COMPOSITION FOR ACTIVATION OF 67 kDa LAMININ RECEPTOR

Abstract

To provide a composition for activating 67LR, which contains, as an active constituent, a new component other than EGCG, which has been conventionally known as a 67LR agonist, and to provide an application of the composition.SOLUTION: A composition for activating 67 kDa laminin receptor includes cinnamtannin as an active constituent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for activating the 67 kDa laminin receptor and uses thereof. [Background technology]

[0002] The 67kDa laminin receptor (hereinafter sometimes abbreviated as "67LR") is a cell membrane protein that binds to laminin, a major component of basement membranes (see, for example, Non-Patent Document 1). Epigallocatechin-O-gallate (hereinafter sometimes abbreviated as "EGCG"), a major catechin found in green tea, has previously been reported to have anticancer effects. Research by the present inventors has revealed that EGCG exerts its anticancer effects by binding to 67LR on the cell membrane (see, for example, Non-Patent Documents 2 and 3). Expression of 67LR is abnormally elevated in cancer cells, and when EGCG binds to 67LR, it activates Akt, activates endothelial nitric oxide synthase (eNOS), induces the production of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), activates protein kinase Cδ (PKCδ), and activates sphingomyelinase (ASM), resulting in cell death. EGCG activates the eNOS / PKCδ / ASM pathway via 67LR, resulting in cell death.

[0003] The effects of EGCG mediated by 67LR are known to include not only the anti-cancer effect described above, but also anti-allergic, anti-inflammatory, anti-arteriosclerotic, antibacterial, insulin sensitivity regulating, reproductive disorder improving, muscle atrophy prevention, anti-angiogenic edema, antihypertensive, cardioprotective, neuroprotective, anti-obesity, cholesterol-lowering, antithrombotic, and immune-enhancing effects (see, for example, Non-Patent Document 3, Patent Documents 1 to 4, etc.). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2011 / 162320 [Patent Document 2] International Publication No. 2015 / 199169 [Patent Document 3] International Publication No. 2019 / 026302 [Patent Document 4] JP 2018-143110 A [Non-patent literature]

[0005] [Non-Patent Document 1] Nelson J., et al., The 67 kDa laminin receptor: structure, function and role in disease., Biosci. Rep. 28 (1), 33-48, 2008. [Non-patent document 2] Tachibana H, et al., A receptor for green tea polyphenol EGCG., Nat. Struct. Mol. Biol., 11 (4), 380-381, 2004. [Non-patent document 3] Y Fujiyama, et al., 67-kDa Laminin Receptor-Mediated Cellular Sensing System of Green Tea Polyphenol EGCG and Functional Food Pairing., Molecules 2022, 27, 5130, https: / / doi.org / 10.3390 / molecules27165130 Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to provide a composition for activating 67LR, which contains as an active ingredient a new ingredient different from EGCG, a conventionally known 67LR agonist, and also to provide uses for said composition. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above-mentioned problems and have found that cinnamtannin A, an oligomer composed of flavan-3-ol units, exhibits binding activity to 67LR similar to that of EGCG. However, they have confirmed that epicatechin and epigallocatechin, which are monomeric polyphenols structurally similar to EGCG, and the oligomeric procyanidins B2, B3, and B5, do not bind to 67LR. This finding indicates that the binding activity of compounds, particularly polyphenols, to 67LR cannot be predicted from their structures. The present invention was completed based on these findings and further investigation, and includes the following embodiments.

