KR20140019277A - Composition containing trail for preventing or treating metabolic disease - Google Patents

Abstract

The present invention relates to a composition comprising a TNF-related apoptosis-inducing ligand (TRAIL) as an active ingredient for preventing or treating a metabolic disease. The TRAIL according to the present invention reduces blood glucose, neutral fat, cholesterol, free fatty acid, and hepatic triglyceride, and can be used for preventing or treating the metabolic disease since the TRAIL has an outstanding effect for reducing lipogenesis and stimulating metabolism.

Description

Composition containing TRAIL for preventing or treating metabolic disease

The present invention relates to a pharmaceutical composition and a food composition for the prevention or treatment of metabolic diseases comprising TRAIL (TNF-related apoptosis-inducing ligand).

Obesity is a biological phenomenon caused by the interaction of genetic, metabolic, environmental, and behavioral complex factors. It is generally recognized as overweight, but medically, the body mass index (BMI) is more than 30 (≒ standard weight). 30% or more) or BMI is 27 or more and other circulatory diseases such as diabetes (diabetes), hypertension (hypertension), hyperlipidemia (hyperlipidemia), etc. are classified as obesity. Obesity is an important cause of various metabolic diseases and adult diseases related to insulin resistance, diabetes, hypertension, cancer, gallbladder disease, hyperlipidemia, arteriosclerosis, etc. In recent years it has been known to cause deterioration of the immune system. Although obesity may be a cause of many diseases, as the obesity population continues to increase in modern society, obesity is a socially important concern, and much research is being conducted to develop effective treatments.

Lipid-related metabolic disease refers to blood lipids among diseases caused by metabolic disorders in vivo, and specifically includes fatty liver, type 2 diabetes, hyperlipidemia, cardiovascular disease, arteriosclerosis, and lipid-related metabolic syndrome. The metabolic syndrome refers to a disease in which various metabolic diseases, such as diabetes, occur simultaneously in one person. The lipid-related metabolic disease also requires the development of an effective therapeutic agent as well as obesity.

Diabetes is a metabolic chronic disease and the incidence of the world's incidence continues to increase, and statistics show that the number of diabetic patients will reach about 220 million in 2010. Diabetes is classified into insulin dependent diabetes mellitus (type 1 diabetes mellitus) and insulin independent diabetes mellitus (type 2 diabetes mellitus), depending on the secretion and action of insulin. Over 90% of patients require effective treatment and prevention.

The pathogenesis of type 2 diabetes is not clear, but it is a complex disease characterized by excessive glucose production in the liver, insulin resistance, and decreased ability to process glucose in muscle and fat cells. In particular, the incidence rate is about 13% higher than the normal weight, and in the United States, 85% of type 2 diabetes patients are obese, and obesity is a major cause of diabetes. Type 2 diabetes is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. In addition, type 2 diabetes is a progressive disease and causes complications such as retinopathy, cataract, nephropathy, neuropathy and atherosclerosis. In order to reduce the incidence of these complications, treatments to maintain blood glucose levels near normal levels are needed for patients with type 2 diabetes and treatment focuses on optimizing and potentially normalizing blood sugar control. have.

As an agent for the treatment of type 2 diabetes, which is currently aimed at controlling blood glucose, pioglitazone and rosiglitazone, a thiazolidinedione family that activates biguanide metformin and PPARγ, and α-glucosidase inhibitors that delay carbohydrate absorption in the small intestine. And oral preparations such as sulfonylureas and non-sulfonylureas that regulate insulin secretion in pancreatic β-cells are being used. However, these drugs have been reported side effects such as digestive disorders, hepatotoxicity has a disadvantage that can cause problems in terms of safety.

TRAIL is a cytokine included in the TNF family, which exists as a type II cell membrane or water-soluble protein. TRAIL is mainly known as an anticancer agent because of its ability to induce apoptosis (apoptosis) in various types of tumor cells. However, little is known about the effect of TRAIL on cell metabolism, and there is little research on this.

As the occurrence of metabolic diseases is increasing recently and the complications thereof are also a problem in modern people, it is necessary to develop medicines or functional foods that are effective in preventing or treating new metabolic diseases.

