Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis

doi:10.1038/s41401-021-00797-z

	Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis
	Chen, Cheng 1; Ren, Yong-mei 2; Zhu, Jian-zhong 1; Chen, Jia-li 1; Feng, Zhe-ling 1; Zhang, Tian 1; Ye, Yang 2; Lin, Li-gen 1
刊名	ACTA PHARMACOLOGICA SINICA
	2021-11-17
页码	13
关键词	Ainsliadimer C interleukin-1 beta macrophages NLRP3 inflammasome Sirtuin 1 adipose tissue inflammation obesity metabolic disorders EX-527 dexamethasone
ISSN号	1671-4083
DOI	10.1038/s41401-021-00797-z
通讯作者	Ye, Yang(yye@simm.ac.cn) ; Lin, Li-gen(ligenl@um.edu.mo)
英文摘要	Interleukin-1 beta (IL-1 beta), a key pro-inflammatory cytokine, is majorly produced by macrophages through NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, which has been identified as the culprit to deteriorate the inflammatory crosstalk between macrophages and adipocytes. Ainsliadimer C (AC) is a disesquiterpenoid isolated from Ainsliaea macrocephala. In the current study, we investigated the effects of AC on adipose tissue inflammation in co-culture of macrophages and adipocytes in vitro as well as in LPS-treated mice in vivo. We showed that AC (20-80 mu M) dose-dependently inhibited the secretion of IL-1 beta from LPS plus ATP-stimulated THP-1 macrophages by inhibiting the activation of NLRP3 inflammasome. Furthermore, we found that AC treatment activated NAD(+)-dependent deacetylase Sirtuin 1 (SIRT1), resulting in reduced acetylation level of NLRP3. Molecular modeling analysis revealed that binding of AC to sirtuin-activating compound-binding domain increased the affinity of the substrate to the catalytic domain of SIRT1. Moreover, AC (80 mu M) significantly attenuated macrophage-conditioned medium-induced inflammatory responses in 3T3-L1 adipocytes. In LPS-induced acute inflammatory mice, administration of AC (20, 60 mg center dot kg(-1)center dot d(-1), ip) for 5 days significantly suppressed the pro-inflammatory cytokine levels in serum and epididymal white adipose tissue (eWAT), attenuated macrophage infiltration into eWAT, and mitigated adipose tissue inflammation. The beneficial effects of AC were blocked by co-administration of a selective SIRT1 inhibitor EX-527 (10 mg center dot kg(-1)center dot d(-1)). Taken together, AC suppresses NLRP3-mediated IL-1 beta secretion through activating SIRT1, leading to attenuated inflammation in macrophages and adipose tissue, which might be a candidate to treat obesity-associated metabolic diseases.
资助项目	National Natural Science Foundation of China[81872754] ; Science and Technology Commission of Shanghai Municipality[20430780300] ; Science and Technology Commission of Shanghai Municipality[19431908100] ; Science and Technology Development Fund, Macao SAR, China[FDCT 0031/2019/A1] ; Research Fund of University of Macau[MYRG2018-00037-ICMS]
WOS关键词	GENE-EXPRESSION ; CELL-SURVIVAL ; FATTY-ACID ; OBESITY ; ACTIVATION ; TARGET ; INTERLEUKIN-1-BETA ; ACETYLATION ; MACROPHAGES ; ADIPOCYTES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000719724100003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299003]
专题	中国科学院上海药物研究所
通讯作者	Ye, Yang; Lin, Li-gen
作者单位	1.Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Nat Prod, Chem Dept, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Chen, Cheng,Ren, Yong-mei,Zhu, Jian-zhong,et al. Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis[J]. ACTA PHARMACOLOGICA SINICA,2021:13.
APA	Chen, Cheng.,Ren, Yong-mei.,Zhu, Jian-zhong.,Chen, Jia-li.,Feng, Zhe-ling.,...&Lin, Li-gen.(2021).Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis.ACTA PHARMACOLOGICA SINICA,13.
MLA	Chen, Cheng,et al."Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis".ACTA PHARMACOLOGICA SINICA (2021):13.