CN115645395B - Application of MYLS22 in preparation of medicine for treating acute liver injury diseases - Google Patents

Abstract

The invention relates to application of MYLS22 in preparing a medicament for treating acute liver injury diseases, wherein after the MYLS22 is applied to treat acute liver injury diseases, the liver injury condition of mice is obviously improved, the levels of serum glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and Lactate Dehydrogenase (LDH) are obviously reduced, the necrosis of liver tissue is obviously improved, and the liver inflammation is obviously reduced.

Description

Application of MYLS22 in preparation of medicine for treating acute liver injury diseases

Technical Field

The invention relates to a new application of MYLS22, in particular to a new application of MYLS22 in treating acute liver injury, belonging to the field of new application of medicines.

Background

The liver is the main metabolic organ of the human body, and about 80% of its blood supply comes from the portal vein where multiple organ venous blood is pooled, which allows all substances absorbed from the stomach and intestines to pass through the liver before reaching the systemic circulation. Acute liver injury refers to injury of liver cells caused by various causes of disease on the basis of no chronic liver disease. The acute injury of liver is caused by various reasons, such as improper main useful medicines, food additives, virus infection, toxic food intake, radiation injury and the like. The clinical symptoms are usually manifested by clear medical history within 72 hours, abnormal increase of liver function indexes, jaundice and the like in a short period. Most of the patients can keep the main functions to be operated normally, and clinically, the patients are slightly elevated in serum transaminase and bilirubin; liver failure, coagulation dysfunction, hepatic encephalopathy, etc. may occur in severe cases. Acute liver failure is a challenging medical emergency requiring active treatment.

Acetaminophen (APAP), also known as tenolin or paracetamol, is a widely used over-the-counter antipyretic analgesic in the clinic. Some chemicals like APAP must first go through an intermediate step in the liver to form highly reactive metabolites that bind to and facilitate the expulsion of macromolecular conjugates like glucuronic acid in the body. After accumulating a large amount of APAP in vivo, part of APAP generates toxic intermediate metabolite N-acetyl-P-benzoquinone imine (NAPQI) under the action of cytochrome P450 enzyme. A small amount of NAPQI can be combined with endogenous substance glutathione to detoxify, but when a large amount of toxic products are accumulated in the body, the glutathione is depleted in the body, and the excessive NAPQI is irreversibly and covalently combined with macromolecular proteins in liver cells, so that serious liver injury is caused.

The use of APAP at relatively low doses (adult <4g/day; child <60-75 mg/kg/day) is safe and effective in adults or children, but when the APAP dose exceeds 4g/day, severe acute liver injury may result, even in the development of acute liver failure (Acute liver failure, ALF). At present, a plurality of brands of medicines containing APAP components are sold, and a plurality of compound preparations are used for treating cold and influenza. Some patients do not know that APAP is commonly present in various over-the-counter drugs, including OTC cold drugs, and are very likely to cause excessive APAP and cause adverse drug events when multiple APAP-containing drugs are taken simultaneously. Involuntary abuse of APAP is one of the major causes of liver damage caused by APAP, and improper use of APAP has been the major cause of ALF. Over 78000 emergency room visits, 33000 hospitalizations and 500 deaths associated with excessive APAP are annually in the united states alone. Currently, the only drug used clinically to treat APAP overdose commonly is N-acetylcysteine (NAC), a prodrug synthesized by Glutathione (GSH). Although NAC can alleviate APAP-induced hepatotoxicity to some extent, it is only effective when APAP is toxic very early, and some patients taking the recommended dose of NAC may still experience adverse effects or develop liver damage. Liver transplantation is still the only long-term effective method of treating ALF. ALF mortality rates are as high as 80% without liver transplantation, but liver transplantation requires long-term waiting for liver supply, and many patients die during the waiting process. In view of the universality of APAP use and the limitation of treatment, research and searching of a new therapeutic target of APAP hepatotoxicity become important problems to be solved in the research of APAP hepatotoxicity.

MYLS22 is a novel small molecule compound of molecular weight 443.52, which is known as N- (1, 5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-YL) -3-methyl-1-PH+, and has the following structural formula:

little research has been done on MYLS22 in disease treatment, which is reported to have an inhibitory effect on tumor angiogenesis and on breast cancer cell migration, proliferation and adhesion. At present, there is no report on MYLS22 for treating acute liver injury induced by excessive use of acetaminophen drugs.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide application of MYLS22 in preparing a medicament for treating acute liver injury diseases, and provides a novel medicament candidate for treatment.

