TW201733619A - Composition for inhibiting carnosine dipeptidase - Google Patents

Abstract

An object of the present invention is to provide a composition for blocking carnosine dipeptidase, a method for inhibiting the use of carnosine dipeptidase, and a method for inhibiting carnosine dipeptidase. Further, the present invention has an object of providing a composition which is highly biosafety and which can exert a carnopeptide dipeptidase inhibitory action to enhance the action effect of carnosine. The solution of the present invention is as follows: It has been found that a specific compound such as polyphenol has a carnopeptide dipeptidase inhibitory action. The present invention provides an effective and novel means for contributing to the suppression of an increase in blood glucose level and the like.

Description

Carnosine dipeptidase inhibitory composition

The present invention relates to a carnopeptide dipeptidase inhibitory composition. More specifically, the present invention relates to a carnosine dipeptidase inhibitor composition containing a specific compound such as polyphenol, a use of a polyphenol which inhibits carnosine dipeptidase, and the like, and a method of inhibiting carnosine dipeptidase. Further, the present invention relates to a composition containing carnosine. In particular, the present invention relates to a composition comprising carnosine and a specific polyphenol.

Carnosine, a dipeptide composed of β-alanine and histidine, is present in muscles and nerve tissues at a high concentration in mammals such as humans. The role of carnosine is known as (1) proton buffer activity, (2) calcium secretion and calcium sensitivity control, (3) antioxidant activity, (4) metal ion chelation, (5) histidine/ Extracellular donors of histamine, (6) improvement of hyperglycemia, (7) anti-inflammatory action, (8) inhibition of wrinkle formation by skin, and (9) fatigue recovery promotion. In addition, regarding the action of carnosine, inhibition of the formation of glycation end products, inhibition of cell death caused by cerebral ischemia, and accumulation inhibition of amyloid β in mice with Alzheimer's disease (AD) model have also been proposed. Immunity Report on the role of regulation, etc. This carnosine exerts various functions in the living body, but carnosine is decomposed by carnosine dipeptidase present in serum or tissue, and hinders the function of carnosine.

Carnosine dipeptidase, known as carnosine dipeptidase 1 (CNDP1) and carnosine dipeptidase 2 (CNDP2). Carnosine dipeptidase 1 and carnosine dipeptidase 2, all known to have a decomposition activity relative to a dipeptide having a histidine residue at the carboxy terminus (expressed as X-His (X is a natural amino acid)) (non-patented) Document 1), carnosine is one of the decomposed dipeptides. These carnosine dipeptidase 1 and carnosine dipeptidase 2, which have different tissue distribution or enzyme properties, are mutually identical proteins. Among them, carnosine dipeptidase 1 indicates that activity is observed only in higher primates (human and large marmosets) in serum, and no activity is observed in most other mammals (Non-Patent Document 2).

Regarding the inhibition of the activity of carnosine dipeptidase 1, for example, there has been proposed a report that phenolin is an inhibitor of the degrading enzyme (Non-Patent Document 1). Further, the above-mentioned pirolin, which is known to have an enzyme blocking activity, exhibits oral toxicity. In addition, reports on inhibitors other than this are scarcely present, and carnosine decomposition inhibitors focusing on the activity of carnosine dipeptidase 1 are still not known. On the other hand, regarding carnosine dipeptidase 2, a well-known person such as Bestatin is used as the inhibitor (Non-Patent Document 3), and other than this, β-alanine or the derivative is proposed. Report that the obstacle of carnosine dipeptidase 2 is effective (patent document 1).

In carnosine dipeptidase, carnosine dipeptidase 1 was introduced into the model of db/db mice by human carnosine dipeptidase 1 gene, and the increase in fasting blood glucose level and HbA1c from adolescence was observed, or it was revealed. A person who has symptoms of diabetes such as weight loss (Non-Patent Document 4). That is, the breakdown of carnosine caused by carnosine dipeptidase 1 is considered to be a cause of illness. Therefore, the inhibitor of carnosine dipeptidase 1 can be used to prevent L-carnosine from being efficiently delivered to plasma, target organs or other organs, and to prevent various diseases caused by diabetes or oxidative stress and saccharification end products. The level of effect is to be considered.

Further, in a plurality of documents such as Non-Patent Document 5, a correlation report between a specific gene polymorphism ((CTG)) n in the carnosine dipeptidase 1 gene and the onset of diabetic renal disorder is proposed. . In connection with this, in Non-Patent Document 6, there is a report that the risk of developing diabetic nephropathy is low and the activity of carnosine dipeptidase 1 is low in the homozygous type (CTG) 5 holder. Therefore, inhibition of carnosine dipeptidase 1 activity is important for the maintenance of carnosine concentration, and may be considered to be effective for prevention or treatment of related diseases.

Further, Non-Patent Document 7 is exemplified as an example of an in vivo dynamic test after oral ingestion of carnosine in humans. According to this document, individuals in the blood concentration of carnosine at various times after ingestion of carnosine 60 mg/kg The difference was large, and there was also a tester (17 out of 25) who did not observe a significant increase in blood carnosine concentration compared with before ingestion. In the group observed to rise, the activity or protein amount of carnosine dipeptidase 1 was significantly lower than that of the non-group. From this point of view, it can be considered to inhibit the action of carnosine dipeptidase 1, which can effectively maintain the concentration of carnosine in the blood.

[Previous Technical Literature] [Patent Document]

[Patent Document 1] Japanese International Publication WO2004/064866

[Non-patent literature]

[Non-Patent Document 1] Molecules, 2014, 19, 2299-2329

[Non-Patent Document 2] Clin. Chim. Acta, 1991, 196, 193-205

[Non-Patent Document 3] Biol. Chem. Hoppe Seyler, 1988, 369, 1281-1286

[Non-Patent Document 4] Diabetes, 2007, 56, 2425-2432. Epub 2007 Jun 29.

[Non-Patent Document 5] Diabetes, 2007, 56, 2410-2413.

[Non-Patent Document 6] Diabetes, 2005, 54, 2320-2327.

[Non-Patent Document 7] Am. J. Physiol. Renal. Physiol., 2012, 302 (12), F1537-F1544.

As shown so far, carnosine dipeptidase has various effects on mammals, especially humans, and development of a technique that can effectively inhibit this activity is extremely important. Further, the above-mentioned pheniramine, which is known to have an enzyme blocking activity, exhibits oral toxicity. Therefore, the composition which blocks the carnosine dipeptidase not only effectively hinders the activity, but also strongly demands high safety. Further, by disposing the composition having the carnosyl dipeptidase inhibitory effect on carnosine, decomposition of carnosine in the composition can be suppressed, and it is expected that the action of the carnosine can be further improved.

An object of the present invention is to provide a carnopeptide dipeptidase inhibitory composition which is highly biosafe and which is useful for maintaining the in vivo concentration of carnosine, and provides a biosafety and can be used to enhance carnosine by carnosine dipeptidase inhibition. The composition of the pharmacological action. Further, an object of the present invention is to provide a method for inhibiting the use of the composition of carnosine dipeptidase and a method for inhibiting carnosine dipeptidase.

The present inventors have carefully studied the above problems, and as a result, it has been found that polyphenols have an inhibitory activity of carnosine dipeptidase. Further, the inventors of the present invention found a composition containing a specific polyphenol having the aforementioned activity and carnosine, and is a novel composition. Based on these findings, the inventors have completed the present invention.

That is, the present invention relates to the following, but is not limited thereto. herein.

(1) A composition for blocking carnosine dipeptidase, which comprises polyphenol.

(2) The composition according to (1), wherein the polyphenol is selected from the group consisting of Flavonoid, Curcuminoid, Stilbenoid, Phenylethanoid, and Phenylpropanoid. The group that makes up.

(3) The composition according to (2), wherein the flavonoid is selected from the group consisting of flavonoids, myricetin, fulvicin, leaf flavonoids, catechins, and artichoke yellow.

(4) The composition of (2), wherein the curcuminoid is curcumin.

(5) The composition of (2), wherein the hydrazine is resveratrol or spruceol.

(6) A composition according to (2), wherein the ethylbenzene is hydroxytyrosol.

