Application of hexangol in preparation of medicine for preventing and treating liver lipid metabolism disorder

Abstract

The invention belongs to the technical field of pharmacotherapeutics, and particularly relates to application of hexangol in preparation of a medicine for preventing and treating liver lipid metabolism disorder. The invention provides an application of hexingerol in preparation of a medicine for preventing and treating liver lipid metabolism disorder, and provides a medicine containing a pharmaceutically effective dose of hexingerol for preventing and treating liver lipid metabolism disorder. The structural formula of the hexingerol is as shown in a formula A: # imgabs0 # experiments show that the hexingerol can regulate and control the expression of lipid deposition related genes and relieve alcohol-induced hepatic lipid metabolism disorder through a targeted PI3K / Akt / mTOR signal channel, and the hexingerol has the potential of being developed into a medicine for preventing and treating the hepatic lipid metabolism disorder.

Description

Technical Field

[0001] The invention belongs to the technical field of drug therapy, and particularly relates to the application of gingerol in preparing a drug for preventing and treating liver lipid metabolism disorder. Background Art

[0002] Hepatic Lipid Metabolism Disorder (HLMD) refers to the functional disorder of the liver in the metabolic process of lipid digestion, absorption, decomposition, synthesis and transportation. This disorder involves multiple metabolic pathways, including abnormal metabolism of cholesterol, triglycerides, fatty acids, etc. The liver, as the most important lipid metabolism organ in the human body, is closely related to blood lipid levels and plays an important role in lipid homeostasis by regulating mechanisms such as de novo cholesterol synthesis and reverse cholesterol transport. In addition, hepatic lipid metabolism disorders are also common in patients with chronic hepatitis, cirrhosis and liver cancer. Changes in lipid metabolism in these disease states are closely related to the progression of liver disease.

[0003] Although liver lipid metabolism disorders pose a huge threat to human health, there are currently relatively limited intervention methods for liver lipid metabolism disorders. Treatment mainly relies on lifestyle changes, such as dietary adjustments and increased exercise, and there is still a lack of specific drugs for clinical treatment.

[0004] Therefore, it is extremely important to develop innovative drugs that can intervene in liver lipid metabolism disorders. Summary of the invention

[0005] In order to solve the above technical problems, the present invention first provides the use of gingerol in preparing a drug for preventing and / or treating liver lipid metabolism disorders. The structural formula of the gingerol is shown in Formula A:

[0006]

[0007] The present invention further provides a drug for preventing and / or treating liver lipid metabolism disorder, which contains a pharmaceutically effective dose of gingerol, and the structural formula of the gingerol is shown in Formula A:

[0008]

[0009] Preferably, the drug further comprises a pharmaceutically acceptable carrier.

[0010] Preferably, the pharmaceutically acceptable carrier includes one or more functional auxiliary materials selected from the group consisting of excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents; such as starch, lipids, wax, dextrin, sucrose, lactose, microcrystalline cellulose, gelatin, citric acid, inorganic salts, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and the like.

[0011] Preferably, the drug is any one of an injection, tablet, pill, capsule, suspension or emulsion.

[0012] The beneficial effects of the present invention are:

[0013] Gingerol is a phenolic compound extracted from ginger, which is distributed in many plants, especially in ginger. As a natural product with multiple biological activities, gingerol has shown wide application potential in anti-inflammatory, antioxidant, and anti-tumor aspects.

[0014] The inventor team of this application found in the experiment that gingerol in Tongling white ginger extract may play an important role in alcohol-induced liver lipid metabolism disorder. Gingerol regulates the expression of lipid deposition-related genes and alleviates alcohol-induced liver lipid metabolism disorder by targeting the PI3K / Akt / mTOR signaling pathway. In view of these positive effects of gingerol in animal models, it shows great application prospects in the preparation of drugs for the prevention and treatment of liver lipid metabolism disorder.

[0015] This application further explores the application of gingerol in the treatment and prevention of liver diseases. The relevant experiments provide support for the treatment and prevention of gingerol in hepatic lipid metabolism disorders, which is of great significance to the application of gingerol and the treatment and prevention of hepatic lipid metabolism disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is an Oil Red staining image of the liver pathological damage of gingerol to mice with liver lipid metabolism disorder in Example 1.