[0008] (I) Composition for activating 67LR (I-1) A composition for activating 67LR, containing cinnamtannin as an active ingredient. (I-2) The composition for activating 67LR has, based on 67LR activation, at least one effect selected from the group consisting of antiallergic effect, anti-inflammatory effect, anti-arteriosclerotic effect, antibacterial effect, insulin sensitivity regulating effect, reproductive disorder improving effect, muscle atrophy prevention effect, anti-angiogenic edema effect, antihypertensive effect, cardioprotective effect, neuroprotective effect, anti-obesity effect, cholesterol lowering effect, antithrombotic effect, immune enhancing effect, and anticancer effect, and / or It is used for applications utilizing at least one of the above-mentioned effects, A composition for activating 67LR described in (I-1). (I-3) A composition for activating 67LR according to (I-1) or (I-2), which is used for suppressing or ameliorating 67LR-related pathologies. (I-4) A composition for activating 67LR according to (I-3), wherein the 67LR-related pathology is at least one selected from the group consisting of allergy, inflammation, arteriosclerosis, infectious disease, insulin resistance disease, muscle atrophy, hypertension, neurodegenerative disease, obesity, hypercholesterolemia, dyslipidemia, metabolic syndrome, thrombosis, and cancer. (I-5) A composition for activating 67LR according to any one of (I-1) to (I-4), wherein the cinnamtannin is cinnamtannin A. (I-6) A composition for activating 67LR according to any one of (I-1) to (I-5), which is an oral composition. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a composition for activating 67LR, which contains as an active ingredient a new ingredient different from EGCG, which has been conventionally known as a 67LR agonist. [Brief explanation of the drawings]

[0010] [Figure 1] The binding of test substance 1 (cinnamtannin A2: CA2) to the host molecule (67LR recombinant protein) was evaluated using a QCM measurement device. Specifically, this is a measurement chart showing the amount of binding (ng) per injection (indicated by the numbers 1, 2, 3, etc.) over time (the same applies to Figures 2 to 16). [Figure 2] 1 shows the results of evaluating the binding between test substance 2 (cinnamtannin A3:CA3) and the host molecule using a QCM measurement device. [Figure 3] 1 shows the results of evaluating the binding between test substance 3 (cinnamtannin A4:CA4) and the host molecule using a QCM measurement device. [Figure 4] 1 shows the results of evaluating the binding between test substance 4 (epigallocatechin: EGC) and host molecules using a QCM measurement device. [Figure 5] 1 shows the results of evaluating the binding between test substance 5 (procyanidin B3:PB3) and the host molecule using a QCM measurement device. [Figure 6]1 shows the results of evaluating the binding between test substance 6 (procyanidin B5:PB5) and the host molecule using a QCM measurement device. [Figure 7] 1 shows the results of evaluating the binding between test substance 7 (delphinidin: DP) and the host molecule using a QCM measurement device. [Figure 8] The results of evaluating the binding between test substance 8 (daidzein: DZ) and the host molecule using a QCM measurement device are shown. [Figure 9] 1 shows the results of evaluating the binding between test substance 9 (genistein: GS) and the host molecule using a QCM measurement device. [Figure 10] 1 shows the results of evaluating the binding between test substance 10 (equol: EL) and host molecules using a QCM measurement device. [Figure 11] The results of evaluating the binding between test substance 11 (quercetin: QC) and host molecules using a QCM measurement device are shown. [Figure 12] 1 shows the results of evaluating the binding between test substance 12 (hesperidin: HP) and the host molecule using a QCM measurement device. DETAILED DESCRIPTION OF THE INVENTION

[0011] (I) Composition for activating 67LR The 67LR activating composition of the present invention (hereinafter also referred to as "the composition") is characterized by containing cinnamtannin as an active ingredient. The composition is used to activate 67LR, a protein present in cell membranes, based on the binding ability of cinnamtannin to 67LR.

[0012] The cinnamtannin of interest in the present invention is preferably cinnamtannin A. Cinnamtannin A is a type of procyanidin whose constituent unit is flavan-3-ol, and is a linear oligomer (simple condensed tannin) in which such flavan units are linked only via a CC single bond (a bond between the C4-C8' positions). Of these, cinnamtannin A2 (tetramer), cinnamtannin A3 (pentamer), and cinnamtannin A4 (hexamer) are particularly preferred. In the present composition, these cinnamtannins can be used as the active ingredient either singly or in any combination of two or more.

