JP6803892B2 - VCAM-1 expression inhibitor - Google Patents

Description

The present invention suppresses a composition containing a turmeric extract and an antioxidant, a VCAM-1 expression-suppressing composition, an anti-inflammatory composition, an alcoholic liver injury suppressing composition, and a decrease in the amount of activity caused by inflammation. With respect to the composition to be. The present invention also relates to a VCAM-1 expression-suppressing composition containing a turmeric extract, an anti-inflammatory composition, a composition for suppressing alcoholic liver injury, and a composition for suppressing a decrease in the amount of activity caused by inflammation.

Vascular cell adhesion molecule-1 (VCAM-1) is a protein with a molecular weight of 110 kDa belonging to the immunoglobulin superfamily and is expressed in vascular endothelial cells and follicular dendritic cells activated by various chemokines and inflammatory mediators. It is known.
The expression of VCAM-1 is known to cause inflammatory diseases such as arteriosclerosis, rheumatism, asthma, nephritis, encephalomyelitis, and hepatitis (Patent Document 1 and Non-Patent Document 1). Substances that suppress expression are thought to have therapeutic effects in these diseases.

It is known that when alcohol is ingested chronically, the endotoxin concentration in the blood rises, and endotoxin activates Kupffer cells in the liver to cause liver damage (Non-Patent Document 2). On the other hand, it is known that liver damage caused by endotoxin is suppressed by inhibition of VCAM-1 function by administration of anti-VCAM-1 antibody (Non-Patent Document 3). Therefore, a substance that suppresses the expression of VCAM-1 is considered to suppress liver damage due to alcohol intake.

One of the pathological behaviors in depression, fatigue, alcohol intake, etc. is a decrease in the amount of behavior (Patent Document 2, Non-Patent Document 5 and Non-Patent Document 8). Inflammation is considered to be involved as one of the causes of these pathological conditions (Non-Patent Documents 4, 9 and 10). It is considered that the substance that suppresses the expression of VCAM-1 can suppress the decrease in the amount of activity caused by the inflammation by suppressing the inflammation.

So far, as a VCAM-1 expression inhibitor, Non-Patent Document 6 states that an ethyl acetate extract of turmeric and curcumin, which is a component thereof, suppress the expression of VCAM-1 induced by TNF-α. It is shown. In addition, Non-Patent Document 7 shows that sesamin analogs suppress the expression of VCAM-1 induced by TNF-α. However, the effects of these VCAM-1 expression inhibitores are not sufficient, and a method for more effectively suppressing the expression of VCAM-1 is required.

Japanese Unexamined Patent Publication No. 11-923382 Japanese Unexamined Patent Publication No. 2005-239579

J Physiol Pharmacol, 59 Suppl 1: 107-17, 2008 Liver, 42 (1): 1-14, 2001 J Immunol, 158 (12): 5941-8, 1997 Current Drug Abuse Reviews, 3 (2): 110-115, 2010 Alcohol & Alcoholism 43 (2): 124-126, 2008 International Journal of Immunophamacology, 21 (11), 745-757, 1999 Biosci. Biotechnol. Biochem., 74 (8), 1539-1544, 2010 Senshu University of Human Sciences Psychology Vol.3, No.1, pp.33-40, 2013 Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb; 29 (2): 201-17. Sports Med. 2009; 39 (5): 389-422.

In view of the above situation, it is an object of the present invention to provide an effective method for suppressing the expression of VCAM-1. The present invention also relates to a method for treating various inflammatory diseases caused by the expression of VCAM-1, a method for suppressing liver damage due to alcohol intake by suppressing the expression of VCAM-1, and an amount of activity caused by inflammation. It is also an issue to provide a method for suppressing the decrease.

As a result of intensive studies to solve the above problems, the present inventors have found that the turmeric extract has an excellent effect of suppressing VCAM-1 expression, and further, the combination of the turmeric extract and the antioxidant is used. , It was found that the effect of using the extract and the antioxidant alone is not a combined effect, but a surprisingly synergistic effect of suppressing VCAM-1 expression is exerted far beyond the effect of each alone.
In addition to the above, the present inventors have obtained various unexpected new findings as described below, and have completed the present invention through further diligent studies.

