WO2006067867A1

WO2006067867A1 - Cell adhesion factor expression inhibitor

Info

Publication number: WO2006067867A1
Application number: PCT/JP2004/019792
Authority: WO
Inventors: Kinya Takagaki; Sadao Mori
Original assignee: Toyo Shinyaku Co., Ltd.
Priority date: 2004-12-24
Filing date: 2004-12-24
Publication date: 2006-06-29
Also published as: WO2006067867A8

Abstract

A cell adhesion factor expression inhibitor comprising a proanthocyanidin, preferably a proanthocyanidin derived from pine bark. This inhibitor is obtained from plants and exerts an excellent cell adhesion factor expression effect.

Description

Cell adhesion factor expression inhibitor

Technical field

The present invention relates to a cell adhesion factor expression inhibitor. Light

Background art

Cell adhesion factors are a group of molecules involved in adhesion between cells or between cells and the written extracellular matrix, many of which are transmembrane glycoproteins. For example, a selectin molecule group, an integrin molecule group, and an immunoglobulin superfamily molecule group are known. These cell adhesion factors are involved not only in adhering cells but also in various important reactions in vivo. For example, in an inflammatory reaction, leukocytes adhere to vascular endothelial cells and infiltrate a place where a foreign substance exists (inflamed area), thereby protecting the body. At this time, adhesion of leukocytes to vascular endothelial cells and infiltration into the local area of inflammation are controlled by respective cell adhesion factors expressed in leukocytes and vascular endothelial cells. Specifically, the invasion described above is (1) capture of leukocytes on vascular endothelial cells, (2) rolling of leukocytes, (3) strong adhesion of leukocytes to endothelial cells, and (4) extravasation of leukocytes Cell attachment factors are involved in these processes. That is, in the above (1) and (2), white blood cells are captured and rolled by binding of a selectin molecule group expressed on leukocytes or vascular endothelial cells to a sugar chain antigen on leukocytes or vascular endothelial cells. Induced. In the above (3) and (4), strong adhesion of leukocytes and migration to the outside of the blood vessel are caused by the selection of the selectin molecule group, the intedarin molecule group on the leukocyte, and the immune globulin superfamily on the vascular endothelial cell. Depends on the connection with the child group. In this way, a normal biological reaction is maintained by appropriately expressing the cell adhesion factor according to the biological reaction.

As described above, expression of cell adhesion factor is induced by stimulation of inflammatory cytokines. Its expression is also thought to be enhanced in various lesions and may be involved in the formation of many pathologies, such as chronic inflammation, due to increased cell adhesion or intercellular responses caused by this adhesion. For example, autoimmune diseases such as rheumatism, and allergic diseases such as hay fever are thought to be caused by an excessive inflammatory reaction due to enhanced cell-cell adhesion due to increased expression of cell adhesion factors. In addition, the above-mentioned cell adhesion factors of leukocytes and vascular endothelial cells have been reported to be involved in cancer cell metastasis and HIV infection. Other diseases involving cell adhesion factors include bronchial asthma, atopic dermatitis, psoriasis, ischemia-reperfusion injury, nephritis, hepatitis, ulcerative colitis, acute respiratory distress syndrome, transplant organ rejection, etc. Inflammatory diseases; diseases related to blood or blood vessels (eg, poor blood circulation due to decreased blood fluidity, arteriosclerosis); sepsis; Furthermore, in the epidermis, it has been suggested to be involved in blistering, keratosis, keratinopathy, acne, and rough skin. Control / suppression of the expression of cell adhesion factors is effective not only in suppressing excessive cell adhesion but also in the prevention and / or treatment of the above-mentioned symptoms and diseases.

In order to suppress the expression of such cell adhesion factors, various chemical compounds or animal-derived components have been proposed as pharmaceuticals so far (Japanese Patent Application Laid-Open No. 10-3300 25 9). (Saihei 10-8 7 4 91, JP 2 0 0 1 3 3 5 4 90 and JP 2 0 0 0-3 1 9 2 7 8). However, since many of these have problems such as a narrow safe capacity range, they are limited to use only as pharmaceuticals and cannot be used easily. Disclosure of the invention Accordingly, an object of the present invention is to provide a plant-derived cell adhesion factor inhibitor having a safer and superior effect.

