CN115998726B - Application of coltsfoot ketone in preparing medicament for preventing and treating liver steatosis or fatty liver - Google Patents
Application of coltsfoot ketone in preparing medicament for preventing and treating liver steatosis or fatty liver Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses application of coltsfoot ketone in preparing a medicine for preventing and treating hepatic steatosis or fatty liver, and belongs to the technical field of medicines. From the aspects of cell experiments and in-vivo experiments, the embodiment of the invention proves that coltsfoot ketone can improve liver steatosis and has prevention and treatment effects on fatty liver, and the coltsfoot ketone can be applied to preparing medicaments for preventing and treating liver steatosis or fatty liver. Meanwhile, coltsfoot ketone is taken as a natural low-toxicity small molecular compound, has obvious relieving effect on lipid accumulation induced by high-fat diet, plays an important role in the treatment of non-alcoholic fatty liver disease, and has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of coltsfoot ketone in preparation of a medicine for preventing and treating hepatic steatosis or fatty liver.
Background
Coltsfoot ketone (TUS) is a sesquiterpene component isolated from flos Farfarae. Early studies showed that TUS has a variety of pharmacological activities. TUS has the partial effects of relieving cough and asthma and protecting the cardiovascular system. TUS can inhibit lipopolysaccharide-induced neuronal apoptosis by scavenging active oxygen. TUS inhibits the release of NO, PGE2, TNF- α, and the expression of iNOS and COX-2 by LPS stimulating BV-2 microglial cells by inhibiting NF-kB pathway, thereby inhibiting the release of inflammatory factors. And has also been found to have antiallergic and anticancer effects, etc. Coltsfoot ketone also has important function in preparing anti-aging medicines and health foods.
With the increasing living standard of people, the life style and the dietary structure are changed, the number of obese people is increased year by year, and the incidence of nonalcoholic fatty liver disease (NAFLD) is also obviously increased. NAFLD is a chronic liver disease, and excessive intake of high fat diet for a long period induces overload of free fatty acids in liver, leading to fatty degeneration of liver cells, and also causes inflammation and fibrosis of liver, and may further develop into liver cirrhosis, liver failure, and liver cancer.
NAFLD is a type of syndrome characterized by fat deposition in liver cells, which has plagued humans for many years, and a definite and effective therapeutic method has not been studied yet. Long-term high-fat high-sugar diet induces liver glycolipid metabolic disorders leading to the occurrence of NAFLD. An imbalance between lipid storage (e.g., triglycerides in lipid droplets) and fatty acid breakdown (primarily through fatty acid beta-oxidation) can lead to an increase in abnormal fat deposition, leading to metabolic syndrome. Oxidative stress, mitochondrial damage, and insulin resistance from lipid metabolism disorders are considered to be major drivers of the pathogenesis of metabolic-related fatty liver. Thus, inhibiting lipid production, inducing fatty acid breakdown, and improving oxidative stress and promoting energy expenditure would be helpful in preventing NAFLD-related diseases.
To date, there is no report in the prior art on coltsfoot ketone in the preparation of a medicament for treating non-alcoholic fatty liver disease and fatty liver degeneration, nor is there a similar suggestion or attempt.
Disclosure of Invention
The invention aims to provide application of coltsfoot ketone in preparing a medicine for preventing and treating hepatic steatosis or fatty liver, and aims to solve the problem that a low-toxicity natural small-molecule medicine for effectively preventing or treating hepatic steatosis or fatty liver is lacking at present.
The aim of the invention is realized by the following technical scheme:
The examples of the present invention show from both living and cellular assays:
TUS has no obvious effect on the activity of HepG2 human liver cancer cell at 120 mu M.
TUS can relieve lipid disorders in human hepatoma cells HepG2 by reducing TG levels in the human hepatoma cells HepG2 and intracellular lipid droplets; TUS can promote the energy metabolism of the human hepatoma cell HepG2 by increasing the number of mitochondria of the human hepatoma cell HepG2 and the DNA level and ATP level of the mitochondria; in addition, TUS exerts an antioxidant effect by reducing the ROS and MDA levels and increasing the levels of antioxidants SOD, CAT and GSH in the human hepatoma cell HepG 2.