(7) The composition of (2), wherein the phenylpropane is caffeic acid or ferulic acid.

(8) The composition according to any one of (1) to (7), which is used for preventing or improving fatigue, wrinkle formation of the skin, reduction of cognitive function, diabetes, reduction of immune function, inflammation of blood vessels or tissues, oxidation A variety of conditions, Alzheimer's disease, or autism caused by the production of stress or glycation end products.

(9) The composition according to any one of (1) to (8) wherein the composition is an agent.

(10) The composition of any one of (1) to (9), wherein There is a representation of the function exerted by carnosine dipeptidase.

(11) A composition comprising a composition of polyphenols and carnosine, wherein the polyphenol is spruceol or hydroxytyrosol.

(12) A composition according to (11), which is used for the purpose of inhibiting carnosine dipeptidase activity.

(13) A composition according to (11) or (12), which is used for the purpose of enhancing the pharmacological action of carnosine.

(14) The composition of (13), wherein the pharmacological action of carnosine is anti-fatigue action, skin wrinkle prevention or improvement, cognitive function maintenance, diabetes prevention or improvement, immune function reduction inhibition, blood vessel or tissue The prevention or amelioration of inflammation, various disease-improving effects caused by oxidative stress or the production of glycation end products, prevention or amelioration of Alzheimer's disease, or prevention or amelioration of autism.

(15) A composition according to any one of (11) to (14), wherein a representation of a function exerted by pharmacological action of carnosine is added.

(16) The composition of (10) or (15), wherein the expression of the function is selected from "the body is not easy to fatigue", "promotes the recovery of physical fatigue", "prevents the formation of wrinkles on the skin", "improves the wrinkles of the skin" "relaxation", "helping beauty", "suppressing the reduction of cognitive function", "expecting the maintenance of cognitive function", "increasing the rise of blood sugar levels", "improving immune function", "anticipating antioxidant effects", "Reducing oxidative stress", "anti-glycation effect", "reducing saccharification pressure", "inhibiting inflammation of blood vessels", "preventing prevention or improvement of Alzheimer's disease", and "preventing prevention of autism" Or improve the group of people.

(17) A composition according to any one of (1) to (16), wherein the composition is in the form of a solid or a liquid.

(18) The composition according to any one of (1) to (17) wherein the composition is a food or beverage composition.

(19) Use of a polyphenol to block carnosine dipeptidase.

(20) A method of blocking carnosine dipeptidase using polyphenol.

According to the present invention, a composition having an excellent carnopeptide dipeptidase inhibitory action can be provided. Further, according to the present invention, it is possible to provide a composition which enhances the action effect of carnosine by using the carnopeptide dipeptidase inhibitory effect. The decomposition delay effect of carnosine accompanied by the inhibition of melanopeptide dipeptidase can be obtained in any composition, so that a high concentration of carnosine can be more efficiently delivered to plasma, a target organ or other organs. Further, the carnosine-containing composition of the present invention can not only decompose carnosine already contained in the composition but also carnosine already present in the body.

As described above, the composition of the present invention can enhance the action effect of carnosine, and thus various pharmacological effects known to the original carnosine (relative to a decrease in cognitive function accompanying integration disorder, diabetes, reduction in immune function, It is effective to improve the inflammation of blood vessels or tissues, the occurrence of various diseases caused by oxidative stress, Alzheimer's disease, or the prevention and improvement of autism. Further, since the composition of the present invention has carnosine dipeptidase inhibitory activity, it is not only carnosine, but also all dipeptides having a histidine residue at the carboxy terminus (expressed as X-His (X) It can also be used for the purpose of decomposition of the natural amino acid)). In addition, since the polyphenol contained in the composition of the present invention is a natural compound present in plants and the like, and there are many materials which can be used as a food component, the composition of the present invention has high safety, and the side effects and the conventional pharmaceuticals are high. Compared to it, it can be seen as very little.

1. Carnosine dipeptidase inhibitory composition

The same state of the present invention is a carnosine dipeptidase inhibitory composition.

1-1. Polyphenols

The term "polyphenol" as used herein means a compound having a plurality of phenolic hydroxyl groups (hydroxy groups bonded to an aromatic hydrocarbon such as a benzene ring or a naphthalene ring). In addition, the glycoside of the compound is also included in the "polyphenol".

The polyphenol contained in the present invention is not particularly limited, and examples thereof include flavonoids, curcuminoids, terpenoids, ethylbenzene, phenylpropane, and the like.

Flavonoids contain flavonols, flavanols, flavonoids, flavanones, isoflavones, anthocyanins, and the like. In the present invention, among these, flavonols, flavanols, and flavonoids are preferred. Specific examples of the flavonols include flavonoids, myricetin, rhodoxanthin, baicalein, fulvicin, methylrhamnosin, and buckthorn. Specific examples of the flavanols include catechins (catechins, epicatechins, epicatechins, epicatechin gallic acid). Ester, epigallocatechin gallate (gallate catechin ester, etc.), theaflavins, and the like. Specific examples of the flavonoids include artichoke yellow, leaf flavonoids, red tangerine flavonoids, artichoke glycosides, and flavonoid oxime esters. Specific examples of the flavanones include eriodictyol, hesperetin, ergophenol, naringin, and the like. Specific examples of the isoflavones include pseudo-lactone, daidzein, soy isoflavone glycosides, genistein, and the like. Specific examples of the anthocyanins include cyanidin, delphinidin, mallow pigment, pelargonidin, and paeoniflorin.

Specific examples of the curcuminoid include curcumin, dimethoxycurcumin, and bisdimethoxycurcumin. Specific examples of the terpenoids include resveratrol, spruceol, and red pine. Rosewood and so on.

Specific examples of the ethylbenzene include tyrosol and hydroxytyrosol.

Specific examples of the phenylpropane include caffeic acid, ferulic acid, coumaric acid, cinnamic acid, lignin, and xylan.

As described above, in the present invention, glycosides of various compounds can also be used. The term "glycoside" as used herein means a compound in which a hydroxyl group of a sugar is bonded to a non-saccharate compound. The sugar in the glycoside may be a monosaccharide or a disaccharide or a plurality of sugars or more. The type of the sugar is not particularly limited, and examples thereof include aldose such as glucose, mannose, galactose, trehalose, rhamnose, arabinose, and xylose; ketose such as fructose; and glucuronic acid and galacturonic acid. , uronic acid such as mannuronic acid; parsley, sucrose, and the like. Further, the sugar used may be a D body or an L body. Specific examples of the glycoside in the polyphenol include rutin, quercetin, isoquercetin, hyperoside, spirulina, myricetin, rhododendron, astragalin, saponin, and locust glycosides. Dehydrogenated cork Glycosides, celery, soy isoflavone glycosides, hesperidin, naringin, etc., but are not limited thereto.

Among the above-exemplified polyphenols, in the present invention, flavonoids are preferably used. Quercetin is also known as quercetin and flavonoids, and is a kind of flavonol which is contained in a large amount of plants such as citrus or onion and buckwheat. The flavonoid is nicknamed 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one, and the CAS accession number is 117-39-5. Examples of the glycoside of the flavonoids include rutin, quercetin, isoquercetin, hyperoside, and spiraea.

Further, other preferred ingredients of the invention are myricetin. Myricetin is a kind of flavonol which is contained in grapes, berries and other fruits, or vegetables, herbs and the like. The name of myricetin is 3,3',4',5,5',7-Hexahydroxyflavone, and the CAS accession number is 529-44-2. Examples of the glycoside of the bayberry flavonoid include bayberry glycoside and myricetin 3-O-rutinoside.

Further, another preferred ingredient of the present invention is luciferin. Kaempferol is a kind of flavonol contained in plants such as tea, broccoli, cabbage, and kale. The name of the scutellaria is 3,5,7-Trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one, and the CAS accession number is 520-18-3.

Further, other preferred ingredients of the invention are leaf flavonoids. Luteolin is a kind of flavonoids contained in plants such as celery, green pepper and perilla. The leaf flavonoid is aliased as 2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4-chromenone, the CAS The login number is 491-70-3.