That is, the present invention relates to a composition containing the following turmeric extract and an antioxidant.
[1] A composition containing a turmeric extract and an antioxidant.
[2] The composition according to the above [1], wherein the extraction solvent of the turmeric extract is water and / or a hydrophilic organic solvent.
[3] The composition according to the above [1] or [2], wherein the turmeric extract contains Bisacurone.
[4] The composition according to any one of [1] to [3] above, wherein the antioxidant is one or more selected from the group consisting of sesamin or an analog thereof, curcumin, and ornithine.
[5] The composition according to any one of [1] to [4] above, wherein the compounding ratio of bisaclone and the antioxidant is as follows in terms of mass ratio.
Bisacurone: Sesamin or its analog = 1: 3 to 1: 300 or Bisacurone: Curcumin = 1: 1 to 1: 100 or Bisacurone: Ornithine = 1: 2 to 1: 200
[6] A VCAM-1 expression-suppressing composition, which comprises a turmeric extract and an antioxidant.
[7] An anti-inflammatory composition containing a turmeric extract and an antioxidant.
[8] A composition for suppressing alcoholic liver injury, which comprises a turmeric extract and an antioxidant.
[9] A composition that suppresses a decrease in the amount of activity caused by inflammation, which comprises a turmeric extract and an antioxidant.
[10] The composition according to the above [9], wherein the inflammation is caused by alcohol.
[11] The composition according to any one of the above [1] to [10], which is a preventive agent, an ameliorating agent or a therapeutic agent for a disease caused by the expression of VCAM-1.
[12] A composition for suppressing the expression of VCAM-1, characterized in that the extraction solvent contains water and / or a turmeric extract which is a hydrophilic organic solvent.
[13] An anti-inflammatory composition, wherein the extraction solvent contains water and / or a turmeric extract which is a hydrophilic organic solvent.
[14] A composition for suppressing alcoholic liver injury, wherein the extraction solvent contains water and / or a turmeric extract which is a hydrophilic organic solvent.
[15] A composition for suppressing a decrease in the amount of activity caused by inflammation, wherein the extraction solvent contains water and / or a turmeric extract which is a hydrophilic organic solvent.
[16] The composition according to the above [15], wherein the inflammation is caused by alcohol.
The above [1] to [11] require antioxidants as essential constituents along with the turmeric extract, while the above [12] to [16] require turmeric extract as an essential constituent. Oxidants are not an essential constituent.

According to the present invention, it is possible to obtain a significantly increased expression-suppressing effect of VCAM-1 as compared with the conventional VCAM-1 expression-suppressing agent, and various diseases mediated by VCAM-1 and various inflammatory diseases. Can be prevented, ameliorated or treated. Further, according to the present invention, liver damage due to alcohol intake can be suppressed, and further, a decrease in the amount of activity caused by inflammation can be prevented, alleviated or ameliorated.

Comparative data of absorbance reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control and sesamine 40 μM and turmeric extract 140 μg / mL (mixture of sesamine 40 μM and turmeric extract 140 μg / mL). is there. Comparative data of absorbance reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control and sesamine 60 μM and turmeric extract 210 μg / mL (mixture of sesamine 60 μM and turmeric extract 210 μg / mL). is there. Comparative data of absorbance reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control and curcumin 3 μM and turmeric extract 48 μg / mL (mixture of curcumin 3 μM and turmeric extract 48 μg / mL). is there. Comparative data of absorbance reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control and curcumin 10 μM and turmeric extract 160 μg / mL (mixture of curcumin 10 μM and turmeric extract 160 μg / mL). is there. Comparative data of absorbance reflecting VCAM-1 production on human umbilical vein vascular endothelial cells in combination with control and ornithine 40 μM and turmeric extract 140 μg / mL (mixture of ornithine 40 μM and turmeric extract 140 μg / mL). is there. It is the data of the AST concentration and the ALT concentration in the mouse plasma before the ethanol administration and after 1, 2, 4 and 6 hours of the administration of the turmeric extract administration group and the control group.

Hereinafter, the present invention will be described in detail.
The composition of the present invention is characterized by containing a turmeric extract or a turmeric extract and an antioxidant.
The composition of the present invention may contain components other than turmeric extract and antioxidants.

In the present invention, "containing" includes a mixed state or a coexisting state. The coexisting state means a state in which each is separated before use, but is in a coexisting combination state, and is mixed and used at the time of use.

Hidden-lilies extract In the present invention, the Hidden-lilies extract refers to an extract (Hidden-lilies extract) of a plant material derived from a plant belonging to the genus Hidden-lilies of the family Zingiberaceae, which is an extraction solvent by further heating and / or depressurizing as necessary. May be volatilized and dried. Conventionally known methods can be used for these heating, depressurizing, and drying methods.
Examples of the plant material include Curcuma longa (turmeric), Curcuma aromatica, Curcuma zedoaria, Curcuma phaeocaulis, Curcuma kwangsiensis, Curcuma wenyujin, and / or the rhizome of Curcuma xanthorrhiza, which are plants belonging to the genus Hidden-lilies of the family Hidden-lilies. These rhizomes may be collected from the soil, and the appropriate part of the rhizome may be cut into the original shape, cut to an appropriate size or shape, or crushed. it can. These plant raw materials may be appropriately dried.
The method for extracting the turmeric extract from the plant material is not particularly limited, and a conventionally known method can be used. Examples of the extraction solvent include water, hot water, a hydrophilic organic solvent, a mixed solvent of water and a hydrophilic organic solvent, and the like, preferably alcohol, water, and a mixed solvent of alcohol and water, and the alcohol is not particularly limited. , Ethanol is preferred. When the composition of the present invention contains a turmeric extract but no antioxidants, the extraction solvent is usually water and / or a hydrophilic organic solvent.
In the present invention, the mixing ratio of the mixed solvent of the hydrophilic organic solvent and water is not particularly limited, but for example, the weight ratio is preferably in the range of 10:90 to 90:10, more preferably in the range of 20:80 to 50:50. preferable. The temperature at the time of extraction is not particularly limited.