While we studied the effects of TRAIL (TNF-related apoptosis-inducing ligand) on glucose synthesis and fat particles, we found that TRAIL was neutral in blood glucose, blood fat, and liver in high fat diet-induced obesity and type 2 diabetes models. It was confirmed that the increase in fat can be reduced, and the present invention has been completed.

An object of the present invention is to provide a composition for the prevention or treatment of metabolic diseases comprising TRAIL as an active ingredient, which can effectively prevent or treat metabolic diseases.

In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of metabolic disease (metabolic disease) comprising TRAIL as an active ingredient.

The present invention also provides a food composition for the prevention or improvement of metabolic diseases comprising TRAIL as an active ingredient.

TRAIL according to the present invention not only reduces blood glucose, blood fat, and hepatic triglycerides, but also has an excellent effect of reducing fat synthesis and promoting metabolism, and thus may be useful for preventing or treating metabolic diseases. .

1 is a diagram showing the results of confirming the progression of diabetes by TRAIL treatment through the glucose tolerance test (A: general diet GFP group (ND-GFP), general diet TRAIL group (ND-TRAIL) B: high fat diet GFP treated group (HF-GFP), high fat diet TRAIL treated group (HF-TRL), C: high fat diet TRAIL treated group (HF-TRL) and control group, D: AUC (area under the curve) ) Conversion value).
2 is a diagram showing the results of confirming the effect of fatty liver recovery by TRAIL treatment after staining the liver tissue with H & E (ND-GFP: general dietary GFP treatment group, ND-TRAIL: general dietary TRAIL treatment group, HF-GFP: high fat diet GFP treated group, HF-TRAIL: high fat diet TRAIL treated group).
Figure 3 is a diagram showing the results of observation of the change in lipids of liver tissue using Oil Red O staining (ND-GFP: general diet GFP treatment group, ND-TRAIL: general diet TRAIL treatment group, HF-GFP: high fat Dietary GFP-treated group, HF-TRAIL: high-fat dietary TRAIL treated group).
4 is a diagram showing the results of confirming the expression changes of G6Pase, PEPCK by TRAIL treatment in liver tissue (ND-GFP: general dietary GFP group, ND-TRAIL: general dietary TRAIL group, HF-GFP: high fat diet GFP treated group, HF-TRAIL: high fat diet TRAIL treated group).
5 is a diagram showing the results of Western blot expression changes of Akt protein involved in hepatic fat metabolism by TRAIL treatment (ND-GFP: general dietary GFP group, ND-TRAIL: general dietary TRAIL group , HF-GFP: high fat diet GFP treated group, HF-TRAIL: high fat diet TRAIL treated group).
Figure 6 is a diagram showing the results confirmed by Western blot expression changes of enzymes and transcription factors involved in the synthesis of liposynthesis by TRAIL (ND-GFP: general dietary GFP group, ND-TRAIL: general dietary TRAIL group, HF -GFP: high fat diet GFP treated group, HF-TRAIL: high fat diet TRAIL treated group).

The present invention provides a composition for the prevention or treatment of metabolic disease (metabolic disease) comprising TRAIL as an active ingredient.

The composition comprises a pharmaceutical composition or a food composition.

Hereinafter, the present invention will be described in detail.

TRAIL according to the present invention reduces blood glucose and triglycerides in the blood and liver. The fat in the blood may include all of triglyceride, cholesterol and free fatty acid in the blood.

In addition, the TRAIL reduces the expression of SREBP-1c (Sterol regulatory element binding protein-1c). TRAIL reduces the expression of SREBP-1c, thereby inhibiting fat synthesis. Inhibition of the fat synthesis can be achieved by the inhibition of the expression of enzymes such as fatty acid synthase (FAS), stearoyl CoA desaturase 1 (SCD1), acyl CoA carboxylase (ACC), glycerol-3-phosphate acyltransferase (GPAT) have.

In addition, the TRAIL can effectively prevent or treat metabolic diseases by inhibiting the synthesis of glucose in the blood. Inhibition of the synthesis of glucose in the blood may be achieved by reducing the gene expression of glucose synthase G6Pase (glucose 6-phosphatase) or PEPCK (phosphoenolpyruvate carboxykinase).

In addition, the TRAIL can promote the fat metabolism in the blood, the promotion of fat metabolism can be achieved through the increase of AKt protein.

