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Application of disulfiram in preparing drugs for preventing and treating diseases related to NLRP3 inflammasome

A technology of inflammasome and disulfiram, which is applied in the field of medicine, can solve problems such as deficiency and achieve strong pharmacological effects

Inactive Publication Date: 2020-03-27
GUANGZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many inhibitors have a certain alleviation effect on NLRP3 inflammasome-related diseases in basic research, there is still a lack of drugs that inhibit the activation of NLRP3 inflammasome in clinical practice.

Method used

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  • Application of disulfiram in preparing drugs for preventing and treating diseases related to NLRP3 inflammasome
  • Application of disulfiram in preparing drugs for preventing and treating diseases related to NLRP3 inflammasome
  • Application of disulfiram in preparing drugs for preventing and treating diseases related to NLRP3 inflammasome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 In vitro study of the inhibitory effect of disulfiram on NLRP3 inflammasome

[0056] 1. On the first day, divide J774A.1 cells into 96-well plate, each well 5×10 5 cells;

[0057] 2. Seed the plate overnight, discard the supernatant, add 100 μL of DMEM medium containing 10% serum containing bacterial lipopolysaccharide (LPS) (1 μg / ml) to each well, and then add different concentrations (0 μM, 2 μM, 5 μM, 10 μM) DSF was treated for 1 hour, and then nigericin (Nigericin, 10 μM) or ATP (5 mM) was added for 1 hour;

[0058] 3. After the treatment in step 2, collect the cell supernatant, and use the Moμse IL-1βELISA kit to measure the IL-1β content. The operation steps are carried out according to the kit instructions. The results are shown in figure 1 .

[0059] figure 1 The results showed that under the joint action of LPS pretreatment and the second signal Nigericin or ATP, the inflammasome was activated, and IL-1β was matured and secreted into the supernata...

Embodiment 2

[0060] Example 2 DSF inhibits the activation of NLRP3 inflammasome

[0061] 1. On the first day, divide the J774A.1 cells into a 6-well plate, each well 2×10 6 cells;

[0062] 2. Seed the plate overnight, discard the supernatant, add 1 mL of DMEM medium containing 10% serum containing bacterial lipopolysaccharide (LPS) (1 μg / ml) to each well, then discard the supernatant, and add different concentrations of (0 μM, 2 μM, 5 μM, 10 μM) DSF opti-MEM medium for 1 hour, then add nigericin (Nigericin, 10 μM) for 1 hour;

[0063] 3. After the treatment in step 2, collect the cell supernatant (Supernant) and cell lysate (Lysate), extract protein from the supernatant and lysate according to conventional methods, use anti-IL-1β antibody, anti-Caspase-1 antibody, anti-NLRP3 antibody and anti-NLRP3 antibody ASC antibody for western blot analysis, see the results figure 2 .

[0064] figure 2 The results showed that under the joint action of LPS pretreatment and the second signal Nige...

Embodiment 3

[0065] Example 3 In vivo study on the inhibitory effect of disulfiram on NLRP3 inflammasome - DSF inhibits LPS-induced peritonitis

[0066] 1. Take 6-8 week-old C57BL / 6 female mice, weigh them, and number them. Then intragastric administration of DSF, 100 mg / kg per mouse, and intragastric administration of PBS containing 10% DMSO in the control group, once a day, for three consecutive days, after intragastric administration of DSF for 1 hour on the third day, intraperitoneal injection of LPS, 20 mg / kg per mouse;

[0067] After 2 and 6 hours, the eyeballs were removed for bloodletting, and the blood was collected. After the bloodletting, the mice were killed by cervical dislocation. Let the blood stand at room temperature for 30 minutes, then centrifuge at 3000rpm for 30 minutes to collect serum;

[0068] 3. Rinse the abdominal cavity with 1ml of normal saline, and centrifuge the suctioned normal saline at 3000rpm for 5 minutes to collect the supernatant;

[0069] 4. The seru...

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Abstract

The invention relates to application of disulfiram in preparing drugs for preventing and treating diseases related to NLRP3 inflammasome. During research, phenomena are found that the disulfiram can effectively inhibit activation of the NLRP3 inflammasome and inhibit maturation and secretion of an inflammatory activation signal molecule Caspase-1P20 and an inflammatory cytokine IL-1[beta], accordingly has good prevention and treatment effects on the diseases related to the NLRP3 inflammasome, and especially has significant prevention and treatment effects on peritonitis and gouty arthritis.

Description

technical field [0001] The invention relates to the field of medicine, in particular to an application of disulfiram in the preparation of medicines for preventing and treating diseases related to NLRP3 inflammasomes. Background technique [0002] NLRP3 inflammasome is a pattern recognition receptor (PRR) and an inflammatory activation platform of Caspase-1. It can recognize exogenous pathogen-associated molecular pattern (pathogen-associated molecμlar pattern, PAMP) such as lipopolysaccharide LPS, viral RNA or endogenous damage-associated molecular pattern (damage-associated molecμlar pattern, DAMP) such as DNA, endotoxin , uric acid, ATP, Aβ and cell debris, etc. Abnormal appearance of these substances in a certain part outside the cell or inside the cell stimulates the homeostasis of the tissue and activates the NLRP3 inflammasome, resisting damage to the body by exogenous or endogenous factors, but excessively activated NLRP3 inflammation Microsomes contribute to the d...

Claims

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Application Information

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IPC IPC(8): A61K31/145A61P29/00A61P19/02A61P19/06
CPCA61K31/145A61P19/02A61P19/06A61P29/00
Inventor 胡文辉杨忠金孙平邓文敏熊兮
Owner GUANGZHOU MEDICAL UNIV
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