Further, other preferred ingredients of the present invention are catechins. The catechins are one type of flavanols which are contained in a large amount of tea such as green tea or oolong tea. The catechins, the specific types include catechins (CAS registration numbers: 7295-85-4, 18829-70-4, 154-23-4), epicatechins (CAS registration number: 490-46) -0, 35323-91-2), catechins (CAS registration number: 3371-27-5, 970-73-0), table catechins (CAS registration number: 970-74-1), children Catechin gallate (CAS accession number: 130405-40-2), epicatechin gallate (CAS accession number: 1257-08-5), catechin gallate ( CAS registration number: 4233-96-9) and epigallocatechin gallate (CAS registration number: 989-51-5), etc., particularly preferably epigallocatechin gallate.

Further, other preferred ingredients of the present invention are artichoke yellow. Apigenin is a kind of flavonoids contained in vegetables such as celery or parsley. The name of artichoke yellow is 5,7-dihydroxy-2-(4-hydroxyphenyl)-4-benzopyrone, and the CAS accession number is 520-36-5. Examples of the glycosides of artichoke yellow include celin, glucose glycoside, vitexin, isovite, and quercetin.

Further, another preferred ingredient of the present invention is curcumin. Curcumin, as described above, is a type of curcuminoid, which is contained in turmeric. The name of curcumin is (E,E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, and the CAS accession number is 458-37-7.

Further, another preferred ingredient of the present invention is resveratrol. Resveratrol, as described above, is a type of terpenoid which is contained in grape skin and the like. Resveratrol is aliased as (E)-5-(p-Hydroxystyryl)resorcinol or (E)-5-(4-hydroxystyryl)benzene-1,3-diol, and the CAS accession number is 501-36-0.

Piceanannol, one of a group of compounds known as terpenoids in polyphenols, is contained in plants such as Picea abies or Aiphanes horrida. The alias for spruce is 3',4',3,5-Tetrahydroxy-trans-stilbene Astringinin, and the CAS accession number is 10083-24-6. Examples of the glycosides of the paclitaxel include piceatannol-3'-O-β-D-glucopyranoside or piceatannol-4'-O-β-D-glucopyranoside.

Further, other preferred ingredients of the invention are ferulic acid. Ferulic acid is a kind of cinnamic acid derivative and is widely contained in plants such as rice, wheat, and barley. The name of ferulic acid is (E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoic acid, and the CAS accession number is 1135-24-6. Γ-oryzanol, which is a lipid contained in rice bran, is a general term for esters of ferulic acid and sterol condensation. After oral ingestion of γ-glutol, ferulic acid of the decomposition product can be observed. The blood concentration rises.

Further, other preferred ingredients of the invention are caffeic acid. Caffeic acid is a kind of cinnamic acid derivative and is widely contained in plants. The name of caffeic acid is (E)-3-(3,4- Dihydroxyphenyl)-2-propenoic acid, the CAS accession number is 331-39-51. A chlorogenic acid contained in a large amount of coffee beans, which is a compound having a structure in which a carboxyl group of caffeic acid and a hydroxyl group at the 3-position of cinchonanic acid are dehydrated and condensed. After oral ingestion of chlorogenic acid, caffeic acid of a decomposition product can be observed. The blood concentration rises.

Further, other preferred ingredients of the invention are hydroxytyrosol. Hydroxytyrosol is a kind of phenylethane which is contained in plants such as olive leaves. The hydroxytyrosol is aliased 4-(2-Hydroxyethyl)-1,2-benzenediol, and the CAS accession number is 10597-60-1. Regarding oleuropein contained in plants such as olive leaves, it is known that hydroxytyrosol is produced by the hydrolysis or metabolism.

In the present invention, the polyphenols may be used alone or in combination of two or more. Various polyphenols can be extracted from natural products such as plants or fruits using water (including hot water) or organic solvents, or chemically synthesized. Extraction of polyphenols (including separation, purification, etc.) or synthesis can be carried out according to the type of the compound and the like, which is generally known to the manufacturer. Various polyphenols can be used by themselves or as a commercial product. In the present invention, it is preferably a commercially available product, although it is not particularly limited. Further, a plant extract containing the above various polyphenols can also be used. The form of the polyphenol to be used is not particularly limited, and may be in the form of a solvate such as a free form (free form), a hydrate or an ethanolate. If the active ingredient is exposed to the blood, it can be used as an ester of the active ingredient and other ingredients as chlorogenic acid, γ-saltol or oleuropein. Further, an extract containing polyphenols can be preferably used.

1-2. Other active ingredients 1-2-1.5 cyclic triterpenic acid

Further, in the present invention, the carnopeptide dipeptidase inhibitor composition may contain pentacyclic triterpenic acid. The 5-ring triterpenic acid is not particularly limited, and examples thereof include ursolic acid, behenic acid, corosolic acid, betulinic acid, and syringin. In the present invention, ursolic acid is preferably used.

Ursolic acid, also known as ursolic acid, is found in apples, basil, mulberry, cranberry, elderflower, mint, rosemary, lavender, oregano, thyme, wild Hawthorn, dried fruit Li in a variety of plants. Especially in apple peel, it contains a lot of ursolic acid. The ursolic acid is aliased as 3 β-Hydroxy-12-ursen-28-oic Acid, and the CAS accession number is 77-52-1.

In the present invention, the pentacyclic triterpenic acid may be used singly or in combination of two or more. The various 5-ring triterpenic acid can be extracted from natural products such as plants or fruits using water (including hot water) or an organic solvent, or chemically synthesized. The extraction (including separation, purification, etc.) or synthesis of 5-ring triterpenic acid can be carried out according to the type of the compound and the like, which is generally known to the manufacturer. A variety of 5-ring triterpenic acids can be used by themselves or as a commercial product. In the present invention, a commercially available product is preferably used. The form of the pentacyclic triterpenic acid to be used is not particularly limited, and may be in the form of a solvate such as a free form (free form), a hydrate or an ethanolate.

1-2-2. Carnosine

Further, in the present invention, the mesin peptide can be contained in the carnopeptide dipeptidase inhibitor composition. Anserine is a dipeptide present in mammals' skeletal muscles and brain, as well as birds. A carnosine, which is a dipeptide formed by the peptide bond of β-alanine with 1-methyl-L-histidine, is also called β-alaninyl-N-methylhistidine, Beta-alanamine-1-N-methylhistamine. In addition, the CAS registration number of myopeptide is 584-85-0.

A carnosine, which can be isolated from animal tissues or chemically synthesized. The isolation or synthesis can be carried out using methods generally known to those skilled in the art. For carnosine, you can use your own or a commercial product. In the present invention, a commercially available product is preferably used. Further, the form of the mesanopeptide is not particularly limited and may be in the form of a salt. The salt of the mesangine may, for example, be a hydrochloride, a nitrate or an acetate, but is not limited thereto.

1-3. Carnosine dipeptidase and carnosine dipeptidase block

The term "carnopeptide dipeptidase" as used herein means a carnosine-degrading enzyme which can decompose carnosine (L-carnosine) into beta-alanine and histidine. Carnosine dipeptidase (carnosine decomposing enzyme), which can be omitted as CNDP ((carnosine dipeptidase), also known as carnosin or carnosin. Carnosine dipeptidase, carnosine dipeptidase containing serum (type) carnosine-degrading enzyme 1 (CNDP1) and carnosine dipeptidase 2 (CNDP2) of a tissue (type) carnosine. Among these, carnosine dipeptidase which is a subject of the present invention, preferably carnosine dipeptidase 1. carnosine dipeptidase 1 and carnosine dipeptidase 2, Known, not only carnosine, but also at the end of the carboxyl group All dipeptides having a histidine residue at the end (expressed as X-His (X is a native amino acid)) also showed decomposition activity.

In the present specification, "carnosine dipeptidase inhibition" means blocking the carnosine decomposition activity of carnosine dipeptidase. The inhibitory effect of carnosine dipeptidase can be assessed according to generally known methods. For example, when carnosine is contacted with carnosine dipeptidase, histidine is produced from carnosine, and at this time, due to the presence of histidine, fluorescence characteristic of histidine can be measured, and the decrease in fluorescence intensity can be investigated by investigating To assess the inhibitory effect of carnosine dipeptidase.

