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Acta Pharmacol Sin

Title:		"1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis"
Author(s):		Pan RY; Kong XX; Cheng Y; Du L; Wang ZC; Yuan C; Cheng JB; Yuan ZQ; Zhang HY; Liao YJ;
Address:		"Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China. Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. haiyansl@163.com. Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China. lyajin@muc.edu.cn. Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. lyajin@muc.edu.cn. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China. lyajin@muc.edu.cn. NHC Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410005, China. lyajin@muc.edu.cn"
Journal Title:		Acta Pharmacol Sin
Year:		2021
Volume:		20210224
Issue:		11
Page Number:		1769 - 1779
DOI:		10.1038/s41401-021-00613-8
ISSN/ISBN:		1745-7254 (Electronic) 1671-4083 (Print) 1671-4083 (Linking)
Abstract:		"NOD-like receptor (NLR) family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in inflammation-associated diseases such as multiple sclerosis, Parkinson's disease, and stroke. Targeting the NLRP3 inflammasome is beneficial to these diseases, but few NLRP3 inflammasome-selective inhibitors are identified to date. Essential oils (EOs) are liquid mixtures of volatile and low molecular-weight organic compounds extracted from aromatic plants, which show various pharmacological activities, including antibacterial, antifungal, antiviral, antioxidant, and anti-inflammatory properties. In this study we screened active ingredients from essential oils, and identified 1,2,4-trimethoxybenzene (1,2,4-TTB) as a selective NLRP3 inflammasome inhibitor. We showed that 1,2,4-TTB (1 mM) markedly suppressed nigericin- or ATP-induced NLRP3 inflammasome activation, thus decreased caspase-1 activation and IL-1beta secretion in immortalized murine bone marrow-derived macrophages (iBMDMs) and in primary mouse microglia. Moreover, 1,2,4-TTB specifically inhibited the activation of NLRP3 inflammasome without affecting absent in melanoma 2 (AIM2) inflammasome activation. We further demonstrated that 1,2,4-TTB inhibited oligomerization of the apoptosis-associated speck-like protein containing a CARD (ASC) and protein-protein interaction between NLRP3 and ASC, thus blocking NLRP3 inflammasome assembly in iBMDMs and in primary mouse macrophages. In mice with experimental autoimmune encephalomyelitis (EAE), administration of 1,2,4-TTB (200 mg . kg(-1) . d(-1), i.g. for 17 days) significantly ameliorated EAE progression and demyelination. In conclusion, our results demonstrate that 1,2,4-TTB is an NLRP3 inflammasome inhibitor and attenuates the clinical symptom and inflammation of EAE, suggesting that 1,2,4-TTB is a potential candidate compound for treating NLRP3 inflammasome-driven diseases, such as multiple sclerosis"
Keywords:		"Animals Benzene Derivatives/pharmacology/*therapeutic use Cell Line, Transformed Encephalomyelitis, Autoimmune, Experimental/*drug therapy/*metabolism Female Macrophages, Peritoneal/drug effects/metabolism Mice Mice, Inbred C57BL Mice, Knockout NLR Family;"
Notes:		"MedlinePan, Rui-Yuan Kong, Xiang-Xi Cheng, Yong Du, Lu Wang, Zhen-Chao Yuan, Chao Cheng, Jin-Bo Yuan, Zeng-Qiang Zhang, Hai-Yan Liao, Ya-Jin eng 2021/02/26 Acta Pharmacol Sin. 2021 Nov; 42(11):1769-1779. doi: 10.1038/s41401-021-00613-8. Epub 2021 Feb 24"