Vascular permeability inhibitor and intolerance-to-cold modifying agent using the same

Abstract

To provide a novel vascular permeability inhibitor.SOLUTION: The above-mentioned problem has been solved by the following disclosures: 1. a vascular permeability inhibitor including extract of yellow strawberry guava fruit as active principle; 2. a vascular permeability inhibitor where extract of yellow strawberry guava includes at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0]; 3. a vascular permeability inhibitor including at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0] as active principle; and 4. an intolerance-to-cold modifying agent including extract of yellow strawberry guava fruit as active principle.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel vascular permeability inhibitor and a cold sensitivity improving agent using the same. The present invention is widely used in foods (including health foods, functional foods, and foods with specified health uses), medicines, quasi-drugs, etc. [Background technology]

[0002] In recent years, it has been discovered that aging and impaired function of blood vessels affect skin characteristics such as wrinkles and rough skin, and it is known that the normality of blood vessels is an effective indicator for judging skin characteristics. Blood vessels are important tissues for maintaining the vital functions of the human body, not only delivering oxygen and nutrients to organs throughout the body through blood, but also carrying waste products from tissues and excreting them from the body. In general, aging and impaired function of blood vessels have a significant impact on human health, as typified by arteriosclerosis, and can also lead to external findings such as wrinkles and swelling.

[0003] In addition, when the vascular structure becomes unstable due to aging of blood vessels, nutrients such as plasma components leak from the blood vessels and the necessary components cannot be transported to the necessary places. As a result, various problems such as deterioration of skin condition are thought to occur. There is a demand for a product that stabilizes vascular endothelial cells, has a vascular permeability suppressing effect, and thereby firmly binds the endothelial cells of blood vessels, thereby distributing nutrients to the skin, improving skin firmness and texture, and preventing wrinkles. Furthermore, there is a demand for a product that improves blood flow by closing the gaps in the endothelial cells of blood vessels and lymphatic vessels, collects moisture and waste products from the tissues, and improves and prevents various symptoms such as chills, stiff shoulders, swelling, and dark circles under the eyes (Patent Document 1). [Patent Document 1] Re-tabled publication No. 2017-183581 DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0004] Under these circumstances, the present inventors discovered that extracts of yellow strawberry guava fruit and its components have an inhibitory effect on vascular permeability, and completed the present invention. That is, an object of the present invention is to provide a novel vascular permeability inhibitor and an agent for improving poor circulation using the same. [Means for solving the problem]

[0005] The features of the present invention for solving the above problems are as follows. 1. A vascular permeability inhibitor whose active ingredient is an extract of yellow strawberry guava fruit. 2. A vascular permeability inhibitor characterized in that an extract of yellow strawberry guava fruit contains at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0]. 3. A vascular permeability inhibitor having as an active ingredient at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0]. 4. A cold remedy containing yellow strawberry guava fruit extract as the active ingredient. 5. An edema reducing agent containing yellow strawberry guava fruit extract as the active ingredient. 6. Effect of the Invention

[0006] The present invention has a vascular permeability suppressing effect, and therefore can improve and prevent various symptoms such as chills, stiff shoulders, swelling, and dark circles under the eyes. [Brief description of the drawings]

[0007] [Figure 1] 1 is a graph showing the effect of various DGDGs and GlcCer derived from yellow strawberry guava on vascular permeability in HUVEC cells. [Diagram 2]1 is a graph showing the effect of various DGDGs and GlcCer derived from yellow strawberry guava on cell viability (MTT assay) in HUVEC cells. [Diagram 3] FIG. 1 is a diagram showing the evaluation results of the effect of yellow strawberry guava extract in improving poor circulation. [Figure 4] FIG. 1 shows the effect of yellow strawberry guava-derived 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0] on VE-Cadherin protein expression. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will now be described in detail. The present invention is characterized in that it contains an extract of yellow strawberry guava fruit as an active ingredient. Yellow strawberry guava (Psidium littorale), also known as yellow pomegranate, is a tropical fruit of the Myrtaceae family. Apart from the color of the skin, there is not much difference between the edible fruit and the congener Psidium littorale, so when the word "guava" is used in the fruit market, it often includes the fruit of this species, but it is a different species from Psidium littorale.

