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Application of UMI-77 as mitochondrial autophagy inducer to preparation of medicine for treating inflammation and neurodegenerative diseases

A UMI-77, mitophagy technology, applied in nervous system diseases, applications, antipyretics, etc., can solve problems such as high toxicity, no MCL1 inhibitor found, no drugs to treat inflammation and Alzheimer's disease, etc. Achieving significant therapeutic effect and improving effect

Active Publication Date: 2020-11-10
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although mitophagy can be induced, it cannot be used in clinical applications due to its high toxicity
[0003] At present, no MCL1 inhibitors have been found as mitophagy inducers, and there are no drugs targeting mitophagy inducers or MCL1 protein inhibitors to treat inflammation and Alzheimer's disease

Method used

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  • Application of UMI-77 as mitochondrial autophagy inducer to preparation of medicine for treating inflammation and neurodegenerative diseases
  • Application of UMI-77 as mitochondrial autophagy inducer to preparation of medicine for treating inflammation and neurodegenerative diseases
  • Application of UMI-77 as mitochondrial autophagy inducer to preparation of medicine for treating inflammation and neurodegenerative diseases

Examples

Experimental program
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Effect test

Embodiment 1

[0046] The establishment of the high-throughput screening model of embodiment 1 mitophagy:

[0047]The present invention uses Keima fluorescent protein and mitochondrial localization sequence to fuse into mtKeima protein, and constructs human embryonic kidney transformed cell HEK293Tmtkeima stable cell line; Construction steps: 1) lentiviral plasmid preparation: mtkeima sequence according to Beijing Boermai Biotechnology Co., Ltd. The MT-mKeima-Red sequence provided by the company (MBL BEIJING BIOTECH CO.,LTD) in the plasmid pMitophagyKeima-Red mPark2 (Hyg) was synthesized and then ligated into the lentiviral plasmid pCDH to form pCDH-mtkeima, Extract endotoxin-free plasmid pCDH-mtkeima, lentiviral packaging plasmid pMD2.0G and psPAX2. 2) Lentivirus preparation: HEK293T cells were prepared in 1*10 6 The cells / ml density was planted in a 15cm culture dish, and after 24 hours, three plasmids pCDH-mtkeima, pMD2.0G and psPAX2 were transfected, 10 μg of each plasmid. 48 hours and ...

Embodiment 2

[0054] Example 2 Confirmation of effective mitophagy inducer UMI-77:

[0055] 1. Experimental method: HEK293T cells were treated with 2*10 5 cells / ml, Hela cells and U2OS cells at 1.5*10 5 Seed in a 6-well plate at a density of 1 / ml, 2ml per well. Seed 6 wells per cell. After 24 hours, UMI-77 was added at 0 hour, 3 hours, 6 hours, and 9 hours, with a final concentration of 5 μM. Collect samples uniformly with 250 μl 2XSDS loading buffer within 12 hours. Heat at 100°C for 10 minutes. Immunoblotting: load 10 μl of each sample, electrophoresis at 90V for 2h; transfer to membrane at 300mA for 1h. 5% skimmed milk was blocked at room temperature for 1 h, and antibodies (Tom20 antibody was purchased from Cell Signaling Technology, #42406S; Tim23 antibody was purchased from Proteintech, #11123-1-AP; Tubulin antibody was purchased from Hangzhou Huaan Biotechnology Co., Ltd., #M1305-2; Calnexin antibody was purchased from Cell Signaling Technology, #2433S) at a certain dilution ra...

Embodiment 3

[0072] Example 3 Application of mitophagy inducer UMI-77 for the treatment of inflammation

[0073] 1. Experimental method: Male 4-8 week old mice with C57BL / 6 genetic background were purchased from Nanjing Model Animal Center. They were divided into 4 groups with 6 rats in each group, and the experiment was carried out after 1 week of normal feeding. All drugs were dissolved in a solvent of 2% DMSO+30% PEG400+water. Each mouse was weighed, and 200 μl of drugs were intraperitoneally injected with UMI-7730 mg / kg and Nec1 2.5 mg / kg according to body weight. In the LPS induction group, 200 μl solvent was injected intraperitoneally. The NC group was not treated. Twenty minutes later, LPS / D-Gal (lipopolysaccharide / D-galactosamine) concentrations (LPS: 100 μg / kg, D-Gal: 400 mg / kg) were injected. After 6 hours, blood was collected from the eyeball, and the liver was fixed with paraformaldehyde. After the fresh blood was allowed to stand at room temperature for 30 minutes, it was...

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Abstract

The invention discloses an application of UMI77 as a mitochondrial autophagy inducer to preparation of a medicine for treating inflammation and neurodegenerative diseases. The invention provides an induction effect of the MCL1 inhibitor UMI77 on mitochondrial autophagy, and the UMI77 has a remarkable inhibition effect on inflammation and a remarkable relieving effect on Alzheimer's diseases through effects on acute hepatitis, inflammatory bowel diseases and APP / PS1 mouse models.

Description

technical field [0001] The invention belongs to the technical field of inflammation treatment, and specifically relates to the application of UMI-77 as a mitophagy inducer in the preparation of medicines for treating inflammation and neurodegenerative diseases. Background technique [0002] Mitophagy plays an important role in the suppression of inflammation, which is the basic strategy of the body to fight infection and is also the main cause of disease exacerbation, such as certain neurodegenerative diseases and Alzheimer's disease. Therefore, screening new safe and effective mitophagy inducers is a possible therapeutic strategy to inhibit inflammation and alleviate disease. The main principle of existing mitophagy inducers is to destroy the function of mitochondria, so that cells are forced to undergo mitophagy. Although mitophagy can be induced, it cannot be used in clinical applications due to its high toxicity. [0003] So far, no MCL1 inhibitors have been found to a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/196A61P29/00A61P25/28A61P1/16A61P1/00C12N5/10C12N15/867
CPCA61K31/196A61P29/00A61P25/28A61P1/16A61P1/00C12N5/0686C12N5/0603C12N15/86C12N2740/15043C12N2800/107C12N5/10C12N15/867
Inventor 夏宏光岑旭峰许正平盛静浩徐晓燕陈艳英
Owner ZHEJIANG UNIV
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