WO2019103248A1 - Composition for preventing or treating atherosclerosis, containing extract of dystaenia takeshimana - Google Patents

Abstract

The present invention relates to a composition for preventing or treating atherosclerosis, containing an extract of Dystaenia takeshimana, and to: a pharmaceutical composition for preventing or treating atherosclerosis and a food composition, which contain, as an active ingredient, an extract of Dystaenia takeshimana or a fraction thereof; a method for preventing or treating atherosclerosis; and a composition for inhibiting triglyceride-induced macrophage cell death. A composition containing an extract of Dystaenia takeshimana, of the present invention, enables the functions of macrophages to be maintained even in a state in which the blood fat concentration is high, thereby being effectively usable for preventing or treating atherosclerosis caused by decreased functioning of macrophages.

Description

Composition for the prevention or treatment of arteriosclerosis, comprising an extract of the island

The present invention relates to a composition for the prevention or treatment of atherosclerosis, which comprises an extract of a sea bream. The present invention relates to a pharmaceutical composition, a food composition, a preventive or therapeutic agent for atherosclerosis, a composition for preventing or treating atherosclerosis, And a composition for inhibiting macrophage death by triglyceride.

Atherosclerosis, sometimes referred to as atherosclerosis, is a disease in which hypertrophy or tissue degeneration occurs in the arterial wall. As the inner wall of the artery thickens and the inside diameter narrows, obstacles appear in the blood stream supplying oxygen and various nutrients, thereby causing various diseases. Arteriosclerosis is prone to develop in the cerebral arteries or coronary arteries. In the case of cerebral artery sclerosis, headache, dizziness, mental disorder and cerebral edema are the causes. In the case of coronary artery sclerosis, it causes pain and arrhythmia in the heart, causing angina and myocardial infarction. In addition, arteriosclerosis is closely related to the development and progression of diseases such as obesity (overweight), thrombosis, hypercoagulability, and thrombotic conditions (arterial and venous), including metabolic syndrome and lipidemia, including central obesity, Causes or aggravates chronic complications.

Such atherosclerosis is caused by excessive cell proliferation in the inner lining of the artery, resulting in atheroma, fibrosis around the atheroma, and progress of the blood vessels becoming harder. Specific mechanisms of onset are as follows. First, the monocytes are differentiated into macrophages, and the differentiated macrophages become dead or foam cells by digesting HDL / LDL-cholesterol or triglycerides. The resulting bubble cells continue to induce inflammatory responses. Over time, the bubble cells are killed by apoptosis and the killed cells are removed by newly migrating macrophages. However, some of the killed foam cells are not removed and secondary necrosis is induced in the surrounding cells, which increases the inflammatory response in the plaque and results in atherosclerosis (Golias C , In Vivo., 2007, 21 (5): 757-69 .; Thorp E, J Leukoc Biol., 2009, 86 (5): 1089-95 .; Tabas I. Antioxid Redox Signal., 2009, 11 ): 2333-9.).

In addition, when the concentration of triglyceride in the blood is increased by obesity, hyperlipidemia, etc., the ratio of macrophages to bubble cells or death due to triglycerides increases. That is, as the macrophages die, their immune function and triglyceride metabolism are lowered, and the function of removing the formed foam cells is lowered, thereby increasing the possibility that arteriosclerosis develops or deteriorates. Therefore, in order to prevent the onset or deterioration of arteriosclerosis, it is important to keep the macrophage functioning to remove the foam cells even when the blood fat concentration is high, or to minimize the killing by the triglyceride.

Currently, statins such as rosuvastatin and simvastatin are mainly used for the treatment of arteriosclerosis, but it is known that there is a side effect of reducing the activity of macrophages that remove foam cells. In addition, it is pointed out that a statin drug causes side effects such as diabetes, muscular dystrophy and hyperglycemia, and it is necessary to study natural products having less side effects.

