of the NLRP3 inflammasome via disturbing the interaction between NEK7 and NLRP3; the alpha, beta-unsaturated carbonyl moiety of Pri was essential for NLRP3 inflammasome inactivation. In LPS-induced systemic inflammation mouse model and MSU-induced mouse peritonitis model, preinjection of Pri (500 mug/kg, ip) produced remarkable therapeutic effects via inhibition of NLRP3 inflammasome in vivo. In HFD-induced diabetic mouse model, administration of Pri (100 mug. kg(-1) .d(-1), ip, for 6 weeks) reversed HFD-induced metabolic disorders via suppression of NLRP3 inflammasome activation. Taken together, our results demonstrate that Pri acts as a NLRP3 inhibitor, suggesting that Pri might be useful for the treatment of NLRP3-associated diseases. FAU - Zhao, Qun AU - Zhao Q AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. AD - State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. FAU - Bi, Yun AU - Bi Y AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. FAU - Guo, Jian AU - Guo J AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. FAU - Liu, Ying-Xiang AU - Liu YX AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. FAU - Zhong, Jing AU - Zhong J AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. AD - Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University, Yichang, 443002, China. FAU - Pan, Long-Rui AU - Pan LR AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. FAU - Tan, Yan AU - Tan Y AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. FAU - Yu, Xian-Jun AU - Yu XJ AD - Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, 442000, China. xjyu@hbmu.edu.cn. LA - eng PT - Journal Article DEP - 20200928 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Pentacyclic Triterpenes) RN - 268B43MJ25 (Uric Acid) RN - 28ZK7PR57S (celastrol methyl ester) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*therapeutic use MH - Cells, Cultured MH - Inflammasomes/*antagonists & inhibitors MH - Inflammation/chemically induced/*prevention & control MH - Lipopolysaccharides MH - Liver/pathology MH - Male MH - Metabolic Diseases/pathology/*prevention & control MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists & inhibitors MH - Pentacyclic Triterpenes/*therapeutic use MH - Peritonitis/chemically induced/prevention & control MH - Uric Acid MH - Mice PMC - PMC8149413 OTO - NOTNLM OT - HFD-induced metabolic disorders OT - IL-1beta OT - LPS OT - LPS-induced systemic inflammation OT - MSU-induced peritonitis OT - NLRP3 inflammasome OT - bone-marrow-derived macrophages OT - caspase-1 OT - pristimerin COIS- The authors declare no competing interests. EDAT- 2020/09/30 06:00 MHDA- 2021/10/08 06:00 PMCR- 2022/06/01 CRDT- 2020/09/29 05:33 PHST- 2020/04/28 00:00 [received] PHST- 2020/09/03 00:00 [accepted] PHST- 2020/09/30 06:00 [pubmed] PHST- 2021/10/08 06:00 [medline] PHST- 2020/09/29 05:33 [entrez] PHST- 2022/06/01 00:00 [pmc-release] AID - 10.1038/s41401-020-00527-x [pii] AID - 527 [pii] AID - 10.1038/s41401-020-00527-x [doi] PST - ppublish SO - Acta Pharmacol Sin. 2021 Jun;42(6):975-986. doi: 10.1038/s41401-020-00527-x. Epub 2020 Sep 28.