As described above, TRAIL according to the present invention not only reduces blood glucose, triglycerides, cholesterol and free fatty acids, and triglycerides of the liver, but also has an excellent effect of reducing fat synthesis and promoting fat metabolism. Therefore, TRAIL according to the present invention can be usefully used for the prevention or treatment of metabolic diseases.

The "metabolic disease" is a concept of a group of cardiovascular diseases and the risk factors of type 2 diabetes clustered into one disease group, including insulin resistance and various complex metabolic abnormalities and clinical features It is a concept that means. In 1988, Reaven insisted that the common cause of these symptoms was insulin resistance in the body, which is poorly insulin-induced, and called it insulin resistance syndrome. In 1998, the World Health Organization (WHO) explained that insulin resistance accounts for all of these symptoms. The term metabolic syndrome or metabolic disease was introduced. Thus, the metabolic disease may include all such diseases as non-alcoholic fatty liver, type 2 diabetes, insulin resistance disease, cardiovascular disease, arteriosclerosis and lipid related metabolic syndrome, hyperglycemia, hyperinsulinemia, hyperlipidemia, and glucose metabolism disorder Can be.

The non-alcoholic fatty liver refers to a condition in which fat is accumulated in an excess amount of hepatic cells due to liver metabolism disorder, which causes various diseases such as angina pectoris, myocardial infarction, stroke, arteriosclerosis, fatty liver and pancreatitis.

Type 2 diabetes refers to insulin-independent diabetes mellitus in diabetes, which refers to a chronic disease characterized by a relative or absolute lack of insulin resulting in glucose intolerance, caused by insufficient insulin secretion after a meal, or It can be caused by insulin resistance. Insulin resistance refers to the ability of insulin to lower blood sugar and the cells to effectively burn glucose. When the insulin resistance is high, the human body produces too much insulin, which can lead to hypertension and abnormal lipidemia as well as heart disease and diabetes. In particular, type 2 diabetes does not notice the increase in insulin in muscle and adipose tissue, and insulin action does not occur.

The insulin resistance disease is a generic term for the disease caused by insulin resistance, the resistance of cells to insulin action, hyperinsulinemia, very low density lipoprotein (VLDL) and triglyceride increase, high density lipoprotein ( It refers to a disease characterized by a decrease in high density lipoprotein (HDL) and high blood pressure, and is a concept recognized as a risk factor for cardiovascular disease and type 2 diabetes (Reaven GM, Diabetes, 37: 1595-607, (1988). )). Insulin resistance is also known to promote atherosclerosis by increasing the intracellular oxidative stress and altering the signaling system along with risk factors such as hypertension, diabetes and smoking (Freeman BA. Et al, Lab Invest). 47: 412-26, (1982)), Kawamura M. et al, J Clin Invest. 94: 771-8, (1994).

TRAIL in the present invention may include all the various forms of TRAIL, but preferably may be adenovirus-mediated hTRAIL (Ad.hTRAIL).

The pharmaceutical composition for the prevention or treatment of metabolic diseases comprising TRAIL of the present invention as an active ingredient may preferably give a synergistic effect to the main effect within the scope of not impairing the main effect of the present invention other than TRAIL. And other components.

In addition, the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient and diluent in addition to the active ingredient described above for administration. For example, carriers, excipients and diluents include lactose, textose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil.

The pharmaceutical composition of the present invention may be prepared in various parenteral or oral administration forms according to known methods. As representative of formulations for parenteral administration, isotonic aqueous solutions or suspensions are preferred for injectable formulations. The injectable formulations may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, each component may be formulated for injection by dissolving in saline or buffer.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, . In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweetening agents, fragrances, preservatives and the like may be included in addition to commonly used simple diluents such as water and liquid paraffin. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The effective dosage of the pharmaceutical composition of the present invention may vary depending on the age and sex weight of the patient, but may be administered at 1 μg / kg to 100 mg / kg, preferably at 10 μg / kg to 10 mg / kg. May be administered.

The composition of the present invention can be used alone or in combination with methods using surgery, chemical therapy, radiotherapy, hormone therapy, drug therapy and biological response modifiers for the prevention or treatment of metabolic diseases.

In addition, the food composition according to the present invention may be added as it is, or used with other foods or food ingredients, and may be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, the composition of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material, in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include dairy products including meats, sausages, breads, chocolates, candies, snacks, confectionery, pizza, ramen noodles, gums, ice cream, soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.