The present inventors have intensively studied a plant-derived substance capable of effectively suppressing the expression of a cell adhesion factor, and found that proanthocyanidins have an excellent cell adhesion factor expression inhibitory action, thereby completing the present invention. It came to.

That is, the cell adhesion factor expression inhibitor of the present invention contains proanthocyanidins.

In a preferred embodiment, the cell adhesion factor is a cell adhesion factor expressed on blood cells.

In a preferred embodiment, the proanthocyanidins are derived from pine bark.

An excellent cell adhesion factor expression inhibitory effect can be obtained by oral administration or transdermal administration of the cell adhesion factor expression inhibitor containing the proanthocyanidins of the present invention. The inhibitor of the present invention can be used as food, pharmaceuticals, cosmetics and the like, and can be applied to the prevention and treatment of various diseases caused by the expression of cell adhesion factors. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the cell adhesion factor expression inhibitor of the present invention will be described. The configurations described below do not limit the present invention, and it will be apparent to those skilled in the art that various modifications can be made within the scope of the gist of the present invention.

The cell adhesion factor expression inhibitor of the present invention contains proanthocyanidins, and may contain other components as necessary. Hereinafter, each component will be described. (Proanthocyanidins)

In this specification, proanthocyanidin means flavan 1-ol. And a compound group consisting of polycondensation polymers having a degree of polymerization of 2 or more and having 1 or 4 or 1 flavan as a structural unit. Proanthocyanidins are known to have various activities such as antioxidant activity.

As the proanthocyanidins used in the present invention, those containing a large amount of a condensation polymer having a low degree of polymerization are suitable. As the condensation polymer having a low degree of polymerization, a condensation polymer having a degree of polymerization of 2 to 30 (2 to 30 mer) is preferable, and a condensation polymer having a degree of polymerization of 2 to 10 (2 to 10 mer). ) Is more preferable, and a condensation polymer (2-4 tetramer) having a polymerization degree of 2-4 is more preferable. This polycondensation polymer having a degree of polymerization of 2 to 4 is referred to as oligomeric proanthocyanidin (hereinafter referred to as OPC). Proanthocyanidins, a type of polyphenols, are powerful antioxidants produced by plants and are concentrated in plant leaves, bark, fruit peels or seed parts. Proanthocyanidins, especially OPC, specifically, the bark of plants such as pine, cocoons, and wild peaches; grapes, blueberries, citrus, avogad, false acacia, berries or seeds of barley; wheat; soybeans; black soybeans Cocoa; red beans; tochi nut shell; peanut thin skin; ichiyo leaves. In addition, it is known that West African cola nuts, Peruvian rattan roots, and Japanese green tea also contain OPC. OPC is a substance that cannot be produced in the human body.

In particular, when proanthocyanidins with a high OPC content or extracts containing proanthocyanidins with a high OPC content are used, proanthocyanidins with a low OPC content (proanthocyanidins with a high degree of polymerization) Compared with the case of using a composition containing anthocyanidin), an excellent cell adhesion factor expression-suppressing effect can be obtained.

As the proanthocyanidins used in the inhibitor of the present invention, materials such as the bark of the above-mentioned plants, fruit or seed pulverized products, or extracts thereof can be used. Among these, it is preferable to use the above extract, In particular, it is preferable to use an extract derived from pine bark. An extract derived from pine bark exhibits a particularly high physiological activity among extracts derived from plants containing the above-mentioned proanthocyanidins. This is thought to be because, among the plants containing proanthocyanidins, pine bark is rich in OPC. Therefore, pine bark is preferably used as a raw material for puffed anthocyanidins.

Hereinafter, an example of using pine bark rich in OPC as a raw material plant will be described with reference to a method for preparing an extract containing puffer anthocyanidin as a main component.