The turmeric extract extracted using water and / or a hydrophilic organic solvent as the extraction solvent is as described in Non-Patent Document 6 extracted using a hydrophobic organic solvent such as ethyl acetate as the extraction solvent. It contains a more water-soluble compound as compared to the turmeric extract. Therefore, these extracts are clearly different from each other in the composition of the components contained.

In the present invention, as the turmeric extract, the turmeric rhizome extract obtained as described above can be used as it is, and the turmeric rhizome extract is further diluted, concentrated, dried or the like. It is also possible to use the one with the above. Conventionally known methods can be used as methods such as dilution, concentration, and drying.
The turmeric extract used in the present invention is characterized by containing Bisacurone. Bisacurone is preferably contained in an amount of 0.15% by weight or more. The amount of Bisacurone in the turmeric extract is a high-performance liquid that is obtained by mixing the turmeric extract with ethyl acetate, distilling off ethyl acetate from the supernatant obtained by centrifugation under reduced pressure, and then dissolving the solution in acetonitrile as an analysis sample. It can be determined by subjecting to chromatography (HPLC).

In the present invention, bisaclone is a compound classified into bisabolan-type sesquiterpenes, and means a compound having the following planar structural formula or a salt thereof. Bisacurone has an asymmetric carbon at the position marked with * in the planar structural formula, and therefore there are several types of optical isomers. Bisacurone in the present specification is a concept that includes any of these optical isomers. is there.

Antioxidants The antioxidants in the present invention are a general term for substances that attenuate or eliminate harmful reactions involving oxygen in living organisms, foods, daily necessities, and industrial raw materials. Especially in biochemistry or nutrition, in a narrow sense, it refers to a substance that suppresses the peroxidation reaction of lipids, and in a broader sense, it also refers to reactive oxygen species (oxygen free radicals, hydroxyl radicals, Contains substances that contribute to the reaction of detoxifying by trapping superoxide anions, hydrogen peroxide, etc.). For example, glutathione, N-acetylcysteine, ascorbic acid, α-tocopherol, butylhydroxyanisole, catechin, quercetin, uric acid, bilirubin, flavonoids, cellulobrasmine, albumin, ferritin, metallothioneine, superoxide dismutase (copper zinc type, manganese type). , Secretory type), glutathione peroxidase (cytoplasmic type, plasma type, phospholipid hydrobeloxide type), glutathione transferase, catalase, thioredoxin (Biochemical Dictionary, Tokyo Chemicals, 1998, 3rd edition), sesamine and its relatives (Vitamin 79 (1), 23-26, 2005), curcumin and its relatives (Biol. Pharm. Bull. 30 (1), 74-78 (2007)) and the like.
In addition, the antioxidant substance in the present invention also includes a substance that indirectly reduces oxidative stress after being ingested by a living body, such as ornithine. Ornithine, a type of amino acid, lowers the level of ammonia in the body (Journal of Hepatology. 26 (1): 174-82, 1997) and oxidative stress induced by ammonia (The Journal of Neuroscinece 26 (18), 4774). -4784 (2006)) is reduced.

The antioxidant used in the present invention is preferably sesamin or an analog thereof, curcumin, ornithine and the like.
Examples of sesamine or its isomers include sesamine, sesaminol, episesamine, episesaminol, sesamolin, 2- (3,4-methylenedioxyphenyl) -6- (3-methoxy-4-hydroxyphenyl) -3,7. -Dioxabicyclo [3.3.0] octane, 2,6-bis- (3-methoxy-4-hydroxyphenyl) -3,7-dioxabicyclo [3.3.0] octane, or 2- ( 3,4-Methylenedioxyphenyl) -6- (3-methoxy-4-hydroxyphenoxy) -3,7-dioxabicyclo [3.3.0] octane and the like can be mentioned, and these are optical isomers. Alternatively, in the case of stereoisomers, each isomer can be used alone or in a mixed state such as racemic. In addition, these can be used in the form of glycosides, or these can be used alone or in combination as appropriate.
Sesamin and its analogs are separated from sesame oil, sesame seeds and sesame meal.
In addition to sesame seeds, those separated from natural products containing sesamin, such as goka bark, ginkgo bark, and white fruit bark, may be used. Moreover, you may use the thing obtained by synthesis.
As a method for separating sesamines from sesame oil, sesame seeds and sesame cake, an organic solvent (acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, etc.) is used for extraction and concentration, and the solvent is evaporated and removed from the solvent fraction. Obtain (extraction separation method). Further, sesamin and the like may be separated from the distillate containing sesamin obtained by steam distillation of sesame oil under reduced pressure. These methods have been well established in the past and may be followed in the present invention.