The beverage composition of the present invention may contain, as an additional ingredient, various flavors or natural carbohydrates such as ordinary beverages. The natural carbohydrates described above may be used as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, and synthetic sweeteners such as saccharin and aspartame. The ratio of the natural carbohydrate is generally about 0.01 to 10 g, preferably about 0.01 to 0.1 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, A carbonating agent used in a carbonated beverage, and the like. In addition, the composition of the present invention may comprise flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the present invention will be described in detail with reference to Examples and Preparation Examples. However, the following examples and preparative examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples and preparative examples.

Example 1 Preparation of Adenovirus Expressing hTRAIL

In order to prepare a recombinant adenovirus vector that is depleted of E1 expressing human TRAIL (hTRAIL), hTRAIL cDNA was introduced into the transport plasmid under CMV (cytomegalovirus) transcription-initial enhancer / promoter transcription control. The prepared adenovirus from which E1 was removed was included as a control group containing only GFP (green fluorescent protein), which is a reporter gene having a CMV promoter. Recombinant adenovirus was amplified in HEK 293 cells and purified through two steps centrifugation step of cesium chloride concentration difference.

Example 2 Preparation of an Obese Type 2 Diabetes Model Through a High Fat Diet

A high fat diet induced obesity type 2 diabetes model. Male, 6-week-old C57BL / 6 rats were divided into two groups and consumed normal diet (ND) and high fat diet (HFD; 14.3% protein, 20.1% carbohydrate, 64.4% fat (kcal%)) by 22 weeks. Mice in the high-fat diet all had obesity and type 2 diabetes. Avenovirus-mediated hTRAIL (Ad.hTRAIL) or control GFP was injected into the vein of the normal and high fat diet groups. Overexpression of Ad.hTRAIL was confirmed by Western blot in liver tissue. Animals were sacrificed 1 week after adenovirus administration, and samples were collected to collect blood glucose levels and insulin, and plasma triglycerides (plasma TG), plasma cholesterol (plasma TC), plasma free fatty acids (plasma FFA) and triglycerides in liver tissues. (hepatic TG) was analyzed.

The results are shown in Table 1.

P <0.05 compared with ND GFP-treated mice; † P <0.05 compared with HF GFP-treated mice

As shown in Table 1, it was confirmed that not only blood glucose but also plasma triglyceride (plasma TG), plasma cholesterol (plasma TC), and plasma free fatty acid (plasma FFA) all decreased in the TRAIL-injected group compared to the GFP-injected control group. . In particular, triglycerides in the liver tissue as well as blood were also reduced, confirming the effects of TRAIL as a fatty liver treatment.

Example 3 Recovery Effect of Sugar Resistance by TRAIL

Blood glucose was measured by an Intraperitoneal glucose tolerance test (IPGTT) test to confirm the progress of diabetes. If you do not have glucose tolerance, it means that diabetes is progressing.

The results are shown in Fig.

As shown in FIG. 1, the control group administered GFP to the high fat diet group showed obesity and no glucose tolerance. However, the treatment group administered TRAIL to the high fat diet group decreased blood sugar and reduced glucose tolerance compared to the GFP group. It was confirmed that the recovery. As a result of converting IPGTT value into AUC (area under the curve), GFP treatment group, which is a control group of high fat diet group, showed no glucose tolerance, so the amount of blood glucose was very high over time. It was clearly seen that the resistance was restored to the general diet group or less. Through this, it was confirmed that TRAIL as a therapeutic agent of type 2 diabetes induced by high fat diet.

Example 4 Fat Reduction in Liver Tissue Following TRAIL Treatment

Histological microscopic examination using H & E staining examined liver lipids and confirmed lipid particles in liver tissues to determine whether TRAIL-treated fatty liver could be recovered by TRAIL.

The results are shown in Fig.

As shown in FIG. 2, livers of the normal diet GFP-treated group (ND-GFP) and the normal diet TRAIL-treated group (ND-TRAIL) showed normal structure of liver cells, and the liver of the high fat dietary GFP control group (HF-GFP). Showed fatty liver with many lipid particles in liver tissue. However, the liver of the high-fat diet TRAIL-treated group (HF-TRAIL) showed a decrease in lipid particles and almost normal liver appearance. As a result, the histological microscopic examination confirmed that the fatty liver was induced by the high fat diet through the control group, and it was confirmed that the induced fatty liver was recovered in the group injected with TRAIL.