[0009] The extract of the yellow strawberry guava fruit is characterized by containing at least one selected from GlcCer[d18:2(4E,8Z) / 16:0], GlcCer [t18:1(8Z) / 22:0], GlcCer [t18:1(8Z) / 23:0], GlcCer [t18:1(8Z) / 24:0], GlcCer [t18:1(8Z) / 25:0], GlcCer [t18:1(8Z) / 26:0], 1,2-dilinolenoyl-3-digalactosylglycerol, 1-palmitoyl-2-linolenoyl-3-digalactosylglycerol, and 1-palmitoyl-2-linoleoyl-3-digalactosylglycerol. The chemical formula of the above compound is as follows:

[0010] [ka] Of these compounds, it is preferable to contain at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0], since these are useful as active ingredients of vascular permeability inhibitors.

[0011] As an extraction solvent for obtaining an extract of yellow strawberry guava fruit, polar solvents such as water, methanol, ethanol, isopropyl alcohol, 1,3-butylene glycol, ethylene glycol, propylene glycol, glycerin, ethyl acetate, etc. Two or more of these solvents may be mixed. Preferably, active ingredients can be extracted efficiently by using aqueous ethanol or a mixture of these, that is, aqueous ethanol, as the extraction solvent.

[0012] When water is used as the extraction solvent, the type of water is not particularly limited, and tap water, distilled water, mineral water, alkaline ionized water, deep sea water, etc. can be used.

[0013] When using aqueous ethanol as the extraction solvent, the concentration of ethanol is not particularly limited, but it is preferable that the ethanol concentration is 10 to 90% (wt / wt), and preferably 20 to 80% (wt / wt). The reason for setting the ethanol concentration at 90% (wt / wt) or less is that if the ethanol concentration is too high, oil will easily dissolve in the aqueous ethanol.

[0014] The extraction temperature should be 20 to 80° C., preferably about 50 to 70° C. If the extraction temperature is too low, it becomes difficult to extract the active ingredients, and if the extraction temperature is too high, the active ingredients decompose, decreasing their physiological activity (health functionality).

[0015] As the extraction method, any method such as stirring extraction, continuous extraction, immersion extraction, countercurrent extraction, and supercritical extraction can be adopted, and any device can be used at room temperature or under reflux heating.

[0016] The specific extraction method is as follows: The raw material, yellow strawberry guava fruit, is placed in a processing tank filled with an extraction solvent, and the active ingredients are dissolved while stirring. For example, when using aqueous ethanol as the extraction solvent, about 2 to 100 times the amount (by weight) of the extraction solvent as the raw material is used, and extraction is carried out for about 30 minutes to 2 hours. After the active ingredients are dissolved in the solvent, the extract is obtained by filtering to remove the extraction residue.

[0017] The extract is then diluted, concentrated, purified, dried, and other processes according to conventional methods to produce the agent according to the present invention. The specific extraction method is as follows: The raw material, yellow strawberry guava fruit, is placed in a processing tank filled with the extraction solvent, and the active ingredients are dissolved while stirring. For example, when using aqueous ethanol as the extraction solvent, about 2 to 100 times the amount (by weight) of the extraction solvent as the raw material is used, and extraction is carried out for about 30 minutes to 2 hours. After the active ingredients are dissolved in the solvent, the extract is obtained by filtering to remove the extraction residue.

[0018] The extract is then diluted, concentrated, purified, dried, and other processes according to conventional methods to produce the agent according to the present invention. The purification method is preferably such that the extract is passed through a synthetic adsorption resin, silica gel resin, gel filtration resin, etc. to adsorb the active ingredient, and then this is eluted with methanol, ethanol, etc. for concentration.