Pine bark extracts include French coastal pine (Pinus Martima), larch, black pine, waka pine, himekomatsu, pine pine, Korean pine, pine, Ryukyu pine, Utsushima pine, Daiyu pine, white pine, and Quebec in Canada An extract of the bark of a plant belonging to the order of pine is preferably used. Among them, the extract of the crustacean of French coastal pine (Pinus Martima) is preferred.

French coastal pine is a marine pine that grows on the Atlantic coast of southern France. It contains bark of French coastal pine, proanthocyanidins, organic acids, and other physiologically active ingredients. Proanthocyanidins, which are the main ingredients, have strong resistance and antioxidative action to remove active oxygen. It is known. The pine bark extract is obtained by extracting the pine bark with water or an organic solvent. When water is used, it is preferable to use warm water or hot water. In order to improve the extraction efficiency, it is preferable to add a salt such as sodium chloride to these waters. As the organic solvent used for extraction, an organic solvent that is acceptable for the production of foods or drugs is used. For example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, Xylene, cyclohexane, propylene glycol, hydrous ethanol, hydrous propylene glycol, methyl ethyl ketone, glycerin, methyl acetate, ethyl acetate, jetyl ether, dichloromethane, edible fats and oils, 1, 1, 1, Examples include 2-tetrafluoroethane and 1,1,2,2-trichloroethene. These water and organic solvents may be used alone or in combination. In particular, water, hot water, ethanol, water-containing ethanol, and water-containing propylene glycol are preferable, and water, hot water, ethanol, and water-containing ethanol are more preferable from the viewpoint of safety when used in foods and pharmaceuticals.

The method for extracting proanthocyanidins from pine bark is not particularly limited. For example, by adding 1 to 100 parts by weight of hot water of 50 to 120 ° C, preferably 70 to 100 ° C, with respect to 1 part by weight of dry weight of pine bark, extraction is performed. A pine bark extract having high bioactivity and high water solubility can be obtained. A warm extraction method, a supercritical fluid extraction method, or the like may be used.

Supercritical fluid extraction is a method that uses a supercritical fluid, which is a fluid that exceeds the critical point (critical temperature, critical pressure) of a substance's gas-liquid. As the supercritical fluid, carbon dioxide, ethylene, propane, nitrous oxide (laughing gas) and the like are used, and carbon dioxide is preferably used.

The supercritical fluid extraction method performs an extraction process of extracting a target component with a supercritical fluid and a separation process of separating the target component and the supercritical fluid. In the separation step, any of extraction separation by pressure change, extraction separation by temperature change, or extraction separation using an adsorbent / absorbent may be performed.

Alternatively, supercritical fluid extraction may be performed by an entrainer addition method. In this method, for example, ethanol, propanol, n-hexane, acetone, toluene, other aliphatic lower alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, or ketones are added to a supercritical fluid. By adding about 20 WZV% and performing supercritical fluid extraction with the extracted fluid, the solubility of the target extract such as OPC and catechins (described later) in the extraction solvent is dramatically increased. Alternatively, it is a method for enhancing the selectivity of separation, and a method for efficiently obtaining a pine bark extract. . The super-field fluid extraction method can be operated at a relatively low temperature, so it can be applied to substances that are altered and decomposed at high temperatures; the advantage that the extraction fluid does not remain; There is an advantage that the desolvation process can be omitted, and the process becomes simple.

Extraction from pine bark may be performed by a liquid carbon dioxide batch method, a liquid carbon dioxide reflux method, a supercritical carbon dioxide reflux method, or the like in addition to the above method. For extraction from pine bark, you can combine several extraction methods. By combining multiple extraction methods, it is possible to obtain pine bark extracts of various compositions.

The pine bark extract obtained by the above extraction may be purified for the purpose of increasing the proanthocyanidin content. For purification, an organic solvent such as ethyl acetate is usually used. However, from the viewpoint of safety as a food or pharmaceutical product, a method that does not use an organic solvent, such as ultrafiltration or Diaion HP-20, It is preferable to purify by a column method or a batch method using an adsorptive carrier such as Cefdex LH20 or chitin.