[0013] These cinnamtannins may be produced by chemical synthesis or isolated and prepared from natural sources. For example, cinnamtannin A2 is known to be contained in cocoa beans and black soybean seed coats. Therefore, it can be extracted and purified from natural products containing cinnamtannin or processed products thereof. Furthermore, the present composition may contain a cinnamtannin A-containing substance prepared by extraction (including crude extraction) or crude purification from such natural products or processed products thereof, as long as the effects of the present invention are achieved. However, as shown in the experimental examples described below, the polyphenols contained in cocoa, such as epicatechin and procyanidins B2 and B5, do not bind to 67LR and do not have 67LR-activating activity. The present composition may also contain polyphenols other than cinnamtannins that do not bind to 67LR as its active ingredient, as long as the effects of the present invention are achieved. However, one embodiment of the present composition includes a composition that is substantially free of polyphenols other than cinnamtannins that do not bind to 67LR, so that the composition can maximize the benefits of the cinnamtannin-based effects. Here, "substantially free" does not exclude the inclusion of polyphenols in amounts that do not exceed a level that would reduce the benefits of the cinnamtannin-based effects.

[0014] The present composition can be prepared and provided as a composition containing at least one selected from the group consisting of cinnamtannins A2, A3, and A4 in a total amount of 0.1% by mass or more. The lower limit of the content is preferably 0.2% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1.0% by mass or more. There is no upper limit to the content, but examples include 99% by mass or less, 10% by mass or less, and 5.0% by mass or less.

[0015] This composition can be effectively used as a composition for activating 67LR based on the binding ability of cinnamtannin, preferably cinnamtannin A, to 67LR. 67LR is a cell membrane protein that binds to laminin, a major component of the basement membrane present in the tissue cells of mammals, including humans (Non-Patent Document 1).

[0016] In the present invention, "67LR activation" refers to the partial or complete activation of 67LR by binding to mammalian (including human) 67LR, thereby inducing intracellular signal transduction. Therefore, the present composition can be used to activate the same intracellular signal transduction system as in vivo substances by binding its active ingredient, cinnamtannin. In this sense, cinnamtannin can also be called a 67LR agonist. Here, agonists include full agonists, which exert full activity similar to that of in vivo substances, and partial agonists, which only exhibit partial activity. The presence or absence and degree of binding to 67LR can be measured and evaluated using a quartz crystal microbalance (QCM), the details of which will be explained in the experimental examples below.

[0017] According to Non-Patent Document 3 and Patent Documents 1-4, EGCG, which, like cinnamtannin, has a flavan-3-ol skeleton, is a 67LR agonist that binds to 67LR, and by binding to 67LR, it activates 67LR, resulting in anticancer, antiallergic, anti-inflammatory, anti-arteriosclerotic, antibacterial, insulin sensitivity regulating, reproductive disorder improving, muscle atrophy preventing, antiangiogenic edema, antihypertensive, cardioprotective, neuroprotective, anti-obesity, cholesterol-lowering, antithrombotic, and immunopotentiating effects. Therefore, cinnamtannin, the active ingredient of the present composition, is also expected to exert effects similar to those of EGCG by binding to 67LR.

[0018] Therefore, this composition, which contains cinnamtannin as an active ingredient, has at least one of the various effects described above and can be used in applications that utilize at least one of these effects (applications in which the above effect can be an effective efficacy). Such uses include contributing to the prevention or amelioration of 67LR-associated pathologies (67LR-associated pathologies) by exerting the above-mentioned effects. Here, "pathologies" is a general term for states that deviate from a healthy or normal state, and includes not only disease states but also pre-disease states. Subjects affected by 67LR-associated pathologies are mammals, including humans, in whom 67LR expression is elevated in tissues or cells (67LR-positive individuals). Humans are preferred.

[0019] Non-limiting examples of applications in which the above-mentioned action can be an effective effect include applications to prevent or improve pathological conditions such as various allergic diseases, various inflammatory diseases, arteriosclerosis, infectious diseases, insulin resistance diseases, muscle atrophy, hypertension, neurodegenerative diseases (including neurodegenerative diseases such as Alzheimer's disease and dementia), obesity, metabolic syndrome including hypercholesterolemia, thrombotic diseases (e.g., pulmonary embolism, DIC, myocardial infarction or cerebral infarction), and cancer.