As the curcumin, a natural product can be used. For example, the curcumin may be extracted from a natural plant containing curcumin. Further, those chemically synthesized by a conventionally known method or commercially available products may be used.
As a method for extracting curcumin from a natural plant, a conventionally known method can be used. For example, an organic solvent (acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, etc.) is used to extract, concentrate, and solvent-paint. A method obtained by evaporating and removing the solvent from the minutes can be used (extraction separation method). Further, a method of extracting by contacting turmeric with carbon dioxide gas in a supercritical state can also be used.

Examples of ornithine include L-ornithine, D-ornithine, and salts thereof. Examples of the salt of ornithine include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates, acetates, maleates, fumarates, citrates, malates, lactates and α-ketoglutarates. , Gluconate, organic acid salts such as caprylate, and the like.
As the ornithine, chemically synthesized products, fermented products, products extracted from materials such as freshwater clams, and commercially available products can be used. As these synthesis methods, fermentation production methods and extraction methods, those using conventionally known methods can be used.

Composition In the composition of the present invention containing a turmeric extract and an antioxidant, the compounding ratio (mass ratio) of the turmeric extract and the antioxidant is an index of bisacron, which is a sesquiterpenoid contained in the turmeric extract. Is preferable. Considering the bioavailability, the compounding ratio (mass ratio) of Bisacurone: sesamin or its analog is preferably about 1: 0.3 to 1: 3000, more preferably about 1: 1 to 1: 1000. Yes, more preferably about 1: 3 to 1: 300. The mixing ratio (mass ratio) of the turmeric extract and curcumin is preferably such that the mass ratio of bisacron: curcumin is about 1: 0.1 to 1: 1000, and more preferably about 1: 0.3 to 1: 1. It is 300, more preferably about 1: 1 to 1: 100. The mixing ratio (mass ratio) of the turmeric extract and ornithine is preferably such that the mass ratio of bisacron: curcumin is about 1: 0.2 to 1: 2000, and more preferably about 1: 0.6 to 1: It is 600, more preferably about 1: 2 to 1: 200.

The composition of the present invention may further contain one or more components other than the essential components (turmeric extract and antioxidant). The ingredients other than the essential ingredients are not particularly limited as long as they are acceptable ingredients in pharmaceuticals, foods and drinks, feeds, food additives, health foods, supplements, feed additives, etc. and can be taken orally. There is no particular limitation. Ingredients other than the essential ingredients include, for example, fructose-glucose liquid sugar, dextrin, acidulant, vitamins, thickener, turmeric pigment, inositol, flavor, cyclic oligosaccharide, sweetener, mineral, antioxidant, emulsifier and the like. Can be mentioned.

Examples of the acidulant include citric acid, malic acid, gluconic acid, tartaric acid, and salts thereof.
Examples of vitamins include niacin, vitamin B1, vitamin B6, vitamin C, vitamin E and the like.
Examples of the thickener include thickening polysaccharides such as gellan gum, xanthan gum, pectin, and guar gum.
The turmeric pigment is obtained by extracting from the rhizome portion of turmeric with warm ethanol, hot fat or propylene glycol, or room temperature to hot hexane or acetone, and it is preferable that it mainly contains curcumin. .. The amount of turmeric pigment in the composition of the present invention contains curcumin in an amount of about 3 mg to 50 mg, more preferably about 5 mg to 40 mg, and particularly preferably about 6 mg to 30 mg per oral ingestion. It is good to be done.

Examples of minerals include magnesium, calcium, sodium and potassium.
Examples of the antioxidant include vitamin C, enzyme-treated rutin and the like.
Examples of the sweetener include sugars such as fructose, glucose and liquid sugar, and high-sweetness sweeteners such as honey, sucralose, acesulfame potassium, thaumatin and aspartame.

The composition of the present invention can be orally administered.
In addition, the composition of the present invention can be used as a pharmaceutical product (for humans or animals), foods and drinks, feeds, food additives, health foods, supplements, feed additives and the like.
The shape of the composition of the present invention is not particularly limited, and may be any property such as liquid, fluid, gel, semi-solid, or solid.

When the composition of the present invention is used as a pharmaceutical product, it is preferably administered in the form of a pharmaceutical composition containing the composition of the present invention and a pharmaceutically acceptable pharmaceutical additive. The pharmaceutical composition may be in the form of an oral solid preparation such as a capsule, a tablet (including a coated tablet such as a sugar-coated tablet or an enteric coated tablet or a multi-layer tablet), a powder or a granule, or an oral liquid preparation. It may be in the form of a parenteral preparation such as an injection, a drip, or a suppository. These preparations can be produced by a method known per se.

