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Application of licochalcone B in preparation of medicine for preventing and treating NLRP3-mediated diseases

A technology of licochalone and drug, which is applied in the fields of biomedicine and drugs, can solve the problems such as the underlying mechanism and the direct target to be elucidated.

Active Publication Date: 2022-02-01
THE FIFTH MEDICAL CENT OF CHINESE PLA GENERAL HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although LicoB exhibits clear beneficial effects, its underlying mechanisms and direct targets remain to be elucidated

Method used

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  • Application of licochalcone B in preparation of medicine for preventing and treating NLRP3-mediated diseases
  • Application of licochalcone B in preparation of medicine for preventing and treating NLRP3-mediated diseases
  • Application of licochalcone B in preparation of medicine for preventing and treating NLRP3-mediated diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1, LicoB inhibits classic and non-canonical NLRP3 activation

[0089] To identify potential candidates for the treatment of NLRP3-mediated diseases, we screened for NLRP3 inhibitors and found that LicoB can block NLRP3 inflammasome activation ( Figure 8 A). In order to further study LicoB( figure 1 A) Effect on NLRP3 inflammasome activation, we first tested the cytotoxicity of LicoB in mouse bone marrow-derived macrophages (BMDM). Cell viability assays showed that LicoB did not exhibit any cytotoxicity at doses below 80 μM in BMDM ( figure 1 B). BMDMs were first primed with LPS, then pretreated with a range of LicoB concentrations, and then stimulated with a 10 μM dose of nigericin or a 5 mM dose of ATP to induce NLRP3 inflammasome activation. The results showed that in LPS-triggered BMDM, LicoB dose-dependently inhibited the production of nigericin ( figure 1 C-E) or ATP ( figure 1 G-I) Triggered caspase-1 activation or IL-1β secretion. Correspondingly,...

Embodiment 2

[0092] Example 2, LicoB is a specific inhibitor of NLRP3 inflammasome

[0093] We then investigated whether LicoB specifically inhibits the activation of the NLRP3 inflammasome. We performed experiments on the effect of LicoB on the activation of AIM2 and NLRC4 inflammasomes, which can also mediate cleavage of caspase-1 and secretion of IL-1β. LPS-primed BMDMs were transfected with the dsDNA analog poly(dA:dT) to activate the AIM2 inflammasome, or stimulated with Salmonella typhimurium to activate the NLRC4 inflammasome. The results showed that LicoB did not inhibit AIM2- or NLRC4-mediated caspase-1 activation and IL-1β secretion ( figure 2 D-F). The results showed that LicoB specifically inhibited the activation of NLRP3 inflammasome.

Embodiment 3

[0094] Example 3, LicoB blocks NLRP3-dependent ASC oligomerization

[0095] After recognizing that LicoB can specifically inhibit the activation of the NLRP3 inflammasome, we further explored the underlying mechanism of this effect. First, an experiment was performed to determine whether LicoB affects ASC oligomerization, a key step in NLRP3 inflammasome activation. LPS-primed BMDMs were stimulated with ATP and higher-order complexes were detected using western blot analysis. The results showed that LicoB attenuated ATP-induced ASC oligomerization in a dose-dependent manner ( image 3 A), which is consistent with the blocking effect of LicoB on caspase-1 cleavage and IL-1β secretion ( image 3 B and C). Further studies showed that LicoB effectively prevented ASC oligomerization induced by other NLRP3 agonists, such as nigericin, poly(I:C), MSU, and cytosolic LPS ( image 3 D). However, LicoB did not affect AIM2 or NLRC4 agonist-induced ASC oligomerization ( image 3 E), ...

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Abstract

The invention provides an application of licochalcone B in preparation of a medicine for preventing and treating NLRP3 mediated diseases. The LicoB is a potential and effective NLRP3 inflammasome inhibitor. Results show that the LicoB is directly combined with the NEK7, and the interaction between the NLRP3 and the NEK7 is interfered, so that the activation of the NLRP3 inflammasome is inhibited. In addition, the LicoB shows a remarkable treatment effect in several mouse models of NLRP3 mediated diseases, and can be developed into a promising candidate medicine for treating NLRP3 inflammasome related inflammatory diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine and medicine, and relates to the application of Licochalcone B (Licochalcone B) to specifically inhibit the NLRP3 inflammasome by destroying the NEK7-NLRP3 interaction to improve NLRP3-mediated diseases, in particular to Licochalcone Application of B in the preparation of medicaments for preventing and treating NLRP3-mediated diseases. Background technique [0002] The inflammasome is mainly composed of receptor protein, apoptosis-associated speck-like protein (ASC) and pro-caspase-1. Protein complex; Among them, the nucleotide oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is composed of NLR family members NLRP3, CARD-containing protein apoptosis Protein complex formed by associated speck-like protein (ASC) and pro-caspase-1. Upon activation, the NLRP3 inflammasome mediates the activation of caspase-1 and the subsequent cleavage of pro-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/12A61P29/00A61P19/06A61P31/00A61P25/00A61P3/10A61P9/10A61P1/16
CPCA61K31/12A61P29/00A61P19/06A61P31/00A61P25/00A61P3/10A61P9/10A61P1/16Y02A50/30
Inventor 柏兆方湛小燕肖小河徐广李强
Owner THE FIFTH MEDICAL CENT OF CHINESE PLA GENERAL HOSPITAL
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