As a result, a composition for treating arteriosclerosis containing an extract of Robinia pseudo-acacia tree (Korean Patent Laid-Open No. 10-2016-0084990), an anti-hyperlipemia and an anti-arteriosclerotic composition comprising a fermented extract of cinnamon ginseng (Korean Patent Laid- (Korean Patent Registration No. 10-1516764), a composition for preventing or treating atherosclerosis, including a horseradish peroxidase, and a composition for preventing or treating arteriosclerosis using a natural substance, such as a composition for preventing or treating atherosclerosis,

On the other hand, the island ( Angelica takeshimana ) is a perennial herbaceous plant belonging to the genus Porphyra , also called pork paste. It is a perennial plant that grows up to about 2m tall. The stem is hollow and leaves are alternate. It grows on Ulleungdo as a Korean species. These islands are believed to be effective against atopic dermatitis because they suppress the activation and expression of inflammatory factors. However, the effects associated with arteriosclerosis have not been known.

The present inventors have made intensive efforts to develop a natural substance exhibiting a preventive or therapeutic effect on arteriosclerosis, and as a result, it has been confirmed that the islet extract has an effect of inhibiting the death of macrophages caused by triglycerides, thus completing the present invention .

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating arteriosclerosis, which comprises an extract of a sea bream or a fraction thereof as an active ingredient.

Another object of the present invention is to provide a method for the prevention or treatment of arteriosclerosis comprising the step of administering the composition to a subject.

It is another object of the present invention to provide a food composition for preventing or ameliorating atherosclerosis, which comprises an islet extract or a fraction thereof as an active ingredient.

It is another object of the present invention to provide a composition for inhibiting macrophage death by triglyceride comprising an extract of the sea bream or a fraction thereof as an active ingredient.

The composition comprising the extract of the present invention can maintain the function of macrophages even when the concentration of blood lipids is high, and thus can be usefully used for the prevention or treatment of atherosclerosis caused by a decrease in macrophage function.

FIG. 1 is a graph showing an effect of inhibiting the death of macrophages by triglyceride of an ethanol extract of islets according to an embodiment of the present invention. Cell viability was expressed as normal control (control). At this time, TG means triglyceride.

FIG. 2 is a graph showing an effect of inhibiting the death of macrophages by triglyceride of a methanol extract of islets according to an embodiment of the present invention. FIG. Cell viability was expressed as normal control (control). Here, TG means triglyceride.

One aspect of the present invention provides a pharmaceutical composition for preventing or treating atherosclerosis, comprising an extract of a sea bream or a fraction thereof as an active ingredient.

Also provided is the use for the prevention or treatment of atherosclerosis of the islet extract or its fractions.

In the present invention, it has been confirmed that the islet extract or its fractions have an effect of preventing or ameliorating atherosclerosis, or preventing or preventing atherosclerosis, by confirming that the islet extract has an effect of inhibiting the death of macrophages caused by triglycerides, And it can be used for treatment.

The term " islands " of the present invention means a plant having the scientific name of Angelica takeshimana . The island is a perennial plant that grows up to 2 meters tall. It has been known that inhibition of the activation and expression of inflammatory factors is effective for atopic dermatitis. However, the effect on arteriosclerosis is not known, and it was first described by the present inventors.

The outpost of the above-mentioned islands may be used for the prevention or treatment of arteriosclerosis, and specifically, leaves, stems, flowers, roots or a combination thereof may be used, but the present invention is not limited thereto as long as it has an effect of preventing or treating arteriosclerosis.

The above-mentioned island can be purchased commercially, sold or cultivated in nature.

The term " extract " of the present invention includes the extract obtained by extracting the island, the diluted or concentrated solution of the extract, the dried product obtained by drying the extract, the adjusted product or the purified product of the extracted solution, And extracts of all formulations which can be formed using extracts.

The method for extracting the above-mentioned islands is not particularly limited, and can be extracted according to a method commonly used in the art. Non-limiting examples of the extraction method include hydrothermal extraction, ultrasonic extraction, filtration, and reflux extraction. These may be performed alone or in combination with two or more methods.

In the present invention, the type of the extraction solvent used for extracting the above-mentioned islands is not particularly limited, and any solvent known in the art can be used. Nonlimiting examples of the extraction solvent include water, alcohols having 1 to 4 carbon atoms, and mixed solvents thereof. These solvents may be used alone or in combination. Specifically, ethanol or methanol may be used, and the methanol may be 10-100% (v / v), more specifically 70-100% (v / v) methanol, but is not limited thereto.

In the present invention, the islet extract may be an ethanol or methanol extract of a sultan.