Formulation additives commonly used in solid preparations such as capsules, tablets, powders or granules include, for example, excipients (eg, lactose, sucrose, glucose, starch, crystalline cellulose, etc.), binders ( For example, starch paste solution, hydroxypropyl cellulose solution, carmellose solution, gum arabic solution, gelatin solution, sodium alginate solution, etc.), disintegrant (for example, starch, carmellose sodium, calcium carbonate, etc.), lubricant (for example, stear). Magnesium acid, talc, stearic acid, calcium stearate, etc.), surfactants (eg, polysolvate 80, polyoxyethylene hydrogenated castor oil, etc.), thickeners (eg, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, etc.) ), Etc., but are not limited to these. Tablets or granules
The coating agent (for example, gelatin, sucrose, gum arabic, carnauba wax, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropyl cellulose phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, etc.) may be used for coating. The capsule may be a microcapsule, a soft capsule, or the like, in addition to a hard capsule. The solid preparation can be produced by a conventionally known method.

Liquid formulations include, for example, sugars (eg, sucrose, sorbitol, fructose, etc.), glycols (eg, polyethylene glycol, propylene glycol, etc.), dispersions or thickeners (eg, gelatin, gum arabic, hydroxyethyl cellulose, hydroxypropyl). Cellulose, polyvinyl alcohol, polyethylene glycol, etc.), emulsifiers (eg, glycerin fatty acid ester, sucrose fatty acid ester, etc.), solubilizers (eg, gum arabic, polysorbitol 80, etc.), pH adjusters (eg, citric acid, citric acid, etc.) (Trisodium, etc.), preservatives (for example, paraoxybenzoic acid esters, etc.) and the like may be blended.

When the composition of the present invention is used as a food or drink, the composition of the present invention may be used as it is, or may be in a form containing the composition, additives permitted in terms of food hygiene, and ordinary food raw materials. .. When the composition of the present invention is used as a food additive, the composition may be used as it is, or may contain an additive that is acceptable for food hygiene.

The food and drink and food additives are, for example, capsules, tablets (including coated tablets such as sugar-coated tablets or multi-layer tablets, mouth disintegrants, etc.), powders, granules, etc., together with additives that are acceptable for food hygiene. It may be in the form of a solid composition or in the form of a liquid composition. Examples of the additive include excipients (eg, lactose, dextrin, corn starch, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, sucrose fatty acid ester, glycerin fatty acid ester, etc.), and disintegrants (eg, glycerin fatty acid ester, etc.). Carboxymethyl cellulose calcium, anhydrous calcium hydrogen phosphate, calcium carbonate, etc.), binders (eg, starch paste solution, hydroxypropyl cellulose solution, Arabic rubber solution, etc.), dissolution aids (eg, Arabic rubber, polysolvate 80, etc.), sweetness Foods (eg sugar, fructose, glucose syrup, honey, aspartame, etc.), colorants (eg β-carotene, edible tar pigments, riboflavin, etc.), preservatives (eg, sorbic acid, methyl paraoxybenzoate, sodium sulfite) Etc.), thickeners (eg, sodium alginate, sodium carboxymethyl cellulose, sodium polyacrylate, etc.), antioxidants (eg, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid, tocopherol, etc.), fragrances (eg, hackers, etc.) Strawberry flavors, etc.), acidity agents (eg, citric acid, lactose, DL-apple acid, etc.), seasonings (eg, DL-alanine, 5'-sodium inosinate, sodium L-glutamate, etc.), emulsifiers (eg, glycerin) Examples thereof include fatty acid esters, sucrose fatty acid esters, etc.), pH adjusters (for example, citric acid, trisodium citrate, etc.), vitamins, minerals, amino acids, pigments, and the like. The solid composition can be produced according to a conventional method. In addition, the liquid composition can be produced in the same manner as the liquid preparation suitable for oral administration.

In addition, a food or drink can be produced by blending the composition of the present invention or a solid composition or a liquid composition containing the composition into a food or drink. Such foods and drinks include, for example, confectionery (eg, gum, candy, caramel, chocolate, cookies, snacks, jelly, gummy, tablet confectionery, etc.), noodles (eg, buckwheat, udon, ramen, etc.), dairy products. (For example, milk, ice cream, yogurt, etc.), seasonings (for example, miso, soy sauce, etc.), soups, beverages (for example, juice, coffee, tea, tea, carbonated beverages, sports beverages, etc.) Examples include foods and nutritional supplements (eg, nutritional drinks, etc.). The food also includes foods containing food additives.

When the composition of the present invention is used as a health food, the composition of the present invention may be used as it is, or may be in a form containing the composition, additives permitted in terms of food hygiene, and ordinary health food raw materials. Good. The health food means a food composition for the purpose of health, health maintenance / promotion, etc., and includes a licensed specific functional food and a so-called health food without a specific functional food approval. The health food is, for example, a liquid or semi-solid or solid product, and examples thereof include sweets such as cookies, senbei, jelly, yokan, yogurt, and manju, soft drinks, nutritional drinks, and soups. Alternatively, it may be dissolved in hot water or water and drunk as it is. These liquid or semi-solid or solid products can be produced according to a conventional method.