In addition, TUS is effective in reducing weight gain in mice caused by a high-fat diet, reducing fat percentage gain, and reducing fat distribution caused by a high-fat diet. And TUS can improve glucose tolerance and insulin sensitivity of the mice, TUS can enhance energy metabolism level of the mice; meanwhile, TUS is found to reduce the TG level of liver, reduce liver lipid deposition and obviously relieve lipid accumulation induced by high-fat diet, and has the effects of improving liver steatosis and preventing and treating fatty liver.
According to the results of in vivo and cell tests in the embodiment of the invention, coltsfoot ketone is applied to preparation of medicines for preventing and treating hepatic steatosis or fatty liver.
As a preferred embodiment, the control includes prevention, alleviation, treatment.
In a preferred embodiment, the fatty liver is a non-alcoholic fatty liver.
As a preferred embodiment, the preparation of the medicine for preventing and treating liver steatosis or fatty liver is carried out, and the prepared medicine is an oral preparation medicine.
The oral preparation medicine is one of capsule preparation, soft capsule preparation, oral liquid preparation, dripping pill preparation or tablet preparation medicine.
The oral preparation also contains pharmaceutically acceptable auxiliary materials and/or carriers.
In a preferred embodiment, the coltsfoot ketone is used in an amount of 15mg/kg to 30mg/kg; preferably 15mg/kg and 30mg/kg.
Compared with the prior art, the invention has the following beneficial effects:
In the embodiment of the invention, it is confirmed that TUS can relieve lipid disorders in the human hepatoma cell HepG2 by reducing the TG level in the human hepatoma cell HepG2 and reducing intracellular lipid drops on the cell test level; TUS can increase the quantity of human liver cancer cell HepG2 mitochondria, and the DNA level and ATP level of mitochondria, and can promote the energy metabolism of human liver cancer cell HepG 2; in addition, TUS exerts an antioxidant effect by reducing the ROS and MDA levels and increasing the levels of antioxidants SOD, CAT and GSH in the human hepatoma cell HepG 2.
In the aspect of in vivo experiments, TUS can effectively reduce the body weight increase caused by high-fat diet, can effectively degrade the fat percentage increase, and can reduce the fat distribution caused by high-fat diet. And TUS can improve glucose tolerance and insulin sensitivity of the mice, TUS can improve energy metabolism level of the mice; meanwhile, TUS is found to reduce the TG level of liver and liver lipid deposition, and has the effects of improving liver steatosis and preventing and treating fatty liver. And it is verified that TUS has no obvious effect on the activity of human hepatoma cells at 120. Mu.M. Therefore, the TUS can be applied to the preparation of the medicine for preventing and treating liver steatosis or fatty liver, and the medicine application has no side effects such as cytotoxicity and the like. Thereby providing a natural micromolecular medicine-coltsfoot ketone for effectively preventing or treating liver steatosis or fatty liver. In addition, coltsfoot ketone is taken as a natural small molecular compound, has obvious effect of relieving lipid accumulation induced by high-fat diet, plays an important role in the treatment of non-alcoholic fatty liver disease, and has wide application prospect.
Drawings
FIG. 1 is a schematic diagram of a cell-related experiment in accordance with an embodiment of the present invention.
FIG. 2 is a schematic diagram of an in vivo study-related experiment in accordance with the first embodiment of the present invention.
FIG. 3 is a graph showing the effect of TUS at various concentrations on the activity of HepG2 human hepatoma cells.
FIG. 4 is a graph showing the results of detecting the TG concentration in HepG2 human liver cancer cells after TUS treatment at various concentrations.
FIG. 5 is a graph showing the results of oil red O staining of HepG2 human hepatoma cells after TUS treatment; wherein the left plot is of a TUS treatment of 0. Mu.M and the right plot is of a TUS treatment of 70. Mu.M.