[0019] Furthermore, the vascular permeability inhibitor of the present invention is characterized in that it contains at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0] as an active ingredient. The method for obtaining 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0] is not particularly limited, but it can be isolated and purified from an extract of yellow strawberry guava fruit. Furthermore, the method for isolating and purifying from an extract of yellow strawberry guava fruit is not particularly limited, but it can be isolated and purified, for example, by the method of the following example. Although 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0] can be used as a single compound, a plant extract that sufficiently contains 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0] as an active ingredient, such as the above-mentioned yellow strawberry guava fruit extract, may also be used.

[0020] The vascular permeability inhibitor of the present invention can be used as an ingredient in various foods and beverages. Examples of foods and beverages include general foods such as confectionery (gum, candy, caramel, chocolate, cookies, snacks, jellies, gummies, tablet candies, etc.), noodles (soba, udon, ramen, etc.), dairy products (milk, ice cream, yogurt, etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, black tea, tea, carbonated drinks, sports drinks, etc.), health foods (tablets, capsules, etc.), and nutritional supplements (nutritional drinks, etc.). It is advisable to appropriately mix the agent of the present invention into these foods and beverages.

[0021] These foods and beverages can contain a variety of ingredients depending on their type, for example, the following food ingredients can be used: glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, gum arabic, carrageenan, casein, gelatin, pectin, agar, B vitamins, nicotinamide, calcium pantothenate, amino acids, calcium salts, colorants, flavorings, preservatives, starch hydrolysates, and fine silicon dioxide.

[0022] As a specific manufacturing method, the agent of the present invention is spray-dried or freeze-dried together with starch hydrolysate, glycerin fatty acid ester, and fine silicon dioxide, and then made into a powder, granules, tablet, or solution, which can be easily incorporated into food and beverages (instant foods, etc.). The agent of the present invention can also be dissolved in, for example, fats and oils, ethanol, glycerin, or a mixture of these to make a liquid, which can be added to beverages or solid foods. If necessary, it can also be mixed with a binder such as gum arabic or dextrin to make a powder or granules, which can be added to beverages or solid foods.

[0023] When the agent of the present invention is applied to food and beverages, since the main purpose is disease prevention and health maintenance, it is preferable that the content of the active ingredient (yellow strawberry guava fruit extract) in the food and beverages be 1 to 20 wt% or less in total.

[0024] The vascular permeability inhibitor of the present invention may be used as a material for medicines (including pharmaceuticals and quasi-drugs). Pharmaceutical preparations can be produced by appropriately mixing the agent of the present invention with raw materials for pharmaceutical preparations. Examples of pharmaceutical raw materials that can be incorporated into the agent of the present invention include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hardened vegetable oil, kaolin, talc, etc.), binders (distilled water, saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrants (sodium alginate, agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearate monoglyceride, starch, lactose, powdered gum arabic, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers (quaternary ammonium bases, sodium lauryl sulfate, etc.), adsorbents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, etc.), etc.

[0025] The vascular permeability inhibitor of the present invention can generally be administered orally in the form of tablets, pills, soft or hard capsules, fine granules, powders, granules, liquids, etc., but may also be administered parenterally. When administered parenterally, it may be administered in the form of a solution or with the addition of a dispersant, suspending agent, stabilizer, etc., by local tissue administration, intradermal, subcutaneous, intramuscular, or intravenous injection. It may also be in the form of a suppository, etc. Furthermore, it may be administered as an eye drop.

[0026] The dosage may vary depending on the method of administration, condition, and age of the patient, but for adults, it is usually 0.5 to 5,000 mg of active ingredient (yellow strawberry guava fruit extract) per day, and for children, it is usually about 0.5 to 3,000 mg. The blending ratio of the vascular permeability inhibitor can be changed appropriately depending on the dosage form, but it is usually about 0.3 to 15.0 wt% when administered orally or via mucosal absorption, and about 0.01 to 10 wt% when administered parenterally. Note that the dosage varies depending on various conditions, so in some cases a smaller dosage than the above is sufficient, and in other cases it may be necessary to administer more than the range. EXAMPLES

[0027] Examples of the present invention are described below. The examples shown below are described to confirm the various actions and effects of the agent of the present invention obtained by the present invention, and the scope of the present invention is not limited to these products and manufacturing methods. Furthermore, in this example, a compound is isolated to identify the active ingredient, but any extract of yellow strawberry guava fruit that contains the main active ingredient 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0] at a required concentration as an active ingredient will be effective.