The technical scheme adopted by the invention is as follows:

application of MYLS22 in preparing medicine for treating acute liver injury diseases is provided.

The Acute Liver Failure (ALF) is drug-induced by acetaminophen.

The dose of MYLS22 used in the present invention is 10mg/kg/day.

According to the invention, MYLS22 is used for treating acute liver injury animal models of mice induced by acetaminophen, under pathological conditions, as drug-induced inflammation is an important cause of liver injury formation, MYLS22 remarkably reduces liver inflammatory reaction, remarkably improves drug-induced liver injury, greatly improves liver pathological structure, greatly inhibits rising of glutamic pyruvic transaminase, glutamic oxaloacetic transaminase and lactic dehydrogenase in blood, and further reduces sustainable development of drug-induced acute liver injury.

The invention has the technical effects that:

1. in a typical animal model of acute liver injury of mice induced by excessive acetaminophen, after the treatment of MYLS22 with small dosage (10 mg/kg/day), the appearance and pathology of the liver of the mice show that the necrosis degree of the liver is obviously reduced and is almost similar to that of the liver of the mice in a normal control group; further detection of serum biochemical indexes (ALT, AST and LDH) shows that liver function indexes of MYLS22 mice are obviously improved, and MYLS22 is an effective means for treating acute liver injury, so that possibility is provided for later development and relevant preparation of acute liver injury disease medicines.

2. We selected a dose of MYLS22 that was a relatively safe low dose (10 mg/kg/day). To assess the toxicity of this dose, we administered normal mice to the drug-alone treatment group, and no toxicity of this dose to mice was observed.

Drawings

FIG. 1 is a bar graph of serum liver function index changes in mice in a control group, a MYS 22 single administration group, an APAP model group, and a MYS 22+APAP treatment group;

fig. 2: control group, MYS 22 pure administration group, APAP model group, MYS 22+APAP treatment group;

fig. 3: pathological section diagrams of mice in a control group, a MYS 22 pure administration group, an APAP model group and a MYS 22+APAP treatment group;

fig. 4: a histogram of liver-related inflammatory factor expression levels in mice of a control group, a MYS 22 single administration group, an APAP model group, and a MYS 22+APAP treatment group;

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments and attached drawings.

MYLS22 used in the following examples of the present invention was purchased from MedChemExpress (MCE); c57BL/6J mice were purchased from Jiangsu Jiyaokang Biotechnology Co., ltd.

Example 1MYLS22 can reduce serum liver function index in APAP-induced acute liver injury mice

The 32 mice were randomly divided into four groups, as follows: normal control (Vehicle), MYLS22 single administration (myl22+vehicle), APAP-induced liver injury model (APAP), and APAP-induced liver injury and MYLS22 treatment (myl22+apap), 8 each. So mice were on a normal diet, MYLS22 alone and APAP induced liver injury and MYLS22 treated mice were given a 10mg/kg/day dose of MYLS22 for intervention by gavage, and the normal control and APAP induced liver injury model groups were gavaged with corresponding volumes of drug dilutions (physiological saline). After 24 hours of modeling, mice were tested for serum liver function index: as shown in fig. 1, in the case of single administration of MYLS22, serum liver function indexes (ALT, AST and LDH) are not significantly increased, and there is no statistical difference, compared with the normal control group, as shown in fig. 1, the dosage of MYLS22 has no toxic effect; second, we observed a significant decrease in serum ALT, AST and LDH in MYLS22 treated mice compared to the APAP model group, nearly near normal levels, with statistical differences.