FIG. 6 is a graph showing the results of detecting the mitochondrial number of HepG2 human hepatoma cells after TUS treatment; wherein the left plot is of a TUS treatment of 0. Mu.M and the right plot is of a TUS treatment of 70. Mu.M.
FIG. 7 is a graph showing the results of detecting mitochondrial DNA levels of HepG2 human hepatoma cells after TUS treatment.
FIG. 8 is a graph showing the results of detecting ATP levels in mitochondria of HepG2 human hepatoma cells after TUS treatment.
FIG. 9 is a graph showing the results of detecting ROS levels in HepG2 human hepatoma cells after TUS treatment.
FIG. 10 is a graph showing the results of MDA levels of HepG2 human hepatoma cells after TUS treatment.
FIG. 11 is a graph showing the results of detecting the SOD level of HepG2 human liver cancer cell after TUS treatment.
FIG. 12 is a graph showing the results of CAT levels in HepG2 human hepatoma cells after TUS treatment.
FIG. 13 is a graph showing the results of detecting GSH levels in HepG2 human hepatoma cells after TUS treatment.
FIG. 14 is a graph showing the results of weight measurement of mice after TUS treatment.
Fig. 15 is a graph showing the results of nuclear magnetic measurement of fat percentage in the mice after TUS treatment.
FIG. 16 is a graph showing the results of CT detection of fat distribution in TUS treated mice.
Fig. 17 is a graph showing the results of HE staining of epididymal adipose tissue after TUS treatment.
FIG. 18 is a graph showing the results of glucose tolerance (GTT) test performed on TUS treated mice.
FIG. 19 is a graph showing the results of insulin sensitivity (ITT) testing of TUS treated mice.
FIG. 20 is a graph of the results of a test for energy metabolism observed in the metabolism cages of TUS treated mice; wherein, A-B is O 2 absorption rate (VO 2); C-D is CO 2 consumption rate (VCO 2); E-F is a respiratory quotient (RER); G-H is energy (EE).
FIG. 21 is a graph showing the results of detecting TG levels in the liver of TUS-treated mice.
FIG. 22 is a graph of results of oil red O staining of lipid deposition in the liver of TUS treated mice.
FIG. 23 is a graph of H & E staining results of lipid deposition in the liver of TUS treated mice.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Currently, there is no low toxicity natural small molecule drug that is effective in alleviating fatty liver degeneration. In order to solve the technical problems, the invention provides application of coltsfoot ketone in preparing a medicine for preventing and treating hepatic steatosis or fatty liver.
Example 1
In this example, the effects and the application prospects of coltsfoot in fatty liver degeneration and fatty liver are explored by injecting coltsfoot into the abdominal cavity of mice with lipid metabolism disorder caused by high-fat diet and adding coltsfoot into liver cancer cells of HepG2 human through living body and cell tests respectively.
The small molecules in the embodiment are solid medicines, and the purity of the small molecules in vivo and in vitro experiments is more than or equal to 99 percent. The drugs for cell experiments were dissolved in DMSO to give a stock solution of 10mM and stored at-20 ℃.
The cell experiments are shown in FIG. 1. The effect of TUS on lipid metabolism was examined in vitro using HepG2 cells. Firstly, TUS with different concentrations is added into DMEM (common growth medium) for cell culture, and when the fusion degree of HepG2 cells reaches about 80%, the toxic effect of TUS on the cells is detected by CCK 8. After detecting the nontoxic effect, the cells are subjected to high-fat induction, namely, the cells are divided into oleic acid/palmitic acid (OA/PA) induced HepG2 human liver cancer cell groups and OA/PA induced HepG2 human liver cancer cell+TUS groups. Resting culture is carried out for 6-12h by using a serum-free culture medium when the fusion degree of the HepG2 cells reaches about 80%; after that, the culture medium was changed to OA/PA (2:1) medium and cultured for 24 hours, and TUS was added to each well of the treated group. Before dosing, small molecules were thawed at 4 ℃ and at final concentration: the concentration of the mother solution is 1: the corresponding small molecule volume was added in a 1000 ratio to give a final TUS concentration of 70. Mu.M. After 24h of treatment, the cells are taken to measure the indexes of lipid metabolism, glycometabolism, energy metabolism and oxidative stress, which are close to fatty liver degeneration. Specifically, the method comprises (1) detecting the influence of TUS on the activity of HepG2 human liver cancer cell; (2) Detecting TUS to regulate and control lipid metabolism of HepG2 human liver cancer cells, measuring intracellular TG level change, and carrying out oil red O staining on the cells to observe the change condition of cell lipid accumulation; (3) Detecting the influence of TUS on the energy metabolism of HepG2 human liver cancer cells, performing fluorescent staining on the cells, and photographing to observe the change of the cell mitochondria quantity; DNA quantification of mitochondria; measuring changes in mitochondrial ATP; (4) And detecting the change of indexes of TUS on oxidation aspects such as ROS, MDA, antioxidants SOD, CAT, GSH and the like in HepG2 human liver cancer cells.
