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Application of tizoxanide and nitazoxanide in preparation of autophagy inducer

A technology of tizoxanide and nitazoxanide, which is applied in the direction of medical preparations containing active ingredients, organic active ingredients, drug combinations, etc., can solve the problems of cell autophagy that have not been reported in any way

Inactive Publication Date: 2019-07-12
SHANGHAI VETERINARY RES INST CHINESE ACAD OF AGRI SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, only studies have shown that tizoxanide and nitazoxanide can resist various parasites, anaerobic bacteria and some viruses, but there is no report on the induction of cell autophagy by tizoxanide and nitazoxanide

Method used

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  • Application of tizoxanide and nitazoxanide in preparation of autophagy inducer
  • Application of tizoxanide and nitazoxanide in preparation of autophagy inducer
  • Application of tizoxanide and nitazoxanide in preparation of autophagy inducer

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Experimental program
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Effect test

Embodiment 1

[0031] Induction of autophagy by tizoxanide in RAW264.7 cells detected by transmission electron microscope

[0032] 1. In vitro culture of RAW264.7 cell line

[0033]The cells used in this experiment were RAW264.7 cells, using DMEM medium supplemented with 10% fetal bovine serum (fetal bovine serum, FBS, Gibco), at 37°C, 5% CO 2 The cells were cultured in an incubator, and when the cells grew to 80-90% of the bottom of the culture dish, they were digested with 0.25% trypsin-EDTA and passaged.

[0034] 2. The effect of drugs on cell viability

[0035] Inoculate the well-grown cells in a 96-well plate at a density of 5×104 cells / mL, 100 μL per well, culture in a 37°C, 5% CO2 incubator for 12 hours, and then add different concentrations of tizoxanide or nitazoxanide , set 5 duplicate wells in each group, continue to cultivate for 12 hours, discard the original culture solution, add 10 μL of CCK-8 reagent to each well, continue to cultivate for 30 minutes, shake and mix well on ...

Embodiment 2

[0042] Detecting the induction effect of tizoxanide on cell autophagy by LC3 protein and p62 protein

[0043] LC3 is a landmark protein in the autophagy signaling pathway, which has two subtypes, LC3I and LC3II. When no autophagy occurs, the protein exists in the cytoplasm as a water-soluble LC3I isoform, and when cells undergo autophagy, the protein is converted into a water-insoluble LC3II isoform. By detecting the change of LC3II content in cells, the strength of autophagy in cells can be determined.

[0044] In addition, p62, also known as SQSTM1, is expressed in a variety of cells and tissues, and can be used as a truck protein to participate in various signal transduction processes. p62 can connect LC3 and ubiquitinated substrates, then be integrated into autophagosomes, and be degraded in autolysosomes; when autophagy is activated, autophagosomes fuse with lysosomes, autophagic vesicles Proteins or organelles such as p62 in vesicles are degraded by lysosomal enzymes, ...

Embodiment 3

[0055] Detecting the induction effect of nitazoxanide on autophagy by LC3 protein and p62 protein

[0056] LC3 is a landmark protein in the autophagy signaling pathway, which has two subtypes, LC3I and LC3II. When no autophagy occurs, the protein exists in the cytoplasm as a water-soluble LC3I isoform, and when cells undergo autophagy, the protein is converted into a water-insoluble LC3II isoform. By detecting the change of LC3II content in cells, the strength of autophagy in cells can be determined.

[0057] p62, also known as SQSTM1, is expressed in a variety of cells and tissues, and can be involved in various signal transduction processes as a truck protein. p62 can connect LC3 and ubiquitinated substrates, then be integrated into autophagosomes, and be degraded in autolysosomes; when autophagy is activated, autophagosomes fuse with lysosomes, autophagic vesicles Proteins or organelles such as p62 in vesicles are degraded by lysosomal enzymes, and p62 levels decrease; wh...

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Abstract

The invention discloses novel medical application of tizoxanide and / or nitazoxanide and a pharmaceutically acceptable salt thereof, namely application of tizoxanide and / or nitazoxanide in the preparation of an autophagy inducer and application of drugs for treating and inhibiting diseases related to mTOR expression. According to the application, the tizoxanide and / or nitazoxanide and the pharmaceutically acceptable salt thereof can achieve related medicine effects by reducing PI3K and AKT protein phosphorylation and reducing ERK protein phosphorylation, the autophagy inhibition function in cells is reduced accordingly, and the cells are induced to achieve autophagy.

Description

technical field [0001] The present invention relates to the field of cell autophagy, in particular to a pharmaceutical composition with tizoxanide and / or nitazoxanide as the active and containing tizoxanide and / or nitazoxanide, more specifically, to Application of Zoxanide and Nitazoxanide in Inducing Cell Autophagy. Background technique [0002] Tizoxanide (Tizoxanide, TIZ) and nitazoxanide (nitazoxanide, NTZ) are both derivatives of nitazoxanide, and tizoxanide is the main active metabolite of nitazoxanide in vivo. Since the 1970s, it has been found that tizoxanide and nitazoxanide have inhibitory effects on anaerobic bacteria, various worms and protozoa that infect humans and animals. Nitazoxanide as an antiparasitic drug has been approved by the US FDA in 2002 for the treatment of diseases caused by intestinal protozoan infections such as Giardia lamblia and Cryptosporidium in children. The results of using the drug in many countries in Africa and South America show th...

Claims

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Application Information

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IPC IPC(8): A61K31/625A61P43/00
CPCA61K31/625A61P43/00
Inventor 张可煜首姣琴王霄旸薛飞群王米费陈忠张丽芳王春梅刘迎春郑海红
Owner SHANGHAI VETERINARY RES INST CHINESE ACAD OF AGRI SCI
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