Application of NS1619 for inhibiting activation of NLRP3 inflammatory corpuscles

A technology for inflammasomes and inflammatory diseases, applied in the directions of anti-inflammatory agents, digestive system, organic active ingredients, etc., can solve problems such as undiscovered functions, and achieve the effects of inhibiting maturation and secretion, inhibiting cell pyroptosis, and reducing peritonitis.

Active Publication Date: 2019-12-17
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As an activator of BK channel, it participates in the regulation of various physiological processes such as intracellular calcium ion level, smooth muscle relaxation and cell excitability, so it can regulate the development of various diseases. For example, NS1619 inhibits the calcification of vascular smooth muscle cells Therefore, it has potential therapeutic effects in the treatment of cardiovascular and cerebrovascular diseases such as atherosclerosis, asthma, cerebral ischemic injury, etc., but the function of NS1619 in the activation of NLRP3 inflammasome has not yet been discovered.

Method used

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  • Application of NS1619 for inhibiting activation of NLRP3 inflammatory corpuscles
  • Application of NS1619 for inhibiting activation of NLRP3 inflammatory corpuscles
  • Application of NS1619 for inhibiting activation of NLRP3 inflammatory corpuscles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 NS1619 specifically inhibits the activation of NLRP3 inflammasome in vitro

[0073] (1) Acquisition and differentiation of mouse bone marrow-derived macrophages (BMDM): take the bone marrow of C57BL / 6 mice about 8 weeks old, and use DMEM medium + 10% fetal bovine serum + 25ng / ml MSCF (macrophage) Phage-colony-stimulating molecule) differentiated for 4-5 days.

[0074] (2) Divide the differentiated BMDM cells into 12-well plates, 5*10^ 5 cells. The next day, the cells were pretreated with opti-MEM medium + 1% fetal calf serum + 50ng / ml LPS for 3-6 hours. Then, different concentrations of NS1619 (0 μM, 5 μM, 10 μM, 20 μM, 30 μM) were added for half an hour, and the cells were stimulated with 3.5 μM nigericin for 15 minutes, and then the cell supernatant and cell lysate were collected. At the same time, the pretreated cells were selected, and the cell supernatant and cell lysate were directly collected as a control. ELISA detects the secretion of IL-1β, and t...

Embodiment 2

[0082] Example 2 NS1619 does not affect the activation of AIM2 inflammasome and IPAF inflammasome

[0083] (1) Acquisition and differentiation of mouse bone marrow-derived macrophages: same as Example 1(1).

[0084] (2) Divide the differentiated BMDM cells into 12-well plates, 5*10^ 5 cells. The next day, pretreat the cells with opti-MEM medium + 1% fetal bovine serum + 50ng / ml LPS for 3-6 hours, divide the pretreated cells into six groups, first, divide them into two groups and add different concentrations NS1619 (0 μM, 30 μM) was treated for half an hour, and then each large group was divided into three groups, and the cells were stimulated with 700 μg / ml NLRP3 inflammasome agonist urate crystals (MSU) for 4 hours and 1 μg AIM2 inflammasome The agonist Poly(dA:dT) stimulated the cells for 2 hours and the non-stimulation group was used as a control, and the cell supernatant and cell lysate were collected. ELISA detects the secretion of IL-1β, and the results are as follows...

Embodiment 3

[0089] Example 3 NS1619 does not affect the activation of LPS-induced NF-κB signaling pathway in the preparation phase of NLRP3 inflammasome activation

[0090] (1) Acquisition and differentiation of mouse bone marrow-derived macrophages: same as Example 1(1).

[0091] (2) Divide the differentiated BMDM cells into 12-well plates, 5*10^ 5 cells. The next day, the cells were treated with opti-MEM medium+1% fetal bovine serum+50ng / ml LPS for 3-6 hours, and different concentrations of NS1619 (0μM, 5μM, 10μM, 20μM, 30 μM) for half an hour, and then stimulate the cells with 3.5 μM nigericin (Nigericin) for 15 minutes, then collect the cell supernatant and cell lysate. At the same time, the pretreated cells were selected, and the cell supernatant and cell lysate were directly collected as a control. ELISA detects the secretion of IL-6 and TNF-α, the results are as follows Figure 6 Shown in A and 6B; Western blot detection of NLRP3 inflammasome key protein NLRP3, pro-caspase-1, p...

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Abstract

The invention belongs to the field of biological medicines. The invention discloses application of NS1619 for inhibiting activation of NLRP3 inflammatory corpuscles. An experiment finds that the NS1619 can inhibit autooligomerization of a NLRP3 protein, thus the activation of the NLRP3 inflammatory corpuscles is specifically inhibited, and maturation and secretion of inflammatory factors IL-1 betaand IL-18 are inhibited. At the same time, the NS1619 can further alleviate peritonitis in vivo induced by NLRP3 inflammatory corpuscle agonist MSU. Therefore, according to application of NS1619 forinhibiting activation of NLRP3 inflammatory corpuscles, the latest insights are provided for the NS1619 to treat the NLRP3 inflammatory corpuscles related inflammatory diseases and preparing drugs fortreatment of related diseases.

Description

technical field [0001] The invention belongs to the field of biology and medicine, and specifically relates to the application of NS1619 in inhibiting the activation of NLRP3 inflammasome, and the application of NS1619 in the treatment of inflammatory diseases related to NLRP3 inflammasome and the preparation of medicines for treating related diseases. Background technique [0002] Innate immunity is the body's first line of defense against pathogen invasion, and pattern recognition receptors (PRRs) play a key role in identifying pathogens. NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is a very Important pattern recognition receptors. When NLRP3 recognizes pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), it can form a multiprotein complex, namely the NLRP3 inflammasome. NLRP3 inflammasome is assembled by NLRP3, apoptosis-associated speck-like protein containing a CARD (apoptosis-associated speck-like protein containi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4184A61P29/00A61P3/04A61P3/10A61P19/06A61P19/02A61P1/00A61P31/04A61P9/10A61P1/16A61P35/00A61P25/28A61P25/16A61P25/24A61P11/00
CPCA61K31/4184A61P29/00A61P3/04A61P3/10A61P19/06A61P19/02A61P1/00A61P31/04A61P9/10A61P1/16A61P35/00A61P25/28A61P25/16A61P25/24A61P11/00Y02A50/30
Inventor 周荣斌王环宇
Owner UNIV OF SCI & TECH OF CHINA
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