The living experiment is shown in FIG. 2, and the experimental animal is a C57BL/6 mouse; five week old male mice were maintained at 24±2 ℃ for 12 hours in light/dark cycle, and were free to obtain food and water; after 2 weeks of adaptive feeding, the mice were randomized into the following four groups (n=7). 1) Normal diet (CK, 3.8 kcal/g, fat calories 10%, protein calories 14%, carbohydrate calories 76%); 2) High fat feed (HFD, 5.5 kcal/g, 60% fat calories, 14% protein calories, 26% carbohydrate calories); 3) High fat feed + intraperitoneal injection of 15mg/kg TUS and 4) high fat feed + intraperitoneal injection of 30mg/kg TUS. The TUS dissolution mode is as follows: 10% DMSO+40% PEG300+5% Tween-80+45% sample. The experimental time period of the mice was 12 weeks. Prior to death, mice were fasted for 4 hours and anesthetized with diethyl ether to reduce pain. Mice were sacrificed at cervical breaks and tissue samples were collected for subsequent index detection associated with fatty liver degeneration. The method specifically comprises the following steps: (5) detecting the effect of TUS on fat deposition in the mouse; (6) Detecting the effect of TUS on glucose tolerance and insulin sensitivity in the mouse; (7) detecting the effect of TUS on energy metabolism in the mouse; (8) detecting the effect of TUS on liver lipid deposition in mice.
The experimental results show that:
TUS has no obvious influence on the activity of HepG2 human liver cancer cell
As shown in FIG. 3, the effects of TUS of 0, 10. Mu.M, 30. Mu.M, 50. Mu.M, 70. Mu.M, 100. Mu.M and 120. Mu.M on the activity of HepG2 human hepatoma cells were tested, respectively, and the results showed that TUS had no significant effect on the activity of HepG2 human hepatoma cells at a concentration of 120. Mu.M or less.
TUS regulates lipid metabolism in HepG2 human hepatoma cells
Fatty liver is generally accompanied by high TG levels, with a decrease in intracellular TG following TUS addition (as shown in fig. 4). Subsequent experiments were then performed with a TUS of 70. Mu.M. To further explore the effect of TUS on lipid metabolism of HepG2 human hepatoma cells, oil red O staining was performed, and FIG. 5 shows an oil red O staining chart of HepG2 human hepatoma cells, and it can be seen that lipid droplets of TUS treated group were significantly reduced. This suggests that TUS may alleviate lipid disorders in HepG2 human hepatoma cells.
TUS increases energy metabolism of HepG2 human liver cancer cell
Mitochondria are the sites of oxidative metabolism of eukaryotes, and are the sites where sugars, fats and amino acids ultimately oxidize and release energy, and ATP produced through oxidative phosphorylation is required by the body. The study of the change of the measured cell mitochondria number shows that TUS can increase the number of the mitochondria of the HepG2 human liver cancer cell (shown in figure 6); DNA quantification of mitochondria revealed that TUS increased mitochondrial DNA levels (as shown in fig. 7); and TUS can increase mitochondrial ATP levels (as shown in figure 8). TUS is shown to increase mitochondrial numbers and has some impact on energy metabolism.