When the composition of the present invention is used as a supplement, the composition of the present invention may be used as it is, or may be in a form containing the composition, food hygiene-acceptable additives, and ordinary supplement raw materials. .. Supplements not only mean dietary supplements, nutritional functional foods, etc. for supplementing nutrients, but also health supplements, health functional foods, etc. that have functions that are useful for maintaining, recovering, and promoting health. Also means. The shapes of such supplements include, for example, tablets, rounds, capsules (including hard capsules, soft capsules, and microcapsules), powders, granules, fine granules, troches, and liquids (syrups, emulsions, suspensions). (Including turbidity) and the like. These can be manufactured according to a conventional method.

When the composition of the present invention is used as a feed, the composition of the present invention may be used as it is, or may be in a form containing the composition and general feed additives or feed raw materials. When the composition of the present invention is used as a feed additive, the composition may be used as it is, or may contain a general feed additive.

When the composition of the present invention is used as a medicine, food or drink, food additive, health food or supplement, the dose or intake of the composition is not particularly limited, but for example, turmeric is extracted per adult per day. About 13-8400 mg of the product, preferably about 67-1700 mg, if the composition contains antioxidants, about 0.04-7500 mg of antioxidants, preferably about 0.20-1500 mg, for example in the case of sesamin. , About 0.12 to 7500 mg, preferably about 0.6 to 1500 mg, about 0.04 to 2500 mg for curcumin, preferably about 0.2 to 500 mg, and about 0.08 to 5000 mg for ornithine, preferably. It is preferable to administer or ingest the amount so as to be about 0.4 to 1000 mg because the effect of suppressing the expression of VCAM-1 can be effectively obtained.

Since the composition of the present invention can suppress the expression of VCAM-1, it can be used as an agent for suppressing the expression of VCAM-1. In addition, since the composition of the present invention can suppress the expression of VCAM-1, it can be used as an anti-inflammatory agent, an inhibitor of alcoholic liver injury, and an inhibitor of activity reduction caused by inflammation.
That is, the present invention comprises a turmeric extract and an antioxidant, which is a VCAM-1 expression inhibitor, an anti-inflammatory agent, an alcoholic liver injury inhibitor, and an inhibitor of activity decrease caused by inflammation. Contains agents. In these agents, the compounding ratio of the turmeric extract and the antioxidant and the preferred embodiment thereof are the same as those of the composition of the present invention described above.
It was unexpected that not only the combined use or combination of the turmeric extract and the antioxidant, but also the composition containing the turmeric extract alone as the active ingredient exerted an excellent effect of suppressing the expression of VCAM-1.

In the present invention, the inflammation in "reduced activity caused by inflammation" is not particularly limited, but is preferably caused by alcohol, that is, inflammation caused by alcohol intake.
Further, in the present invention, the amount of action indicates the amount of action of a human or an animal. The method for measuring the amount of activity is not particularly limited, but in the case of a mouse, for example, it may be calculated by measuring the amount of activity using an infrared sensor, measuring the amount of spontaneous exercise using a rotating wheel, or the like.
To measure the amount of activity of a mouse using an infrared sensor, a mouse is placed under an activity amount measuring device (manufactured by Muromachi Kikai Co., Ltd., Supermex PYS-001) using an infrared sensor, and the device is used. It can be calculated by sensing the body temperature (far infrared rays) of the mouse with the lens to be held, counting the number of times per hour, and using the counted number as the amount of activity.
The measurement of the spontaneous momentum of the mouse using the rotating wheel can be obtained by the number of rotations (count number) using the rotating wheel as described in Examples described later.

Moreover, since the composition of the present invention can suppress the expression of VCAM-1, a method for preventing, ameliorating or treating a disease caused by the expression of VCAM-1 (excluding medical practice). Can be used for. Diseases caused by the expression of VCAM-1 include, for example, arteriosclerosis, rheumatism, asthma, nephritis, encephalomyelitis and the like.
That is, the composition of the present invention is characterized by preventing, ameliorating or treating a disease caused by the expression of VCAM-1.

The present invention will be specifically described with reference to the following Examples and Comparative Examples, but the present invention is not limited thereto.

