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Application of MLN4924 in preparation of medicine for preventing or treating APAP-induced acute liver injury

A technology for acute liver injury and liver injury, applied in drug combinations, pharmaceutical formulations, organic active ingredients, etc.

Inactive Publication Date: 2021-06-04
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The prior art lacks a study on the protection of the liver from APAP damage by prior or simultaneous use of drugs through transcriptomics-related mechanisms

Method used

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  • Application of MLN4924 in preparation of medicine for preventing or treating APAP-induced acute liver injury
  • Application of MLN4924 in preparation of medicine for preventing or treating APAP-induced acute liver injury
  • Application of MLN4924 in preparation of medicine for preventing or treating APAP-induced acute liver injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] This example proposes the establishment of an APAP-induced acute liver injury model and related mechanisms.

[0043] 1. Experimental program design

[0044] The mouse model of acute liver injury induced by excessive APAP is a classic model of drug-induced liver injury. Previous studies have shown that the severity of APAP liver injury has a certain relationship with the gender of mice. In order to better establish the model, we purchased 6-8 week-old C57BL / 6 mice, 12 males and 12 females, and counted the survival rate of the mice within 72 hours. In order to further study the indicators of APAP-induced acute liver injury model in wild mice, after intraperitoneal injection of 350 mg / kg APAP in mice, APAP-induced acute liver injury was observed by HE staining, TUNEL staining, and F4 / 80 immunohistochemical staining. In the model, liver injury, apoptosis, immune cell recruitment and other conditions in mice.

[0045] 2. Results Analysis

[0046] The results showed that ...

Embodiment 2

[0048] This example presents changes in Neddylation modification in an APAP-induced acute liver injury model.

[0049] 1. Experimental program design

[0050] Preliminary studies have confirmed that Neddylation modification can occur in mitochondria. Based on this, the design of this experiment is divided into in vivo experiment and in vitro experiment to study the changes of Neddylation modification in APAP-induced acute liver injury model. In animal experiments, mice were killed by cervical dislocation at 0, 0.5, 1, 2, and 4 hours after 350 mg / kg APAP injection, and about 100 mg of fresh liver tissue was taken and washed with pre-cooled PBS buffer Twice, and then ground with liquid nitrogen to separate the mitochondria and cytoplasmic proteins of the liver tissue. The mitochondria were fully lysed with RIPA protein lysate, and then samples were prepared together with the isolated cytoplasmic proteins, and western blot experiments were performed to detect changes in the lev...

Embodiment 3

[0054] This example proposes to use MLN4924 to inhibit Neddylation modification and analyze the changes of acute liver injury in mice induced by APAP.

[0055] 1. Experimental program design

[0056] Mice were injected with MLN4924 to inhibit Neddylation modification, and the changes of APAP-induced acute liver injury in mice were analyzed. Initial experiments found that excessive injection of APAP in mice damaged liver cells accompanied by enhanced Neddylation modification. We further studied the role of APAP-induced acute liver injury and its related mechanism through the inhibition of Neddylation modification in vivo by MLN4924. MLN4924 was dissolved in DMSO, and the mice were injected intraperitoneally at a dose of 60 mg / kg. The control mice were injected with the same volume of DMSO, and the injection volume of each mouse did not exceed 70 μl. Mice were sacrificed 12 hours after administration, and liver tissue samples were collected for western blot experiments to detec...

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Abstract

The invention discloses application of MLN4924 in preparation of a medicine for preventing or treating APAP-induced acute liver injury, and belongs to the technical field of biomedicine. According to the invention, an APAP-induced acute liver injury model is provided, and tests show changes of related mechanisms of liver injury, apoptosis, immune cell recruitment and the like; furthermore, in in-vivo and in-vitro tests of the APAP-induced acute liver injury model, the Neddylation modification is enhanced; furthermore, the MLN4924 acts on preparation of the medicine for preventing or treating APAP-induced acute liver injury, and through the liver injury model, the MLN4924 has an effect of inhibiting Neddylation modification; through the action of the MLN4924, APAP- induced liver injury is relieved, and neutrophil recruitment is remarkably reduced; and a mechanism that MLN4924 affects APAP-induced liver injury cytokine change, which may indicate the reduction of the liver injury degree is provided. The application of the MLN4924 in preparation of the medicine for preventing or treating the APAP-induced acute liver injury has the beneficial effect of effectively reducing the APAP-induced acute liver injury.

Description

technical field [0001] The invention relates to the field of biomedical technology, especially the field of transcriptomics and pharmacological activity, and specifically relates to the application of MLN4924 in the preparation of drugs for preventing or treating APAP-induced acute liver injury. Background technique [0002] Acetaminophen (Acetaminophen, APAP) was approved for clinical use in the 1950s and is currently one of the most widely used antipyretic and analgesic drugs in the world. However, due to its narrow safe therapeutic dose, APAP-induced liver toxicity has become an important cause of drug-induced liver injury in many countries in the world. For people with reduced UGT and SULT enzyme activities, glucuronidation and sulfation disorders, APAP metabolism is blocked. Differences in non-synonymous coding SNPs (nsSNPs) in the sulfotransferase gene and reduced glucuronidation may affect hepatic pharmacokinetics, making certain individuals more susceptible to APAP...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P1/16
CPCA61K31/519A61P1/16
Inventor 董洁张纪岩何佳程倩倩杨锡琴牛春晓郭璐
Owner ACADEMY OF MILITARY MEDICAL SCI
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