In the present invention, the pine husk extract containing proanthocyanidin as a main component is specifically prepared by the following method, but this is an example and is not limited to this method.

1 kg of French coastal pine bark is placed in 3 L of a saturated solution of salted chickatolium and extracted at 100 ° C for 30 minutes to obtain an extract (extraction process). Thereafter, the extract is filtered, and the resulting insoluble matter is washed with 50 O mL of a saturated solution of sodium chloride to obtain a washing solution (washing step). The extract and washing solution are combined to obtain a crude extract of pine bark.

Next, the crude extract is added with ethyl acetate 25 O mL and separated, and the ethyl acetate layer is collected five times. Combine the recovered ethyl acetate solution and add directly to 200 g of anhydrous sodium sulfate for dehydration. Then this acetate The solution is filtered and the filtrate is concentrated under reduced pressure until the original volume is reduced to one-fifth. The concentrated ethyl acetate solution is poured into 2 L of chloroform and the precipitate obtained by stirring is collected by filtration. After that, the precipitate is dissolved in 10 mL of ethyl acetate, and then added to 1 L of black mouth form again to cause precipitation to be repeated twice. By this method, for example, about 5 g of pine bark extract containing 20% by weight or more of OPC and 5% by weight or more of strong and strong tekins can be obtained. The extract derived from the raw material plant such as pine bark preferably contains 40% by weight or more of proanthocyanidins. Further, the extract derived from the raw material plant preferably contains 20% by weight or more of OPC, more preferably 30% by weight or more. As described above, a pine bark extract is preferably used as a raw material containing proanthocyanidins in a high proportion. The plant extract such as the above-mentioned pine peel extract preferably contains catechins together with proanthocyanidins, particularly OPC. Catechin is a general term for polyhydroxyl furan-3-ol. The catechins are: (+)-force techin (referred to as catechin in the narrow sense), (1) one-epipe force tekin, (+)-gallocatechin, (1) one-epigalocatechin, epicarocatechin gallate, epicatechin gallate, Afzerekin is known. From the above-mentioned extracts derived from raw materials such as pine bark, in addition to the above (+)-power techin, gallocatechin, affazechin, (+)-catechin 3-galloyl derivative, and 3-galloyl of gallocatechin The derivative has been isolated. Catechin alone has poor water solubility and low physiological activity. However, catechins have the property of being activated at the same time as water solubility increases in the presence of OPC, and act effectively when ingested with OPC.

Catechins are preferably contained in the raw material plant extract in an amount of 5% by weight or more, preferably 10% by weight or more. More preferably, the extract contains 0 to 20% by weight or more and 5% by weight or more of catechins. Example For example, if the catechin content of the extract is less than 5% by weight, force techins may be added to adjust the final content to 5% by weight or more. It is most preferable to use a pine bark extract containing 20% by weight or more of the same and 5% by weight or more of the strength techins.

(Other ingredients)

The inhibitor of the present invention may contain ascorbic acid or a derivative thereof and various components as necessary.

Ascorbic acid or a derivative thereof is preferably contained in the inhibitor of the present invention in that the effect of proanthocyanidins used in the present invention, particularly OPC, can be exhibited more efficiently. Ascorbic acid or a derivative thereof is ascorbic acid or a derivative thereof used as a food additive, for example, ascorbic acid glycoside, sodium ascorbate, magnesium ascorbate, or the like. Natural materials rich in ascorbic acid (for example, natural materials derived from fruits such as lemon, orange, and acerola, or natural materials derived from vegetables such as broccoli, me cabbage, peppers, komatsuna, and cauliflower) In the invention, it can be used as ascorbic acid.

Ingestion of ascorbic acid or its derivatives with proanthocyanidins (especially OPC) increases the absorption rate of ascorbic acid and the sustainability of physiological activity. In the present invention, ascorbic acid or a derivative thereof may be contained for the purpose of protecting blood vessels, particularly for enhancing the flexibility and strength of blood vessels, and for lowering cholesterol in the blood. In particular, ascorbic acid or its derivatives promotes the synthesis of collagen, which is a constituent protein of not only blood vessels but also all tissues, reduces stress (especially oxidative stress), enhances antithrombotic activity, and enhances immunity Blood is known to have an effect In addition to the effects of tube protection and blood fluidity improvement, it also has the effect of improving the tissue throughout the body.