The term " fraction " of the present invention means a product obtained by performing fractionation to separate a specific component or a specific component group from a mixture containing various components.

In the present invention, the fractionation method for obtaining the fraction of the above-mentioned islands extract is not particularly limited and may be carried out according to a method commonly used in the art. Non-limiting examples of the fractionation method include a solvent fractionation method performed by treating various solvents, an ultrafiltration fractionation method performed through an ultrafiltration membrane having a constant molecular weight cut-off value, various chromatography (size, charge, hydrophobicity Or affinity-based separation), and a combination thereof, and the like. Specifically, the extract of the present invention can be obtained by treating a predetermined solvent with an extract obtained by extracting the island of the present invention to obtain a fraction from the extract.

The kind of the fraction solvent used for obtaining the fraction in the present invention is not particularly limited, and any solvent known in the art can be used. Non-limiting examples of the fraction solvent include polar solvents such as water and alcohols having 1 to 4 carbon atoms; Non-polar solvents such as hexane (Hexan) and ethyl acetate (Ethyl acetate); Or a mixed solvent thereof. These may be used alone or in combination of one or more, but the present invention is not limited thereto.

In addition, the extract or fraction may be prepared and used in the form of a dry powder after extraction, but is not limited thereto.

The term " arteriosclerosis " of the present invention means a disease in which blood vessels become narrowed or clogged, causing the blood vessels to cause peripheral blood flow disorders. The arteriosclerosis is also called atherosclerosis. Atherosclerosis can be caused by macrophage-mediated elimination of HDL / LDL-cholesterol or triglycerides in the blood. In addition, macrophages are converted into bubble cells by phagocytosing HDL / LDL-cholesterol or triglycerides. If the bubble cells are not removed by macrophages, they may cause a continuous inflammatory reaction, resulting in the development or worsening of atherosclerosis. Therefore, maintenance or maintenance of macrophage function is essential for prevention or treatment of arteriosclerosis.

In the present invention, the islet extract may inhibit the death of macrophages by triglycerides. The above-mentioned islands extract has an effect of inhibiting the death of macrophages that cause the onset or aggravation of arteriosclerosis, and thus can be used for the prevention or treatment of arteriosclerosis.

The term " prophylactic " of the present invention refers to any act that inhibits or delays arteriosclerosis by administration of a composition comprising the above-mentioned sumbird extract or fractions thereof.

The term " treatment " of the present invention refers to any action that improves or alters the symptoms of arteriosclerosis by administration of a composition comprising the above-mentioned isabide extract.

In one specific embodiment of the present invention, it has been confirmed that the islet ethanol or methanol extract can increase the survival rate of macrophages by inhibiting the death of macrophages by triglycerides (FIGS. 1 and 2).

This suggests that the composition of the present invention containing the above extract may be useful for the prevention or treatment of arteriosclerosis because the above-mentioned extract of the present invention can maintain the function of the macrophage even in a state of high blood fat concentration .

The pharmaceutical composition of the present invention may include, but is not limited to, 0.001 to 80, specifically 0.001 to 70, more specifically 0.001 to 60% by weight of the above-mentioned sumbird extract or fraction thereof, based on the total weight of the composition.

In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent conventionally used in the manufacture of a pharmaceutical composition, which carrier comprises a non-naturally occuring carrier can do. Specific examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, But are not limited to, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

In addition, each of the pharmaceutical compositions may be formulated into tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, nonaqueous solutions, suspensions, emulsions, , And may be oral or parenteral formulations of various types. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. The solid preparation for oral administration may be a tablet, a pill, a powder, a granule, a capsule, etc. The solid preparation may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, Gelatin and the like may be used. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may be used. As the liquid preparation for oral administration, suspensions, solutions, emulsions, syrups and the like may be used. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Can be used. For parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations or suppositories may be used. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. Examples of suppositories include, but are not limited to, witepsol, macrogol, tween 61, cacao butter, laurin, and glycerogelatin.

Another aspect provides a method of preventing or treating arteriosclerosis comprising administering the composition to a subject.

Herein, the definitions of "arteriosclerosis", "prevention" and "treatment" are as described above.

The term " administering " of the present invention means introducing the pharmaceutical composition into a subject in an appropriate manner.