In addition, in order to further confirm the effect of improving the fatty liver, fat was stained red in the liver tissue through Oil Red O staining and then microscopic examination was performed.

The results are shown in Fig.

As shown in FIG. 3, red fat particles rarely appeared in the general diet GFP (ND-GFP) treated liver and the general diet TRAIL (ND-TRAIL) treated liver. However, the liver of the high fat diet GFP control group (HF-GFP) was able to observe a lot of red fat particles, indicating that the fatty liver was found by the high fat diet. However, in the high fat diet TRAIL treated group (HF-TRAIL), it was confirmed that the red fat particles were reduced. These results confirm that TRAIL can reduce fat induced by high fat diet in liver tissue.

Example 5 Inhibition of Glucose Synthase Expression by TRAIL

As insulin resistance is a major cause of various metabolic diseases, high blood sugar levels have been pointed out as a problem in each metabolic disease. Therefore, in order to confirm the effect of TRAIL on the expression of G6Pase (glucose 6-phosphatase) and PEPCK (phosphoenolpyruvate carboxykinase), which are important enzymes in blood glucose synthesis, expression analysis of G6Pase and PEPCK genes was performed in liver tissues.

The results are shown in Fig.

As shown in Figure 4, compared with the high-fat diet GFP control group (HF-GFP), the gene expression of G6Pase and PEPCK decreased in the TRAIL-treated liver in the high-fat diet TRAIL treated group (HF-TRL). Therefore, TRAIL was confirmed to be a substance that can inhibit the synthesis of glucose to lower blood sugar levels.

Example 6 Increase of Akt Protein by TRAIL Treatment

Western blot confirmed whether TRAIL protein is effectively expressed in the liver of the TRAIL-injected group and whether the expression of Akt protein involved in liver fat metabolism in liver tissue is changed by TRAIL.

The results are shown in Fig.

As shown in Figure 5, TRAIL protein showed high expression in the liver of the TRAIL treatment group. In addition, Akt protein associated with fat metabolism was increased, and phosphorylation of Akt protein was also increased. Through this, TRAIL confirmed that it could promote the metabolism of fat in liver through Akt pathway in liver.

Example 7 Inhibition of Fat Synthesis by TRAIL Treatment

Sterol regulatory element binding protein-1c (SREBP-1c) is a transcription factor synthesized as a precursor in the cell membrane of ER (endoplasmic reticulum). Since SREBP-1c can induce the expression of gene families involved in glucose transport and fatty acid synthesis, the fatty acid synthase FAS, an important enzyme for the synthesis of fatty acids that TRAIL regulates SREBP-1c and becomes its target gene ), High fat diet in type 2 diabetes-induced rats to determine whether they can regulate the expression of SCD1 (stearoyl CoA desaturase 1), ACC (acyl CoA carboxylase), and GPAT (glycerol-3-phosphate acyltransferase). Expression changes of enzymes and transcription factors involved in fat synthesis by TRAIL were confirmed by Western blot.

The results are shown in Fig.

As shown in FIG. 6, the expression of SREBP-1c was increased in the high-fat diet rats compared to the normal diet rats, as expected by the high lipid producing ability. However, as a result of comparing liver SREBP-1c expression in rats treated with GFP and TRAIL-treated rats, the expression of TRAIL increased SREBP-1c expression in liver. However, in the group inducing type 2 diabetes through high-fat diet, the expression of lipogenic genes FAS, SCD1, ACC, and GPAT, which are important enzymes related to fat synthesis, which are the target genes by reducing the expression of SREBP-1c by TRAIL administration Expression was significantly reduced.

Formulation Example 1 Preparation of Pharmaceutical Composition

1.1 Manufacture of Powder

TRAIL 20 mg

Lactose 100 mg

Talc 10 mg

The above components are mixed and filled in airtight bags to prepare powders.

1.2 Preparation of tablets

TRAIL 10 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.

1.3 Preparation of capsules

TRAIL 10 mg

Crystalline cellulose 3 mg

Lactose 14.8 mg

Magnesium stearate 0.2 mg

The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.