There is no restriction | limiting in particular in content of ascorbic acid or its derivative (s). Preferably, the weight ratio of proanthocyanidins to ascorbic acid is 1: 0.1 to: I: 50, more preferably 1: 0.2 to 1:20. Contained in the agent.

Various ingredients include, for example, ingredients that can be added as normal foods and pharmaceuticals (excipients, extenders, binders, thickeners, emulsifiers, lubricants, wetting agents, suspending agents, coloring agents, Fragrances, nutritional ingredients, food additives, etc.). The above components may be contained alone or in combination.

Examples of the nutritional component include, but are not limited to, a component having an effect of preventing diseases and diseases associated with cell adhesion factors; and a component that further imparts functionality.

Ingredients that have the effect of preventing diseases and disorders related to cell adhesion factors include, for example, components that suppress the expression of cell adhesion factors, like proanthocyanidins (derived from animals such as mucopolysaccharides and amino sugars). Ingredients); Increased blood sugar, increased blood lipids, or suppresses hypertension, antithrombotic, anti-inflammatory, anti-moon ulcer, etc. (sulfur-containing organic compounds, vitamins, vitamin E, Chitin and chitosan and derivatives thereof, collagen and the like); and components having hepatoprotective or antioxidant action (such as hesperidin, quercetin, rutin and derivatives thereof).

For example, flavonoids; vitamins other than ascorbic acid such as vitamins A and B; water-soluble dietary fiber; oral jelly; protein; minerals; lecithin; chlorella powder; Examples include the end.

Food additives include stevia powder, matcha powder, lemon powder, and honey Examples include mitsu, reduced maltose, lactose, sugar solution, and seasonings. (Cell adhesion factor expression inhibitor)

As described above, the cell adhesion factor expression inhibitor of the present invention contains proanthocyanidin, and may contain ascorbic acid or a derivative thereof and various components as necessary.

There is no restriction | limiting in particular in content of proanthocyanidin in the inhibitor of this invention. For oral administration, preferably 0.001 wt% to 50 wt%, more preferably 0.005 wt% to 20 wt ⁰ /. It is. In the case of transdermal administration, proanthocyanidins are preferably contained in the inhibitor in an amount of 0.0001% to 20% by weight, more preferably 0.0001% to 20% by weight, and even more preferably 0.001% by weight. It can be contained in a proportion of ˜15% by weight. In the case of oral administration, the daily intake of an adult is 0.001 to 1. O g, preferably 0.002 to 0.5 g, more preferably 0.002 as proanthocyanidins. It is contained so as to be g to 0.2 g.

The inhibitor of the present invention can be prepared in various forms depending on the purpose, for example, as a food, a pharmaceutical, a quasi-drug, a cosmetic.

Among the above-mentioned uses, when the inhibitor of the present invention is orally ingested (orally administered) as food, pharmaceuticals, quasi drugs, etc., there is no particular limitation on the form. For example, capsules such as hard capsules and soft capsules, tablets, pills, powders (powder), granules, tea bags, bowl-like viscous liquids, liquids, pastes, etc., in the form normally used by those skilled in the art Used. Depending on the shape or preference, these may be taken as they are, or may be taken by dissolving in water, hot water, milk, etc., or may be taken by leaching the ingredients.

Even when the inhibitor of the present invention is applied to the skin as a quasi-drug, cosmetic or the like (transdermal administration), these forms are not particularly limited, and ointments, gels, creams, Any form such as an emulsion, lotion, pack, poultice, bath preparation, etc., which is usually used as a skin external preparation by a person skilled in the art may be used.