[0020] Therefore, based on this effect, the composition can also be used as a composition for preventing or ameliorating at least one pathology selected from the group consisting of the above-mentioned allergies, inflammation, arteriosclerosis, infectious diseases, insulin resistance diseases, muscle atrophy, hypertension, neurodegenerative diseases, obesity, hypercholesterolemia, dyslipidemia, metabolic syndrome, thrombosis, and cancer, which are 67LR-related pathologies.

[0021] (II) Use in foods, beverages, medicines, quasi-drugs, feed, etc. The present composition is preferably in an oral administration form, but the form is not particularly limited. Furthermore, as long as it is in an oral administration (orally ingested) form, its use (foods and beverages [including health functional foods and supplements such as foods for specified health uses, foods with functional claims, and nutritionally functional foods], pharmaceuticals, and quasi-drugs) is not particularly limited. Furthermore, the present composition may be used in feed or pet food for animals other than humans (including livestock, poultry, and pets). Furthermore, the present composition may be an additive added to foods and beverages, pharmaceuticals, quasi-drugs, feed, or pet food.

[0022] The oral dosage form is not limited, and examples thereof include liquids (including extracts and syrups), jellies, powders, fine granules, or granules; capsules (hard capsules, soft capsules) in which liquids, powders, or granules are filled into capsules; or tablets obtained by further compressing powders or granules (solid preparations). Compositions having such dosage forms can be prepared by blending cinnamtannin with conventionally known edible carriers, excipients, etc. that are acceptable for pharmaceutical use or as food or feed, and molding the mixture into various dosage forms (oral dosage forms).

[0023] When the present composition is in the form of a liquid preparation, a wide variety of carriers conventionally known in the art can be used. Examples of suitable additives for preparing liquid preparations and syrups include water, ethanol, sucrose, invert sugar, glucose, maltose, and reduced starch syrup. When the present composition is in the form of a solid preparation, such as a tablet, a wide variety of carriers conventionally known in the art can be used. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, crystalline cellulose, hydroxypropylcellulose, hypromellose, and sodium alginate; and binders such as dry starch, powdered agar, powdered laminaran, sodium bicarbonate, and polyisoprene. Disintegrants such as ethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, crospovidone, povidone, and low-substituted hydroxypropyl cellulose can be used. Disintegration inhibitors such as stearin, cocoa butter, and hydrogenated oils can be used. Absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate can be used. Wettable tablets can be coated with conventional coatings, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, and film-coated tablets, or can be double- or multi-layered tablets. Furthermore, capsules containing the active ingredient can be prepared by filling conventional capsules made from materials such as gelatin, pullulan, starch, gum arabic, and hydroxypropylmethylcellulose (HPMC).

[0024] In addition to the above, additives such as surfactants, absorption enhancers, adsorbents, fillers, preservatives, stabilizers, emulsifiers, solubilizers, etc. may be appropriately selected and used depending on the form of the preparation.

[0025] All of these forms can be prepared by conventional methods in the art, for example, tablets can be obtained by adding the above-mentioned active ingredient and other excipients necessary for obtaining tablets as appropriate, mixing and dispersing them well, and then compressing them into tablets, while powders can be obtained by adding the above-mentioned active ingredient and other excipients necessary for obtaining powders as appropriate, mixing them by a suitable method, and pulverizing them.

[0026] The present composition may be in the form of a formulation as described above, or may be in the form of a conventional food or beverage. Such a food or beverage can be produced by adding the above-described cinnamtannin or an additive containing cinnamtannin to various foods or beverages. The food or beverage may be in any form that can be orally ingested, such as a solution, suspension, emulsion, jelly (gel), sol, powder, or solid molding, and is not particularly limited. Specific examples include beverages such as soft drinks, fruit juice drinks, vegetable drinks, soy milk drinks, coffee drinks, cocoa drinks, tea drinks, powdered drinks, concentrated drinks, nutritional drinks, and alcoholic beverages; flour products such as bread, pasta, noodles, cake mixes, fried chicken flour, and breadcrumbs; confectioneries such as candy, caramel, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, and dessert sweets; and instant foods such as instant noodles, retort pouch foods, canned foods, microwaveable foods, instant soups and miso soups, and freeze-dried foods. Examples include: condiments such as sauces, processed tomato seasonings, flavor seasonings, cooking mixes, sauces, dressings, soups, and curry and stew bases; dairy products such as milk drinks, yogurts, cheese, fermented milk, lactic acid bacteria drinks, ice cream, and cream; processed egg products such as pudding and mayonnaise; processed seafood products such as fish ham and sausage, and fish paste products; processed livestock products such as meat ham and sausage; processed agricultural products such as canned agricultural products, jams and marmalades, pickles, boiled beans, and cereals; frozen foods, nutritional foods, etc.