[0028] Example: Preparation of Yellow Strawberry Guava Fruit Extract and Isolation and Identification of Various DGDG and GlcCer Yellow strawberry guava raw fruits were crushed and extracted with ethanol to obtain the extract of yellow strawberry guava fruits in this example. TM XAD TMColumn chromatography was performed using 4. After elution with water, methanol, and ethanol, the ethanol fraction was concentrated and subjected to medium pressure preparative liquid chromatography. The fractionation conditions were as follows: hexane:ethyl acetate (9:1 → 7:3 → 5:5) → ethyl acetate → chloroform:methanol (9:1 → 7:3 → 5:5) → methanol, using a Yamazen Corporation Universal Silica Gel Column Premium. The chloroform:methanol (7:3) fraction was subjected to reversed-phase HPLC [InertSustain C18, methanol (DGDG) or methanol:tetrahydrofuran = 9:1 (GlcCer)] to purify three types of DGDG and six types of GlcCer. The purified GlcCer and DGDG were identified by comparing their NMR and MS spectra with those of the following literature 1 to 5. literature 1. Kang SS et al., Chem. Pharm. Bull., 49, 321-323 (2001) 2. Luo Y. et al., Lipid, 39(9), 907-914 (2004) 3. Zhang WK ​​et al., Chem. Phys. Lipids., 148, 77-83 (2007) 4. Ryu J. et al., Arch. Pharm. Res., 26(2), 138-142 (2003) 5. Xu ML et al., Molecules, 28, 1010 (2023).

[0029] Test Example 1: Vascular permeability inhibition test using HUVEC cells (1) Method for culturing human umbilical vein endothelial cells (HUVEC cells) Human umbilical vein endothelial cells purchased from Lonza Japan Co., Ltd. were cultured and used for the experiment. The medium was EGM. TM -2 BulletKit TM (EBM TMThe medium used was 0.1% (v / v) hEGF, 2% (v / v) FBS, 0.1% (v / v) VEGF, 0.4% (v / v) hFGF-B, 0.04% (v / v) hydrocortisone, 0.1% (v / v) R3-IGF-1, 0.1% (v / v) ascorbic acid, and 0.1% (v / v) GA-1000. The cells were cultured in a 75 cm 2 The culture was carried out in a culture flask at 37°C in the presence of 5% CO2. The cultured cells were washed twice with PBS (-) and then detached from the flask with a phenol red-containing 0.25 w / v% Trypsin-1 mM EDTA·4Na solution for use in the experiment.

[0030] (2) Evaluation method for vascular permeability inhibition test using HUVEC cells The vascular permeability inhibition test was performed using a HUVEC cell suspension (3.2 × 10 5 200 μl / well of 1000 cells / mL were seeded in the upper chamber (collagen-coated Millicell® Cell Culture Inserts 24-Well Hanging Inserts 0.4 mm PET) and EGM was placed in the lower well (24-well plate). TM -2 BulletKit TM After adding 500 μl / well, the cells were cultured for 7 days. 5 The cells were seeded in a 96-well plate (100 μL / well) and cultured for one day. After pre-culture, EBM containing the test substance (final concentration 10 μM) was added. TM The medium was replaced at -2. The test substance was dissolved in DMSO, and the final concentration of DMSO in the medium was adjusted to 0.1% (v / v). After 24 hours of culture, a vascular permeability inhibition test and an MTT test (96-well plate, cytotoxicity) were performed.