The term " individual " of the present invention means all animals such as mice, mice, livestock, etc., including humans who have developed or can develop arteriosclerosis. The animal may be, but is not limited to, a mammal such as a cow, a horse, a sheep, a pig, a goat, a camel, a nutrient, a dog, or a cat, which requires prevention or treatment of similar symptoms.

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.

The term " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the species and severity, age, sex, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts.

The pharmaceutical composition may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. In addition, it can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by a person skilled in the art.

In addition, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be determined depending on the condition and the weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art. As a specific example, the pharmaceutical composition may be administered in an amount of generally 0.001 to 1000 mg / kg, more particularly 0.05 to 200 mg / kg, most specifically 0.1 to 100 mg / kg, However, the desired dosage can be suitably selected by those skilled in the art depending on the condition and the weight of the individual, the degree of disease, the drug form, the administration route and the period.

Another aspect provides a food composition for preventing or ameliorating atherosclerosis, which comprises an islet extract or a fraction thereof as an active ingredient.

It also provides a use for the prevention or amelioration of atherosclerosis of the island extract or its fractions.

Herein, the definitions of "islands", "extracts", "fractions", "arteriosclerosis" and "prevention" are as described above.

The food composition of the present invention can be ingested routinely and unlike ordinary medicines, it has a merit that there is no side effect that may occur when a natural product is used as a raw material for a long time, and therefore, it is very useful for prevention or improvement of arteriosclerosis Lt; / RTI >

The term " improvement " of the present invention means any action that reduces the degree of a parameter associated with a condition to be treated, such as a symptom, by the ingestion of the food composition.

The term " food " of the present invention includes dairy products such as meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, various soups, drinks, tea, , A vitamin complex, a health functional food, and a health food, all of which include foods in a conventional sense.

The health functional food is the same term as food for special health use (FoSHU). In addition to the nutritional supply, the health functional food has a high medical effect, It means food. Here, 'function (sex)' refers to the structure and function of the human body to obtain nutritional effects or obtain a beneficial effect for health use such as physiological action. The health food refers to a food having an active health promotion or promotion effect compared with a general food, and a health supplement food refers to a food for health assistance. In some cases, the terms health functional foods, health foods, and health supplements may be used.

Specifically, the health functional food is a food prepared by adding the extract of the present invention or a fraction thereof to a food material such as a beverage, a tea, a spice, a gum, or a confection, or by preparing an encapsulation, a powder or a suspension, However, unlike general medicines, there is an advantage that there is no side effect that can occur when a drug is taken for a long time by using the food as a raw material.

The food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and components which are conventionally added in the art. In addition, the food composition can be produced in various forms without limitations as long as it is a food-acceptable formulation.

In addition, the food composition may further comprise a physiologically acceptable carrier. The carrier is not particularly limited and any carrier conventionally used in the art can be used.

In addition, the food composition may contain additional components that are commonly used in food compositions and can improve odor, taste, visual appearance, and the like. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid and the like. Minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu) and chromium (Cr); And amino acids such as lysine, tryptophan, cysteine, valine, and the like.

In addition, the food composition may contain at least one kind selected from the group consisting of preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate), disinfectants (such as bleaching powder and highly bleached white powder, sodium hypochlorite), antioxidants (butylhydroxyanisole (BHA) (Sodium nitrite), bleach (sodium sulfite), seasoning (sodium MSG glutamate, etc.), sweeteners (dicin, cyclamate, saccharin, etc.), coloring agents , Sodium, etc.), perfume (vanillin, lactones, etc.), swelling agents (alum, potassium hydrogen D-tartrate), emulsifiers, thickeners (foams), encapsulating agents, gum bases, foam inhibitors, solvents, And may include food additives. The additives can be selected according to the type of food and used in an appropriate amount.

Another embodiment provides a composition for inhibiting macrophage death by triglycerides comprising an extract of the island or a fraction thereof as an active ingredient.

It also provides an anti-macrophage anti-apoptotic use of the triglyceride of the islands extract or its fractions.

