CN111658623A

CN111658623A - Application of nootkatone in medicine for preventing and treating non-alcoholic fatty liver disease

Info

Publication number: CN111658623A
Application number: CN202010749358.XA
Authority: CN
Inventors: 张勇; 张小坡; 胡小媛; 刘启兵; 刘嫱; 姚宏纪; 姜承祚
Original assignee: Hainan Medical College
Current assignee: Hainan Medical College
Priority date: 2020-07-30
Filing date: 2020-07-30
Publication date: 2020-09-15

Abstract

The invention relates to application of a traditional Chinese medicine monomer, namely nootkatone, in preventing and treating non-alcoholic fatty liver disease. Scientific experiments show that the nootkatone can obviously improve fat accumulation and hepatocyte vacuolation and inflammation of non-alcoholic fatty liver disease mice, reduce serum triglyceride and cholesterol levels and protect liver functions for the first time; nootkatone is able to reduce free fatty acid-induced accumulation of triglycerides in liver cells. In a word, the nootkatone can be developed into a brand-new drug for preventing and treating the non-alcoholic fatty liver disease.

Description

Application of nootkatone in medicine for preventing and treating non-alcoholic fatty liver disease

Technical Field

The invention relates to the technical field of medicines, relates to a new application of a medicine, and particularly relates to an application of nootkatone in a medicine for preventing and treating non-alcoholic fatty liver disease.

Background

Non-alcoholic fatty liver disease (NAFLD) refers to a series of pathological syndromes induced by excessive accumulation of liver parenchymal cell fat and steatosis due to Non-alcohol, and is clinically classified into Non-alcoholic fatty liver (NAFL), Non-alcoholic steatohepatitis (NASH), and hepatic fibrosis, cirrhosis and hepatocellular carcinoma developed by NASH according to disease progression. NAFLD is the most common chronic liver disease in the world, and the prevalence rate is as high as 6.3% -45% [ 25.2% median, 95% Confidence Interval (CI): 22.1% -28.7% ], wherein 10% -30% is NASH. Mate analysis of large sample disease cases in 2018 years in China shows that the prevalence rate of NAFLD is as high as 32.9% (95% CI: 28.9-36.8%), and the number of patients in 2030 years is predicted to reach 3.14 hundred million. For obese and diabetic patients, the prevalence of NAFLD is even as high as 70-80%. NAFLD, particularly NASH, has a risk of further progression to liver fibrosis, cirrhosis, and even liver cancer, and the risk of death of patients is higher and higher with the progression of the disease course, and once the progression to cirrhosis decompensation stage, the average survival time of the patients is about 2 years. The wide popularity of NAFLD also places a significant economic burden on the global medical system. Currently, the prevalence of NAFLD is continuously increasing and the number of patients is rapidly increasing worldwide, but no FDA approval for any effective therapeutic drug for NAFLD is found in the clinic. Discovering and exploring effective therapeutic drugs aiming at NAFLD is one of effective methods for preventing and treating NAFLD, and is a scientific difficult problem to be solved urgently.

Nootkatone (C)₁₅H₂₂O, 5, 6-dimethyl-8-isopropenyl-bicyclo- (4,4,0) -dec-1-en-3-one, nootkatone), is a sesquiterpene ketone compound separated from grapefruit peel oil and phellodendron alaskum oil, and has the following molecular structure:

the nootkatone has a lasting and strong citrus-like aroma, presents a typical grapefruit aroma at a lower dilution, and is mainly used for preparing various citrus-type essences. At present, no medicine research and report about the application of the nootkatone to the nonalcoholic fatty liver disease exists.

Disclosure of Invention

In view of the defects of the prior art, the invention provides application of nootkatone in medicaments for preventing and treating non-alcoholic fatty liver disease.

The scheme of the invention comprises the following aspects:

the invention is found to have the effect of improving the non-alcoholic fatty liver based on a non-alcoholic fatty liver disease mouse model test for the first time, and shows that the liver cell fatty liver disease mouse model test obviously reduces fat accumulation in liver tissue cells, liver cell foaming, liver tissue cell inflammation and protects liver functions. The nootkatone is prompted to have good application prospect in the medicine for preventing and treating the non-alcoholic fatty liver disease.

More specifically, the non-alcoholic fatty liver disease is non-alcoholic fatty liver disease, non-alcoholic steatohepatitis NASH, and liver fibrosis, cirrhosis and hepatocellular carcinoma developed by NASH.

On the other hand, the invention provides a medicament for preventing and treating non-alcoholic fatty liver disease, and the active ingredient of the medicament is nootkatone.

More specifically, the medicine can also contain pharmaceutically acceptable auxiliary materials, and can be prepared into pharmaceutically acceptable dosage forms according to a conventional preparation method of the medicine. The dosage form is selected from powder, tablet, granule, capsule, solution, emulsion or suspension. For example, for the purpose of tablet preparation, a wetting agent and a binder such as water, glycerin, polyethylene glycol, ethanol, sodium carboxymethylcellulose, honey, polyvinylpyrrolidone, etc. may be used, a disintegrant such as starch, calcium carbonate, sodium dodecylsulfate may be used, and the tablet may be further prepared into a coated tablet such as a film-coated tablet, an enteric-coated tablet, etc.