[0031] (3) Vascular permeability test measurement and calculation method After incubation, 200 μL / well of 0.1% Evans Blue (EB) in 0.1% BSA / PBS solution was added to the upper chamber, and 500 μL / well of PBS was added to the lower well. After incubation for 30 minutes, 200 μl of the solution that had permeated from the upper chamber to the lower well was transferred to a 96-well plate, and the OD value was measured using a microplate reader. (Measurement wavelength: 620 nm) The transmittance was calculated as the ratio of the absorbance of the sample divided by the average absorbance of the control. The results are shown in Figure 1.

[0032] (4) MTT test method using HUVEC cells (evaluation of cell viability) After incubation, 10 μL / well of MTT solution [5 mg / mL in PBS(-)] was added to the 96-well plate. After 4 hours of incubation, the formation of formazan crystals was confirmed and the medium was removed by aspiration. Then, DMSO solution (100 μL / well) was added. After stirring for about 30 minutes with a plate mixer, the OD value was measured with a microplate reader. (Measurement wavelength: 570 nm, reference wavelength: 660 nm) The results are shown in Figure 2.

[0033] Test Example 2: Evaluation of the effect of yellow strawberry guava extract in improving poor circulation The effect of taking 100 mg of the Yellow Strawberry Guava Extract of this example on improving poor circulation was examined using in-house volunteers. First, participants took a placebo capsule, and 30 minutes later, they were asked to soak their hands in 4°C water for one minute. The change in skin surface temperature was then measured using thermography. Next, a capsule containing the yellow strawberry guava extract (100 mg) of this example was ingested, and thermographic measurements were performed in the same manner. The results are shown in Figure 3.

[0034] Test Example 3: Evaluation of vascular endothelial (VE)-Cadherin protein expression level Vascular permeability is regulated by endothelial cell-cell adhesion mediated by vascular endothelial (VE)-cadherin, an adhesion molecule specifically expressed in blood vessels. Therefore, we evaluated the protein expression level of vascular endothelial (VE)-cadherin. (1) Evaluation method As a preculture, a HUVEC cell suspension (3.2 × 10 5 cells / mL, EGM TM -2 BulletKit TM ) was seeded in 6-well plates at 2 ml / well and cultured for 2 days. After pre-culture, EBM containing the test substance (final concentration 10 μM) was added. TMThe medium was replaced at -2. The test substances were dissolved in DMSO, and the final DMSO concentration in the medium was adjusted to 0.1% (v / v). After 24 hours of culture, proteins were extracted using a radioimmunoprecipitation assay (RIPA) buffer containing a protease phosphatase inhibitor cocktail (0.5 M) and EDTA (0.5 M). The protein concentration was adjusted to 220 mg / ml, and one-third of the sample buffer (131.6 mM Tris-HCl, 5% 2-mercaptoethanol, 4.2% SDS, 52.6% glycerol, and 0.02% bromophenol blue) was added, and the sample was heated (95°C) for 5 minutes in a heat block for denaturation to prepare an electrophoresis sample. Proteins were separated by electrophoresis using a 10% SDS-PAGE gel, and then transferred to a polyvinylidene difluoride (PVDF) membrane. After transfer, the membrane was blocked with 5% skim milk (Fujifilm Wako Pure Chemical Industries, Ltd.) and then subjected to primary and secondary antibody reactions in sequence. The primary and secondary antibodies used are shown in Table 1 below. After the antibody reaction, Super Signal West Femto Maximum Sensitivity Substrate (ThermoFisher) or Super Signal West Pico Maximum Sensitivity Substrate (ThermoFisher) was used as a chemiluminescent reagent, and bands were detected and quantified using an imaging analyzer (LAS500). The expression level of VE-Cadherin protein was corrected by the expression level of GAPDH protein. The results are shown in Figure 4. [Table 1]