1-4. Function

As described above, by inhibiting carnosine dipeptidase, the in vivo concentration of carnosine decomposed by carnosine dipeptidase in a mammal such as a human is maintained, or the decrease in the concentration is suppressed. The role of carnosine may include proton buffer activity, calcium secretion and calcium sensitivity control, antioxidant action, metal ion chelation, extracellular donor of histidine/histamine, improvement of hyperglycemia, anti-inflammatory effect, fatigue Resilience, skin wrinkle formation inhibition, inhibition of glycation end product formation, inhibition of cell death caused by cerebral ischemia, accumulation inhibition of amyloid β in mice with Alzheimer's disease (AD) model, Immunomodulatory effects, etc. Therefore, by keeping the in vivo concentration of carnosine high, it is expected to prevent or improve the cognitive function reduction or the effects of Alzheimer's disease, autism, and the improvement of hyperglycemia accompanying the symptoms of integration disorder. And preventing or ameliorating the effects of various diseases caused by diabetes or oxidative stress or the production of glycation end products, and preventing or improving the inflammation of blood vessels or tissues according to anti-inflammatory effects, And according to the effect of immune regulation, prevent or improve the effect of reducing immune function.

The content of the component such as the polyphenol in the carnopeptide dipeptidase inhibiting composition of the present invention is not particularly limited as long as the dosage form, the administration method, and the like are considered, and the desired effect of the present invention can be obtained. The content of the polyphenol in the carnopeptide dipeptidase inhibiting composition of the present invention can be 0.001% by weight or more, preferably 0.003% by weight or more, and more preferably 0.01% by weight or more. Further, the upper limit of the content may be, for example, 50% by weight or less, 70% by weight or less, or 90% by weight or less. The form of the carnosine dipeptidase inhibitor composition of the present invention may, for example, be a solid (a tablet or the like) or a liquid (a bottle drink or the like), especially when the carnosine dipeptidase inhibiting composition of the present invention is a solid. The content of the polyphenol in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. Further, when the carnopeptide dipeptidase inhibiting composition of the present invention is a liquid, the content of the polyphenol in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight. the above.

When using flavonoids, myricetin, fulvicin, leaf flavonoids, artichoke yellow, catechin, epicatechin, epigallocatechin, epigallocatechin gallate, curcumin, white When resveratrol, spruceol, hydroxytyrosol, ferulic acid, or caffeic acid is used as the polyphenol, the content of such compounds in the carnopeptide dipeptidase inhibiting composition of the present invention can be, for example, 0.001 weight, respectively. % or more is preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more. In addition, flavonoids, myricetin, phoenix, and leaves Flavonoids, artichoke yellow, catechin, epicatechin, epigallocatechin, epigallocatechin gallate, curcumin, resveratrol, spruceol, hydroxytyrosol, awei The upper limit of the content of the acid or the caffeic acid in the composition can be, for example, 50% by weight or less, 70% by weight or less, or 90% by weight or less. Particularly when the carnosine dipeptidase inhibiting composition of the present invention is a solid, flavonoids, myricetin, fulvicin, leaf flavonoids, artichoke yellow, catechin, epicatechin, epigallocatechin, The content of epigallocatechin gallate, curcumin, resveratrol, spruceol, hydroxytyrosol, ferulic acid, or caffeic acid in the composition may be, for example, 0.1% by weight or more. Preferably, it is 0.3% by weight or more, and particularly preferably 1.0% by weight or more. Further, when the carnopeptide dipeptidase inhibiting composition of the present invention is a liquid, flavonoids, myricetin, fulvicin, leaf flavonoids, artichoke yellow, catechin, epicatechin, epigallocatechin The content of epigallocatechin gallate, curcumin, resveratrol, spruceol, hydroxytyrosol, ferulic acid, or caffeic acid in the composition may be, for example, 0.001% by weight. The above is preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more.

When the 5-ring triterpenic acid is used, the content of the carnopeptide dipeptidase inhibiting composition of the present invention can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more. Further, the upper limit of the content may be, for example, 50% by weight or less, 70% by weight or less, or 90% by weight or less. In particular, when the carnopeptide dipeptidase inhibiting composition of the present invention is a solid, the content of the pentacyclic triterpenic acid in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. In addition, when the carnosine dipeptide enzyme of the present invention is blocked When the composition is a liquid, the content of the pentacyclic triterpenic acid in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and more preferably 0.01% by weight or more.

When ursolic acid is used as the pentacyclic triterpenic acid, the content of ursolic acid in the carnopeptide dipeptidase inhibiting composition of the present invention can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more. More preferably, it is 0.01% by weight or more. Further, the upper limit of the content of ursolic acid in the composition can be, for example, 50% by weight or less, 70% by weight or less, or 90% by weight or less. In particular, when the carnosine dipeptidase inhibiting composition of the present invention is a solid, the content of ursolic acid in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight. the above. Further, when the carnopeptide dipeptidase inhibiting composition of the present invention is a liquid, the content of ursolic acid in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight. %the above.

When the carnosine is used, the content of the carnopeptide dipeptidase inhibitor composition of the present invention can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more. Further, the content may be, for example, 50% by weight or less, 70% by weight or less, or 90% by weight or less. In particular, when the carnosine dipeptidase inhibiting composition of the present invention is a solid, the content of the carnosine in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. . Further, when the carnosine dipeptidase inhibiting composition of the present invention is a liquid, the content of the carnosine in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight. the above.

The "% by weight" used in the present specification means the weight % of weight/weight (w/w) unless otherwise specified. Further, when the various components are in the form of a salt or a hydrate, the above content is calculated after converting this into a free form (free form).

The content of components such as polyphenols can be measured according to methods generally known to those skilled in the art. For example, LC-MS/MS, HPLC, or the like can be used, and appropriate conditions can be set and measured according to the type of the component.

1-5. Other ingredients

The carnosine dipeptidase inhibiting composition of the present invention may contain, in addition to the above components, any additives or any components which are usually used, depending on the form. Examples of such additives and/or components include, in addition to vitamins E, vitamin C, and the like, vitamins, minerals, nutrients, flavors, and the like, and a setting agent formulated for formulation. , but not limited to, binders, emulsifiers, tensioning agents (isoterizing agents), buffers, dissolution aids, preservatives, stabilizers, antioxidants, colorants, coagulants, or coating agents This is the case.

1-6. Use

The carnosine dipeptidase inhibitor composition of the present invention is characterized in that it contains the polyphenol or the like, and the component is expected to inhibit the activity of carnosine dipeptidase, maintain the concentration of carnosine decomposed by carnosine dipeptidase in vivo or The decrease in this concentration is suppressed. By maintaining carnosine at a high concentration in the body, it can effectively prevent or improve the reduction of cognitive function, diabetes, fatigue, wrinkles of the skin, and avoidance. The disease machine can reduce inflammation of blood vessels or tissues, various diseases caused by oxidative stress or the production of glycation end products, Alzheimer's disease, or autism. Therefore, the composition of the present invention is a disease caused by a decrease in cognitive function, diabetes, fatigue, wrinkle formation of the skin, reduction of immune function, inflammation of blood vessels or tissues, various causes of oxidative stress or production of glycation end products, Azhai A composition for carnolin dipeptidase inhibition for the prevention or improvement of autism. According to these uses, the carnosine dipeptidase inhibitory composition of the present invention may also be a cognitive function reduction, diabetes, fatigue, wrinkle formation of the skin, reduction of immune function, inflammation of blood vessels or tissues, oxidative stress or glycation end products. A composition for the prevention or improvement of various diseases, Alzheimer's disease, or autism. In the present specification, the term "prevention or improvement" includes both the state in which the current state is better and the state in which the state is made worse than the current state, and therefore includes treatment, recovery, mitigation, and relaxation. And other terms.

Further, the carnosine dipeptidase inhibitory composition of the present invention has not only carnosine but also all dipeptides having a histidine residue at the carboxy terminus due to the inhibitory activity of carnosine dipeptidase 1 and/or carnosine dipeptidase 2 ( It can also be used for the purpose of decomposition of X-His (X is a natural amino acid).