[0017] Figure 2 The effects of gingerol on lipid metabolism-related genes in Example 2 include detection of mRNA expression levels of ACLY, FASN, ACC-α, PPAR-γ and ChREBP and immunohistochemical results of FASN.

[0018] Figure 3 This is the molecular docking result of gingerol and PIK3CA in Example 3.

[0019] Figure 4 The molecular dynamics simulation results of gingerol and PIK3CA in Example 3 include root mean square deviation (A in the figure), root mean square fluctuation (B in the figure) and the number of hydrogen bond fluctuations during the molecular dynamics simulation (C in the figure).

[0020] Figure 5 The effects of gingerol on the PI3K-Akt signaling pathway in Example 3 include changes in the protein expression level of PI3KCA (A and D in the figure), and changes in the protein phosphorylation levels of AKT T (B in the figure) and MTOR (C in the figure). DETAILED DESCRIPTION

[0021] Unless otherwise specified, the terms used herein have the meanings commonly understood by those skilled in the art.

[0022] The technical solution of the present invention is described in more detail below in conjunction with the examples. The gingerol used in the experiment was purchased from Lemeitian Biopharmaceutical Technology Co., Ltd., CAS: 23513-14-6.

[0023] Example 1

[0024] Effects of gingerol on alcohol-induced liver lipid metabolism disorder

[0025] Forty C57BL / 6J male mice aged 8-10 weeks and weighing 20-22g were selected and fed with free access to food and water for one week to establish the mouse ALD model. After one week of adaptive feeding, the mice were randomly divided into 4 groups (n=10): control feed feeding group (Control), alcohol feed feeding group (ETOH), control feed feeding + gingerol group (Control+6G), and alcohol feed feeding + gingerol group (ETOH+6G). Alcohol causes imbalance in liver lipid metabolism through direct and indirect effects. ALD is closely related to imbalance in liver lipid metabolism, and its core mechanisms include increased fatty acid synthesis, reduced fatty acid oxidation, and blocked lipid output. High NADH levels, ROS, and inflammatory factors produced by alcohol metabolism play a key role in this process.

[0026] During the establishment of the mouse ALD model, the control group (Control) continued to be fed with ordinary liquid feed, and the alcohol model group (ETOH) was only fed with ethanol liquid feed; the gingerol-administered group was also given gingerol by gavage (8 mg / kg) from the 5th day for 10 days to observe the preventive effect of gingerol on liver lipid metabolism disorders. On the 15th day, the ETOH group and the ETOH+6G group were gavaged with a 30% ethanol solution (0.2 ml / 10 g), and the Control group and the Control+6G group were gavaged with the same amount of normal saline. After 9 hours, the mice were anesthetized by inhalation of 5% isoflurane to draw blood and liver tissue samples.

[0027] The results are as follows Figure 1 As shown, when the liver tissue was stained with oil red, it was observed that the number of lipid droplets in the liver was significantly reduced after gingerol treatment compared with the EtOH group, indicating that gingerol effectively improved alcohol-induced liver lipid metabolism disorders and that gingerol has a potential preventive and therapeutic effect in regulating liver lipid metabolism.

[0028] The experimental results confirmed that gingerol has a positive effect in reducing liver lipid accumulation, and it is speculated that gingerol may protect the liver from alcohol damage by improving lipid metabolism disorders.

[0029] Example 2

[0030] Effects of gingerol on genes related to lipid metabolism

[0031] Genes and pathways related to hepatic lipid metabolism have been shown to be associated with liver disease. Alcohol-induced liver damage can induce hepatic lipid metabolism disorders, which can further aggravate lipid accumulation in the liver.

[0032] By extracting and analyzing RNA from liver samples of four groups of mice, namely, the control feed feeding group (Control), the alcohol feed feeding group (ETOH), the control feed feeding + gingerol group (Control+6G), and the alcohol feed feeding + gingerol group (ETOH+6G) in Example 1, the expression of genes related to lipid metabolism was detected.

[0033] like Figure 2 As shown in Figure 2, the expression levels of genes related to lipid accumulation were significantly decreased in the liver of mice treated with gingerol. Figure 2 In Figure A, the expression of key lipid metabolism regulators ACLY, FASN, ACC-α, PPAR-γ, and ChREBP was significantly inhibited, see Figure 2 In Figure B, the results of immunohistochemistry experiments further verified the above conclusions, and gingerol could significantly inhibit the expression of FASN, indicating that gingerol may improve alcohol-induced liver lipid metabolism disorders by regulating the expression of these key genes.