[0035] Test Example 4: Evaluation of the swelling-reducing effect of yellow strawberry guava fruit extract (clinical) (1) Subjects The ages of the 13 participants in each of the placebo group and strawberry guar fruit extract intake group (3 men, 9 women) were 40.7±13.3 years (57.3±5.5 years for men, 35.7±10.4 years for women). (2) Test specimen The test product was a hard capsule containing 25 mg of strawberry guava fruit extract and excipients in the yellow strawberry guava fruit extract intake group, and a hard capsule filled with excipients only in the placebo group. (3) Test method Before the test, the subjects did not eat breakfast and consumed only a small amount of water. Before taking the test substance, their body weight and ECW / TBW were measured, and then they ate breakfast (one sandwich, 350 ml of water) and the test substance. Three hours after taking the test substance, they ate lunch (two rice balls, 350 ml of water), and three hours later their body weight and ECW / TBW were measured. During the test, the subjects spent as much time as possible in a sitting position. The ECW / TBW of the legs refers to the ratio of the extracellular water (ECW) to the total body water (TBW), and the higher this value, the greater the degree of swelling. These were measured by the bioelectrical impedance method using the Inbody S10. The results are shown in Table 2.

[0036] [Table 2]

[0037] Results and Effects of the Examples (1) Structures of various GlcCer and DGDG The structures of the isolated and identified GlcCer and DGDG are shown in Chemical Formula 1. The six GlcCer species with different sphingoid bases and fatty acid lengths were eluted in the following order by HPLC: (1) d18:2(4E,8Z) / 16:0, (2) t18:1(8Z) / 22:0, (3) t18:1(8Z) / 23:0, (4) t18:1(8Z) / 24:0, (5) t18:1(8Z) / 25:0, (6) t18:1(8Z) / 26:0. Among these, (1) d18:2(4E,8Z) / 16:0, (3) t18:1(8Z) / 23:0, and (5) t18:1(8Z) / 25:0 were not isolated in the previous study of GlcCer from rice. On the other hand, the three DGDGs with different fatty acid species were eluted in the following order by HPLC: (1) 1,2-dilinolenoyl-3-digalactosylglycerol, (2) 1-palmitoyl-2-linolenoyl-3-digalactosylglycerol, and (3) 1-palmitoyl-2-linoleoyl-3-digalactosylglycerol. These molecular species were different from the molecular species of DGDG isolated from rice (1,2-dilinoleoyl-3-digalactosylglycerol).

[0038] (2) Evaluation results of vascular permeability and cytotoxicity As shown in Figure 1, 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0], isolated from the fruit of yellow strawberry guava, was found to have an inhibitory effect on vascular cell permeability (Figure 1). In addition, as shown in Figure 2, although no significant difference was observed, some GlcCer that did not have an inhibitory effect on vascular permeability were observed to cause cytotoxicity (Figure 2). These results suggest that only 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E, 8Z) / 16h:0], had an inhibitory effect on vascular cell permeability. Based on the above, yellow strawberry guava fruit extract and the 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E, 8Z) / 16:0] contained in it are useful as vascular permeability inhibitors, which improve blood flow by sealing gaps in the endothelial cells of blood vessels and lymphatic vessels, and collect water and waste products from tissues, thereby improving and preventing various symptoms such as chills, stiff shoulders, swelling, and dark circles under the eyes.

[0039] (3) The effect of yellow strawberry guava extract in improving poor circulation As shown in Figure 3, especially in the images of subject B (right side of each image) (comparison of the images surrounded by dashed and solid lines), the recovery of skin surface temperature was promoted after ingestion of Yellow Strawberry Guava Extract. From these results, it was confirmed that Yellow Strawberry Guava Extract has an effect of improving chills and that Yellow Strawberry Guava Extract is useful as an agent for improving chills.