[0027] The composition may also be in the form of a conventional feed or pet food, which can also be produced by adding the above-mentioned cinnamtannin to various feeds or pet foods.

[0028] The content of cinnamtannin in the present composition can be set as appropriate depending on the type of form and type of use (food, beverage, pharmaceutical, quasi-drug, feed, pet food, etc.) as described above, with an upper limit of 100% by mass. The dosage (intake) of the present composition can be varied as appropriate depending on the type of human or animal, the sex and age of the subject, and the condition and severity of symptoms (pathological condition) of the subject. For example, the daily dosage (intake) for a human adult (body weight 50 kg) can be, without limitation, typically about 5 to 100 mg in terms of the amount of cinnamtannin contained in the present composition.

[0029] The subjects to whom this composition is administered (ingested) are those who are at risk of developing or have already developed the aforementioned 67LR-related pathology. Such subjects include the aforementioned 67LR-positive individuals. Note that those at risk of developing 67LR-related pathology include those who have subjective symptoms of 67LR-related pathology and those who wish to prevent the onset of 67LR-related pathology.

[0030] 67LR-related conditions include, but are not limited to, various allergic diseases, various inflammatory diseases, arteriosclerosis, infectious diseases, insulin resistance diseases, muscle atrophy, hypertension, neurodegenerative diseases (including neurodegenerative diseases such as Alzheimer's disease and dementia), obesity, metabolic syndrome including hypercholesterolemia, thrombotic diseases (e.g., pulmonary embolism, DIC, myocardial infarction or cerebral infarction), and cancer.

[0031] By orally taking (administering, ingesting) this composition, due to the 67LR activating activity of its active ingredient, cinnamtannin, it is believed to exert at least one effect selected from the group consisting of anti-allergic effect, anti-inflammatory effect, anti-atherosclerotic effect, antibacterial effect, insulin sensitivity regulating effect, reproductive disorder improving effect, muscle atrophy prevention effect, anti-angiogenic edema effect, antihypertensive effect, cardioprotective effect, neuroprotective effect, anti-obesity effect, cholesterol lowering effect, antithrombotic effect, immune enhancing effect, and anti-cancer effect, thereby making it possible to prevent or ameliorate the onset of the above-mentioned 67LR-related diseases.

[0032] (III) How to use cinnamtannin The present invention also provides methods of using cinnamtannin. One of the methods of use is a method of using cinnamtannin to impart 67LR binding activity and / or 67LR activation activity via 67LR binding to oral compositions (including foods, beverages, medicines, quasi-drugs, feed, pet food, etc.). Another method of use is a method of using cinnamtannin to impart at least one effect selected from the group consisting of antiallergic effect, anti-inflammatory effect, anti-atherosclerotic effect, antibacterial effect, insulin sensitivity regulating effect, reproductive disorder improving effect, muscle atrophy prevention effect, anti-angiogenic edema effect, antihypertensive effect, cardioprotective effect, neuroprotective effect, anti-obesity effect, cholesterol-lowering effect, antithrombotic effect, immune-enhancing effect, and anti-cancer effect to oral compositions (including foods, beverages, medicines, quasi-drugs, feed, pet food, etc.). This method can be carried out by incorporating an effective amount of cinnamtannin into the oral composition to exert 67LR binding activity. The type of cinnamtannin to be incorporated, the method for evaluating 67LR binding activity, and the type of oral composition to be incorporated are as described in (I) above, and the descriptions therein are incorporated herein by reference.