[0034] Example 3

[0035] Effects of gingerol on PI3K-Akt signaling pathway

[0036] Molecular docking technology was used to simulate the binding mode of 6G and PIK3CA. Figure 3 The simulation results shown in the figure show that 6G forms three hydrogen bonds with the amino acid residues ARG-274, GLU-176 and SER-174 of PIK3CA. Subsequently, an all-atom molecular dynamics (MD) simulation was performed based on the protein complex structure obtained by the above docking: Figure 4 Middle A, within the first 10 nanoseconds of the simulation, the root mean square deviation (RMSD) of the PIK3CA protein bound to 6G reached a stable state and fluctuated less (orange line), while the RMSD of the PIK3CA protein not bound to 6G was difficult to stabilize throughout the simulation (green line); see Figure 4In Figure B, the RMSD of the PIK3CA protein bound to 6G is more stable, indicating that the binding of 6G to PIK3CA is stable. The root mean square fluctuation (RMSF) can reflect the flexibility of the protein in the MD simulation. The PIK3CA protein bound to 6G is maintained within the RMSF value range of 2.5 Å as a whole, indicating that the flexibility of the PIK3CA protein bound to 6G is low and 6G is tightly bound to PIK3CA.

[0037] The binding energy was calculated from the MD simulation trajectory using the MM-GBSA method to more accurately evaluate the interaction between the small molecule and the target protein. In this experiment, the binding energy of the 6G / PIK3CA complex was calculated to be -19.85±3.29 kcal / mol. The negative value indicates that there is a high affinity between 6G and PIK3CA. Therefore, according to the calculation, the 6G / PIK3CA complex exhibits a strong binding affinity.

[0038] When analyzing the energy components, van der Waals forces are the main contributors to the binding energy of the 6G / PIK3CA complex, followed by electrostatic interactions and nonpolar solvation free energy. Hydrogen bonds are one of the strongest non-covalent binding interactions, and the greater the number, the better the binding. The number of hydrogen bonds of PI3K / Gingerol was monitored during the simulation to reflect the contribution of hydrogen bonds to the binding of the two, such as Figure 4 As shown in C, the number of hydrogen bonds in the PI3K / 6-Gingerol complex during the simulation is generally between 2 and 3, indicating that during the dynamic simulation, hydrogen bonds play a partial role in the binding of small molecule Gingerol and protein PI3K.

[0039] Finally, see Figure 5 The WB experimental results shown in the figure show that alcohol treatment significantly activated the PI3K / Akt / mTOR signaling pathway. As shown in Figure AD, the expression of p-AKT, PIK3CA, and p-mTOR proteins in the model group increased significantly compared with the control group. Compared with the alcohol group, the expression levels of p-AKT, PIK3CA, and p-mTOR proteins in the gingerol group were significantly downregulated. This further verifies that gingerol can inhibit the activation of the PI3K / Akt / mTOR signaling pathway by targeting PIK3CA.

[0040] The above experimental results collectively indicate that gingerol may regulate the expression of lipid metabolism-related genes by inhibiting the PI3K-Akt signaling pathway, thereby improving alcohol-induced hepatic lipid metabolism disorders. Gingerol has the potential to be developed into a drug for the prevention and treatment of hepatic lipid metabolism disorders.

[0041] The above are only preferred practical examples of the present invention and are not intended to limit the invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person of ordinary skill in the art should understand that any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. The use of gingerol in the preparation of a drug for preventing and / or treating liver lipid metabolism disorders, wherein the structural formula of the gingerol is shown in formula (A):

2. A drug for preventing and / or treating liver lipid metabolism disorders, comprising a pharmaceutically effective dose of gingerol, wherein the structural formula of the gingerol is as shown in formula (A):

3. The drug according to claim 2, characterized in that The drug also contains a pharmaceutically acceptable carrier.

4. The drug according to claim 3, characterized in that The pharmaceutically acceptable carrier includes one or more functional carriers selected from the group consisting of excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents.

5. The drug according to claim 3, characterized in that The medicine is any one of injection, tablet, pill, capsule, suspension or emulsion.

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