[0040] (4) Effect of VE-Cadherin on protein expression As shown in Figure 4, 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0] isolated from yellow strawberry guava was found to have an inhibitory effect on vascular cell permeability. As a result of evaluating the effects of these components on the protein expression level of VE-Cadherin, an adhesion factor between vascular endothelial cells, a significant increase in protein expression was observed for both components. These results suggest that only 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E, 8Z) / 16h:0], inhibited vascular cell permeability. Furthermore, when inflammation or other factors weaken the adhesion between vascular endothelial cells, the barrier function of the blood vessels breaks down and the permeability of blood components to tissues increases, which can cause swelling.The results of this test confirmed that yellow strawberry guava-derived 1,2-dilinolenoyl-3-digalactosylglycerol, GlcCer [d18:2(4E,8Z) / 16:0], enhances the adhesion between vascular endothelial cells, suppressing the permeability of blood components to tissues, and thus preventing swelling.

[0041] (5) Evaluation of the edema reducing effect of extracts from yellow strawberry guava fruit Table 2 above shows the results of measuring the ECW / TBW in the legs before and 6 hours after ingestion. As shown in Table 2 above, no significant differences were observed between the two groups, but the placebo group had an increased leg ECW / TBW 6 hours after ingestion compared to before ingestion, whereas the yellow strawberry guava extract group had a decreased leg ECW / TBW 6 hours after ingestion compared to before ingestion. This confirmed that the extract of yellow strawberry guava fruit has the effect of reducing leg swelling.

[0042] The following are examples of formulations of the vascular permeability inhibitor (yellow strawberry guava fruit extract) of the present invention. Note that the following formulation examples do not limit the present invention. Formulation example 1: Chewing gum Sugar 53.0wt% Gum base 20.0 Glucose 10.0 Syrup 16.0 Fragrance 0.5 Vascular permeability inhibitor 0.5 100.0wt%

[0043] Mixture Example 2: Gummies Reduced starch syrup 40.0wt% Granulated sugar 20.0 Glucose 20.0 Gelatin 4.7 Wednesday 9.68 Yuzu juice 4.0 Yuzu flavor 0.6 Dye 0.02 Vascular permeability inhibitor 1.0 100.0wt%

[0044] Mixture example 3: Candy Sugar 50.0wt% Syrup 33.0 Wednesday 14.4 organic acid 2.0 Fragrance 0.2 Vascular permeability inhibitor 0.4 100.0wt%

[0045] Mixture example 4: Yogurt (hard / soft) Milk 41.5wt% Skim milk powder 5.8 Sugar 8.0 Agar 0.15 Gelatin 0.1 Lactic acid bacteria 0.005 Vascular permeability inhibitor 0.4 fragrance trace amount water residue 100.0wt%

[0046] Formulation example 5: Soft drink Fructose glucose liquid sugar 30.0wt% Emulsifier 0.5 Vascular permeability inhibitor 0.3 Fragrance (appropriate amount) Purified water remainder 100.0wt%

[0047] Formulation example 6: Tablet confectionery Sugar 76.4wt% Glucose 19.0 Sucrose fatty acid ester 0.2 Vascular permeability inhibitor 0.5 Purified water 3.9 100.0wt%

[0048] Formulation example 7: Soft capsule Brown rice germ oil 47.0wt% Yuzu seed oil 40.0 Emulsifier 12.0 Vascular permeability inhibitor 1.0 100.0wt%

[0049] Formulation Example 8: Tablets Lactose 54.0wt% Crystalline cellulose 30.0 Starch decomposition product 10.0 Glycerin fatty acid ester 5.0 Vascular permeability inhibitor 1.0 100.0wt% [Industrial Applicability]

[0050] As described above, the present invention can provide a novel vascular permeability inhibitor and an agent for improving poor circulation using the same.

Claims

1. A vascular permeability inhibitor containing yellow strawberry guava fruit extract as an active ingredient.

2. The vascular permeability inhibitor according to claim 1, characterized in that the extract of yellow strawberry guava fruit contains at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0].

3. A vascular permeability inhibitor containing at least one of 1,2-dilinolenoyl-3-digalactosylglycerol and GlcCer [d18:2(4E,8Z) / 16:0] as an active ingredient.

4. A cold remedy containing yellow strawberry guava fruit extract as its active ingredient.

5. An edema relieving agent containing yellow strawberry guava fruit extract as the active ingredient.

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