The cell adhesion factor expression-suppressing agent of the present invention can be administered orally (ingested) or transdermally (applied) to cause cell adhesion factors such as blood cells, vascular endothelial cells and fibroblasts, particularly cells on blood cells. The expression of the adhesion factor can be suppressed. Examples of cell adhesion factors include cadherin family, immunoglobulin superfamily, integrin family, selectin family, link protein family, and sialomtin family. The inhibitor of the present invention is particularly excellent in the effect of suppressing the expression of integrin buamily and selectin family. The inhibitor of the present invention can be used as food, pharmaceuticals, quasi-drugs, cosmetics, etc., and is caused by the expression of cell adhesion factors such as autoimmune diseases, inflammatory diseases, cardiovascular diseases, tumor metastasis, etc. It can be applied to the prevention and treatment of other diseases. Example

Hereinafter, the present invention will be described with reference to examples, but it goes without saying that the present invention is not limited to the examples.

(Example 1: Cell adhesion factor expression inhibitory effect)

(Preparation of human peripheral blood mononuclear cells)

First, 5 mL of blood was collected from a subject using a syringe with heparin added in advance, and 5 mL of phosphate buffered saline (PBS (-)) was added to this blood to prepare a blood mixture. did. This mixture is layered on 6 mL of Perco 11 (Sigma), centrifuged at room temperature at 1,500 rpm for 10 minutes, and human peripheral blood mononuclear cells ( (Hereinafter referred to as “h PBMC”). Next, PBS (-) was added to the collected h PBMC to a total volume of 12 mL and again. Centrifugation was performed under the same conditions. After centrifugation, RPMI 1640 (Sigma) containing 5 mL of 1% non-activated fetal bovine serum (FBS) was added and suspended in hPBMC from which the supernatant was removed. After counting the number of cells in this suspension, the solution diluted with 1 ^? ^ 41 1 64 0 containing 1% 83 above to 1 X 10 ⁶ cells 1111 ^ 1 mL each was seeded. Two such 6-well plates were prepared.

(Expression suppression test)

For the two seeded plates above, in a solution containing 2 well cells out of 6 wells, 80% by weight of proanthocyanidins (40% by weight of OPC in the total extract) and A pine bark extract containing 10% by weight of catechin (trade name: Flavangenol, Toyo Shinyaku Co., Ltd.) was added to give In ng Zm L. Another 2well cell-containing solution was supplemented with the above matsutake peel extract to 10 ngZmL. The remaining 2 uel cell-containing solution was used as a control without adding pine husk extract. These plates 5 volume% C0 ₂ atmosphere, were cultured for 48 hours at 37 ° C. Each culture solution was collected and then centrifuged at 1,500 rpm for 10 minutes at room temperature, and the supernatant was removed. To the resulting precipitate, 1 mL of 5% non-activated FBS-containing RPMI 1 640 was added and centrifuged again under the same conditions as above to remove the supernatant (this operation is called a washing operation). This washing operation was performed twice in total to obtain each test cell.

Using three types of test cells obtained from one plate (pine bark extract 1 ng Zm L added cells, pine bark extract 10 ng / mL added cells, and control cells), CD 18 (integrin) The expression level of CD 62 L (selectin) is expressed as follows using the three types of test cells obtained from the other plate.

• was measured. (Measurement of CD 18 expression level)

Add 10% 0.5% non-immobilized FBS-containing RPM I 1640 containing 5 μg / mL anti-CD18 antibody (MEM-18, manufactured by MON OS AN) to the above test cells. Hold at 30 ° C for 30 minutes. Next, the mixture was centrifuged at 1,500 rpm for 10 minutes at room temperature, the supernatant was removed, and the above washing operation was performed. After washing, add 100 μL of 0.5% non-immobilized FBS-containing RPM I 1640 containing 5 gZmL FI TC-labeled anti-mouse antibody (manufactured by BECT ON DIKI NS ON) at 0 ° C Hold for 30 minutes. Thereafter, the supernatant was removed and the washing operation was performed after centrifugation as described above. After suspending these cells in 1 mL of RPMI 1640 containing 0.5% non-immobilized FBS, the peak of fluorescence intensity per cell was measured by flow cytometry (FACSCa libur, manufactured by BECTON DIKI NSON). The average value of each test cell obtained from 2wells was determined. Further, using the obtained fluorescence intensity average value, the expression suppression rate was determined from the following formula. The results are shown in Table 1. Expression / / _{) = 100-} (Matsuki light intensity) 100

