CN107028927B

CN107028927B - Application of aspirin C and analogues thereof in preparation of liver regeneration drugs

Info

Publication number: CN107028927B
Application number: CN201710413986.9A
Authority: CN
Inventors: 吴亮; 廖有为; 胡蝶; 汪小燕; 陈星光; 张陆勇
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2017-06-05
Filing date: 2017-06-05
Publication date: 2021-02-26
Anticipated expiration: 2037-06-05
Also published as: CN107028927A; WO2018223851A1

Abstract

The invention discloses an application of aspirin C and analogues thereof in preparation of liver regeneration drugs, and researchers of the invention find that: the apigenin C and the analogues thereof can promote liver regeneration in liver injury. The apigenin C and analogues thereof can improve liver function after liver injury. The cetirizine C and the analogues thereof can stimulate hepatocyte proliferation in liver injury. The atopirrine C and its analogues can stimulate hepatocyte proliferation in liver cirrhosis, hepatitis, liver cancer, hepatic fibrosis, fatty liver disease, and hepatic failure. The aspirin C and the analogues thereof can improve the liver/body weight ratio recovery capability.

Description

Application of aspirin C and analogues thereof in preparation of liver regeneration drugs

Technical Field

The invention relates to an application of aspirin C and analogues thereof in preparation of liver regeneration drugs, and belongs to the technical field of biological medicines.

Background

The liver is an important metabolism and detoxification organ and plays an important role in maintaining the dynamic balance of the body and the like. In normal liver tissue, most of liver cells are relatively quiescent without undergoing mitosis, but many chemicals, drugs, viruses, etc. cause liver damage, eventually leading to various acute and chronic liver injuries. Liver cancer is one of the common malignant tumors with high mortality rate in China and is also one of the most serious liver diseases. Currently, the main treatment of various hepatobiliary tumors and acute and chronic end-stage liver diseases is liver resection. Among clinical applications, hepatectomy and live liver transplantation are currently the most effective worldwide methods for treating liver cancer and end-stage liver disease. The reason why hepatectomy and live liver transplantation are possible is the unique, powerful regenerative capacity of hepatocytes; after the liver is partially cut, hepatocytes are rapidly activated, proliferate through DNA synthesis and mitosis, stop dividing when they proliferate to a certain number, and differentiate into mature hepatocytes, which are the process of liver regeneration. After the operation, if the remaining liver lacks the regeneration ability, delays the regeneration ability or has weak regeneration ability, various adverse syndromes such as acute liver failure after the operation, septic infection, ascites, hemorrhage, renal failure or hepatic encephalopathy can be caused. Among them, acute liver failure after surgery is still the main cause of death after surgery, and is directly related to the prognosis of patients. Therefore, the search for safe and effective drugs for regulating liver regeneration has important theoretical significance and clinical application value for reducing the risk of liver resection operation and shortening the postoperative recovery time of patients.

Cells are the fundamental unit of body structure and function. Liver cell damage is a common pathological and pathophysiological basis, regardless of the cause of the liver pathology. The liver is an important organ of the human body which integrates a plurality of functions such as metabolism, synthesis, detoxification, bile secretion, endocrine, immunity and the like, and is very easy to be attacked by various harmful factors such as viruses, medicines, poisons, alcohol, excessive fat and the like. The rate, extent and quantity of hepatocyte damage and the state of regeneration and repair are intrinsic determinants of the progression and severity of liver disease. Controlling or eliminating the etiology of liver injury, blocking the continuous damage of liver cells, and promoting the regeneration and repair of liver cells are common treatment principles of various liver diseases. Therefore, the promotion of hepatocyte regeneration is not only beneficial to protecting hepatocyte, but also beneficial to delaying or blocking hepatic fibrosis, hepatitis, cirrhosis and hepatic failure, and can reduce the occurrence risk of hepatocellular carcinoma. Meanwhile, the aspirin C is firstly widely concerned as a tumor inhibition component, can play an anticancer role by inducing human cancer cells to generate apoptosis, inhibiting tumor angiogenesis, inducing cancer cell cycle block and other mechanisms, and further strengthens the reduction of the risk of hepatocellular carcinoma caused by the aspirin C

Disclosure of Invention

The invention provides an application of apiolin C and analogues (Artepillin C, ARC) thereof in preparation of liver regeneration drugs.

The atorvastatin C and the analogues thereof have the following structure shown in the formula (I):

wherein R is₁Selected from H or isopentenyl;

R₂is OH;

R₃selected from H or isopentenyl;

R₄is selected from H or CH₂Ph or

Or CH₂CHPh。

Preferably, the formula I is atorvastatin C, the formula of the aspirin C is: 3- [ 4-hydroxy-3, 5-bis (3-methyl-2-butenyl) phenyl ] -2- (E) -acrylic acid, molecular weight 300.40 and chemical structure:

the medicine also comprises pharmaceutically acceptable salts of the aspirin C and the analogues thereof, wherein the pharmaceutically acceptable salts refer to salts generated by the reaction of the compound with inorganic acid, organic acid, alkali metal or alkaline earth metal. These salts include (but are not limited to):

salts with the following inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Salts with the following organic acids: acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, arginine, and the like.

Salts with the following alkali or alkaline earth metals: sodium, potassium, calcium, magnesium, and the like.