Compared with the prior art, the invention has the beneficial effects that:

the experiment of the invention proves that the nootkatone obviously reduces the accumulation of triglyceride in the liver tissue cells, obviously improves the vacuolation phenomenon of the liver tissue cells, obviously improves the inflammation of the liver tissue, reduces the level of inflammatory cytokine IL-1 beta in serum and obviously protects the function of the liver. Therefore, the nootkatone has an important effect on preventing and treating the non-alcoholic fatty liver disease.

Drawings

FIG. 1 pathological results of HE staining of liver tissue

FIG. 2 liver histopathological outcome score

FIG. 3 IL-1. beta. levels in serum

Detailed Description

In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.

The nootkatone of the present invention may be a commercially available product or may be prepared by a known conventional method.

Example Effect of Citrulli on the prevention and treatment of non-alcoholic fatty liver disease in Experimental mice

(1) A non-alcoholic fatty liver animal model is constructed by inducing C57BL/6 mice with Tipoe high-fat feed. C57BL/6 mice were divided into normal group (fed with normal diet), model group (fed with high-fat diet), administration group (low dose group 20mg/kg/d, high dose group 50mg/kg/d), 10 mice per group, and administered by gavage, with free food intake and free water intake. The model was continuously made and dosed for 8 weeks, each group of mice was sacrificed, and plasma (serum separated) and liver tissues were taken for subsequent testing, respectively.

(2) Blood physical and chemical index inspection: comprises alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), Triglyceride (TG) content, total Cholesterol (CHO), Fasting Blood Glucose (FBG), IL-1 beta;

(3) and (3) pathological examination: the livers of each group were fixed with 4% formaldehyde, individually trimmed, dehydrated with gradient alcohol, paraffin embedded, sectioned (thickness 5 μ M), HE stained, light-microscopic and scored.

(4) Statistical analysis: all measurements are expressed as X. + -. S and the comparison between groups is performed using the t-test.

(5) And (3) test results:

TABLE 1 nootkatone improvement of blood physicochemical index of non-alcoholic fatty liver disease mice

Note: p <0.05, P <0.01, P <0.001, compared to normal group; # P <0.05, # P <0.01, # P <0.001, compared to the model group.

1. Normal group: normal liver function and normal blood physicochemical indexes (table 1, fig. 1 and fig. 2);

2. model group: compared with the indexes of ALT, AST, TG, CHO and FBG of the normal group, the indexes of ALT and AST of the model group are obviously higher than those of the normal group, which indicates that the liver function of rats of the model group is damaged (table 1), and the pathological results of liver tissues show that the model group has serious fatty liver, inflammation of a manifold area and liver tissue damage (figure 1 and figure 2), and shows the symptoms of clinical non-alcoholic fatty liver disease; TG and CHO in the serum of the model group are obviously higher than those of a normal control group, which shows that the model group shows obvious hyperlipemia symptoms and accords with clinical symptoms of non-alcoholic fatty liver disease (Table 1).

3. Administration group (20mg/kg, 50 mg/kg): after the treatment of the dose groups of the nootkatone with high dose (50mg/kg/d) and low dose (20mg/kg/d), the analysis result of the physical and chemical indexes of the blood shows that the nootkatone can obviously reduce the AST and ALT levels in the serum compared with the model group, and the nootkatone has a protective effect on the liver function (table 1); nootkatone also reduced TG and CHO in serum, indicating that it exerts hypolipidemic effects (table 1); the liver histopathological results show that the liver tissue cell foaming degree of the high-low dose group is obviously lighter than that of the model group (figure 1); pathological results also show that the high-dose and low-dose nootkatone groups all show obvious anti-inflammatory effect, the inflammation in the sink area is obviously reduced, and the infiltration of immune cells is obviously weakened (figures 1 and 2); further detecting the IL-1 beta level in the serum, the nootkatone can obviously reduce the IL-1 beta level in the serum and shows obvious anti-inflammatory effect (figure 3). IL-1 beta is a main inducing factor for the occurrence and development of nonalcoholic fatty liver diseases. The results show that the nootkatone has obvious curative effect on non-alcoholic fatty liver disease resistance and has potential to be developed into a drug for resisting the non-alcoholic fatty liver disease.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims

1. Application of nootkatone in preparing medicine for preventing and treating non-alcoholic fatty liver disease is provided.

2. The use of claim 1, wherein the non-alcoholic fatty liver disease comprises non-alcoholic fatty liver disease, non-alcoholic steatohepatitis NASH, and liver fibrosis, cirrhosis and hepatocellular carcinoma developed by NASH.

3. Use according to claim 1, wherein the medicament is in a dosage form selected from the group consisting of powder, tablet, granule, capsule, solution, emulsion and suspension.

4. A medicine for preventing and treating non-alcoholic fatty liver disease is characterized in that the active ingredient is nootkatone.

5. The drug for preventing and treating non-alcoholic fatty liver disease according to claim 4, further comprising pharmaceutically acceptable auxiliary materials, and being prepared into pharmaceutically acceptable dosage forms.

6. The drug for preventing and treating non-alcoholic fatty liver disease according to claim 5, wherein the dosage form is selected from powder, tablet, granule, capsule, solution, emulsion or suspension.