[0033] As described above, in this specification, the terms "comprise" and "contain" encompass the meanings of "consist of" and "consist essentially of." [Example]

[0034] The present invention will be explained below using experimental examples to aid in understanding the configuration and effects of the present invention. However, the present invention is not limited by these experimental examples. Unless otherwise specified, the following experiments were carried out at room temperature (25±5°C) and atmospheric pressure. Unless otherwise specified, "%" and "parts" in the following descriptions mean "% by mass" and "parts by mass," respectively.

[0035] The materials used in the following experiments and their sources are as follows: Host molecule (67LR): 67LR recombinant protein (obtained from xxxxxx) Test substance 1: Cinnamtannin A2 (CA2) (obtained from Kanto Chemical Co., Ltd.) Test substance 2: Cinnamtannin A3 (CA3) (obtained from Meiji Co., Ltd.) Test substance 3: Cinnamtannin A4 (CA4) (obtained from Meiji Co., Ltd.) Test substance 4: epigallocatechin (EGC) (obtained from Tokyo Chemical Industry Co., Ltd.) Test substance 5: Procyanidin B3 (PB3) (obtained from Funakoshi Co., Ltd.) Test substance 6: Procyanidin B5 (PB5) (obtained from Meiji Co., Ltd.) Test substance 7: Delphinidin (DP) (obtained from Extrasynsethese) Test substance 8: Daidzein (DZ) (obtained from Tokyo Chemical Industry Co., Ltd.) Test substance 9: Genistein (GS) (obtained from Tokyo Chemical Industry Co., Ltd.) Test substance 10: Equol (EL) (obtained from Tokyo Chemical Industry Co., Ltd.) Test substance 11: Quercetin (QC) (obtained from Tokyo Chemical Industry Co., Ltd.) Test substance 12: Hesperidin (HP) (obtained from Mitsui Norin Co., Ltd.) PBS: Phosphate buffer solution (pH 7.4) was prepared by dissolving 8.0 g / L of NaCl, 0.2 g / L of KCl, 1.15 g / L of NaHPO, and 0.2 g / L of KHPO in ultrapure water.

[0036] Experimental Example 1: 67LR binding evaluation The binding affinity of test substances to 67LR was evaluated using a quartz crystal microbalance (QCM). In the following experiments, 67LR recombinant protein was used as 67LR.

[0037] The QCM technique utilizes the mass-dependent decrease in the frequency of a quartz crystal oscillator due to the weight load of molecules accumulated on a sensor chip to measure (quantitate) minute weight changes (ng-level) of molecules adsorbed on the sensor chip surface in real time. By analyzing the adsorption process, it is possible to calculate the binding constant, which indicates the strength of the intermolecular interaction, and the binding rate constant, which indicates the rate of interaction. A quartz crystal oscillator is a very thin quartz crystal slice with thin metal films on both sides. When an alternating current electric field is applied to each thin metal film, it vibrates at a certain frequency (resonant frequency). When nanograms of a substance are adsorbed onto this thin metal film, the resonant frequency decreases in proportion to the mass, making it suitable for use as a microbalance. In QCM measurements, one molecule to be analyzed is immobilized on the sensor surface as a host molecule, and the other molecule is added to the solution as a guest molecule (test substance). The increase in mass on the sensor surface due to the interaction between the two molecules is measured as a frequency change.

[0038] Commercially available QCM measurement devices monitor the frequency of the quartz crystal oscillator in real time, and the frequency data is usually plotted in real time on the measurement software at one point per second. A decrease in frequency indicates an increase in the amount of substance adsorbed to the sensor surface, while an increase in frequency indicates a decrease in the amount of substance adsorbed to the sensor surface, i.e., dissociation of the substance. For example, the dissociation constant (K d This parameter can be used to evaluate the strength of affinity in the interaction between two molecules, for example, the dissociation constant (K d The smaller the dissociation constant (K), the stronger the force of attraction and binding between the target molecule (host) and the ligand (guest). d ) is larger, the weaker the interaction, and smaller, the stronger the interaction.

[0039] In the following experiments, the following analytical equipment was used as the QCM measurement device. QCM molecular interaction analysis device Single-Q: AS ONE Corporation Measurement method: Crystal oscillator Oscillation frequency: 27MHz Injection volume: 5 μL Set temperature: 25℃ A 1Hz change in frequency corresponds to a 30pg change in mass.