TUS has antioxidant effect on HepG2 human liver cancer cells
ROS is a highly reactive radical. When oxidative stress occurs, ROS increase, resulting in varying degrees of cellular damage and destruction, primarily manifested as oxidative damage to lipids, amino acids and proteins, nucleic acids and chromosomes. Measuring changes in oxidative aspects such as cellular ROS, and finding that ROS decrease after TUS is added (as shown in FIG. 9); MDA is a metabolic product of an important oxygen free radical in the body, can better reflect the peroxidation degree of tissues, and has a reduction after TUS is added (as shown in figure 10); SOD is an antioxidant metalloenzyme present in organisms and increases after TUS is added (as shown in fig. 11); CAT is an enzyme scavenger for scavenging hydrogen peroxide in vivo, and CAT rises after TUS is added (as shown in FIG. 12); GSH acts as an antioxidant, with GSH rising after the addition of TUS (as shown in fig. 13).
TUS has effect in reducing lipid deposition in mice
The deposition of excess lipid by high fat diet resulted in metabolic disturbance of the body, and increased body weight and body fat rate, and TUS was found to have an effect of effectively reducing body weight of mice after weighing the mice (as shown in FIG. 14). Nuclear magnetic measurements of fat percentage in mice revealed that TUS was effective in reducing the increase in fat percentage (as shown in FIG. 15).
High fat was prone to cause lipid deposition in the organism and CT examination of the fat distribution in mice revealed that the fat distribution in mice in hfd+tus group was reduced compared to HFD group (as shown in fig. 16).
The mouse epididymal fat was HE stained and TUS was found to reduce lipid droplets caused by high fat (as shown in fig. 17).
TUS can increase glucose tolerance and insulin sensitivity in mice
High fat is liable to cause insulin resistance of glucose, causes body glucose metabolism disorder, and further aggravates lipid metabolism disorder. Glucose tolerance (GTT) and insulin sensitivity (ITT) assays were performed on mice, and it was found that TUS could increase glucose tolerance (as shown in fig. 18) and insulin sensitivity (as shown in fig. 19) in mice as measured by its effect on glucose metabolism in vivo.
TUS has effect in improving energy metabolism of mice
The high fat is easy to cause energy metabolism disorder, and the improvement of energy metabolism is helpful for relieving obesity caused by the high fat and reducing fat deposition of organisms. Mice were placed in metabolic cages for observation of the mice 'O 2 absorption rate (VO 2), CO 2 consumption rate (VCO 2), respiratory quotient (RER) and energy (EE), and TUS was found to increase the mice' energy metabolism level (as shown in fig. 20).
TUS has blood lipid reducing effect on mouse liver
High fat is liable to cause liver injury, thereby leading to liver degeneration, NAFLD can be formed, and liver fibrosis and even liver cancer can be seriously induced. TG detection, oil red O staining and H & E on mouse livers found that TUS reduced TG levels in the livers (as shown in figure 21) and reduced liver lipid deposition (as shown in figures 22 and 23), indicating improved steatosis.
In summary, the experimental results show that in the embodiment of the invention, the experimental results are shown from two aspects of living body and cell tests:
TUS has no obvious effect on the activity of HepG2 human liver cancer cells within 120 mu M.
TUS can relieve lipid disorders in human hepatoma cells HepG2 by reducing TG levels in the human hepatoma cells HepG2 and intracellular lipid droplets; TUS can increase the quantity of human liver cancer cell HepG2 mitochondria, and the DNA level and ATP level of mitochondria, and can enhance the energy metabolism of human liver cancer cell HepG 2; in addition, TUS exerts an antioxidant effect by reducing the ROS and MDA levels and increasing the levels of antioxidants SOD, CAT and GSH in the human hepatoma cell HepG 2.