(Fluorescence intensity of control cells)

(Measurement of CD 62 L expression level)

The above test cells were treated with 5 ng / mL PE-labeled anti-CD 62 L antibody (CL

8918 PE, CEDEARLANE) containing 0.5% non-immobilized FB S containing RPMI 1640 was added 100 // L and held at 0 ° C for 30 minutes. Subsequently, the supernatant was removed by centrifugation at 1,500 rpm for 10 minutes at room temperature, and then the above washing operation was performed. For these cells, the peak of fluorescence intensity per cell was measured by flow cytometry in the same manner as described above, and the average value of fluorescence intensity and the expression suppression rate were determined. The results are shown in Table 1. table 1

From Table 1, it can be seen that the expression of CD18 and CD62L is suppressed in the pine bark extract-added cells. This indicates that the pine bark extract containing proanthocyanidins has an excellent inhibitory effect on cell adhesion factor expression. In particular, the expression of CD 18 and CD 62 L was suppressed when the pine bark extract contained 1 ng ZmL, about 20%, and when it contained 10 ng ZmL, about 40%. This suggests that proanthocyanidins contained in pine bark extracts can exert their effects even at very low concentrations. Therefore, it is considered that sufficient effects can be obtained by adding a small amount to foods and pharmaceuticals. .

(Example 2: Preparation of tablets)

The following ingredients were mixed to prepare a 20 Omg glaze per tablet:

Pine bark extract

Asconolevic acid

Vitamin mix *

Crystalline cenorelose

Reduced maltose

Sucrose Estenore Silicon dioxide 2mg Dolomite 38mg

* 1: Contains vitamin B group (Nippon Fragrance Chemicals)

* 2: Containing calcium and magnesium (Sankyo Fusha Co., Ltd.

(Example 3: Preparation of beverage)

A beverage was prepared by mixing the following ingredients:

<Beverage ingredients> Weight (per liter) Pine crust extract 7 Omg Fructose Glucose liquid sugar 20 g Lemon juice 10 g Quenic acid 2 g

L-Ascorbic acid 2 g Fragrance 15 Omg Vitamin B ₁ 0. 8 mg Vitamin 8 ₂ 1. 2 mg Vitamin B ₆ 1. 8 mg Gnoretamic acid 100 mg Arginine 2 Omg Valine 100 mg Leucine 10 Omg Isoleucine 10 Omg Pure water Remaining

(Example 4: Preparation of external preparation for skin)

The following components were mixed to prepare a skin external preparation. <Ingredients for external preparations for skin> (Unit:% by weight)

Pine bark extract: 0. 0 0 1

Ascorbic acid glycosides: 0.1

Glycerin: 6

1, 3—Butylene Grunole: 4

Ethanore: 5

Polyoxyethylene Laurinoleetenore: 1

Fragrance: Small amount

Pure water: remainder Industrial applicability

The cell adhesion factor expression inhibitor of the present invention can suppress the expression of cell adhesion factors, particularly the expression of cell adhesion factors in blood cells, by oral administration (ingestion) or transdermal administration (application). The inhibitor of the present invention can be used as food, pharmaceuticals, quasi drugs, cosmetics, etc., and is caused by the expression of cell adhesion factors such as autoimmune diseases, inflammatory diseases, cardiovascular diseases, tumor metastasis, etc. It can be applied to the prevention and treatment of various diseases.

Claims

The scope of the claims

1. A cell adhesion factor expression inhibitor containing proanthocyanidins.

2. The inhibitor according to claim 1, wherein the cell adhesion factor is a cell adhesion factor expressed on blood cells.

3. The inhibitor according to claim 1 or 2, wherein the proanthocyanidins are derived from pine bark.