Example 2MYLS22 significantly improves liver morphology in APAP-induced acute liver injury mice

The 32 mice were randomly divided into four groups, as follows: normal control (Vehicle), MYLS22 single administration (myl22+vehicle), APAP-induced liver injury model (APAP), and APAP-induced liver injury and MYLS22 treatment (myl22+apap), 8 each. So mice were on a normal diet, MYLS22 alone and APAP induced liver injury and MYLS22 treated mice were given a 10mg/kg/day dose of MYLS22 for intervention by gavage, and the normal control and APAP induced liver injury model groups were gavaged with corresponding volumes of drug dilutions (physiological saline). After 24 hours of modeling, the liver morphology of the mice is observed, as shown in fig. 2, firstly, compared with a normal control group, the liver surface of the mice is smooth in a MYLS22 pure administration group, and no obvious difference exists between the two groups, which indicates that the MYLS22 dose has no toxic effect; secondly, we observe that the liver morphology of MYLS 22-treated mice is obviously improved compared with that of APAP model groups, the liver surface of APAP model groups can observe obvious abnormal phenomena such as particles or stripes, and the liver surface of treated mice is smooth and almost close to the normal level, and the abnormal phenomena such as particles or stripes disappear.

Example 3MYLS22 significantly improves the extent of liver necrosis in APAP-induced acute liver injury mice

The 32 mice were randomly divided into four groups, as follows: normal control (Vehicle), MYLS22 single administration (myl22+vehicle), APAP-induced liver injury model (APAP), and APAP-induced liver injury and MYLS22 treatment (myl22+apap), 8 each. So mice were on a normal diet, MYLS22 alone and APAP induced liver injury and MYLS22 treated mice were given a 10mg/kg/day dose of MYLS22 for intervention by gavage, and the normal control and APAP induced liver injury model groups were gavaged with corresponding volumes of drug dilutions (physiological saline). After 24 hours of molding, taking the liver of the mice and carrying out H & E staining, and the microscopic examination result is shown in figure 3, wherein firstly, compared with a normal control group, the MYS 22 pure administration group has similar pathology of the liver of the mice, no obvious necrosis exists, and the dose of MYS 22 has no toxic effect; secondly, the liver of the mice in the APAP model group is more normal, the arrangement of hepatic cell lines is disordered, a great amount of necrosis exists in the peripheral cells of a collecting tube region and a central vein, and the necrosis of the hepatic cells of the mice treated by MYLS22 is obviously reduced, which is close to the situation of normal mice. MYLS22 can reduce the level of liver necrosis in APAP-induced acute liver injury mice.

Example 4MYLS22 can reduce the extent of liver necrosis in APAP-induced acute liver injury mice

The 32 mice were randomly divided into four groups, as follows: normal control (Vehicle), MYLS22 single administration (myl22+vehicle), APAP-induced liver injury model (APAP), and APAP-induced liver injury and MYLS22 treatment (myl22+apap), 8 each. So mice were on a normal diet, MYLS22 alone and APAP induced liver injury and MYLS22 treated mice were given a 10mg/kg/day dose of MYLS22 for intervention by gavage, and the normal control and APAP induced liver injury model groups were gavaged with corresponding volumes of drug dilutions (physiological saline). After 24 hours of modeling, liver tissues are taken and RNA is extracted, and then mRNA transcription levels of inflammation related factors (MCP-1, ICAM1, cd68, TNF-alpha and IL-1 beta) in the liver are detected through reverse transcription and real-time fluorescence quantitative PCR, and the result is shown in FIG. 4, firstly, compared with a normal control group, MYS 22 pure administration group, the liver inflammation factors of mice are not significantly up-regulated, which indicates that MYS 22 has no toxic effect in the dosage; secondly, compared with the normal group, the liver of the mice in the APAP model group has obviously up-regulated expression level of inflammatory factors, and after being treated by MYLS22, the up-regulated inflammatory factors induced by APAP are greatly inhibited, and MYLS22 can reduce liver inflammatory response of the mice with acute liver injury induced by APAP. The differences are statistically significant.

Claims (6)

1. Application of MYLS22 in preparing medicine for treating liver injury.
2. Application of MYLS22 in preparing medicine for treating acute liver injury.
3. 3. The use of MYLS22 of claim 2 in the manufacture of a medicament for treating acute liver injury caused by an excess of an antipyretic analgesic.
4. 4. Use of MYLS22 according to claim 3 for the preparation of a medicament for the treatment of acute liver injury, said antipyretic analgesic being acetaminophen.
5. 5. Use of a MYLS22 according to claim 3 for the preparation of a medicament for the treatment of acute liver injury, said MYLS22 being at a dose of 10mg/kg/day.
6. 6. Use of MYLS22 as claimed in claim 3 in the manufacture of a medicament for the treatment of acute liver injury, said MYLS22 being by the oral route.

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