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Application of dimethyl fumarate (DMF) in preparation of medicine for inhibiting pyroptosis of macrophages induced by silicon dioxide crystals and medicine for treating silicosis

A technology of dimethyl fumarate and silicon dioxide, applied in the field of chemical biology, to relieve pulmonary inflammation and pathological changes of pulmonary fibrosis, simple synthesis, and remarkable therapeutic effect

Inactive Publication Date: 2021-09-03
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Recent studies have found that DMF succinylates multiple cysteine ​​sites of Gsdmd and Gsdme, thereby inhibiting its cleavage by upstream caspase proteases, inhibiting the oligomerization of the N-terminal domain and the formation of holes that lead to cellular The process of lytic death; the recent study reported that DMF can inhibit the cleavage of Gsdmd and Gsdme, but the cleavage of Gsdmd by DMF and the cleavage of Gsdme by DMF do not occur simultaneously

Method used

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  • Application of dimethyl fumarate (DMF) in preparation of medicine for inhibiting pyroptosis of macrophages induced by silicon dioxide crystals and medicine for treating silicosis
  • Application of dimethyl fumarate (DMF) in preparation of medicine for inhibiting pyroptosis of macrophages induced by silicon dioxide crystals and medicine for treating silicosis
  • Application of dimethyl fumarate (DMF) in preparation of medicine for inhibiting pyroptosis of macrophages induced by silicon dioxide crystals and medicine for treating silicosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: DMF has an inhibitory effect on macrophage pyroptosis induced by silica crystals

[0040] Primary macrophages induced to differentiate in vitro were cultured in 12-well plates with 1 ml of culture medium. First add 1ug / ml LPS for pretreatment, add DMF after 3h, and then add silica crystal suspension with a final concentration of 0.25mg / ml after 1h. The working concentrations of DMF added to the DMF treatment group were 25uM, 50uM and 100uM, respectively, and the same amount of DMSO was added to the control group. Two hours after the addition of silica crystals, images of cell morphology were collected, and then the cell culture medium was collected to analyze cell death by LDH release Assay, and the supernatant was collected for detection of inflammatory cytokines IL-1β and IL8.

[0041] The experimental results showed that DMF exhibited a concentration-dependent inhibitory effect on silica crystal-induced macrophage pyroptosis.

[0042] Characterization de...

Embodiment 2

[0046] Example 2: DMF inhibits pyroptosis by inhibiting the shearing of Gsdmd and Gsdme, but does not affect the activation of Caspase-1

[0047] Primary macrophages were cultured in 12-well plates with 1 ml of culture medium. Firstly, 1ug / ml LPS was added for pretreatment, and after 3 hours, DMF with final concentrations of 25uM, 50uM and 100uM were added, and the same amount of DMSO was added to the control group. After 1 hour, 0.25 mg / ml silica crystals were added to induce pyroptosis in the cells. After the silica crystals were treated for 2 hours, the protein in the cells was extracted and detected by Western blot. The antibodies used were anti-Caspase-1, anti-Gsdmd and anti-Gsdme antibodies, which were used to detect the shear activation of Caspase-1, Gsdmd and Gsdme, respectively.

[0048] Such as image 3 As shown, the results showed that the cleavage of Gsdmd and Gsdme was significantly inhibited, while the activation of Caspase-1 had no significant change, indicat...

Embodiment 3

[0049] Example 3: Different concentrations of DMF inhibit macrophages from releasing inflammatory cytokines IL-1β and IL-18 in response to silicon dioxide crystal stimulation

[0050] Mouse bone marrow-derived macrophages were cultured in a 12-well plate with 1 ml of culture medium. Firstly, 1ug / ml LPS was added for pretreatment, and after 3 hours, DMF with final concentrations of 25uM, 50uM and 100uM were added, and the same amount of DMSO was added to the control group. After 1 hour, 0.25 mg / ml silica crystals were added to induce pyroptosis in the cells. After the silica crystals were treated for 2 h, the cell supernatant was collected to detect the contents of inflammatory cytokines IL-1β and IL-18.

[0051] Such as Figure 4 As shown, IL-1β and IL-18 in the DMF treatment group with gradient concentrations were significantly decreased compared with the silica crystal group. The results indicated that DMF could inhibit the release of inflammatory cytokines IL-1β and IL-1...

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Abstract

The invention relates to application of dimethyl fumarate (DMF) in preparation of a medicine for inhibiting pyroptosis of macrophages induced by silicon dioxide crystals and a medicine for treating silicosis. The specific mechanism is that shearing of Gsdmd and Gsdme is remarkably inhibited at the same time, and release of inflammatory cytokines IL-1beta and IL-18 is inhibited. DMF has a function of inhibiting pyroptosis of macrophages induced by silicon dioxide crystals by inhibiting activation of Gsdmd and Gsdme, and has an effect of inhibiting lung inflammation and pulmonary fibrosis in a mouse silicosis model induced by the silicon dioxide crystals.

Description

technical field [0001] The invention belongs to the field of chemical biology, and specifically relates to the application of the compound dimethyl fumarate in inhibiting the pyroptosis of macrophages induced by silicon dioxide crystals and treating silicosis by inhibiting the protein activity of Gsdmd and Gsdme. [0002] technical background [0003] Pyroptosis is a new form of programmed cell death discovered in recent years. Specifically, pyroptosis is a kind of programmed cell death in which the body makes a rapid immune response to external stimuli (such as bacteria, viruses, etc.). Its function is to release a large amount of inflammatory factors and DNA, RNA and other substances that stimulate the immune system in a short period of time under the condition of pathological infection, so as to activate the downstream immune response. According to molecular pathways, pyroptosis can be divided into classic pyroptosis pathway, non-classical pyroptosis pathway and apoptosis...

Claims

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Application Information

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IPC IPC(8): A61K31/225A61P29/00A61P11/00
CPCA61K31/225A61P29/00A61P11/00
Inventor 高翔林兆宇王雨芳史培良
Owner NANJING UNIV
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