The form of the carnosine dipeptidase inhibitor composition of the present invention is not particularly limited, and is, for example, a solid or a liquid. Examples of the solid composition include a tablet (including a coated tablet), a granule, a powder, a powder, a capsule, and the like. The carnosine dipeptidase inhibitor composition of the present invention can be subjected to a generally known method. Formulation is provided for this solidifying agent. liquid Examples of the composition include a oral liquid preparation, a suspension, an emulsion, a syrup, a beverage, and the like. The carnosine dipeptidase inhibitor composition of the present invention can be formulated into a liquid according to a generally known method. Provided by the agent. Further, the carnosine dipeptidase inhibitor composition of the present invention may be configured as a beverage (including a beverage bottle, a refreshing beverage, a tea beverage, etc.), a yogurt or a lactic acid bacteria beverage, a dairy product, a seasoning, and a processed food. , desserts, desserts (such as chewing gum, candy, jelly). These compositions can be taken directly or taken with water or the like. Further, after being prepared into a form that can be easily formulated (for example, a powder form or a particle form), it can be used, for example, as a raw material for a pharmaceutical or a food or drink, but is not limited to this form.

The carnosine dipeptidase inhibitor composition of the present invention can be provided in the form of a drug as an example, but is not limited to the present embodiment. The agent may be used as a composition as it is or as a composition containing the agent. Examples of the composition of the present invention include pharmaceuticals (pharmaceutical compositions), foods and drinks (including foods, beverages, food and beverage compositions, food compositions, beverage compositions), cosmetics (cosmetic compositions), and the like. It is not limited to this. Non-limiting examples of the food composition include functional foods, health supplement foods, nutritional function foods, special purpose foods, specific health foods, nutritional supplement foods, food therapy foods, health foods, supplements, food additives. Wait.

The carnosine dipeptidase inhibitor composition of the present invention can be applied to any of therapeutic use (medical use) and non-therapeutic use (non-medical use). Specifically, it can be used as a medicine, a medical external product, a cosmetic material, etc., and the pharmaceutical law does not belong to this, but it may also Listed as a manifestation or suggestion that the cognitive function is reduced, diabetes, fatigue, wrinkles formation of the skin, decreased immune function, inflammation of blood vessels or tissues, various diseases caused by oxidative stress or the production of glycation end products, Alzheimer's The use of the composition of the claim, or the prevention or improvement of autism.

In the other aspect, the present invention relates to the above-described composition of the carnopeptide dipeptidase inhibitor which is expressed by a function of blocking by carnosine dipeptidase. The expression or the function is not particularly limited, and examples thereof include "the body is not easily fatigued", "promoting the recovery of physical fatigue", "preventing the formation of wrinkles on the skin", "improving wrinkles or sagging of the skin", "helping beauty" "Suppressing the reduction of cognitive function", "Improving the maintenance of cognitive function", "Inhibiting the rise of blood sugar levels", "Improving immune function", "Responding to anti-oxidation", "Reducing oxidative stress", "Expectable Anti-glycation, "reducing saccharification stress", "inhibiting inflammation of blood vessels", "preventing prevention or improvement of Alzheimer's disease", and "preventing prevention or improvement of autism", or as This equivalent representation or functional representation. In the present specification, the expression or function means that it can be attached to the composition itself or to a container or package attached to the composition.

The carnosine dipeptidase inhibitor composition of the present invention can be ingested by an appropriate method in accordance with the form. The method of ingestion is not particularly limited as long as the active ingredient of the present invention can be moved in circulating blood. For example, it may be in the form of an oral liquid preparation such as an oral solid preparation, an internal liquid preparation or a syrup preparation, or a non-oral preparation such as an injection preparation, an external preparation, a sitting preparation or a transdermal absorption preparation, etc., but It is not limited to this. This description The so-called "ingestion" in the book is used as a form of inclusion, taking, or drinking.

The applicable amount of the carnosine dipeptidase inhibitor composition of the present invention can be appropriately set depending on the form, the administration method, the purpose of use, and the age, body weight, symptoms, and the like of the patient or the subject to be administered, and is not necessarily constant. The effective human intake of the composition of the present invention is not limited and is not particularly limited. The effective human intake of the composition of the present invention, when the component is polyphenol, is 10 mg or more, preferably 30 mg or more per day, based on the weight of the polyphenol, for example, a human body having a body weight of 50 kg. When the component is a 5-ring triterpenic acid, the effective human intake of the composition of the present invention is 10 mg or more, preferably 30 mg or more per day, based on the weight of the 5-ring triterpenic acid, for example, a human body having a body weight of 50 kg. When the component is mycartopeptide, the effective human intake of the composition of the present invention is 10 mg or more, preferably 30 mg or more per day, based on the weight of the myopeptide, for example, a human having a body weight of 50 kg. Further, the administration can be carried out in a single or divided number of times within one day within a desired dose amount. The period of investment is also arbitrary. The effective human intake of the composition of the present invention is an intake amount of the carnosine dipeptidase inhibitor composition of the present invention which exhibits an effective effect in humans, and the composition of the active ingredient contained in the composition is not particularly specific. limited.

The object of application of the carnopeptide dipeptidase inhibitory composition of the present invention is preferably human, but may be a livestock animal such as a cow, a horse or a sheep, a pet such as a dog, a cat or a rabbit, or a mouse or a mouse. Experimental animals such as guinea pigs, marmosets, and the like. When the animal is administered to an animal other than human, about 20 g per one mouse, the amount per day is due to the composition. The content of the active ingredient, the state of the subject, the weight, the sex, and the age vary.

1-7. Combination with carnosine (combined)

The above components such as polyphenols can be used in combination with carnosine. Therefore, the present invention can provide a composition in which a component such as the above polyphenol and a carnosine are combined (hereinafter also referred to as "combination composition of the present invention").

By combining the above components with carnosine, it is expected that the carnolin dipeptidase inhibitory action of this component delays the decomposition of carnosine derived from carnosine dipeptidase, and efficiently delivers the carnosine to the target tissue or organ. Not only the carnosine originally present in the body, but also the carnosyl dipeptidase blocking composition of the present invention and the carnosine are used together, and it is expected that the carnosine concentration in the body is maintained higher and the action of carnosine is effectively enhanced.

Since the composition for use in the present invention contains a component such as the above polyphenol, it can be a composition for blocking carnosine dipeptidase. Further, the combined composition of the present invention is preferably used in the above-described use from the viewpoint of enhancing the effect of carnosine action. That is, the combined composition of the present invention preferably has various cognitive disorders such as reduced cognitive function, diabetes, fatigue, wrinkle formation of the skin, reduction of immune function, inflammation of blood vessels or tissues, and oxidative stress or production of glycation end products. , Alzheimer's disease, or a composition for the prevention or improvement of autism.

The composition for use in combination of the present invention is not particularly limited, and may be provided in the form of a dose (mixture) as one of the above examples of the carnopeptide dipeptidase inhibitor composition. The combined composition of the present invention can be used The pharmaceutical (medicinal composition) or the food or beverage (including food, beverage, food and beverage composition, food composition, beverage composition) is provided, but is not limited to this embodiment. Non-limiting examples of the food composition include functional foods, health supplement foods, nutritional function foods, special purpose foods, specific health foods, nutritional supplement foods, food therapy foods, health foods, supplements, food additives. Wait.

The carnosine of the present invention is a dipeptide composed of β-alanine and histidine, which is also called β-alaninyl histidine. Carnosine, which contains any one of D body (D-carnosine), L body (L-carnosine), and DL body (DL-carnosine), but in the present invention, L body (L-carnosine) and DL body are preferred ( DL-carnosine), especially L-body (L-carnosine). The CAS accession number of D body (D-carnosine) is 5853-00-9, and the CAS accession number of L body (L-carnosine) is 305-84-0.

The content of the polyphenol, pentacyclic triterpene acid, or carnosine in the concomitant composition of the present invention is as described above. The content of carnosine in the composition for use in the present invention can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more. Further, the upper limit of the content may be, for example, 50% by weight or less, 70% by weight or less, or 90% by weight or less. In particular, when the combined composition of the present invention is a solid, the content of carnosine in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. Further, when the combined composition of the present invention is a liquid, the content of carnosine in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more.