[0040] Experimental Method The 67LR recombinant protein (host molecule) was diluted to 10 μg / mL with purified water, immobilized on a 5 μL sensor chip attached to a QCM measurement device, and dried overnight. The sensor chip was then placed in the QCM measurement device, 500 μL of PBS was added, and each test substance (guest molecule) adjusted to 50 μM was injected into the sensor chip. The test substances used were polyphenols, such as epigallocatechin gallate (EGCG), which is known to be a "67LR agonist" that binds to 67LR and exerts various effects through this binding. Specifically, the test substances used were the aforementioned test substances 1 to 12 (cinnamtannin A2 (CA2), cinnamtannin A3 (CA3), cinnamtannin A4 (CA4), epigallocatechin (EGC), procyanidin B3 (PB3), procyanidin B5 (PB5), delphinidin (DP), daidzein (DZ), genistein (GS), equol (EL), quercetin (QC), and hesperidin (HP)). Each test substance was injected 5 to 7 times at regular intervals, and the frequency of the quartz crystal oscillator was monitored in real time to evaluate the binding of each test substance to the host molecule.

[0041] Experimental results The measurement results for test substance 1 (CA2) are shown in Figure 1. Figure 1 is a measurement chart showing the amount of binding (ng) per injection over time. Similarly, the measurement results for test substances 2 to 12 are shown in Figures 2 to 12. As shown in Figures 4 to 12, no change in the amount of binding was observed after injection of test samples 4 to 12 (EGC, PB3, PB5, DP, DZ, GS, EL, QC, and HP). This confirmed that none of these test substances bind to host molecules. On the other hand, it was confirmed that the amount of binding for test samples 1 to 3 (cinnamtannin) increased cumulatively with each injection. This confirmed that cinnamtannin commonly binds to host molecules.

[0042] Table 1 shows the binding ability of each test substance to 67LR (◯: binding ability, ×: no binding ability). In addition, for test substances 1 to 3 that showed binding ability to 67LR, the dissociation constant (Kd) and R calculated from the amount of binding to the host molecule were also shown. 2 The values ​​are also shown.

[0043] [Table 1]

[0044] EGCG is known to bind to 67LR and act as a 67LR agonist. This experiment confirmed that cinnamtannins, particularly cinnamtannin A (cinnamtannin A2-4), have the ability to bind to 67LR, and it is believed that they may also act as 67LR agonists, similar to EGCG. On the other hand, although EC and EGC are structurally similar to EGCG, neither of them has been shown to bind to 67LR. Similarly, it was confirmed that other polyphenols do not bind to 67LR.

Claims

1. A composition for activating the 67 kDa laminin receptor (67LR), which contains cinnamtannin as an active ingredient.

2. The composition for activating 67LR has, based on 67LR activation, at least one effect selected from the group consisting of an antiallergic effect, an anti-inflammatory effect, an anti-arteriosclerotic effect, an antibacterial effect, an insulin sensitivity regulating effect, an effect of improving reproductive disorders, an effect of preventing muscle atrophy, an anti-angiogenic edema effect, an antihypertensive effect, a cardioprotective effect, a neuroprotective effect, an anti-obesity effect, a cholesterol-lowering effect, an antithrombotic effect, an immune-enhancing effect, and an anti-cancer effect; and / or It is used for applications utilizing at least one of the effects. The 67LR activating composition according to claim 1.

3. The composition of claim 1, which is used to suppress or improve 67LR-related pathologies.

4. The composition for activating 67LR according to claim 3, wherein the 67LR-related pathology is at least one selected from the group consisting of allergy, inflammation, arteriosclerosis, infectious disease, insulin resistance disease, muscle atrophy, hypertension, neurodegenerative disease, obesity, hypercholesterolemia, dyslipidemia, metabolic syndrome, thrombosis, and cancer.

5. The composition for activating 67LR according to claim 1 or 2, wherein the cinnamtannin is cinnamtannin A.

6. The composition for activating 67LR according to claim 1 or 2, which is an oral composition.

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