In addition, TUS can effectively reduce the body weight increase caused by high-fat diet, can effectively reduce the fat percentage increase, and can reduce the fat distribution caused by high-fat diet. And TUS can improve glucose tolerance and insulin sensitivity of the mice, TUS can improve energy metabolism level of the mice; meanwhile, TUS is found to reduce the TG level of liver, reduce liver lipid deposition and obviously relieve lipid accumulation induced by high-fat diet, and has the effects of improving liver steatosis and preventing and treating fatty liver.
According to the results of in vivo and cell tests in the embodiment of the invention, coltsfoot ketone is applied to preparation of medicines for preventing and treating hepatic steatosis or fatty liver.
The prevention and treatment include prevention, alleviation and treatment.
The fatty liver is nonalcoholic fatty liver.
The prepared medicine for preventing and treating liver steatosis or fatty liver is an oral preparation medicine.
The oral preparation medicine is one of capsule preparation, soft capsule preparation, oral liquid preparation, dripping pill preparation or tablet preparation medicine.
The oral preparation also contains pharmaceutically acceptable auxiliary materials and/or carriers.
The dosage of coltsfoot ketone is 15mg/kg-30mg/kg; preferably 15mg/kg and 30mg/kg.
Compared with the prior art, the invention has the following beneficial effects:
In the embodiment of the invention, on the aspect of a cell test, TUS can relieve lipid disorders in the human hepatoma cell HepG2 by reducing the TG level in the human hepatoma cell HepG2 and reducing intracellular lipid drops; TUS can promote the energy metabolism of the human hepatoma cell HepG2 by increasing the number of mitochondria of the human hepatoma cell HepG2 and the DNA level and ATP level of the mitochondria; in addition, TUS exerts an antioxidant effect by reducing the ROS and MDA levels and increasing the levels of antioxidants SOD, CAT and GSH in the human hepatoma cell HepG 2. In the aspect of in vivo experiments, TUS can effectively reduce the body weight increase caused by high-fat diet, can effectively reduce the fat percentage increase, and can reduce the fat distribution caused by high-fat diet. And TUS can improve glucose tolerance and insulin sensitivity of the mice, TUS can improve energy metabolism level of the mice; meanwhile, TUS is found to reduce the TG level of liver and liver lipid deposition, and has the effects of improving liver steatosis and preventing and treating fatty liver. And it is verified that TUS has no obvious effect on the activity of human hepatoma cells at 120. Mu.M. Therefore, the TUS can be applied to the preparation of the medicine for preventing and treating liver steatosis or fatty liver, and the medicine application has no side effects such as cytotoxicity and the like. Thereby providing a nontoxic natural micromolecular medicine-coltsfoot ketone for effectively preventing or treating liver steatosis or fatty liver. In addition, coltsfoot ketone is taken as a natural small molecular compound, has obvious effect of relieving lipid accumulation induced by high-fat diet, plays an important role in the treatment of non-alcoholic fatty liver disease, and has wide application prospect.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (6)
1. The coltsfoot ketone is used as an active ingredient in the preparation of a medicament for treating non-alcoholic fatty liver.
2. Use of coltsfoot according to claim 1 for the preparation of a medicament for the treatment of non-alcoholic liver fat, characterized in that: the medicine is an oral preparation.
3. Use of coltsfoot according to claim 2 for the preparation of a medicament for the treatment of non-alcoholic liver fat, characterized in that: the oral preparation is one of a capsule preparation, an oral liquid preparation, a dripping pill preparation or a tablet preparation.
4. Use of coltsfoot according to claim 2 for the preparation of a medicament for the treatment of non-alcoholic liver fat, characterized in that: the oral preparation also contains pharmaceutically acceptable auxiliary materials and/or carriers.
5. Use of coltsfoot according to claim 1 for the preparation of a medicament for the treatment of non-alcoholic liver fat, characterized in that: the dosage of coltsfoot ketone is 15 mg/kg-30 mg/kg.
6. Use of coltsfoot according to claim 1 for the preparation of a medicament for the treatment of non-alcoholic liver fat, characterized in that: the dosage of coltsfoot ketone is 15 mg/kg and 30 mg/kg.
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