1.4 Manufacture of Injection

TRAIL 10 mg

180 mg mannitol

Sterile sterilized water for injection 2974 mg

Na2HPO4H2O 26 mg

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

1.5 Preparation of Liquids

TRAIL 20 mg

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.

Formulation Example 2 Preparation of Food Composition

2.1. Manufacture of health food

TRAIL 100 mg

Vitamin mixture quantity

Vitamin A acetate 70 μg

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

0.15 mg of vitamin B2

Vitamin B6 0.5 mg

Vitamin B12 0.2 μg

Vitamin C 10 mg

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 μg

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

2.2 Manufacture of beverages

TRAIL 100 mg

Vitamin C 15 g

Vitamin E (powder) 100 g

19.75 g of ferrous lactate

3.5 g of zinc oxide

Nicotinic acid amide 3.5 g

Vitamin A 0.2 g

Vitamin B1 0.25 g

Vitamin B2 0.3g

Water quantification

After mixing the above components according to a conventional healthy beverage manufacturing method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2L container, sealed sterilization and refrigerated and then stored in the present invention For the preparation of healthy beverage compositions.

Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.

Claims (14)

Pharmaceutical composition for the prevention or treatment of metabolic disease (metabolic disease) comprising TRAIL (TNF-related apoptosis-inducing ligand) as an active ingredient.
According to claim 1, wherein the metabolic disease in the group consisting of non-alcoholic fatty liver, type 2 diabetes, insulin resistance disease, cardiovascular disease, arteriosclerosis, lipid-related metabolic syndrome, hyperglycemia, hyperinsulinemia, hyperlipidemia and glucose metabolism disorder A pharmaceutical composition for the prevention or treatment of metabolic diseases, characterized in that the selected one.
The pharmaceutical composition for preventing or treating metabolic diseases, according to claim 1, wherein the TRAIL reduces glucose in blood.
The method of claim 1, wherein the TRAIL is characterized in that to reduce one or more blood fats selected from the group consisting of triglycerides, cholesterol and free fatty acids in the blood, pharmaceutical composition for the prevention or treatment of metabolic diseases.
The pharmaceutical composition for preventing or treating metabolic diseases according to claim 1, wherein the TRAIL reduces liver triglycerides.
The pharmaceutical composition for preventing or treating metabolic diseases according to claim 1, wherein TRAIL inhibits fat synthesis by reducing expression of SREBP-1c (Sterol regulatory element binding protein-1c).
The method of claim 6, wherein the fat synthesis is at least one enzyme selected from the group consisting of fatty acid synthase (FAS), stearoyl CoA desaturase 1 (SCD1), acyl CoA carboxylase (ACC) and glycerol-3-phosphate acyltransferase (GPAT) Pharmaceutical composition for the prevention or treatment of metabolic diseases, characterized in that inhibited through inhibition of expression.
The pharmaceutical composition for preventing or treating metabolic diseases according to claim 1, wherein the TRAIL reduces the expression of G6Pase (glucose 6-phosphatase) or PEPCK (phosphoenolpyruvate carboxykinase) which is a glucose synthase.
According to claim 1, wherein TRAIL is characterized in that to promote fat metabolism, pharmaceutical composition for the prevention or treatment of metabolic diseases.
The method of claim 9, wherein the fat metabolism is promoted through the increase of the AKt protein, a pharmaceutical composition for preventing or treating metabolic diseases.
The pharmaceutical composition for preventing or treating metabolic diseases according to claim 1, wherein the TRAIL is adenovirus-mediated hTRAIL (Ad.hTRAIL).
Food composition for the prevention or improvement of metabolic disease (metabolic disease) comprising TRAIL as an active ingredient.
The method of claim 12, wherein the metabolic disease is in the group consisting of non-alcoholic fatty liver, type 2 diabetes, insulin resistance disease, cardiovascular disease, arteriosclerosis, lipid-related metabolic syndrome, hyperglycemia, hyperinsulinemia, hyperlipidemia and glucose metabolism disorders Food composition for the prevention or improvement of metabolic diseases, characterized in that the selected one.
The food composition for preventing or ameliorating metabolic diseases according to claim 12, wherein the TRAIL is adenovirus-mediated hTRAIL (Ad.hTRAIL).

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