The method for obtaining carnosine used in the present invention is not particularly limited, and may be either natural from animals or obtained by chemical synthesis or the like. In the present invention, commercially available carnosine is preferably used. In addition, the content of the carnosine of the composition for use in the present invention is not particularly limited as long as the administration form, the administration method, and the like are considered, and the desired effect of the present invention can be obtained.

2. Use of polyphenols to block carnosine dipeptidase

The same state of the present invention is the use of polyphenols to block carnosine dipeptidase.

The polyphenol used in the present invention is preferably a flavonoid, a curcuminoid, a terpenoid, a phenylethane, and a phenylpropane. Among the flavonoids, preferred are flavonoids, myricetin, fulvicin, leaf flavonoids, artichoke yellow, and catechins, and particularly preferred are epigallocatechin gallate. Among the curcumin-like compounds, curcumin, preferably sputum, preferably resveratrol or spruceol, preferably hydroxytyrosol, phenylpropane, preferably caffeic acid or argon. Wei acid.

Further, other aspects of the invention are the use of pentacyclic triterpenic acid to block carnosine dipeptidase. Among the 5-cyclic triterpenic acids, ursolic acid is preferred. Further, another aspect of the present invention is the use of a myopeptide which is used to block carnosine dipeptidase.

In the use of the present invention, for example, it is useful in the reduction of cognitive function, diabetes, fatigue, wrinkle formation of the skin, reduction of immune function, inflammation of blood vessels or tissues, by oxidative stress or production of glycation end products. Use of polyphenols, 5-cyclic triterpenic acid, or carnosine, etc., for various diseases, Alzheimer's disease, or prevention or improvement of autism. Furthermore, the use is for human or non-human animals and may be therapeutic or non-therapeutic. Here, the term "non-therapeutic" means that there is no medical action, that is, the concept of treating the human body by treatment.

3. Method for blocking carnosine dipeptidase

The same state of the present invention is a method of blocking carnosine dipeptidase using polyphenol.

The polyphenol used in the present invention is preferably a flavonoid, a curcuminoid, a terpenoid, or a phenylpropane. Among the flavonoids, preferred are flavonoids, myricetin, fulvicin, leaf flavonoids, artichoke yellow, and catechins, and particularly preferred are epigallocatechin gallate. Among the curcumin-like compounds, curcumin, preferably sputum, preferably resveratrol or spruceol, preferably hydroxytyrosol, phenylpropane, preferably caffeic acid or argon. Wei acid.

Further, another aspect of the present invention is a method of blocking carnosine dipeptidase using 5-ring triterpenic acid. Among the 5-cyclic triterpenic acids, ursolic acid is preferred. Further, another aspect of the present invention is a method of using a carnosine to block carnosine dipeptidase.

Other aspects related to the above method include the use of polyphenols, pentacyclic triterpenic acid, or myopeptide as an active ingredient, and the therapeutically effective amount is administered to the obstructive carnosine which is a target of carnosyl dipeptidase inhibition. Method of dipeptidase. Among the polyphenols, preferred are flavonoids, curcuminoids, terpenoids, ethylbenzene, and phenylpropane. Among the flavonoids, flavonoids and bayberry yellow are preferred. Ketone, fulvicin, leaf flavonoids, artichoke yellow, and catechins, particularly preferably epigallocatechin gallate. Among the curcumin-like compounds, curcumin, preferably sputum, preferably resveratrol or spruceol, preferably hydroxytyrosol, phenylpropane, preferably caffeic acid or argon. Wei acid. Among the 5-cyclic triterpenic acids, ursolic acid is preferred.

In the above method, the inhibition by carnosine dipeptidase is essential, for example, human, but is not limited thereto. The therapeutically effective amount in the present specification is an amount which inhibits carnosine decomposing activity of carnosine dipeptidase when compared with an unadministered individual when the carnosine dipeptidase inhibitory composition of the present invention is administered to an individual. The specific effective amount may be appropriately set depending on the form of administration, the method of administration, the purpose of use, and the age, body weight, symptoms, and the like of the subject, and is not necessarily limited.

In the method of the present invention, the polyphenol, the 5-ring triterpenic acid, or the mesangine may be directly administered as a therapeutically effective amount, or as a polyphenol, a 5-ring triterpenic acid, or a The composition of carnosine is administered.

According to the method of the present invention, carnosine dipeptidase can be blocked without causing side effects. Further, the method of the present invention can prevent or ameliorate, for example, fatigue, wrinkle formation of the skin, reduction of cognitive function, diabetes, reduction of immune function, inflammation of blood vessels or tissues, by oxidative stress or saccharification through the inhibition of carnosine dipeptidase. The various causes of the production of the product, Alzheimer's disease, or autism.

4. Composition containing polyphenols and carnosine

In the same manner as the present invention, it is a composition containing polyphenols and carnosine, and the polyphenol is spruceol and/or hydroxytyrosol.

4-1. Carnosine

The carnosine contained in the composition of the present invention is as described above. The content of carnosine in the composition of the present invention can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more. Further, the upper limit of the content may be, for example, 50% by weight or less, 70% by weight or less, 80% by weight or less, or 90% by weight or less. Examples of the form of the composition of the present invention include a solid (a tablet or the like) and a liquid (a bottled beverage, etc.). Particularly, when the composition of the present invention is a solid, the content of carnosine in the composition can be set, for example. It is 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. Further, when the composition of the present invention is a liquid, the content of carnosine in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more.

The content ratio of spruceol to carnosine (sphingol: carnosine) in the composition of the present invention is, for example, 1:1000 to 100:1, preferably 1:100 to 50:1 by weight, particularly preferably It is 1:10~10:1. Further, the content ratio of hydroxytyrosol to carnosine (hydroxytyrosol: carnosine) in the composition of the present invention is, for example, 1:1000 to 100:1, preferably 1:100 to 50:1 by weight, Especially good is 1:10~10:1.

4-2. Spruceol and hydroxytyrosol

The polyphenol contained in the composition of the present invention is spruceol and/or hydroxytyrosol. Regarding piceatannol, as described above. The physiological role of spruceol is to suppress the aging of blood vessels in humans, to improve the aging of blood vessels, to improve the expression of eNOS (endothelial nitric oxide synthase), or to promote the formation of freckles in cell-level skin. Reports on the effects of action, wrinkle formation inhibition, and ultraviolet defense, and materials containing spruce have been used as raw materials for health foods.

The hydroxytyrosol contained in the composition of the present invention is as described above. The physiological action of hydroxytyrosol indicates the whitening effect of the experimental animal level, the preventive effect of arteriosclerosis, and the antioxidant effect, the cell level smoothing of blood smooth muscle cell proliferation, the wound healing effect against vascular endothelial cells, and Hydroxytyrosol is widely used as an active ingredient in health foods or cosmetics with respect to the cytoprotective effect of oxidative stress and the like.

Both paclitaxel and hydroxytyrosol can be glycosides. The sugar in the glycoside may be a monosaccharide or a disaccharide or a plurality of sugars, and is not particularly limited. The type of the sugar is not particularly limited, and examples thereof include aldose such as glucose, mannose, galactose, trehalose, rhamnose, arabinose, and xylose; ketose such as fructose; and glucuronic acid and galacturonic acid. , uronic acid such as mannuronic acid; parsley, sucrose, and the like. Further, the sugar used may be a D body or an L body. The glycoside of the paclitaxel may, for example, be piceatannol-3'-O-β-D-glucopyranoside or piceatannol-4'-O-β-D-glucopyranoside, but is not limited thereto.

Further, spruceol and hydroxytyrosol may be extracted from natural products such as plants or fruits using water (including hot water) or an organic solvent, or may be chemically synthesized. The extraction (including liberation, purification, etc.) or synthesis of such compounds can be carried out according to the type and using methods generally known to the manufacturer.

