4.7 Article

Coptisine from Coptis chinensis blocks NLRP3 inflammasome activation by inhibiting caspase-1

期刊

PHARMACOLOGICAL RESEARCH
卷 147, 期 -, 页码 -

出版社

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2019.104348

关键词

Coptisine; Caspase-1; NLRP3 inflammasome; NF-Kb; Gout

资金

  1. National Natural Science Foundation of China [81773974, 81473419, 21861142007]
  2. National Key Research and Development Program of China [2017YFC1703900]
  3. Biological Resources Programme, Chinese Academy of Sciences [KFJ-BRP-008]
  4. National New Drug Innovation Major Project of China [2018ZX09711001-001-006]

向作者/读者索取更多资源

Inflammasome mediates the activation of caspase-1, which promotes the secretion of proinflammatory cytokines. In this work, we aimed to investigate whether natural compounds from a Traditional Chinese Medicine prescription called San-Huang-Xie-Xin-Tang exert its clinical efficacy by inhibiting inflammasome activation and the underlying mechanism. The inhibitory effects of compounds on caspase-1 were evaluated in recombinant expressed caspase-1 protein and macrophages. Molecular docking was conducted to examine the interaction between compounds and caspase-1. The effects of the compounds on pro-inflammatory cytokines were examined by enzyme-linked immunosorbent assay. The mechanism of the compounds on nucleotide oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome activation was investigated in macrophages. The anti-inflammasome effects of compounds were examined in mice stimulated by lipopolysaccharide (LPS) and monosodium urate crystal (MSU). Coptisine was the most potent inhibitor of caspase-1 in the San-Huang-Xie-Xin-Tang prescription. Coptisine adopted a favorable conformation at the active site of caspase-1. Coptisine significantly attenuated mature interleukin (IL)-1 beta secretion in RAW264.7 macrophages stimulated with LPS plus ATP, nigericin, or MSU, by blocking caspase-1 activation. Coptisine not only prevented NLRP3 inflammasome assembly by affecting the binding between pro-caspase-1 and apoptosis-associated speck-like protein containing a CARD, but also inhibited inflammasome priming by decreasing NLRP3 expression through inactivation of the nuclear factor-kappa B pathway. Moreover, coptisine prevented LPS-mediated IL-1 beta production and MSU-mediated mice paw edema by blocking NLRP3 inflammasome activation in vivo. Coptisine blocks NLRP3 inflammasome activation by inhibiting caspase-1 and may be useful for treating NLRP3 inflammasome-involved gouty arthritis.

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