PMID- 33424855 OWN - NLM STAT- MEDLINE DCOM- 20210623 LR - 20220103 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction. PG - 607564 LID - 10.3389/fimmu.2020.607564 [doi] LID - 607564 AB - Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti-inflammatory agent with an IC(50) of ~20 microM. In this study, we synthesized a new anti-inflammatory 4-HAB analogue, F240B, which has an IC(50) of less than 1 microM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1beta (IL-1beta) precursor expression, promoted degradation of NLRP3 and IL-1beta, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1beta, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future. CI - Copyright (c) 2020 Wu, Gan, Li, Chang, Chen, Menon, Cheng, Yang, Ho, Chernikov, Lin, Lam and Hua. FAU - Wu, Chun-Hsien AU - Wu CH AD - Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. AD - Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. FAU - Gan, Chin Heng AU - Gan CH AD - Department of Chemistry, National University of Singapore, Singapore, Singapore. FAU - Li, Lan-Hui AU - Li LH AD - Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan. AD - Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. FAU - Chang, Jen-Che AU - Chang JC AD - Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. FAU - Chen, Shin-Tai AU - Chen ST AD - Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. FAU - Menon, Mridula P AU - Menon MP AD - Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. FAU - Cheng, Shu-Meng AU - Cheng SM AD - Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. FAU - Yang, Shih-Ping AU - Yang SP AD - Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. FAU - Ho, Chen-Lung AU - Ho CL AD - Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan. FAU - Chernikov, Oleg V AU - Chernikov OV AD - G.B. Elyakov Pacific Institute of Bioorganic Chemistry FEB RAS, Vladivostok, Russia. FAU - Lin, Chi-Hung AU - Lin CH AD - Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. AD - Department of Biological Science & Technology, National Chiao Tung University, Hsinchu, Taiwan. FAU - Lam, Yulin AU - Lam Y AD - Department of Chemistry, National University of Singapore, Singapore, Singapore. FAU - Hua, Kuo-Feng AU - Hua KF AD - Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. AD - Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan. AD - Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201218 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Autophagy-Related Proteins) RN - 0 (Cytokines) RN - 0 (Inflammasomes) RN - 0 (Inflammation Mediators) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Nlrp3 protein, mouse) RN - 268B43MJ25 (Uric Acid) SB - IM EIN - Front Immunol. 2021 Dec 15;12:738591. PMID: 34975836 MH - Animals MH - Anti-Inflammatory Agents/chemical synthesis/*pharmacology MH - Autophagy/*drug effects MH - Autophagy-Related Proteins/metabolism MH - Cytokines/metabolism MH - Disease Models, Animal MH - Humans MH - Inflammasomes/*metabolism MH - Inflammation Mediators/metabolism MH - Macrophages/*drug effects/metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mitochondria/drug effects/metabolism/pathology MH - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism MH - Peritonitis/chemically induced/metabolism/pathology/*prevention & control MH - Protein Stability MH - RAW 264.7 Cells MH - Signal Transduction MH - THP-1 Cells MH - Uric Acid PMC - PMC7793731 OTO - NOTNLM OT - NLRP3 inflammasome OT - autophagy OT - conjugated polyenes OT - mitochondria OT - peritonitis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/01/12 06:00 MHDA- 2021/06/24 06:00 PMCR- 2020/01/01 CRDT- 2021/01/11 05:37 PHST- 2020/09/17 00:00 [received] PHST- 2020/11/18 00:00 [accepted] PHST- 2021/01/11 05:37 [entrez] PHST- 2021/01/12 06:00 [pubmed] PHST- 2021/06/24 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.607564 [doi] PST - epublish SO - Front Immunol. 2020 Dec 18;11:607564. doi: 10.3389/fimmu.2020.607564. eCollection 2020.