Spruceol and hydroxytyrosol can be used as they are prepared or commercially available, and are not particularly limited. In the present invention, it is preferably a commercially available product, although it is not particularly limited. In addition, plant extracts containing spruceol or plant extracts containing hydroxytyrosol may also be utilized. The form of the spironolol and the hydroxytyrosol is not particularly limited, and may be in the form of a solvate such as a free form (free form), a hydrate or an ethanolate. If the active ingredient is exposed to the blood, it can be used as an ester of the active ingredient and other ingredients as oleuropein.

The content of the spruceol in the composition of the present invention can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more. Further, the content may be, for example, 50% by weight or less, 70% by weight or less, 80% by weight or less, or 90% by weight or less. In particular, when the composition of the present invention is a solid, the content of the spruceol in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. Further, when the composition of the present invention is a liquid, the content of the spruceol in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more.

The content of hydroxytyrosol in the composition of the present invention, for example It can be 0.001% by weight or more, preferably 0.003% by weight or more, and more preferably 0.01% by weight or more. Further, the content may be, for example, 50% by weight or less, 70% by weight or less, 80% by weight or less, or 90% by weight or less. In particular, when the composition of the present invention is a solid, the content of the hydroxytyrosol in the composition can be, for example, 0.1% by weight or more, preferably 0.3% by weight or more, and particularly preferably 1.0% by weight or more. Further, when the composition of the present invention is a liquid, the content of the hydroxytyrosol in the composition can be, for example, 0.001% by weight or more, preferably 0.003% by weight or more, and particularly preferably 0.01% by weight or more.

In the composition of the present invention, when the various compounds are in the form of a salt, a hydrate or a glycoside, the above content is calculated by converting the compound into a free form (free form). Further, the content of each component in the present invention is as described above, and can be measured according to a method generally known to the manufacturer.

When both spruceol and hydroxytyrosol are used, the ratio of the two (sphingol: hydroxytyrosol) can be, for example, 1:100 to 100:1, 1:10 to 10:1 by weight ratio. , or 1:5~5:1.

4-3. Other ingredients

The composition of the present invention may contain any additives or components in addition to the above-mentioned two kinds of polyphenols and carnosine depending on the form. Examples of such additives and/or components include, in addition to vitamins E, vitamin C, and the like, vitamins, minerals, nutrients, flavors, and the like, and a setting agent formulated for formulation. , adhesive, emulsifier, Zhang The tightening agent (isoterizing agent), the buffering agent, the dissolution aid, the preservative, the stabilizer, the antioxidant, the colorant, the coagulant, or the coating agent are not limited thereto.

4-4. Composition

The composition of the present invention is not particularly limited, and is, for example, a pharmaceutical or food or drink containing carnosine and the above two kinds of polyphenols (that is, spruceol and/or hydroxytyrosol), and is preferably a beverage or a food. The content of carnosine and the above two kinds of polyphenols in the pharmaceutical or food and drink is as described above.

When the composition of the present invention is a pharmaceutical, the administration route is not particularly limited, and it is preferably administered orally. A form suitable for oral administration of a pharmaceutical composition, comprising a solid preparation of a tablet (including a coated tablet), a granule, a powder, a powder, or a capsule, or a liquid preparation, a suspension, an emulsion Liquid preparations such as syrups and beverages.

When the composition of the present invention is a food or drink, the form may be in the form of a health food such as a tablet (including a coated tablet), a capsule, a powder, a granule, or a beverage, or may be configured as a beverage ( It includes dairy products such as beverages, refreshing drinks, and tea drinks, yogurts, seasonings, processed foods, desserts, and desserts (such as chewing gum, candy, and jelly).

The form of the composition of the present invention is not particularly limited and is, for example, a solid or a liquid, and the specific examples are as described above. The composition of the present invention can be directly consumed or taken together with water or the like. In addition, after being modulated into an easily configurable form (for example, a powder form or a particle form), for example, it can be used as Raw materials for pharmaceuticals or foods.

In the composition of the present invention, for example, when a generally known pharmaceutical or food or drink is prepared, a specific amount of carnosine may be mixed with the above-mentioned two kinds of polyphenols (that is, spruceol and/or hydroxytyrosol). In addition, the above-mentioned two kinds of polyphenols and carnosine may be added to the generally known pharmaceuticals or foods and beverages, and dissolved and/or the above-mentioned two kinds of polyphenols and carnosine may be added to the above-mentioned specific amounts. Or suspended to modulate. The pharmaceuticals and foods and beverages which are generally known may be those which have already contained carnosine and the above two kinds of polyphenols, and may be prepared by appropriately blending the carnosine and the two polyphenols of the present invention in a specific amount.

The composition of the present invention can be applied to any of therapeutic use (medical use) and non-therapeutic use (non-medical use). Specifically, it can be used as a pharmaceutical product, a medical external product, a cosmetic material, and the like. In addition, although it is not included in the pharmaceutical law, it may be mentioned as an express or suggestive reduction in cognitive function, diabetes, fatigue, and skin. The formation of wrinkles, decreased immune function, inflammation of blood vessels or tissues, various diseases caused by oxidative stress or the production of glycation end products, Alzheimer's disease, or the prevention or improvement effect of autism Use of objects.

The object of application of the present invention is preferably a human, but may also be a livestock animal such as a cow, a horse, or a sheep, a pet such as a dog, a cat, or a rabbit, or an experiment of a mouse, a mouse, a guinea pig, a marmoset, or the like. animal. When the animal is administered to an animal other than a human, the amount varies depending on the content of the active ingredient in the composition, the state of the subject, the body weight, the sex, and the age.

4-5. Function and use

The composition of the present invention is characterized in that it contains carnosine and spruceol and/or hydroxytyrosol, and spruceol and hydroxytyrosol have carnosine dipeptidase inhibitory action.

As described above, the carnosine dipeptidase is preferably carnosine dipeptidase 1 (CNDP1) which is a serum (type) carnosine decomposing enzyme.

Regarding "carnopeptide dipeptidase inhibition", as described above, since the composition of the present invention contains spruceol and/or hydroxytyrosol, the carnosine can be delayed in the body by the carnosyl dipeptidase inhibitory action. Decomposes and efficiently delivers carnosine to the target tissue or organ. Thereby, the composition of the present invention can effectively enhance the pharmacological action of these carnosines with respect to carnosine contained in the composition or carnosine originally present in the body.

Regarding the pharmacological action of carnosine, the action as carnosine is as described above. According to this carnopeptide dipeptidase inhibitory action, the composition of the present invention can be constituted as a composition for enhancing the pharmacological action of carnosine (a composition used for the purpose of enhancing the pharmacological action of carnosine). Further, the composition of the present invention may be constituted by a decrease in pharmacological action of carnosine, a reduction in cognitive function, diabetes, fatigue, formation of wrinkles in the skin, reduction in immune function, inflammation of blood vessels or tissues, oxidative stress or glycation end products. A composition for causing various diseases, Alzheimer's disease, or prevention or improvement of autism.

Further, the composition of the present invention has an inhibitory activity of carnosine dipeptidase 1 and/or carnosine dipeptidase 2, Therefore, not only carnosine, but also the purpose of inhibiting decomposition of all dipeptides having a histidine residue at the carboxy terminus (expressed as X-His (X is a natural amino acid)) can be used.

The present invention, at other levels, relates to a composition to which a function expressed by the pharmacological action of carnosine is added. The expression or the function is not particularly limited, and examples thereof include "the body is not easily fatigued", "promoting the recovery of physical fatigue", "preventing the formation of wrinkles on the skin", "improving wrinkles or sagging of the skin", "helping beauty" "Suppressing the reduction of cognitive function", "Improving the maintenance of cognitive function", "Inhibiting the rise of blood sugar levels", "Improving immune function", "Responding to anti-oxidation", "Reducing oxidative stress", "Expectable Anti-glycation, "reducing saccharification stress", "inhibiting inflammation of blood vessels", "preventing prevention or improvement of Alzheimer's disease", and "preventing prevention or improvement of autism", or as This equivalent representation or functional representation. In the present specification, the expression or function means that it can be attached to the composition itself or to a container or package attached to the composition.