<Turmeric extract>
(Example 1)
The turmeric extract was prepared by extracting the rhizome portion of turmeric (Curcuma longa) with water and drying the obtained extract under reduced pressure to remove water. The amount of bisacurone in the turmeric extract is high performance using the solution obtained by mixing the turmeric extract solution and ethyl acetate, centrifuging and distilling ethyl acetate under reduced pressure, and then dissolving the solution in acetonitrile as an analysis sample. Obtained by subject to liquid chromatography (HPLC). HPLC was performed under the following conditions.
Column: Thermo ODS HYPERSIL (registered trademark) 250 mm x φ4.6 mm (manufactured by Thermo Scientific)
Mobile phase: 65% acetonitrile (20min) ⇒ 80% acetonitrile (5min) ⇒ 65% acetonitrile (10min)
Flow velocity: 0.7 ml / min
Temperature: 40 ℃
Detection wavelength: 242nm
As a result, the amount of Bisacurone in the turmeric extract was about 0.30% by mass. In addition, curcumin was measured by a conventional method, and it was confirmed that curcumin was not detected in the turmeric extract.

<Evaluation of VCAM-1 expression inhibitory effect>
(Example 2)
Human umbilical vein vascular endothelial cells (HUVEC) were seeded on a collagen-coated 96-well plate at a concentration of 0.4 × 10 ⁵ per hole, and F-12K (10% bovine fetal serum, Endothelial Cell Growth Supplement 30 μg /). The cells were cultured in a 5% carbon dioxide gas incubator at 37 ° C. for 18 hours in mL (containing 10 U / mL of heparin sodium). Ukon extract (140 μg / mL, 210 μg / mL, 48 μg / mL, or 160 μg / mL) or antioxidant (Sesamine (Tokyo Kasei Co., Ltd., 40 μM or 60 μM), curcumin (Wako Junyaku Co., Ltd., 3 μM or 10 μM) Ornitin (manufactured by Wako Pure Chemical Industries, Ltd., 40 μM)) or a mixture thereof (mixture of sesamine 40 μM and turmeric extract 140 μg / mL, sesamine 60 μM and turmeric extract 210 μg / mL, curcumin 3 μM and turmeric extract 48 μM , A mixture of 10 μM curcumin and 160 μg / mL turmeric extract, or a mixture of 40 μM ornithine and 140 μg / mL turmeric extract) was replaced with F-12K (containing 2% bovine fetal serum) and 5% carbonated at 37 ° C. Incubated in a gas incubator for 18 hours. Replace with F-12K (containing 2% bovine fetal serum) containing 100 ng / mL of tumor necrosis factor-α (TNF-α) with the above-mentioned turmeric extract or antioxidant (sesamin, curcumin, ornithine) or a mixture thereof. , Incubated in a 5% carbon dioxide incubator at 37 ° C. for 4.5 hours. The amount of VCAM-1 protein on the cell surface was measured by the Cell-ELISA method using an anti-VCAM-1 monoclonal antibody.

FIG. 1 shows the absorbance reflecting the amount of VCAM-1 produced. In addition, the absorbance of the control and the treated product of sesamine 40 μM was compared by the student t test, and the absorbance of the treated product in combination with turmeric extract 140 μg / mL (a mixture of turmeric 40 μM and turmeric extract 140 μg / mL) was compared. The results are shown. Treatment with 40 μM sesamin was not significantly different compared to the control, but treatment with 140 μg / mL turmeric extract reduced VCAM-1 production compared to the control. Furthermore, the combined treatment further reduced the amount of VCAM-1 produced, which was significantly reduced as compared with the treatment of 140 μg / mL of turmeric extract. It can be said that this is a result of the combined use of both of them exerting a synergistic action that exceeds the additive action in which the action of each is added. In addition, as shown in FIG. 2, the treatment with 60 μM sesamin reduced the amount of VCAM-1 produced by about 19% in terms of absorbance as compared with the control. Treatment of 210 μg / mL of turmeric extract reduced VCAM-1 production by about 42% as an absorbance compared to the control, and significantly reduced VCAM-1 production compared to the control. In addition, the combination (mixture of 60 μM sesamin and 210 μg / mL turmeric extract) reduced by about 81% compared to the control, well above the addition of the combined effects of both, about 61% (19% + 42%). Therefore, it can be said that this is the result of the synergistic effect of the two.
FIG. 3 shows curcumin 3 μM and turmeric extract 48 μM and their combined use, FIG. 4 shows curcumin 10 μM and turmeric extract 160 μg / mL and their combined use, and FIG. 5 shows ornithine 40 μM and turmeric extract 140 μg / mL and their combined use. The results of the combined use are shown. From these results, it was confirmed that the VCAM-1 production amount was reduced by the treatment with the turmeric extract, and that the synergistic effect was exhibited by the combined use of the turmeric extract and the antioxidant.
In addition, in FIGS. S. Means that there is no significant difference, and Ab 492 nm means that the measurement wavelength of absorbance is 492 nm.

Further, from the above results, in the case of the turmeric extract alone in the in vitro test, the concentration of the turmeric extract contained in the medium is preferably 50 μg / mL or more, more preferably 140 μg / mL or more. ..