The present investigators find the following applications:

the aspirin C and the analogues or the pharmaceutically acceptable salts thereof can promote liver regeneration in liver injury.

The hepatic injury comprises physical hepatic injury or chemical hepatic injury, the physical hepatic injury is hepatectomy, hepatic rupture or hepatic puncture, and the chemical hepatic injury is hepatotoxic injury.

The cetirizine C and the analogue or the pharmaceutically acceptable salt thereof can improve the liver function after liver injury.

The cetirizine C and the analogue or the pharmaceutically acceptable salt thereof can stimulate the proliferation of liver cells in liver injury.

The atopirrine C and the analogue or the pharmaceutically acceptable salt thereof can stimulate the proliferation of normal liver cells in liver cirrhosis, hepatitis, liver cancer, liver fibrosis, fatty liver disease and liver failure.

The cetirizine C and the analogue or the pharmaceutically acceptable salt thereof can improve the liver/body weight ratio recovery capability.

Drawings

FIG. 1 shows the results of liver weight ratio in the liver regeneration experiment in examples;

FIG. 2 is a bar graph of biochemical index AST of liver tissue in the examples;

FIG. 3 is a bar graph of the biochemical indicator of liver tissue ALT in the examples;

FIG. 4 is a bar graph of the biochemical indicator of liver tissue Albumin in the examples;

FIG. 5 is a graph of the effect of different doses of ARC on liver histopathomorphology (HE, 200X) in the liver resection model mice in the examples;

Detailed Description

The present invention will be further described with reference to the following examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.

Example (b):

1. design of animal experiments

The animal model is a 70% hepatectomy model. Before the experiment, the mice are divided into three groups, namely a solvent group and an administration group, wherein the dosages of the administration group are 0.2 mg/mouse and 0.3 mg/mouse respectively. After administration, 4% chloral hydrate was used for intraperitoneal injection for anesthesia, the abdomen of the mouse was disinfected with alcohol, the skin and flesh were cut off from the xiphoid process to a width of 1-2cm below the xiphoid process to expose the liver, the middle lobe was pressed with a cotton swab, and the sickle ligament on the middle lobe was cut off. Ligating the left lobe of the liver with a thread, and cutting off the left lobe of the liver slightly above the ligation site; ligating the middle lobe, and cutting off the middle lobe of liver 2-3mm below the bifurcation of middle lobe. Meat and skin were sutured separately, 0.4ml of physiological saline was intraperitoneally injected, and the rats were placed in a warm environment. The dosing was timed daily and three days after dosing, mice were sacrificed on the fourth day of the experiment.

2. Liver weight ratio

On day 4, the mice were sacrificed, and the liver weight and body weight of the mice were respectively measured, and the liver regeneration index was calculated as a ratio of the two.

Liver regeneration experiments the results of liver weight ratios are shown in figure 1 and table 1,

TABLE 1

As can be seen from table 1 and fig. 1, ARC significantly accelerated the recovery of liver/body weight ratio in hepatectomized mice compared to the solvent group.

(liver weight recovery measured according to the academic recognized formula of liver/body weight ratio: liver/body weight ratio regeneration liver weight/postoperative body weight 100%, wherein P <0.05, P <0.01, P <0.001)

3. Biochemical index detection of liver tissue

Killing mice on day 4, collecting blood, and measuring serum contents of glutamic-oxaloacetic transaminase (AST), glutamic-pyruvic transaminase (ALT) and Albumin (Albumin)

P <0.05 x P <0.01 x P <0.001 x P, compared to solvent group

TABLE 2

And (4) analyzing results: as shown in figures 2-4 and table 2, ARC significantly reduced liver transaminase ALT and AST levels. In the process of liver injury treatment, the rising of albubin level in serum is considered as one of the classic indications of liver function recovery, in the experiment, the albubin level in serum of mice of an ARC administration group is obviously higher than that of a solvent group, which indicates that ARC can not only play a role in reducing injury degree in the process of liver injury, but also play a positive role in the process of liver recovery.

4. Histological analysis of liver

H & E staining of liver tissue to observe liver damage condition

Liver tissue is fixed by 4% paraformaldehyde, trimmed, washed by distilled water, dehydrated, embedded by paraffin and sliced conventionally to obtain 4 μm slices. And then deparaffinizing, dyeing, dehydrating, transparentizing and sealing the slices, and observing the inflammatory infiltration and edema conditions of the liver cells by an optical microscope. The results are shown in FIG. 5:

and (4) analyzing results:

in the solvent group, the degeneration of liver cells is obvious and is shown as swelling and vacuolar degeneration with different degrees, and lesions are in diffuse distribution (shown by "+"); a few nuclear fission images ("arrows"), with nuclear enlargement and binuclear cells are visible; in the ARC (0.2mg/kg) group, the degree of hepatocyte degeneration is improved, and the nuclear enlargement and the binuclear cells are also seen, and the nuclear fission image is obviously increased; in the ARC (0.3mg/kg) group, the degree of hepatocyte degeneration was improved, and nuclear enlargement and binuclear cells, increased nuclear fission, were also observed.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims

1. The application of the apidrin C and the pharmaceutically acceptable salts thereof in preparing the liver regeneration medicine is the medicine capable of improving the recovery capability of the liver/body weight ratio.

2. The use of claim 1, wherein the pharmaceutically acceptable salt is a salt of the compound with an alkali metal or alkaline earth metal.