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Application of microRNA-302c-3p as an NLRP3 inhibitor

An inhibitor and dosage form technology, applied in the application field of MicroRNA-302c-3p as an NLRP3 inhibitor, can solve the problem of the large influence of NLRP3 function, and achieve inhibition of endothelial inflammation and pyroptosis, aortic inflammation and pyroptosis improvement, treatment Effects of atherosclerosis

Active Publication Date: 2022-06-28
THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this regard, emerging literature suggests that miRNAs also fine-tune the process of NLRP3 inflammasome activation by reducing NLRP3 expression at the translational level. However, which miRNAs have the greatest impact on NLRP3 function in the cardiovascular domain remains to be further investigated

Method used

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  • Application of microRNA-302c-3p as an NLRP3 inhibitor
  • Application of microRNA-302c-3p as an NLRP3 inhibitor
  • Application of microRNA-302c-3p as an NLRP3 inhibitor

Examples

Experimental program
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Effect test

Embodiment 1

[0077] This example is to screen miRNAs that directly target NLRP3:

[0078] Four bioinformatics websites, miRmap, Targetscan, miRWalk, and miRanda, were used to screen miRNAs directly targeting NLRP3; 21 miRNAs were identified in the intersection region by online Venn diagram analysis ( Figure 1A ); 4 miRNAs were identified from 21 miRNAs in 4 databases, namely miR-302c-3p, miR-490-5p, miR-421, miR-876-5p; Next, the expression levels of these four miRNAs and NLRP3 in human normal arterial tissue and plaque tissue were detected; the detection results were: the expression of miR-302c-3p was significantly correlated with that of NLRP3. were negatively correlated, while the expression of the other three miRNAs was positively correlated with the expression of NLRP3 as detected by qRT-PCR ( Figures 1B1 to 1B4 and Figure 1C ). Therefore, miR-302c-3p is a potential miRNA targeting NLRP3. Analysis of miR-302c-3p by RNA fluorescence in situ hybridization experiments revealed that...

Embodiment 2

[0081] This example is the study of MiR-302c-3p directly targeting and inhibiting the expression of NLRP3

[0082] To determine whether miR-302c-3p directly targets NLRP3, the binding site between miR-302c-3p and NLRP3 was predicted and found to be highly conserved in primates and mammals ( Figure 2A ). Subsequently, the mimic and inhibitor of miR-302c-3p were synthesized and transfected into HUVECs, respectively, and the transfection efficiency was detected ( Figure 2B ). It was observed that the mRNA expression of NLRP3 decreased after miR-302c-3pmimic transfection of HUVECs, while the mRNA expression of NLRP3 increased after miR-302c-3p inhibitor transfected HUVECs ( Figure 2C ). NLRP3 protein expression also had the same result ( Figure 2D , E).

[0083] Biotin-labeled miR-302c-3p and its mutant mimics were used to examine whether miR-302c-3p could downregulate NLRP3 in HUVECs. After transfection, HUVECs were collected to extract enriched RNA for pull down experime...

Embodiment 3

[0086] This example is the study of overexpression of miR-302c-3p to reverse the pyroptosis of HUVECs induced by ox-LDL

[0087] Pyroptosis is an inflammatory programmed cell death caused by activation of the NLRP3 inflammasome. Therefore, it was investigated whether the abnormal expression of miR-302c-3p regulates endothelial cell pyroptosis by targeting NLRP3. ox-LDL-treated HUVECs were used to reveal the effect of miR-302c-3p on pyroptosis, as ox-LDL is a known atherogenic factor that induces endothelial damage and pyroptosis. Mimics and NCs of miR-302c-3p were transfected into HUVECs, respectively, and then treated with ox-LDL for 24 h. RT-PCR confirmed that ox-LDL treatment of HUVECs could activate pyroptosis and increase the mRNA levels of NLRP3, IL-1β and caspase-1 ( Figure 3A ). Notably, miR-302c-3p mimic transfection resulted in significant reductions in NLRP3, IL-1β, and caspase-1 mRNA levels ( Figure 3A ). The anti-pyroptotic effect of miR-302c-3p was also co...

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Abstract

The invention discloses the application of MicroRNA-302c-3p as an NLRP3 inhibitor; the invention screens and identifies miRNAs directly targeting NLRP3 through an online bioinformatics database, and screens out the most significant miR-302c through various experimental verifications ‑3p; miR‑302c‑3p inhibits endothelial inflammation and pyroptosis by directly binding to a specific site of NLRP3 mRNA; and after injecting miR‑302c‑3p agomir through the tail vein, aortic inflammation and pyroptosis in ApoE‑ / ‑ mice were both improved; studies have shown that miR-302c-3p / NLRP3 has a new regulatory signaling pathway and its mechanism of action in endothelial cells; MicroRNA-302c-3p can directly bind to specific sites of NLRP3 mRNA to inhibit NLPR activation, thereby inhibiting endothelial inflammation and pyroptosis can achieve the purpose of treating atherosclerosis.

Description

technical field [0001] The invention relates to the technical field of NLRP3 inhibitors, in particular to the application of a MicroRNA-302c-3p as an NLRP3 inhibitor. Background technique [0002] Atherosclerosis (AS) is a chronic inflammatory disease with lipid accumulation and endothelial dysfunction. Early diagnosis is critical for subclinical atherosclerosis, which has a relatively long latency and is closely associated with cardiovascular disease. Ox-LDL is a key factor in the progression of atherosclerotic cardiovascular disease. Briefly, ox-LDL is recognized by pattern recognition receptors on endothelial cells and causes endothelial dysfunction by triggering cascades of oxidative stress and inflammatory responses that are characteristic of early atherosclerosis. In this sense, timely intervention of endothelial cell inflammation and immunity can delay atherosclerosis. [0003] The NLRP3 inflammasome is a multimeric protein complex that functions as an innate immun...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/113A61K31/7105A61P9/10
CPCC12N15/113A61K31/7105A61P9/10C12N2310/141
Inventor 于涛褚现明杨艳艳柏宝辰
Owner THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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