<Evaluation of alcoholic liver injury inhibitory effect>
(Example 3)
20 mg / kg b. Turmeric extract for B6N mice. w. Orally administered so as to become. A 0.2% (w / v) turmeric extract dispersion was used as the administration solution. Only the solvent (0.5 w / v% methylcellulose 400 solution) was orally administered to the control group of mice. After 30 minutes, add a 15% (w / v) ethanol solution to 3 g / kg b. w. Orally administered so as to. Blood is collected before ethanol administration and 1, 2, 4, and 6 hours after administration to prepare plasma, and AST (aspartate aminotransferase) and ALT (alanine aminotransferase) activities in plasma are measured by Transaminase CII Test Wako (Wako Pure Chemical Industries, Ltd.). Was measured using. FIG. 6 shows the mean ± standard deviation (Mean ± SD) of the measured values (N = 6) of AST and ALT activities at each time. In addition, the measured values of the turmeric-administered group and the control group at each time were compared by unpaired t-test, and the significance probability was shown in FIG. As shown in FIG. 6, since the turmeric extract suppresses the increase in AST and ALT induced by ethanol administration, it can be said that it has an inhibitory effect on alcoholic liver injury.

<Evaluation of the effect of alcohol administration on the decrease in locomotor activity>
(Example 4)
B6N mice were acclimatized in a wire mesh cage for 3 days, then transferred to a plastic cage containing a rotating wheel and bred for 12 days. The breeding room was set to a 12-hour light-dark cycle (light period: 7:00 to 19:00). On the 13th day of breeding, treatment was performed according to the following schedule. On the day of treatment, the water was fasted from 8:30 to 11:00 and fasted from 8:30 to 15:00. At 10:30, turmeric extract was added at 20 mg / kg b. w. Orally administered so as to become. A 0.2% (w / v) turmeric extract dispersion was used as the administration solution. Only the solvent (0.5 w / v% methylcellulose 400 solution) was orally administered to the control group of mice. At 11:00, a 15% (w / v) ethanol solution was added at 3 g / kg b. w. Oral administration (first time) was performed so that, and at 15:00, a 15% (w / v) ethanol solution was added at 2.5 g / kg b. w. Oral administration (second time) was performed so as to be. On the day before and on the day of ethanol administration, the cumulative locomotor activity was measured for 3 hours (19:00 to 22:00) from the start of the dark period. A rotating vehicle (mouse rotating momentum measuring device, manufactured by Muromachi Kikai Co., Ltd., Igloo Fast Track FT-713) was installed in the mouse breeding environment, and the number of times the mouse turned the rotating vehicle was counted to measure the spontaneous movement amount. The value obtained by accumulating the measured locomotor activity in 1-hour units is used as the integrated locomotor activity, and the ratio (%) of the cumulative locomotor activity on the day of administration to the day before administration is calculated, and the group with and without turmeric extract (N = 7) The average value is shown in the table. In addition, the two groups were compared by the unpaired t-test, and the significance probabilities are shown in Table 1. In Table 1, the P value indicates a significant probability.

As shown in the results of Table 1, the cumulative locomotor activity for 3 hours from the start of the dark period on the day of administration decreased as compared with the day before ethanol administration, indicating that the amount of activity of the mice decreased by the administration of ethanol. By comparing the case with and without the turmeric extract, it was found that the decrease in the cumulative locomotor activity on the day of administration with respect to the day before the administration of ethanol was suppressed by the administration of the turmeric extract. That is, it is considered that the turmeric extract suppressed the decrease in the amount of activity caused by the inflammation caused by the administration of ethanol.

Since the composition of the present invention can suppress the expression of VCAM-1, various diseases such as inflammatory diseases caused by the expression of VCAM-1 can be prevented, ameliorated or treated, or particularly by alcohol intake. It can suppress liver damage and suppress the decrease in the amount of activity caused by inflammation.

Claims (4)

A composition for suppressing a decrease in activity caused by inflammation (excluding alcoholic hepatitis) caused by alcohol intake, which is characterized by containing turmeric extract and an antioxidant (however, turmeric extract and sucralose). And compositions containing erythritol)
The turmeric extract contains Bisacurone and
The antioxidant comprises one or more selected from the group consisting of sesamin or its analogs and ornithine.
A composition in which the compounding ratio of Bisacurone and an antioxidant is as follows in terms of mass ratio.
Bisacurone: sesamin or its analog = 1: 3 to 1: 300 or Bisacurone: ornithine = 1: 2 to 1: 200 A composition for suppressing a decrease in the amount of activity caused by inflammation caused by alcohol intake, which comprises a turmeric extract in which the extraction solvent is water and an antioxidant (provided that the turmeric extract, curcumin and sucralose are contained. (Excluding compositions containing erythritol) , wherein the turmeric extract contains bisacron and the antioxidant contains curcumin. The composition according to claim 1 or 2 , wherein the turmeric extract contains 0.15% by weight or more of Bisacurone. The composition according to any one of claims 1 to 3 , wherein the turmeric extract is administered or ingested so as to be 67 to 1700 mg per day per adult.