The composition of the present invention can be ingested by an appropriate method in accordance with the form. The method of ingestion is not particularly limited as long as it can move the active ingredient contained in the composition in the circulating blood. For example, it may be in the form of an oral liquid preparation such as an oral solid preparation, an internal liquid preparation or a syrup preparation, or a non-oral preparation such as an injection preparation, an external preparation, a sitting preparation or a transdermal absorption preparation, etc., but It is not limited to this.

[Examples]

The invention is illustrated in more detail below by way of examples, but the scope of the invention is not limited thereto. The present invention can be used in various ways and modifications to the method of the present invention, and these are also included in the scope of the present invention.

Example 1. Discussion on the effect of carnosine dipeptidase 1 inhibition

The compound was evaluated using flavonoids, myricetin, guarannisin, leaf flavonoids, artichoke yellow (above, manufactured by Extrasynthese Co., Ltd.), catechin (manufactured by Nagara Science Co., Ltd.), and epigallocatechin (Kurida). Industrial company), epicatechin, epigallocatechin gallate, curcumin, ferulic acid, caffeic acid (above: Nacalai Tesque), resveratrol, ursolic acid (above Sigma company, spruceol, hydroxytyrosol (the above is manufactured by Tokyo Chemical Industry Co., Ltd.), and methyl carnosine (manufactured by Wako Pure Chemical Industries, Ltd.). In addition, human carnosine dipeptidase 1 was recombinant Human Carnosine Dipeptidase 1 / CNDP1 (R&D systems), and carnosine (manufactured by Tokyo Chemical Industry Co., Ltd.) was used to investigate the enzyme reaction. Follow the steps below to investigate the blocking effect of carnosine dipeptidase 1 activity at room temperature.

50 μL of a 2 ng/μL carnosine dipeptidase 1 solution dissolved in a buffer (50 mM Tris, pH 7.5) and 25 μL of an aqueous solution containing the evaluation compound were added to a 1.5 mL small centrifuge tube (Eppendorf Tube), and dissolved in the same buffer. The reaction was started by 25 μL of a 4 mM carnosine solution. The reaction solution was incubated at room temperature for 60 minutes. Thereafter, 50 μL of a 1% aqueous solution of trichloroacetic acid (TCA) dissolved in deionized water was added, and blending was carried out by vortexing to terminate the reaction. A 1.8 M sodium hydroxide aqueous solution (containing 10% DMSO) containing 5 mg/mL o-phthalaldehyde (OPA; o-Phthaldialdehyde) (Sigma) was added to the sample after the reaction, and after blending, further culture was carried out at room temperature. 30 minutes. Using a buffer solution, a L-histamine acid dilution series was prepared in the range of 15.625 to 250 μM, and after adding TCA and OPA in the same manner, the solution after 30 minutes of incubation was used as a calibration line solution. Water containing DMSO of the same content rate was added to replace the aqueous solution containing the evaluation compound, and it was used as a control group. The sample and the calibration curve solution were added in a total amount to a 96 well black plate, and the fluorescence intensity of histidine at an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm was measured using a fluorescence photometer. For each group, the discussion was carried out with n=2.

Regarding the result, the correction value was calculated by subtracting the fluorescence intensity in the sample of the enzyme (carnosine dipeptidase 1) by adding a buffer, and the evaluation was performed when the correction value of the fluorescence intensity of the control group was 100%. The correction value of the fluorescence intensity in the compound group was set to carnosine dipeptidase 1 residual activity (%). The results are shown in Tables 1 to 4.

From the above results, it was found that the compounds shown in the first to fourth tables all have an inhibitory effect on the activity of carnosine dipeptidase 1. Since these compounds have a carnolin dipeptidase inhibitory action, the combination of these compounds and carnosine shows the possibility of enhancing the action of carnosine in the composition and carnosine originally present in the body.

The production examples of the composition of the present invention are as follows.

(Manufacturing Example 1) Lozenge

These were mixed and tableted by a single-type tableting machine to produce a tablet having a diameter of 9 mm and a mass of 300 mg.

(Production Example 2) granules

Curcumin 10g

After the above powders were uniformly mixed, 100 ml of a 10% hydroxypropylcellulose ethanol solution was added, and kneaded, extruded, and dried by a usual method to obtain granules.

(Production Example 3) Beverage agent

The above ingredients were formulated and water was added to become 1 liter. This beverage is consumed more than 100ml per time.

(Production Example 4) Lozenge

These were mixed and tableted by a single-type tableting machine to produce a tablet having a diameter of 9 mm and a mass of 300 mg.

(Production Example 5) granules

After the above powders were uniformly mixed, 100 ml of a 10% hydroxypropylcellulose ethanol solution was added, and kneaded, extruded, and dried by a usual method to obtain granules.

(Manufacturing Example 6) Beverage agent

The above ingredients were formulated and water was added to become 1 liter. This beverage is consumed more than 100ml per time.

(Manufacturing Example 7) Juice

(Manufacturing Example 8) Yogurt

(Production Example 9) Lactic acid bacteria drink

(Production Example 10) Lactic acid bacteria beverage

(Production Example 11) Coffee drink

(Production Example 12) Alcoholic beverage

Refined water 85.74 parts by weight

[Industrial Applicability]

The present invention provides a composition for blocking an angiopeptide dipeptidase containing a polyphenol or the like. Further, the present invention provides a composition comprising carnosine and a specific polyphenol having an inhibitory effect on carnosine dipeptidase. According to the present invention, since a novel means for suppressing an increase in blood sugar level and the like is provided, the industrial applicability is high.

Claims (20)

A carnosine dipeptidase inhibitory composition containing polyphenols. The composition of claim 1, wherein the polyphenol is selected from the group consisting of Flavonoid, Curcuminoid, Stilbenoid, Phenylethanoid, and Phenylpropanoid. Group of people. The composition of claim 2, wherein the flavonoid is selected from the group consisting of flavonoids, myricetin, fulvicin, leaf flavonoids, catechins, and artichoke yellow. The composition of claim 2, wherein the curcuminoid is curcumin. The composition of claim 2, wherein the steroid is resveratrol or spruceol. The composition of claim 2, wherein the ethylbenzene is hydroxytyrosol. The composition of claim 2, wherein the phenylpropane is caffeic acid or ferulic acid. The composition according to any one of claims 1 to 7, which is used for preventing or improving fatigue, wrinkle formation of the skin, decreased cognitive function, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or glycation end products The cause of the disease, Alzheimer's disease, or autism. The composition of any one of claims 1 to 8, wherein the composition is an agent. The composition according to any one of claims 1 to 9, wherein a representation of the function exerted by the carnosine dipeptidase is added. A composition comprising a composition of polyphenols and carnosine, wherein the polyphenol is spruceol or hydroxytyrosol. The composition of claim 11 which is used for the purpose of inhibiting carnosine dipeptidase activity. A composition according to claim 11 or 12, which is used for the purpose of enhancing the pharmacological action of carnosine. The composition of claim 13, wherein the pharmacological action of carnosine is anti-fatigue action, wrinkle prevention or improvement of skin, cognitive function maintenance, prevention or improvement of diabetes, inhibition of immune function, inflammation of blood vessels or tissues A preventive or ameliorating action, various disease-improving effects caused by oxidative stress or production of glycation end products, prevention or amelioration of Alzheimer's disease, or prevention or amelioration of autism. The composition according to any one of claims 11 to 14, wherein a representation of the function exerted by the pharmacological action of carnosine is added. In the composition of claim 10 or 15, the expression of the function is selected from "the body is not easy to fatigue", "to promote the recovery of physical fatigue", "to prevent the formation of wrinkles in the skin", "to improve the wrinkles or sagging of the skin", " "Helps beauty", "suppresses cognitive function reduction", "expects maintenance of cognitive function", "suppresses blood sugar level", "improves immune function", "antioxidation effect", "reduces oxidative stress" "It is expected to anti-glycation", "reducing saccharification pressure", "inhibiting inflammation of blood vessels", "preventing prevention or improvement of Alzheimer's disease", and "preventing prevention or improvement of autism" Group of people. The composition of any one of claims 1 to 16, wherein the composition The form is solid or liquid. The composition of any one of claims 1 to 17, wherein the composition is a food or beverage composition. A use of polyphenols to block carnosine dipeptidases. A method of blocking carnosine dipeptidase using polyphenols.