Here, the definitions of the above-mentioned " islands ", " extracts " and " fractions "

The term " macrophage death by triglycerides " of the present invention means that macrophage function is lost or damaged by triglyceride, and macrophages are necrosis, apoptosis, And the conversion of phagocytes to other types of different cells. The macrophage removes various substances unnecessary for the human body such as the triglyceride and dead cells. When the function of the macrophage is lost, the inflammation reaction is caused by the above-mentioned substances, and a disease such as atherosclerosis may develop. Therefore, macrophage death caused by triglycerides can also be useful for preventing or treating diseases caused by macrophage death caused by triglycerides such as arteriosclerosis.

In one specific example of the present invention, it was confirmed that the extract of the sea bass can inhibit the death of macrophages by triglycerides and increase the survival rate of macrophages (Fig. 1).

Since the above-mentioned extract of the present invention can maintain the function of the macrophage even in a state of high blood lipid concentration, the composition of the present invention containing the extract can be effectively used for inhibiting macrophage death by triglycerides It is suggestive.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided for illustrating the present invention, and the scope of the present invention is not limited thereto.

Production Example 1. Preparation of an island extract

After shaking the shrimp shell outcrop, 200 g of 100% (v / v) ethanol (alcohol), 10 to 100% (v / v) methanol or 2 L of 100% (v / v) acetone was added, The extract was filtered. The above procedure was repeated twice to obtain 6 L of the total extract, which was then concentrated under reduced pressure at 35 DEG C to obtain each of the islands' extracts.

Example 1. Confirmation of anti-arteriosclerotic effect of an islet extract

In order to confirm the anti-arteriosclerotic effect of the islet extract prepared according to Preparation Example 1, the effect of inhibiting macrophage death by triglyceride was confirmed.

Specifically, a human mononuclear cell line THP-1 was inoculated into a 96-well plate at a number of 1.5 × 10 ⁴ cells / well, treated with 200 nM phorbol-12-myristate-13-acetate for 24 hours, Differentiation was induced. The differentiated macrophages were maintained in RPMI medium containing 1% penicillin-streptomycin and 10% fetal bovine serum at 37 ° C under 5% carbon dioxide and treated with 0.2-2 μl / ml of the islet extract for 24 hours Respectively. The cells were then washed twice with DPBS and treated with triglyceride (TG) at a concentration of 1 mg / ml for 24 hours. Cell viability was measured using the Ez-Cytox (dozinbio) for the macrophages that had undergone the above process.

As a result, as shown in FIG. 1, it was confirmed that the survival rate of macrophages decreased by neutral fat was increased when the extract of the island (ethanol) was treated, and this increase was similar to that of the normal control .

In addition, as shown in FIG. 2, the survival rate of macrophages reduced by the triglyceride was increased in the case of treatment with the methanol extract of the island. Specifically, 70, 90 or 100% (v / v) It was confirmed that the extract had a better survival rate increase effect than that extracted with 10, 30 or 50% (v / v) methanol extract.

From the above results, it can be seen that the extract of the sea bass effectively inhibits the death of macrophages due to triglycerides, thereby suppressing the immune function, the degradation of triglyceride metabolism, the formation of foam cells, and the deterioration of the formed foam cells due to the macrophage death Thus being useful for preventing or treating arteriosclerosis.

From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all aspects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention without departing from the scope of the present invention as defined by the appended claims.

Claims (9)

1. A pharmaceutical composition for preventing or treating atherosclerosis, comprising an extract of the island or a fraction thereof as an active ingredient.
2. The composition of claim 1, wherein the islands are leaves, stems, flowers, roots, or combinations thereof.
3. The composition according to claim 1, wherein the extract is prepared by extracting a human body with at least one solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, and a mixed solvent thereof.
4. 4. The composition of claim 3, wherein the extract is an ethanol or methanol extract of a shell.
5. The method according to claim 1, wherein the fraction is prepared by fractionating an extract of a human body with a solvent selected from the group consisting of water, an alcohol having 1 to 4 carbon atoms, hexane, ethyl acetate and a mixed solvent thereof ≪ / RTI >
6. The composition of claim 1, wherein the extract inhibits the death of macrophages by triglycerides.
7. A method for preventing or treating arteriosclerosis comprising administering to a subject a composition of any one of claims 1 to 6.
8. A food composition for preventing or ameliorating atherosclerosis, which comprises an extract of the island or a fraction thereof as an active ingredient.
9. A composition for inhibiting macrophage death by triglyceride, comprising an extract of the island or a fraction thereof as an active ingredient.

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